Microsoft Word - Braund 1 - 230

Braund's Clinical Neurology in Small Animals: Localization, Diagnosis and
Treatment
C.H. Vite1 and K.G. Braund2 (Eds.)
1
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
2
Veterinary Neurological Consulting Services, Dadeville, Alabama, USA.
Page
I Neuroanatomical Localization and Syndromes
Neurological Examination 2
Neurological Syndromes 10
• Lumbosacral Syndrome
• Thoracolumbar Syndrome
• Cervicothoracic Syndrome
• Cervical Syndrome
• Pontomedullary Syndrome
• Cerebellar Syndrome
• Vestibular Syndrome
• Midbrain Syndrome
• Diencephalic Syndrome
• Cerebral Syndrome
• Multifocal Syndrome
• Paroxysmal Syndrome
• Myopathic Syndrome
• Neuropathic Syndrome
II Etiological Categories of Neurological Diseases

Developmental Disorders 36
Degenerative and Compressive Structural Disorders 58
Storage Disorders 74
Degenerative Disorders of the Central Nervous System 88
Myopathic Disorders 122
Neuropathic Disorders 161
Endogenous Metabolic Disorders 196
Neurotoxic Disorders 211
Nutritional Disorders 226
Neurovascular Disorders 231
Neoplasia of the Nervous System 241
Inflammatory Diseases of the Central Nervous System 260
Traumatic Disorders 292
Epilepsy 301
Paroxysmal Disorders 318
III Neurodiagnostic Techniques

Electrodiagnostics 323
Cerebrospinal Fluid 338
Neuroimaging 345
IV Special Therapeutic Techniques

Canine Rehabilitation 392
Radiation Therapy 427
Evaluation and Management of Behavioral Conditions 437
I. Neuroanatomical Localization and Syndromes
Neurological Examination
A. A. De Lahunta
Department of Clinical Sciences and Department of Biomedical Sciences, College of Veterinary Medicine, Cornell
University, Ithaca, New York, USA.
Learn to do the neurological examination on a cooperative small breed dog and then you can adapt it to
accommodate the size and attitude of other dogs and cats as well as large animals and exotics. When asked how
I do a neurological examination on a maniacal aggressive cat or dog my pat answer is: I don’t ! However you can
make many reliable observations by just observing the animal while it is caged as long as you understand what
the normal examination is determining.
Why do the neurological examination?

- To determine if the nervous system is affected in a disease process.
- To establish as accurate an anatomic diagnosis as possible when the nervous system is affected.
Making the anatomic diagnosis should always precede consideration of the differential diagnosis. Despite the
tremendous contribution of imaging to neurological diagnosis and one can only guess what innovations lie ahead
in the future, the basic hands-on neurological examination is the most valuable cost effective determinant of the
clinical diagnosis.
In most cases the anatomic diagnosis is a regional diagnosis and there are essentially 8 regions of the nervous
system for consideration.
The prosencephalon (forebrain) - includes the two cerebrums and the diencephalon which is the most rostral
part of the brain stem and is comprised of the thalamus and hypothalamus. The pons and medulla are usually
considered together as they are the source of the upper motor neuron responsible for the generation of the gait.
The cerebellum may be the sole anatomic diagnosis or often is considered together with the pons and medulla.
This region is sometimes referred to as the caudal fossa which is the space these 3 anatomical areas occupy.
The spinal cord is divided into 4 anatomical regions: C1 - C5, C6 - T2, T3 - L3, L4 - Cd.
The peripheral nervous system components are usually considered collectively as the neuromuscular system,
realizing that there are important sensory systems here as well. Any of these 8 areas can be further divided into
smaller components but this serves as a starting point in your anatomic diagnosis.
There are 5 components to the neurological examination:
1. Sensorium
The owner is the best observer of any change in the patient's behavior. Significant changes will be obvious but
you will often notice subtle changes as you examine the animal. Expressions used to describe these subtle
changes include - a vagueness - seems out of touch with reality - is in a world of its own. More acceptable
medical terms for the progressive loss of a patient's sensorium are: dullness, lethargy, obtundation, semicoma
(stupor) and coma. In my experience the most common site for a focal lesion to cause progressive obtundation or
stupor is the diencephalon - presumably from the interruption of the ascending reticular activating system (ARAS)
at this level.
2. Gait
The most important aspect of the gait examination is to be able to walk the dog on a non-slippery surface. These
are often scarce in most hospitals. If there is no convenient built in carpet in the hospital then purchase a
reasonable sized indoor - outdoor carpet that can be rolled out for the exam and rolled out of the way afterwards
and can be hosed off in your runs after your patient excretes on it - which is a guarantee. This is just as important
for evaluating orthopedic lameness cases. A major objective of the gait evaluation is to determine if a lameness is
caused by a neuromuscular disorder or an orthopedic problem. Lower motor neuron disease can mimic an
orthopedic lameness and is often overlooked as the latter problems are so much more common. As you gain
experience you will recognize specific gait patterns that suggest the anatomic diagnosis ie., the "two engine" dog
with short strides in the thoracic limbs and long delayed strides in the pelvic limbs that has a C6 - T2 disorder.
The following is an attempt to dissect what it is that you are looking for when you evaluate the gait of a patient
with a neurological problem. From a neurological perspective, you are assessing the gait for both paresis and
ataxia.
A - Paresis (weakness) can be defined as a deficiency in the generation of the gait or the ability to support weight.
There are two qualities of paresis - upper motor neuron and lower motor neuron.
1 - Lower motor neuron (LMN) paresis is seen as an inability to support weight and the patient walks
short-strided -"lame". Other signs include a tendency to collapse, trembling, bunny hopping, and neck
flexion. Thoracic limb support requires neurons in the radial nerve to be intact whereas those in the
femoral nerve are necessary for pelvic limb support. Lesions that affect specific peripheral nerves to the
limbs excluding the radial and femoral nerves will cause abnormal limb postures but still the ability to
support weight.
2 - Upper motor neuron (UMN) paresis is seen as a delay in the onset of protraction (the swing phase)
and a longer stride with a variable degree of stiffness - spasticity to the stride. Because the UMN tracts
and the general proprioceptive (GP) tracts are adjacent to each other at every level of the spinal cord and
caudal brain stem lesions at any of these levels usually will cause dysfunction in both systems, therefore,
the gait reflects both deficits. GP lesions cause an ataxia in which the patient loses awareness of where
its limbs are in space. This also may contribute to the delay in the onset of protraction and be the cause
of excessive flexion, adduction or abduction of the limb during protraction and the tendency to bear
weight on the dorsal aspect of the paw often referred to as "scuffing or knuckling".
The pattern of gait observed reflects the loss of both of these functional systems and it is not necessary to
distinguish between the two systems for your anatomic diagnosis.
Patients that have C1 - 5 lesions and are still ambulatory often have a prolonged stride with the limb kept in
extension that appears as if the patient is overreaching its landing site. This is especially evident on turns.
Although by strict defintion this is a form of hypermetria, I avoid calling it that as there is a strong tendency to
relate any hypermetria to a cerebellar disorder which this is not. I refer to this overextension as overreaching or
floating. Cerebellar hypermetria has a sudden bursting quality to the onset of protraction and an overflexion of the
joints as opposed to the overextension seen here.
B - Ataxia is incoordination and comes in three qualities-general proprioceptive, vestibular (special proprioceptive)
and cerebellar.
1 - General proprioceptive ataxia represents a loss of awareness of where the limbs are in space and was
discussed above with the UMN system which it accompanies.
2 - Vestibular ataxia is a loss of balance reflected in a head tilt, and a tendency to lean, drift, fall or roll to
one side. The ataxia is often accompanied by an abnormal nystagmus.
3 - Cerebellar ataxia reflects the inability to modulate the gait generating systems in the brain stem
resulting in abnormal "uncontrolled" limb movements that usually are excessively abrupt in onset with an
overflexion of the limbs on protraction and abnormal sites of limb placement. These excessive
movements are usually referred to as hypermetria. This abnormal gait is usually accompanied by
vestibular signs with a loss of balance because there are significant components of the central portions of
the vestibular system in the cerebellum.
3. Postural Reactions - Muscle Size

I usually assess these at the same time by standing over the patient with both of us headed in the same direction.
In assessing muscle size it is important to try to have the patient bearing the same amount of weight on the two
limbs that are being compared. I palpate both thoracic limbs simultaneously from proximal to distal and then flex
and extend each for range of motion and as an assessment of muscle tone. When I place the paw back on the
floor I place it on its dorsal surface to test for its return to a normal supporting position - the paw placement
response. I then move caudally palpating the axial muscles and then palpate and move the pelvic limbs in a
manner similar to the thoracic limbs and complete it with the paw placement test.
To test the hopping responses I then move back to the thoracic limbs and while still standing over - straddling -
the patient, I pick up one thoracic limb and hop the patient laterally on the other limb then I shift limbs and hop it
back on the first limb. Only hop the dog laterally on the limb. I keep doing this back and forth shifting limbs when
the patient reaches the limit of my stance. I do not move during this procedure and with heavy animals I brace my
supporting elbow on my thigh to avoid the strain on my back. The patient does not have to be lifted off the floor for
this, only supported so that it is bearing as much weight as possible on the limb being hopped.
To test the hopping responses in the pelvic limbs I stand beside the patient and place my forelimb between the
thoracic limbs of the patient so I can lift it up off the floor by its sternum. I then pick up the pelvic limb on the side
that I am on and push the dog away from me making it hop on the opposite pelvic limb. I have to change sides to
test the other pelvic limb. For heavy animals these hopping responses can be evaluated as you make the patient
hemiwalk. I stand beside the patient and pick up both limbs on that side and push the dog away from me. It is
important to compare one thoracic limb with the other and one pelvic limb with the other as they are usually faster
in the thoracic limbs normally.
These hopping responses essentially test all components involved in voluntary limb movement from sensory
receptors in the limb, to ascending spinal cord tracts, to medullary relay proprioceptive nuclei, to thalamic relay
nuclei to the thalamocortical pathways, to the internal capsule, to the sensory cortex and the return of the UMN
pathways. The latter begin in projection neurons in the adjacent motor cortex, pass into the internal capsule and
crus cerebri, to descending UMN pontomedullary systems, into the spinal cord in pyramial and extrapyramidal
UMN tracts, to the ventral grey column LMN, to the muscles in the limb. One might conclude that this is fairly non-
specific!! Correct - so why is it so useful? Because first - it tells you if there is an abnormality somewhere in the
nervous system and therefore, is a reliable screening test.
Second - its importance in localizing lesions is dependent on what else is abnormal. A patient with a normal gait in
the environment of your examination that has hopping deficits on one side most likely has a contralateral
prosencephalic lesion. This is a very common relationship and may be the only indication of a prosencephalic
lesion. This is one of only 3 tests that you can use in your neurologic examination to determine if a prosencephalic
lesion is present and on which side. If you have a patient with a head tilt and a mild loss of balance to one side
but otherwise has a normal gait and there is a hopping deficit then if the lesion is focal it is central at the medulla
and not in the inner ear. Postural reactions are normal with inner ear - peripheral vestibular system - disorders.
Misleading neurologic description - It is important to be clear and precise with your neurologic descriptions. What
does it mean when you read a description in a published case study that describes an 8 year-old Beagle dog as
having a right hemiparesis? If the author means that this dog has a normal gait but a right side postural reaction
deficit then I would make an anatomic diagnosis of most likely a left prosencephalic lesion. If the author means
this dog has a right sided gait deficit with a delay in protraction of the right limbs with spasticity and a tendency to
float with the right thoracic limb then my anatomic diagnosis is right C1 - C6. It is important to remember that
animals with neuromuscular disorders that still have voluntary movements will hop fast as long as their weight is
held up because their proprioception is normal. This observation may help you distinguish between a subtle LMN
and UMN paresis.
There are many other postural reactions that can be tested but in my experience the hopping responses are the
most reliable and they are all that I routinely perform in this examination.
Many clinicians rely solely on what they call the CP - conscious proprioception response. This is an incorrect term
as this tests more than just conscious proprioception. The late Ralph Kitchell published a paper in which he made
a point of this common mistake describing that in this test there are somatic afferents that are responding to light
touch and pressure in addition to the general proprioceptive neurons. In reality the failure to return the paw to its
normal position can be caused by a LMN denervation of the digital extensors, an UMN paresis, or a loss of any of
the sensory innervation just described. In addition to this lack of specificity it is my experience that there are some
normal patients that when their paw is placed on its dorsal surface they will continue to stand on it until you make
them move. This paw placement test should not be relied on in the absence of testing the hopping responses.
Recumbent Animals - It is very important in evaluating these patients to pick them up and hold them in a standing
position. Get help if it is a heavy patient. By holding them in this position and lifting them up and down you can
determine the quality of muscle tone ie., whether they have a flaccid or spastic paralysis as well as determine if
any voluntary movements can be elicited. If there are voluntary movements, while still supporting them you can
determine the presence and quality of the hopping response.
4. Spinal Reflexes - Muscle Tone

Ideally these spinal reflexes and muscle tone will be diminished to absent in LMN disorders and increased in
UMN disease. The degree of hypertonia that results from UMN disease will be determined by the amount the
lesion interferes with the upper motor neurons that are inhibitory to extensor motor neurons. It is important to
evaluate the tone and spinal reflexes together with the gait abnormality. Dogs can exhibit profound neuromuscular
paresis with myasthenia gravis and still have normal tone and reflexes. Similarly some dogs with T3 - L3 lesions
often have normal muscle tone and reflexes.
For evaluating the spinal reflexes the patient should be placed in lateral recumbency and be as relaxed as
possible. The limbs can be flexed and extended to assess the degree of muscle tone that is present . The only
reliable tendon reflex in my experience and the only one that I routinely test is the patellar reflex. Holding the
stifle in partial flexion the patellar ligament is struck lightly with a hard object. The human pediatric patellar
hammer is the best size for our small animals. Both the sensory and motor components of this reflex are
contained in the femoral nerves and their components in the L4, 5 and 6 spinal nerves, roots and segments. If you
do not get this reflex in either the recumbent limb or non-recumbent limb do not consider it absent until you can
not get it in the other position. For some reason that I do not know, this reflex is occasionally absent on either the
recumbent or the non recumbent side. You only need to get it once to know it is intact. If the patient will not relax
you may not be able to elicit this reflex. It is my experience that the other tendon reflexes are not consistently
present in normal dogs and I do not routinely test them.
The withdrawal (flexor) reflex is done on both limbs by squeezing a digit with enough pressure to elicit the reflex
and a conscious response in a normal patient. Sometimes your digital pressure may be enough. Otherwise use a
pair of forceps on the base of the toenail adding enough pressure to get the response or not get it if there is a
lesion. Remember that you can have a reflex loss without loss of nociception so you must use care in the amount
of pressure you apply to avoid excessive discomfort to the patient and injury by the patient !!
This is a more complex reflex. The sensory neurons tested depend on the digit being tested or the autonomous
zone that you select for this stimulus and the motor response involves primarily the sciatic nerve in the pelvic limb
(stifle flexion) and its branches, the tibial nerve (digital flexion) and peroneal nerve (tarsal flexion). Beware that the
hip flexion that results involves the femoral nerve and most all the ventral branches of the lumbar spinal nerves to
the psoas major muscle. An animal with a complete sciatic nerve lesion can flex the hip when the medial aspect
of the paw is stimulated (saphenous nerve - sensory branch of the femoral nerve). The segments of spinal cord,
roots and spinal nerve ventral branches involved with the sciatic nerve are L6 L7 and S1.
In the thoracic limb there are multiple nerves involved with the withdrawal reflex thus it is a crude test of the entire
brachial plexus and cervical intumescence. The sensory nerve or nerves tested depend on the autonomous or
cutaneous zones selected. Squeezing the base of the 2nd or 3rd digital nail stimulates the sensory components of
the radial nerve dorsally and the median and ulnar nerves on the palmar aspect. The motor neurons involved are
in the axillary nerve (shoulder flexion) musculocutaneous nerve (elbow flexion) and median and ulnar nerves
(digital flexion). Both the sensory and motor neurons that are involved are associated with the C6 to T2 spinal
cord segments - the cervical intumescence.
These flexor responses only require the peripheral nerves and the segments of spinal cord where synapses occur
between the afferent and efferent components. A transverse lesion in the spinal cord cranial to these segments
that isolates the segments from the rest of the CNS will not cause a loss of these reflexes. They can persist
independent of the rest of the CNS.
Nociception
By increasing the amount of pressure on the digit the stimulus becomes a noxious one and in the normal animal
will elicit a conscious response. This response is the patient’s manifestation of pain. As an anatomist I try to
strictly adhere to the approved nomemclature to avoid ambiguity. This is published in the Nomina Anatomica
Veterinaria. No such Bible exists for medical terminology and is sorely needed. Therefore I appreciate it when I
am corrected for an improper use of terminology. In my textbook I refer to this noxious stimulus as the pain
stimulus which is incorrect. Once again, my neuroanatomical critic Ralph Kitchell pointed out to me the error of my
ways and I applaud him for that. Pain is not a sensory modality. Pain is the subjective response of the patient to a
noxious stimulus and varies between individual patients and is dependent on many other factors surrounding the
origin of the noxious stimulus. We should all adhere to this terminology! Having clarified that - the conscious
perception of the noxious stimulus known as nociception is primarily at the level of the sensory (somesthetic)
neocortex in the area of the postcruciate gyrus. To reach this level the entire pathway from the intumescence
involved with receiving the noxious stimulus to this sensory cortex must be intact. In general when the afferents
that have been stimulated by the noxious event enter the spinal cord dorsal grey column, they synapse on
projection neurons there. Most of these will cross to form an ascending pathway in the oppsite lateral funiculus
but some will form a similar pathway on the same side as the source of the stimulus. In reality there are
nociceptive pathways in all funiculi. However there are enough that are contralateral that in a cooperative patient
with a prosencephalic lesion involving this pathway or the sensory neocortex there will be a degree of hypalgesia
in the limbs on the opposite side. Only a transverse spinal cord lesion cranial to the intumescence involved will
produce analgesia. Such a lesion in the cervical spinal cord is usually lethal due to the interruption of UMN
respiratory tracts. Recognizing a hypalgesia in the limbs and trunk on one side in a patient with a normal gait is
one of the 3 tests used to localize a prosencephalic lesion. It is easier to appreciate in the nasal mucosa which
will be described with the cranial nerve part of this examination.
Because there is so much variation between animals in their response to noxious stimuli I do not believe I can
reliably recognize the difference between the response to a mild and more severe noxious stimulus - referred to
incorrectly as superficial and deep pain. Even if I could, I am not convinced it contributes to my ability to make the
anatomic diagnosis.
Obviously the presence or absence of nociception with severe transverse thoracolumbar spinal cord lesions is
important for prognosis as well as to specifically locate the site of the transverse lesion. There is one more reflex
that I usually test and always test when I am concerned about a possible transverse T3 - L3 lesion in the spinal
cord. This is the cutaneous trunci reflex - which I have incorrectly called the panniculus reflex. The sensory
neurons stimulated by lightly squeezing or poking the skin over the epaxial muscles of the thoracolumbar
vertebrae are contained in the dorsal branches of the spinal nerves innervating the skin at about the level of your
stimulus. Synapse occurs in the spinal cord dorsal grey column on long interneurons that then project cranially in
the fasciculus proprius. These interneurons terminate on LMN cell bodies in the ventral grey column at C8 and T1
which in turn enter the lateral thoracic nerve that innervates the cutaneous trunci muscle causing the skin to twitch.
Rarely this reflex can not be elicited in a normal dog. Starting at the L7 region and stimulating the skin over each
successive vertebrae the reflex in most animals does not start to about the midlumbar level but there are many
individual variations here. In patients with complete transverse T3 -L3 lesions, this reflex will be absent caudal to
the lesion - and more specifically about 2 spinal cord segments caudal to the lesion because of the normal short
caudal course of the dorsal branches after they leave the spinal nerve.
This reflex will also be absent with lesions that affect the lateral thoracic nerve or its origin from the C8 and T1
spinal nerves ie., avulsion of the roots of the brachial plexus, nerve sheath neoplasms of these spinal nerves.
The tail should be moved to assess the tone of its muscles and the anal tone should be determined. The perineal
reflex can be performed by mild digital pressure on the anus or with the blunt end of closed forceps or by
squeezing the anal or adjacent perineal skin with forceps and observing contraction of the anal sphincter and tail
flexion. The degree of stimulus can be gauged to avoid upsetting the patient when this innervation is still intact.
This reflex is dependent on the sacral segments and their spinal nerves and the branches of the pudendal nerves.
The tail response is dependent on the caudal segments and nerves. LMN bladder dysfunction is often indirectly
assessed by loss of the perineal reflex because of similar involvement of sacral segments and the proximal sacral
spinal nerves.
5. Cranial Nerves
The cranial nerve exam should be done when the patient is the most relaxed. With very young animals this is
often before you handle them at all. In most instances with these young animals - the less restraint the better. For
larger patients I prefer to do this cranial nerve exam while standing over the patient as I have been for the
postural reactions. For small dogs and all cats I prefer to sit on the floor with my back against the wall - all very
comfortable - flex my knees and place the patient with its back lying on my thighs. It is very easy to control the
patient this way and especially its head that you are going to examine. Aggressive cats can be rolled in a towel
before placing them in this position. The cranial nerve exam can be done "by the numbers" or by region. I much
prefer the latter. Either part or all of cranial nerves II thru VIII are evaluated in the region of the eyes.
Menace - Vision - Pupils
I always start with the menace response and cover one eye as I menace the other. This is a learned response
and may not occur until 10 to 12 weeks in puppies and kittens in which case I have to use their ability to follow
objects moving in their environment to assess vision. Anatomically this is a II - central visual pathway - VII
response. The majority of the central visual pathway is contralateral to the eye being menaced. Some normal
animals need a mild stimulus to get a response. I usually tap their orbital region with my hand a couple of times
before I do the menace. Then be sure you are not too close with your menacing hand so that you avoid long
vibrissae or a sudden air movement that stimulate sensory components of cranial nerve V. If I do not get a
response then I immediately touch the eyelids and look for the palpebral response to be sure the facial nerve is
functioning. If it is not, then I have to look for eyeball retraction or a head movement as a response to the menace
if the patient is visual. Occasionally it is necessary to set up a maze of objects in the animal’s environment to see
if they can avoid the objects when walking around them.
Immediately following the menace test, the pupil size and response to light should be examined. Some pupil size
can be seen in room light - I love cats that have a yellow iris. Most patients have a dark iris which will require
some additional light to see the borders of the iris. Hold your pen-light on the midline over the nose to give each
eye the same amount of light to look at pupillary size and determine if any anisocoria is present. Then place the
light source as close to the eye as possible and if no response occurs move the light around the fundus to be sure
all areas are stimulated. After observing this in one eye quickly swing the light into the other eye, observe that
eye’s response and then swing the light source back to the first eye and keep repeating this. In the normal patient
the pupil will constrict rapidly (depending on the species - this is always slow in horses) and as you move the light
source from one eye to the other the pupils in both eyes will stay constricted. This is how I observe the indirect or
consensual response rather than try to see the response in the opposite eye while I hold the light in the stimulated
eye.
When I am teaching, writing examinations or publications I never use the terms direct response (eye stimulated)
or indirect - consensual (the other eye) as these terms can be confusing unless you are very careful in your
description and in many publications this care is absent. Avoid this confusion by indicating that when the light is
directed into OS what happens to the pupil in OS and what happens in OD and do the same for the light directed
into OD.
This light reflex is mediated through the rostral brain stem. The retinal ganglion layer neurons involved with this
reflex in each optic nerve presumably are directed at the chiasm either into the opposite optic tract (about 75%
dog, 65% cat) and the remainder enter the ipsilateral optic tract. These light reflex processes pass over the lateral
geniculate nucleus and enter the dorsal thalamus to synapse on neurons in the pretectal nucleus on that side.
The majority of these pretectal neurons project thru the caudal commissure to terminate in the oculomotor
nucleus on the opposite side of the rostral mesencephalon.
Based on this anatomy, light directed into one eye will have a greater influence on the ipsilateral oculomotor
nucleus and the response in the stimulated eye may be more rapid and complete than the indirect response in the
opposite eye. This is not always obvious in your examination. You would also expect that a lesion limited to one
optic tract would cause a decreased response when the contralateral eye was stimulated but this too may be
difficult to appreciate.
Examples
If the menace response is absent in one eye with a normal palpebral response and pupils are normal and equal in
size and have normal pupillary light reflexes then the lesion causing the unilateral menace deficit is most likely in
the contralateral optic tract, lateral ciliary nucleus, thalamocortical fibers, optic radiation part of the internal
capsule or visual neocortex primarily in the occipital lobe. This is the central visual pathway for perception. In the
dog about 75% of the pathway is contralateral to the eye menaced after the optic chiasm and about 25% remains
ipsilateral. Therefore, lesions in this central visual pathway on one side cause a 75% loss of vision in the
contralateral eye and 25% loss in the ipsilateral eye but the owners rarely recognize this deficit. The menace test
can only determine the contralateral 75% deficit and it is fairly reliable. Even though the contralateral optic tract
contains the majority of the pupillary light reflex fibers - assuming that their portion that cross in the optic chiasm is
similar to the visual perception pathway - there usually will be no recognizable loss of pupillary light response in
the eye tested. This menace test is one of the 3 examinations to determine structural disorders in the
prosencephalon.
A patient has no menace response OS with a normal palpebral reflex. There is no anisocoria. Light directed into
OS causes no response OU (in both eyes or in each eye). Light directed into OD causes a normal response OU.
As you swing the light from OD, where the pupil constricted,back to OS, the OS pupil which was constricted from
the OD stimulation is now dilating back to its original size. This asymmetry is repeated as you swing the light back
and forth between the two eyes. When you cover OD with your hand, the pupil in OS dilates to its full extent.
Where is the lesion?

Answer - In OS or the left optic nerve. Most of the time with these lesions there is enough room light entering the
normal eye to keep the pupil in the abnormal eye constricted. Occasionally it will be slightly larger than the normal
pupil in room light.
A patient has normal menace responses. The pupil OD is widely dilated. Light in OD only causes the pupil to
constrict in OS. Light in OS only causes the pupil to constrict OS.

Answer - Right oculomotor nerve - parasympathetic visceral efferent fibers, or ciliary ganglion or its ciliary nerve
branches. Be aware of this as the first sign of an extramedullary mass lesion ventral to the diencephalon
compressing the oculomotor nerve with loss of the preganglionic parasympathetic function before the somatic
efferent neurons to extraocular muscles are affected.
A patient has no menace OD with a normal palpebral reflex. The OD pupil is widely dilated. Light directed into OD
causes no response OU. Light directed into OS causes only the OS pupil to constrict.

Answer - Right optic and oculomotor parasympathetic visceral efferent fibers or the ciliary ganglion or its ciliary
nerve branches. A retrobulbar tumor or abscess could do this.
A patient is blind OU - no menace OU - with normal palpebral reflexes. In room light the pupils are mildly dilated.
Light directed into OS causes the pupils to constrict OU. Light directed into OD causes the pupils to constrict OU.

Answer - Both eyeballs, optic nerves optic chiasm or optic tracts. The two most common disorders that cause
these specific signs are a retinal degeneration (SARDS-sudden acquired retinal degeneration) and optic neuritis.
From my clinical experience it appears that animals with lesions in the sites just described can lose their visual
perception and be clinically blind but still have light responsive pupils when a bright light is directed into the eyes.
However, in room light there is insufficient light to permit normal constriction. This may reflect that the disease
processes involved tend to spare the pupillary light reflex neurons in cranial nerve II or more likely to lose the light
reflex completely it is necessary to interfere with the function of all of these neurons whereas vision is lost after a
certain threshold percentage of retinal ganglion layer neurons are dysfunctional. In other words the pupillary light
reflex neurons are the last to go when lesions disrupt the retina or optic nerve.
Anisocoria can result from many intraocular disorders. Iris atrophy is fairly common in older animals and creates
dilated unresponsive pupils with no interference with vision. Neurological causes of anisocoria include
disturbances to cranial nerves II, III and the sympathetic ocular innervation.
Complete sympathetic paralysis of the head (Horner’s syndrome) causes a miosis, smaller palpebral fissure and a
protuded third eyelid. Facial hyperthermia and decreased nasal air flow on the affected side are very difficult to
appreciate in small animals. This sympathetic paralysis most commonly involves some component of the pre or
postganglionic sympathetic LMN. In very acute severe C1 - C8 spinal cord lesions an UMN Horner’s syndrome
may occur. This is most commonly seen in hemiplegic dogs associated with ischemia or infarction caused by
fibrocartilaginous emboli. A persistently miotic pupil in a small animal with the signs of an avulsion of the
components of the brachial plexus localizes the injury to the level of the roots or spinal nerves at the vertebral
column.
It is important to remember that in general the size of the pupils represents a balance between the amount of light
entering the eye and stimulating the oculomotor neurons that innervate the iris constrictor muscle and the
emotional state of the patient which influences the sympathetic innervation of the iris dilator muscle.
Strabismus
While examining the eyes you can appreciate whether they are normally positioned in the orbits. Abnormal eye
positions reflect a lack of innervation of the extraocular muscles or a disorder with the vestibular system. The
latter is most common and the vestibular strabismus only occurs in some positions of the head. Somatic efferent
neurons in the oculomotor nerve prevent a lateral and slightly ventral strabismus. The abducent neurons prevent
a medial strabismus. The trochlear neurons prevent an excessive extorsion of the eye which can only be seen in
the cat with the lateral positioning of the dorsal aspect of its vertical pupil. In the dog you would have to do a
fundic exam and look at the position of the normally vertical superior vein at the optic disc. A quick assessment of
the function of the oculomotor nerve innervation to the medial rectus muscle and the abducent nerve innervation
to the lateral rectus is to test for normal physiologic nystagmus by moving the head side to side. As you move the
head to the right both eyes will move abruptly - jerk in that direction, which tests the abducent nerve in the right
eye and the oculomotor nerve in the left eye as both eyes will jerk together. On moving the head back to the left
the opposite nerves will be tested. The stimulus for this response is the movement of fluid in the semicircular
ducts and stimulation of vestibular nerve (VIII) receptors in the inner ear. These impulses will be projected thru the
vestibular nuclei into the medial longitudinal fasciculus in the brain stem which projects to the somatic efferent
neurons of the oculomotor and abducent nerves. This normal response can be readily elicited in most dogs but in
some cats the eye movements will only occur at the end of the head excursion. This takes a long time to write and
just a few seconds to do.
Nystagmus
As I stand over the dog's head, following the menace and pupil examination, I look for any strabismus or any
abnormal resting - spontaneous nystagmus. I then move the head side to side to see if the eye movements are
normal and then hold the head still in one lateral position and see if any abnormal positional nystagmus
develops - then move the head to the opposite side and hold it still and look for abnormal nystagmus in that
position and then I extend the head and neck and hold it still and look for abnormal nystagmus. In dogs and cats
when the head and neck are extended, the eyes normally elevate to stay in the center of the palpebral fissure.
With vestibular system disorders the eye on the affected side usually fails to elevate completely giving you a
vestibular strabismus. When the head is held still there should be no nystagmus. Nystagmus is normal whenever
the head is moved. In a severe vestibular system disorder a nystagmus occurs continuously regardless of the
position of the head. This is an abnormal nystagmus referred to as a resting or spontaneous nystagmus. In less
severe vestibular system disturbances an abnormal nystagmus may only occur when the head is held in various
positions as just described. This is referred to as an abnormal positional nystagmus. Occasionally in very mild
cases it will only show up when the patient is placed in dorsal recumbency with the head and neck extended. The
direction of the nystagmus is defined as the direction of the fast phase of the eye movements. The one rule that
can be relied on is that when the vestibular disturbance involves the inner ear receptors or the vestibular part of
the vestibulocochlear nerve (VIII), the direction of the jerk nystagmus is always opposite to the side of the lesion.
The latter is the direction of the head tilt and loss of balance.
Facial and Trigeminal Neurons

Although portions of these cranial nerves have already been assessed, I routinely reconsider them now. I gently
touch the eyelids with a pair of forceps coming at the eyes from caudally so the forceps will not be seen. There is
considerable overlap of the eyelid innervation by the trigeminal nerve ophthalmic branches medially and the
maxillary branches laterally therefore I make no attempt to distinguish between the two. The sensory nerves
stimulated are branches of the trigeminal nerve (CN V) and the motor response is via branches of the facial nerve
(CN VII). Connections between the two involve the pons and medulla. For other areas of facial nerve innervation I
look for normal flaring of the nostrils on inspiration, hold the head and neck in extension and look at the corners of
the lips for evidence of mucosa showing on the paretic side and abnormal drooling on that side. I also assess the
abiltiy to move the ears in those patients with erect ears but do not spend much time on flop-eared dogs to avoid
frustration. Sometimes a normal ear will move when you blow air into it. There is no need for the examiner to get
excessively stressed in this process. Remember that dogs and cats with facial paralysis will not have a smaller
palpebral fissure (ptosis) unlike the herbivores nor will their nose deviate to the normal side. When you see the
nose deviated to one side in a dog this usually is a reflection of excessive contraction of the facial muscles on that
side referred to as hemifacial spasm but it is not spasmodic-episodic as it is described in humans. It is a continual
deviation. This is most commonly associated with a presumed irritation of the facial nerve from an otitis media.
These dogs will have a narrowed palpebral fissure and an ear pulled dorsally and medially on that side. On
testing the palpebral reflex there may be slight movement of the eyelids. This has been described as a
denervation contracture of the facial muscles but these muscles will often relax during local or general anesthesia
which refutes that consideration at least for most cases. This rarely occurs in the cat.
To complete my evaluation of the trigeminal nerve I palpate the muscles of mastication. The only evidence of a
unilateral motor trigeminal nerve deficit will be the denervation atrophy that can be palpated. They can still bite!!
You need bilateral loss of this mandibular nerve innervation to get a loss of the ability to use the jaw. When this
occurs the lower jaw will be dropped so the mouth is continually open and can not be closed. The most common
cause of a sudden onset of a dropped lower jaw is an immune-mediated trigeminal neuritis. The most common
cause of unilateral atrophy of these muscles is a nerve sheath neoplasm in the dog and more likely lymphoma in
the cat. Bilateral atrophy of the muscles of mastication is often seen in older dogs with no evidence of any
dysfunction. One cause may be a chronic myositis. Occasionally this atrophy and accompanying fibrosis is severe
enough to prevent the jaw from opening.
On a routine examination I always touch the nasal septum with the end of my closed forceps as a test of both the
sensory innervation by the trigeminal nerve - specifically ophthalmic branches via the ethmoidal nerve, but also as
a very sensitive test for nociception and therefore this projection pathway which involves the contralateral
prosencephalon. This is one of the three tests that I have described that will evaluate prosencephalic function.
With prosencephalic lesions this nasal septum will never be analgesic just hypalgesic because some of the
nociceptive pathway stays ipsilateral and the incomplete crossing occurs in the pons and medulla.
When you determine that there is nasal hypalgesia the lesion responsible for this can either be in the ipsilateral
trigeminal nerve or in the contralateral prosencephalon. You differentiate between the two locations based on the
rest of the clinical signs that are present. Are they related to the caudal brain stem and therefore this is a
trigeminal nerve problem or are they prosencephalic and that is the basis for the hypalgesia?
IX - X - XII
These 3 cranial nerves are examined together with the so-called "gag reflex". This is done rapidly as the patient
usually objects to the manipulation that is necessary and especially cats. You grasp the upper jaw with one hand
and pull down on the lower jaw with the other hand opening the mouth. This effort will test the tone - resistance in
the muscles of mastication (CN V). You quickly look at the size of the tongue for atrophy - hypoglossal nerve (CN
XII) and push the tongue with your finger to see if it moves. Then insert your finger deep into the oropharynx to
assess the tone and sensory perception that you will stimulate. These latter functions are dependent on the
innervation by the pharyngeal branches of the glossopharyngeal (IX) and vagal (X) nerves. This assessment of
the gag response is difficult to evaluate and is usually very subjective. A more reliable indication of dysphagia
usually comes in the form of a complaint by the owner as they watch their pet try to eat and swallow.
The following is an outline of the order of the cranial nerve exam just described:
- Menace Response II - central visual pathway to occiptal lobe

VII = closure of palpebral fissure
- Pupil Size - Light II - brain stem
Response III parasympathetic-ciliary ganglion - nerves = pupil
constriction direct and indirect
- Eye Position Strabismus - III = ventrolateral
Strabismus - VI = medial
- Eye Movements Normal vestibulo-ocular nystagmus
VIII - brain stem - III = adduction
VIII - brain stem - VI = abduction
- VIII - Vestibular Strabismus in some eye positions
Abnormal nystagmus (head not moving)
- Facial Muscles VII - position, tone, movement: eyelids, ears, lips, nose
- Menace Response II - VII
- Palpebral Reflex V - VII
- Facial Sensation V
- Palpebral Reflex V - VII - cutaneous, autonomus zones
- Nociception Nasal mucosa - Ophthalmic branch V
- Masticatory muscles V - Mandibular branch V

Muscle size, tone-jaw closure
- Gag Reflex Jaw tone - V
- Tongue Size Movement XII
- Reflex Gagging, IX, X

Swallowing
Neurological Syndromes
K. G. Braund
The nervous system, unlike other body systems, is comprised of myriad subparts that typically have unique
neuroanatomical and neurophysiological functions. Accordingly, localizing lesions within different areas of the
nervous system can be quite a challenge. This task is made easier by utilizing the neurological syndrome
approach. A "syndrome" is defined as a group of clinical signs that are usually seen together and are
representative of specific organ system involvement. The syndrome concept has special importance in the
nervous system, since specific lesions within the central nervous system, peripheral nervous system, and skeletal
muscle result in predictable, specific clinical signs. Therefore, through the recognition of certain key clinical signs
(i.e., a syndrome) a lesion can be localized within any of these areas. This concept of neurological syndromes
provides the basis for lesion localization, without which differential diagnosis of disease cannot logically be
pursued [1-3]. Note that in localizing a lesion, it is not necessary that all the clinical signs listed for each syndrome
be observed: a sufficient number of key clinical signs are usually present to permit accurate identification of the
syndrome. Diseases commonly seen with each syndrome are listed and designated as more likely to be seen in
dogs (D), cats (C), or in both species (D + C).
The following syndromes will be discussed:
Lumbosacral Syndrome
Thoracolumbar Syndrome
Cervicothoracic Syndrome
Cervical Syndrome
Pontomedullary Syndrome
Cerebellar Syndrome
Vestibular Syndrome
Midbrain Syndrome
Diencephalic Syndrome
Cerebral Syndrome
Multifocal Syndrome
Paroxysmal Syndrome
Myopathic Syndrome
Neuropathic Syndrome
Lumbosacral Syndrome
Lesions involving spinal cord segments L4 - 5 through S1 - 3 (+ coccygeal segments) or lumbosacral nerve roots
that form the cauda equina (including femoral, obturator, sciatic, pudendal, pelvic, and coccygeal nerves) will
result in a lumbosacral syndrome. The lumbosacral syndrome reflects various degrees of involvement of the
pelvic limbs, bladder, anal sphincter, and tail. Clinical signs will range from flaccid weakness to paralysis of pelvic
limbs and tail. Patellar and withdrawal reflexes (as well as gastrocnemius and cranial tibial reflexes) may be
depressed or absent in pelvic limbs, as may be perineal (anal) and bulbocavernosus (in male dogs) reflexes.
Tone in pelvic limb muscles may be reduced or absent. After 1 to 2 weeks of clinical signs, segmental muscle
atrophy due to denervation will be observed. "Segmental" refers to the particular spinal cord segment involved in
the lesion (e.g., segmental atrophy may develop in the iliopsoas, quadriceps, and sartorius muscles following an
injury to the L4 - 6 spinal cord segments). Pain perception in pelvic limbs, tail, and perineum may be reduced or
absent. Pelvic limb postural reactions such as hopping and placing may be depressed. Thoracic limb function is
unaffected. Normal micturition requires synchronized contraction of the urethral smooth muscle and relaxation of
the urethral skeletal muscle. Urethral smooth muscle is supplied by pelvic (parasympathetic) and hypogastric
(sympathetic) nerves; pelvic and hypogastric nerves form the pelvic plexus. The pudendal nerve innervates the
urethral skeletal muscle. Lesions involving the pelvic nerves, sacral cord segments, or pathways to and from the
brainstem will abolish the micturition reflex. Consequently, the bladder will distend with urine and eventually
overflow. Lesions of the sacral segments will also result in loss of innervation to the skeletal muscle of the urethra.
As a result of minimal urethral resistance, manual expression of the bladder is easy in such cases. Thus, animals
with sacral cord lesions may suffer from continual overflow incontinence. The anal sphincter may be flaccid and
dilated, resulting in fecal incontinence. Since the external anal sphincter is innervated by the pudendal nerve,
which also originates in the sacral segments, the perineal (anal) reflex provides a good assessment of sacral
spinal cord function.
In some animals with lumbosacral disk extrusion, one pelvic limb may be held in partial flexion or a repetitive
"stamping" motion may be observed. These animals frequently show considerable pain on manipulation of the
limb and lumbosacral spine. This combination of signs is termed "root signature" and is believed to be associated
with nerve root compression or entrapment by a fragment of extruded disk material.
Note that some animals with the lumbosacral syndrome may be paretic or paralyzed in the pelvic limbs, with
reduced reflexes and muscle tone, but have normal anal sphincter function. In other animals, anal sphincter and
bladder dysfunction may be the principal clinical signs, with only mild pelvic limb weakness. Both groups of
animals have a lumbosacral syndrome, but the lesion occurs at slightly different levels of the lumbosacral spinal
cord or lumbosacral nerve roots.
The principal clinical signs of the lumbosacral syndrome are listed in Table 1, and the diseases known to produce
this syndrome are outlined in Table 2.
Table 1. Principal Signs of the Lumbosacral Syndrome
• Weakness/paralysis of pelvic limbs and tail

• Depressed pelvic limb reflexes and flaccid muscle tone
• Muscle atrophy in pelvic limbs, and/or hip muscles
• Postural reaction deficits in pelvic limbs
• Dilated anal sphincter
• Depressed bulbocavernosus reflex
• Reduced sensitivity (hypesthesia) in perineal area, pelvic limbs, or
tail
• Urinary incontinence
• Fecal incontinence
• Root signature
Modified from: Braund KG. An approach to diagnosing neurological disease. Waltham Focus 1999; 9:23-30 [2].
Table 2. Diseases Associated with the Lumbosacral Syndrome
Degenerative Disorders None

Lumbosacral stenosis; disk disease; spondylosis deformans; dural
Degenerative Structural and
ossification; nervous system degeneration in Ibizan Hounds; spinal synovial
Compressive Disorders
cysts
Spina bifida; sacrocaudal dysgenesis; dermoid sinus; myelodysplasia;
Developmental Disorders
transitional vertebrae
Endogenous Metabolic
None
Disorders
Rabies;granulomatous meningoencephalomyelitis; mycotic diseases;
Inflammatory Disorders
parasitic encephalomyelitis; abscessation
Neoplasia Spinal cord tumors; peripheral nerve tumors
Neurotoxic Disorders None

Infarction; fibrocartilaginous embolization; hemorrhage; hemorrhagic
Neurovascular Disorders
myelomalacia; traumatic feline ischemic myelopathy
Nutritional Disorders None
Storage Disorders None
Traumatic Disorders Spinal trauma
Modified from: Braund KG. Clinical Syndromes in Veterinary Neurology. St Louis: Mosby, 1994 [1].
Notes -
a) In canine neural angiostrongylosis caused by Angiostrongylus cantonensis, neurological signs are commonly
seen in puppies from 5 to 16 weeks of age and are characterized by a lumbosacral syndrome (See parasitic
encephalomyelitis).
b) Several conditions such as transitional vertebrae, dural ossification, and spondylosis deformans may be
detected by radiography/imaging but are usually subclinical.
c) Spinal trauma in the lumbosacral region is usually associated with pelvic or sacrocaudal fractures.
d) Inflammatory disorders affecting the lumbosacral region are not commonly reported. Multiple granulomas with
fungal elements have been observed in the lumbosacral subarachnoid space with compression of the cauda
equina.
e) Signs of a lumbosacral syndrome may result from certain polyneuropathies, such as cauda equina
polyradiculoneuritis (See neuropathic disorders) and motor neuron diseases
f) In nervous system degeneration in Ibizan Hounds, patellar reflexes are absent, but without evidence of muscle
atrophy.
g) In cats with nemaline myopathy, patellar reflexes are also depressed/absent and there may be gluteal muscle
atrophy.
h) Common causes of the lumbosacral syndrome seen in practice
- Pelvic fractures and luxations (D + C)
- Lumbar stenosis (D)
- Fibrocartilaginous embolization (D)
- Sacrococcygeal dysgenesis (C)
Thoracolumbar Syndrome
A spinal cord lesion located between cervical and lumbar enlargements (intumescences), i.e., between T3 and L3
cord segments, will produce a thoracolumbar syndrome, which is commonly encountered in dogs and cats. The
thoracolumbar syndrome is characterized by spastic weakness or paralysis of pelvic limbs (spasticity is
associated with increased muscle tone, especially in extensor muscles). Ataxia may be observed in ambulatory
animals (e.g., crossing of the pelvic limbs when walking, knuckling, or abnormal abduction or protraction of the
pelvic limbs). Pelvic limb reflexes are intact (normal or increased); however, postural reactions such as hopping
and placing are depressed in pelvic limbs. In some animals, reflex testing may induce clonus - spasms in which
contraction and relaxation of limb muscles alternate in rapid succession. Flexor reflex testing may also induce
prolonged, repetitive flexion of the limb being tested in the absence of repeated stimuli [4]. A crossed extensor
reflex may be observed. Thoracic limb function is normal. Animals with thoracolumbar disk disease may keep
their backs slightly arched ("kyphosis"). The cutaneous trunci reflex can be a valuable test for localizing a focal
lesion in the thoracolumbar spinal cord as reflex contraction of the subcutaneous musculature will be reduced or
absent caudal to the level of the lesion, but exaggerated at the level of, or immediately above, the area of cord
involvement. Similarly, there is reduced cutaneous sensation along the dorsal spine behind the lesion site, but
sensation is increased at, or immediately above the level of the lesion. In dogs with thoracolumbar disk disease,
digital pressure on the spine at the level of disk extrusion will usually elicit back pain. Spinal cord lesions rostral to
the sacral segments can result in increased tone (spasticity) in the skeletal muscle of the external urethral
sphincter, making the bladder very difficult to express manually, so that catheterization or pharmacologic
intervention is usually required. Consequently, bladder distension and occasional overflow incontinence are
usually present. A reflex bladder with detrusor asynergia may develop after a few weeks and an incontinence is
often characterized by sporadic spurting of urine.
Segmental muscle atrophy is not a feature of the thoracolumbar syndrome; however, atrophy caused by disuse
can occur in animals with long-term or permanent paralysis. Such atrophy is usually generalized and involves all
muscles of the spine caudal to the level of the spinal cord lesion, as well as muscles of the pelvic limbs.
An acute, compressive lesion of the thoracolumbar spinal cord occasionally may be accompanied by a Schiff-
Sherrington posture, which is observed as rigid extension of the thoracic limbs with the animal in lateral
recumbency. However, voluntary movement (with support) and postural reactions, such as wheelbarrowing and
hopping, are normal in the thoracic limbs. The wheelbarrow reaction is particularly useful for testing thoracic limb
function: it is usually depressed in animals with cervicothoracic or cervical syndromes. It should be noted that this
test is manipulative and should not be performed on animals with vertebral column injuries. The principal clinical
signs of the thoracolumbar syndrome are listed in Table 3, and the diseases known to produce this syndrome are
outlined in Table 4.
Table 3. Principal Signs of the Thoracolumbar Syndrome
• Weakness or paralysis of pelvic limbs

• Pelvic limb reflexes normal or brisk (may seen clonus)
• No muscle atrophy in pelvic limbs
• Postural reaction deficits in pelvic limbs
• Reduced/absent cutaneous trunci reflex behind level of lesion
• Increased local sensitivity (hyperesthesia) at level of lesion
• Reduced sensitivity (hypesthesia) behind level of lesion
• Thoracolumbar kyphosis
• + Schiff-Sherrington posture
Modified from Braund KG: An approach to diagnosing neurological disease. Waltham Focus 1999; 9:23-30 [2].
Table 4. Diseases Associated with the Thoracolumbar Syndrome

Afghan Hound myelopathy; degenerative myelopathy; encephalomyelopathy in
Degenerative Disorders young cats; Hound ataxia; Kooiker Dog myelopathy; Labrador Retriever
axonopathy; nervous system degeneration in Ibizan Hounds
Degenerative Structural
Calcinosis circumscripta/tumoral calcinosis; disk disease; dural ossification;
and Compressive
osteochondromatosis; spinal synovial cysts; spondylosis deformans
Disorders
Arachnoid cysts; dermoid sinus; hemivertebra; myelodysplasia; spina bifida;
stenosis of the vertebral canal; syringomyelia and hydromyelia
Endogenous Metabolic
None
Disorders
Distemper; feline infectious peritonitis; feline leukemia virus; granulomatous
Inflammatory Disorders meningoencephalomyelitis; mycotic diseases; parasitic encephalomyelitis;
protothecosis; rabies;toxoplasmosis and neosporosis
Neoplasia Spinal cord tumors; paraneoplastic myelopathy

myelomalacia
Nutritional Disorders Nutritional secondary hyperparathyroidism
Storage Disorders Globoid leukodystrophy; mucopolysaccharidosis type VI
Notes -
a) Several conditions such as hemivertebra, dural ossification, spondylosis deformans, and stenosis of the
vertebral canal (e.g., in the thoracic region) may be detected by radiography/imaging but are usually subclinical.
Similarly, spina bifida may be subclinical.
b) Spinal trauma in the thoracolumbar region is frequently associated with thoracolumbar fractures or
luxations/subluxations. In animals (especially cats) with Nutritional secondary hyperparathyroidism, neurological
signs of a thoracolumbar syndrome most often relate to spinal fractures associated with severe vertebral
osteopenia.
c) Epidural migration of parasites, e.g., adult heartworms (Dirofilaria immitis) is occasionally seen in dogs
producing a thoracolumbar syndrome.
d) A degenerative myelopathy associated with malignant tumors located outside of the nervous system may
occasionally result in a thoracolumbar syndrome (see paraneoplastic myelopathy)
e) Common causes of the thoracolumbar syndrome seen in practice
- Intervertebral disk disease(D)
- Spinal fractures (D + C)
- Degenerative myelopathy (D)
- Diskospondylitis (D)
- Metastatic lymphosarcoma (C)
Cervicothoracic Syndrome
The cervicothoracic spinal cord segments that extend from C6 through T2 form an enlarged area of the cord
known as the cervical intumescence. The gray matter of these segments gives rise to various nerves (e.g.,
suprascapular, musculocutaneous, axillary, radial, median, and ulnar nerves) supplying thoracic limb muscles. A
lesion in this region of the spinal cord produces signs of a cervicothoracic syndrome. The hallmarks of the
cervicothoracic syndrome are weakness or paralysis in both thoracic limbs, in all four limbs (i.e., tetraparesis or
tetraplegia), in limbs on the same side of the body (i.e., hemiparesis or hemiplegia), or in only one thoracic limb
(i.e., monoparesis or monoplegia). Ataxia may be observed in ambulatory animals. Other signs include depressed
or absent reflexes (tricipital, bicipital, withdrawal) and decreased or flaccid muscle tone in one or both thoracic
limb(s). As with a lumbosacral syndrome, segmental muscle atrophy due to denervation is usually observed in the
thoracic limb(s) of animals 1 - 2 weeks after spinal injury. In pelvic limbs, reflexes are intact and may be increased
(brisk), but there is no atrophy. Postural reactions, such as hopping and placing, may be depressed in all limbs,
especially in the thoracic. In some instances, animals will clumsily propel themselves on their chins using their
pelvic limbs, with thoracic limbs drawn to their flanks. The cutaneous trunci reflex, mediated by the lateral thoracic
nerve which originates in cord segments C8 - T2, may be depressed or absent unilaterally or bilaterally,
depending on the extent and location of the lesion. In animals with unilateral loss, there may still be a twitch on
the contralateral trunk (called the consensual response, which is caused by fibers crossing within the spinal cord)
and this can sometimes be mistaken for an ipsilateral twitch. Urinary incontinence (similar to that seen with the
thoracolumbar syndrome) is usually observed. Animals with lesions in cord segments T1 - T3 may have signs of a
Horner's syndrome - miosis (small pupil), ptosis (upper lid droop), enophthalmos (sunken globe) and prolapse of
the third eyelid.
A cervicothoracic syndrome may occur in animals (usually dogs) with hydrosyringomyelia (See Syringomyelia and
Hydromyelia), often in association with Chiari malformations. With continuing expansion of the
hydrosyringomyelia, ventral horn cells may become involved leading to neurogenic muscle atrophy and weakness,
while dorsal expansion of the lesion may impact the dorsal horn and decussating spinothalamic tracts leading to
segmental sensory loss and/or paraesthesia over shoulder and neck dermatomes (leading to persistent
scratching at the flank or shoulder/neck area). This group of signs has been termed a "central cord syndrome".
The central cord syndrome may also occur with intramedullary spinal cord tumors (See Intramedullary Tumors).
The principal clinical signs of the cervicothoracic syndrome are listed in Table 5, and the diseases known to
produce this syndrome are outlined in Table 6.
Table 5. Principal Signs of the Cervicothoracic Syndrome
• Weakness/paralysis in:
- all four limbs (i.e., tetraparesis/tetraplegia),
- limbs on the same side of the body (i.e., hemiparesis/hemiplegia),
- only one thoracic limb (i.e., monoparesis/monoplegia)
• Depressed reflexes and flaccid muscle tone in thoracic limb(s),
muscle atrophy after 1 - 2 weeks
• Normal/increased reflexes and muscle tone, without muscle atrophy,
in pelvic limb(s)
• Postural reaction deficits in one thoracic limb, in limbs on the same
side, or in all limbs
• Increased local sensitivity (hyperesthesia) at level of lesion
• Reduced sensitivity (hypesthesia) behind level of lesion
• Persistent scratching at one side of the shoulder/neck region
• Cutaneous trunci reflex depressed or absent (unilaterally or
bilaterally)
• Horner's syndrome
- Miosis (may be the only signs of Horner’s syndrome)
- Enophthalmos
- Ptosis
- Protrusion of third eyelid
Table 6. Diseases Associated with the Cervicothoracic Syndrome

Afghan Hound myelopathy; motor neuron disease in German Shepherds;
Degenerative Disorders
hereditary polioencephalomyelopathy of the Australian cattle dog
Calcinosis circumscripta/tumoral calcinosis; cervical spondylomyelopathy;
disk disease; dural ossification; osteochondromatosis; spinal synovial
cysts
Arachnoid cysts; dermoid sinus; syringomyelia and hydromyelia; spina
bifida
Endogenous Metabolic Disorders None
Distemper; feline leukemia virus; granulomatous
rabies;toxoplasmosis and neosporosis
Neoplasia Spinal cord tumors

myelomalacia
Nutritional Disorders Hypervitaminosis A
Storage Disorders Globoid leukodystrophy
Traumatic Disorders Spinal trauma; brachial plexus avulsion
Notes -
a) One condition that mimics a unilateral cervicothoracic syndrome is traumatic avulsion of the brachial plexus
(see brachial plexus avulsion). Animals with this disorder may show evidence of areflexia, muscle atrophy, and
weakness/paralysis (i.e., monoparesis/monoplegia) of one thoracic limb, together with signs of a partial Horner's
syndrome in which only miosis is observed. The miosis will be ipsilateral, i.e., on the same side as the paralyzed
thoracic limb. In animals with brachial plexus avulsion, postural reactions will be depressed in the affected limb
but normal in all other limbs.
b) Another neuropathic condition that mimics a cervicothoracic syndrome is brachial plexus neuropathy (See
Neuropathies).
c) Spinal trauma in the cervicothoracic region may be associated with cervicothoracic fractures or
luxations/subluxations.
d) Brachial plexus sheath tumors often extend into the vertebral canal and produce spinal cord compression and
signs of a cervicothoracic syndrome (See Intradural-extramedullary Tumors).
e) Subclinical spina bifida has been found involving C7 vertebra in some puppies with Labrador Retriever
axonopathy.
f) Common causes of the cervicothoracic syndrome seen in practice:
- Brachial plexus avulsion (D)
- Brachial plexus sheath tumors (e.g., neurofibroma) (D + C)
- Cervical spondylomyelopathy (D)
- Disk disease (D)
Cervical Syndrome
A lesion between C1 and C5 spinal cord segments produces the cervical syndrome. As with the thoracolumbar
syndrome, clinical signs reflect disruption of white matter pathways rather than gray matter involvement (as seen
in lumbosacral and cervicothoracic syndromes). With a cervical syndrome, clinical signs may range from
weakness to spastic paralysis of all four limbs (i.e., tetraparesis or tetraplegia) or of limbs on the same side of the
body (i.e., hemiparesis or hemiplegia). Ataxia may be observed in ambulatory animals. Postural reactions are
usually depressed or absent in all limbs, and urinary incontinence, similar to that seen in the thoracolumbar
syndrome, may be evident. Dorsal and lateral compressive lesions of the cervical spinal cord may result in signs
being more severe in the pelvic limbs (perhaps because of the more superficial location of the ascending
proprioceptive pathways from the pelvic limbs), while a ventral median compressive lesion may produce more
severe signs in the thoracic limbs (perhaps because of the more medial location of descending motor tracts
projecting to the cervical intumescence [5]. A more centrally located lesion within the spinal cord (e.g., a centrally
expanding intramedullary tumor or central necrosis secondary to acute spinal trauma) may produce more severe
signs in the thoracic limbs because motor tracts of the thoracic limbs lie more centrally than do those of the pelvic
limbs [6]. Reflexes and muscle tone are intact or increased in all limbs. In some animals with a severe cervical
cord lesion, muscle tone may be increased to the point of pronounced extensor rigidity that may be clasp-knife in
character (in which a rigidly hyperextended limb suddenly gives way to forced flexion). There is no evidence of
segmental muscle atrophy in any of the limbs. Affected animals may experience variable loss of pain perception
in all limbs and in the neck caudal to the level of the lesion; however, it is unusual to detect complete loss of pain
sensation, since spinal cord injury of such magnitude would most likely be accompanied by respiratory failure.
Cervical muscle spasms, pain on palpation or manipulation, and cervical rigidity due to splinting of the neck
muscles will be present in some animals, e.g., dogs with cervical disk disease. These dogs strenuously resist
flexion and extension of their necks and they may assume an abnormal posture with the nose held close to the
ground and the back arched. In some dogs with cervical disk disease, one thoracic limb may be held in partial
flexion, or a repetitive "stamping" motion may be observed. These animals frequently show considerable pain on
manipulation of the limb and neck. This combination of signs is termed "root signature" and is believed to be
associated with nerve root compression or entrapment by a fragment of extruded disk material.
Occasionally, an animal may manifest a variable degree of respiratory difficulty. Rarely, an ipsilateral Horner's
syndrome may be present in an animal with a severe destructive lesion in the cervical cord, e.g., infarction
secondary to fibrocartilaginous embolization.
The central cord syndrome mentioned in the cervicothoracic syndrome may also occur in the cervical region in
conjunction with hydrosyringomyelia or an intramedullary tumor. In affected animals, segmental sensory loss
and/or paresthesia, along with lower motor neuron signs affecting the paraspinal musculature (e.g., torticollis from
muscle weakness) may ensue, while scoliosis may develop if the muscle atrophy is severe. Unilateral epaxial
cervical muscle spasms may also play a role in the scoliosis. The observation of scoliosis and cervical pain in an
animal may be the first clinical sign of cervical hydrosyringomyelia.One other sign commonly seen in dogs with
this lesion is persistent scratching at the neck/shoulder or flank area. Expansion of the hydrosyringomyelia
centrifugally may eventually compromise the descending corticospinal/rubrospinal tracts and produce upper motor
neuron signs to the pelvic limbs while extension into the dorsal columns may result in loss of proprioception.
The principal clinical signs of the cervical syndrome are listed in Table 7, and the diseases known to produce this
syndrome are outlined in Table 8.
Table 7. Principal Signs of the Cervical Syndrome
• Weakness or paralysis in:

- all four limbs (tetraparesis/tetraplegia) or
- limbs on the same side of the body as the lesion
(hemiparesis/hemiplegia)
• Normal or increased reflexes and muscle tone in all limbs + clasp-
knife extensor rigidity in limbs on the same side as the lesion, or in
all limbs
• Postural reaction deficits in limbs on the same side as the lesion or
in all limbs
• Cervical muscle spasms, pain and/or rigidity (animals may resist
neck flexion/extension)
• Root signature (a thoracic limb either held in partial flexion or
moving in a repetitive "stamping" motion)
• Persistent scratching at the neck/shoulder
• + Torticollis/scoliosis
• + Respiratory difficulty
• + Horner's syndrome
Table 8. Diseases Associated with the Cervical Syndrome

Afghan Hound myelopathy; hereditary ataxia; Kooiker Dog myelopathy;
Labrador Retriever axonopathy; Rottweiler leukoencephalomyelopathy
Calcinosis circumscripta/tumoral calcinosis; cervical spondylomyelopathy;
Degenerative Structural and nervous system degeneration in Ibizan Hounds; disk disease; dural
Compressive Disorders ossification; Miniature Poodle demyelination; osteochondromatosis;
Rottweiler leukoencephalomyelopathy; spinal synovial cysts
Arachnoid cysts; atlantoaxial subluxation; Chiari malformations; dermoid
sinus; occipital dysplasia; spina bifida; syringomyelia and hydromyelia
Abscessation; distemper; feline infectious peritonitis; granulomatous
meningoencephalomyelitis; meningitis; mycotic diseases; parasitic
Inflammatory Disorders encephalomyelitis; protothecosis; pyogranulomatous
meningoencephalomyelitis; rabies; toxoplasmosis and neosporosis;
leishmaniasis
Neoplasia Spinal cord tumors

myelomalacia
Nutritional Disorders Hypervitaminosis A
Storage Disorders Globoid leukodystrophy;mucopolysaccharidosis type 1
Notes -
a) Spinal trauma in the cervical region may be associated with cervical fractures, luxations/subluxations, or
accidental penetrating injuries of the vertebral canal such as those associated with oropharyngeal stick injuries.
b) Atlantoaxial subluxation is a common cause of cervical spinal cord trauma.
c) Atlantoaxial subluxation may also occur in dogs and cats in association with occipitoatlantoaxial malformation.
d) Epidural migration of parasites, e.g., adult heartworms (Dirofilaria immitis) is occasionally seen in dogs
producing a cervical syndrome. Spinal nematodiasis associated with Ancylostoma caninum may produce a similar
syndrome in dogs.
e) Occipital dysplasia occurs commonly in small/medium and toy breed dogs and is usually considered to be a
subclinical entity, although recent reports of hydrosyringomyelia occurring in conjunction with occipital dysplasia
suggest this malformation may not be as benign as originally thought.
f) Chronic neck pain may result from oropharyngeal stick injuries and their sequelae, including cervical
osteomyelitis [25].
- Spinal trauma (D + C)
- Disk disease (D)
- Cervical spondylomyelopathy (D)
- Meningitis (D)
- Atlantoaxial subluxation (D)
- Diskospondylitis (D)
- Hypervitaminosis A (C)
Pontomedullary Syndrome
Diseases involving the pons and medulla oblongata can produce the pontomedullary syndrome. This syndrome is
characterized by the presence of multiple cranial nerve deficits in an animal showing signs of ipsilateral
hemiparesis/hemiplegia or tetraparesis/tetraplegia. Ataxia may be observed in ambulatory animals. Postural
reactions can be depressed in all limbs or in limbs on one side only, ipsilateral to the side of the lesion. Reflexes
are intact in all limbs. Heightened muscle tone may cause limb spasticity, similar to that seen in animals with a
cervical syndrome. Pontomedullary lesions involving cranial nerve nuclei and/or cranial nerves may produce a
variety of clinical signs, including: jaw paralysis, masticatory muscle atrophy, decreased facial sensation, and
depressed palpebral reflex (cranial nerve V; trigeminal); medial strabismus (cranial nerve V; abducent); inability to
close eyelid(s), lip paralysis, ear droop, facial spasms (cranial nerve VII; facial); head tilt, rolling, nystagmus
(cranial nerve VIII; vestibular); pharyngeal paralysis resulting in dysphagia and depressed gag reflex (cranial
nerve IX; glossopharyngeal); laryngeal/esophageal paralysis resulting in cyanosis, dysphonia, inspiratory distress,
and megaesophagus (cranial nerve X; vagus); and tongue paralysis (cranial nerve XII; hypoglossal). Mental
depression may be observed as a consequence of disruption of the ascending reticular activating system (e.g., in
animals with cranial trauma). In animals with severe pontomedullary lesions, several types of respiration
abnormalities may be detected [7]:
a. Central neurogenic hyperventilation characterized by rapid and regular respiration at a rate of about 25
per minute. This respiratory pattern is due to injury to the pons and lower midbrain, but also occurs with
cerebral hypoxia/acidosis;
b. Apneustic respiration, characterized by a cyclic pattern of prolonged inspiration followed by expiration and
an apneic phase. This form is seen with lower brainstem (e.g., medulla oblongata) injury and carries a
poor prognosis;
c. Central alveolar hypoventilation characterized by shallow, slow but regular, ventilation most often seen
with lesions in the medulla oblongata.
The principal clinical signs of the pontomedullary syndrome are listed in Table 9, and the diseases known to
Table 9. Principal Signs of the Pontomedullary Syndrome
• Weakness or paralysis in:

- all four limbs or
- limbs on the same side of the body as the lesion
• Normal or increased reflexes and muscle tone in all limb(s)
• Postural reaction deficits in limbs on the same side as the lesion or
in all limbs
• Multiple cranial nerve deficits
- Jaw paralysis, decreased facial sensation (cranial nerve V)
- Depressed palpebral reflex (cranial nerves V, VII)
- Facial paralysis (cranial nerve VII)
- Head tilt, falling, rolling, nystagmus (cranial nerve VIII)
- Pharyngeal/esophageal/laryngeal paralysis (cranial nerves IX, X)
- Tongue paralysis (cranial nerve XII)
• Irregular respiration
• Mental depression
Table 10. Diseases Associated with the Pontomedullary Syndrome
Degenerative Disorders Alaskan Husky encephalopathy

None
Developmental Disorders Chiari malformations; intracranial intra-arachnoid cysts

Acanthamebiasis; abscessation; Aujeszky’s disease; babesiosis;
distemper; feline infectious peritonitis; granulomatous
meningoencephalomyelitis; meningitis; mycotic diseases; parasitic
encephalomyelitis; protothecosis; pyogranulomatous
meningoencephalomyelitis; rabies;rickettsial meningoencephalitis;
toxoplasmosis and neosporosis
Neoplasia Brain tumors
Neurotoxic Disorders Tetanus
Neurovascular Disorders Infarction; hemorrhage
Nutritional Disorders None
Storage Disorders Fucosidosis; globoid leukodystrophy
Traumatic Disorders Cranial trauma
Notes -
a) Certain primary tumors, such as medulloblastomas, choroid plexus papillomas and certain cysts (epidermoid
and dermoid cysts) (See neoplasia), as well as some inflammatory diseases, including canine distemper, rabies,
and the disseminated form of granulomatous meningoencephalomyelitis, have a predilection for this area of the
brainstem.
b) Extension of hydrosyringomyelia into the brainstem (known as syringobulbia) may produce asymmetrical
cranial nerve involvement.
c) Hemorrhage and edema from severe trauma to the upper cervical cord (e.g., from atlantoaxial subluxation)
may extend to the caudal brainstem resulting in multiple cranial nerve deficits
d) In animals with Chiari malformations, a small caudal fossa and cerebellar herniations into the foramen magnum
would also suggest appearance of cerebellar signs (e.g., ataxia, dysmetria, absent menace response, and
intention tremors); however, to date, this has not been the case, although some animals have shown ataxia and
hypermetria, signs that may be related to the underlying pathology in the cervical spinal cord.
e) Multiple cranial nerves (including trigeminal, hypoglossal, glossopharyngeal) are thickened in animals with
fucosidosis.
f) Multiple cranial nerve deficits may occur in Alaskan Husky encephalopathy and in animals with intracranial
intra-arachnoid cysts.
g) Multiple cranial nerve stimulation may be seen in animals with tetanus.
h) Common causes of the pontomedullary syndrome seen in practice
- Cranial trauma (D + C)
- Distemper (D)
- Granulomatous meningoencephalomyelitis (reticulosis) (D)
- Rabies (D)
- Feline infectious peritonitis (C)
- Neoplasia e.g. choroid plexus papilloma (D)
Cerebellar Syndrome
This is one of the most readily recognizable syndromes in veterinary practice. The cerebellum is a reinforcing and
coordinating organ that plays an important role in harmonizing muscle contraction. Cerebellar disease results in
an inability to regulate the rate, range, and force of a movement (i.e., dysmetria). Clinical signs include an
exaggerated limb response when a movement is initiated, such as "goose-stepping" (hypermetria) when walking,
a delayed and then exaggerated response during postural reaction testing, such as hopping and placing, or
overshooting a food bowl when attempting to eat. Limb movements are typically spastic, clumsy, faltering, and
jerky. The animal assumes a broad-based stance at rest, and swaying of the trunk (i.e., truncal ataxia) may be
observed when the animal is walking. Initiation of movement is delayed and often accompanied by tremors (i.e.,
intention tremors). Tremors are especially noticeable involving the head. Intention tremors disappear at rest. Fine,
pendular, or oscillatory eye movements also may be present. A bilateral menace deficit may be noted, although
vision is not affected. If the lesion involves only one side of the cerebellum, the menace deficit will be ipsilateral.
Anisocoria is sometimes detected in animals with cerebellar lesions. Usually the pupil contralateral to the side of
the lesion will be slightly dilated. Both pupils respond normally to light directed into either eye.
Infrequently observed signs associated with specific areas of the cerebellum include opisthotonus (e.g., when a
lesion involves the rostral lobe of the cerebellum), and vestibular signs (e.g., when a lesion occurs in the
flocculonodular lobe or fastigial nuclear area of the cerebellum) [8].
The principal clinical signs of the cerebellar syndrome are listed in Table 11, and the diseases known to produce
Table 11. Principal Signs of the Cerebellar Syndrome
• Spastic, goose-stepping gait in all limbs, especially thoracic, with

preservation of strength
• Truncal ataxia
• Intention tremors of head, eyes
• Broad-based stance
• Postural reactions delayed with exaggerated responses
• Menace deficit (ipsilateral), with normal vision
• + Anisocoria (pupil dilated contralateral to side of lesion)
• + Opisthotonus (rare)
• + Vestibular signs (rare)
Table 12. Diseases Associated with the Cerebellar Syndrome

Central axonopathy in Scottish Terriers; cerebellar cortical abiotrophies;
hereditary ataxia; hypomyelination; Labrador Retriever axonopathy;
Degenerative Disorders mitochondrial encephalomyelopathy; multisystem neuronal abiotrophy
(Cairn Terriers, Miniature Poodles); nervous system degeneration in Ibizan
hounds; neuroaxonal dystrophy; spongy degeneration of the CNS
None
Chiari malformations; congenital cerebellar disorders; Dandy-Walker
syndrome; intracranial intra-arachnoid cysts
Shaker dog disease; toxoplasmosis and neosporosis
Neoplasia Brain tumors (e.g., malformation tumors, medulloblastomas)
Neurotoxic Disorders Hexachlorophene; metronidazole
Nutritional Disorders Thiamine deficiency

Gangliosidosis; galactosialidosis; Gaucher's disease; globoid
Storage Disorders leukodystrophy; mannosidosis; mucopolysaccharidosis type IIIB;
sphingomyelinosis
Notes -
a) Congenital cerebellar disorders are either primary developmental defects/malformations or hypoplasia and
atrophy secondary to an in utero or perinatal viral infection such as feline panleukopenia virus and feline
parvovirus (See hydranencephaly).
b) Clinical signs in animals with spongy degeneration of the CNS (involving white or gray matter) suggest
cerebellar syndrome but other white matter and/or gray matter areas of the brain may also be affected. In
Rottweilers with spongy degeneration in gray matter, signs of laryngeal paralysis may be present.
c) Clinical signs in animals with hypomyelination suggest cerebellar syndrome but white matter in other areas of
the brain and/or spinal cord is also affected. Similarly with hereditary ataxia, although with this condition the signs
appear to result from lesions in the spinocerebellar pathways in the spinal cord rather than in the cerebellum itself.
d) Clinical signs of Shaker dog disease suggest cerebellar syndrome but mild inflammatory lesions may also be
seen in other areas of the brain.
e) Cerebellar signs are seen in some forms of multisystem neuronal abiotrophies (e.g., Cocker Spaniels, Cairn
Terriers, Miniature Poodles).
f) I have listed intracranial intra-arachnoid cysts under Developmental disorders, although they also appear in the
Neoplasia chapter under malformation tumors. Cerebellar signs may be seen when these cysts or other
malformation tumors (such as epidermoid and dermoid cysts, teratomas, and teratoids) involve the
cerebellopontine angle.
g) Cerebellar signs are not usually a clinical feature of feline ischemic encephalopathy, although cerebellar
lesions may be found.
h) Puppies surviving the acute disease of canine herpesvirus encephalitis (usually resulting in sudden death) may
develop cerebellar dysplasia.
i) Cerebellar signs may be seen in dogs and cats with mercury poisoning, although myriad signs of a multifocal
syndrome may be present.
j) Common causes of the cerebellar syndrome seen in practice
- Congenital cerebellar disorders (C)
- Distemper (D)
- Feline infectious peritonitis (C)
- Cerebellar cortical abiotrophies (D)
- Neoplasia e.g. choroid plexus papilloma, medulloblastoma (D)
Vestibular Syndrome
The vestibular syndrome is another commonly recognized syndrome in clinical practice. Clinical signs may be
caused by (a) central lesions involving the vestibular nuclei located on either side of the medulla oblongata
beneath the floor of the fourth ventricle, the brainstem, or the cerebellum (central vestibular dysfunction) [9], or (b)
peripheral lesions involving the vestibular portion of the eighth cranial nerve or, more commonly, the vestibular
receptors in the membranous labyrinth located within the petrous portion of the temporal bone. Vestibular disease
results in loss of equilibrium. Peripheral vestibular dysfunction (PFD) is more common than central vestibular
disease. Common causes of PFD in dogs and cats are congenital and idiopathic vestibular disease and otitis
media-interna. Clinical signs of PFD include ipsilateral head tilt, falling, rolling, nystagmus, or walking in tight
circles. There may be exaggerated extensor tone of the contralateral limbs, accompanied by decreased tone in
ipsilateral limbs [10]. Strength is preserved in PFD. Nystagmus is present in the acute stages of most PFD and is
usually jerking in nature with fast and slow components. The quick phase of horizontal nystagmus is in a direction
away from the side of the lesion and it is the compensatory phase of the eye movement. Sometimes in animals
with vestibular disease, nystagmus can be initiated by moving and holding the head in a different position (i.e.,
positional nystagmus). Normal, physiological nystagmus can be induced by rapid head movements in vertical or
horizontal planes. The fast phase of the nystagmus is in the direction of the head movement. This response may
be depressed or absent in animals with vestibular disease when the head is moved towards the side of the lesion.
A ventrolateral strabismus (abnormal position of the eyeball) may be elicited in affected animals by extending the
head. The strabismus is ipsilateral. Horner's syndrome and facial paralysis are frequently observed with PFD that
is associated with otitis media-interna, since both facial and sympathetic nerves pass through the middle ear.
Righting reactions are diminished or absent in affected animals. Presence of abnormal resting nystagmus is
reportedly more commonly observed in dogs with PFD [23].
Signs of central vestibular disease (CDV) in animals are similar to those seen with PVD. However, in central
disease, there may be evidence of other cranial nerve dysfunction due to involvement of various brainstem nuclei
(e.g., trigeminal or abducent disorders), altered mental status, vertical or positional nystagmus, cerebellar signs,
and evidence of paresis and/or proprioceptive deficits resulting from brainstem involvement of descending and
ascending long tracts. Note that lesions of the thalamus and/or extrapyramidal basal nuclei may also cause
abnormal head posture and signs of CVD (see Diencephalic syndrome). Also, animals with CVD have a tendency
to roll in one direction. Central signs do not include Horner's syndrome, although facial paresis/paralysis
secondary to involvement of the facial nucleus or fibers within the facial tract may be observed. Unilateral lesions
in the brainstem usually produce an ipsilateral hemiparesis and postural reaction deficiencies (associated with
lesions in the general proprioceptive and/or upper motor neuron systems). However, central lesions occasionally
result in a "paradoxical" vestibular syndrome in dogs in which the lesion is located on the opposite side to that
expected from certain clinical signs, including head tilt, strabismus, and body tilt [11-13]. The lesion, typically a
space-occupying one in the area of the cerebellopontine angle (such as tumor or granulomatous mass) is
considered to be located on the same side of the body in which deficits in proprioception/postural reactions are
detected. Presumably, presence of unilateral deficits of other cranial nerves would be another indicator of the side
on which a lesion is located. This syndrome may occur with involvement of vestibular pathways in either the
caudal cerebellar peduncle (particularly the supramedullary juxtarestiform body) or the flocculonodular lobe of the
cerebellum. The paradoxical vestibular syndrome occurs less frequently in cats.
The principal clinical signs of the vestibular syndrome are listed in Table 13, and the diseases known to produce
Table 13. Principal Signs of the Vestibular Syndrome

Central Vestibular Peripheral Vestibular
Disease Disease
Loss of Balance Yes Yes
Head Tilt Yes Yes

Yes (greater
Falling/rolling Yes
tendency to roll)
Nystagmus Yes Yes
- Horizontal Yes Yes
- Rotatory Yes Yes
- Vertical Yes No
- Positional Yes No
Strabismus (ventrolateral) Yes Yes
Cranial Nerve Deficits Possible V, VI, VII Possible VII
Horner's Syndrome No Possible
Cerebellar Signs Possible No
Mental Depression Possible No

Hemiparesis with Ipsilateral Postural
Possible No
Reaction Deficits
Table 14. Diseases Associated with the Vestibular Syndrome

(Idiopathic vestibular disease); multisystem neuronal abiotrophy (Miniature
Poodles)
None
(Congenital vestibular disease); Dandy-Walker syndrome; intracranial
intra-arachnoid cysts;
Endogenous Metabolic Disorders Hypothyroidism;
meningoencephalomyelitis; (inflammatory polyps); mycotic diseases; (otitis
Inflammatory Disorders media-interna); parasitic encephalomyelitis; protothecosis;
pyogranulomatous meningoencephalomyelitis; rickettsial disorders;
Neoplasia Brain tumors (see notes, below)
Neurotoxic Disorders (Aminoglycosides); metronidazole
Neurovascular Disorders Infarction; hemorrhage; feline ischemic encephalopathy
Storage Disorders Galactosialidosis
Disorders in parentheses refer to peripheral vestibular conditions.
Notes -
a) Brain tumors causing central vestibular disease may be surface tumors (include meningioma, choroid plexus
papilloma, medulloblastoma, neurofibroma, and lymphosarcoma) or parenchymal tumors (e.g., granulomatous
meningoencephalomyelitis and metastatic tumors) (also, see central vestibular disease). Forebrain tumors also
may result in central vestibular disease secondary to caudal transtentorial herniation.
b) Neoplasia is an infrequent cause of peripheral vestibular disease (see miscellaneous causes of peripheral
vestibular disease).
c) Cranial trauma may produce central vestibular disease as well as peripheral vestibular disease, e.g., secondary
to fractures in the petrous temporal bone or tympanic bulla.
d) Achiasmatic Black Belgian Sheep dogs have a congenital rapid pendular nystagmus with unimpaired vision
(see optic nerve hypoplasia).
e) Common causes of the vestibular syndrome seen in practice
Peripheral vestibular disease
- otitis media-interna (D + C)
- idiopathic vestibular disease (D + C)
- drug ototoxicity (D + C)
- congenital vestibular disease (D + C)
- inflammatory polyps (C)
Central vestibular disease
- Distemper (D)
- granulomatous meningoencephalomyelitis (D)
- choroid plexus papilloma of the 4th ventricle (D)
- toxoplasmosis (D + C)
- mycotic diseases (e.g., cryptococcosis) (D + C)
Midbrain Syndrome
This is a relatively uncommon syndrome. Animals may be depressed or comatose, and there may be rigid
extension of all limbs (opisthotonus). If the lesion is located on one side of the midbrain, limbs on the contralateral
side will show signs of hemiparesis or hemiplegia. Ataxia may be observed in ambulatory animals. If the
oculomotor nucleus and/or nerve are involved, animals will have a ventrolateral strabismus, a widely dilated pupil
that is unresponsive to light stimulation in either eye, and ptosis (drooping) of the upper eyelid. These signs may
be ipsilateral or bilateral, depending on the location and extent of the lesion. Vision is usually normal. Rarely,
visual impairment and menace deficit contralateral to the side of the lesion may be noted in animals with lesions
involving the lateral geniculate body. Central neurogenic hyperventilation characterized by rapid and regular
respiration at a rate of about 25 per minute is seen in some animals associated with injury to the pons and lower
midbrain. In animals with severe cranial trauma that diffusely involves the midbrain, bilateral pupillary miosis may
be seen initially, with a gradual change to fixed, dilated pupils. Lesions located in the ventral midline (i.e.,
interpeduncular area) in cats can produce signs of obstinate progression in which cats propel themselves forward
until meeting an obstacle and continue to push against it (head pressing) [14].
The principal clinical signs of the midbrain syndrome are listed in Table 13, and the diseases known to produce
Table 15. Principal Signs of the Midbrain Syndrome
• Spastic weakness/paralysis in:

- all four limbs or
- limbs on the contralateral side of the body
• Increased reflexes and muscle tone in limbs on the contralateral
side or in all limbs (all limbs may be held in rigid extension, i.e.,
opisthotonus)
• Postural reaction deficits in limbs on the contralateral side or in all
limbs
• Mental depression or coma
• Ipsilateral deficits of cranial nerve III (oculomotor):
- ventrolateral strabismus
- dilated pupil unresponsive to light, with normal vision
- drooping of upper eyelid (ptosis)
• Hyperventilation
• + Bilateral miosis
• + Obstinate progression/head pressing (cats)
Modified from Braund KG. An Approach to Diagnosing Neurological Disease. Waltham Focus 1999; 9:23-30 [2].
Table 16. Diseases Associated with the Midbrain Syndrome
Degenerative Disorders Fibrinoid leukodystrophy
Degenerative Structural and Compressive Disorders None
Developmental Disorders Hydrocephalus

Abscessation; distemper; feline infectious peritonitis;
granulomatous meningoencephalomyelitis; mycotic
diseases; parasitic encephalomyelitis; protothecosis;
Neurovascular Disorders Cardiac arrest; infarction; hemorrhage
Notes -
a) Although intracranial intra-arachnoid cysts appear to have a predilection for the quadrigeminal cistern (typically
situated above the midbrain and lying between the rostral and caudal colliculi), clinical signs of a midbrain
syndrome are not seen; instead, a mass effect and cerebrocortical compression may occur leading to a cerebral
syndrome).
b) Common causes of the midbrain syndrome seen in practice
Cranial trauma with midbrain compression and/or hemorrhage (D + C)
Thiamine deficiency (D + C)
Granulomatous meningoencephalomyelitis (D)
Diencephalic Syndrome
The diencephalon is the caudal part of the prosencephalon (forebrain) composed of the epithalamus (habenula,
pineal body), thalamus, hypothalamus, and a subthalamus (subthalamic nuclei, endopeduncular nucleus, and
zona incerta) [15]. The hypothalamus is the ventral and medial region of the diencephalon forming the walls of the
ventral half of the 3rd ventricle. It extends from the optic chiasm to the mamillary bodies. The hypothalamus
extends ventrally as the infundibulum (pituitary stalk), a distal expansion of which is the pituitary gland. The
pituitary gland (hypophysis) consists of the adenohypophysis (pars distalis, imtermedia, and tuberalis) and the
neurohypophysis (pars nervosa). The neurohypophysis (posterior lobe) is associated with storage and release of
oxytocin and antidiuretic hormone. The adenohypophysis is concerned with secretion of somatotropins, prolactin,
thyroid-stimulating hormone, gonadotropins, adrenal corticotropin, and other related peptides.
Clinical signs associated with lesions of the diencephalon are uncommon, but when they occur, are most often
the result of hypothalamic lesions, and usually associated with pituitary tumors. The hypothalamus is intimately
involved in autonomic visceral body functions, including appetite, sexual activity, sleep-wake cycle, body
temperature, blood pressure regulation, heart rate, and emotions [16]. It also regulates much of the body's
endocrine activity. Animals with the hypothalamic syndrome may show signs of altered mental status (e.g.,
disorientation, lethargy, or coma); and/or behavior changes (e.g., aggression, hyperexcitability, pacing, wandering,
hiding, tight circling, head pressing, and trembling). Gait is usually normal. Abnormal temperature regulation may
be manifested as hyperthermia, hypothermia, or poikilothermia. Abnormalities in appetite are seen as
hyperphagia and obesity, or anorexia and cachexia. Vision is frequently impaired if the lesion extends to involve
the optic chiasm, in which case pupils may be dilated and weakly or non-responsive to light stimulation. Endocrine
disturbances most often include diabetes insipidus or hyperadrenocorticism (clinical signs include polydypsia,
polyuria, alopecia, pendulous abdomen, and muscular weakness). Eighty per cent or more of cases of pituitary-
dependent hyperadrenocorticism in dogs are reportedly associated with a pituitary tumor (usually chromophobe
adenomas). Abnormalities in carbohydrate metabolism (e.g., hyperglycemia) may also be detected in dogs and
cats. In cats, pituitary acidophil adenomas have been associated with acromegaly and nervous system signs
(circling and seizures), accompanied by insulin-resistant diabetes mellitus and high serum growth hormone
concentrations. More than 75% of cats with Cushing’s syndrome have diabetes mellitus [17].
Hemorrhages within a pituitary adenoma with secondary compression of the hypothalamus leading to "pituitary
apoplexy" have been observed in a 7 year old female German Shepherd with central diabetes insipidus and
hypernatremia, hyperthermia, and visual impairment [18].
Pure thalamic lesions are infrequently reported in dogs and cats, however, signs might include postural reaction
deficits (contralateral), mild ataxia, visual deficits (contralateral), hypalgesia (contralateral and especially involving
the head), an "adversive" syndrome (propulsive circling and head/eye deviation toward the side of the lesion) with
rostral thalamic lesions, and possible disturbances in consciousness (depression, semicoma) or seizures [15].
Abnormal head/neck postures, termed "cervical dystonia" [24] have been described in dogs associated with
infarction of the thalamus/subthalamus or closely related extrapyramidal basal nuclei (including caudate nucleus,
pallidum and putamen). The signs ranged from head tilt (laterocollis), torticollis, retrocollis, sometimes in
conjunction with nystagmus, circling and postural deficits/forelimb hypermetria. The abnormal head/neck posture
may be permanent, transient or episodic. In humans, a "diencephalic syndrome" is characterized by emaciation,
despite a normal or slightly diminished caloric intake, endocrine abnormalities, and a mentally alert appearance
[19]. This syndrome usually occurs in infants and children and is typically associated with space-occupying
lesions of the hypothalamic-optic chiasm region (especially astrocytomas). A similar condition, has been reported
in a 3 year old female Doberman Pinscher associated with an astrocytoma in the rostral hypothalamus with signs
of chronic weight loss with adequate caloric intake, alert mental status, bradycardia, hypothermia and lack of
shiver response, lack of thirst despite negative water balance, and hypothyroidism [20].
The principal clinical signs of the diencephalic syndrome are listed in Table 17 and the diseases known to
Table 17. Principal Signs of the Diencephalic Syndrome
• Gait may be normal (hypothalamic lesions) or abnormal (ataxic) with

thalamic lesions
• Altered mental status
- disorientation, lethargy, coma
• Change in behavior
- aggression or hyperexcitability
• Abnormal movements/postures
- trembling, pacing, wandering, hiding, tight circling, or head
pressing, cervical dystonia
• Bilateral deficits of Cranial nerve II (optic) at the level of the optic
chiasm
- visual impairment
- dilated pupils
- depressed pupillary reflexes
• Abnormal temperature regulation
- hyperthermia, hypothermia, or poikilothermia
• Abnormal appetite - hyperphagia/obesity, or anorexia/cachexia
• Endocrine disturbances
- diabetes insipidus
- diabetes mellitus
- hyperadrenocorticism
- acromegaly/excess growth hormone
• + Seizures
Table 18. Diseases Associated with the Diencephalic Syndrome
Degenerative Disorders None
Degenerative Structural and Compressive Disorders None
Developmental Disorders None

Abscessation; distemper; feline infectious peritonitis;
granulomatous meningoencephalomyelitis; mycotic
diseases; parasitic encephalomyelitis; toxoplasmosis
and neosporosis
Neurotoxic Disorders Ivermectin
Notes -
a) Brain tumors associated with the diencephalic syndrome are most commonly pituitary tumors, although
occasionally suprasellar germ cell tumors and malformation tumors (including teratomas) may be implicated.
Craniopharyngiomas are rare suprasellar tumors in dogs that may cause hypophyseal-hypothalamic injury.
Extension of primary nasal cavity tumors (e.g., nasal adenocarcinoma) into the cranial vault is relatively common,
and these masses may involve the base of the brain and the pituitary area.
b) Hypothalamic hamartomas are rare malformation tumors that may be associated with cataplexy-like attacks
(see paroxysmal disorders, narcolepsy).
c) Contralateral hypalgesia may sometimes be found associated with lesions in the thalamic relay projections to
the cerebral cortex.
d) Seizures might occur from mass lesions extending into the cerebral cortex and/or the attendant increased
intracranial pressure, or from perturbations in the thalamic-cerebral cortex projection fibers, e.g., generalized
absence seizures in humans [21].
e) Common causes of the diencephalic syndrome seen in practice
- Neoplasia e.g. pituitary and extension tumors (D)
- Granulomatous masses, e.g., toxoplasmosis and neosporosis, granulomatous
meningoencephalomyelitis, or mycotic diseases such as cryptococcosis and blastomycosis (D + C)
Cerebral Syndrome
This commonly occurring syndrome is often characterized by abnormal movements, such as circling (usually to
the same side as the lesion), continual pacing, or head pressing into a wall or cage. In some animals, the head
and trunk may be twisted (pleurothotonus) toward the side of the lesion. Altered behavior and mental status are
frequently observed: apathy, depression, stupor, disorientation, failure to recognize the owner or environment,
loss of trained habits (e.g., house training), and sometimes aggression, or hyperexcitability. While animals may
have a normal gait, postural reactions such as hopping, placing, and hemiwalking are usually depressed in the
contralateral limbs. In comatose animals, breathing may be characterized by waxing and waning of the depth of
respiration, with regularly recurring periods of apparent apnea (i.e. Cheyne-Stokes respiration), although the
periods of "apnea" actually reflect extremely low respiratory amplitudes [22]. Vision may be impaired (bumping
into objects, depressed menace reflex) on the side opposite the lesion; however, pupillary light reflexes are
normal. Seizures and papilledema (edema of the optic disk, often due to increased intracranial pressure) may be
observed. Seizures (see epilepsy) may be (a) generalized, with loss of consciousness and uncontrolled
autonomic activity (e.g., salivation, urination, defecation, pupillary dilation, and chewing movements) and
abnormal motor function (e.g., muscular rigidity, followed by running and paddling movements of the limbs), or (b)
partial, where there is no loss of consciousness and where signs may indicate the location of the seizure focus,
e.g., motor cortex - head turning, spasms in one limb, tail chasing; visual cortex - light or fly biting; or limbic
system - confusion, viciousness, screaming, attacking inanimate objects, or fear behavior. Partial seizures may
spread to become generalized seizures.
The principal clinical signs of the cerebral syndrome are listed in Table 19, and the diseases known to produce
Table 19. Principal Signs of the Cerebral Syndrome
• Normal gait
• Altered mental status (apathy, depression, disorientation, lethargy,
coma)
• Change in behavior (loss of trained habits, failure to recognize
owner, aggression, or hyperexcitability)
• Abnormal movements/postures such as pacing, wandering, circling,
head pressing, twisted head and trunk (pleurothotonus)
• Postural reaction deficits in contralateral limbs
• Visual impairment (e.g. bumping into objects, menace deficit
contralateral to side of lesion) with normal pupillary light reflexes
• Seizures
• + Papilledema
Table 20. Diseases Associated with the Cerebral Syndrome

Alaskan Husky encephalopathy; Dalmatian leukodystrophy; spongy
Degenerative Disorders degeneration in gray matter (Salukis); encephalomyelopathy and organic
acidopathies; Yorkshire Terrier encephalopathy
None
Developmental Disorders Lissencephaly; hydranencephaly; meningoencephalocele; hydrocephalus
Diabetes mellitus; hepatic encephalopathy; hypernatremia; hypoglycemia;
Endogenous Metabolic Disorders hyponatremia; hypothyroidism; uremic encephalopathy; acidosis; alkalosis;
hyperthyroidism; hypophosphatemia; hypercalcemia
Abscessation; distemper (see notes); encephalitozoonosis (dogs);
eosinophilic meningoencephalitis; feline immunodeficiency virus
encephalitis; feline infectious peritonitis; feline spongiform encephalopathy;
granulomatous meningoencephalomyelitis; infectious canine hepatitis; La
Crosse virus encephalitis; mycotic diseases; old dog encephalitis; parasitic
encephalomyelitis; parvovirus encephalitis; Pug Dog encephalitis;
rabies;toxoplasmosis and neosporosis
Cyanogenic plants; ethylene glycol toxicity; lead poisoning; methionine;
Neurotoxic Disorders
metoclopramide
Neurovascular Disorders Cardiac arrest; infarction; hemorrhage; feline ischemic encephalopathy
Storage Disorders Ceroid lipofuscinosis; fucosidosis; gangliosidosis; globoid leukodystrophy
Notes -
a) In Dalmatian leukodystrophy, behavioral disturbances are not a feature.

b) In the cerebral syndrome, contralateral facial hypalgesia is sometimes found, presumably associated with
lesions in the somatosensory cortex or the cortical projection systems from the thalamus.
c) Cerebral signs of rabies are usually associated with the "furious" form and can be very similar to those seen in
dogs with post-vaccinal canine distemper encephalitis.
d) Meningoencephalocele is usually lethal at birth.
e) Infarction in animals is rarely seen associated with atherosclerosis (arterial xanthomatosis) but when it does
occur, it may be as a complication of hypothyroidism (in dogs).
f) Myxedema coma is an extremely rare form of decompensated hypothyroidism
g) Common causes of the cerebral syndrome seen in practice
Cranial trauma (D + C)
Hydrocephalus (D)
Brain tumors such as meningiomas in dogs and cats, and gliomas (e.g., astrocytomas,
oligodendrogliomas) in brachycephalic dogs
Hepatic encephalopathy (D + C)
Feline ischemic encephalopathy (C)
Multifocal Syndrome
In all the preceding syndromes, a single lesion is presumed to account for the clinical signs. However, a situation
may arise in which an animal has signs that reflect two or more different syndromes, e.g., cerebral and
lumbosacral syndromes. This indicates that more than one lesion site is present and this is termed a "multifocal
syndrome".
Multifocal syndromes are usually seen in animals with infectious diseases of the nervous system. Multifocal
syndromes also tend to be the hallmark of the rare, degenerative storage diseases (e.g., gangliosidosis, globoid
cell leukodystrophy, etc.) which, in the majority of cases, result from a genetically-determined enzyme defect with
subsequent accumulation and storage of substrates within various areas of the nervous system. Another, more
common example of a multifocal syndrome is progressive, diffuse hemorrhagic myelomalacia that can develop
secondary to an explosive intervertebral disk extrusion. With this disorder, an initial thoracolumbar syndrome may
be followed by a lumbosacral syndrome and then by a cervicothoracic syndrome, as the lesion descends and
ascends the spinal cord. Multiple clinical signs may be found in animals with brain tumors as a result of secondary
changes such as cerebral edema, hemorrhage, increased intracranial pressure, obstructive hydrocephalus, brain
herniations, tissue necrosis, and tumor spread within the brain. In addition, multifocal syndromes may be seen
with several degenerative disorders of the CNS and are commonly encountered in animals with intoxications (see
Neurotoxicities), in which signs may include excitation, depression, tremors, clonic-tonic seizures, hyperactivity,
ataxia, circling, salivation, hyperthermia, and coma. Tetanic spasms involving multiple areas of the nervous
system are seen in tetanus and in strychnine poisoning, and may occur in dogs with Aujeszky's disease. The
presence of constant tremors in animals is also usually indicative of a diffuse disturbance of the CNS. Tremors
are typically intensified by voluntary movement. Coarse tremors of the head and body may be first seen in young
animals beginning to walk as a result of congenital/hereditary disorders, such as hypomyelination of the CNS,
spongiform encephalopathies (see spongy degeneration of the CNS), and central axonopathy in Scottish Terriers.
Similar tremors may occur suddenly in young mature dogs, often of small white breeds (see shaker dog disease).
Coarse whole body tremors can also be caused by toxins such as hexachlorophene. In conjunction with other
neurological signs, tremors in dogs and cats may also be seen in a variety of diseases, including Lafora’s disease,
cerebellar disorders, lysosomal storage diseases, metabolic diseases (see hypocalcemia, hypoglycemia, and
uremic encephalopathy), and following ingestion of certain neurotoxins such as metaldehyde (snail bait),
chlorinated hydrocarbons, strychnine, organophosphates/carbamates, bromethalin, caffeine, 5-fluorouracil,
levamisole, pyrethrin and pyrethroid insecticides, thallium, toluene/dichlorophen, and tricyclic antidepressants.
Tremors may also accompany muscle weakness associated with peripheral neuropathies or primary myopathies.
The principal clinical signs of the multifocal syndrome are listed in Table 21 and the diseases known to produce
Table 21. Principal Signs of the Multifocal Syndrome
- Presence of clinical signs that reflect two or more

syndromes
Table 22. Diseases Associated with the Multifocal Syndrome
Central axonopathy in Scottish
Terriers; encephalomyelopathy
in young cats;
encephalomyelopathy and
organic acidopathies; fibrinoid
leukodystrophy; hereditary
polioencephalomyelopathy of
Degenerative Disorders Australian cattle
dogs;hypomyelination;
idiopathic vascular calcification;
Lafora's disease; multisystem
neuronal abiotrophies; spongy
degeneration in gray matter
(Bull Mastiffs, Cocker Spaniels,
Rottweilers; Birman cats)
None
Hydranencephaly;
hydrocephalus
Hypocalcemia; hypoglycemia;
Endogenous Metabolic Disorders hyponatremia (see note);
uremic encephalopathy
Abscessation; Aujeszky's
disease; Borna disease;
distemper; eosinophilic
meningoencephalitis; feline
infectious peritonitis; feline
polioencephalomyelitis; feline
spongiform encephalopathy;
granulomatous
meningoencephalomyelitis;
meningitis; multifocal distemper
encephalomyelitis in mature
dogs; mycotic diseases;
parasitic encephalomyelitis;
parvovirus encephalitis;
protothecosis; protozoan
encephalitis-encephalomyelitis
(see notes); Pug Dog
encephalitis; rabies;Rickettsial
Meningoencephalitis; Shaker
dog disease
Lead poisoning;
Neurotoxic Disorders hexachlorophene; mercury
poisoning;
organophosphates/carbamates;
chlorinated hydrocarbons;
tetanus;strychnine; toad
toxicity; tick paralysis and
various therapeutic
agents/drugs (see
neurotoxicities);
Cardiac arrest; infarction;
Neurovascular Disorders hemorrhage; feline ischemic
encephalopathy
Ceroid lipofuscinosis;
fucosidosis; gangliosidosis;
globoid leukodystrophy; I-cell
Storage Disorders
disease; glycogenosis type IV;
mannosidosis; Niemann-Pick
disease type C
Notes -
a) Too rapid correction of hyponatremia will result in multifocal clinical signs.

b) Megaesophagus and laryngeal paralysis may be seen in dogs and cats with lead poisoning.
c) In some animals, tetanus is characterized by stiffness in one limb before gradually spreading to involve the
opposite limb and eventually, the entire body.
d) Tick paralysis frequently results in a flaccid, ascending motor paralysis in animals.
e) A wide variation of clinical signs commensurate with a multifocal syndrome is usually anticipated in animals
with cranial trauma since lesions may be dispersed at multiple levels of the brain.
f) Multifocal signs may be seen in animals with bacterial meningitis.
g) While the overall incidence of CNS involvement by mycotic diseases is low, C. neoformans may be more likely
to be incriminated than the other mycotic organisms in dogs and cats.
h) Multifocal signs of rabies are usually associated with the "dumb" form.
i) Protozoan encephalitis-encephalomyelitis associated with the multifocal syndrome include toxoplasmosis and
neosporosis, sarcocystosis, encephalitozoonosis, trypanosomiasis, acanthamebiasis, and babesiosis.
j) A peripheral neuropathy may be seen in animals with hypoglycemia caused by an insulinoma.
k) Signs of cerebellar and/or vestibular syndromes may occur in animals with hydrocephalus associated with
Dandy-Walker syndrome.
l) In animals with hypomyelination, CNS lesions may be diffuse, although clinical signs appear to be mainly
cerebellar.
m) In Rottweilers with spongy degeneration in gray matter, signs of laryngeal paralysis may be present.
n) Common causes of the multifocal syndrome seen in practice
Cranial trauma (D + C)
Granulomatous meningoencephalomyelitis (D)
Feline infectious peritonitis (C)
Toxoplasmosis and neosporosis (D)
Feline ischemic encephalopathy (C)
Hemorrhagic myelomalacia (D)
Neurotoxins (e.g., lead poisoning, organophosphates/carbamates, strychnine, hexachlorophene) (D + C)
Paroxysmal Syndrome
Paroxysmal syndromes encompass a group of sporadically occurring disorders that often have no structural
lesions within the nervous system. Each paroxysmal syndrome tends to manifest distinctive clinical signs, and the
animal is typically alert and responsive (i.e., without neurological deficits) between episodes. The pathophysiology
of these disorders involves (or is considered to involve) abnormal neurotransmitter function. With the exception of
epilepsy, none of these conditions is commonly seen in clinical practice. For more information on these conditions,
see the chapter on paroxysmal disorders.
Myopathic Syndrome
Over the past 10 to 15 years, myopathic disorders in both dogs and cats have become better recognized in
clinical practice. Many myopathies are breed-related, and some have a predilection for males, such as the X-
linked dystrophinopathies. Myopathies tend to have a bilaterally symmetrical distribution. Reflexes are usually
preserved (with the notable exceptions of Labrador Retriever hereditary myopathy, nemaline myopathy in cats,
animals with hyperkalemic myopathy, and in advanced cases of muscular dystrophy in dogs) and sensory
perception of pain is not impaired. The myopathic syndrome is characterized by generalized weakness with
animals sometimes assuming a palmigrade and/or plantigrade stance (see notes), exercise intolerance, fatigue, a
stiff, stilted gait, and often, ventroflexion of the head and neck, and trismus (see notes). While gait disturbance is
worsened by exercise in the majority of myopathies (often with variable return of muscle strength following rest),
in certain myotonic disorders, such as those reported in Chow Chows, Staffordshire Terriers, and Miniature
Schnauzers with myotonia congenita, stiffness becomes less apparent with exercise. Also, in these breeds, as
well as in cats with dystrophinopathic muscular dystrophy, muscle mass is increased (hypertrophy), especially in
proximal limb muscles, neck muscles and tongue. Proximal limb muscles may appear enlarged and bulging in
some dogs with hyperadrenocortical (Cushing’s) myopathy. Focal muscle hypertrophy may be seen in
semimembranosus and semitendinosus muscles of Golden Retrievers with muscular dystrophy. In some animals,
muscles appear hypertrophic because of inflammation or spasms. In many other myopathies, muscle wasting
(atrophy) tends to be a feature, often generalized and including muscles of mastication. Focal masticatory muscle
atrophy (particularly temporal muscle atrophy) is prominent in several myopathies, including masticatory myositis,
atrophic myopathy/myositis, myositis associated with leishmaniasis, dermatomyositis, and in cats with nemaline
myopathy. A temporary, dimple contracture in a muscle (e.g., limb muscle or tongue) can be induced in certain
myotonic myopathies, such as myotonia congenita, following a sudden tap with the hand or percussion hammer.
Muscle pain, elicited by palpation, is often present in animals with myositis/polymyositis. Limited joint movement
resulting from contracture is the hallmark of certain myopathies, e.g., pelvic limb hyperextension in puppies with
myositis associated with toxoplasmosis and neosporosis. Skeletal deformities such as lumbar kyphosis that may
develop into lordosis by 1 year of age, curvature of the costal arch, and various muscle/limb contactures may also
be observed in dogs with dystrophinopathies. Muscle contractures resulting in rigidity and extension of the pelvic
limbs has been observed in one cat with congenital muscular dystrophy. Tremors and muscle fasciculations are
sometimes seen in animals with myopathic disease. Some myopathies are potentially lethal, e.g., X-linked
myopathy in Golden Retrievers, hypertrophic feline muscular dystrophy, some forms of mitochondrial myopathies
associated with lactic acidosis, exertional myopathy, malignant hyperthermia, and megaesophagus.
The principal clinical signs of the myopathic syndrome are listed in Table 23, and the diseases known to produce
Table 23. Principal Signs of the Myopathic Syndrome
• Generalized weakness
• Exercise intolerance
• Stiff, stilted gait
• Body/limb tremors
• Localized or generalized muscle atrophy
• Localized or generalized muscle hypertrophy
• Dimple contracture
• Muscle pain on palpation
• Limited joint movement (e.g., contracture)
• Regurgitation or altered esophageal motility (megaesophagus)
• Ventroflexion of head and neck
• Trismus
Table 24. Diseases Associated with the Myopathic Syndrome

Bouvier des Flandres myopathy; familial dysphagia; central core
myopathy; Devon Rex cat hereditary myopathy; Labrador Retriever
Degenerative Disorders hereditary myopathy; megaesophagus; mitochondrial myopathy; muscular
dystrophy; dystrophinopathies; distal myopathies; congenital muscular
dystrophy; myotonic myopathy; myotonia congenita; adult-onset myotonic
myopathy; secondary myotonia; nemaline myopathy; polyglucosan
myopathy; congenital myasthenia gravis (see notes)
None
Developmental Disorders Hypotrophic myopathy
Exertional myopathy; hyperadrenocortical (Cushing's) myopathy;
Endogenous Metabolic Disorders hyperkalemic myopathy; hypokalemic myopathy; hypothyroid myopathy;
malignant hyperthermia; canine stress syndrome; secondary myotonia
Hepatozoon myositis; masticatory myositis; atrophic myopathy/myositis;
polymyositis; extraocular myositis; dermatomyositis; myositis ossificans
Inflammatory Disorders (generalized); laryngeal myositis; infectious myositis; toxoplasmosis and
neosporosis; drug-induced myositis; acquired myasthenia gravis (see
notes)
Neoplasia Paraneoplastic myositis; skeletal muscle tumors
Neurotoxic Disorders Drug-induced myositis; toxic myopathy
Neurovascular Disorders Ischemic neuromyopathy;
Nutritional Disorders Vitamin E / selenium-responsive myopathy
Storage Disorders Glycogenosis;

Fibrotic myopathy; immobilization myopathy; limber tail; myositis ossificans
Traumatic Disorders
(localized)
Notes -
a) Junctionopathies, such as myasthenia gravis, may mimic signs of a myopathic syndrome.

b) Devon Rex cats with hereditary myopathy often assume a unique "dog-begging" position.
c) In dogs and cats with gracilis and/or semitendinosus muscle involvement, the hind-limb gait is characterized by
a shortened stride with a rapid, medial rotation of the paw, external rotation of the hock, and internal rotation of
the stifle during the swing phase of the stride.
d) Hyperesthetic animals with hepatozoon myositis may be reluctant to move and often assume a sitting posture
with rigidity of the trunk and neck ("master's voice" posture)
e) One potential complication of hyperadrenocorticism is thromboembolism and signs of pelvic limb weakness,
pain and collapse as a result of occlusion of the distal aorta and/or the iliac arteries.
f) Potential complications of hypertrophic feline muscular dystrophy are insufficient water intake, dehydration,
hyperosmolar syndrome, acute renal failure, and rhabdomyolysis.
g) A plantigrade and/or palmigrade stance is also seen in Golden Retrievers with muscular dystrophy, in
Rottweilers with distal myopathy, and in some dogs with nemaline myopathy. Cats with ischemic neuromyopathy
often have the affected hindlimb rigidly extended early in the disease and may develop a residual plantigrade
stance.
h) Carpal knuckling can be a distinctive clinical feature in Burmese kittens with hypokalemic myopathy and some
cats sink on their hocks.
i) Joint posture is often abnormal in Labrador Retrievers with hereditary myopathy, with affected dogs having
carpal overextension, carpal valgus, splaying of the digits, and a "cow-hocked" stance.
j) In dogs and cats with myotonia congenita, signs are worse in cold weather and improve with exercise, while
laryngeal paralysis has been noted in affected Miniature Schnauzers.
k) Trismus (or lock-jaw), either partial or complete, may occur with masticatory myositis, atrophic masticatory
myopathy/myositis, myotonia congenita in kittens, muscular dystrophy, myotonic myopathy, Devon Rex cat
hereditary myopathy, malignant hyperthermia, myositis ossificans (localized form), and in English Springer
Spaniels with dyserythropoiesis, polymyopathy, and cardiac disease.
l) Tongue protrusion may be noted in feline muscular dystrophy, hyperkalemic myopathy (dogs), Cushings'
disease/myotonia, and in cats with nemaline myopathy.
m) I have included myasthenia gravis (MG) in the "myopathic syndrome" because of convenience; MG is a
congenital or acquired disorder acting at the level of the neuromuscular junction (just as botulism and tick
paralysis).
n) Common causes of the myopathic syndrome seen in practice
Myositis associated with toxoplasmosis and neosporosis (D)
Masticatory myositis (D)
Polymyositis (D)
Atrophic myopathy (D)
Steroid/Cushing's myopathy (D)
Labrador Retriever hereditary myopathy (D)
Ischemic neuromyopathy (C)
Neuropathic Syndrome
The neuropathic syndrome is one of the more commonly observed syndromes in clinical practice, and is
frequently associated with trauma of peripheral and sometimes cranial nerves (see traumatic neuropathy). The
hallmarks of this syndrome are reduced or absent reflexes (hyporeflexia, areflexia), reduced or absent muscle
tone (hypotonia, atonia or flaccidity), weakness (paresis), or paralysis of limb/head muscles, and after 1 to 2
weeks, neurogenic muscle atrophy. This syndrome relates to motor nerve dysfunction and as such, has been
called "lower motor neuron disease" in other texts. Chronic neurogenic atrophy may result in severe fibrosis and
limited joint movement from contractures (e.g., infectious polyradiculoneuritis due to toxoplasmosis or
neosporosis). A variable degree of loss of sensation (hypesthesia) may be detected upon cutaneous
(dermatomal) testing, since most nerves contain motor and sensory components. Tremors and muscle
fasciculations (e.g., post-denervation) are sometimes seen in animals with neuropathic disease. Note that
neuropathies may also be predominantly (or purely) sensory or autonomic. In animals with primary sensory
neuropathies (e.g., sensory ganglioradiculitis, or breed-related sensory neuropathies in Boxers, Longhaired
Dachshunds, English Pointers), the syndrome may include loss of pain sensation (anesthesia) and/or
proprioception, abnormal sensitivity about the face or trunk (paresthesia), self-mutilation (perhaps as a result of
paresthesia), and hyporeflexia/areflexia without muscle atrophy. While signs of autonomic nerve dysfunction, e.g.,
anisocoria, decreased tear secretion, bradycardia, etc., (see notes, below) are infrequently observed in animals
with polyneuropathies, they are the dominant feature in dogs and cats with dysautonomia.
Traumatic peripheral neuropathies commonly involve a single nerve (i.e., mononeuropathy), such as common
peroneal, radial, or facial nerves. Polyneuropathies involve several nerves, are usually bilaterally symmetrical,
and are best exemplified by polyradiculoneuritis (e.g., Coonhound paralysis), in which the nerve changes show a
preferential proximal distribution early in the course of the disease. Other less common degenerative
polyneuropathies may also have a proximal distribution, e.g., hereditary spinal muscular atrophy in Brittany
Spaniels (note that disorders of the parent cell bodies located in the spinal cord and/or brainstem are discussed
under motor neuron diseases). Conversely, a distal distribution of nerve changes may be seen in several distal
axonopathies ("dying-back" disorders) including several toxic neuropathies, giant axonal neuropathy in German
Shepherds, and distal polyneuropathy in adult Rottweilers (see Rottweiler distal sensorimotor polyneuropathy).
Pelvic limbs are usually first affected in generalized polyneuropathies. Whereas some neuropathies may have an
acute (e.g., traumatic neuropathy or ischemic neuromyopathy) or subacute onset (e.g., polyradiculoneuritis), the
majority of neuropathies often are insidious in onset and have a chronic course. Chronic, relapsing
polyneuropathies are becoming more commonly observed in dogs and cats. Some of these conditions are self-
limiting and/or steroid-responsive. While most neuropathies involve spinal nerves, cranial nerve dysfunction may
also be present in animals with polyneuropathies, e.g., facial nerve paresis/paralysis in Coonhound
paralysis/idiopathic polyradiculoneuritis and hypothyroid neuropathy, and involvement of the vagus nerves (or
their branches, e.g., recurrent laryngeal nerves) resulting in dysphagia/megaesophagus in German Shepherds
with giant axonal neuropathy, and laryngeal paralysis/megaesophagus in young dogs with laryngeal paralysis
polyneuropathy complex. Certain disorders of the neuromuscular junction, namely botulism and tick paralysis,
produce signs that mimic those observed in a diffuse polyneuropathy. Metabolic neuropathies, such as diabetic
neuropathy (dogs and cats) and hypothyroid neuropathy (dogs), are now well recognized, while hypoglycemic
neuropathy is seen sporadically in dogs with insulinomas. Ill-defined peripheral nerve dysfunction in older dogs
may be an immunological manifestation of various systemic malignant tumors (see paraneoplastic neuropathy).
Nerve sheath tumors (see peripheral nerve tumors) are a relatively common cause of brachial plexus neuropathy.
The principal clinical signs of the neuropathic syndrome are listed in Table 25, and the diseases known to
Table 25. Principal Signs of the Neuropathic Syndrome
Motor Neuropathy
• Flaccid paresis/paralysis of structures innervated (e.g., limb/facial

muscles, esophagus, larynx, anal sphincter)
• Neurogenic muscle atrophy
• Reduced/absent reflexes and muscle tone
• Muscle fasciculations
Sensory Neuropathy
• Decreased pain response (hypalgesia) or sensation (hypesthesia)

• Proprioceptive deficits
• Abnormal sensation/sensitivity (paresthesia) of face, trunk, or limbs
• Self-mutilation
• Reduced/absent reflexes without muscle atrophy
Autonomic Neuropathy (may be seen alone or in combination with

sensorimotor neuropathies)
• Anisocoria or dilated pupils

• Decreased tear secretion
• Decreased salivation
• Bradycardia
Modified from Braund KG. An approach to diagnosing neurological disease. Waltham Focus 1999; 9:23-30 [2].
Table 26. Diseases Associated with the Neuropathic Syndrome

Alaskan Malamute polyneuropathy; Birman cat distal
polyneuropathy; congenital hypomyelination neuropathy;
Dancing Doberman disease; deafness (congenital sensorineural
deafness); familial German Shepherd neuropathy; giant axonal
neuropathy; hyperlipidemia; hyperoxaluria; hypertrophic
neuropathy; laryngeal paralysis (laryngeal paralysis
polyneuropathy complex); Rottweiler distal sensorimotor
polyneuropathy; progressive axonopathy in Boxers; sensory
neuropathy in Longhaired Dachshunds; sensory neuropathy in
English Pointers; congenital vestibular disease
None
Developmental Disorders None
Diabetic neuropathy; hyperadrenocortical (Cushing's)
Endogenous Metabolic Disorders
neuropathy; hypoglycemic neuropathy; hypothyroid neuropathy
Brachial plexus neuropathy-neuritis; optic neuritis;
polyradiculoneuritis; Coonhound paralysis; idiopathic
polyradiculoneuritis; cauda equina polyradiculoneuritis; chronic
Inflammatory Disorders inflammatory demyelinating polyneuropathy; infectious
polyradiculoneuritis; trigeminal neuritis; sensory
ganglioradiculitis; otitis media-interna; postvaccinal
polyradiculoneuritis
Neoplasia Paraneoplastic neuropathy; peripheral nerve tumors
Neurotoxic Disorders Deafness (acquired sensorineural deafness); toxic neuropathies
Neurovascular Disorders Ischemic neuromyopathy
Nutritional Disorders None (see notes)

Gangliosidosis; fucosidosis; globoid leukodystrophy;
Storage Disorders glycogenosis type IV; mannosidosis; sphingomyelinosis
(phenotypic variant of Niemann-Pick disease type A)
Traumatic Disorders Brachial plexus avulsion; traumatic neuropathy
Facial paralysis; distal denervating disease; distal symmetrical
Unclassified neuropathies
polyneuropathy; dysautonomia; idiopathic self-mutilation;
idiopathic vestibular disease; sensory trigeminal neuropathy
Notes -
a) Neuropathies under the "Degenerative disorders" category are hereditary or considered to be so.
b) Optic neuritis is included as a "neuropathy" although the optic nerve (Cranial nerve II) is not a true peripheral
nerve developmentally, structurally or in its pathological manifestations, but rather it is a tract of the CNS.
c) While nutritional disorders per se have not been directly implicated in peripheral neuropathies in dogs or cats,
nerve roots are often damaged secondary to exostoses encroaching on intervertebral foramina in cats with
Hypervitaminosis A.
d) Some forms of megaesophagus are considered to be neurogenic (e.g., in young dogs with laryngeal paralysis
polyneuropathy complex).
e) Neck trauma in cats may lead to Horner’s syndrome and subclinical ipsilateral laryngeal hemiplegia.
f) Dysphonia/laryngeal paralysis may also be observed in animals with coonhound paralysis/idiopathic
polyradiculoneuritis, chronic inflammatory demyelinating polyneuropathy, in German Shepherd dogs with giant
axonal neuropathy, and in dogs with sensory ganglioradiculitis and hypothyroid neuropathy.
g) While many of the clinical signs of dysautonomia (e.g., dry mucous membranes, decreased tear production,
mydriasis, regurgitation/constipation) suggest involvement of the parasympathetic nervous system, sympathetic
nervous system dysfunction is suggested by bradycardia, hypotension, signs of Horner’s syndrome (prolapsed
third eyelidptosis, enophthalmos), and distended easily expressible bladder. Note that some signs, such as
proprioceptive deficits and anal sphincer dysfunction, are non-autonomic.
h) Clinical signs of brachial plexus avulsion are predominantly those of radial nerve paralysis at the level of the
shoulder.
i) Multiple cranial nerve dysfunction may be seen in dogs with fucosidosis, in cats with hyperlipidemia, and in
animals with disseminated neoplasia (lymphosarcoma, leukemia).
j) Common causes of the neuropathic syndrome seen in practice
Hypothyroid neuropathy (D)
Idiopathic polyradiculoneuritis (D)
Traumatic neuropathies (e.g., brachial plexus avulsion) (D + C)
Ischemic neuromyopathy (C + D)
Toxoplasma/neospora polyradiculoneuritis (D)
Chronic relapsing inflammatory demyelinating polyneuropathy (D + C)
Idiopathic facial paralysis (D)
II. Etiological Categories of Neurological Diseases
C. H. Vite
This chapter reviews the major structural malformations and developmental defects encountered in dogs and cats
and their related effects on the central nervous system. Note that congenital deafness and congenital vestibular
disorders are discussed with deafness and vestibular disease in the chapter on peripheral nerve disorders (See
Myopathies and Neuropathies).
An outline of this chapter is as follows:
• Arachnoid Cysts
• Atlantoaxial Subluxation
• Congenital Cerebellar Disorders
• Chiari Malformations
• Dandy-Walker Syndrome
• Dermoid Sinus
• Hydranencephaly
• Hydrocephalus
• Lissencephaly
o Neuronal Heterotopia in Lagotto Romagnolos
• Meningoencephalocele
• Myelodysplasia
• Fetal Akinesis Deformation Sequence
• Occipital Dysplasia
• Optic Nerve Hypoplasia
• Osteochondromatosis
• Sacrocaudal Dysgenesis
• Spina Bifida
• Syringomyelia and Hydromyelia
• Vertebral Anomalies
o Hemivertebra
o Block Vertebrae
o Butterfly Vertebra
o Transitional Vertebrae
o Scoliosis
o Stenosis of the Vertebral Canal
o Miscellaneous Disorders
Arachnoid Cysts
Arachnoid cysts, also known as intra-arachnoid cysts, meningeal cysts, leptomeningeal cysts, and arachnoid
diverticula, have been reported with increasing frequency over the past few years in dogs and cats [1-13]. It has
been suggested that spinal arachnoid cysts in dogs most closely resemble type III spinal meningeal cysts in
people [297]. As far as breed predilection is concerned, Rottweilers are often cited cited (in one report, 8/14 dogs
were Rottweilers [297]) and the condition has been observed in related Schipperkes [7] and Shih Tzu littermates
[10], suggesting an inherited etiology. The cysts are characterized as cerebrospinal fluid (CSF)-filled, dorsal
midline, intradural, extramedullary cavitational lesions associated with coarse arachnoid trabeculation, that result
in spinal cord compression. Occasionally, cysts located in ventral and dorsolateral locations in the cervical spinal
region have been observed [14]. The cystic cavities are reportedly separated from the compressed spinal cord by
an intact pia mater. In one series of affected dogs, numerous blood vessels with enlarged perivascular spaces
were noted caudal to the cyst [4]. A cranial opening to the cysts, presumably continuous with the subarachnoid
space and allowing flow of CSF, has been noted [7]. Usually there is no evidence of inflammation within the
meninges or tissues lining the cysts, however, a mixed cellular inflammatory reaction and reactive connective
tissue proliferation was reported in the cyst wall surgically removed in one case [7]. In this dog, the cyst wall was
composed of pia-arachnoid meningothelial cells [7]. Many animals are less than 1 year of age, but cysts have
been reported in animals up to 12 years of age. Onset of signs between 11 and 24 months was reported in one
series of cases [7]. Arachnoid cysts have been observed mainly in rostral cervical and caudal
thoracic/thoracolumbar sites; however, multiple cysts in the caudal cervical area of three Rottweiler dogs have
been observed [14]. Cysts may also be multilobed or bilobed [297].
The pathogenesis is unknown [15] although congenital spinal dysraphism due to failure of fusion of the neural
crest has been suggested [4], and indeed, in people, primary arachnoid cysts are regarded as a developmental
abnormality of the arachnoid [16]. Ultrastructurally, the cyst is formed by splitting of the arachnoid membrane and
the wall of the cyst is independent of the inner layer of the dura mater [16]. The wall of the cyst consists of an
outer collagenous membrane and an inner layer of cells that appear similar to normal arachnoid cells.
Immunocytochemically, in people, arachnoid cysts react positively with antibody to epithelial membrane antigen,
but are negative for glial fibrillary acidic protein, S-100 protein (a glial-associated protein), prealbumin, and
carcinoembryonic antigen [17]. In people and in animals, arachnoid cysts reportedly may occur secondary to
trauma, infection, inflammation, or subarachnoid hemorrhage [14,16]. While no evidence of trauma, other
diseases, or malformations was found in Frykman’s series of cases [7], disk herniation was thought to contribute
to cyst formation in at least one dog in the study by Rylander’s group [297].
Clinical syndromes will reflect the location of the lesion. To date, cervical syndromes and thoracolumbar
syndromes have been observed. Pain is usually not a feature. Curiously, behavioral changes of depression and
aggression in one Rottweiler with a C2 - C3 arachnoid cyst, disappeared following surgery, suggesting possible
relief of pain [7]. Scoliosis has been reported in one dog [18]. Analysis of CSF is usually normal, although
changes may include mild protein and/or mononuclear cell increase [297]. Survey radiographs tend to be non-
diagnostic, although vertebral canal enlargement, possibly secondary to pressure atrophy of bone caused by the
cyst [14], may be found in some cases [12]. Additionally, presence of spinal curvature, such as scoliosis, can be
detected [18].
Diagnosis can be made using myelography, since the cysts usually fill with contrast agent, and there is often
partial blockage to flow of the contrast medium, with associated moderate to severe (usually dorsal) spinal cord
compression [19]. The cysts often appear as drop-shaped or oval contrast-filled cavities [7]. Computed
tomography provides additional information on localization and lateralization of the cyst, and allows measurement
of the degree of spinal cord compression [8]. Cysts may extend over several spinal cord segments. Magnetic
resonance imaging may identify spinal cord parenchymal changes, such as presence of syringomyelia [8].
Sonography can be used to define the cyst wall, to characterize the internal architecture of the cyst wall, and to
orientate the surgeon to the location and extent of the cyst [8]. Surgical decompression of the spinal cord appears
to be the treatment of choice, using dorsal laminectomy or hemilaminectomy, in association with durotomy,
drainage and/or partial excision of the cyst (surgical fenestration), and dural marsupialization often leads to
permanent clinical improvement in a majority of dogs [2,4,12,13,297]; however, recurrences can occur [7,10] and
neurologic deficits may persist [297]. Long-term follow-up studies (e.g., up to 4 years post-surgery) suggest that
durectomy around the border of the cyst and dissecting it free from pia mater may give a more permanent
recovery than durotomy and drainage [7]. Medical treatment alone, using a decreasing anti-inflammatory dosage
of prednisolone, was reported to be successful in one dog [4].
Arachnoid cysts (see also intracranial intra-arachnoid cysts) have also been reported in brainstem locations,
including cerebellar pontine area in a cat [20] and in the pineal region and quadreminal system of dogs [21,293].
Atlantoaxial Subluxation
Atlantoaxial subluxation is instability of the atlantoaxial articulation that produces excessive flexion of the joint
causing the cranial aspect of the axis to rotate dorsally into the vertebral canal with subsequent spinal cord
compression often resulting in severe, acute neurological deficits. The disorder occurs most frequently in dogs
and it may result from fracture, separation, absence, or malformation of the dens (odontoid process), from
hypoplastic deformity of the dens along with shortening of the atlas, from fracture of the body of the axis or
fracture of the atlas, from rupture or stretching of the atlantoaxial ligaments with an intact normal dens, or from
absence of the transverse ligament of the atlas [22-30].
The pathogenesis of the developmental malformations remains uncertain. Anatomical studies indicate that the
dens develops from 2 separate ossification centers [31]. In this report, the authors suggested that dens dysplasia
was unlikely to be a result of failure of development of one of the ossification centers but that vascular-related
ischemia might lead to postnatal resorption of at least the middle part of the dens and result in dens dysplasia
with subsequent atlantoaxial subluxation [31]. While hereditary factors may be involved in some lines of miniature
and toy breeds of dogs in which this congenital anomaly is most common (e.g., Yorkshire Terrier, Chihuahua,
Pomeranian, Japanese Chin, Toy Poodle, Pekingese, etc.), fracture and insufficient ligamentous support of the
dens may occur in any breed. The condition has been reported as a congenital disorder in several large breeds,
including Rottweiler and Doberman Pinscher [32,33]. Congenital atlantoaxial subluxation occurs most commonly
in dogs less than one year of age; however, older animals exposed to various stresses also may be affected.
Atlantoaxial subluxation has been sporadically reported in cats [34-36]. Atlantoaxial subluxation may also occur in
dogs and cats in association with occipitoatlantoaxial malformation (OAAM) [37-39], a congenital deformity of the
upper cervical spine that is characterized by absence of occipital condyles with fusion of the atlas to the occiput
and hypoplasia of the atlas, axis and dens [40]. The atlanto-occipital and atlantoaxial joints are regarded as a
single complex on both anatomical and biomechanical grounds [40,41]. Fusion of the atlanto-occipital joint may
exacerbate instability of the atlantoaxial joint and complicate surgical attempts to correct it [42]. Atlantoaxial
subluxation associated with dorsal dens angulation [43] and abnormal occipitoatlantal articulation [44] have been
seen in adult Cavalier King Charles Spaniels with Chiari malformations.
Clinical signs vary according to the degree of luxation. They may range from cervical rigidity and pain to spastic
paraparesis, and sometimes tetraplegia (see cervical syndromes). The signs may develop slowly over several
months or they may occur acutely. In some instances, hemorrhage and edema from severe trauma to the upper
cervical cord may extend to the caudal brainstem resulting in cranial nerve deficits [45] (see pontomedullary
syndrome).
When atlantoaxial subluxation is suspected, survey radiographs should be made without anesthesia before
manipulating the animal excessively. Lateral view radiographs will reveal widening of the space between the arch
of the atlas and spinous process of the axis, angulation of the axis relative to the atlas, a fractured dens, or the
rounded end of the axis indicating the absence of the dens. Oblique lateral or ventrodorsal views may be useful in
determining the presence or absence of the dens. Open mouth frontal and flexed lateral views are not necessary
in most cases and are likely to cause severe compression of the spinal cord [46]. Use of specialized
neuroimaging techniques, including computed tomography (CT) and computed tomographic myelography, are
also recommended [14,47].
The prognosis is guarded. In a recent study on risk factors affecting the outcome of surgery for atlantoaxial
subluxation in 46 dogs, an age of onset less than 24 months, duration of clinical signs less than 10 months, and
preoperative neurological status were found to be significant positive prognostic factors [48]. In an earlier surgical
study involving 23 dogs with atlantoaxial subluxation, only 4 of 7 non-ambulatory dogs recovered [49]. A potential
complication from myelography and/or surgical manipulation in animals with atlantoaxial subluxation is
cardiopulmonary arrest [50,51]. Medical treatment involves similar protocols as outlined under acute spinal
trauma. Neck and head splinting in extension for animals with mild luxations and cervical pain or minimal
neurological deficits followed by cage rest for at least 6 weeks has been successful [14,45,52]. Internal
stabilization of the luxation generally is regarded as the therapy of choice [53], especially in animals with
moderate to severe neurological deficits or in animals treated conservatively having recurring episodes of pain.
Results of several studies [49,54] suggest that vertebral stabilization using a ventral approach [55] may be safer
than dorsal stabilization of the atlas and axis. The application of ventral pins and polymethylmethacrylate has
been used successfully in the surgical treatment of congenital and traumatic atlantoaxial instability [56,294]. In
one case report involving an 8 month old Rottweiler with hypoplasia of the dens, use of cannulated screws was
considered superior to K-wires and conventional screws for arthrodesing the atlantoaxial joint [57]. Stabilization
with bone plates via a ventral approach has been successful in dogs [51]. The subluxated atlantoaxial joint of a
tetraplegic Yorkshire terrier was reduced and secured in position by means of a novel cross pinning technique
applied via a dorsal approach [58]. Use of the nuchal ligament as a means of securing the spinous process of the
axis to the dorsal arch of the atlas has also been reported to be successful in small- and large-breed dogs [59]. In
dogs and cats with OAAM, a combination of substantial internal and external fixation, odontectomy, and
arthrodesis of the atlantoaxial articulation is recommended [39,42]. Poor results have been reported [60] using the
Kishigami atlantoaxial tension band [61].
Congenital Cerebellar Disorders
Congenital cerebellar abnormalities tend to be either:
A. Primary developmental defects or malformations or

B. Hypoplasia and atrophy secondary to an in utero or perinatal viral infection [62].
As with most other congenital anomalies, malformations of the cerebellum in domestic animals usually result from
unknown causes. Various forms of cerebellar agenesis (absence of the whole or parts), aplasia (faulty
development with no tissue differentiation) and cerebellar hypoplasia (faulty development with some tissue
differentiation), have been reported in dogs, including Beagle, Silky Terrier, Airedale Terrier, Chow Chow, Irish
Setter, Boston Terrier, Bull Terrier, and Wire-Haired Fox Terrier [63-68]. The Wire-haired Fox Terriers and Irish
Setter puppies also had lissencephaly [65]. An unusual, probably inherited cerebellar cortical dysplasia has been
reported in St. Bernard puppies characterized by abnormal laminar cytoarchitecture of the cerebellar cortex: loss
of distinction between granule cell, Purkinje cell or molecular layers along with pallor and cavitation of the
subcortical white matter of cerebellum and cerebum [306]. Cerebellar abiotrophy (see cerebellar cortical
abiotrophies) is a post-natal degenerative disorder associated with an intrinsic developmental abnormality of
various neurons, especially Purkinje cells, causing their premature death [62]. Affected animals are normal at birth
or at the time they first begin to ambulate (around 3 to 4 weeks of age) [65]. Occasionally, a neonatal cerebellar
abiotrophy is seen in which animals show cerebellar signs at birth [65,69]. The cerebellum may also be involved
with heterogeneous developmental disorders seen in animals with Dandy-Walker Syndrome and Chiari
malformations.
In utero infection with feline panleukopenia virus (parvovirus) results in destruction of actively dividing cells in the
external germinal layer, which is actively proliferating at birth and for the first 2 weeks postnatally [70-73].
Postnatal infections with this virus rarely involve the central nervous system; however, since the cerebellum
continues to develop postnatally, viral infection at birth might be expected to result in significant cerebellar
hypoplasia [62]. Gross cerebellar lesions vary from marginal overall reduction in size to extensive loss of
cerebellar tissue and associated reduction in size of the transverse fibers in the pons and the pontine nuclei [62].
Microscopically, lesions range from mild granuloprival hypoplasia (depletion of granule cells and heterotopia of
Purkinje cells within narrowed molecular layers) to rudimentary folia without any neurons [62,70,71]. Rarely, other
developmental anomalies can occur in affected kittens, such as hydrocephalus (from aqueductal stenosis) and
hydranencephaly. Infrequently, perivascular necrosis and mineralization in cerebral internal capsules or
periventricular tissues may be observed [62]. Cerebellar agenesis or hypoplasia in conjunction with
hydrocephalus and hydranencephaly has also been reported in kittens secondary to in utero parvovirus infection,
possibly due to vaccination that occurred late in the first, or early in the second, trimester of pregnancy [74]. To
date, a comparable viral-related cerebellar disorder is less clearly defined in dogs, although microscopic lesions
similar to those seen in cats following in utero viral infection was observed in a young adult Beagle [62,65].
Further, results of recent molecular studies suggest that cerebellar hypoplasia may be associated with in utero
parvoviral infection in dogs [295].
The signs of cerebellar disease are generally symmetrical and include limb spasticity, dysmetria, head tremor,
truncal swaying, loss of balance, and wide-based stance. Some animals have difficulty standing and are unable to
take more than a few steps without falling [65]. Ataxia in Samoyeds with neonatal cerebellar abiotrophy is most
severe in pelvic limbs with marked spasticity and hypermetria. Irish Setter puppies with HQA are unable to walk.
Abnormal nystagmus is unusual in these conditions [65], although it was observed in Irish Setter puppies with
HQA [69]. Generalized seizures were observed in one Wire-Haired Fox Terrier with cerebellar malformation and
lissencephaly after reaching one year of age [65]. Signs in St. Bernard puppies included inability to stand,
spontaneous searching nystagmus, ventrolateral strabismus, and occasional thoracic limb paddling movements
[306].
Diagnosis of congenital cerebellar disorders usually is based on age, breed/species, history (e.g., of viral
infection), histopathology, immunofluorescence, or DNA studies using polymerase chain reaction. It has recently
been shown that parvoviral DNA can be amplified from archival and fresh tissues from both cats and dogs with
cerebellar hypoplasia [295]. As the condition usually is non-progressive, prognosis for longevity may be favorable.
There is no treatment.
Chiari Malformations
Chiari malformations are complex developmental disorders involving the caudal brainstem, cerebellum and
cranial cervical spinal cord. In people, Chiari malformations have been divided into two types based on severity of
the hindbrain deformity [75]. In patients with Chiari I, there is elongation and caudal displacement of the cerebellar
tonsils (vermis and paravermis lobes) and sometimes, part of the medulla oblongata, through the foramen
magnum into the cranial cervical vertebral canal. The cord, pushed caudally by medulla and the fourth ventricle, is
kinked. Syringohydromyelia (this term is used to denote presence of either syringomyelia or hydromyelia since it
is often impossible to differentiate syringomyelia and hydromyelia using imaging techniques [76], although some
authors prefer the term "syrinohydromyelia") may be associated with the Chiari I malformation and may develop
secondary to overcrowding of the foramen magnum and obstruction of CSF flow, although its pathogenesis
remains unclear. In Chiari II patients, there is herniation of the cerebellar vermis and sometimes, the inferior
lateral cerebellar hemispheres, over the dorsal aspect of the cervical spinal cord. The fourth ventricle, pons, and
medulla are also elongated and partially located in the spinal canal, usually in association with meningomyelocele
[75].
Chiari I malformations, similar to those in people, have been described in dogs with herniation of the cerebellar
vermis [43,44,76-78]. The condition is over represented in Cavalier King Charles Spaniels (CKCS) and a
familial/genetic basis is suspected, with the disease having an earlier onset and increased severity with increased
inbreeding [299,312]. It has been reported also in a Maltese Poodle [76]. The condition in CKCS appears to be
associated with occipital bone hypoplasia (often called caudal occipital malformation syndrome) which results in
caudal fossa overcrowding, obstruction of CSF pathways and secondary hydrosyringomyelia [299]. Trauma
superimposed on a pre-existing Chiari type 1 congenital abnormality may play a role in some clinical cases [44].
In published reports, the age range of affected animals extends from 6 months to 10 years. The clinical course
may be acute [76] or run an extended course over several months or years [43,44,78].
Clinical signs may include cervical pain, torticollis, spinal hyperesthesia, exercise intolerance, paresis in one or
both thoracic limbs or tetraparesis, ataxia/hypermetria in thoracic or in all four limbs, bunny-hopping hindlimb gait,
poor hopping responses, and proprioceptive deficits. Spinal reflexes may be exaggerated. In a recent study of
affected CKCS, a variety of cranial signs were also seen, including facial nerve deficits (9/22 dogs), seizures (7/22
dogs), and vestibular syndrome (7/22 dogs) [300]. Paroxysmal involuntary flank scratching, sometimes extended
over several years, has been noted in CKCS, of either gender, usually between 6 months and 2 years of age
[77,78,299]. There is no dermatologic cause and the scratching seems to be intensified by excitement, barking,
exertion, wearing of collars, or when the shoulder, neck or ear of the "scratched" side are touched [77,78].
Affected animals often showed evidence of pain or hyperesthesia around the neck, ear or thoracic limb. This
unusual scratching feature may be due to disinhibition of hindlimb reflex activity [44] or to some form of
paresthesia secondary to the hydrosyringomyelia [78] (that was present in all 7 dogs of this study and all of whom
manifested this peculiar scratching reaction), possibly related to interruption of the decussating spinothalamic
tracts and dorsal/ventral horn damage due to a progressively expanding hydrosyringomyelia [44,78]. Interestingly,
syringohydromyelia was lacking in one report in a CKCS, in whom the persistent flank scratching was not present
[43]. Variable lower motor neuron deficits, such as muscle atrophy, weakness, and decreased spinal reflexes,
have been noted in several dogs, especially affecting the thoracic limb ipsilateral to the "scratched" side [78].
Presumably, these signs of a cervicothoracic syndrome could be explained if the syringohydromyelic lesions
extended to low cervical and cranial thoracic cord levels. Denervation of spinal epaxial muscles may lead to
muscle atrophy and scoliosis [18,79] and, when cervical muscles are involved, torticollis. Electromyographic
studies may reveal evidence of denervation in paraspinal and thoracic limb muscles [78]. Analysis of CSF in
animals with Chiari I malformation may be normal or show a mild, mononuclear pleocytosis. Radiographs of skull
and cervical spine are usually normal, however, cervical scoliosis has been observed [78], and in another case,
radiography revealed a developmental angulation of the dens with spinal cord compression and scalloping of the
dorsal arch of C1 [43]. Magnetic resonance imaging (MRI) may show varying degrees of ventricular
enlargement/hydrocephalus, syringohydromyelia of cervical spinal cord that occasionally is seen to extend all the
way to the caudal lumbar spinal cord segments, and sometimes, caudal displacement of the caudal lobe of the
cerebellum to the level of or through the foramen magnum [43,44,76,78,300]. In one series of cases involving the
CKCS, the foramen magnum was small using MRI and the shape of the caudal fossa was abnormal due to a
rostral indentation of the occipital bone, leading to overcrowding within the foramen magnum and apparent
compression of the brainstem at the cervicomedullary junction [78]. Additionally, the tentorium cerebelli appeared
more horizontal than normal, the caudal medulla oblongata had a kinked and elongated appearance, and the
dorsoventral diameter of the craniocervical vertebral canal was small [78]. In other dogs, there may be abnormal
alignment of the occipito-atlantal articulation and dorsal displacement of the caudal medulla and C1 spinal cord
segment. MRI studies in CKCS have also revealed that the malformation may also be clinically silent in some
dogs [300].
Treatment has been empirical with variable success although a flowchart for therapy has been proposed [313]. In
one dog, furosemide (2 mg/kg, bid, over a 2-week period) resulted in moderate neurological improvement,
reduced frequency of paroxysmal scratching episodes, and clinical stability 3 years after diagnosis [44]. In the
study of 7 CKCS [78], low levels of oral prednisone (0.5 mg/kg PO every other day) and dexamethasone (0.25 to
0.5 mg, PO sid or every other day) provided an initial mild improvement in neurological signs that subsequently
remained stable or slowly deteriorated. Use of neuralgesics carbamazepine and amitriptyline was unsuccessful.
Carprofen (2mg/kg PO bid) had some temporary effect but was considered to be less effective than the
glucocorticoids. Meloxicam (0.1 mg/kg PO sid) improved clinical signs in one dog. Drugs to decrease
cerebrospinal fluid production (omeprazole, carbonic anhydrase inhibitors) and to modulate sensation
(gabapentin) have been recommended [313]. More recent studies of CKCS suggest that mild cases may not
require treatment or may be managed using non-steroidal anti-inflammatory agents [299], while surgical
management (eg, subtotal occipital craniectomy with durotomy to relieve obstruction at the level of the foramen
magnum) for dogs with progressive signs. In a study of 16 affected dogs treated with foramen magnum
decompression, clinical signs resolved in seven dogs and improved in six dogs [314]. A surgical subdural shunt
draining to the abdomen has also been successfully employed (Dr. G. Skerritt, personal communications, 2002).
Anti-inflammatory doses of prednisolone are recommended for dogs where surgery is not possible or results in
limited improvement [299].
Dandy-Walker Syndrome
The eponym, Dandy-Walker syndrome, refers to complex heterogeneous developmental anomalies in people
characterized by the morphological triad of aplasia or hypoplasia of the cerebellar vermis (especially the caudal
portion), cyst-like dilatation of the fourth ventricle, and hydrocephalus [75]. The Dandy-Walker syndrome is
believed to be a disorder of fusion of dorsal midline structures of the primitive neural tube [80]. Failure of
development of the midline portion of the cerebellum forms the basis of this syndrome with subsequent
enlargement of the posterior fossa, abnormally high placement of the tentorium, and elevation of the transverse
sinuses. The syndrome may also be associated with syringomyelia and agenesis of the corpus callosum. A
similar syndrome has been reported in several breeds of dogs including Beagle, Silky Terrier, Chow Chow,
Tervuren, Boston Terrier, Briard, Labrador Retriever, Bull Terrier, Weimaraner, and Dachshund [64,81,82] and in
a Domestic shorthair kitten [83]. Cases are characterized by cerebellar vermian aplasia or hypoplasia, often
associated with a fluid-filled, cyst-like structure in continuity with a dilated fourth ventricle that fills the posterior
fossa. A communicating hydrocephalus is frequently present. The pyramis, uvula, and nodulus cerebellar lobules
were commonly involved in several reports involving dogs [64,82]. Additionally, portions of the cerebellar
hemispheres and flocculus can be affected. Microscopic changes may include focal or scattered Purkinje cell
chromatolysis and atrophy, indistinct deep cerebellar nuclei, scattered axonal spheroids, and reduction of granule
cells in the cerebellar cortex. Retrograde transynaptic neuronal degeneration, such as chromatolysis or
vacuolation of neurons, may be noted in brainstem nuclei that project to the cerebellum, including olivary, lateral
reticular, lateral cuneate and vestibular nuclei. The lateral apertures through which the fourth ventricle
communicates with the subarachnoid space appear to be microscopically normal in dogs [82]. Similarly, no
evidence of foraminal atresia was found in the affected kitten [83]. The wall of the posterior fossa cyst may be
lined by pia-arachnoid, neuropil, and an inner layer of flattened ependymal cells [64] or by ependymal cells alone
[82]. Hydromyelia is not usually a feature but has been reported in two adult dogs [76]. A comparison of
pathological features seen in animals with Dandy-Walker syndrome and Chiari I malformation is shown in Table 1.
Table 1. Comparison of features of Chiari I malformation and Dandy-Walker Syndrome in dogs *.
Chiari I Malformation Dandy-Walker Syndrome
Hydrocephalus Variable Common
Cystic and may descend

Fourth Ventricle Normal
into cervical cord
Cerebellum Ectopic Hypoplastia / aplasia
caudal displacement of the caudal lobe of the cerebellum to the

Cerebellar position Normal
level of or through the foramen magnum
Posterior fossa
None Present
cysts
Hydromelia Common Uncommon
Meningomyelocele None None
*Modified from Kirberger RM et al., [76].
Clinical signs of ataxia, dysmetria, absent menace response, and intention tremors reflect a cerebellar syndrome.
In addition, some animals with flocculonodular lobe lesions may show a vestibular syndrome, such as head tilt,
nystagmus, ventromedial strabismus, circling, and falling. Seizures, behavioral abnormalities and visual
impairment may be seen in animals with hydrocephalus [82,83]. A bunny-hopping gait was observed in one 12
week old Beagle [64]. Clinical signs tend to be non-progressive and may be seen in young animals as early as 2
weeks of age or may be delayed until 3 or 4 months of age. The condition has also been reported in adult dogs: a
4 year old Cavalier King Charles Spaniel and a 2.5 year old Maltese Poodle with signs of intermittent pain and
paresis/hypermetria, respectively [76]. The 4 month old kitten was presented with acute-onset collapse and
lethargy. Signs of stupor, intermittent rotatory nystagmus, partially constricted pupils, lack of menace response,
but with normal pupillary light reflexes, were noted. Tactile and visual placing reactions were diminished. Late-
onset aggression occurred in this kitten [83].
Analysis of cerebrospinal fluid is normal. Radiographic studies may reveal a very thin and dome-shaped
calvarium with a smooth ground glass" appearance, suggestive of hydrocephalus. Scalloping of the inner table of
occipital bone was observed in one dog [81]. A dilated ventricular system and cystic dilatation of the fourth
ventricle can be identified using MRI [76,83] or cisternography [81]. Hydromyelia was diagnosed in two adult dogs
using myelography and MRI [76].
Prognosis depends on severity of clinical signs. If the signs are mild, prognosis for longevity and quality of life
may be good, especially since signs tend to be non-progressive. Ventriculoperitoneal shunting was performed in
the kitten that did well for 13 weeks before its condition deteriorated [83].
Dermoid Sinus
A dermoid sinus, also termed pilonidal sinus, pilonidal cyst or dermoid cyst, is a neural tube defect resulting from
incomplete separation of skin and neural tube during embryonic development. Dermoid sinus was once
considered to be unique to the Rhodesian Ridgeback breed or Ridgeback crosses [84-90], however, the condition
has now been reported in several breeds of dogs [91-96] and rarely in cats [97,98]. It is believed that the sinus is
hereditary in nature in Ridgebacks, probably as a simple autosomal recessive gene.
The dermoid sinus typically occurs in the dorsal midline in the cervical, cranial thoracic, and sacrococcygeal
regions. One or more may occur in the same animal. The sinuses form a small external opening about 1 mm in
diameter and the hair around the orifice is concentrated in a little tuft. The sinus is lined by modified skin,
incorporating hair follicles and sebaceous glands, so that the lumen contains hair, exfoliated cells, and sebum.
There may be histological evidence of a pyogranulomatous foreign body-type reaction to hair fragments and other
debris. The sinus runs from the skin toward the supraspinous ligament to which it may or may not be attached by
fibrous tissue. Occasionally, the sinus may extend through the vertebral canal to communicate with the dura
mater and subarachnoid space, especially in the sacrococcygeal region, and less commonly in the thoracic and
cervical regions. This seems to be the case for Rhodesian Ridgeback dogs, but may be seen in other breeds too
[91]. There is the suggestion, based on limited case numbers, that dermoid sinus in non-Rhodesian Ridgeback
breeds may occur more commonly in cranial thoracic (e.g., T1 - T4) [92,93,96] or mid thoracic regions (e.g., T6 -
T7) [93], and that there may be a proportionally higher prevalence for dermoid sinus-dural mater communication
in these breeds [91]. The dermoid sinus occurred at T3 vertebral level in the affected cat [98]. In the cervical area,
the sinus is commonly attached to the area of the spinous process of the second cervical vertebra. In one report,
a C2 transosseous communication with the vertebral canal was reported in a Rhodesian Ridgeback/Dalmatian
cross [87]. Some dogs with dermoid sinus have other congenital anomalies as spinal cord myelodysplasia [96]
and vertebral anomalies including rachischisis, vertebral fusion, and hemivertebra [91,93].
The sinus tract is often palpable as a firm cord of tissue that continues ventrally to the level of the dorsal spinous
processes of the underlying vertebrae [91]. An exudate may be seen emanating from the skin orifice. Neurological
signs can occur in dogs at any age when the sinus communicates with the subarachnoid space and becomes
infected, leading to meningitis, myelitis, or spinal cord compression. To the author's knowledge, only a single case
of spinal cord involvement has been reported in cats (in a 16 month old Balinese cat, at the level of the third
thoracic vertebra) [98]. According to the location of the sinus, and degree of involvement of the spinal cord and/or
meninges, neurological signs may reflect either a cervical syndrome, cervicothoracic syndromethoracolumbar
syndrome, or lumbosacral syndrome. Not every animal in which the sinus communicates with the subarachnoid
space will show clinical or neurological deficits [89]. Various organisms, including Staphylococcus intermedius,
may be cultured from the sinus. Analysis of CSF may reveal increased protein content and elevated white cell
count if there is an underlying meningitis/myelitis present [91]. Radiography can be used to identify presence of
any vertebral anomalies, while contrast studies such as fistulography/sinography (e.g., using a non-ionic contrast
medium, such as Omnipaque) may help determine the extent of the sinus, the central region of which may be
enlarged to form a cyst-like cavity. Myelography can be used to detect the presence of meningeal abnormalities
and possible spinal cord compression [93,96]. The sinus and adjacent vertebrae may also be characterized using
special imaging techniques, including computed tomography and ultrasonography [87,93]. In one dog, computed
tomography identified schisis (cleft) of the T7 dorsal arch, displacement of the spinal cord and dural sac, and the
dermoid sinus dorsal to the vertebra [93]. Surgical excision, typically in conjunction with dorsal laminectomy, is the
treatment of choice, along with appropriate antibiotic therapy based on culture of the sinus and sensitivity testing.
Prognosis is guarded, as recurrence of infection may occur with incomplete surgical removal [87].
Nasal dermoid sinus cysts, rare developmental defects, and characterized by intermittent discharge from a small
opening in the midline on the bridge of the nose at the junction between the nasal planum and the skin, have
been reported in dogs (3 of 6 dogs were Golden Retrievers). These cysts have the potential for extending into the
cranial vault causing cerebral abscesses or recurrent meningitis. Complete surgical excision has a good
prognosis.
Fetal Akinesis Deformation Sequence

A lethal developmental disorder called fetal akinesis deformation sequence has been described in a breeding
colony of dogs that is inherited as an autosomal recessive trait [301]. Fetal akinesis was demonstrated by
abdominal ultrasonography of late-gestation bitches. Puppies died at birth due to respiratory failure and exhibited
scoliosis and arthrogryposis. Grossly, changes included microencephaly, small cerebellum and brainstem,
reduced caudal cerebal sulcation, thin spinal cord, and generalized neurogenic muscle atrophy. Neuronal
degeneration and gliosis were found in spinal cord, brainstem nuclei, and cerebellum in which there was reduced
foliation, marked loss of Purkinje cells in some folia, loss of cells in the external granular layer, and absence of
cells in the deep cerebellar nuclei. The cerebral cortex had normal layers but with reduced cell numbers. The
condition is thought to be associated with slowing or arrest of CNS development due to accelerated neuronal
degeneration in mid to late gestation, with the ensuing neurogenic fetal immobility causing contracture of skeletal
muscles leading to global arthrogryposis and respiratory failure at birth. The disorder is considered to resemble
pontocerebellar hypoplasia type I in humans, an autosomal recessive neurodegeneration disorder associated with
anterior horn cell disease and neurogenic muscle atrophy [302].
Hydranencephaly
Hydranencephaly and porencephaly are rare, related malformations associated with failure of development
(hypoplasia) and destruction (secondary atrophy) of primarily the neopallial part of the telencephalon (the
neocortex and the ventricular zone) [62,99,100]. Dogs and cats may be affected. The pathogenesis of this
anomaly is not always certain. In people, a fetal cerebrovascular accident may result in massive necrosis and
resorption of tissue [99]. In animals, the most common cause is in utero viral infection [62,100]. While many
different viruses (including Akabane, Bluetongue and Rift Valley fever) are implicated in large animals,
hydranencephaly in cats has been linked with vaccine-induced intrauterine feline panleukopenia / parvovirus
infections [74,101]. Porencephaly refers to the occurrence of single or multiple cystic cavities in the cerebrum,
usually communicating with the lateral ventricles or subarachnoid space. According to Summers and colleagues
[62], porencephaly might occur if infection occurs later in the period of fetal nervous system vulnerability or if it is
less destructive. Hydranencephaly is characterized by virtual absence of the cerebral hemispheres usually with
preservation of olfactory and hippocampal components, fornix, and basal nuclei [62]. The cerebral hemispheres
are replaced by cerebrospinal fluid-filled sacs lined by leptomeninges, a glial membrane, and ependymal
remnants. Microphthalmia has been reported [102] and there may be loss of nerve fibers and reduced myelin
staining in optic nerves. Other structures including the brainstem and cerebellum may or may not be affected. In
kittens with in utero parvovirus infection, hydranencephaly occurred in conjunction with cerebellar agenesis and
hypoplasia [74]. Involvement of structures other than the cerebral cortex may depend on the developmental stage
of the nervous system at the time of fetal infection.
Clinical signs are usually seen within several weeks after birth and depend upon nervous structures involved.
Animals with predominant cerebral cortex involvement may have behavioral changes, including dummy-like
characteristics, indifference to their environment, and episodes of rage, are usually blind, and may be unable to
suckle. Urinary and fecal incontinence may be present. In animals with cerebellar involvement ataxia, dysmetria,
and difficulty standing may be noted. Other animals can appear active but have difficulty in prehending food and
drinking water. Unilateral hydranencephaly has been observed in an 8-month old Miniature Poodle whose only
clinical sign was a visual defect [100]. Accordingly, prognosis varies from guarded to poor. Diagnosis is suggested
by clinical signs and neuroimaging techniques, such as MRI, and confirmed by histopathology,
immunofluorescence, or DNA studies using polymerase chain reaction [74].
Hydrocephalus
Hydrocephalus is one of the most common manifestations of developmental disorders in dogs and cats [103-105]
and is the result of a disturbance in the normal cerebrospinal fluid (CSF) fluid dynamics [75]. It is characterized by
increased CSF volume and dilatation of the cerebral ventricles. It may be congenital or acquired postnatally. It
may occur passively in which the increased volume of CSF fills voids left by loss of brain parenchyma [106]. This
has been called compensatory hydrocephalus or hydrocephalus ex vacuo and is often seen with congenital
defects or malformations, such as hydranencephaly and cerebellar hypoplasia, and may follow severe destructive
parenchymal lesions, such as cranial trauma or ischemic encephalopathy in adult cats [107]. The most common
form of hydrocephalus in animals is obstructive (non-communicating) hydrocephalus [108] typically caused by
obstruction to CSF flow in the intraventricular pathway, in which ventricular dilatation occurs proximal to the
obstruction site, with preservation of normal ventricular size distal to the block. Obstruction may also occur at the
point of CSF resorption by the arachnoid villi in the subarachnoid spaces (e.g., meningitis, malformation of
arachnoid villi, or tumors compressing the venous sinuses [107]). CSF pressure tends to be increased
(hypertensive) in cases of obstructive hydrocephalus [107]. While obstruction may occur anywhere along the
ventricular pathway in congenital hydrocephalus, it occurs most commonly in the mesencephalic aqueduct of
Sylvius. Obstructive hydrocephalus in dogs and cats may be associated with various developmental defects, e.g.,
myelodysplasia, Dandy-Walker syndrome, spina bifida, syringomyelia and hydromyelia, optic nerve hypoplasia,
occipital dysplasia, craniofacial abnormalities in Burmese cats [109], polymicrogyria in Poodles [110], triploidy (a
fatal condition characterized by the presence of three haploid sets of chromosomes, instead of two, in all cells) in
a stillborn puppy [111], aphakia (absence of the lens) and multiple ocular defects in Saint Bernard puppies [112],
and griseofulvin teratogenesis [113], as well as intra-uterine infectious diseases such as parvovirus [74] and
panleukopenia virus [114]. Postnatal, acquired obstructive hydrocephalus, again often involving the
mesencephalic aqueduct, has been associated with feline infectious peritonitis [115-117], parainfluenza virus
[118,119], necrotizing periventricular encephalitis [120-122], cryptococcal granulomatous ependymitis [123],
methylmercury poisoning [124], parasitic migration[125,126] and occasionally it may be caused by mass lesions
that block CSF flow at the interventricular foramen, third ventricle, mesencephalic aqueduct, or lateral apertures
[107,125,127-131]. Meningitis may also result in blockage of CSF flow at the lateral apertures [107,132].
Hydrocephalus has been seen in several miscellaneous disorders, including galactosialidosis in a 5 year old
Schipperke dog [133], cerebellar degeneration in Bull Mastiff puppies [134,135], neuroaxonal dystrophy in a 9-
week-old Jack Russell Terrier [136], primary ciliary dyskinesia in dogs [137-139], hypertrichosis (growth of hair in
excess of normal) in Golden Retrievers [140], hereditary cerebellar abiotrophy in Australian Kelpie dogs [141],
arachnoid cysts within the quadrigeminal cistern [308], and in a dog presented with continuous tail chasing [142].
Hydrocephalus is thought to play a role in the development of hydrosyringomyelia (see syringomyelia and
hydromyelia) in dogs and hypodypsic hypernatremia in dogs and cats [143,144].
The use of additional classification terms as non-obstructive or communicating hydrocephalus can be confusing
and has been challenged in people, in whom increased pressure leading to hydrocephalus is virtually always a
result of blockage, whether it is along the pathway of CSF flow or at the site of resorption [75]. Overproduction of
CSF in cases of choroid plexus papillomas is considered a rare cause of hydrocephalus in people, and to my
knowledge, has yet to be reported in animals. At this time, the form of hydrocephalus in people termed "normal
pressure hydrocephalus" which is the result of an imbalance between production and resorption of CSF, usually
around the brain convexities, and is seen in late middle-aged and elderly groups, has not been reported in
animals. The term "external" hydrocephalus refers to excessive collection of CSF within the subarachnoid space
rather than in the ventricular system and is seen in cases of generalized brain atrophy. This form has been
reported in a 12 week old Fox Terrier presented with hydrocephalus [304].
On gross inspection the brain may be enlarged with loss of gyral pattern and decreased depth of sulci. In severe
cases the cerebral hemispheres contain extremely large, fluid-filled lateral ventricles, with the cerebral cortex
often being reduced to 3 - 4 mm in thickness. The loss of white matter from distension and atrophy is generally
more severe than the gray matter loss [106]. The lateral ventricle may extend into the olfactory peduncle and bulb.
Pressure from ventricular enlargement may result in atrophy of the corpus callosum, disruption of the septum
pellucidum and atrophy of associated structures, including subcortical white matter, optic radiation, internal
capsule and auditory radiation. The basal nuclei are usually intact. Blockage of the lateral apertures will result in
extensive dilatation of the entire ventricular system. Dilatation of the fourth ventricle may result in marked
cerebellar compression along with flattening of the pons and medulla oblongata [106]. Distension of the central
canal (hydromyelia) and syrinx formation may also occur in the cervical spinal cord due to the increased
intraventricular pressure [145,146]. A developmental stenotic mesencephalic aqueduct is typically associated with
fused rostral colliculi [106]. Microscopically, the ependymal lining is frequently disrupted and there may be
evidence of forking, gliosis and septum formation. A pronounced subependymal edema is usually present. In one
report of acquired hydrocephalus in puppies, there was severe periventricular, choroidal, and meningeal
inflammation with fibrinous exudate and neutrophilic and mononuclear cell infiltrates, and multiple false diverticula
emanating from the lateral ventricles [120]. Severe meningitis, choroid plexitis, and ependymitis can occur with
feline infectious peritonitis virus [117]. Bleeding is a potential complication of hydrocephalus. Chronic subdural
hematomas have been reported in a hydrocephalic 2 month old Newfoundland puppy [307].
Small, toy, and brachycephalic breeds (Maltese, Yorkshire Terrier, English Bulldog, Chihuahua, Lhasa apso,
Pomeranian, Toy Poodle, etc.) are at high risk for hydrocephalus. In one study, 53% of 564 hydrocephalic dogs
manifested clinical signs by 1 year of age [108]. A distinction between congenital and acquired forms of
hydrocephalus may be very difficult from a clinical viewpoint especially since infectious agents may cause
hydrocephalus postnatally in young puppies [120]. Furthermore, the confusion in terminology is reflected in the
results of one epizootiologic study from 14 veterinary schools in the United States in which 30% of 564 dogs
classified as having "hydrocephalus due to congenital origin" were over 2 years of age [108]. Genetic disease has
been reported. In Siamese cats, hereditary hydrocephalus is transmitted as an autosomal recessive trait [147].
The congenital hydrocephalus seen in New Zealand Golden Retriever puppies with hyertrichosis appears to have
an autosomal mode of inheritance [140].
Clinical examination of newborn and immature hydrocephalic animals typically reveals an enlarged, dome shaped
cranium, and open sutures and/or fontanelles that may be bulging in an animal that continuously cries out, has
visual and auditory impairment, and altered mental status (ranging from hyperexcitability to severe depression).
Other signs may include sporadic seizures, a gait that is uncoordinated, spastic, and clumsy, head tilt, circling,
dilated and fixed pupils, and head pressing [148]. Ventrolateral strabismus may occur as a result of encroachment
on the orbit from expanding frontal bones, in which case eye movements are normal. Less common signs are
positional and spontaneous nystagmus, vomiting, and cervical pain. Some adult Golden Retrievers with
hydrocephalus and hypertrichosis manifest behavioral abnormalities (e.g., aggression, hyperactivity, slow learning
and other temperament changes) that make them unacceptable pets [140].
Hydrocephalus may be confirmed by radiographic demonstration of enlarged lateral ventricles. Plain radiography
will often reveal a ground glass appearance throughout the cranial vault. Cranial sutures and/or open fontanelles
may be evident after the normal age for closure and skull ossification. Ultrasonography through open fontanelles
[149], CT, or MRI are very useful diagnostic aids [129,150]. Measuring ventricular volume using quantitative MRI
also appears to be a useful tool and may help in understanding the relationship between ventricular volume and
neurological disease [151]. In one study, a high incidence of asymptomatic (ventricular enlargement or
ventriculomegaly) was noted in clinically normal dogs [152], a finding sometimes termed "occult hydrocephalus".
Measurement of basilar artery resistance index (a correlate of intracranial pressure) using transcranial dopler
ultrasonography, a non-invasive and relatively inexpensive technique, reportedly correlates with neurologic status
in dogs with congenital hydrocephalus [296]. Electroencephalographic traces usually have a characteristic pattern
of high amplitude (25 - 200 mV), slow wave (1 - 5 Hz) activity, often with a superimposed fast frequency of 10 to
12 Hz. Fundic examination may reveal papilledema. Collection of CSF for analysis is usually not performed since
it may precipitate brain herniation due to the presence of increased intracranial pressure.
Prognosis is sometimes related to an underlying disease (such as cerebral neoplasm), but tends to be guarded to
poor. Treatment of animals with severe congenital hydrocephalus is futile due to the large amount of tissue
destruction and atrophy. Indeed, the efficacy of corticosteroids and surgical shunt procedures in animals with
"acquired" hydrocephalus remains uncertain due to the lack of well controlled clinical trials and to incomplete
knowledge of the underlying pathogenesis of hydrocephalus. Treatment of the cause of acquired, adult-onset
hydrocephalus would seem to be a logical pursuit. Successful surgical shunting procedures have been reported in
"acquired" hydrocephalus in both immature and mature dogs [104,153-156]. A ventriculoperitoneal shunt has
been used to treat cats with hydrocephalus [157]. Common complications include catheter blockage and sepsis.
Dexamethasone, administered at an oral dose of 1 mg divided 4 times daily, for 2 to 3 kg dogs has been used
empirically [104]. This dose is gradually reduced over a 2 to 3 week course of therapy . Some animals may be
maintained on alternate day dosage schedules. Dexamethasone at 2 - 4 mg/kg has been suggested for patients
with exacerbated/progressive signs [107]. In cats with mild signs, intermittent or short- and long-term
corticosteroid usage may be helpful, e.g. prednisone at 1 - 2 mg/kg, sid or bid, PO, along with (or given
separately) furosemide at 2 mg/kg bid or tid, PO [105]. Corticosteroids are believed to primarily affect brain bulk
and CSF production, not CSF absorption [158]. In humans, acetazolamide, isosorbide, and furosemide can
reduce CSF production considerably and may provide short-term benefits [75].
Lissencephaly
Lissencephaly is a rare developmental defect characterized by a small, smooth-appearing cerebrum with
rudimentary or no gyri (agyria) or sulci present and derangement of cells of the cerebral cortex. This anomaly has
been reported in Lhasa apso dogs, in several breeds of dogs with cerebellar hypoplasia and dysplasia, including
Wire-Haired Fox Terriers, Irish Setters, and Samoyeds [65,159,160,309] and in Korat cats with associated
microencephaly [106]. Lissencephaly results from disturbance of neuronal migration and proliferation during
development. The condition involves only the neocortex, with the hippocampal and olfactory lobes being normal
[106,159]. The neocortex is thicker than normal (pachygyria) and contains scattered heterotopic white matter
bundles, especially in the thin superficial molecular layer and in the 4th cortical layer. Randomly arranged neurons
may be seen in the deeper cortical layers, suggesting arrested migration. In affected Lhasa apso dogs in which
the cerebellum was grossly normal, changes were also observed in the flocculonodular lobe of the cerebellum
that were characterized by marked heterotopic changes in several folia in which Purkinje cells were irregularly
dispersed within the granular layer, the molecular layer was hypercellular and nests of heterotopic glial cells were
in the roof nuclei [159].
Clinical signs usually are detected in the first year of life and are characterized by erratic behavior patterns,
including episodic aggression, growling at imaginary objects, confusion, depression, hyperactivity, visual deficits,
and seizures. Behavior alterations, including self-mutilation, also occur in cats. Gait and posture are usually
normal but slight hypermetria may be present when running. Postural reactions tend to be sluggish but normal,
although mild proprioceptive deficits have been observed [159]. Spinal reflexes are normal. Bilateral menace
deficit may be the only deficit in cranial nerve testing. The observation that neurological abnormalities were mild
or delayed in onset after birth suggests the dog is less dependent on the cerebral cortex for sensorimotor function
than is man [159]. Abnormal wave tracings are detected electroencephalographically. Neuroimaging studies in
animals have demonstrated a smooth cerebral brain surface, as in humans, along with a broad cortex in relation
to a narrow white matter layer [75,309].
Prognosis is guarded. Treatment is symptomatic. Seizures may be controlled with anticonvulsant therapy.
Neuronal Heterotopia in Lagotto Romagnolos

Neuronal heterotopia in Lagotto Romagnolo dogs is a recently reported disorder that remains to be classified,
although it may be within the spectrum of lissencephalic malformations [298]. Clinical signs began around 7
weeks of age and included tetraparesis with hypermetria, intention tremor, and poor conscious proprioception.
Mentation and spinal reflexes are normal. Affected dogs have facial dysmorphism characterized by inferior
prognathia and an atypical brachycephalic skull. With time, cerebellar signs progressively improve to apparent
clinical normality by 1 year of age. Gross examination of the brain is normal (including normal gyration).
Microscopic lesions are characterized by diffuse abnormal neuronal migration and maturation in the cerebral
cortex, cerebellum and pons. The abnormal neurons appear monomorphic with vesicular nuclei and basophilic
cytoplasm. Similar cells are also present in hemispheric and cerebellar white matter. A genetic disorder is
suspected.
Meningoencephalocele
This is a lethal malformation characterized by herniation of part of the brain and meninges through a defect in the
skull (cranioschisis or cranium bifidum) [106,109]. The condition may occur spontaneously in animals [161]. It has
been seen in kittens following exposure of pregnant cats to a variety of teratogenic agents, including
methylmercury, hydroxyurea and griseofulvin [113,162-164], and it occurs in male and female Burmese kittens in
which it is inherited as an autosomal recessive trait (the phenotype is impenetrant in at least some homozygote
cats) [165,166]. Other related dysraphic anomalies associated with failure of closure of the neural tube include
meningocele, exencephaly, anencephaly, and meningomyelocele. In affected animals, the two cerebral
hemispheres develop but do not separate from the skin ectoderm that inhibits normal intramembranous
ossification from which the calvaria develop. This results in the large skull defect that allows the brain to protrude
[106]. Lateral ventricles may be dilated. The cerebrum is often herniated through openings in frontal and parietal
bones and may contain a central cavity. Medulla oblongata, midbrain, cerebellum, hypothalamus, and sometimes
the thalamus remain in the skull, but are often compressed and distorted. Craniofacial abnormalities in Burmese
kittens are characterized by skin-covered masses (encephaloceles) bulging from the top of the head, shortened
maxilla, bifid tongue, and absence of eyes, eyelids, and external nares [109,166]. Controlled breeding in Burmese
colonies may eliminate the trait; however, a high rate of carriers reportedly exists in the Burmese breed.
Myelodysplasia
Myelodysplasia refers to spinal cord malformation and in humans this developmental disorder may involve several
structures including spinal cord, vertebral column, muscles, and skin [167-170]. Myelodysplasia in dogs primarily
affects the spinal cord and as such, has been termed "neurospinal dysraphism" [171] or "spinal dysraphism" [172].
This myelodysplastic condition most commonly occurs in Weimaraner dogs [172-175] in which it is transmitted by
a codominant lethal gene with reduced penetrance and variable expression [176]. The homozygous condition is
lethal. This disorder has also been reported sporadically in other breeds of dogs, including but not limited to
Dalmatian, Rottweiler, West Highland White Terrier, German Shepherd, Golden Retriever, and an Alaskan
Malamute [177-183] (see also links to other developmental disorders, below). Prenatal studies have shown that
dysplastic changes, resulting from abnormal migration of mantle cells, are evident in embryos (24 - 28 days of
gestation) obtained by mating severely dysplastic Weimaraner dogs [171,184]. Pathologically, the malformation
includes hydromyelia, duplicated, stenotic, or absent central canal, syringomyelia (usually in dorsal columns and
often delayed in its formation until dogs are several months old [106,172, 175], chromatolysis and loss of nerve
cell bodies in gray matter, disrupted dorsal median septum and ventral median fissure, and gray matter ectopias.
In any affected animal, these morphological changes may be present in varying degrees in different cord
segments, but occur most commonly in thoracic and upper lumbar spinal cord segments. However, in one
prenatal Weimaraner study, major histological differences between normal and dysraphic fetuses were confined
to the lumbosacral region of the cord [171,184]. Dysraphic lesions in fetuses included failure of the dura mater to
differentiate/separate from the vertebral canal periosteum, absence of the ventral median fissure and fusion of
ventral white matter, and gray matter architectural disruption. In some dysraphic fetuses, misplaced gray matter
caused marked reduction in size of the central canal. Central canal diverticula were common and the ratio of gray
matter diameter to spinal cord diameter was significantly greater in affected fetuses [171,184].
Clinical signs usually appear by 4 to 6 weeks of age; however, abnormal spinal reflexes reportedly are observed
in newborn dysplastic puppies. Affected animals have a symmetrical bunny hopping pelvic limb gait, wide based
stance, and overextended pelvic limbs with depressed proprioception. Less constant signs include scoliosis,
abnormal hair streams in the dorsal neck region, and koilosternia (gutter-like depression of the chest) [172].
Clinical signs neither progress nor retrogress. There is often a poor correlation between the severity of the clinical
signs and the histopathological lesions [174]. Indeed, Summers and colleagues [106] have seen affected
Weimaraner puppies without microscopic spinal cord lesions. Routine hematology, radiography and CSF analysis
are usually within normal limits. Animals can lead a normal life. There is no treatment.
Note that vertebral anomalies may be associated with myelodysplasia as a result of the close embryonic origin of
the spinal cord and vertebral column (i.e. notochord, neural tube, and sclerotomal mesoderm), e.g., malformations
of the vertebral bodies and ribs have been reported in a Pekingese dog with spinal dysraphism, along with
agenesis of the cauda equina [185]. Similarly, myelodysraphism may be seen with other developmental
conditions, such as spinal canal stenosis [45,181], spina bifida, meningoencephalocele, syringomyelia,
hydrocephalus, and arachnoid cysts.
Occipital Dysplasia
Occipital dysplasia refers to an abnormally large foramen magnum, resulting from a defect in development of the
occipital bone (incomplete ossification of the ventromedial part of the supraoccipital bone [186], has been
described in small/medium and toy breed dogs that are often brachycephalic, including Yorkshire Terrier,
Pomeranian, Maltese Terrier, Chihuahuas, Pekingese, as well as in Miniature and Toy Poodle, Miniature
Keeshond, and Beagle [186-191]. The abnormality, which is readily revealed by frontal radiographs of the skull,
consists of a key shaped dorsal midline extension of the foramen magnum into the occipital bone. In one
morphometric radiographic study of skulls from 80 Pekingese dogs (75 adult and 5 juvenile), the shape of the
foramen varied from ovoid to rectangular and the dorsal notch was observed in all but 2 skulls [192]. Variability in
the area of the foramen was mainly correlated with total height of the foramen, including the dorsal notch. The
foramen magnum index (the ratio between the maximum width and the total height of the foramen) was not
significantly correlated with age, but was significantly larger in female dogs. It was concluded that the large
variability in the shape and size of the foramen magnum and the absence of any neurological problems in dogs of
this study indicated that the dorsal notch of the foramen magnum in brachycephalic dogs is a normal
morphological variation, rather than a pathological condition [192]. This has been confirmed by other studies
[186,193]. In another morphometric study involving German Shepherd puppies, occipital dysplasia was not found
[194].
The absence of neurological deficits in animals of the above-mentioned studies is consistent with earlier reports of
occipital dysplasia being a subclinical (or nonclinical) condition [100,186], and that presence of neurological signs
such as ataxia, cervico-occipital pain, personality changes, convulsions, pawing at the side of the face, ear or
neck, protrusion of the tongue, and dysphagia in dogs with this malformation reflects some other underlying
condition, such as hydrocephalus [195]. A more recent report suggests that intramedullary CNS abnormalities,
such as hydrosyringomyelia, may be present concurrently with occipital dysplasia and should be considered as a
possible cause of clinical signs such as cervical hyperesthesia and paresis/tetraparesis [196]. Occipital dysplasia
and hydrosyringomyelia are sometimes seen in people with Chiari malformations. Interestingly, some of the signs
originally described by Bardens [195], especially the cervical pain and frequent scratching, have been reported in
dogs with Chiari I malformation, usually with accompanying hydrosyringomyelia (see Chiari malformations). It is
has also been suggested that there may be an increased potential for herniation of the cerebellum or brainstem
through the enlarged foramen magnum [197], although such prolapse is normally prevented by a fibrous
membrane (dura mater and connective tissue) covering the dorsal notch [186,192]. In the report by Bagley and
colleagues, this membrane appeared to compress the underlying spinal cord and brainstem in one dog [196].
Optic Nerve Hypoplasia

Optic nerve hypoplasia is an uncommon congenital abnormality of the posterior segment that may be unilateral or
bilateral and may be accompanied by microphthalmia or other congenital ocular defects, such as retinal dysplasia,
retinal detachment, and sometimes, hydrocephalus. The underlying pathogenesis has not been established.
Pathologically, the optic nerve is atrophic with reduced numbers of optic nerve fibers. Vacuolation and paucity of
neurons may be observed in ganglion cells of the retina. The optic nerve foramen/canal may be markedly
narrowed in some affected animals. Optic nerve hypoplasia is thought to be inherited in Miniature Poodles and
has been seen occasionally in several canine breeds, including Beagle, Dachshund, German Shepherd, Miniature
Schnauzer, Rough Coated Collie, St. Bernard, Miniature and Toy Poodle, Russian Wolfhound, Tervuren, English
Cocker Spaniel, and Great Pyrenees [198-206]. Unilateral optic nerve hypoplasia and hydrocephalus were
reported in a 3 year old Pekingese [207]. A possible relationship between small optic nerve heads and optic nerve
hypoplasia was described in colony Beagles [208]. Optic nerve dysplasia was reported in American Cocker
Spaniels with inherited (probably autosomal recessive) multifocal retinal dysplasia [209]. Congenital blindness
associated with multiple ocular anomalies, including optic nerve hypoplasia, has been reported in a family of
Bouvier des Flandres (successive litters from the same parents as well as from father x daughter matings were
affected) [210]. The diameter of the optic nerve was reportedly reduced in a colony of Dachshunds homozygous
for the merle (dappled M) gene [211]. Optic nerve hypoplasia and microphthalmia have also been reported in cats
as a sporadic condition [212], in kittens secondary to griseofulvin treatment of the queen during gestation [113],
and in association with the inherited craniofacial malformation of Burmese cats [166].
Clinical signs of severe unilateral optic nerve hypoplasia include ipsilateral mydriasis, blindness, menace deficit,
and absent direct pupillary reflex, but with a normal consensual reflex in the affected eye following stimulation of
the normal eye. Severe bilateral involvement will result in blindness, bilateral mydriasis, absent menace response,
and reduced/absent pupillary reflexes.
Diagnosis is suggested by a history of visual impairment from birth. Ophthalmoscopic examination reveals
variable reduction in the size of the optic disk with normally appearing retinal vessels. Visual evoked potentials will
be absent while ultrasonography may be a useful diagnostic technique [213,214] (also see Electrodiagnostics).
Note that electroretinography will be normal since neuroretinal structures (e.g., rods and cones) responsible for
generating the electroretinogram are not affected. The pattern evoked response, generated more from ganglion
cells than photoreceptors, may also be abnormal (Dr. J.E. Steiss, Tuskegee University, personal communication,
2002). Prognosis is poor. There is no treatment.
Optic nerve aplasia is a very rare congenital anomaly characterized by absence of optic nerve, optic disk and
retinal vessels. Interestingly, the size of the optic nerves, density of axons, and total number of axons were not
affected in the autosomal recessive mutation carried in a family of achiasmatic (lacking an optic chiasm) black
Belgian sheep dogs [106,215]. In these dogs each optic nerve was continued by an ipsilateral optic tract. Affected
dogs had a congenital rapid pendular nystagmus with unimpaired vision.
Osteochondromatosis
Osteochondromatosis is a relatively uncommon clinical disease entity in dogs and, especially, in cats (based on
few reported cases in cats) in which multiple cartilage-capped, partially ossified protuberances or exostoses arise
(usually near metaphyseal growth plates) from the cortex of bones of endochondral origin [45,216-222].
Synonyms for osteochondromatosis include multiple cartilaginous exostoses, hereditary multiple exostoses,
multiple osteochondromatosis, diaphyseal aclasis, dyschondroplasia, and hereditary deforming chondrodysplasia
[223]. Osteochondromatosis implies involvement of several bones (polyostotic), although single bone involvement
(monostotic) may be seen, in which case the term chondroma has been used, indicating that the growths are
benign tumors. However, osteochondromas are not true chondromas but developmental disturbances since their
growth is controlled by growth hormone and cease enlargement at time of growth plate closure and are, therefore,
unlike true tumors that demonstrate uncontrolled growth (Dr. R. Pool, Mississippi State University, personal
communication, 2001). The cartilage-cap portion of osteochondromas undergo endochondral ossification with
subsequent replacement of much of their central mass by bone, so that eventually the cortical surfaces of the
parent bone and the developing bony stalk are continuous and have confluent marrow spaces [223]. Although
canine osteochondromas are a developmental, chondrodysplastic anomaly [223], for purposes of differential
diagnosis they are also included as one of several primary skeletal tumors (see spinal cord tumors).
The etiology of canine osteochondromas is uncertain. They may arise directly from growth plate cartilage as a
result of a defect in the perichondrial ring, from physical stresses causing proliferative responses at the margin of
the physis, or from some form of periosteal disturbance that induces perichondrial growth. Any bone of
endochondral origin may be affected; however, in decreasing frequency, vertebrae (especially spinous processes,
but also body and arch), ribs, long bones, feet and pelvis are most often involved in dogs [223]. Bones of
intramembranous origin (i.e., calvarium and facial bones) are not affected in dogs. Growth of osteochondromas in
dogs typically ceases at the time of skeletal maturation, although occasionally, some may progress after skeletal
maturity [224]. While a familial or genetic etiology is suspected [223,225], there is no apparent breed or sex
predisposition, although several reports involve Alaskan Malamutes, and in one study, seven of the eight affected
dogs had mixed Terrier breeding [221].
Osteochondromatosis is frequently a subclinical condition diagnosed as an incidental radiographic finding.
However, neurological signs occasionally occur in animals associated with spinal cord compression secondary to
vertebral osteochondromas in any region of the spinal column, but most commonly cervical and/or thoracic areas
[219,224, 226,227]. Signs observed will depend on the location of the masses (e.g., cervical syndrome,
cervicothoracic syndrome, and thoracolumbar syndrome).
There may be variable signs of pain on palpation of the thoracic or cervical spine. Onset of neurological signs
typically occurs prior to 1 year of age, although osteochondromatosis may be first diagnosed in older dogs (see
also, malignant transformation, below). Osteochondromatosis may involve other tissues such as synovial joints,
and tracheal rings. Concurrent skeletal and tracheal osteochondromatosis has been observed in a young Alaskan
Malamute [226].
Diagnosis may be made using survey radiography but evidence of cord compression will require myelography
and/or imaging [311]. Radiographically, osteochondromas usually appear as large, smoothly contoured cystic
bony masses, with irregular or well-delineated borders, sometimes with mottled patterns of radiolucency and
radiodensity [223,224]. Fusion of vertebrae at articular facets in the presence of normal intervertebral disks, may
be observed [224]. Microscopic examination of a biopsy specimen, which includes the cartilage cap and bony
stalk covered by a membrane continuous with the periosteum, will confirm the diagnosis [223]. During active
growth, the cartilage resembles a physis with typical endochondral ossification present. The cartilage cap may be
incomplete or absent in mature lesions. Osteochondromas may also be characterized using special imaging
techniques, such as CT [227].
Surgical excision (including removal of the perichondrial membrane on the surface of the cartilage cap), spinal
cord decompression, and perhaps vertebral stabilization, are necessary in animals with clinical evidence of spinal
cord attenuation. While post-operative vertebral fracture has been reported [228], there are several reports of
successful surgical outcomes [226,227,229]. Surgical removal may be easier when osteochondromas are less
well developed, at which time they are softer and poorly vascular, since within a few months, the cancellous bone
becomes harder and much more vascular [226]. Recurrences may occur. Prognosis is guarded, especially in
young animals with osteochondromas involving multiple vertebral sites where subclinical masses may assume
importance as they grow until the skeleton matures. Early surgical removal may eliminate development of clinical
complications. Furthermore, there is evidence that osteochondromas may undergo malignant transformation to
chondrosarcoma and osteosarcoma in older dogs, frequently between 7 and 10 years of age [224](7), with
potential for metastasis [221,230,231]. Thus, early removal will also remove this latent threat of malignancy.
Breeding of affected dogs should be discouraged because of the occurrence of osteochondromas in 2 dogs from
a litter of 5 sired by a dog that also had the condition [225]. Recently, malignant transformation of solitary spinal
osteochondroma to an osteosarcoma was reported in 2 mature dogs [232].
Osteochondromatosis in cats differs significantly from the condition in dogs. The osteochondromas typically first
appear in the skeletons of mature cats (e.g., from 2 to 4 years of age), growth of the bony mass is progressive,
and the lesions show microscopic transformation from hyperplasia to characteristics of virus-induced parosteal
sarcomas [223]. Virus particles have been identified ultrastructurally from feline osteochondromas and are
morphologically identical to feline leukemia virus [233]. Other viruses suggested are feline fibrosarcoma virus or
another member of the feline retrovirus family [223]. Any bone can be affected in cats, including the flat bones of
the skull. Most common sites, in decreasing frequency, are rib cage, scapulae, vertebrae, skull and pelvis [223].
Osteochondromatosis in cats has no breed or sex predisposition or hereditary pattern. Prognosis is grave for any
affected cat. Some tumors undergo transformation into osteosarcoma and chondrosarcoma and no cat has lived
longer than a year after onset of clinical signs [223].
There are sporadic reports of a focal cartilaginous lesion, termed solitary cartilaginous exostosis, resulting in
spinal cord compression [25,234]. Young and mature, large-breed dogs (4 month old Rottweiler, 5 month old
Bernese Mountain dog, 3.5 month old St. Bernard, and a 3.5 year old Bernese Mountain dog) were affected and
the mass in each dog occurred between the dorsal arch of the atlas and the spinous process of the axis.
Radiographically, the masses were partially calcified, seemed to arise from the dorsal arch of the atlas or from the
dorsoatlantoaxial ligaments and extended into the vertebral canal [25]. In some cases, the dorsal arch of the atlas
was irregular or thickened with erosion and shortening of the pedicles and spinous process. Histologically, the
masses were composed of a fibrocartilaginous matrix, but without bone formation. Surgical removal of the mass
in one dog resulted in a complete recovery [234]. At this time, these focal cartilaginous lesions remain difficult to
classify. They seem to be radiographically similar to calcinosis circumscripta/tumoral calcinosis (CC-TC) [235], a
possible metabolic disorder [236] having an apparent predilection for the atlantoaxial articulation. However, CC-
TC is histopathologically different from osteochondroma and cartilaginous exostosis (Dr. R. Pool, Mississippi
State University, personal communication, 2001). A lesion of CC-TC consists of a radiodense aggregation formed
of multiple loculi of amorphous calcareous deposits located in periarticular soft tissue. The calcium deposits are
bordered by macrophages and giant cells and are encapsulated by fibrous tissue septa of variable thickness that
may rarely contain foci of metaplastic
cartilage and bone tissue [237].
Sacrocaudal Dysgenesis
Congenital malformations of the sacrocaudal (sacrococcygeal) spinal cord and vertebrae have been well
described in tailless Manx cats, in which the disease is transmitted as an autosomal dominant trait [238-241]. This
disease is also known as "caudal dysgenesis" and exemplifies a malformation brought about by breeders
selecting for tailless cats. The disorder is associated with varying degrees of agenesis/aplasia (absence of
formation) or dysgenesis/dysplasia (defective development) of caudal lumbar, sacral and caudal (coccygeal)
vertebrae, and spina bifida. The variable expression of Manx taillessness is a salient and consistent feature of the
Manx syndrome [242]. Pathologically, subcutaneous cyst formation, meningocele, meningomyelocele, shortening
of the spinal cord and absence of cauda equina, and myelodysplasia of the caudal lumbar, sacral, and caudal
spinal cord segments including central canal defects, syringomyelia, myeloschisis (cleft within spinal cord) and
abnormal gray matter differentiation have been described in affected animals [106,240, 243,244].
Clinical signs in seriously affected cats may be progressive after birth, perhaps associated with progressive
syringomyelia [14], or they may remain static in cats with a partial disability. Neurological signs include plantigrade
posture, hopping gait, pelvic limb paresis/paraplegia, fecal and urinary incontinence, and perianal sensory loss.
Urodynamic studies have shown significant abnormalities of vesiculourethral function: detrusor areflexia,
autonomous pressure response to bladder filling, a dysfunctional proximal urethra, and poor quality pelvic floor
electromyographic activity [245]. Catecholaminergic histochemical studies of the bladder and urethra have
demonstrated complete absence of adrenergic fibers, including the trigone area [245]. Myelography or MRI may
outline the meningocele or meningomyelocele, if present.
Prognosis is guarded. There is no treatment. Mildly affected animals may attain longevity if fecal and urinary
incontinence are managed. Sacrococcygeal dysgenesis may be seen sporadically in other breeds of cats and in
dogs [246], the English Bulldog in particular [247].
Spina Bifida
Spina bifida is a developmental anomaly characterized by the presence of a midline cleft in the vertebral arch of a
single or several vertebrae. The cleft may involve most of the vertebral arch or only the dorsal spinous process.
This anomaly results from failure of fusion of the halves of the dorsal spinous processes and may be
accompanied by protrusion of the spinal cord or its membranes. Spina bifida manifesta, cystica, and operta are
synonymous subclassifications indicating presence of meningocele cyst (protrusion of the spinal cord membranes
through a defect in the spinal column), myelocele (protrusion of the spinal cord) or meningomyelocele (protrusion
of the spinal cord and its membranes through a defect in the spinal column) [247]. Rarely, rachischisis (embryonic
failure of fusion of the vertebral arches and neural tube) and myeloschisis (cleft spinal cord resulting from failure
of the neural folds to close normally in the formation of the neural tube) are reported together [248]. Spina bifida
occulta is characterized by a bony defect without visible protrusion of enclosed vertebral canal structures and is
usually associated with smaller defects in the lamina. Most meningoceles and meningomyeloceles occur in the
lumbosacral area and mainly involve nerve roots and spinal nerves of the cauda equina rather than spinal cord
itself [106]. In such conditions, the meninges and their associated subarachnoid space extend through the
vertebral defect to attach to the overlying skin from which CSF may leak. Subdermal or epaxial accumulation of
CSF may also be found. As a consequence of the meningeal attachment in the meningomyelocele, abnormal
tension may be exerted on the spinal cord. This has been termed tethered cord syndrome [106,249]. The degree
of spinal cord dysfunction in tethered cord syndrome appears to be related to both the force and duration of
traction [250]. Other anomalies, such as hydrocephalus, multiple thoracic and/or sacral hemivertebrae, may also
be present in affected animals [45,247,251,252].
Myelodysplasia, especially in sacrocaudal and lower lumbar segments, consisting of gliosis, hydromyelia (dilation
of the central canal), syringomyelia (cavitations within the spinal cord), myeloschisis, or abnormal position of the
central gray matter and anomalies of dorsal and ventral horns, may occur with spina bifida. In some instances of
myelodysplasia, necrosis of dorsal horns and dorsal white columns has been observed, creating a spongiform
appearance to the parenchyma. Astrocytosis may be seen in affected white matter [253].
The embryonic pathogenesis of this anomaly is controversial: it may represent overgrowth of cells of the dorsal
neural tube that, in turn, interferes with fusion of the neural tube and vertebral arches; or the vertebral arches may
fail to fuse as a result of a neuroschistic bleb [247]. Developmental arrest and hydrodynamic theories have also
been suggested [45]. Spina bifida (involving cervical vertebrae C1 to C4) was found among multiple congenital
malformations in kittens of cats treated during gestation with griseofulvin [113]. Spina bifida/meningomyelocele
has also been observed in kittens following methylmercury and ethylenethiourea toxicity studies in pregnant
queens [163,254].
While spina bifida has been reported in a wide variety of dogs and cats [253,255-258], there is a high incidence of
this condition in young English Bulldogs [247,253] and in Manx cats with sacrocaudal dysgenesis. Spina bifida
may occur anywhere along the spinal column but is most common in the lumbar region. In some instances, the
defect can be extensive, involving most of the thoracic, lumbar, and caudal vertebrae [257]. Spina bifida is often a
subclinical condition and an incidental radiographic finding [259]. Clinical signs in animals with spina bifida usually
indicate an associated myelodysplasia or protrusion of the meninges, spinal cord or cauda equina and are usually
noticed when affected animals begin to ambulate. Signs may include pelvic limb ataxia and paresis, fecal and
urinary incontinence, perineal analgesia, and flaccid anal sphincter [247,252,260]. The analgesia may extend to
the most proximal part of the posterior surface of the thighs, to the level of the scrotum and prepuce anteriorly, in
male dogs, and to the tail caudally. The site of the bony defect may be marked by dimpling of the overlying skin,
streaming of hair coat, and palpable cavitation in the dorsal spinous process. Meningocele alone can be present
without neurological deficits [255,261]. Decreased serum and CSF chloride concentrations were documented in a
5 year old Manx cat with spina bifida associated with chloride loss through a fistulated meningomyelocele [261]. In
an 8 month old Manx-type cat with neurological deficits and CSF draining from a skin mass dorsocaudal to the
sacrum, exploratory surgery and histopathology confirmed a tethered spinal cord and an intradural lumbosacral
lipoma associated with a meningocele [262].
Plain radiographs will demonstrate abnormalities ranging from non-fusion of dorsal laminae to a cleft spinous
process; however, myelography or advanced imaging techniques (e.g., ultrasonography, CT, or MRI) may
demonstrate protrusion of spinal cord, nerve roots, and/or meninges through the sacral defect to the skin or
subcutaneous spaces [251,262,263].
Prognosis is guarded to poor, particularly when myelodysplasia is present. In some animals with a fistulated
meningocele/ meningomyelocele, surgical ligation of the meningocutaneous tract can correct problems
associated with loss of CSF [261,262] and surgical untethering may reverse some of the neurological dysfunction
caused by the tethered cord syndrome and prevent further deterioration of the motor, sensory and urinary
functions [251,262,264].
Syringomyelia and Hydromyelia

Congenital syringomyelia (cavitation of the spinal cord parenchyma) and hydromyelia (dilatation of the central
canal within the spinal cord) are relatively uncommon malformations of the spinal cord that result from incomplete
closure or development of the neural tube [259]. They may occur in isolation or together (syringomyelia) and may
be localized to a short segment of the spinal cord or along great distances. These conditions are most often seen
as primary developmental defects in association with congenital conditions such as myelodysplasia [182,185],
spina bifida, sacrocaudal dysgenesis, meningomyelocele, and other CNS malformations such as hydrocephalus,
Chiari malformations [44,78,313], occipital dysplasia [196], and Dandy-Walker syndrome [76]. Since
syringomyelia and hydromyelia may coexist in the same patient at different locations, and cannot be distinguished
with imaging, the term syringohydromyelia will be used [76,313 ].
The pathogenesis of primary syringomyelia is uncertain. It may be a hydrodynamic compensatory lesion that
occurs in some animals with hydrocephalus and increased intraventricular pressure, especially where there is an
obstruction of CSF circulation through the lateral apertures of the fourth ventricle [106,107,265]. Experimental
syringomyelia has been induced in dogs with cisternal kaolin injection [266]. The dogs had arachnoiditis,
hydrocephalus, and syringomyelia that communicated with the fourth ventricle. In a dog with spontaneous disease,
partial obstruction to CSF was found associated with cervical cord pachymeningeal fibrosis [79]. Dynamic
changes in cervical spinal cord intramedullary pressure with the neck in the flexed position have been postulated
to play an important role in syrinx growth in experimental studies using dogs [267]. Syringomyelia may also occur
secondary to edema of neoplasms, spinal cord trauma, vascular compromise, or inflammation [79,106,268].
Cervical syringomyelia with communication to the 4th ventricle has been observed in a dog with a nerve sheath
tumor involving a C6 nerve root [269]. A rare vascular malformation primarily involving thick-walled veins was
causally implicated in an 8.5 year old Lhasa apso dog with syringomyelia (the condition in this dog was
considered similar to Foix-Alajouanine syndrome in people, an angiodysgenetic necrotizing myelopathy) [146].
Obstructive hydrocephalus and malformations of the cerebellar vermis and hypoplasia of the roof of the fourth
ventricle were also present. Hydrosyringomyelia has also been described as an idiopathic condition in absence of
a primary or developmental cause [79,106,270].
Syringomyelia is considered to result from a rupture of the ependymal lining of a dilated central canal with
dissection of adjacent spinal cord parenchyma or is the result of edema collecting in the dorsal funiculi secondary
to the hydromyelia [106]. The syrinx is often found in the center of the dorsal funiculi and may expand into the
median areas of the dorsal gray columns [106]. In many cases, a communication between the syrinx and the
dilated central canal is not apparent. Accordingly, syringomyelia may be communicating or non-communicating.
The cavity may be glial-lined (e.g., by astrocytes) but is not lined by ependymal cells. Syringohydromyelia is often
prominent in the cervical cord and may communicate with the fourth ventricle [76,196,271], but also may occur in
thoracic and lumbar spinal cord segments [78,106]. It is possible that the syrinx may progressively expand,
especially through planes of structural weakness, such as the gray matter of the dorsal horns [79,106], leading to
progressive clinical signs [14,78,79]. Neuronal necrosis and chromatolysis, edema and variable fibrillary
astrocytosis in gray matter, and presence of spheroids and swollen axonal sheaths have been reported in dogs
with hydrosyringomyelia [79,106].
A review paper considering the variety of proposed mechanisms for the cause of syringomyelia states that, in the
most recent theory, syringomyelia may occur due to repeated mechanical distension of the spinal cord with
cavitation occurring from extracellular fluid accumulation within the cord. The cause of the distension and
cavitation is the pressure wave of CSF displaced from the head during arterial pulsations. Partial obstruction of
the subarachnoid space results in increased CSF velocity and decreased hydrostatic pressure of the CSF
(Venturi effect) causing a "suction effect" on the cord. The syrinx then forms where the CSF velocity is the
greatest (within the C2-C4 spinal cord segments or at the cervical-thoracic junction) [313].
Affected animals of various breeds (not including Weimaraners with myelodysplasia) range in age from 12 weeks
to 12 years. Clinical signs are variable depending on the location and severity of the syringomyelia as well as
presence or absence of other congenital CNS malformations. Cervical syringomyelia, with or without hydromyelia,
has been reported in several immature and mature dogs in conjunction with signs of paraparesis, tetraparesis,
scoliosis, torticollis, or cervical pain [78,79,145,182,196,269,271,272]. Signs of a central canal spinal cord lesion
extending to cervicothoracic cord segments may include dermatomal paresthesia over the shoulder or neck,
leading to persistent intense scratching at the shoulder or flank region, muscle atrophy of cervical epaxial muscles
and/or thoracic limb muscles, weakness, especially in thoracic limbs, and decreased spinal reflexes [77,78]. A
direct causal relationship between scoliosis and hydrosyringomyelia has been suggested via progressive
destruction of gray matter by the cavitation resulting in denervation and atrophy of epaxial muscles unilaterally
[78,79,107,145]. Mild dysphagia has been reported in one affected dog [271]. Progressive paresis, paraparesis
and pelvic limb proprioceptive deficits were reported in an 11 year old Fox Terrier dog with what was believed to
be an acquired syringomyelia localized in upper lumbar cord levels [270]. Onset of signs may be peracute [269] or
insidiously progressive over several weeks, months or years [79,271]. Weimaraners with myelodysplasia typically
do not show progressive clinical signs. Cervicothoracic syringomyelia and myelodysplasia (including
thoracolumbar cord hypoplasia), but without hydrocephalus, was observed in a 5 month old West Highland White
Terrier puppy with urinary and fecal incontinence, bunny-hopping pelvic limb gait, and mild scoliosis of the
thoracolumbar spine [182]. Syringomyelia has also been identified in animals with arachnoid cysts [8].
CSF analysis is usually normal in animals with hydrosyringomyelia; however, it should be noted that a CSF tap
led to respiratory arrest and death in one affected dog [79]. Electromyography may reveal abnormal spontaneous
potentials in cervical epaxial or thoracic limb muscles (with cervical hydrosyringomyelia). In some cases,
myelography has revealed diffuse spinal cord enlargement [76,145,270,272] and presence of contrast agent
within the central canal (canalogram) [76,79,272]. In other cases, myelography has been negative. Imaging
techniques such as CT and MRI may help outline the extent and location of the lesions [8,76,196 269-271]. The
latter is considered better for defining intraparenchymal spinal cord abnormalities [196,269,273].
The exact nature of the hydrosyringomyelia and its variable progressive or non-progressive course, as well as
possible presence of other congenital CNS malformations, make prognosis difficult to assess. At this stage of our
knowledge, prognosis is probably guarded, at best. However, successful medical, e.g., long-term prednisolone
and furosemide [8,272] or surgical treatment, including syringotomy [270] and drainage [196] have been reported.
Hydrocephalus and cervical/thoracic syringomyelia in 3 month old Japanese cat appeared to resolve following
establishment of a ventriculoperitoneal shunt [305].
Vertebral Anomalies
A wide variety of congenital developmental abnormalities of the spinal column can occur in animals, but the
majority, at least in dogs, are minor and cause no clinical signs [274]. Vertebral anomalies often result from
disruption of normal development and regression of the embryonic notochord, segmentation of mesoderm into
somites, or vascularization and ossification of the vertebrae [45,259]. The term "complex congenital vertebral
anomalies" denotes the presence of several vertebral malformations occurring in an animal.
Hemivertebra
Is a malformation that may be the result of hemimetameric displacement of somites, resulting in right and left
hemivertebrae, or it may result from altered vascularization and ossification of vertebrae. While the majority of
cases do not produce any obvious clinical signs, hemivertebra is more often associated with neurological deficits
than any other congenital vertebral anomaly . Affected animals are usually less than one year of age [275-277].
Neurological signs may result from:
a. Progressive, severe angulation of the spine, e.g., kyphosis (associated with dorsal hemivertebra), lordosis
(ventral hemivertebra), or scoliosis (most often associated with lateral hemivertebra);
b. Narrowing of the spinal canal (spinal stenosis);
c. Instability of the involved segments ultimately producing spinal cord compression;
d. Vertebral luxation or fracture at the site of hemivertebra following a sudden jump, fall or trauma.
The spinal curvatures depend on the number of involved vertebrae and degree of individual vertebral deformity
[197]. The breeds of dogs that have been reported to be most commonly affected are the "screw-tailed" breeds:
English Bulldog, French Bulldog, Pug, Pekingese, and Boston Terrier (the kinked tail is itself due to hemivertebrae
in the coccygeal region). Thoracic hemivertebra was present in a 3 month old English Bull dog with tethered cord
syndrome, spina bifida and myeloschisis, and hydrocephalus [251]. The condition has also been seen
sporadically in other breeds, e.g., West Highland White Terriers, Fox Terriers, and Yorkshire Terriers. Vertebrae
most commonly affected are in the region T7 to T9. Hemivertebra has also been reported in dogs (Rottweiler and
Pekingese) with spinal cord dysraphism [181,185] (see myelodysplasia) and in a 4 year old Beagle with an
associated arachnoid cyst [2]. Hemivertebra of the 2nd and 3rd lumbar vertebrae was present in an 8 week old
Rottweiler puppy with associated scoliosis and syringomyelia of the 2nd lumbar spinal cord segment [278].
Clinical signs may include varying degrees of pelvic limb paresis and paralysis, muscle atrophy, pain on palpation
of the spinal column, and often fecal and urinary incontinence. Radiographs show an obvious abnormality of the
spinal column affecting a single, or in some cases, several vertebrae. There is usually a marked dorsal deviation
of the thoracic or lumbar vertebral column with one or more wedge-shaped vertebral bodies. Disk spaces are
usually well preserved. The vertebral end plates are smooth and of normal thickness. Missing vertebrae may be
detected [277]. Myelography will often outline compression of the subarachnoid space over one or more of the
anomalous vertebrae. Thoracic hemivertebra has been reported as an autosomal recessive disorder in some
lines of German Shorthair Pointers [279] and has been associated with rapidly developing flaccid paraplegia in
puppies about 6 weeks of age. In these dogs, hemivertebra was found at T4, along with kyphosis (from T3 to T5),
incomplete development of end-plates at the caudal aspect of T3 and cranial aspect of T4, and misshapen dorsal
spinal processes in this region. Necropsy revealed narrowing of the vertebral canal and compression of the spinal
cord adjacent to T3, T4, and T5 vertebrae in each of the affected puppies. The parents were clinically normal and
had no phenotype characteristic of the carrier state. An association between vertebral anomalies, including
hemivertebra, and neonatal mortality has been noted in Bulldogs [276]. Note that dogs with hemivertebra often
have other vertebral malformations, such as transitional vertebrae (see below) [258].
Diagnosis of clinically significant hemivertebrae is based on age, breed, clinical history, clinical signs, radiography,
myelography, or specialized imaging techniques. In one radiographic study in Pugs, interpretation of findings was
difficult, especially in the thoracic spine due to the massive thorax and the sternum superimposing on the spine
[258]. Dogs may be treated with surgical decompression, vertebral realignment and stabilization.
Block Vertebrae
May involve vertebral bodies, arches, or the entire vertebra in any spinal region, and result from disturbed somite
segmentation [259]. Partial blocking may occur along with incomplete intervertebral disk development. While
abnormal spinal angulation can occur, block vertebrae tend to be stable and be clinically insignificant. Block
vertebrae might be confused with traumatic intervertebral disk protrusion or with fused vertebrae following
diskospondylitis, vertebral neoplasia, or vertebral fracture-luxation [197], although reactive bone associated with
these processes is not present in block vertebrae [45]. The presence of both block vertebrae and hemivertebrae
were reported in a 12 week old Rottweiler with clinical and radiographic features of severe cervical scoliosis and
mild kyphosis [280]. Apart from pain when head and neck were manipulated, no other neurological deficits were
observed. Radiographs revealed a misshapen and foreshortened C6 vertebra, while C3, C4 and C5 vertebrae
were largely fused to each other from the caudal aspect of the axis. There was marked left-right asymmetry,
normal disc spaces and articular processes were not recognized, and dorsal spinous processes were
considerably shortened. The vertebral canal did not appear to be severely compromised. Block vertebrae may
occasionally be associated with a stenotic vertebral canal [45] and have been observed in a 7 month old dog with
an intracranial arachnoid cyst [281]. Vertebral canal stenosis was noted at the C3 vertebral level in a 5 month old
Afghan Hound presented with pronounced cervical kyphosis and moderate cervical scoliosis [282]. The vertebral
defects were associated with a reduction in length and diameter of the body of C3, aplasia of the facets between
C2 and C3 vertebrae, dorsal arching of C3, duplication of the dorsal spine of C3, and rotation of C1 and C2 about
their long axis. No neurological deficits were identified.
Butterfly Vertebra
Results from persistence of the notochord or sagittal cleavage of notochord producing a sagittal cleft of the
vertebral body that extends through the body dorsoventrally. The cranial and caudal vertebral end-plates are
funnel shaped and this produces a butterfly effect when viewing a dorsovental radiograph [259]. Butterfly
vertebrae are most often detected in brachycephalic, screw-tailed breeds. This anomaly is rarely clinically
significant.
Spina bifida
Is a developmental vertebral anomaly characterized by the presence of a midline cleft in the vertebral arch of a
single or several vertebrae. The cleft may involve most of the vertebral arch or only the dorsal spinous process. It
is often an incidental finding but sometimes severe neurological signs ensue with involvement of the spinal cord
or cauda equina. There is a high incidence of spina bifida in young English Bulldogs and in Manx cats with
sacrocaudal dysgenesis.
Transitional Vertebrae
Are abnormal vertebrae occurring at cervicothoracic, thoracolumbar, lumbosacral or sacrocaudal junctions that
possess characteristics of other vertebral spinal regions, e.g. a rib present on the transverse process of C7 or a
transverse process present on the first sacral vertebra [197]. Only the transitional lumbosacral vertebral
anomalies appear to be clinically significant, presumably by affecting the size, shape, and plane of the vertebral
body, vertebral canal, and intervertebral disk [14,197,283]. Transitional lumbosacral vertebral anomalies are
considered to be inherited in German Shepherd dogs and a possible cause of cauda equina syndrome associated
with degenerative lumbosacral stenosis [284,285]. The anomaly is characterized by separation of the first sacral
segment, identified on the lateral view by the presence of a radiolucent disc space between what are normally the
first and second sacral segments. On the ventrodorsal view, the anomaly is characterized by separation of the
spinous processes between what are normally the first and second sacral segments. It is hypothesized that in the
presence of the transitional segment, the sacroiliac joint at the level of the anomaly is weakened leading to
instability, spinal canal stenosis and intervertebral disk degeneration [284]. Lumbosacral transitional vertebra has
also been reported in a 3 month old Chihuahua puppy with thoracic limb malformations but without neurological
signs [286]. Transitional vertebrae were also one of several subclinical CT abnormalities found in the lumbosacral
spine of older large- breed dogs [287].
Scoliosis
As mentioned above, may develop in animals with hemivertebra. It also occurs in cats with hypervitaminosis A.
The important association between developmental anomalies of the spinal cord, including Weimaraners with
spinal dysraphism/myelodysplasia, and vertebral anomalies such as scoliosis has been previously noted
[172,288]. In particular, there are increasing reports of scoliosis occurring in animals with congenital or acquired
cystic lesions involving the spinal cord, especially with cervical hydrosyringomyelia (see syringomyelia and
hydromyelia), in which the spinal curvature often presents clinically as torticollis [78,79,145,271]. A direct causal
relationship between scoliosis and hydrosyringomyelia has been suggested via progressive destruction of gray
matter by the hydrosyringomyelic cavitation resulting in denervation and atrophy of epaxial muscles unilaterally,
followed by asymmetrical lateral muscle tension and subsequent vertebral deviation [78,79,145]. Unilateral
epaxial cervical muscle spasms may also play a role in the scoliosis [145]. Because of this relationship, it has
been suggested that the observation of scoliosis and cervical pain in an animal may be the first clinical sign of
hydrosyringomyelia [145]. Mid-lumbar scoliosis and mild kyphosis has also been reported in a dog with an
arachnoid cyst at T11 - T13 vertebral levels [18]. The focal point of the scoliosis was at L1 - L2. Denervation
atrophy was present in the paraspinal epaxial muscles at this level, presumably secondary to the cyst. The cranial
endplate of L1 and the articular facets of L1 - L2 were malformed. Thoracolumbar scoliosis has been reported in
association with severe myelodysplastic hypoplasia of the thoracolumbar spinal cord in a 5 month old West
Highland White Terrier, with accompanying cervicothoracic cord hydrosyringomyelia [182]. The scoliosis in this
case may have been the result of asymmetric denervation atrophy of the paravertebral muscles associated with
the localized myelodysplasia in the caudal thoracic cord segments.
Stenosis of the Vertebral Canal

May occur with congenital vertebral anomalies, especially in animals with hemivertebrae and block vertebrae (see
above), and may be focal, segmental or generalized throughout the vertebral column [45]. A segmental stenosis
in the cranial thoracic spine (T3 - T6) of Doberman Pinschers (mainly mature but occasionally, immature dogs)
has been reported, sometimes in association with mild lordosis and kyphosis, but usually without clinical spinal
cord compression [45]. Most of these cases were incidental findings in dogs being investigated for cervical
spondylomyelopathy (Dr. C.S. Bailey, University of California, Davis, personal communication, 2001), a condition
in which stenosis of the cervical vertebral canal seems to be a developmental anomaly. Focal vertebral canal
stenosis due to malformation of the vertebral lamina of T12 and cranial portion of T13, with associated spinal cord
compression and progressive hindlimb paresis, has been reported in a 3 month old Basset Hound [289].
Myelographic studies may help confirm focal vertebral stenosis in animals with signs commensurate with spinal
cord compression [45,289,290]; however note that not all animals with vertebral anomalies have spinal cord
compression at the site of spinal deformity [290]. Routine decompressive surgery is indicated in cases with clinical
signs of spinal cord compression [45,290]. Lumbosacral stenosis of the vertebral canal is sometimes seen in
young animals as a developmental anomaly [291]. Cervical stenosis may be seen in developmental
malformations of the axis and/or atlas resulting in instability of the atlantoaxial joint and potential attenuation of the
upper cervical spinal cord (see atlantoaxial subluxation). Some animals with odontoid process malformations also
have a malformed atlas or occipital dysplasia.
Miscellaneous Developmental Disorders

Caudal vertebral malformations occur in Scottish Fold cats (immature and mature) with short, thick, inflexible tails,
including shortened vertebrae with enlarged bony vertebral endplates, reduced vertebral spaces and new bone
formation tending towards ankylosis of adjacent vertebrae [292]. This osteochondrodysplastic condition appears
to be inherited as an autosomal recessive trait. Signs of pain and gait abnormalities are typically orthopedic rather
than neurological. A monolateral hippocampal cortical hamartia characterized by pyramidal cells arranged in a
gyrus-like pattern and intermingled with gemistocytic and fibrillary astrocytes was an incidental finding in a 4 year
old Pekingese dog with encephalitis [310].
Degenerative and Compressive Structural Disorders
K. G. Braund
In this chapter we will review a variety of neurological disorders that result from abnormalities of bones, ligaments,
and other mesenchymal tissue that compress the nervous system. Most of these conditions are degenerative in
nature, although some represent developmental disorders. The spinal cord and occasionally nerve roots are the
nervous tissues most commonly compressed. One condition, disk disease, represents the most common cause of
spinal cord compression in dogs.
Calcinosis Circumscripta/tumoral Calcinosis

Cervical Spondylomyelopathy
Disk Disease
Diskospondylitis
Dural Ossification
Lumbosacral Stenosis
Spinal Synovial Cysts
Spondylosis Deformans
Miscellaneous Disorders
Calcinosis Circumscripta/tumoral Calcinosis

Focal nodular aggregations of ectopic calcification occurring in the soft tissues have been referred to by several
synonyms that include calcinosis circumscripta, apocrine cystic calcinosis, tumoral lipocalcinosis, lipocalcinosis,
calcium gout and tumoral calcinosis. In man [1,2] the term calcinosis circumscripta is used to distinguish between
those generally smaller nodular calcareous lesions occurring in the skin, subcutaneous sites and skeletal muscle
and those histologically similar but often larger multinodular lesions of tumoral calcinosis occurring in the deep
peri-articular sites, i.e. soft tissues located adjacent to joints. This nomenclature is beginning to be more
commonly accepted to describe similar distribution patterns of nodular deposits of ectopic calcification in animals
[3-5].
In the veterinary literature calcinosis circumscripta and tumoral calcinosis have been used as synonyms to
describe histologically similar idiopathic conditions characterized by the formation of circumscribed single or
multiple nodular masses due to deposition of calcinous material, located either in periarticular connective tissue or
in cutaneous tissues over pressure points and bony prominences, in footpads, or in the mouth [6-11]. Etiology and
pathogenesis remain obscure. Most reports involve dogs, but the condition has occasionally been seen in cats
[12]. Concurrent illness is usually not associated with the different patterns of nodular ectopic mineralization in
animals; however, some animals may have underlying renal disease [4-6,13,14]. The prevalence of the condition
in young large-breed dogs, particularly German Shepherds, Great Danes and Viszlas, suggests possible
hereditary predilection. Calcinosis circumscripta has occasionally been seen following surgical procedures, use of
polydioxanone suture material, and progestin (medroxyprogesterone acetate) injections in dogs and cats [15-19].
Calcinosis circumscripta-like lesions have also been reported in dogs associated with the use of choke chains [20].
The pattern of deposition referred to as tumoral calcinosis usually does not directly involve bones or joints [4,8,11].
Clinical signs include one or more hard or fluctuant, spherical, well-circumscribed, non-painful subcutaneous
masses [8]. When incised, the masses discharge a chalk-like material. Histopathologically, the masses are
characterized by lobular areas of mineralization and degeneration in a fibrous, collagenous matrix with large
foamy macrophages, giant cells, lymphocytes, and neutrophils. Some calcific foci are embedded by osseous
tissue [4,8]. The mineralized material stains positively for calcium, phosphorus, carbonates and hydroxyapatite
crystals. The ground substance stains positive for acid mucopolysaccharides (glycosaminoglycans). The
crystalline structures can be identified using scanning electron microscopy [21]. The heterotopic ossification seen
in a 7 year old German Shepherd with fibrodysplasia ossificans may have resulted from the metaplastic change of
calcinosis circumscripta lesions [22]. In this dog, several mineralized densities were seen radiographically
ventrolateral to the lateral processes of the 6th cervical vertebra.
There have been several reports of calcinosis circumscripta/tumoral calcinosis (CC-TC) causing spinal cord
compression in young dogs (usually less than 1 year of age) in several breeds including Bernese Mountain dog,
German Shepherd, English Springer Spaniel, Rottweiler, and Great Dane [23-26]. With the exception of upper
thoracic cord compression (T2 - T3) in two littermate German Shepherd puppies [25], all CC-TC masses resulting
in spinal cord compression have been localized at the atlantoaxial articulation [23,24,26,27], often in the area of
atlantoaxial ligament. The focal calcified masses are usually found lying over the spinal cord in the space between
the caudal aspect of the dorsal arch of the atlas and the cranial edge of the spinous process of the axis, and
extending into the vertebral canal. In the report involving the two young German Shepherd littermates [25], a
solitary mineralized mass was found on the dorsal laminae between the dorsal spines of T2 and T3 and impinged
ventrally on the intervertebral foramina. The mass projected above the articular facets between the dorsal spinous
processes. Hematological and biochemical analysis of blood samples from affected animals are within normal
limits, as is cerebrospinal fluid (CSF) evaluation. Clinical signs of CC-TC will reflect either a cervical syndrome or
a thoracolumbar syndrome. Myelography will confirm spinal cord compression associated with these masses.
Special imaging, such as computed tomography and computed tomographic myelography , may provide
additional information on the extent of the mass and on the degree of spinal cord compression [26]. In the cases
of CC-TC reported to date with spinal cord compression, the initiating mineralized mass lesion was the only lesion
observed radiographically. There has been a report of unilateral and bilateral mineralized masses associated with
the deep tendinous attachments on the lateral processes of the caudal cervical vertebrae [28]. In this report, the
masses occurred in three related Great Dane puppies (around 5 to 6 months of age) but were non-clinical and
only of cosmetic significance. Surgical removal of CT-TC masses in dogs with spinal cord compression is the
treatment of choice and prognosis is favorable.
Reports of solitary cartilaginous exostoses in three young, large breed dogs (Rottweiler, Bernese Mountain dog,
and St. Bernard), from 3.5 to 5 months of age [29], as well as in a 3.5 year old Bernese Mountain dog [30], may
actually be further examples of CC-TC, or, at least variants. In each case, solitary, partially calcified lesions were
localized to the atlantoaxial articulation and caused tetraparesis from spinal cord compression. The radiographic
features appear identical to those described for CC-TC, including thickening of the dorsal arch of the atlas and
malformation and shortening of the spinous process of the axis [23,26,29,30]. The histopathological features of
the masses, however, appear to be different from those reported in CC-TC [5]. Surgical removal of the mass was
successfully achieved in the older dog [30].
Note: I thank Dr. Roy Pool, Mississippi State University, for his valuable comments on this condition.
Cervical Spondylomyelopathy
Cervical spondylomyelopathy is a neurological disorder affecting Doberman Pinschers, Great Danes and other
large and medium-sized breeds in which abnormalities of the cervical spine cause compression of the spinal cord
[31]. Synonyms include wobbler syndrome, cervical malformation-malarticulation, cervical vertebral instability,
cervical vertebral malformation, vertebral subluxation, cervical spondylolisthesis, cervical stenosis, caudal cervical
spondylomyelopathy, and cervical spondylopathy. Approximately 80% of cases occur in Great Dane and
Doberman Pinscher dogs and lesions are generally confined to the caudal cervical spine (i.e., C5 to C7). The age
of onset of clinical signs is variable, ranging from 3 months to 9 years. In general, Great Danes are affected less
than 2 years of age, while Doberman Pinschers more frequently manifest signs when 2 years of age or older, with
a clinical incidence peak between 4 and 8 years [32-34]. Several reports suggest male dogs are more commonly
affected [35,36], although no gender predilection was revealed in one study involving 170 dogs [32]. Cervical
spondylomyelopathy appears to involve both bony, fibrocartilaginous, and ligamentous abnormalities of the
caudal cervical spine.
These include:
a. Chronic degenerative disk disease,

b. Congenital bony malformation (stenosis of the vertebral canal and abnormal articulation of the articular
facets),
c. Vertebral instability or "tipping",
d. "Hourglass" compression by the dorsal (ligamentum flavum) and ventral (dorsal longitudinal ligament and
dorsal annulus fibrosus) ligaments, and
e. Hypertrophy of the ligamentum flavum. These changes, occurring alone or in combination, can result in
caudal cervical spinal cord compression [32].
The cause of cervical spondylomyelopathy remains uncertain but it may be multifactorial. Some authors consider
the disease to be a developmental malformation-malarticulation disorder [35,37,274]. Hereditary factors have
been suggested [38,39]. A possible familial trait was suggested for affected Dobermans in New Zealand [32].
Other reports failed to find support for a genetic basis, although recognizing the problem was more prevalent in
certain lines of Dobermans [33,35]. Nutritional status has been implicated, including a hypercalorific diet and
calcium excess in rapidly growing dogs [40-42], yet cervical spondylomyelopathy does occur in animals reared on
a balanced diet [33]. The impact of conformation, such as longer neck and heavier head in affected dogs [42]
playing a biomechanical role in this disease, was not confirmed in one study in which radiographic changes were
independent of several body dimensions measured [32]. Interestingly, there was a positive correlation between
longer rump length and increased risk of neurological disease in this study. Cervical trauma from use of a choker
chain was not found to influence the presence of the disease [32].
Clinical signs are related to the severity of spinal cord compression and therefore are variable in nature and
degree. Clinical signs usually are first noticed in pelvic limbs. Eventually, all four limbs are affected, with signs
often being more pronounced in the pelvic limbs. There is ambulatory tetraparesis with the thoracic limbs moving
in a short, choppy manner. The neck is often carried in flexion. There may be varying degrees of atrophy of
infraspinatus and supraspinatus muscles. An affected animal can have difficulty rising from lateral recumbency or
from a sitting position. The digits may knuckle when the animal walks and nails are often worn excessively as a
result of scuffing and dragging. Most dogs have a conscious proprioceptive deficit and demonstrate a wide-based
stance. Sometimes pain may be elicited upon neck manipulation. Clinical signs tend to be slowly progressive but
can be abrupt in onset when external trauma is suspected as playing a major precipitating role. A Horner's
syndrome may be present, perhaps more often in dogs with severely herniated intervertebral disks, especially at
the C6 - C7 region [35].
Diagnosis is based on historical data, signalment, clinical data, and radiography. Most dogs have the following
radiographic abnormalities [43]:
a. Tipping of the craniodorsal aspect of the vertebral body into the spinal canal which may be exaggerated
by neck flexion;
b. Stenosis of the vertebral canal, especially at the cranial aspect of the vertebrae. Normal and abnormal
values for vertebral canal dimensions have been established [32,44,275];
c. Malformations of the vertebral bodies (see below);
d. Narrowed disk spaces, often with accompanying spondylosis deformans; and
e. Degenerative changes in the articular facets. These changes may be seen radiographically, alone or in
combination.
In adult dogs, the most important abnormalities seen using survey radiography are narrowed intervertebral disk
space, vertebral malalignment (e.g., tilting or subluxation), ventral spondylosis deformans, and a misshapen
vertebral body [31,35,45]. Vertebral tilting and coning of the vertebral canal with stenosis of the cranial orifice is
primarily recognized in dogs less than 1 year of age [31,32]. Vertebral changes may be seen radiographically in
puppies as early as 3 months of age [32] and the observation of normal radiographic appearance of cervical
vertebrae at 6 weeks of age in one of these puppies suggested the possibility of vertebral deformity occurring
between the ages of 6 and 12 weeks.
Many animals have more than one site of compression, which may not be apparent on survey radiography. In one
study, plain films were inaccurate in 18 of 45 dogs (40%) [46]. Therefore, myelography is essential to establish an
accurate diagnosis and prognosis, especially if surgery is to be considered. Conventional myelography is
considered the technique of choice for initial evaluation of dogs with cervical spondylomyelopathy since it
provides an image of the entire cervical spine [47].
Furthermore, myelographic studies may reveal various types of extradural spinal cord compression:
a. Dorsal compression associated with hypertrophied ligamentum flavum;

b. Ventral compression from a bulging/hypertrophied annulus fibrosus;
c. Lateral compression from malformation of articular facets;
d. Compression from a stenotic vertebral canal or vertebral instability associated with vertebral tipping [43].
Some clinicians are advocates of stress radiography/myelography (i.e., use of flexion, extension, or traction of the
cervical vertebrae) in order to better define the nature of the compressive lesion (dynamic versus static) and
better define the subsequent treatment. The measurement of "stepping" of the vertebral floor of cervical vertebrae
when the neck is flexed has diagnostic significance [33]. However, complications may follow stress radiography.
Hyperflexion of the neck may exacerbate cord compression caused by vertebral tipping and neck hyperextension
may aggravate cord compression by closing the dorsal aspect of the intervertebral disk space which can force
additional disk material (nucleus pulposus and/or annulus fibrosus) into the spinal canal. Neck hyperextension
may also worsen pre-existing compression from the ligamentum flavum [43] (it remains to be proved whether or
not the apparent increase in cervical hyperextension in the Doberman Pinscher breed as a whole, between 1934
and 1972, has a role in cervical spondylomyelopathy [47]). Conversely, with soft tissue lesions, traction on the
cervical spine will often reduce the degree of cord compression by stretching or flattening redundant annulus
fibrosus and ligamentous structures [31,46]. While non-contrast and intravenous contrast-enhanced computed
tomography appears to have little advantage over conventional myelography in cervical spondylomyelopathy [47],
other specialized imaging techniques may also play an important diagnostic role, e.g., computed tomography-
myelography may provide more information than conventional myelography as to the exact nature and degree of
compression, particularly in cases of severe spinal cord atrophy [47].
Gross pathologic findings include stenosis of the rostral end of the involved vertebrae, unstable vertebrae
associated with flattened, expanded and elongated articular facets, and hyperplasia of the dorsal annulus fibrosus
and ligamentum flavum in young animals. The abnormal relationship of one vertebra to another may result in
static or dynamic cord compression. Similar changes occur in older animals along with degenerative lesions
affecting the articular facets including osteophyte formation, sometimes with encroachment onto the spinal cord
[48]. In older dogs, the fibers of the dorsal annulus fibrosus of the intervertebral disk appear hypertrophic or
hyperplastic and may be partially or totally ruptured, with disk material extruded up beneath the dorsal annulus,
although herniated disk material into the vertebral canal is infrequent. The nucleus pulposus may show
degenerative changes and can be mineralized [35]. Disks at C5 - 6 and C6 - 7 are most frequently affected
[33,35,49]. In both young and older dogs, gross vertebral deformity may be found, often involving C6 and/or C7 in
Dobermans and Great Danes [33,35,50]. The deformity can vary from rounding off of the cranioventral epiphysis
to its total loss producing a triangular wedge-shape. Redundant ligamentum flavum resulting in dorsal cord
compression is reported in Great Danes [46]. Similarly, the above-mentioned hourglass compression by dorsal
and ventral ligaments as well as joint capsule of the facets, is seen principally in Great Danes [31]. In the spinal
cord, varying degrees of compression and spinal cord atrophy may be present. Degenerative changes
characterized by white and gray matter necrosis, neuronal loss, and cavitation may be seen at the site of spinal
cord compression. At this level, lesions may be seen in all funiculi. Wallerian-like degeneration of white matter is
seen above (e.g., ascending tracts in the dorsal funiculi and more superficial portions of dorsolateral funiculi) and
below (e.g., descending tracts in ventral and deeper portions of lateral funiculi ) the compressive lesion [37].
Myelin degeneration is often more predominant than axonal degeneration. Arachnoid fibrosis is not uncommon.
Prognosis for spontaneous recovery is poor. In mildly affected cases, conservative treatment may sometimes be
beneficial over a 4 to 6 week period. This includes strict confinement, neck brace to immobilize the caudal cervical
spine, and anti-inflammatory medication. However, long-term conservative therapy tends to be palliative [49].
Marked improvement has been reported in many cases following decompressive and/or stabilizing surgery.
A plethora of reports are available on surgical treatment that generally falls into three categories:
a. Dorsal laminectromy for bony compression,

b. Ventral slot decompression, which is especially useful for ventral soft tissue compressions that are not
traction-responsive (such as annular protrusions or nuclear extrusions), and
c. Distraction or ventral slot decompression for traction-responsive soft tissue compressions [34,51-58].
Distraction may be achieved with vertebral body pins/screws and bone cement, distraction rods, or
intervertebral washers, often in association with bone grafts in order to encourage vertebral fusion
[31,52,59].
The choice of surgical technique will vary according to the location of spinal cord compression (ventral, dorsal, or
lateral), the nature of the compression (soft tissue or bony), and whether or not the lesion is single or multiple: up
to 30% of cases in mature Dobermans may have multiple protrusions of the annulus fibrosus [34,53]. The most
common lesions are ventrally located, involve soft tissue, and tend to be traction-responsive [31,46]. All surgical
procedures have a high potential for morbidity and post-operative complications, which include infection, implant
failure, and additional disk protrusions ("domino effect") in disks adjacent to fused or immobilized segments
[49,53,60]. It has been reported that short-term success rates are high (approximately 80 per cent) after any of
the surgical procedures, but there is a high rate of recurrence (around 20 per cent) [276]. Iatrogenic Horner’s
syndrome has been reported associated with cervical surgery, presumably due to traumatic stretching of
preganglionic pathways in the thoracic vagosympathetic trunk within the carotid sheath [61]. Furthermore,
neurological signs may be more pronounced the day following myelography in dogs with cervical
spondylomyelopathy [62]. Non-ambulatory patients require special care and intensive nursing (see spinal trauma)
for bladder control and prevention of urine scald and decubital ulcers. Physical therapy (see rehabilitation) is
extremely important to combat disuse and neurogenic muscle atrophy [49,63]. One suggested prognostic guide is
as follows [64]:
1. Favorable - If there is one lesion and the dog is ambulatory upon presentation;
2. Favorable to guarded - If there are two lesions and the dog is ambulatory upon presentation;
3. Guarded - If there is one lesion and the dog is non-ambulatory upon presentation;
4. Guarded to unfavorable - If there are two lesions and the dog is non-ambulatory upon presentation.
The demonstration of spinal cord atrophy and/or pooling of contrast material within the spinal cord in computed
tomography-myelographic studies may also suggest a guarded to unfavorable prognosis in dogs with cervical
spondylomyelopathy [47].
Control measures might include identifying Dobermans with radiographic features of cranial canal stenosis,
vertebral tipping, and "stepping" of the cervical vertebrae once skeletal maturity has been reached and removing
them from any breeding program since these identifiable abnormalities offer a reasonably accurate
prognostication for future development of cervical spondylomyelopathy in this breed [33]. Additionally, use of
balanced rations without excessive nutrition or mineral supplementation and perhaps neutering larger, faster-
growing puppies might be considered [33]. Cervical vertebral ratios may have potential as a breed-specific
screening tool for cervical vertebral instability [275].
There have been isolated reports of a similar wobbler syndrome in other canine breeds including Rhodesian
Ridgeback, Old English Sheepdog, Weimaraner, German Shepherd, Chow Chow, Rottweiler, Pyrenean Mountain
Dog, Golden Retriever, Labrador Retriever, Boxer, Irish Wolfhound, St. Bernard, Airedale Terrier, Bernese
Mountain Dog, Bull Mastiff, English Setter, Irish Deerhound, and Old English Mastiff. In these breeds, the
predominant sites of cord compression were C2 - C3 and/or C3 - C4 [35]. A possible hereditary malformation of
C2 - C3 vertebrae occurs in Basset Hounds less than 8 months of age [65]. Involvement of the C2 - C3
articulation has been noted in Beagles [35].
The wobbler condition has also been reported in older female Borzoi dogs (from 5 to 8 years) [66]. The condition
is believed to have a recessive mode of inheritance. The C6 - C7 articulation was always involved in a spectrum
of abnormalities that included vertebral instability, vertebral luxation, intervertebral disk herniation, and spinal cord
compression.
Disk Disease
Spinal cord compression secondary to intervertebral disk protrusion-extrusion continues to be one of the most
common neurological disorders seen in clinical practice [67]. Terms used for this disorder include ruptured disk,
prolapsed disk, slipped disk and herniated disk. Disk protrusion-extrusion more accurately describes this process.
Protrusion implies that the disk is bulging into the vertebral canal as a result of dorsal shifting of central nuclear
material. The outer fibrous envelope of the disk is still intact. Disk extrusion indicates that the outer fibrous layers
have ruptured with subsequent extrusion of nuclear material into the vertebral canal. The clinical expression of
disk extrusion is referred to as disk disease. The term intervertebral disk displacement is presently in vogue as
another descriptor of disk disease.
There are 26 intervertebral disks in the canine and feline spinal column, excluding the coccygeal region, and they
form approximately 18% of the length of the spine. Disks are widest in the cervical and lumbar regions, and
narrowest in the thoracic spine. Each disk consists of two structurally different regions: (a) a central gelatinous
area, the nucleus pulposus (NP), and (b) a surrounding fibrous envelope, the annulus fibrosus (AF), which
contains an inner, more fibrocartilaginous matrix termed the "transitional zone" (TZ) [68-71]. The NP is oval-
shaped and eccentrically positioned between the middle and dorsal thirds of the disk. It is a highly specialized
tissue originating from the embryonic notochord. Throughout fetal life, the NP is the fastest growing region of the
disk, and in the neonate, it occupies a considerable area of the disk. The AF is a fibrocartilaginous tissue
consisting of bands of parallel fibrous bundles that run obliquely between adjacent vertebrae. The ventral annulus
is about twice as wide as the dorsal annulus. Biochemically, the major macromolecular components of the canine
disk include collagenous and non-collagenous protein (NCP), proteoglycan (PG) aggregates, and glycoproteins.
The PG subunits consist of glycosaminoglycans (GAGs) covalently bound to a central protein core. The main
GAGs in canine intervertebral disks are hyaluronic acid, chondroitin sulfate-4, chondroitin sulfate-6, and keratan
sulfate. Higher orders of aggregation intimately involve hyaluronic acid. Aggregated PGs are formed by the
association of many PG molecules with a single chain of hyaluronic acid, the complex being stabilized by a
glycoprotein link. The GAGs are long-chained, sulfated polyanions that attach to the central protein core like the
bristles of a brush.The greatest concentration of the GAGs in disk occur in NP and TZ regions of the disk.
Structures that are anatomically and physiologically closely related to disks include cartilaginous end-plates,
vertebral end-plates, and conjugal and dorsal longitudinal ligaments. Conjugal ligaments, also known as
transverse intercapital ligaments, are present between the second and tenth thoracic vertebral bodies in dogs,
and between the second and ninth thoracic vertebral bodies in cats. Conjugal ligaments run over the dorsal part
of the disk, ventral to the dorsal longitudinal ligament (a flat structure that lines the floor of the vertebral canal),
and connect the heads of each set of ribs. The conjugal ligaments play an important role in the prevention of disk
extrusion into the vertebral canal in the thoracic region. Dorsal longitudinal ligaments run the length of the
vertebral canal, are attached to the dorsal borders of the vertebral bodies and form fan-like coverings over the
dorsal aspects of each disk. Stretch of this ligament is thought to partially account for pain associated with disk
protrusion-extrusion. Cartilaginous end-plates are thin layers of hyaline cartilage that cover vertebral body
epiphyses and form the rostral and caudal boundaries of each disk. Vertebrae on either side of the disk have a
specialized plate of dense, smooth bone termed the vertebral end-plate. These plates are perforated by
numerous small canals that are related to the underlying marrow spaces. Each plate consists of an outer
peripheral zone and an inner zone that accommodates the NP region of the disk.
Intervertebral disks function as very effective shock absorbers of the vertebral column, largely due to the gel-like
properties of the central NP. Specialized PGs within the nucleus bind many water molecules to form a fluid
system that is virtually incompressible. This hydrophilic property allows the nucleus to deform and dissipate forces
equally over the AF and cartilaginous end-plates. The transformation of an axial compressive force applied to the
spine into tangential stresses on the annulus is the function of the NP, thereby reducing the compressive force on
the annulus itself. Disks also provide support for the spinal column, since they represent amphiarthrodial joints in
intervertebral articulations.
After birth, the canine disk undergoes structural changes that are most prominent in the NP [71-73]. The gel-like
nucleus is eventually replaced by more mature fibrocartilage. This process occurs gradually in most breeds of
dogs, so that by 7 to 8 years of age, the entire nucleus has changed, and the distinction between nucleus and
annulus is lost. In several other breeds of dogs, however, the aging pattern is quite different. These breeds have
been designated chondrodystrophoid due to their characteristic endochondral ossification and intervertebral disk
morphology, and include Dachshunds, Beagles, Pekingese, French Bulldogs, Basset Hounds, Welsh Corgis and
Cocker Spaniels [70,71]. Such breeds are characterized by varying degrees of short-limbed dwarfism. Other
breeds such as Shih-tzus and Lhasa apsos probably should also be included in this group. In chondrodystrophoid
breeds, replacement of notochordal cells and the gelatinous NP occurs as early as 4 months of age. This process
is generally complete in all disks by 12 to 18 months of age. The central areas of the NP are usually the last to be
affected, and extensive degenerative changes frequently precede the final chondrification of this area. With
increasing age, degenerative changes observed in the NP include matrix disintegration, peripheral/central
calcification, and localized areas of cell death. Radial fissures and clefts may appear in the AF. Commensurate
with the morphologic transmutation of the NP, collagen levels approach 30 - 40% dry weight within 6 - 12 months.
Extraordinary changes in all other biochemical parameters occur during the first 2 to 3 years [74-76]. In
comparison with disks from non-chondrodystrophoid animals of similar age, PG levels in NP are 40 - 50% lower,
glycoprotein and non-collagenous protein values are 30 - 40% lower, and chondroitin sulfate values are 30 - 50%
lower. Also, during this period, keratan sulfate replaces chondroitin sulfate(s) as the major GAG. The degree of
hydration of disks likely decreases with reduction in GAG content, as has been shown in people. Degenerated
disks have a depressed imbibition index, which is a measure of the water-binding capacity of the disk.
The etiology of intervertebral disk protrusion-extrusion remains elusive. It is hypothesized that significant changes
in morphology and biochemical parameters of the disk during the first 2 years of life result in a reduction of the
disk's shock absorbing mechanisms [68,69]. While still retaining limited properties of incompressibility, the NP
loses its ability to adequately deform and distribute forces in a centrifugal manner. As a result, the AF is subjected
to increased loading from axial compression and lower tangential stress, which is disproportionately distributed in
the disordered disk. The mechanical failure of the NP ultimately results in disruption of AF fibers and subsequent
protrusion-extrusion. Results of biochemical studies suggest that the mechanical efficiency of disks is
compromised in chondrodystrophoid dogs by 2 to 3 years of age [74-76]. This time-frame is consistent with the
occurrence of clinical disease. Nevertheless, this theory does not explain why clinical disk disease occurs with a
relatively high frequency in some non-chondrodystrophoid breeds, such as Miniature Poodles and mixed-breeds;
nor does it elucidate why clinical disk disease occurs infrequently in older dogs of any breed. Studies in dogs
have shown that disk metabolism in the NP is mainly anaerobic, the main route of nutrient supply into the NP is
via the endplate, and that diffusion of nutrients is the main mechanism of metabolite transport [77]. There is
probably an optimal, but as yet undefined, range of vertebral stress that is needed to promote and maintain
nutritive requirements of disks. Half an hour of moderate exercise per day has been shown to increase nutrient
flow into canine disks [78]. In contrast, spinal fusion in the dog results in significant biochemical changes in disks-
metabolism is depressed in the immobilized disks but increased in the disks adjacent to the fusion mass [79]. In
addition, water content and imbibition of water in NP and AF are significantly depressed in fused disks. That disk
displacement occurs with some frequency in disks adjacent to totally calcified disks may also reflect an
overstressed disk. Finally, it is conceivable that loss of PGs and mechanical failure of the NP profoundly influence
disk nutrition. Whether disk matrix changes are the cause or the effect of nutritional diffusion impairment remains
to be determined.
There is no evidence that external trauma plays a role in disk degeneration. A force of sufficient magnitude to
result in spinal fractures and/or luxations rarely produces traumatic disk protrusion-extrusion. Nevertheless,
trauma has been implicated in several large-breed, non-chondrodystrophoid dogs in which tearing of the dural
mater secondary to intervertebral disk injury occurred during periods of vigorous running and or struggling [80].
Although trauma does not appear to play a role in the initiation of disk degeneration per se, it may be a factor in
the precipitation of protrusion-extrusion once the normal mechanical efficiency of the disk is impaired. It is not
unusual for dogs with clinical disk disease to be presented with a history of spinal trauma of variable degree, such
as jumping or falling. Perhaps the most logical explanation for the prevalence of disk disease in certain breeds of
dogs is a genetic one. Earlier studies suggested that genetic factors are involved in the accelerated aging
patterns of disks in Beagles [81]. The heightened susceptibility to disk disease in Dachshunds has been explained
by a genetic model that involves the cumulative effect of several genes, with no dominance or sex linkage, subject
to environmental modification [82]. In some families of Dachshunds, the prevalence of disk disease was found to
be 62%, compared with the estimated breed prevalence of 19%. %. Genetic osteological factors probably play a
role as well. For example, midsagittal and interpedicular diameters of the cranial and caudal aspects of cervical
vertebral foramina (C3 - C7) are reportedly significantly larger in small breeds than in large breeds and
Dachshunds, with seemingly potential predisposition to cervical spinal cord compression [274]. There is no
evidence that autoimmune mechanisms are a factor in the pathogenesis of disk degeneration. The roles of
inactivity and obesity in disk disease have not been fully evaluated, although in one study, excess body weight did
not appear to be a predisposing factor in Cocker Spaniels with disk disease [83].
Neurological signs after extrusion of disk material are caused by impact injury [84], or mechanical compression of
the spinal cord [85], or both. While disk protrusion usually precedes extrusion, protrusion or bulging of the disk
dorsally into the vertebral canal without rupture of the AF is not usually associated with clinical signs, with the
possible exception of pain. This is exemplified in dogs and cats over 7 years of age in which dorsal disk protrusion
is relatively common but is subclinical. The velocity with which the disk material extrudes into the canal appears to
be more important than the size of the mass. An explosive herniation results in far more severe damage than a
slow extrusion. With acute impact injuries, hemorrhage and attendant inflammatory reaction may also contribute
to epidural compression. Results of a quantitative radiographic study [86] suggest that the lumbar epidural space
in Dachshunds is less than that in German Shepherds (a non-chondrodystrophoid breed) which implies that
epidural masses of similar size would cause more spinal cord compression and more severe neurological deficits
in Dachshunds. For a review of the pathophysiological events and biochemical cascade occurring with acute
trauma to the spinal cord see spinal cord trauma.
Most dogs with disk disease are between 3 and 7 years of age. Eighty-five percent of disk extrusions in dogs
occur in the thoracolumbar area and 15% are cervical. Approximately 80% of thoracolumbar extrusions occur
between T11 and L3, with less than 2% occurring in the terminal lumbar region (L5 - S1). In one study of large-
breed, non-chondrodystrophoid dogs with thoracolumbar disk disease, the mean age was approximately 7 years,
and 57 dogs (92%) had Hansen type 1 disk disease, usually at the L1 - L2 site [87]. In this report, 58% of cases
were acute in onset. Disk extrusion normally does not occur between T2 and T10, probably because of the
presence of the conjugal ligament, although a Hansen type 1 disk extrusion has been reported at the T1 - T2 level
in a 7 year old Dachshund with acute neurological deficits to the hind limbs following trauma [88]. Several studies
indicate that the most common site in the cervical region is C2 - 3 [89,90]; although results of one study (105
cases) indicated no significant difference in prevalence of disk disease affecting the first four disk spaces (C2 - 3
to C5 - 6) [91] (in this study, prevalence of disk disease at C7 - T1 was significantly less than that involving the
first 4 disk spaces).
Disk disease also occurs in cats but mainly as a subclinical event [89]. One study on clinically normal cats
showed that degenerative changes in disks increased with age, with dorsal protrusions found in 30% of cats 6 to
10 years of age, in 50% of cats 11 to 14 years of age, and in all cats 15 years of age and older [92]. In another
report, type I disk protrusion in cats, again as a subclincial condition, was encountered most commonly in upper
cervical and L4 - L5 areas [93]. Nevertheless, clinical signs of disk disease have been reported sporadically in
cats [94-96]. In a recent study of disk disease in 10 cats, there was no breed or sex predilection and clinical signs
included back pain, difficulty ambulating, and incontinence [96]. All herniations occurred in the thoracolumbar
spine, with a peak incidence at the L4 - L5 disk space. Eight cats had a Hansen type I protrusion.
The onset of clinical signs in dogs may be acute (minutes), subacute (hours), or chronic (several days or weeks).
These signs may be rapidly progressive, slowly progressive, or may remain static. Clinical signs also may
undergo remission, only to recur at a later date. Clinical signs in dogs with recurrent attacks frequently are more
severe than those seen at the initial episode. Recurrences have often been considered to be the result of multiple
extrusions at the same disk level [97,98]. However, in a recent study, 22 of 25 dogs had a second operation (> 4
weeks after the initial surgery) at a site distinct from the initial lesion [99]. In this study, Dachshunds were at
higher risk for recurrences than other breeds.
The two most common neurological syndromes associated with disk disease are thoracolumbar and cervical
syndromes. With cervical disk disease, the majority of affected animals will have a history of pain, with or without
paresis [90], and frequently, spasms of cervical musculature. Animals may assume a posture with the nose held
close to the ground and the back arched. In some dogs, one thoracic limb may be held in partial flexion, with
reluctance to support weight or walk on this limb. These animals frequently show considerable pain on
manipulation of the head and neck. This combination of signs is termed root signature, since it is believed to be
associated with nerve root entrapment near the intervertebral foramen as a result of lateral disk extrusion [100]. A
lumbosacral syndrome is uncommonly associated with disk disease. In some animals with lumbosacral disk
extrusion, one pelvic limb may be held in partial flexion or a repetitive "stamping" motion may be observed. These
animals frequently show considerable pain on manipulation of the limb and lumbosacral spine. This combination
of signs has also been termed root signature and is believed to be associated with nerve root compression or
entrapment by a fragment of extruded disk material. In a small percentage of dogs, a multifocal syndrome may
develop as a result of an acute, explosive extrusion of disk material from a thoracolumbar disk that produces
hemorrhagic myelomalacia. With this irreversible disorder, an initial thoracolumbar syndrome may be followed by
a lumbosacral syndrome as the lesion descends the cord. As the lesion also frequently ascends the cord, signs of
thoracic limb rigidity give way to flaccidity and areflexia followed by death due to respiratory paralysis.
A definitive diagnosis of disk disease requires radiographic confirmation of presence of a mass lesion or, in
absence of a mass lesion, evidence of characteristic changes in the disk-vertebral articulations. Typical
radiographic features of disk disease include narrowing of the disk space, intervertebral foramen and articular
facet at the site of the herniated disk, wedging of contiguous vertebral bodies so that the dorsal part of the disk
space appears narrower than the ventral part, and presence of an opacified mass in the vertebral canal. In situ
calcified disks, in the absence of any other abnormality, are a common finding in chondrodystrophoid breeds of
dogs and are of little significance-it has been estimated that dystrophic calcification occurs in 20 to 77% of disks in
some chondrodystrophoid breeds within the first year or two of life [71,101-103], especially in Dachshunds in
whom calcification appears to be inherited [104,272]. Recent studies suggest that exercise has a modulating
effect on rate of occurrence of disk calcification in Dachshunds (moderate exercise reduced the rate of
occurrence of disk calcification) [105]. In some cases, particularly in acute extrusions, plain radiographic findings
may be minimal or equivocal and myelographic studies will be necessary to define the extent and location of
spinal cord compression. In one study, accuracy for determining sites of intervertebral disk protrusion using
survey radiography was only in the 51 - 61% range [280]. The importance of accurate localization of lesions is
demonstrated by the presence of asymmetrical neurological signs contralateral to the myelographic and surgical
lesion in some dogs, especially those with Hansen type 1 extrusion [106]. Contrast studies also are indicated
when there is evidence of more than one disk lesion. The most common myelographic change is narrowing and
dorsal deviation of the ventral contrast column at the level of disk protrusion/extrusion. If the disk extrusion is
acute, spinal cord swelling may result in complete blockage of contrast material at, or immediately rostral to the
level of the disk extrusion. Note that dogs with thoracolumbar or cervical disk disease that have clinical signs of
back or neck pain alone, without neurologic deficits, may have substantial compression of the spinal cord [90,107].
Results of experimental studies suggest that high-dose contrast enhancement (e.g., 0.3 mmol/kg of gadoteridol)
might facilitate the detection of recurrent herniated disk fragments [108]. While plain radiography and
myelography have long been the methods of choice for the diagnosis of disk disease, other non-invasive
neuroimaging procedures such as magnetic resonance imaging (MRI) [109] and computed tomography (CT)
[110-112] may be more accurate, technically easier, and safer (myelography may exacerbate clinical signs and
induce seizures). In one report, preoperative CT confirmation of the relationship between the spinal cord and the
protruded disk was used in planning the surgical approach in dogs with cervical disk disease [113]. MRI is
considered to give better information about the condition of the intervertebral disk (e.g., the hydration status of the
nucleus pulposus) than radiography [114]. In fact, classification of degenerating intervertebral disks and
identification of MR imaging characteristics of each type have been reported in experimental studies in dogs [115].
Hemorrhage may also be identified using MRI [278]. Analysis of CSF, especially if sampled from the lumbar
subarachnoid space, may reveal markedly elevated protein levels and increased numbers of mononuclear white
blood cells [116]. These changes are more likely to be found in dogs with severe and acute neurological signs.
Recent studies have shown a significant increase in lumbar CSF glutamate concentrations in both acute and
chronic cord compression injuries secondary to disk herniation in dogs [117].
Gross pathological findings occurring subsequent to disk disease usually depend on whether disk protrusion-
extrusion is partial or complete and whether it occurs acutely or gradually. While many disks in older animals of
any breed may protrude, it is uncommon to find more than one extruded disk, even in animals that have had a
history of multiple episodes. This suggests that many recurrences are due to multiple extrusions from single disks
(see below). In disk protrusion, the AF may bulge dorsally into the vertebral canal, without rupturing. This is
known as a Hansen type 2 disk [71], and it appears as a small, round to dome-shaped bulging of the dorsal
surface of the disk. A Hansen type 1 disk [71] is characterized by rupture of the dorsal annulus, with extrusion of
degenerate NP into the vertebral canal around the spinal cord. In some instances, the extruded nuclear material
will be contained by the dorsal longitudinal ligament. Typically, disks extrude in a dorsomedian, paramedian, or
dorsolateral plane. In the cervical region, where the vertebral canal/spinal cord ratio is larger than that of the
thoracolumbar region, lateral and intraforaminal extrusions may be more common than in other spinal regions,
producing spinal root rather than spinal cord compression. Rarely, disk material may herniate through the
cartilaginous end-plate into the vertebral body (resulting in an intravertebral herniation or Schmorl’s node) [118],
or into the spinal cord itself (intramedullary extrusion) [279].
The spinal cord may be swollen, indented, flattened, or atrophic. In chronic cases, a fibrous adhesion may be
evident between the extruded mass and the dura mater. In many instances of Hansen type 1 disk extrusion,
hemorrhage will be associated with the extruded disk material, producing a soft, granular, salt and pepper
consistency. In some cases, the volume of epidural hemorrhage may exceed that of the extruded disk material.
The extruded material may form a circumscribed mass or may lie flattened around the sides of the dura mater.
The extruded material may have migrated one or two vertebral levels away from the site of the affected disk. This
form of extrusion is usually present in dogs with thoracolumbar disk disease. Since extruded disks are not
completely absorbed, single disks that may have had multiple extrusions are recognized by their stratified
appearance. The oldest component may be dark gray, hard, and adherent to the dura. Subsequent laminations
are lighter in color and more friable [97]. In chronic disk disease with slow, progressive extrusion, the degenerate
material frequently has a gritty consistency and an opaque and cheesy appearance. This type of extrusion is
more often observed in dogs with cervical disk disease.
Microscopic changes in the spinal cord are dependent on the rate of disk extrusion and duration of cord
compression. Gradual or mild compression produces varying degrees of demyelination and axonal degeneration.
Sudden, massive extrusions often result in focal or multifocal hemorrhage and necrosis in gray and white matter.
Localized edema may result in pronounced cord swelling and collapse of the subarachnoid space. Rarely, disk
material will be present within the cord parenchyma. In necrotic areas of the spinal cord, vessels and
mesenchymal (connective tissue) elements are usually preserved. Lipid macrophages are observed in those
cases of a few days duration. In more chronic cases, marked proliferation of astrocytes and microglial cells may
be a feature, especially in areas that border the necrotic zone, together with trabeculae of blood vessels and
connective tissue that cross the necrotic areas [84]. In longer standing lesions, the gray matter often has a
fenestrated appearance due to loss of neurons and fibers. Astrocytic gliosis may result in marked sclerosis of the
gray matter. An epidural inflammatory reaction composed of neutrophils, red blood cells, fibroblasts, large
mononuclear cells, occasional multinucleate giant cells, chondrocytic-like cells, and fibrocartilaginous debris may
be present.
Medical management usually is directed at animals with their first signs of disk disease. Mild clinical signs often
resolve after at least three weeks of confinement with outside activity limited to leash exercise. Recurrences of
clinical signs are common in this group of animals. Severe, unremitting pain may be managed with prednisolone,
0.5 mg/kg, PO, bid, for 72 hours. Muscle spasms may respond to muscle relaxants, e.g., methocarbamol
(Robaxin), 20 mg/kg, PO, tid, for 7 to 10 days, or diazepam, 2 - 5 mg, PO, tid, for several days. High dose
methylprednisolone succinate should be considered in paraplegic/tetraplegic animals with acute spinal cord injury
(see spinal trauma). Acupuncture is considered another form of conservative treatment [119-122]. The analgesic
response to acupuncture is reportedly most effective in dogs showing pain with or without mild paresis. Animals
receiving this treatment should have restricted activity.
Surgical treatment is indicated in animal with clinical signs unresponsive to medical management, recurrent
and/or progressive clinical signs, or in animals that are paralyzed. The approaches most widely used are
dorsolateral hemilaminectomy / pediculectomy or dorsal laminectomy for thoracolumbar diskdisease and ventral
slot-decompression for cervical disk extrusions, although a thoracolumbar lateral approach has its proponents
[89,123-128]. In a recent study, significant improvement in clinical results was seen in caudal cervical disk
protrusions when additional surgical distraction and stabilization were provided following ventral slot
decompression [129]. Dorsal laminectomy has also been successfully performed in dogs (especially those < 15
kg) with cervical disk disease [130].While some studies of thoracolumbar disk disease indicate that removal of
disk material using these techniques significantly improves the degree of completeness of recovery [131],
successful results have been reported using fenestration alone [98,132-134]. Prophylactic fenestration [89] in
addition to decompression remains somewhat controversial [135] but is still performed by many surgeons in order
to reduce the chance of subsequent herniation involving other disks [136-138]. A variety of other surgical
procedures have been described, including percutaneous diskectomy [139], but their effectiveness await large
clinical trials. Although still not commonly employed for the treatment of disk disease, chemonucleolysis (e.g.,
using collagenase or chymopapain injected directly into the disk) has its exponents [140-143] and may be more
effective than fenestration at removing nuclear material from the disk [144]. Experimental autographic disk
transplantation for potential use in humans with chronic disk disease is in its infancy but initial surgical studies in
dogs showed promise [145]. Potential treatment complications include cardiac dysfunction from manipulation of
the vagosympathetic trunk during cervical surgery, and vertebral luxation as a complication of the ventral slot
procedure, especially in mid to lower cervical vertebrae [146]. Furthermore, cervical vertebral fusion may
predispose adjacent disks to herniation [147]. Corticosteroid therapy (usually associated with use of
dexamethasone) may lead to gastrointestinal hemorrhage, ulceration, colonic perforation and pancreatitis [148-
150].
Complications may be kept to a minimum by administering corticosteroids for as short a time as possible.
Prophylactic use of intestinal protectants, e.g., bismuth subsalicylate (Pepto-Bismol®) in conjunction with frequent
administration (at least four times daily) of antacids, e.g., magnesium or aluminum hydroxide, or H2 antagonists
such as cimetidine (Tagamet®, at 20 mg/kg, PO, tid) also may reduce the prevalence of gastrointestinal
hemorrhage. Corticosteroids should be stopped immediately, when gastrointestinal complications are noted. In a
recent study in dogs with acute degenerative disk disease treated by surgery and corticosteroid administration,
both omeprazole (a gastric acid pump inhibitor) and misoprostol (a synthetic prostaglandin E1 analog) were
ineffective in treating or preventing the further development of gastric mucosal lesions [150].
Paralyzed patients need to be maintained in a sanitary environment, with twice daily bladder catheterization,
frequent removal of soiled bedding, and use of foam rubber pads or water beds to prevent development of
decubital ulcers. In addition , active physiotherapy (see also spinal trauma and chapter on rehabilitation) that
includes assisted standing and walking exercises, and supervised swimming for 15 minutes twice daily, is an
integral part of the nursing care since it will delay disuse muscle atrophy.
The following statements may be used as a general guide to assess prognosis:
1. Animals that are paretic or paralyzed but have normal pain sensation have a good prognosis following
medical and/or surgical management. Results of a recent surgical study (using hemilaminectomy and
fenestration) with an 86% success rate indicated that the rate of onset of clinical signs significantly
influenced the clinical outcome but not the length of recovery time, while the duration of clinical signs did
not seem to significantly affect the outcome, but did affect the length of recovery time [281]. The presence
of postoperative voluntary motor function is also reported to be a favorable prognostic indicator for early
return to ambulation [282].
2. Animals that are paralyzed with loss of bladder control and with reduced pain sensation have a guarded-
to-favorable prognosis following surgical intervention (decompression and/or fenestration).
3. Animals that are paralyzed with loss of bladder control and loss of pain sensation have a guarded-to-
unfavorable prognosis.
Dogs with absent deep pain perception that undergo surgery within 12 to 36 hours have a better chance of
recovery (more complete and over a shorter time-period) than those in which surgery is delayed [100]. Evaluation
of the degree of myelographic spinal cord swelling might also assist in establishing a prognosis in severely
affected animals [151]. As a caveat to prognostication, several studies have shown that severity of spinal cord
dysfunction, based on clinical signs, does not necessarily predict outcome. In one recent report, 50% of dogs with
loss of bladder control and loss of deep pain sensation recovered completely or partially [152].
A functional scoring system for pelvic limb gait of dogs with acute thoracolumbar spinal cord trauma (from
spontaneously-occurring disk disease) has been developed to allow quantification of recovery to be assessed and
potentially facilitate evaluation of pharmacotherapeutic clinical trials [153]. Spinal cord evoked potentials and
somatosensory potentials may be useful in localizing spinal cord lesions and assessing lesion severity [154,155].
Other evoked potentials such as magnetically elicited transcranial motor evoked potentials may be sensitive
indices of severity of spinal cord lesions in dogs with disk disease but do not appear to be reliable predictors of
neurologic recovery [156]. In one report involving 10 cats with disk disease, prognosis was adjudged to be most
favorable in cats following surgical decompression [96].
Diskospondylitis
Diskospondylitis is intervertebral disk infection with concurrent osteomyelitis occurring in contiguous vertebral
bodies [157-169]. This disorder occurs in young to middle-aged adult dogs (typically non-chondrodystrophoid)
usually of the larger breeds. Male dogs outnumber females by approximately 2:1. Diskospondylitis has also been
reported in cats, albeit infrequently [170-174]. Diskospondylitis may occur following iatrogenic trauma of the
vertebral column (e.g., disk curettage), foreign body migration, paravertebral injection, extension from a body
organ abscess, or more commonly from blood-borne septic emboli that reach the avascular intervertebral disk via
the capillary networks in the vertebral end-plates [158-161,175,176]. The source of infection is not established in
most cases. Possible initiating sites include the genitourinary tract, skin, gingiva, and infected heart valves. In one
dog, epidural abscess and diskospondylitis developed after administration of a lumbosacral epidural analgesic
[177]. Diskospondylitis has also been found in a Bernese Mountain dog with immune-mediated polyarthritis [178].
Bacterial infection is the most common cause of diskospondylitis and coagulase positive Staphylococci (S. aureus
or S. intermedius) are the most frequent isolates. Other organisms identified include Brucella canis, Nocardia,
Streptococcus canis, Escherichia coli, Acaligenes sp, Micrococcus spp, Proteus sp, Corynebacterium
diphtheroides, Mycobacterium avium, Erysipelothrix tonsillarum and Actinomyces viscosus. In a recent study,
novel organisms incriminated in canine diskospondylitis included Pseudomonas aeruginosa, Enterococcus
faecalis and Staphylococcus epidermidis [179]. Fungal organisms including Aspergillus terreus, Paecilomyces sp
(e.g.,Paecilomyces varioti), Penicillium sp, Chrysosporium sp, Pseudallescheria boydii, and Coccidioides immitis
have also been cultured [163,164,166,180,181]. In one retrospective study involving 135 dogs with
diskospondylitis, the prevalence of dogs with Brucella canis was approximately 10% and sexually intact male
dogs were at risk as were dogs from the southeastern United States [182]. Immunosuppression may predispose
some breeds, such as German Shepherds, Airedale Terriers, and Basset Hounds to bacterial or fungal infection
and subsequent diskospondylitis [181,183-185]. Respiratory or gastrointestinal portals of entry are suggested for
animals with aspergillosis. Curiously, the majority of reports of disseminated aspergillosis in dogs have involved
German Shepherds [181,186-188] with organisms localizing most frequently in kidneys, spleen, and vertebrae. In
one dog with diskospondylitis due to Aspergillus terreus, multiple granulomas with fungal elements were also
found in the subarachnoid space associated with the nerve roots of the cauda equina [183]. Hypothyroidism does
not appear to be a predisposing factor in the development of diskospondylitis.
Clinical signs are variable according to vertebral involvement, ranging from subtle spinal hyperesthesia and
stiffness, to severe paresis/paralysis. In more than 80% of affected dogs, spinal pain is observed [189]. Affected
animals may manifest depression, anorexia, and pyrexia. Often they are reluctant to exercise or jump. Heart
murmurs can be detected on auscultation in some animals. Pleural effusion associated with paecilomycosis was
reported in one dog [284]. Spinal cord and/or nerve root compression may result from proliferation of inflammatory
tissue and exostosis, subarachnoid or epidural abscessation, vertebral pathological fractures, intervertebral disk
protrusion/herniation, or excessive vertebral instability [177,187,190,191]. Spinal cord myelitis may also occur by
extension of infection through the meninges.
Radiographic abnormalities include a concentric area of lysis of adjacent vertebral end-plates early in the disease
process. More chronic lesions are characterized by varying degrees of bone lysis and proliferation, vertebral
sclerosis, shortening of vertebral bodies, narrowed intervertebral disk spaces, and ventral osseous proliferation
that may bridge the affected disk space. Extensive destruction of a vertebra may result in its collapse.
Diskospondylitis may be present in more than one disk space and commonly occurs in one or more adjacent disk
spaces. Common sites of diskospondylitis are the caudal cervical area, midthoracic and thoracolumbar regions,
and the lumbosacral joint. In dogs with grass awn migration, reactive bony changes may be seen on ventral and
lateral surfaces of vertebrae L2 through L4 [189]. The nature and location of the changes along the spine may
help differentiate diskospondylitis from malignant bone disease [192]. The severity of the radiographic changes do
not necessarily correlate with the degree of clinical involvement. Results of a recent multicenter, retrospective
study evaluating contrast radiographic findings (myelograms or epidurograms) in canine bacterial diskospondylitis
revealed that 15 of 27 cases (56%) showed some degree of spinal cord compression, although in the majority
(approximately 73%) soft tissue was the compressive mass and the median compression for all cases was only
5% of the vertebral canal [193]. Vertebral subluxation was evident in 20% of these dogs. Stress radiography has
been recommended for further evaluating dogs with vertebral instability [193]. Radiographic signs of the disease
may not appear for several weeks after the onset of clinical signs. Hence, a radiographically normal spine does
not preclude the diagnosis of diskospondylosis. Magnetic resonance imaging can be diagnostic prior to
development of definitive radiographic abnormalities [194]. MRI findings in affected dogs have revealed increased
T2 and decreased T1 signal intensity of the soft tissues ventral to vertebral bodies, the end plates of the same
vertebral bodies and the intervertebral disk [195].
Blood and urine cultures should be obtained before starting antibiotic therapy. Reports of positive blood cultures
range from 45% to 75% of affected dogs, while urine cultures can be positive in up to 50% of dogs [189,196]. In
one report, fungal hyphae were identified in urine sediment from 6 dogs [181]. While serologic Brucella titers
should be checked because of the public health significance, positive blood cultures are reportedly lower in dogs
with Brucella canis-induced diskospondylitis [182]. Percutaneous aspiration of the infected vertebrae using
fluoroscopy is a very useful diagnostic aid. In one study, positive bacterial cultures were obtained from 9 of 12
aspirated disk spaces including 2 dogs in which blood and urine cultures were negative [197].
Prognosis is usually favorable with aggressive long-term antibiotic therapy (e.g., from 2 to 4 months) if
neurological signs are mild and the vertebrae are stable [198,199]. As a rule of thumb, until culture results are
available, the organism should be assumed to be a Staphylococcus. The cephalosporins have been effective in
the majority of small animal cases, e.g., cephalexin, at 22 mg/kg, PO, tid or cefazolin 20 mg/kg IV, qid for up to 5
days initially, if animals have fever or progressive neurological signs, followed by oral antibiotics. The following
drugs have been recommended for treating diskospondylitis caused by other organisms [189,200,201]:
Microorganism Antibiotic Dose
beta-hemolytic
Amoxicillin 20 mg/kg, PO sid
Streptococcus sp.
Enrofloxacin 10 - 20 mg/kg PO sid
Brucella canis Doxycycline 25 mg/kg PO sid
Gentamycin 5 mg/kg IM or SQ sid
Actinomyces sp. Penicillin G 100,000 U/kg IV, IM, or SQ qid
Ketoconazole 10 mg/kg PO bid (dog); 50 mg (total) PO bid or sid (cat)

Coccidioides immitis
Fluconazole 5 mg/kg PO bid (dog); 25 - 50 mg(total) PO bid or sid (cat)
Amphotericin B 0.25 mg/kg IV every 48 hours until a cumulative dose of 8 -
Aspergillus sp. (deoxycholate) 12 mg/kg (dog) or 4 - 8 mg/kg (cat) is reached
Itraconazole 5 mg/kg PO bid (dog and cat)
Prognosis for dogs with fungal diskospondylitis is guarded. In one report of 10 cases, 8 dogs were euthanized
because of severe neurological signs, although one dog was alive after 4 years of continuous treatment with
itraconazole [181]. Prognosis may also remain guarded in dogs with Brucella canis infection since serologic
testing and radiographically active lesions may remain positive long after resolution of clinical signs [182]. Dogs
with brucellosis should be neutered and clients advised of potential zoonotic infection. Vertebral curettage may
expedite clinical resolution in cases refractory to medical treatment. In animals with severe neurological signs,
spinal cord decompression and/or vertebral immobilization are indicated. In one report, surgical treatment
involving distraction and stabilization to obtain intervertebral fusion was effective in treating lumbosacral instability
caused by diskospondylitis [191]. Prognosis for surgically treated animals with severe neurological signs is often
favorable [179]. Analgesics may also be required in some dogs because of pain. Recurrences may be common,
especially in dogs with Brucella canis and in those with fungal infections, thereby necessitating re-treatment. The
resolving lesion is characterized radiographically by cessation of the lytic process and by gradual replacement
with new bone, sometimes causing fusion of the adjacent vertebrae. Radionuclide bone imaging, especially using
gallium scans, may be a sensitive technique for confirming successful treatment [189]. Note that there is no
apparent correlation between the ambulatory status and the ultimate outcome of dogs with diskospondylitis [193].
Dural Ossification
Dural ossification is a degenerative disorder of dogs characterized by deposition of bone plaques on the inner
surface of the dura mater [202-204]. Synonyms are osseous metaplasia of the dura mater and, incorrectly
[205,206], ossifying pachymeningitis. These plaques occur in more than 60% of large and small breeds, of either
gender, over 2 years of age and occur most often in the cervical region (e.g., C3 - T1) and lumbar (L1 - L6) areas
of the spine [202,207]. Over 40% of 2 year old dogs had lesions in one report [202]. The etiology of this condition
is unknown but seems unrelated to mechanical stress due to distribution of the changes [202]. Dural ossification
is a common, incidental necropsy finding in dogs [203]. In extreme cases, the dura may be transformed into a
solid bony tube[205]. The plaques often contain marrow cavities. The majority of plaques in one study were
located ventrally while the remainder were found on dorsal and lateral aspects of the dural tube [202]. In general,
dural ossification rarely causes clinical disease, but spinal cord compression with secondary degenerative
changes in white and gray matter including edema, loss of neuronal cells, gliosis, and rarely, marked spinal cord
compression with malacia have occasionally been reported in the dog [203,205]. Degenerative changes also may
occur in nerve roots closely associated with the bony plaques [205]. Affected animals may be presented with a
history of chronic paresis over several months, or tetraparesis, according to the location of the bony plaques,
sometimes with atrophy of limb musculature and pain. Dural ossification is characterized radiographically (often
as an incidental finding) by thin radiopaque linear shadows in cervical and lumbar areas, especially at the site of
intervertebral foramina. The plaques sometimes may be confused with calcified herniated intervertebral disk
material, vertebral osteophytes, or accessory processes on thoracic and lumbar segments [202]. They may be
further defined using advanced imaging techniques, such as computed tomography [112].
If a definitive diagnosis is made in a dog with neurological signs, decompressive surgery may be attempted [202].
More common disorders should be given priority in the differential diagnosis of chronic spinal cord compression.
Lumbosacral Stenosis
Stenosis (narrowing) of the vertebral canal and/or the intervertebral foramina in the lumbosacral area with
compression of the nerve roots that form the cauda equina (L6 - 7 + S1 - 3 + coccygeal segments) and/or their
related vasculature is an entity reported in dogs [208-211] and rarely, in cats [171]. This condition has been
termed cauda equina syndrome, spondylolisthesis, lumbosacral instability, lumbar spinal stenosis, degenerative
lumbosacral stenosis, and lumbosacral malarticulation and malformation. In most dogs, the spinal cord usually
ends within the sixth or cranial half of the seventh lumbar vertebra, although in chondrodystrophoid and small-
breed dogs the cord extends to the L7 - S1 level [86,212]. Most cases of acquired lumbosacral stenosis appear to
be related to intervertebral disk degeneration at L7 - S1, especially Hansen type 2 protrusion (see disk disease)
[211] with subsequent development of osteophytes at L7 - S1 endplates and articular facets, narrowing of the disk
space at L7 - S1, subluxation of articular facets, thickening and in-folding of the normally taut interarcuate
ligament, and thickened lamina and pedicles. The end result is degenerative stenosis with compression of the
cauda equina. Lumbosacral instability, including dorsal dislocation of L7, has also been reported [213].
Morphometric studies suggest that multilevel congenital or developmental stenosis of the lumbosacral canal may
contribute to acquired lumbosacral stenosis in large-breed dogs [214]. Other causes of acquired stenosis include
diskospondylitis, neoplasia, and traumatic fracture/luxation of L7 - S1, sacrum, or the sacrococcygeal junction.
Also, lumbosacral osteochondrosis, a developmental disturbance of the end plate of either the sacrum or L7
vertebra, with subsequent separation of an osteochondral flap, has been reported as a cause of lumbosacral
stenosis in mature dogs [269-271]. This condition is often associated with disk disease, consequently,
compressive lesions result from the flaps alone or in combination with disk material. An infrequently reported form
of congenital ("idiopathic") stenosis in dogs occurs unassociated with disk disease. It is characterized by
shortening of the pedicles, thickened and sclerotic apposition of the lamina and articular processes, in-folding and
hypertrophy of the ligamentum flavum, and sclerotic and bulbous articular facets that bulge into the dorsal half of
the canal, sometimes accompanied by malformations (e.g., hemivertebra, block vertebra, and transitional vertebra,
such as lumbarization of S1 [215]. This congenital condition is thought to be associated with a developmental
defect in the neural arch.
Acquired degenerative stenosis occurs most commonly in large breed dogs, many of which are highly trained or
working dogs, including Border Collies [216-218]. German Shepherds are especially at risk for this degenerative
disorder [219], possibly because of the presence of destabilizing transitional lumbosacral vertebral anomalies that
predispose to premature disk degeneration [220]. The vertebral anomalies in the German Shepherd are
considered to be inherited [221]. Smaller breed dogs appear to be more often affected by the congenital form of
lumbosacral stenosis. In both forms, clinical signs are noted usually when dogs are mature to middle-aged (e.g., 5
to 8 years), possibly associated with age-related soft tissue and bony changes, along with altered spinal
mechanics, resulting in cauda equina compression [222]. Males appear to be at higher risk than females in the
acquired disease. In dogs with lumbosacral osteochondrosis, the mean age was 6.3 years, German Shepherds
(56%), Boxers (11%) and Rottweilers (9%) were overrepresented, and the male:female ratio was 4:1 [271].
Irrespective of etiology, dogs with lumbosacral stenosis usually show varying signs of a lumbosacral syndrome
depending on the level and extent of the lesion. Owners often note that affected dogs have difficulty rising or
climbing stairs, and show signs of pain or stiffness during extensive physical activity [218]. Clinical signs may
include pain (the most commonly reported sign) during direct palpation (especially downward pressure) of the
lumbosacral area or during lumbosacral hyperextension, unilateral or bilateral pelvic limb paresis or lameness,
proprioceptive deficits, tail paresis, hypotonia of anal sphincter with fecal incontinence, and urinary incontinence
[211,216,222]. In some animals self-mutilation of pelvic limbs, tail, perineum, anal area, and genitalia may be
noted. The occurrence of exercise-induced pain in some affected dogs, termed neurogenic intermittent
claudication [222], may be related to dilatation of radicular vessels and subsequent compression of adjacent
nerve roots in a stenotic region, e.g., intervertebral foramen or lateral recess of the caudal L7 vertebral foramen
[223] narrowed by a degenerative process.
On plain films, indirect evidence of degenerative lumbosacral stenosis includes spondylosis deformans, disk
space narrowing, and end-plate sclerosis. There may be evidence of lumbosacral fracture/luxation, osseous
neoplasia, intradiskal osteomyelitis associated with diskospondylitis, or congenital lumbosacral stenosis. In dogs
with lumbosacral osteochondrosis, a radiolucent defect occurs in the dorsal aspect of the affected end-plate along
with one or more bone fragments in the vertebral canal and lipping, angling, and sclerosis of the dorsal part of the
end-plate [271]. Stress radiography, such as dynamic flexion/extension studies, may accentuate the lumbosacral
instability. Epidurography and diskography may provide useful information. In one study, combined survey
radiography and discography-epidurography were correctly positive in 16 of 18 dogs (89%) [224]. Myelography
has limited value in the evaluation of the cauda equina because the dural sac is elevated from the vertebral canal
floor and often ends before the lumbosacral junction [225]. Computed tomography and MRI are probably the
diagnostic procedures of choice [217,222,223,225-227], although findings of similar CT changes (but not vertebral
subluxation) in the lumbosacral spine of older dogs without clinical disease may complicate diagnosis [112]. MRI
can clearly reveal soft tissue, such as cauda equina, epidural fat, and intervertebral disk, at the lumbosacral
region without use of contrast medium [228]. MRI is also considered to give better information about the condition
of the intervertebral disk (e.g., the hydration status of the nucleus pulposus) in dogs with degenerative lumbar
spine diseases, than radiography [114]. CT scans also have an important diagnostic role. In a study evaluating
canine lumbosacral stenosis using intravenous contrast- enhanced CT, the positive predictive values for
compressive soft tissues involving the dorsal canal, ventral canal and lateral recesses were 83%, 100%, and 81%
respectively [229]. However, no correlation was found between severity of the clinical signs and the severity of
cauda equina compression as assessed by MRI in another study [277]. A gas-filled lumbosacral disk space
(vacuum disk phenomenon) along with smaller gas bubbles in between the degenerated L5 - L6 dorsal articular
facets (vacuum facet phenomenon) has also been revealed by CT in a 7 year old Rottweiler with cauda equina
syndrome [230]. A diagnostic role for CT densitometry awaits further studies [283]. Electromyographic studies can
demonstrate fibrillation potentials in lumbosacral paraspinal muscles, pelvic limbs, coccygeal muscles, and anal
sphincter. In those cases where results of ancillary aids are equivocal, exploratory surgery may be the only
means available for definitive diagnosis and treatment [222].
Grossly, marked compression and indentation of nerve roots may be seen, associated with stenotic lesions, bone
fragments, disk material, inflammatory lesions, neoplasia, etc. Histological sections of samples removed from
dogs with lumbosacral osteochondrosis revealed the osteochondral flaps consisted of a core of bone with or
without a hyaline cartilage cap covering its margin, with the cartilage present consisting of a mixture of
cartilaginous overgrowth and cartilage separation-necrosis [271]. I have commonly found extensive axonal
degeneration characterized by linear rows of ovoids and balls, along with variable demyelination and
remyelination in teased nerve fiber studies of biopsied nerve roots. In semithin sections, nerve fiber loss can be
pronounced. Evidence of nerve regeneration may be seen in chronic lesions. In experimental studies in dogs, the
involvement of intrinsic spinal cord neurons in the compression-induced cauda equina syndrome includes
anterograde, retrograde and transneuronal degeneration in the lumbosacral segments [231] as well as marked
changes in NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) diaphorase-exhibiting and Fos-
like immunoreactive neurons and heat-shock protein 72 (a cytoprotective protein whose expression is induced by
a variety of harmful stimuli) [232].
Prognosis will depend on the underlying cause and the degree of damage to the nerve roots of the cauda equina.
For congenital lumbosacral stenosis, prognosis is usually favorable with surgical decompression alone. Animals
with acquired lumbosacral stenosis presenting with severe neurological deficits that include urinary or fecal
incontinence have a guarded prognosis [222]. In dogs with less severe clinical signs, prognosis may be favorable
when decompression by dorsal laminectomy is combined with foraminotomy and/or mass removal (e.g., disk,
facets, ligaments, joint capsule, or osteophytes) [211,216,218,222,233]. In one report, dogs with lumbosacral
osteochondrosis and instability treated with distraction-fusion along with dorsal laminectomy had a better
prognosis than dogs without instability that were treated with dorsal laminectomy alone [271]. Medical treatment,
such as rest, weight loss, anti-inflammatory or analgesic drugs, has usually been disappointing for congenital or
acquired degenerative lumbosacral stenosis [222]. As for other acquired causes of lumbosacral stenosis,
diskospondylitis can be successfully managed with antimicrobial therapy (see diskospondylitis), traumatic
lumbosacral stenosis has a guarded prognosis (see spinal trauma), while lumbosacral neoplasia (see neoplasia)
has a poor prognosis.
Spinal Synovial Cysts

Extradural spinal synovial cysts originating from articular facet joint capsules and causing spinal cord
compression have recently been described in dogs [109,234-237]. These cysts are characterized by a lining of
single or multiple layers of flattened or cuboidal synovial cells with a wall composed of hypercellular synovium or
fibrocollagenous tissue that may have cellular infiltrates (e.g., lymphocytes, plasma cells and macrophages) and
focal areas of mineralisation or mucoid material. Another histological intraspinal articular facet joint cyst, called a
ganglion cyst, is very similar to the synovial cysts but has no synovial lining. This form of cyst has also been
recently reported involving L6 - L7 and L7 - S1 articular process joints in a 6 year old German Shepherd [238].
Adipose tissue and numerous capillaries were present on the outer surface of the cyst and foci of metaplastic
cartilage were noted within the cyst wall. In humans, there is no clinical distinction between synovial and ganglion
cysts of the spine that collectively have been termed "juxta-facet" cysts [239-244]. The pathophysiology of these
cysts is uncertain, although they appear to develop secondary to osteoarthritis of the facet joints, e.g., synovial
cysts arising from the synovial outpouchings through areas of weakened or destroyed capsular tissue; or ganglion
cysts developing from mucinous degeneration of periarticular connective tissue [239,240]. In the canine cases
reported to date, there has been no antecedent history of trauma or signs of vertebral instability. Furthermore, the
cysts do not appear to be associated with concurrent degenerative structural disorders such as cervical
spondylomyelopathy.
Preliminary data indicate that juxta-facet cysts in dogs occur most commonly in the cervical vertebrae, followed by
thoracic vertebra, and least commonly in lumbar vertebrae. Dickinson and colleagues identified two groups [237]:
a) young (e.g., 12 - 36 months), giant breed dogs (e.g., Mastiffs and Great Danes) with multiple cysts involving
one or more levels of the cervical spinal cord usually affecting several vertebrae from C4 - C5 to C6 - C7; and
b) older (e.g., 7 - 9 years), large breed dogs (including German Shorthaired Pointer and German Shepherds) with
solitary cysts involving the thoracolumbar spinal cord and affecting vertebrae T13 - L1 or L1 - L2.
This classification seems appropriate since the 4 cases reported by Levitski and colleagues included 3 Mastiffs
and a Great Dane aged between 15 and 18 months with variable cervical lesions from C3 - C4 to C6 - C7
associated with single or multiple cystic lesions [234]. The case reported by Flegel and colleagues also involved
an 18 month old Great Dane with multiple cervical synovial cysts [235]. Consistent with the above-mentioned
classification, the case report of an 8 year old Siberian Husky involved a single cyst located at the level of T13 -
L1 vertebral level [236].
Clinical signs reflect location of spinal cord compression, e.g., cervical, cervicothoracic, thoracolumbar, or
lumbosacral. Many dogs with cervical lesions show evidence of cervical pain [234]. The clinical course may be
slowly progressive over several months. In one Great Dane, progressive ataxia and tetraparesis was noted over a
1 year period [237]. In the single case report to date on lumbar ganglion cysts in a 6 year old German Shepherd,
the dog had a 6 month history of intermittent hind limb lameness, especially after exercise, difficulty handling
stairs, and evidence of lumbosacral pain on hip extension and tail dorsiflexion [245]. Radiographic studies in dogs
are usually unremarkable except for presence of degenerative arthritis of the facet joints and/or degenerative
changes in intervertebral disks [234,237,238]. Lumbarization of S1 vertebra and fusion of the first caudal vertebra
to the sacrum were present in the dog with multiple lumbar ganglion cysts [238]. Spinal cord compression has
been demonstrated using myelography, usually with areas of axial deviation at sites of articular degeneration, and
typically medial to the articulations [236,237]. In one report, a 1 by 2 cm cyst was found in the ventral epidural
space associated with a pedicle attachment of the right T13 - L1 vertebral articular processes [236]. In a magnetic
resonance imaging study, cysts appeared as well-defined circular defects, slightly hyperintense on post-contrast
T1-weighted axial images and hyperintense on T2-weighted scans [234]. MRI revealed presence of multiple cysts
arising from the L6 - L7 and L7 - S1 articular processes in one dog with lumbar lesions [245]. In addition to the
presence of extradural transparent, fluid-filled cysts (typically 0.2 - 1 cm in size) usually adjacent to articular facets,
surgical findings may include hypertrophic interarcuate ligaments, articular facets, and joint capsules [234].
Cerebrospinal fluid may be normal or characterized by mild to moderate protein increase ranging from 40 to 500
mg/dL, with normal cellularity or mild pleocytosis (usually mononuclear but sometimes with occasional
neutrophils) [234,236,237].
Treatment by surgical decompression (e.g., hemilaminectomy or dorsal laminectomy) and removal of the cysts
has usually resulted in satisfactory resolution of clinical signs and improvement in function postoperatively
[234,236,237]. Vertebral stabilization using arthrodesis (lumbosacral) or a dynamic compression plate
(thoracolumbar) has been performed in some dogs in addition to spinal cord decompression. Long-term prognosis
appears to be good [234,236,237], although in one case, clinical recovery was incomplete following
decompressive surgery [235]. To date, recurrence has been reported in one dog with a cervical lesion that
improved with conservative treatment [237].
Spondylosis Deformans
Spondylosis deformans is a degenerative, proliferative disease of the vertebral column characterized by the
presence of vertebral osteophytes at intervertebral spaces, resulting in the formation of spurs or complete bony
bridges [246,247]. Synonyms include spondylitis ossificans deformans, ankylosing spondylitis, spondylitis
deformans, deformative ossifying spondylitis, spondyloarthritis, and spondylitis [246,247], all of which incorrectly
imply the presence of inflammation [248].
Spondylosis deformans has been reported in dogs and cats, usually middle-aged, but some as early as 2 years of
age. The incidence increases with age. Spondylosis occurs in about 50% of dogs by 6 years of age and 75% by 9
years [247]. It reportedly occurs in about 70% of asymptomatic domestic cats. A high incidence has been noted in
the Boxer breed in which the condition is considered to be inherited [249]. In Boxers, dogs as young as one year
of age may be affected, females are more often affected than males, and a positive correlation between hip
dysplasia and spondylosis deformans has been noted [250,251]. In several comprehensive canine studies, Flat-
coated Retrievers, Irish Setters, Bloodhounds, Rhodesian Ridgebacks, German Shepherds, Airedale Terriers,
and Cocker Spaniels were identified as having a medium-high risk of spondylosis deformans, and females had a
significantly higher incidence than males [246,252]. In dogs, vertebral sites most often affected were T9 - T10 and
L7 - S1 in one study based on radiography of vertebral columns removed after death [246]. In some animals, the
entire spine may be extensively involved [253]. Thoracic vertebrae are more commonly affected in cats [247].
While heritability appears to be a factor in some (perhaps all ?) of the high-susceptibility breeds [249], the
underlying mechanisms responsible for spondylosis deformans remain unclear. It may be associated with
degenerative changes in the annulus fibrosus of the intervertebral disks [246,254], particularly where the
peripheral fibers of the annulus fibrosus (Sharpey’s fibers) attach to the vertebral rim [247]. Interestingly, in an
experimental collagenase chemonucleosis study in cervical disks of normal dogs, spondylosis deformans
developed at the sites of cervical enzyme injections [143], suggesting that trauma may be a predisposing factor in
some instances (curiously, osteophytes did not develop in injected thoracic or lumbar disks). Spondylosis
deformans has been observed 1 - 4 years after intervertebral disk fenestration [255]. While spondylosis may
occur secondary to disk degeneration/herniation (see cervical spondylomyelopathy), some consider the condition
to be simply a manifestation of chronic degenerative disk disease, with bony spurs forming around diseased disks
in an attempt to re-establish stability to the weakened disk spaces [246,254,256]. This view is not universally held
(at least by me), especially since spondylosis deformans is uncommonly observed in chondrodystrophoid breeds
predisposed to disk disease, such as Dachshunds and Poodles [246]. In one study involving 30 healthy Beagles
[257], histological evidence of disk degeneration and changes in the mechanical properties of the intervertebral
disk joint preceded radiographic changes of spondylosis. Karkkainen and colleagues, using magnetic resonance
imaging, noted the presence of marked spondylosis deformans adjacent to intervertebral disks without evidence
of disk degeneration [114]. Also, it is difficult to see a relationship between radiographic spondylosis deformans
and disk degeneration in dogs one to two years of age [246,250,251]. While a radiographic study of a closed
colony of Beagles (a chondrodystrophoid breed) did reveal the presence of spondylosis deformans that was age-
related and located principally at low cervical, mid thoracic and cranial lumbar vertebral sites, these sites were
somewhat different from the usual reports, and it is noteworthy that the lumbosacral site was minimally involved
[258]. The role of spinal stress in spondylosis remains enigmatic. Some workers favor the idea that the sites most
frequently involved represent those regions subjected to greatest mechanical stresses [256], while Morgan and
colleagues state that normal or abnormal spinal motion, trauma, or areas of ligamentous attachment do not
satisfactorily explain the variable frequency of lesions [246]. Lumbosacral osteophyte formation secondary to
lumbosacral joint instability was considered as an unlikely event, based on quantitative lumbosacral angulation
measurements [259]. Conversely, results of a recent radiographic study examining position and shape of
osteophyte formations at canine vertebral endplates favored a role for mechanical factors in the pathogenesis of
spondylosis deformans [260]. Anatomical dissection of the lumbosacral spinal columns from German Shepherds
with spondylosis deformans revealed that diseased vertebrae have more flexibility than healthy vertebrae in the
sagittal and frontal planes than but less so for dorsal flexion [261]. An imperfect L7 facet geometry may also
predispose dogs, especially German Shepherds, to spondylosis deformans and may be influenced by congenital
factors as well as body weight and locomotion in immature dogs [262]. Immunogenetic studies of Boxers failed to
show any significant correlation between spondylosis deformans and leukocyte antigens and complement C4
allotypes [263].
Osteophytes tend to develop on ventral, lateral, or dorsolateral aspects of vertebral margins. Dorsally projecting
osteophytes are rare. Classification based on extent of osteophytic proliferation has been proposed [246], ranging
from small spurs projecting vertically from the vertebral body (grade 1), larger osteophytes with parrot’s beak
shape on both sides of the joint space (grade 2), osteophytic projection beneath the intervertebral space (grade 3),
to extensive bridging of the intervertebral space resulting in bony fusion (grade 4). Osteophytic projections into the
spinal canal, with compression of the spinal cord, is rare [264]. Similarly, osteophyic compression of spinal nerves
at the level of the intervertebral foramina is infrequently encountered. In animals with spondylosis deformans, the
disk space is usually of normal width [247,264]. Osteophytes seen after disk disease, with narrowing of the
intervertebral spaces, tend to develop perpendicular to the vertebral body rather than bridge the disk space, and
sclerosis may be seen in the vertebral end-plates [264].
In spite of the often dramatic radiographic changes, spondylosis deformans in dogs and cats tends to be a
subclinical disorder, although stiffness, restricted motion, and pain might be attributed to spondylosis deformans
in a small percentage of patients [247,265], sometimes in association with fracture of bony spurs or bridges. It is
possible that subtle signs may be more easily detected in dogs required to be agile in work or sport [266].
Diagnosis is based on spinal radiography, with osteophytic presence often seen as incidental findings. Standard
ventrodorsal and lateral radiographs without oblique views may miss many ventrolateral osteophytes [247,264].
Langeland and Stigen [267] found that oblique views contributed to a more exact localization of osteophytes,
especially in the region of L6 - 7 and L7 - S1 where the intervertebral spaces are overlapped by the os ilium. In
general, however, they considered that oblique views provided only minimal additional information for evaluating
number and size of osteophytes. Advanced imaging, such as magnetic resonance imaging, may demonstrate
evidence of nerve root impingement [227] and demonstrate soft tissue changes suggestive of degeneration of
intervertebral disks, including loss of hydration of the nucleus pulposus [114]. Note that spondylosis deformans is
commonly seen radiographically in dogs with degenerative lumbosacral stenosis [268]. Spondylosis deformans
was also present in a 6 year old German Shepherd with intraspinal cysts (see spinal synovial cysts) of the L6 - L7
and L7 - S1 articular process joints along with lumbarization of the first sacral vertebra and fusion of the first
caudal vertebra to the sacrum [238]. Treatment of spondylosis deformans is usually unnecessary. Nevertheless,
analgesics can be given if spinal pain can be attributed to spondylosis deformans [265]. Surgery is only indicated
in those rare instances in which both pain and neural deficit are present due to spinal cord or nerve root
compression. Prognosis in animals with spondylosis deformans is usually very favorable.
Miscellaneous Disorders
Several structural disorders, some of which are quite uncommon, may also be associated with compressive
neurological signs. These include Chiari malformations, atlantoaxial subluxation, and
scoliosis/kyphosis/hemivertebrae/block vertebrae (see vertebral anomalies). These conditions are discussed in
the chapter on Developmental Disorders. Skeletal abnormalities occasionally causing spinal cord and or nerve
root compression include mucopolysaccharidoses (see Mucopolysaccharidosis type VI), osteochondromatosis,
hypervitaminosis A, and osteopenia-related spinal fractures and lordosis/kyphosis associated with nutritional
secondary hyperparathyroidism. Compression of neural structures (spinal cord, brainstem, nerve roots) may be
caused by a variety of mesenchymal and/or ectodermal cysts, including arachnoid cysts / intra-arachnoid cysts,
and epidermoid and dermoid cysts (see malformation tumors. Cervical fibrotic stenosis (at C2 - C3 articulation)
associated with yellow ligament proliferation, but without evidence of cervical instability, has been reported in an
18 month old neutered male Rottweiler [273]. Clinical signs were similar to those seen in dogs with cervical
spondylomyelopathy. The stenosis was confirmed using myelography (no abnormalities were seen with survey
radiography) and at surgery. Severe degeneration of the spinal cord affecting all funiculi and gray matter was
found at the level of the yellow ligament compression. Identical myelographic and necropsy findings were
observed by the authors in another young Rottweiler (15 months of age) presented for progressive ataxia. Acute
and chronic spinal cord compression may occur from foreign bodies such as wood fragments secondary to
oropharyngeal stick injuries [285,286].
Storage Disorders
K. G. Braund
Storage diseases, or lysosomal enzymopathies are rare, degenerative disorders which, in the majority of cases
result from a genetically-determined defect of a specific lysosomal acid hydrolase enzyme. There is subsequent
accumulation and storage of substrate(s) within the cytoplasm of neurons throughout the nervous system, as well
as in cells in other organs. Neurons are typically involved since they are post-mitotic, permanent cell populations
[1]. Peripheral nerves are affected in some lysosomal enzymopathies. Most storage diseases have an autosomal
recessive mode of inheritance, affect both males and female animals, have an onset early in life, manifest diffuse
neurological dysfunction, and have a progressive, inexorable course, leading to death. These conditions tend to
be infrequently seen in clinical practice and most published reports emanate from institutions where colonies are
maintained for research as animal models of human disease. Lysosomal storage diseases in dogs and cats have
been categorized as follows [1]:
Sphingolipidoses Mucolipidoses
Gangliosidosis I-cell Disease
Globoid Leukodystrophy Miscellaneous
Gaucher's Disease Glycogenoses
Sphingomyelinosis (Niemann-Pick Disease) - Glycogenosis Type Ia
Niemann-Pick Disease Type A - Glycogenosis Type II
- Phenotypic Variant of Niemann-Pick Disease Type A - Glycogenosis Type III
Niemann-Pick Disease Type C - Glycogenosis Type IV
Glycoproteinoses - Glycogenosis Type VII
Fucosidosis Ceroid Lipofuscinosis
Mannosidosis
Galactosialidosis
Mucopolysaccharidoses
Mucopolysaccharidosis Type I
Mucopolysaccharidosis Type II
Mucopolysaccharidosis Type III A
Mucopolysaccharidosis Type III B
Mucopolysaccharidosis Type VI
Mucopolysaccharidosis Type VII
Ceroid Lipofuscinosis
Ceroid lipofuscinosis (neuronal ceroid lipofuscinosis, or ceroidosis) is a putative neurodegenerative lysosomal
storage disease associated with accumulation of lipofuscin and its related pigment, ceroid, in many organs,
including neurons and glial cells of the CNS. The lipopigment complexes in ceroid lipofuscinosis and those
reported with normal aging are biochemically different. Neuronal ceroid lipofuscinosis occurs as an autosomal
recessive trait in English Setters [2], Tibetan Terriers [3,4], and Border Collies [5]. Males and females are affected.
There have been sporadic case reports in a variety of breeds, including Chihuahua [6], Dachshund [7], Terrier-
cross [8], Saluki [9], Corgi, as unpublished data, see [10], Japanese Retriever [11], Blue Heeler [12,13],
Yugoslavian Sheepdog [14], Dalmatian [15], Cocker Spaniel [16-19], Poodle [20], Gordon Setter [21], Polish
Owczarec Nizinny [22], and Miniature Schnauzer [23]. Ceroid lipofuscinosis has also been reported in cats [24-27].
The underlying pathogenesis remains unclear. In some forms of the disease in people, ceroid lipofuscinosis is
considered to represent a lysosomal storage disorder characterized by the absence of a specific protease activity,
e.g., a deficiency of pepstatin-insensitive acid proteases has been reported in classical late-infantile neuronal
ceroid lipofuscinosis in children, but not in Tibetan Terriers, English Setters, or Border Collies with ceroid
lipofuscinosis [28]. Some researchers suggest that this neurodegenerative disease is associated with the disease
process rather than storage of fluorescent lipopigment per se, and that the pathogenesis may involve
mitochondria rather than a primary defect of lysosomal catabolism [29,30,267]. Lysosomal accumulation of
subunit c of mitochondrial ATP synthase has been found in these three canine breeds, as well as in most forms of
the disease in people [4,29,31]. Subunit c has also been identified in an affected cat [25]. Another class of
neuronal ceroid lipofuscinosis is suggested by the finding of storage of sphingolipid activator proteins (SAPs) A
and D, but not the c subunit, in affected Miniature Schnauzer dogs [32,33]. In people, five disease genes have
been isolated [34]. Two of these (CLN1 and CLN2) encode lysosomal enzymes palmitoyl-protein thioesterase and
tripeptidyl peptidase 1. The remaining three (CLN3, CLN5 and CLN8) encode putative membrane proteins of
unknown function. A molecular genetic study on English Setters with ceroid lipofuscinosis did not indicate any
linkage between the canine form of the disease and homologues of human CLN3 or CLN2 genes [35], and
another study eliminated CLN3 as the locus for the disease in English Setters [36].
Clinical signs usually occur in young adult or mature animals between 1 and 9 years of age, although most
animals are under 2 years of age. Signs are extremely variable but will usually include some form of abnormal
behavior (e.g., aggression, depression, dullness, hyperactivity, loss of learned behavior, and acral mutilation) and
visual impairment. These signs are often seen between 1 and 2 years of age. Other signs may include
generalized ataxia, head tremors, seizures, and tetraparesis. Signs tend to slowly evolve over several years,
especially in Tibetan Terriers [3], often with an accompanying loss of condition. The course in English Setters may
be quicker with death within a year of initial signs [37]. The visual loss appears to be cortical, since, in contrast
with human neuronal ceroid lipofuscinosis, severe retinopathy does not develop in most affected dogs [37-40];
however, retinal lesions appear to be more severe in Tibetan Terriers [4], in whom one of the early signs is
nyctalopia (night blindness). Cocker Spaniels are clinically affected in adulthood and show progressive hind limb
paresis, incoordination, and deficient postural reactions and proprioception [16]. Visual deficit is not a feature of
the disease in the adult Dachshund [7,41].
Hematology, blood chemistries, urinalysis, CSF, and skull-spinal radiographs are normal, although
autofluorescent sea-blue histiocytes have been described in bone marrow aspirates from affected English Setters
[42]. Electrocardiographic changes have been reported in some affected dogs [43]. In contrast with early onset
ceroid lipofuscinosis in English Setters, plasma carnitine concentrations are not decreased in the late-onset
disorder in Tibetan Terriers [271]. Ophthalmoscopy may reveal a pigmented central retinal atrophy [16]. Early
diagnosis of affected dogs has been reported with the use of quantitative ocular fundic autofluorescence [44].
Electroretinography has shown that the c-wave is typically either decreased in amplitude, lacking or replaced by a
negative wave in English Setter dogs and Polish Owczarec Nizinny dogs with ceroid lipofuscinosis and associated
damage of the retinal pigment epithelium [22]. These c-wave changes were seen early in the disease, when the
a- and b-waves of the electroretinogram were still within normal limits. Computed tomography of the brain may
show dilatation of the ventricles and atrophy of the cerebral cortex [45,46]. Since many cell types are affected by
lipopigment accumulation, skin biopsies offer a useful antemortem diagnostic test [15].
Grossly, the cerebrum and/or cerebellum may be atrophic [1]. Microscopically, neuronal ceroid lipofuscinosis is
characterized pathologically by distention of large and small neurons with fine granular storage material that
stains gray to pale yellow with hematoxylin and eosin, bluish-black with Sudan Black and Luxol Fast Blue, orange
with Sudan III, is periodic acid-Schiff (PAS) positive, and shows yellow autofluorescence with ultraviolet light.
Affected neurons are distributed throughout the brain and spinal cord (including neurons of the peripheral nervous
system), the intensity of which varies with the particular canine breed involved [1], e.g., Purkinje cell pigmentation
is slight compared to that in large pyramidal cells of the cerebral cortex in Cocker Spaniels [16]. Loss of functional
neuronal cytoplasm results from increasing pigment accumulation. Nerve cells may eventually die and disappear,
with subsequent reactive astrogliosis [37]. This is especially evident in cerebellar Purkinje cells [1,3], although this
was not observed in affected older Dachshunds [7]. In Cocker Spaniels, degenerative changes are reportedly
more common in medulla and spinal cord [16,47]. Axonal spheroids occur in variable numbers throughout the
brain and spinal cord [1,16]. Wallerian type degeneration may be seen, along with widespread swelling of
astrocytes, and abundance of lipopigment-laden and vacuolated macrophages [3]. Histochemical and
immunocytochemical methods have demonstrated abnormal neuronal mitochondria and loss of GABAergic
neurons and synapses in cortex and cerebellum of affected English Setters [30]. Ultrastructurally, lipofuscin
granules may appear as electron dense bodies with multilamellar profiles, bodies with fingerprint patterns, zebra
crystalloids, or curvilinear profiles within neuronal membrane-bound cytosomes [9,13]. Macrophages tend to have
more vacuolar cytosomes and less lipofuscin [1]. Storage inclusions may also be observed in retinal ganglion
cells, autonomic ganglia, and cells in kidney, liver, pancreas, and smooth muscle fibers [18]. A distinct syndrome
occurs in some Cocker spaniel dogs in which there is a generalized accumulation of a lipofuscin-like pigment with
such a heavy accumulation in smooth muscle that the intestine and other organs have a brown discoloration [16-
18]. In some cats, pigment deposition appears to be restricted to neural tissues [26].
Prognosis is guarded to poor. Attempts to treat the canine disease using allogeneic bone marrow transplantation
have so far been unsuccessful [48].
Fucosidosis
Fucosidosis is a lysosomal storage disease resulting from a deficiency of the enzyme -L-fucosidase responsible
for metabolism of glycoasparagines with terminal fucose residues [49]. As a consequence of this enzyme
deficiency, there is an intralysosomal accumulation of substrate (fugoglycoproteins, oligosaccharides, and
glycosaminoglycans) in various tissues including central nervous system (CNS), peripheral nervous system (PNS),
kidney, pancreas, lymph nodes and lung. Fucosidosis occurs in English Springer Spaniels and has a worldwide
distribution with reports from Australasia, the United Kingdom, and North America [50-54]. The disease is
transmitted as an autosomal recessive trait [55].
Clinical signs are seen in young English Springer Spaniels and are characterized by progressive motor and
mental deterioration. From 6 to 12 months of age, affected dogs may be anxious, apprehensive, and slow to learn.
Ataxia, hypermetria, and proprioceptive deficits may be noted after 12 to 18 months [51]. Hearing, visual, and
menace deficits may develop from 18 to 24 months, followed by severe incoordination over the next 6 months.
During the third year of life, the bark frequently becomes monotonal and hoarse and dysphagia may be present,
sometimes accompanied by regurgitation (although without evidence of megaesophagus). Most dogs over 24
months of age have episodic pendular nystagmus elicited by positional change of the head. Death is not
uncommon in animals 3 to 4 years of age [54]. Enlarged ulnar nerves can be palpated in dogs with advanced
disease. In Canada, a confirmed case of fucosidosis has been reported in a 10 month old English Springer
Spaniel in which the initial problem was visual impairment [56]. Affected male dogs are infertile because of
decreased total sperm output, low sperm motility, and morphologic abnormalities of the spermatozoa [57,58]. In
contrast, affected females reproduce successfully, although estrus cycles are abnormal.
Hematological studies indicate that up to 40% of lymphocytes have marked cytoplasmic vacuolation. Bone
marrow macrophages show vacuolation also. CSF analysis is usually normal (WBC count, protein), although
vacuolated mononuclear cells may be detected [54]. Clinically affected homozygotes have < 5% of normal
enzyme activity in tissues, leukocytes, plasma, or cultured skin fibroblasts while carriers have approximately 50%
of normal activity [54,55,59]. Motor and sensory nerve conduction studies are normal and no EMG abnormalities
are present [54].
A notable gross autopsy finding is the pronounced enlargement of various nerves, associated with edema,
fibroplasia, and aggregates of vacuolated endoneurial macrophages [1]. The cervical vagus is the most severely
enlarged, sometimes measuring 10 mm in diameter [54]. Other involved nerves include optic, trigeminal,
hypoglossal, glossopharyngeal, and spinal nerve roots, especially those supplying the brachial plexus. Dorsal root
ganglia can also be enlarged. The lesions in the CNS are characterized by extensive cytoplasmic vacuolations
and swelling of many neurons and supporting glia throughout the brain and spinal cord. Loss of neurons may be
detected, especially of cerebellar Purkinje cells, and neurons in cuneate and gracile nuclei. Numerous vacuolated
macrophages are found in the meninges. Axonal spheroids are frequently seen, especially in hypothalamic,
cerebellar, cuneate, and gracile nuclei, usually associated with hypertrophic astrocytes [1]. Many phagocyte-like
cells with a foamy, vacuolated, PAS-positive cytoplasm are present either free in the parenchyma or as
pronounced cuffs around large vessels. Endoneurium and perineurium of peripheral nerves are infiltrated by
foamy macrophages and nerve fibers are separated by edematous, finely fibrillar ground substance. There are
minimal degenerative changes in peripheral nerves. Vacuolation is also found in cells of most visceral organs.
Ultrastructurally, the vacuoles are seen either as membrane-bound, rounded cytosomes with an empty interior, or
as amorphous, faintly stained material. Lectin staining of various paraffin-embedded tissues from human and
canine fucosidosis has demonstrated a species-specific histochemical variability [60]. Unlike several other
lysosomal storage diseases, Golgi staining of cortical pyramidal neurons in dogs with fucosidosis failed to
demonstrate evidence of ectopic dendrite growth, although there is GM2-like immunoreactivity limited to glia
and/or to non-pyramidal neurons [61].
Prognosis is guarded to poor. There is no treatment at present; however, treatment strategies in established
colonies of dogs with fucosidosis are being assessed as a potential animal model for gene therapy and enzyme
replacement therapy [62-71]. Bone marrow engraftment in dogs with fucosidosis has resulted in increased levels
of alpha-L-fucosidase enzyme activity in leukocytes, plasma, and neural and visceral tissues, accompanied by a
rapid improvement in the peripheral nerve and visceral lesions of fucosidosis and a more gradual improvement in
the CNS pathology [72]. Long-term engraftment from an early age reduced the severity and slowed the
progression of clinical neurological disease. In this study, transplantation after the onset of clinical signs was not
effective.
The molecular defect underlying canine fucosidosis has been identified [73] and a polymerase-chain-reaction
(PCR)-based diagnostic test for fucosidosis in English Springer Spaniels is now available, enabling detection of
both carriers and homozygotes [71,74,75]. Using this screening test, fucosidosis can be controlled and ultimately
eradicated from the English Springer Spaniel population [74].
Galactosialidosis
An adult-onset lysosomal storage disorder has been reported in a 5 year old Schipperke dog with progressive
cerebellar and central vestibular signs [76]. It is characterized by cerebellar atrophy with extensive loss of Purkinje
and granular cells, and hydrocephalus. Enlarged and vacuolated neurons are observed in spinal cord, brain and
autonomic ganglia. Ultrastructurally, enlarged secondary lysosomes filled with lamellated bodies are present in
neurons and empty enlarged vacuoles are found in pancreatic centroacinar, ductal, and islet cells. Neurons stain
with luxol fast blue, PAS, Concanavalia ensiformis agglutinin, and are autofluorescent. These findings are
consistent with an accumulation of glycolipids containing terminal beta-galactosyl and alpha-sialyl residues, and
N-linked oligosaccharides. Tissue activity of lysosomal beta-galactosidase was 50% of normal and the activity of
beta-hexosaminidase was elevated. Brain lipid-bound sialic acid level was twice normal, with a small increase of
GM1-ganglioside, but there was a significant elevation of GM2- and GM3-gangliosides. In addition, significant
elevations of sialylated and non-sialylated oligosaccharides were noted. These clinical, biochemical and
pathological findings are similar to those observed in human patients with adult-onset galactosialidosis.
Gangliosidosis
Ganglioside storage diseases are inherited (autosomal recessive) defects of lysosomal hydrolase enzymes that
result in accumulation of gangliosides (glycosphingolipids that are major constituents of plasma membranes in a
variety of cells, especially neurons) and glycolipid substrates of these hydrolases within lysosomes of most
neurons and glia throughout the nervous system [77-79], including brain, spinal cord, and autonomic ganglia.
In dogs and cats, several gangliosidoses have been identified and categorized according to the enzyme deficit
and degree of visceral involvement. GM1 gangliosidosis has been reported in cats (Siamese, Korat, and
Domestic Shorthair), and dogs (English Springer Spaniel, Portuguese Water dog, mixed-breed Beagle, Alaskan
Huskies, Shiba, and cross-breed dogs) [77,79-93]. The accumulation of ganglioside in the brain is due to
deficiency of acid -galactosidase. In people, there are infantile (type 1), juvenile (type 2), and adult (type 3)
variants of GM1. GM2 gangliosidosis has been reported in German Shorthair Pointers, Japanese Pointers, mixed-
breed cats, and Korat cats [94-101]. Four major enzymatic variants of GM2 gangliosidosis are recognized in
people based on their defective subunits or activator protein [100,101]:
a. Type B, or Tay Sachs disease, due to deficiency of hexosaminidase A;

b. Type O, or Sandoff's disease, due to deficiency of hexosaminidase A and B;
c. Type AB, due to deficient or defective GM2 activator; and
d. Type B-1, due to a mutation in the -subunit of -hexosaminidase.
Massive accumulation of ganglioside occurs in all animals with GM2 gangliosidosis; however, the biochemical
defect varies. A marked deficiency in activity of hexosaminidase A and B is reported in Korat cats (similar to
Sandoff's disease in people). In the Japanese Spaniel, the biochemical basis is thought to be due to attenuation in
stimulatory activity of the GM2 activator (similar to Type AB in people), and -hexosaminidase activity may be 12
fold higher than that in normal brain [100]. In a report of GM2 gangliosidosis in a German Shorthair Pointer,
massive accumulation of GM2 ganglioside was found in the brain and in other organs; however, -
hexosaminidase activity in plasma, liver, kidney and brain was normal, suggesting either an activator protein
disorder or a B-1 variant [101]. A partial deficiency of -hexosaminidase activity has also been reported in this
breed [99].
In most of the gangliosidoses, total ganglioside content of brain is high in clinically affected animals. Asialo (sialic
acid free) derivatives of the gangliosides also accumulate in brain and liver [79]. High levels of other neutral
glycosphingolipids may also be found. In some instances, different substrates are stored in neural and visceral
tissues, probably reflecting the heterocatalytic activity of the deficient enzyme. For example, English Springer
Spaniels and Portuguese Water dogs (PWDs) with GM1 gangliosidosis reportedly store GM1-ganglioside, asialo-
GM1, and oligosaccharides in brain but only the PWDs store glycoproteins containing polylactosaminoglycans in
visceral organs, and neither breed stores them in the brain [89]. Visceral storage of glycolipids and glycoproteins
occurs in canine and feline GM1 gangliosidoses. Visceral involvement was not observed in the Japanese Spaniel
with GM2 gangliosidosis [98], but in a report of GM2 gangliosidosis in a German Shorthair Pointer, storage of
ganglioside was observed in liver, kidney, and spleen [101].
Clinical signs of GM1 gangliosidosis are first noted in dogs around 4 to 5 months of age and in cats from 2 to 5
months of age. In animals with GM2 gangliosidosis, onset of clinical signs is from 1 to 3 months of age in kittens,
6 to 12 months of age in German Shorthair Pointers, and around 18 months of age in Japanese Spaniels. Stunted
growth and failure to eat may be noted early in life. Neurological signs are very similar in both species and are
highlighted by their relentlessly progressive nature [79]. Cerebellar-like signs of ataxia-dysmetria, discrete head
tremor, loss of balance, and abnormal nystagmus are often the first signs observed, followed by spastic
paraplegia or tetraplegia, visual impairment, depression, sometimes dementia, seizures, aggression, and death.
Corneal clouding has been seen in feline GM1 and GM2 gangliosidosis associated with proteoglycan storage in
corneal endothelial cells and fibroblasts [83,102]. Proportional dwarfism has been reported in English Springer
Spaniel (these dogs also have coarse facial features, including ocular hypertelorism or increased width between
the eyes), Portuguese Water dog, and Alaskan Husky puppies [90,103]. In addition, skeletal lesions such as
deformed, irregular and abnormally widened intervertebral disk spaces, have been reported in English Springer
Spaniels and Portuguese Water dogs [89]. Some cats with GM1 gangliosidosis manifest facial dysmorphia and
hepatomegaly.
Note that clinical signs in cats with panleukopenia (parvo) virus-induced cerebellar hypoplasia and the
gangliosidoses are similar; however, cats with the former disorder typically show signs at birth or shortly thereafter
and the signs remain relatively static. Several electrodiagnostic abnormalities have been reported in cats with
GM1 gangliosidosis, including slow spinal evoked potentials in cats over 200 days of age and prolonged latencies
of brainstem auditory evoked responses in cats over 90 days of age [104], findings consistent with the hypothesis
that at least some of the abnormalities in cats with this lysosomal enzymopathy may be associated with altered
CNS synaptic activity [105] (see also neurotransmission derangement, below). Motor and sensory nerve
conduction velocities were normal and no abnormal spontaneous potentials were found by needle EMG [104].
Gross changes are usually not present although the liver may appear swollen and pale [1]. Microscopically, the
storage material produces widespread neuronal distension (in CNS, autonomic ganglia, and retina) with a foamy
to granular cytoplasm due to tightly packed vacuoles that displace the Nissl substance. Nuclei are eccentrically
placed and there may be variable neuronal loss. Astrocytes may be similarly affected. Vacuoles in frozen sections
often stain positively with Luxol fast blue and Grocott's method, PAS, and Sudan Black [1]. Axonal spheroids are
variably seen in white matter in GM1 and GM2 gangliosidosis [106]. These structures may involve axons of
inhibitory GABAergic neurons, suggesting that a resulting defect in neurotransmission in inhibitory circuits may be
an important factor underlying brain dysfunction in animals with gangliosidosis [107]. Abnormal myelin
development in the CNS (based on magnetic resonance imaging, white matter histopathology, and
immunostaining) has been reported in dogs (English Springer Spaniel and Portuguese Water Dog) with GM1
gangliosidosis [108] and in cats with Sandhoff-like GM2 gangliosidosis [109]. In Alaskan Huskies with GM1
gangliosidosis, mild demyelination and axonal degeneration were accompanied by a significant astrogliosis in the
gray matter and a significant loss of oligodendrocytes in the gray and white matters [90]. I have observed
paranodal demyelination in up to 10% of single teased peripheral nerve fibers from some cats with GM2
gangliosidosis. Wallerian degeneration has also been reported in peripheral nerves, ventral and dorsal nerve
roots, and in dorsal funiculi of all spinal cord segments in a 2 year old mixed breed dog with GM2 gangliosidosis
(due to a presumed defect or deficiency of hexosaminidase activator protein) [257]. Ultrastructurally, cells are
packed with membrane-bound vacuoles containing a membranous, lamellar material arranged in whorls, called
membranous cytoplasmic bodies, or stacks of membranes in parallel arrays that have been termed zebra bodies
[110]. The axonal spheroids are filled with electron-dense bodies, degenerating mitochondria, tubulovesicular
profiles but little or no storage material [1]. Endothelial cells and perivascular macrophages in many organs are
vacuolated in the gangliosidoses, including endoneurial macrophages in nerves from cats with GM2
gangliosidosis. The vacuoles tend to be empty or contain variable amounts of fibrillar or granular remnants of
oligosaccharides which have been washed out during tissue fixation [1]. Golgi and ultrastructural studies reveal
the presence of conspicuous enlargements (meganeurites - a manifestation of the storage process) located
between the axon and cell body which appear to give rise to neurites and dendritic spines in cortical pyramidal
neurons in canine and feline gangliosidoses [98,105,106,111]. These structures are postsynaptic to afferent fibers
of unknown origin, are thought to contribute to neuronal dysfunction, and their distribution varies with cell type and
brain region. The meganeurites are distended with membranous cytoplasmic bodies [111].
Skeletal lesions in English Springer Spaniel, Portuguese Water dog, and Alaskan Husky puppies are
characterized by retarded endochondral ossification and osteoporosis [90,103]. Older puppies have focal cartilage
necrosis within lumbar vertebral epiphyses. At the cellular level, lesions are characterized by chondrocytic
hypertrophy and lysosomal accumulation of storage compounds. Premature thymic involution has been
demonstrated in feline GM1 gangliosidosis [112].
In animals with peripheral nerve lesions, there may be slow motor nerve conduction velocities and reduced
amplitude of evoked muscle potentials [257]. A tentative diagnosis is suggested by presence of cytoplasmic
inclusions in peripheral blood leukocytes. In animals with GM1 gangliosidosis, oligosaccharides may be detected
in urine in abnormally high quantities. Definitive diagnosis requires biochemical identification of the storage
product and absence or marked reduction in activity (e.g., only 3 to 5% of the activity seen in homozygous
normals) of specific lysosomal enzymes required for hydrolysis of accumulated compounds (e.g.,
chromatographic analyses may indicate a 5 to 10 fold increase in ganglioside storage). Note that the enzyme
level in clinically unaffected heterozygotes is approximately 50% that of normal animals. Antemortem diagnosis
can be made by enzyme assay of whole skin, cultured skin fibroblasts, liver, and purified leukocytes. Neonatal
diagnosis using enzyme assays of placenta and umbilical cord has been reported in GM1 gangliosidosis [89].
Postmortem diagnosis is made most reliably by enzyme assay of brain. Prognosis is grave. There is no definitive
treatment at present but different strategies that have been tested in animal models include gene transfer and cell
engraftment of neural stem cells engineered to express the specific enzyme deficiencies [113]. Allogeneic bone
marrow transplantation early in life was found to be ineffective in canine GM1 gangliosidosis [114].
A suspected lysosomal storage disease has been reported in Abyssinian kittens in which the clinical signs are
very similar to those reported above [115-118]. In human patients with gangliosidosis, peripheral nerve lesions
are usually not significant, although motor neuronopathy tends to be common in late onset GM2 cases [258].
Gaucher's Disease
Gaucher's disease, or glucocerebrosidosis, is a rare lysosomal storage disease caused by a deficiency of
glucocerebrosidase (glucocerebroside -glucosidase) that catalyzes the hydrolysis of glucocerebroside to
ceramide and glucose [119]. A form of Gaucher's disease (similar to the type 2, infantile form in people) has been
reported in Australian Silky Terriers [120-122].
Clinical signs reportedly occur around 4 to 6 months of age, are progressive, and are characterized by severe
incoordination, wide-based stance, stiff gait, generalized tremors, hyperkinesis, and hypermetria. No gross
findings have been noted in brain or spinal cord. Microscopically, the cytoplasm of many neurons in the brain, but
not in the spinal cord, is distended and has a foamy, finely vacuolated appearance that often contains weakly
eosinophilic, PAS-negative granules [122]. Nissl granules appear lost or peripherally displaced. Neurons of the
dorsal and lateral thalamic nuclei and the dorsal hippocampus are especially affected, with less severe changes
occurring in cerebral cortical gray matter, inferior colliculus, oculomotor nucleus, cochlear nucleus, trigeminal
motor nucleus, superior olivary nucleus, dentate nucleus, fastigeal nucleus, and ventral pontine gray matter.
Gaucher cells (foamy, distended macrophages) are found in the cerebellar granule cell layer that may be mildly to
severely atrophic. In addition to variable granule cell loss, degenerating Purkinje cells may be noted. At all levels
of the brain there is mild to moderate spongy vacuolation of white matter and breakdown of myelin sheaths. The
most severely affected areas include central white matter of the cerebral hemispheres, corpus callosum, optic
tracts, cerebral peduncles, trapezoid body, central cerebellar white matter, and spinocerebellar and corticospinal
tracts. Axonal spheroids may be seen, especially in ventral pontine gray matter. Gaucher cells are also found in
several visceral organs, including liver (without signs of hepatomegaly) and lymph nodes. Ultrastructurally, the
storage material in neuronal cytosomes appears laminated (zebra-like bodies) with variable fine fibrillar material.
These structures, as well as twisted tubular material, are also seen in Gaucher cells.
Premortem diagnosis can be established by determining enzyme activity in leukocytes. Negligible -glucosidase
activity can be determined at pH 4.0 to 4.25 [123]. Postmortem diagnosis is made most reliably by enzyme assay
of brain and liver as well as finding elevated levels of glucocerebroside, especially in liver [122]. Prognosis is poor.
There is no treatment at this time.
Globoid Leukodystrophy
Globoid cell leukodystrophy (Krabbe's disease or galactocerebrosidosis) is a rare lysosomal storage disease that
results in progressive degeneration of white matter of the CNS and PNS. The disease is caused by mutations in
the gene for the lysosomal enzyme galactosylceramidase (GALC) (or galactocerebroside -galactosidase), which
results in an accumulation of psychosine (galactosylsphingosine), a lipid that is highly toxic to oligodendrocytes
and Schwann cells [124-127].
Globoid cell leukodystrophy is inherited as an autosomal recessive trait in young (3 to 6 month-old) West
Highland White Terriers (WHWT) and Cairn Terreirs [128-136]. The disease also has been reported in a 4 month
old Beagle [137] a 2 year old Poodle [138], a 4 year old Basset Hound [139], 4 month old Blue Tick Hounds [140],
two Pomeranians - 5 1/2 months and 14 years of age [139,141] and in Domestic Shorthair and Longhair kittens
[142,270]. Recently, the condition has been reported in Irish Setter puppies around 6 weeks of age [143].
The clinical signs associated with this disease are variable and may reflect a multifocal syndrome. Animals often
present with either signs of an ascending posterior paralysis or signs of a cerebellar syndrome, or both. Signs of a
neuropathic syndrome are infrequently observed (e.g., in Irish Setters) and include depressed spinal reflexes,
reduced muscle tone, and muscle atrophy. As the disease progresses, signs of a cerebral syndrome may be
observed (including behavioral abnormalities, depressed mentation, visual deficits, etc.). In terminal cases,
usually prior to 1 year of age, animals may become prostrate, demented, anorexic, and cachectic [134]. The
progression of clinical signs appears more rapid in Irish Setters. Partial motor seizures characterized by repetitive
jaw movements, muscle twitching, licking and chewing movements, fly biting and opisthotonus have been
observed in some affected Irish Setters. Prolonged postrotatory nystagmus can be induced by rotating affected
animals [144].
Results of ancillary aids usually are non-specific. Hematology, blood biochemistry, ophthalmology and spinal-skull
radiography are normal. Analysis of CSF, however, can reveal an elevated protein level with cell counts usually
within normal limits (albuminocytologic dissociation). Mononucleated or multinucleated PAS-positive cells are
sometimes identified in CSF [145]. Magnetic resonance and magnetization transfer imaging in affected dogs are
compatible with diffuse, symmetrical white matter disease [146,147], while electrodiagnostic testing may reveal an
abnormal brainstem auditory evoked response, abnormal spontaneous muscle activity (fibrillation potentials and
positive sharp waves), and slow motor nerve conduction velocities [144,146]. Electroencephalographic traces also
may be abnormal.
Grossly, involved regions of fixed white matter of the CNS are gray and soft compared to normal white matter,
while leukodystrophic peripheral nerves may appear normal or enlarged and whiter than normal nerves [134].
Ventricles may be enlarged 2 to 3 times normal size in some animals [148]. Significant lesions typically are
confined to the white matter of the nervous system where any level of the brain and spinal cord may be affected,
although lesions were limited to the brainstem and spinal cord in an older Basset Hound [139], and subcortical
lesions were minimal in the affected Beagle [137]. Lesions tend to be symmetrical but with variable intensity at
different levels within the neuraxis. In WHWT and Cairn Terriers, most severe changes may be seen in central
and gyral white matter of the cerebrum, optic tracts, corpus callosum, fimbria, subcortical and adjacent folial white
matter of the cerebellum, and outer one-half of the funiculi of the spinal cord [148]. The disease is characterized
by destruction of white matter and replacement by aggregates (often in a perivascular fashion) of nonsudanophilic,
nonmetachromatic, PAS-positive macrophages called "globoid cells", usually with accompanying hypertrophic
astrocytes. Globoid cells are CD68 and ferritin positive, verifying their monocytic origin [270]. Myelin stains weakly
in affected areas and there may be loss of oligodendrocytes. Axons are lost in the larger globoid cell collections.
Changes in gray matter are minimal. In peripheral nerves, lesions may be typified by multifocal presence of
segmental demyelination, variable axonal degeneration, and endoneurial accumulation of globoid macrophages
[144,149,150]. In a recent study, a significant increase in the G-ratio (axon diameter divided by fiber diameter)
was identified in affected dogs suggesting a decrease in total fiber diameter which appeared to be due to myelin
loss or hypomyelination [144]. Ultrastructurally, intracytoplasmic vacuoles in Schwann cells and macrophages
may contain myelin debris and characteristic twisted or straight-to-arched tubular inclusions [133]. Endoplasmic
reticulum is often dilated and there may be evidence of mitochondrial degeneration [150].
Antemortem diagnosis may be suggested by nerve biopsy and demonstration of the characteristic ultrastructural
inclusions [144,149,150] and established by levels of GALC activity in blood leukocytes of affected dogs or from
cultured fibroblasts - the mean enzyme activity is reportedly 18% of the activity in normal dogs, whereas
heterozygous carriers have a mean enzyme activity of about 50% of normal [151]. A screening test for clinically
normal heterozygote carriers among WHWT and Cairn terriers, based on the molecular defect, has been
established and provides rapid and accurate genotyping for all WHWT and Cairn terriers using any tissue sample
available [152]. A similar DNA-based PCR test is available for Irish Setters [143]. Mutation analysis for carrier
identification is superior to measurement of GALC activity because of the wide range of GALC values in
peripheral blood leukocytes [127]. PCR testing will also facilitate prenatal diagnosis based on small fetal tissue
samples (e.g., chorionic villus biopsy and amniotic fluid cells). Lipid analysis of brain reveals marked elevations in
psychosine [127]. Deficient enzyme activity may also be found in liver and kidney [151].
Researchers and clinicians at the University of Pennsylvania, School of Veterinary Medicine, are investigating
treatment strategies. To date, studies have shown successful transduction of cultured skin fibroblasts from an
affected dog and normal canine bone marrow using a retroviral vector containing the human GALC cDNA [127].
However, intracerebral inoculation of an affected dog with transduced bone marrow stromal cells did not result in
improved brain pathology (Dr. Charles Vite, personal communication, 2001).
Glycogenosis
Glycogen storage diseases or glycogenoses, are uncommon disorders in dogs and cats. These diseases
represent inborn errors of metabolism due to deficient activity of one of the enzymes involved in glycogen
metabolism. The enzyme defects result in inadequate glycogen utilization and accumulation of glycogen of normal
or abnormal chemical structure within various tissues, including muscle.
Glycogenosis Type Ia - a Von Gierke-like disease associated with glucose-6-phosphatase (G-6-Pase) deficiency
has been reported in related Toy Breed puppies between 6 and 12 weeks of age [153], with signs of depression,
coma, hypothermia, hypoglycemia, hepatomegaly and histological evidence of excessive glycogen accumulation
in liver, kidney and sometimes myocardium, [154,155]. G-6-Pase deficiency has recently been reported in two 47-
day-old littermate Maltese puppies presented for necropsy with a history of failure to thrive, mental depression,
and poor body condition, [156] and the genetic mutation has been identified [157]. Gross findings included small
body size and emaciation, severely enlarged pale livers, and pale kidneys. Histologically, there was marked
diffuse vacuolation of hepatocytes with large amounts of glycogen and small amounts of lipid. Renal tubular
epithelium was mildly to moderately vacuolated. Biochemical analysis showed that levels of G-6-Pase were
markedly reduced in liver and kidney and that glycogen content was increased in liver. A colony has been
established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective G-6-Pase gene [158].
Puppies from this colony exhibited tremors, weakness, and neurologic signs when hypoglycemic. They had
postnatal growth retardation and progressive hepatomegaly. Biochemical abnormalities included fasting
hypoglycemia, hyperlactacidemia, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia. Microscopic
and biochemical findings were similar to those found in the Maltese puppies [158]. Gene therapy has resulted in
sustained G-6-Pase expression and improvement in liver histology and in biochemical parameters [266].
Glycogenosis Type II - or Pompe's disease in people, due to acid -glucosidase enzyme deficiency, has been
reported in related Lapland dogs [154,159-161]. Clinical signs developed in animals after 6 months of age and
were characterized by progressive muscle weakness, frequent vomiting and regurgitation, megaesophagus,
dysphonia, persistent panting and cardiac abnormalities. Death occurred before the age of 2 years.
Electromyographic studies revealed prolonged insertion activity, bizarre high frequency discharges, and
occasional fibrillation potentials and positive sharp wave activity. The main lesions consisted of massive glycogen
accumulation in membrane-bound vacuoles (glycogenosomes), involving most organs (including cerebral cortex
and skeletal, cardiac, and smooth muscle) [160]. The disease has an autosomal recessive mode of inheritance
[162] and may be confirmed by low leukocyte activity of acid -glucosidase. The enzyme protein is present in
affected tissues, although in an inactive form [163]. Heterozygous animals may be identified by their partial
deficiency of acid -glucosidase in leukocytes [162]. Prognosis is poor. There is no treatment.
Glycogenosis Type III - or limit dextrinosis, a glycogenosis similar to Cori's disease in people, is associated with
a deficiency of the debranching enzyme amylo-1,6-glucosidase (reduced to between 0 and 7% of normal activity)
and has been reported in German Shepherds and Akitas [164-167]. Muscular weakness and exercise intolerance
was noted as early as 2 months of age. Other clinical signs included progressive abdominal distention as a result
of hepatomegaly. Abnormal glycogen-like material occurred in liver, muscle (smooth, cardiac and skeletal) and
neurons and glial cells of the CNS [154]. The stored substance lay freely dispersed in the cell cytoplasm without
any indication of lysosomal storage [164]. The molecular basis for this disease has been characterized and a
PCR screening test is available for diagnosis [259,260].
Glycogenosis Type IV - (Andersen disease, amylopectinosis), an inherited (autosomal recessive) deficiency of

the glycogen branching enzyme -1,4-D-glucan: -1,4 glucan 6-glucosyl transferase, has been reported in a
family of young Norwegian Forest cats [168,169]. Two cats developed fever, generalized muscle tremors, bunny-
hopping gait, and weakness at 5 months of age which progressed to tetraplegia by 8 months of age. Fever
disappeared at 8 months of age. Severe generalized muscle atrophy with contracture of the caudal antebrachial
and cranial thigh muscles were present at the time 2 cats were euthanized (at 8 and 13 months). The older cat
had ventricular hypertrophy. Abnormal fibrillation potentials were recorded in most muscles of one cat. The third
cat died at 5 months of age before clinical signs developed. In another report, an unrelated Norwegian Forest cat
had similar clinical signs beginning at 5 months of age [170]. In addition, this cat developed generalized, tonic-
clonic seizures.
Microscopically, glycogen storage disease type IV is characterized by granular to globular intracytoplasmic
storage of PAS-positive, diastase-resistant material that stains blue with hematoxylin and eosin and purple-blue
with Lugol's iodine and is found in many organs, including skeletal muscle. Stored material was found in neurons
throughout the CNS and PNS including dorsal and ventral horns, dorsal root ganglia, sensory and motor nuclei
throughout the brainstem, Purkinje cells in the cerebellum, ganglion cells of the retina, autonomic ganglia, and
myenteric plexi of the intestinal tract [168]. Accumulation of abnormal glycogen is accompanied by severe
degeneration in the CNS and PNS, skeletal muscle, and heart. There is extensive loss of axons and myelin in
peripheral nerves, spinal cord white matter, and cerebellar peduncles [171]. In peripheral ganglia and neurons
within the CNS in which there is extensive storage, there is loss of neuronal cell bodies and astrogliosis.
Ultrastructural evaluation of the stored material demonstrates irregular, non-membrane bound, finely granular
cytoplasmic deposits [168,171]. Analysis of the glycogen in affected cats indicates less branching than normal
and branching enzyme activity less than 10% of normal levels in liver and muscle [168]. Partial deficiency was
found in muscle and leukocytes of the parents of affected cats. The molecular basis for this disease has been
characterized and a PCR screening test is available for diagnosis [259,260].
Glycogenosis Type VII - an inherited (autosomal recessive) deficiency of phosphofructokinase (PFK),

comparable to type VII glycogen storage disease in people, is recognized in English Springer Spaniels less than
12 months of age [172-175]. Muscle and erythrocyte PFK activities are deficient [174,175]. Characteristically,
enzyme-deficient dogs have compensated hemolytic anemia and sporadic episodes of intravascular hemolysis
with hemoglobinuria. Typically, clinical signs of muscle or CNS disease are not features of this disorder; however,
muscle cramping has been noted in affected field trial dogs and in hunting dogs, both in the USA and in Europe
[176,177]. Further studies are needed to determine if the behavioral abnormality observed sporadically in some
affected dogs (called "Springer rage" syndrome by the breeders) is related to PFK deficiency. Interestingly, a
severe, progressive myopathy characterized by weakness and muscle atrophy has been reported in an 11 year
old PFK-deficient English Springer Spaniel [178]. Muscle changes included large accumulations of basophilic
floccular material in hematoxylin and eosin sections that stained strongly with PAS. Ultrastructurally, the non-
membrane bound deposits were composed of short granular filaments, 8 to 12 nm in diameter and 100 to 160 nm
in length, small granules, and amorphous material. Based on staining characteristics, the deposits were thought
to represent an amylopectin-like polysaccharide with possible sialic acid residues. Total PFK activities were
markedly reduced when assayed in skeletal muscles of this dog. In contrast with other PFK-deficient dogs,
muscle glycogen in this animal was not increased above that of normal dogs [178].
A PCR-based diagnostic test has been developed for detecting dogs with PFK deficiency and clinically normal
carriers [177,179]. Preliminary treatment attempts using bone marrow transplantation have shown promise. An
identical condition, having the same molecular mutation, has been found in American Cocker Spaniels [180].
Screening for PFK deficiency is recommended for English Springer Spaniels with suspicious clinical signs and
before using any for field trials or breeding in order to prevent the further spread of this hereditary disorder [177].
A suspected glycogen storage disease that was accompanied by growth retardation, progressive muscular
weakness, atrophy of pelvic limbs, and death has been reported in cats between 1 and 4 months of age [181].
There was hepatomegaly, splenomegaly, and focal necrosis of muscle and elevated serum creatine kinase and
aldolase activity. Glycogen-like material occurred in reticuloendothelial cells, liver and muscle cells.
Mucolipidoses
I-cell Disease - I-cell disease is a rare lysosomal storage disease caused by a deficiency of the enzyme N-
acetylglucosamine-1-phosphotransferase (GlcNAc-phosphotransferase) recently reported in cats [261,262] and
considered homologous to I-cell disease (or mucolipidosis type 3) in humans [199]. The disease is characterized
by facial dysmorphism, large paws in relation to body size, dysostosis multiplex, and poor growth. Affected cats
appear dull, ataxic, and may have decreased muscle tone. Radiographic abnormalities are seen as early as 2
weeks of age and lesions include long bone metaphyseal flaring, radial bowing, and antebrachial-carpal joint
luxation. Fusion of cervical and lumbar vertebral bodies develop within the first 5 months of life. In some severely
affected cats, spina bifida and hemivertebraw have been noted. Retinal degeneration may be detected around 2 -
3 months of age. The condition has an autosomal recessive mode of inheritance and affected cats either die or
require euthanasia within 1 day to 7 months of age. The urine mucopolysaccharide spot test is negative. The
enzyme GlcNAc-phosphotransferase is deficient in leukocytes and cultured fibroblasts. Inclusion bodies have
been detected in cultured fibroblasts but not in white blood cells. Inclusions have also been seen in endothelial
cells and chondrocytes. Storage lysosomes contained oligosaccharides, mucopolysaccharides, and lipids.
Tissues most affected are bones, cartilage, skin, and other connective tissues. Parenchymal cells of liver and
kidney are unaffected, as is skeletal muscle. Few cerebral cortical neurons show lipid inclusions and peripheral
nerves appear normal. It should be noted that the subtle neurologic signs in affected cats are believed to be
secondary to the orthopedic changes [262].
Mannosidosis
Mannosidosis is a lysosomal storage disease resulting from a deficiency of the enzyme alpha-D-mannosidase in
various organs, including brain, kidney and liver. Lysosomal alpha-D-mannosidase is involved in the catabolism of
N-linked glycoproteins through the sequential degradation of high-mannose, hybrid, and complex
oligosaccharides [182]. In feline alpha-mannosidosis, the accumulated oligosaccharides primarily represent intact
oligomannosyl moieties of N-linked glycans rather than the products of residual alpha-mannosidase activity [183].
As a consequence of this enzyme deficiency, there is intralysosomal accumulation of glycoprotein-derived,
mannose-rich oligosaccharides. This rare disease has been reported in a 7 month old Domestic Shorthair (DSH)
cat [184,185], in Domestic Longhaired (DLH) cats aged between 7 and 15 months [186], and in Persian kittens
[187-189]. There is considerable heterogeneity among these reports regarding clinical onset, clinical course, and
pathology. All cats have signs of apparent cerebellar dysfunction, including ataxia-dysmetria and intention tremors.
However, stillbirths and neonatal deaths may occur in Persian litters and many affected animals may not survive
the first 6 months of life [189]. Some affected cats show gingival hyperplasia, bizarre behavior, such as running in
circles, jumping without provocation, and standing in the water bowl, and progressive dementia and apathy [187].
Other findings include corneal changes, open suture lines in calvaria, thymic aplasia, hepatomegaly, and
polycystic kidneys. In the DSH cat, thoracic limb deformation due to lateral dysplasia of the carpus was noted at 4
months of age [184]. Other findings included radiographic abnormalities of the spine and long bones, cataracts
and tapetal changes, hepatomegaly, lymphadenopathy, and thickened peripheral nerves. In DLH cats, additional
clinical signs such as lurching, falling, opisthotonus, paraplegia, megaesophagus and systolic heart murmur have
been reported; however, none had evidence of hepatomegaly, skeletal deformities or ocular abnormalities [186].
Microscopic lesions are characterized by extensive vacuolation of neurons and glial cells of the nervous system
(more in astrocytes than oligodendrocytes), as well as in spinal and enteric ganglia [186]. Numerous vacuolated
macrophages may be seen in peripheral nerves and in perivascular spaces of the CNS, and in a variety of
parenchymal organs. Poor myelination of the cerebral white matter (especially in the corona radiata) and axonal
spheroid formation (torpedoes, neuroaxonal dystrophy) in cerebral and cerebellar white matter, thalamic
radiations, and cerebellar roof nuclei have been observed in Persian kittens, while abnormally thin myelin was
noted in DSH cats. Neither these changes nor the extensive vacuolation of hepatocytes and pancreatic acinar
cells seen in Persian and DSH cats, were observed in the DLH cats [186], although abundant axonal spheroids
were found ultrastructurally in DLH cats. Immunocytochemical studies showed that the spheroids reacted
positively with glutamic acid decarboxylase, the synthetic enzyme for the inhibitory neurotransmitter, gamma-
aminobutyric acid [107]. Extensive Purkinje cell loss was seen only in the DLH cats. In all cats, ultrastructural
findings indicate that most neurons contain empty membrane-bound vacuoles or only small amounts of finely
granular material. Some neuronal cytosomes have linear membranous profiles and vesicular or lamellar,
membranous cytoplasmic bodies [184,186]. Lipofuscin-like inclusions may be seen in larger neurons. Vacuoles
are present in CNS vascular endothelial cells and pericytes. Neuritogenesis, as determined by Golgi staining, is
not as prominent in cortical neurons of mannosidosis cats as it is in other storage disorders, such as
gangliosidosis, sphingomyelinosis, and mucopolysaccharidosis; however, meganeurites, secondary neurite
formation, and various types of dendritic changes have been observed [190]. Very similar changes have been
reported in swainsonine-induced feline -mannosidosis [191].
Diagnosis is based on demonstrating a deficiency of acidic -mannosidase in brain, liver or kidney, or detecting
mannose-rich oligosaccharides in urine [192]. A three-fold increase in the level of alpha-D-mannoside has been
reported in liver and brain of affected cats [193]. Lectin histochemistry on formalin-fixed, paraffin-embedded tissue
sections is also a simple, reliable method for diagnosing alpha-mannosidosis [194]. Cytoplasmic vacuolation is
seen in blood lymphocytes and monocytes in Giemsa-stained blood smears [188]. It is possible to distinguish
between heterozygous and affected kittens by using enzyme assay and oligosaccharide determination in
placenta: -mannosidase activity is < 10% of control in affected kittens, and < 50% in heterozygous kittens [195].
Prognosis is poor. Treatment strategies are being investigated in colonies of affected cats. The cDNA encoding
lysosomal alpha-mannosidase has been cloned in the Persian cat, and not surprisingly, in accordance with the
variable clinical and pathological features, genetic studies have shown there is molecular heterogeneity for feline
alpha-mannosidosis [196]. Researchers at the University of Pennsylvania, School of Veterinary Medicine, have
also reported that retrovirus vector transfer of a new human alpha-mannosidase cDNA resulted in high-level
expression of alpha-mannosidase enzymatic activity in deficient human and feline fibroblasts [197]. In a recent
study by this group using Persian crossbred cats with a four base pair deletion in the gene encoding alpha-
mannosidase [198], there was evidence of defective myelination in both CNS and PNS. Magnetic resonance
imaging of the brains of affected cats revealed diffuse white matter signal abnormalities throughout the brain.
Quantitative magnetization transfer imaging showed a 8 - 16% decrease in the magnetization transfer ratio in the
white matter of affected cats compared to normal cats indicating myelin abnormalities. Histology confirmed myelin
loss throughout the cerebrum and cerebellum. Affected cats showed slow motor nerve conduction velocity and
increased F-wave latency. Single nerve fiber teasing revealed significant demyelination-remyelination in
peripheral nerves. Ultrastructural findings in peripheral nerves included presence of numerous membrane-bound
vacuoles within Schwann cell cytoplasm, endoneurial and perineurial macrophages, endothelial cells, and
pericytes. The cytosomes were either empty or contained a fine fibrillar material. Many myelinated fibers were
thinly myelinated and there was scattered presence of onion-bulbs and naked axons [198]. A significant increase
in the G-ratio (axon diameter divided by fiber diameter) was identified in affected cats suggesting a decrease in
total fiber diameter associated with myelin loss and/or hypomyelination.
Mucopolysaccharidoses
The mucopolysaccharidoses are a diverse group of inherited lysosomal diseases that result from deficits in the
metabolism of certain glycosaminoglycans or acidic mucopolysaccharides, such as dermatan, heparan,
chondroitin, and keratan sulfates, which accumulate in various connective tissues, as well as in brain, and are
excessively excreted in urine. Thirteen subclasses of mucopolysaccharidosis have been described in people [199].
Clinically these diseases are characterized by multisystem abnormalities including skeletal alterations (e.g., facial
dysmorphism), limited joint mobility, corneal clouding, hepatosplenomegaly, and mental retardation. Similar signs
have been seen in dogs and cats, but usually without neurological involvement, despite accumulation of
incompletely degraded glycosaminoglycans in the CNS. The mucopolysaccharidoses described in cats and dogs
are considered to be recessively inherited.
Mucopolysaccharidosis Type I (MPS I) - caused by a deficiency of alpha-L-iduronidase, has been reported in

Domestic Shorthair cats less than 6 months of age [200]. Signs include lameness, broad face with depressed
nasal bridge and frontal bossing, small ears, corneal clouding, and multiple bone dysplasia, including fusion of
vertebrae over the cervicothoracic junction, pectus excavatum, and bilateral coxofemoral subluxation.
Neurological signs are usually not seen or mild, however exaggerated myotatic reflexes, impaired pelvic limb
proprioception, along with reduced cervical mobility range and apparent pain on cervical palpation have been
recently described suggesting possible cervical myelopathy [265]. Slowing of CNS conduction, predominantly in
the cervical spinal cord, as determined by somatosensory evoked potentials, is supportive of some form of
cervical cord dysfunction in affected cats [265]. Cats excrete excessive amounts of glycosaminoglycans in urine,
and glycosaminoglycan storage is evident in fibroblasts and neurons. Gross postmortem findings include
hepatosplenomegaly, opaque meninges, and lateral ventriculomegaly. Membrane-bound vacuoles, either empty
or containing a fibrillar material or lamellar cytoplasmic inclusions (zebra-like bodies) are present in CNS neurons,
hepatocytes, chondrocytes, vascular and splenic smooth muscle cells, bone marrow leukocytes, and fibroblasts of
the skin, eye, and cardiac valves [201]. Activity of alpha-L-iduronidase is deficient, e.g., approximately 5% of that
of control cats in cultured fibroblasts and leukocytes [202]. An ill-defined relationship between MPS I and
meningiomas has been reported in young cats less than 3 years of age [203]. Enzyme replacement therapy
(recombinant alpha-L-iduronidase) was effective in reversing storage in some tissues at the biochemical and
histological level in MPS I cats, although the enzyme was not consistently detected in cerebral cortex, brainstem,
or cerebellum and the histological appearance and ganglioside profiles did not improve [204]. The mutation
causing MPS I in cats has been identified and characterized [205]. Feline MPS I resembles Hurler's disease in
people.
In dogs, a similar enzyme deficiency has been noted in Plott Hounds [206,207], which more closely matches
Hurler-Scheie syndrome in people, a form of alpha-L-iduronidase deficiency of intermediate severity [207]. Clinical
signs are seen in dogs less than 6 months of age, and are similar to those seen in cats with MPS I: corneal
clouding, abnormal facies, impaired mobility, pain upon handling, stunted growth, joint stiffness, cardiac changes,
and hepatosplenomegaly. Neurons at all levels of the CNS have varying degrees of cytoplasmic vacuolation, but
neuronal loss or necrosis is not appreciable. There is vacuolation of perivascular mononuclear cells in the CNS,
and leptomeninges are thickened and hypercellular [208]. Ultrastructural findings are similar to those seen in
affected cats with both empty membrane-bound vacuoles and lamellar structures resembling zebra bodies.
Cytoplasmic vacuolation, usually involving fibroblasts or fixed tissue macrophages, occurs in most extraneural
tissues. Activity of alpha-L-iduronidase in the dogs is profoundly deficient (from 0 - 1% of the control mean values)
in cultured fibroblasts and leukocytes [207]. Reduced levels of brain beta-galactosidase and increased levels of
brain beta-hexosaminidase have been reported [208]. Increased amounts of dermatan sulfate and heparin sulfate
are found in brain and many extraneural tissues (especially in liver) [208] and these glycosaminoglycans are
excreted in urine. While Golgi impregnation studies in feline MPS I reveal that cortical pyramidal neurons may
have axon hillock enlargements (meganeurites) and/or ectopic secondary neuritic processes, aspiny
meganeurites without ectopic neurite growth have been reported in the canine disorder [209]. Fluorometric assays
of alpha-L-iduronidase in serum are available for identifying affected, carrier, and normal dogs [210]. Allogenic
bone marrow transplantation reportedly diminishes MPS I-related lesions in affected dogs [211,212]. In contrast,
hematopoietic stem cell gene therapy has not produced clinical improvement in dogs [213,214].
Mucopolysaccharidosis Type II (MPS II) - or Hunter syndrome, has recently been reported in a 5 year old male
Labrador Retriever with signs of progressive incoordination, visual impairment, and exercise intolerance [215].
Coarse facial features, macrodactylia, unilateral corneal dystrophy, generalized osteopenia, progressive
neurologic deterioration, and a positive urine spot test for acid mucopolysaccharides suggested
mucopolysaccharidosis. Intracytoplasmic vacuoles were most prevalent in epithelial cells, endothelial cells, and
histiocytes of liver, kidney, thyroid gland, and spleen. Ultrastructural examination disclosed electron-lucent
floccular or lamellar membrane-bound storage material characteristic of mucopolysaccharides. PAS-positive
intracytoplasmic material was identified in multiple neurons in the medulla, pontine nucleus, cerebellum, and
spinal gray matter horns. Biochemical assays identified a deficiency in iduronate-2-sulfatase (IDS) activity in
cultured dermal fibroblasts compared with normal dogs. Hair root analysis for IDS showed that the dam was a
carrier of X-linked Hunter syndrome and that a phenotypically normal male littermate of the affected dog was
normal.
Mucopolysaccharidosis Type III A (MPS III A) - associated with a deficiency of the lysosomal enzyme heparan
sulfate sulfamidase, has been reported in adult Wire-haired Dachshunds [216,217], and more recently, in New
Zealand Huntaway dogs [273]. Around 3 years of age, dogs develop progressive neurological signs of ataxia and
intention tremor. Dysuria may be seen late in the condition. Mentation remains normal throughout the course of
the disease, which may extend over several years. A mucopolysaccharide storage is indicated by positive
toluidine blue spot tests of urine. The diagnosis of MPS III A is confirmed by documentation of urinary excretion
and tissue accumulation of heparan sulfate and decreased sulfamidase activity in fibroblasts and hepatic tissue.
Mild cerebral cortical atrophy and dilation of the lateral ventricles may be grossly evident. Light microscopically,
fibroblasts, hepatocytes, and renal tubular epithelial cells are vacuolated. Within the nervous system, cerebellar
Purkinje cells, neurons of brainstem nuclei, ventral and dorsal horns, and dorsal ganglia are distended with
brightly autofluorescent, PAS-positive, and sudanophilic material. Vacuolated macrophages may be seen in the
meninges. Ultrastructurally, visceral storage presents as membrane-bound vacuoles with finely granular, variably
electron-lucent contents. Neuronal storage appears as membranous concentric whorls, lamellated parallel
membrane stacks, or electron-dense lipid-like globules. In one dog, additional lesions included calcium oxalate
uroliths, severe secondary calcification of tissues including the brain, and storage deposits in some neurons [217].
This condition is being studied as a model of Sanfilippo syndrome type A in people. The molecular defect has
been identified in both canine breeds [218,273].
Mucopolysaccharidosis Type III B (MPS III B) - or Sanfilippo B syndrome, has recently been reported in
Schipperke dogs in which pedigree analysis supported an autosomal recessive mode of inheritance [219,263]. In
this report, clinical signs were seen in male and female Schipperkes around 3 years of age that were
characterized by pelvic limb ataxia-dysmetria, wide-based stance, truncal swaying, occasional stumbling and
falling, fine head intention tremor, and whole body tremor. The menace reaction was absent although pupillary
light reflexes were normal, and peripheral retinal degeneration was noted. The condition was slowly progressive
over several years. Granules in mononuclear blood cells stained positively with toluidine blue. The urinary
mucopolysaccharidosis spot test was positive due to presence of heparan sulfate. Pathological findings revealed
marked cerebellar atrophy, Purkinje cell loss, and neuronal and hepatic storage material that stained positively
with toluidine blue and PAS. Activity of N-acetyl- -D-glucosaminidase was <5% of normal. Other measured
lysosomal enzyme activities were elevated. Note that the clinical signs described are similar to those seen in a 5
year old Schipperke with adult-onset galactosialidosis [76].
Mucopolysaccharidosis Type VI (MPS VI) - or Maroteaux-Lamy syndrome, has been reported in 2 to 3 month
old Siamese cats [220], and recently in a 3 year old Siamese/shorthaired European cat [272]. This disorder,
transmitted as an autosomal recessive trait, is caused by a deficiency of the enzyme arylsulfatase B (N-
acetylgalactosamine-4-sulfatase) [221]. The clinical features of affected animals include small head, flat, broad
facies, wide-spaced eyes, depressed bridge of the nose, corneal clouding, small ears, large forepaws, and a
concave deformity of the sternum [222]. These signs are almost identical to cats with MPS I; however, Siamese
cats have long bone epiphyseal dysplasia and toluidine blue-positive granules in circulating neutrophils. Signs of
intracranial disease are usually not seen, although seizures have also been reported in a 2 year old Siamese cat
with MPS VI [223]. Additional radiographic findings in Siamese cats may include long bone exostoses, severe
spondylosis, severe osteoarthrosis of the articular facets of the entire spine, pectus excavatum, hypoplasia and
fragmentation or abnormal ossification of the dens, and aplasia or hypoplasia of frontal and sphenoid sinuses.
Hepatosplenomegaly is not a prominent feature [224]. Membrane-bound cytoplasmic inclusions have been noted
in hepatocytes, bone marrow, granulocytes, vascular smooth muscle cells, and fibroblasts in skin, cornea, and
cardiac valves. Lesions in CNS are reportedly restricted to mild ventricular dilatation, and perithelial cell
vacuolation in the connective tissue of the meninges and choroid plexus, with membrane-bound inclusions in the
cytoplasm of perivascular cells of the brain and spinal cord [224]. Neurons and glial cells are unaffected. It has
been estimated that approximately 25% of immature cats with MPS VI develop clinical signs of a thoracolumbar
syndrome secondary to cord compression from focal bony protrusions into the vertebral canal [222]. Signs are
characterized by varying degrees of pelvic limb paresis that may progress to paraplegia, incontinence and
depressed pain sensation caudal to the level of the thoracolumbar lesion. Spinal cord compression can be
confirmed with myelography. Microscopic changes in the cord include myelin loss, Wallerian degeneration,
astrocytosis, neuronal dropout, and neovascularization.
Affected cats with MPS VI excrete excess dermatan sulfate in the urine. Arylsulfatase B activity is less than 10%
of normal in affected homozygous cats and 50% lower than normal in asymptomatic obligate heterozygous cats.
Prognosis can be favorable in cats manifesting spinal cord signs with surgical decompression early in the course
of the disease. The genetic mutation of this disorder has been identified and a rapid PCR-based screening
method to genotype individuals has been developed [225]. It has been reported that two mutations within a feline
mucopolysaccharidosis type VI colony cause three different clinical phenotypes [226]. Allogenic bone marrow
transplantation can produce significant and sustained clinical and biochemical improvement in cats with MPS VI
[227]. Resolution of corneal clouding and improvement in facial dysmorphia, walking ability, and better coat
condition were reported, together with leukocyte arylsulfatase B activity and urinary dermatan sulfate excretion
returning to normal. Enzyme replacement therapy in the MPS VI cat is also effective at reducing or eliminating
pathology in most connective tissues, including bone development [228,229]. In one study, enzyme replacement
therapy (recombinant feline N-acetylgalactosamine-4-sulfatase administered at a dose of 1 mg/kg of body weight),
altered the clinical course of the disease in two affected cats treated from birth [230]. After 170 days of therapy,
both cats were physically indistinguishable from normal cats with the exception of mild corneal clouding.
MPS VI has also been reported in several canine breeds, including Miniature Pinschers, Miniature Schnauzers,
Chesapeake Bay Retreivers and Corgis [231,264] with clinical, radiographic, and biochemical findings similar to
those seen in affected Siamese cats. Levels of both dermatan sulfate and chondroitin sulfate were increased in
urine. Activity of arylsulfatase B was less than 1% of control values. The genetic mutation of this disorder has
been identified and a DNA test is now available to distinguish between normal, carrier and affected animals [264].
Mucopolysaccharidosis Type VII (MPS VII) - associated with beta-glucuronidase deficiency has been reported
in a dog, the offspring of a father-daughter mating [232]. Pelvic limb weakness was evident at 8 weeks of age and
became progressively worse. The dog had a large head, a shortened maxilla, and corneal granularities. Most
joints were extremely lax and easily subluxated, with joint capsules that were swollen and fluctuant. The dog was
alert and had apparently normal pain perception. No neurological signs were noted. At 13 months of age, there
was radiographic evidence of extensive skeletal disease. The electrophoretic pattern of precipitated
glycosaminoglycans indicated a predominance of chondroitin sulfate. The animal died suddenly from gastric
dilatation. There was generalized hepatomegaly, thickening of the atrioventricular heart valves, and generalized
polyarthropathy. Vacuolated cytoplasm was observed in hepatocytes, keratocytes, fibroblasts, chondrocytes and
cells of the synovial membrane, retinal pigment epithelium, and cardiac valves. Neurons had cytoplasmic
vacuoles. Electron microscopy demonstrated membrane-bound cytoplasmic inclusions in polymorphonuclear
leukocytes, hepatocytes, synovium, heart valves and spleen. Levels of chondroitin sulphates were increased in
urine. Tissue levels of beta-glucuronidase were very low. This disorder is similar to Sly syndrome in people. The
biochemical and molecular defect in affected colony dogs have now been characterized [233,234] and a
diagnostic screening test is available for detecting clinically normal carriers [235]. Bone marrow transplantation
results in some improvement in the cardiovascular abnormalities in canine mucopolysaccharidosis VII [236], while
gene transfer of low levels of beta-glucuronidase corrects hepatic lysosomal storage [237]. Recent studies
indicate that neonatal gene therapy can prevent the clinical manifestations of MPS VII in dogs [268].
MPS VII has also been reported in a 12 to 14 week old male Domestic Shorthair cat with signs of walking
difficulties (most of the weight was shifted to the front legs) and an enlarged abdomen. Facial dysmorphism,
plump paws, corneal clouding, small ears, granulation of neutrophils, vacuolated lymphocytes, and a positive
urine test for sulfated glycosaminoglycans suggested mucopolysaccharidosis. Activity of beta-glucuronidase was
absent in leukocytes and markedly reduced in fibroblasts, thus establishing the diagnosis of
mucopolysaccharidosis VII. Light microscopic examination revealed foam cells in virtually all organs examined,
and electron microscopic examination showed pancytic storage of floccular material characteristic of
mucopolysaccharides. Stored sphingolipids in the form of zebra bodies were seen in ganglion cells of the CNS
and in smooth muscle cells of blood vessels. The molecular basis of feline beta-glucuronidase deficiency has
been determined and a screening test is available for detecting clinically normal carriers in a breeding colony
[238].
Sphingomyelinosis (Niemann-Pick Disease)

Sphingomyelinosis or sphingomyelin lipidosis denotes a heterogeneous group of lysosomal storage disorders
marked by prominent organomegaly. In people, this condition is known as Niemann-Pick disease, and recent
publications suggest there are several types (types A, B, C, D, and E) all of which have neurological involvement
except types B and E [199]. Approximately 50% of the affected human patients with severe neurological signs
belong in the type A group. Type C disease produces moderate neurological signs. The enzyme defect in types A,
B, and C is sphingomyelinase; no defect has been identified as yet in type D disease, and the storage product in
all types is sphingomyelin, a molecule containing a ceramide, a phosphoric acid ester, and choline [199].
Sphingomyelinase catalyses the hydrolysis of sphingomyelin to ceremide and phosphorylcholine.
In small animals, sphingomyelinosis has been reported in a 5 month old Miniature Poodle dog [239], a 5 month
old Domestic Shorthair cat [240], in 3 to 4 month old Siamese cats [241], and in a 7 month old Balinese cat [242].
In the Siamese cats, the condition is inherited as an autosomal recessive trait. The disease results from a
profound deficiency of lysosomal sphingomyelinase activity and is thought to be similar to Niemann-Pick disease
type A [241,243], the most common and most severe form of Niemann-Pick disease that occurs frequently in
individuals of Ashkenazi background [244]. Clinical signs in animals include ataxia, hypermetria, continuous head
tremors, loss of equilibrium, and splaying of legs. Some animals manifest a stereotypic chewing behavior, lack of
appetite and lack of interest in their surroundings. Signs can progress to visual impairment, total paresis and
death before animals reach 1 year of age [241]. Hepatosplenomegaly has been seen in affected Siamese cats. In
one report in an 11 month old Siamese cat, hepatomegaly but not splenomegaly was observed [245].
Pathological lesions are characterized by widespread cytoplasmic swelling and vacuolation of neurons in CNS
and PNS, and foamy macrophages (so-called Niemann-Pick cells) in the bone marrow, lung, spleen, lymph nodes,
liver, kidneys, adrenal glands and intestine. Storage material in the foamy cells of non-nervous tissues is
reportedly different from those in affected cells of nervous tissues [246] where changes are most marked in
Purkinje cells of the cerebellum, neurons of the cerebellar roof nuclei and hippocampus, and in dorsal roots and
peripheral ganglion cells. In the spinal cord, affected neurons are especially numerous in the region of the ventral
horns [240]. The neuronal changes are associated with nuclear margination and displacement of Nissl substance.
Spheroids are commonly seen throughout the brain. Myelination of the brain and spinal cord is normal [242].
Ultrastructurally, neurons contain numerous membranous cytoplasmic bodies and occasional zebra-like bodies,
while membranous and vacuolar profiles are reportedly more common in glial cells [242]. Membranous whorls are
present in CNS endothelial cells and pericytes. Axonal spheroids contain membrane-bound dense bodies,
mitochondria and variable membranous profiles. Many neurons in cerebral cortex, basal ganglia, amygdala,
thalamus, and cerebellum show aberrant neurite growth and meganeurite formation, which may indicate
dysfunction in the production and regulation of neuronal surface membranes [247]. Most lymphocytes and
monocytes in blood smears contain cytoplasmic vacuoles.
A total deficiency of lysosomal (pH 5.0) sphingomyelinase is found in leukocytes, liver, and brain of the cats,
although the activity of the microsomal (pH 7.4, magnesium-dependent) sphingomyelinase is normal in brain
[241,243]. Cat brains contain an excess of GM2- and GM3-gangliosides, and a nine- to ten-fold excess of
sphingomyelin and cholesterol occurs in liver of affected cats. Leukocyte sphingomyelinase levels are about half
of the normal level in phenotypically normal littermates of affected kittens suggesting an autosomal recessive
mode of inheritance [241].
Phenotypic Variant of Niemann-Pick Disease Type A - Characterized by a neuropathic syndrome, with mild or
no CNS signs, has been observed in several related and unrelated Siamese cats [248]. Signs in affected animals
include absent conscious proprioception, severely depressed to absent spinal reflexes, hypotonia, fine
generalized muscle tremors (especially in pelvic limbs), a palmigrade-plantigrade stance, and moderate
hepatosplenomegaly. Pain perception and cranial nerve function are normal. Motor nerve conduction velocities
are markedly depressed. Positive sharp waves and fibrillation potentials are recorded only sporadically in muscles.
While little changes are present in skeletal muscles, peripheral nerves show widespread myelin degeneration
associated with many vacuolated macrophages interspersed within the nerve fibers. Remyelination and/or
hypomyelination are prominent. Marked vacuolation and granular distension are seen in neurons, glial cells,
endothelium, choroid plexus epithelium, and ependyma. Neurons in autonomic and dorsal root ganglia are
similarly affected. Vacuolated macrophages, with metachromatic granules, are widely scattered throughout the
CNS parenchyma. There is widespread infiltration of virtually every body system with distended granular
macrophages. Biochemical analysis of CNS and viscera suggested that the condition in one of these cats was
similar to Niemann-Pick disease type A in people [248]. In the other cats, a type A variant was suggested, based
on less dramatic increase in sphingomyelin content in liver and kidney, modest increase in brain sphingomyelin
content, and lack of detectable enzyme deficiency in known heterozygotes. All cats tested showed severe
reduction in CNS and visceral lysosomal sphingomyelinase activity.
Niemann-Pick Disease Type C - Another form of sphingomyelinosis has been recognized in Domestic Shorthair
cats, similar to the infantile form of Niemann-Pick disease type C (NPC) in people [249-251], an autosomal
recessive neurovisceral lysosomal storage disorder in which cholesterol lipidosis results from defective
intracellular transport of unesterified cholesterol. A recent study suggests that the underlying defect in the major
form of human NPC and this feline model of NPC involve orthologous genes [252]. Affected animals manifest
clinical signs around 6 to 9 weeks of age that are similar to those previously described above in cats with
Niemann-Pick disease type A: ataxia-dysmetria, whole body tremor, intention tremor of the head, with progression
over 4 to 6 months to moving in a crouched gait, loss of menace deficit, inability of cats to right themselves from
lateral recumbency, and eventually, generalized disuse muscle atrophy [249]. Other CNS signs seen infrequently
in some cats include depressed mentation, vestibular signs, anisocoria and hemiparesis. Affected cats have
abdominal enlargement due to palpable hepatomegaly around 8 weeks of age, without clinical manifestations of
liver disease [249]. Pathological findings in the CNS included distention and vacuolation of many neuronal cell
populations in brain, spinal cord and ganglia, accompanied by extensive neuroaxonal dystrophy (eosinophilic
axonal spheroids), especially in the cerebellar folia. Myelin loss and macrophage infiltration in the white matter of
the spinal cord, particularly involving the spinocerebellar tracts have been observed in some cats [249]. Many
foamy macrophages are found in liver, spleen, lymph nodes and lungs. Ultrastructural studies of affected tissues
and organs show heterogeneous membranous inclusions. Immunocytochemical, histochemical, and Golgi studies
indicate that gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex,
cerebellum, and hippocampus, as well as in liver [253]. Clinical neurological signs in feline NPC occur in parallel
with neuronal structural alterations suggesting that GABAergic neuroaxonal dystrophy is a contributor to brain
dysfunction in this disease [254]. In affected NPC cats, lipid analysis reveals excess cholesterol,
glucosylceramide, lactosylceramide and phospholipids, including sphingomyelin, in liver [250]. In addition, levels
of brain GM2- and GM3-gangliosides are increased. Sphingomyelinase activity in liver is partially deficient or low
normal. Cultured skin fibroblasts have partially decreased sphingomyelinase activity and a decreased ability to
esterify exogenous cholesterol [250]. Liver lipid analyses of obligate heterozygote cats demonstrates intermediate
cholesterol and sphingomyelin concentrations. Furthermore, vacuolated skin fibroblasts, cortical neurons with
intracellular inclusions immunoreactive for GM2-ganglioside, and ultrastructural studies with evidence of storage
in liver and brain have been reported in heterozygote NPC cats [255].
Prognosis is poor in cats with sphingomyelinosis. Treatment strategies are being investigated in institutions
containing colonies of cats with varying forms of sphingomyelinosis, e.g., therapeutic bone marrow transplantation
in cats with NPC [249]. Dietary cholesterol restriction does not appear to alter disease progression in NPC-
affected kittens [249,269].
A heterogeneous lipid storage disease similar to the human NPC has also been reported in a 9 month old boxer
dog with progressive neurological abnormality [256]. Histological examination revealed marked neuronal storage
throughout the CNS and histiocytic storage in the reticuloendothelial system. Ultrastructurally, the neuronal
storage consisted of accumulation of concentric membranous inclusions and clusters of dense bodies. The
biochemically unesterified cholesterol content was high in the liver and spleen. The brain showed increased levels
of lactosylceramide and GM2 and GM3 gangliosides [256].
Degenerative Disorders of the Central Nervous System
K. G. Braund
The classification of degenerative disorders of the nervous system is difficult and somewhat arbitrary. Many of
these conditions are familial or hereditary, breed-related, and involve degeneration of the nervous system within
the first few months after birth. Premature degeneration of any component of the CNS, such as neurons, myelin
sheaths or axons, can be considered under the broad panoply of abiotrophies which are disorders associated with
an inherent lack of vital trophic or nutritive factor(s) [1]. Other degenerative conditions are yet to be classified and
remain in the idiopathic grouping. Nevertheless, it is my intent to discuss the degenerative conditions and not
necessarily fit them into tight classification schemes, which can vary from year to year, especially as new
information becomes available. Despite this caveat, I have tended to follow a classification scheme used by
Summers and colleagues in their veterinary neuropathology text [2], which includes leukodystrophies,
hypomyelinogenesis, spongy degenerations, neuronal abiotrophies, motor neuron diseases, and several
idiopathic degenerative disorders, including Lafora’s disease, a degenerative condition usually seen in young
adult dogs. Leukodystrophies may be viewed among the group of degenerative, abiotrophic disorders affecting
dogs and cats [1]. These conditions are considered to be disorders of myelin synthesis and maintenance and
involve CNS myelin with a typically bilaterally symmetrical, often regional, distribution [3]. While axonal necrosis
and primary demyelination may be seen, lymphoplasmacytic inflammation is usually not a feature. In people,
leukodystrophies are genetic diseases and are thought to represent an inborn error of metabolism due to a
defective gene that produces an enzymatic abnormality and metabolic derangement that affects myelin [4].
Abnormalities of central myelinogenesis also occur with hypomyelinating disorders and spongy degenerations.
Neuronal abiotrophies are disorders characterized by early or premature neuronal degeneration and death [1].
These disorders most commonly target cerebellar Purkinje cells but can also involve neurons more diffusely.
Motor neuron diseases in dogs and cats are further examples of abiotrophic processes, are usually familial or
hereditary affecting animals early in life, and typically involve the lower motor neuron, and as such, present with
signs associated with a neuropathic syndrome.
The degenerative disorders reviewed in this chapter are presented in alphabetical order, based on the commonly
used English names and terminolgy. The disorders are listed in the table below in relation to their classification
within the categories of leukodystrophy, hypomyelination, spongy degeneration of the central nervous system,
neuronal abiotrophy, motor neuron diseases, and idiopathic degenerative disorders. This listing also provides
direct hyper-links to the sections for each individual disorder within the chapter. Commonly used abbreviations
include the following: CT, computerized tomography; EMG, electromyogram; NCV, nerve conduction velocity test;
PNS, peripheral nervous system.
Leukodystrophies Neuronal Abiotrophy Motor Neuron Diseases with

Dalmatian Leukodystrophy Cerebellar Cortical Neurofibrillary Accumulation
Fibrinoid Leukodystrophy Abiotrophies Brittany Spaniels
Afghan Hound Myelopathy - Neonatal Cerebellar Rottweilers
Miniature Poodle Cortical Abiotrophy Collie
Demyelination - Kerry Blue Terriers Cats
Rottweiler - Gordon Setters Idiopathic Degenerative Disorders
Leukoencephalomyelopathy - Rough Coated Collies Alaskan Husky
Hypomyelination - Border Collies Encephalopathy
Chows - Australian Kelpies Yorkshire Terrier
Lurcher Hounds - Labrador Retrievers Encephalopathy
Springer Spaniels - Rhodesian Ridgebacks Central Axonopathy in
Samoyeds - Coton de Tuléar Dogs Scottish Terriers
Weimaraners - Beagles Degenerative Myelopathy
Bernese Mountain Dogs - Miniature Poodles Encephalomyelopathy in
Dalmatians - Brittany Spaniels Young Cats
Cats - Schnauzer-Beagle Encephalomyelopathy and
Miscellaneous - Portuguese Podencos Organic Acidopathies
Spongy Degeneration of the CNS - Old English Sheepdogs Hereditary Ataxia
Spongy Degeneration in - Bernese Mountain Dogs Hereditary
White Matter - American Staffordshire Polioencephalomyelopathy of
- Labrador Retrievers Terriers the Australian Cattle Dog
- Shetland Sheepdogs - English Bulldogs Hound Ataxia
- Samoyeds - Other Canine Breeds Idiopathic Vascular
- Silky Terriers - Cats Calcification
- Egyptian Mau Kittens Multisystem Neuronal Kooiker Dog Myelopathy
Spongy Degeneration in Abiotrophies Labrador Retriever
Gray Matter - Swedish Lapland Dogs Axonopathy
- Bull Mastiffs - Cocker Spaniels Lafora's Disease
- Salukis - Cairn Terriers Mitochondrial
- Cocker Spaniels - Miniature Poodles Encephalomyelopathy
- Malinois Shepherd Motor Neuron Diseases Nervous System
Crosses Giant-Breed Crosses Degeneration in Ibizan
- Rottweilers Swedish Lapland Dogs Hounds
- Birman Kittens English Pointers Neuroaxonal Dystrophy
German Shepherds - Rottweilers
Doberman Pinchers - Collie Sheep Dogs
Griffon Briquet Vendéens - Chihuahuas
Salukis - Papillons
Other Canine Breeds - Jack Russell Terrier
- Cats
Afghan Hound Myelopathy

This neurodegenerative disease (also called Afghan Hound hereditary myelopathy) occurs in Afghan Hounds, of
either sex, and has an autosomal recessive mode of inheritance [5-9]. Clinical signs have been noted in dogs
between 3 and 13 months of age. Pelvic limb paresis and ataxia often are the first signs observed and affected
animals may have a synchronous (bunny hopping) pelvic limb gait. Within 1 to 3 weeks, these signs progress to
paraplegia, thoracic limb paresis and/or tetraplegia. Spinal reflexes are usually intact or increased but may be
depressed as a consequence of gray matter lesions, and breathing may be abdominal. Urinary incontinence is
often seen especially in dogs with decreased pelvic limb sensation [6]. Fecal incontinence may also be present in
paraplegic dogs [8]. Death frequently results from respiratory failure. Pelvic limbs and caudal thorax may be
analgesic. CSF examination may reveal slight elevations in protein level (40 to 80 mg/dl) without increase in cell
count [6]. Blood chemistry values, routine spinal radiography and myelography are usually normal.
Grossly, grayish softenings of the white matter may be seen in formalin fixed tissue [8]. Histological lesions are
limited to the CNS where they tend to be bilaterally symmetrical. Macro- and microcavitation and necrosis occur in
white matter extending from mid-cervical to mid-lumbar segments and are especially severe in mid-thoracic cord
segments where all funiculi are affected. Dorsal and lateral funicular damage tapers off in the caudal thoracic
region, while ventral funicular lesions continue along the ventral median fissure to mid- or caudal lumbar
segments. Rostrally, the dorsal and/or ventral funicular lesions extend to caudal or mid-cervical levels [5]. The
fasciculus proprius is usually intact [5,6]. Myelin breakdown is characterized by swelling and fragmentation of
myelin sheaths and macrophage infiltration, giving the white matter a vacuolar appearance. The largest cavities
tend to occur in the dorsal funiculus and usually contain lipid-laden macrophages and proliferating vessels.
Funicular axons remain intact. Gray matter involvement, when present, is confined to the dorsal nucleus of the
trapezoid body and to the periphery of the spinal ventral gray columns. In the former, lesions are characterized by
spongiform degeneration of the white matter, neovascularization, and hypertrophic astrocytes [5,6]. In areas of
gray matter adjacent to affected white matter, variable increase in glial cells and mild central chromatolysis of
neurons has been noted [8]. In one report, small foci of malacia were observed in the caudal brainstem and
medial olivary nucleus [8]. Ultrastructurally, splitting of the myelin sheath occurs at the intraperiod line. Axonal
spheroids are sometimes seen with pleiomorphic membranous bodies and variable whorled neurofilaments.
The cause of these lesions has not been determined. Urine methyl malonic acid is negative and serum vitamin
B12 levels are normal [6]. The disorder has been termed myelomalacia [7,8] and necrotizing myelopathy [6]. I
have chosen to follow the lead of Summers and colleagues [10] in calling this condition a leukodystrophy because
of the apparent preservation of axons, since malacia and necrotizing myelopathy connote destruction of all
neurectodermal elements [5]. This leukodsytrophy has some clinical and pathological similarities to the
degenerative myelopathy in Kooiker dogs [11]. Prognosis is poor to grave. There is no treatment.
Alaskan Husky Encephalopathy

An episodic, incapacitating and ultimately fatal familial neurodegenerative disorder has been described in Alaskan
Husky dogs [12,234]. Four dogs showed neurological signs before the age of 1 year (7 - 11 months) and one
animal presented at 2.5 years old. Clinical signs in all dogs were acute in onset and included ataxia, seizures,
behavioral abnormalities (including obtundation and propulsive pacing), blindness, facial hypalgesia and
difficulties in prehension of food. In surviving dogs, the disease was static but with frequent recurrences of gait
abnormalities and seizures. Pathological findings were limited to the CNS and bilateral and symmetrical soft gray
cavitated foci were seen grossly in the thalamus and sometimes extended into the caudal brainstem. Microscopic
lesions were characterized by neuronal loss, spongiosis, vascular hypertrophy and hyperplasia, gliosis, cavitation
and mixed inflammatory infiltration. These lesions were seen as foci of bilateral and symmetrical degeneration in
the basal nuclei (caudate nucleus, putamen, and claustrum), midbrain, pons and medulla, in addition to multifocal
lesions at the base of sulci in the cerebral cortex and in the gray matter of cerebellar folia in the ventral vermis.
The cerebellar changes varied from partial to widespread granule cell depletion and loss of Purkinje cells, but with
isolated surviving Golgi neurons in the gliotic granule cell layer. Reactive gemistocytic astrocytes with prominent
cytoplasmic vacuolation were observed in the thalamus. Spinal cord lesions were restricted to white matter and
were characterized by Wallerian degeneration. In 2 dogs, the lesions were severe, bilaterally symmetrical, and
involved the deep areas of the dorsolateral funiculus (corresponding to descending upper motor neurons running
within the reticulorubrospinal tract) and the ventral funiculus flanking the ventral sulcus. These changes were
most severe in the cervical cord.
The nature and distribution of lesions were considered to resemble Leigh's disease (subacute necrotizing
encephalomyelopathy) of man, in which several enzyme complexes involved in mitochondrial respiratory
metabolism show defects, singly or in combination [13]. Neuronal sparing and astrocytic vacuolation suggested
possible astrocytic dysfunction. Initial pedigree studies and test mating suggest an autosomal recessively
inherited metabolic derangement of unknown nature as the cause of this breed-specific disorder.
Yorkshire Terrier Encephalopathy

A severe subacute/chronic necrotizing encephalomyelopathy has been reported in young Yorkshire Terriers
(onset of signs was between 4 months and 1 year of age) with signs and pathology (Fig. 1, Fig. 2, Fig. 3, Fig. 4
and Fig. 5) similar to those found in the above-mentioned encephalopathy of the Alaskan Huskies [221,238,240].
Figure 1. Bilaterally symmetrical thalamic cavitation (*). Woelcke-Schroeder stain. Courtesy, Dr. Kaspar Matiasek,
University of Munich.
Figure 2. Intact nerve fiber (arrowhead) within cavitation. Bodian stain. Courtesy, Dr. Kaspar Matiasek, University
of Munich.
Figure 3. Gitter cells and intact neurons within cystic lesions. Hematoxylin & eosin (HE). Courtesy, Dr. Kaspar
Matiasek, University of Munich.
Figure 4. Spongy change and vascular proliferation, cerebral cortex. HE. Courtesy, Dr. Kaspar Matiasek,
University of Munich.
Figure 5. Severe depletion of Purkinje cells and granule cells, along with proliferation of Bergmann glia. HE.
Courtesy, Dr. Kaspar Matiasek, University of Munich.
CSF findings may include elevated protein concentration and a mononuclear pleocytosis. Multifocal, extensive
areas of decreased opacity throughout the cerebral hemispheres, asymmetric ventriculomegaly, and lack of
contrast enhancement were found on CT images of 3 affected dogs with multiple malacic cavitations within the
brain [238]. In this report, the condition was termed a "necrotizing meningoencephalitis" which needs to be
differentiated from the multifocal non-suppurative necrotizing encephalitis reported in Yorkshire Terriers in
Switzerland [239], in which no malacic cavitations were described.
Central Axonopathy in Scottish Terriers
A central axonopathy in 2 male and 1 female Scottish Terrier puppies from 3 different but related litters (sharing a
common sire) has been reported [189]. Clinical signs consisting of severe whole-body tremors and ataxia were
first detected at the age of 10 to 12 weeks. They worsened with activity and excitement and diminished during
rest or sleep. Two dogs also had paraparesis. In one dog the neurological deficits progressed over several
months. No abnormalities were seen on gross examination. Neuropathological examination revealed widespread
axonal changes, vacuolation, and gliosis in the white matter of the CNS. Diffuse thickening or increased diameter
was seen in many axons in the lateral and ventromedial funiculi and to a lesser extent in other white matter areas.
Some axons appeared quite large, but with little fragmentation or dystrophic swellings. Myelin sheaths were thin
or absent around these fibers. Myelin stains revealed decreasing staining intensity in the spinal cord. Similar, but
less intense changes were present throughout white matter of the brainstem, cerebellum, and cerebrum. Status
spongiosis and gliosis were seen in the white matter of the brain, brainstem, and spinal cord, and in gray matter of
some nuclei of the brainstem, thalamus, and cerebellum. Occasional dystrophic axons were seen in nuclear areas
of the brainstem and thalamus, in the granular layer of the cerebellum, and in the internal capsule, suggesting that
the thickened axons might eventually progress to degeneration. Peripheral nerves were normal. The authors
suggested that this may be an inherited condition with a poor prognosis, based on the progressive clinical course
in one puppy.
Cerebellar Cortical Abiotrophies

Cerebellar cortical abiotrophies are characterized by premature aging, with degeneration and death of various
neuronal cell populations, and are the most common neuronal abiotrophies in small animals [1]. Clinical signs of
cerebellar syndrome (e.g., ataxia-dysmetria, head tremor, broad-based stance, and loss of balance) occur most
commonly in young animals that are clinically normal at birth, usually within a few weeks or months after birth.
This "juvenile" onset encompasses most cases of cerebellar abiotrophy, although in some instances, the there is
an adult onset. Occasionally, a neonatal cerebellar abiotrophy is seen in which animals show cerebellar signs at
birth (see below). The clinical course is typically progressive.
Antemortem diagnosis is suggested by clinical signs, age, breed, and by rule-out of acquired diseases.
Examination of biopsy material from selected sites such as the cerebellum may confirm an antemortem diagnosis
in some instances. Some cerebellar disorders are limited to Purkinje cells and to the anatomically- and
developmentally-related granule cell layer. Reduction in numbers of granule cells might reflect degeneration or
loss of Purkinje cells. Occasionally, retrograde degeneration occurs in other neuronal populations that project to
the cerebellar cortex, such as olivary neurons that project to Purkinje neurons, and pontine neurons that project to
granule cell neurons [1]. Regressive changes in neurons of cerebellar nuclei are regarded as transsynaptic
degeneration following the Purkinje cell damage [14]. More recent reports indicate that some cerebellar disorders
are accompanied by cerebral cortical neuronal degeneration (see multisystem neuronal abiotrophy in Miniature
Poodles). In general, electrodiagnostic studies, serum biochemistry, and CSF analysis are of limited value in the
diagnosis of degenerative cerebellar disorders, although imaging techniques might demonstrate cerebellar
atrophy. Prognosis is guarded to poor. Presently, there is no treatment.
Cerebellar cortical abiotrophies have been reported in several breeds of dogs, as well as in cats, and each
condition is discussed separately.
Neonatal cerebellar cortical abiotrophy has been identified in beagles [14,65] (see below), Samoyeds [65], and
in Irish Setter puppies with hereditary quadriplegia and amblyopia (HQA), a condition associated with a fully
penetrant, autosomal recessive gene [69]. Microscopic lesions included diffuse loss of Purkinje cells and variable
loss of granule cells in the Beagles and Irish Setters, and swollen axons of Purkinje cells along with occasional
myelin degeneration and axonal necrosis in the folia white matter of Beagles, Irish Setters, and Samoyeds [65,69].
Interestingly, microscopic lesions were not detected in the Irish Setters until around 3 months of age. A similar
condition has been reported in Coton de Tuléar and Rhodesian Ridgeback puppies (see below).
Cerebellar Cortical Abiotrophy in Kerry Blue Terriers

This is an autosomal recessive disease that affects Kerry Blue Terriers [15]. Clinical signs of pelvic limb stiffness
and head tremors reflect cerebellar disease and are seen between 9 and 16 weeks of age. Subsequent signs
include dysmetria-hypermetria and often, an inability to stand by 1 year of age. The CNS lesions are progressive
and tend to follow a relatively well-defined temporal course [16]. Degeneration of Purkinje cells in the cerebellar
cortex is evident at the onset of clinical signs (approximately 2 to 4 months of age). After two weeks to one month
of clinical illness, retrograde transsynaptic neuronal degeneration occurs in the olivary nucleus. Degeneration of
both large and small neurons in the caudate nucleus begins approximately two to three months after the onset of
clinical signs, and by seven to eight months of clinical illness, the caudate nucleus is reduced to numerous
microcystic cavities and is almost devoid of neurons except for a narrow subependymal zone and the tail of the
nucleus. Neuronal depletion in the pars reticularis of the substantia nigra, evident after five to seven months of
clinical illness, is attributed to an anterograde transsynaptic mechanism of neuronal degeneration. Ultrastructural
changes have been reported [17]. In the caudate nucleus, the initial lesion was mitochondrial hypertrophy in
dendrites of intrinsic neurons. Degeneration of these neurons became widespread while axons of passage and
terminal boutons were spared. During the final stages, there was severe disruption of the neuropil with loss of
both neurons and glia. In the cerebellar cortex, the lesions involved principally Purkinje cells and progressed
through a pattern of degeneration comparable to that involving intrinsic neurons of the caudate nucleus, with
eventual astroglial scarring of the molecular layer. In contrast to the caudate nucleus, there was no disruption of
the neuropil with loss of structure in the cerebellum. A disorder of glutamate metabolism with associated
excitotoxic injury to Purkinje cells and neurons of the caudate nucleus has been proposed [16,17]. The condition
is progressive and prognosis is poor.
Cerebellar Cortical Abiotrophy in Gordon Setters

This is believed to be an autosomal recessive, late-onset cerebellar disease affecting mature Gordon Setters
between 6 and 30 months of age [18,19]. Dogs appear normal during the first 6 months of life, but between 9 and
18 months, they develop a mild thoracic limb stiffness, hypermetria, broad-based stance, and occasional
stumbling. Nystagmus can occur late in the condition. These signs progress very slowly (e.g., over several years)
or remain static after a short period of progression. Lesions are restricted to the cerebellum. There may be gross
atrophy of the cerebellar cortex, particularly the pars intermedia. Microscopic changes are characterized by
profound loss of Purkinje cells throughout most of the cerebellar cortex, although the vermis and paravermian
regions of lobules IV, V, and VI were especially affected in one report [20]. The molecular layer is moderately
thinned and the granule cell layer varies in thickness. Ultrastructural findings include a reduction in the size of
Purkinje cells, axonal degeneration, and synaptic abnormalities in the cerebellar glomeruli and deep nuclei of the
cerebellum, suggesting that the degenerative process begins in Purkinje cells and that granule cells may be
secondarily affected [21]. Prognosis is guarded.
Cerebellar Cortical Abiotrophy in Rough Coated Collies

This is an autosomal recessive disease reported in Rough Coated Collie dogs in Australia [22]. Posterior
incoordination occurs between 1 and 2 months of age. Subsequently, animals develop a broad based stance,
hypermetria and head tremors and occasionally, a bunny-hopping gait. Affected animals frequently fall sideways
or forwards with their legs in extension. Severely affected dogs typically spend most of their time lying down.
Clinical signs may stabilize after 12 months of age. Pathologically, there is early and rapid degeneration of
Purkinje cells and granule cells of the cerebellum. Other changes include neuron depletion in cerebellar roof
nuclei, lateral vestibular nuclei, inferior olivary nuclei, and ventral horns of spinal cord. Additionally, Wallerian
degeneration may be observed in the brainstem and in lateral and ventral funiculi of the spinal cord.
Cerebellar Cortical Abiotrophy in Border Collies

This condition appears to be very similar to that described in the Rough Coated Collie [23]. Clinical signs are first
noted at 6 to 8 weeks of age and are characterized by ataxia, hypermetria and head tremor. There is loss of
granule and Purkinje cells from the anterior folia of the cerebellar vermis, which is flattened grossly. The disease
is believed to be familial. Prognosis is guarded to poor since clinical signs reportedly deteriorate with time. An
unusual form of abiotrophy has been reported in two sibling Border Collies in which there was extensive loss of
the cerebellar granular cell layer with relative sparing of Purkinje cells [229].
Cerebellar Cortical Abiotrophy in Australian Kelpies

This degenerative canine condition is thought to be genetically transmitted as an autosomal recessive trait [24].
Clinical signs usually begin around 6 weeks of age, but may be delayed until 12 weeks of age, and are
characterized by ataxia, hypermetria, head tremor, truncal ataxia, and proprioceptive deficits. Menace response
may be absent. There is regional loss of Purkinje cells and granule cells and mild spongiosis and Wallerian
degeneration in white matter tracts of affected cerebellar folia. Changes are most severe in lingula, central and
culmen lobules of the cerebellar vermis. Occasionally, necrotic Purkinje cells are present. White matter
spongiform changes may be seen in cerebellar dentate nuclei and in vestibular nuclei. Prognosis is poor.
Cerebellar Cortical Abiotrophy in Labrador Retrievers

This degenerative condition has been described in three Labrador Retriever puppies from a litter of twelve [25].
Clinical signs occur about 12 weeks of age and include pelvic limb ataxia, hypermetria, truncal ataxia, and wide-
based stance. Within a week, signs progress rapidly to thoracic limb involvement, falling, and inability to walk
without assistance. Positional nystagmus and reduced menace response may be noted. Results of laboratory
diagnostic testing for toxoplasmosis, canine distemper virus, Cryptococcus capsular antigen, and
electroencephalography were normal. The genetic status of this condition remains to be confirmed. Grossly, the
cerebellum is smaller than normal. There is loss of Purkinje cells and granule cells, granule layer thinning, and
folia white matter gliosis in all regions of the cerebellar cortices, especially in central and lingula lobules of the
rostral vermis. The culmen and declive lobules are affected later in the disease. Retrograde degeneration of
brainstem nuclei is not observed.
A similar disorder has been seen in a puppy of predominantly Labrador Retriever breeding (the mother was a
purebred Labrador Retriever and the father was a Labrador-Chesapeake Retriever cross) [26]. The clinical signs
were similar to those described above; however, the progression was very slow and the dog required no
assistance to walk, even at one year of age. Also, abnormal nystagmus was not seen. This dog exhibited seizure-
like episodes similar to those described for Gordon Setters (see above), characterized by progressing episodes of
recumbency with opisthotonus and muscle rigidity. Gross and microscopic findings were similar to those seen in
the Gordon Setters, although neuronal loss and/or axonal swelling was found in the olivary and vestibular nuclei,
along with swollen axons in the vestibular nerve in the region of the cochlear nucleus. Axonal spheroids were
seen in the cerebellar nuclei. These changes were considered to represent transynaptic degeneration as a
consequence of Purkinje cell loss. Increased numbers of Bergmann’s astrocytes were seen around Purkinje cells
and there were increased numbers of astrocytes in the cerebellar white matter.
Cerebellar Cortical Abiotrophy in Rhodesian Ridgebacks

An unusual syndrome of cerebellar Purkinje's cell degeneration and coat color dilution has been reported in a
family of Rhodesian Ridgeback dogs [27]. Three puppies were presented for growth retardation, inability to
ambulate, and progressive ataxia. Signs were usually seen by 2 weeks of age. By 4 weeks, ataxia was so severe
that affected pups were unable to stand or maintain a sternal posture, and tended to lie on their sides making
spasmodic limb movements when stimulated. At this time, affected puppies were one-half the size of their normal
littermates. They often assumed an opisthotonic posture with rigid extension of forelimbs, and the hind limbs were
flexed at the hip, bringing these limbs forward under the body. Intention tremor of the head was noted, especially
during eating and playing. Horizontal nystagmus was also observed, particularly after stimulation of the retina with
a light beam. All affected pups and none of the normal littermates had a dilute coat color at birth. The iris of
affected pups was blue rather than the dark brown to light amber color normally seen in this breed. Results of
routine laboratory tests, urine metabolic screenings, and karyotype analyses were normal. Grossly, the
cerebellum was smaller than normal, including the vermis and hemispheres. Microscopic changes were limited to
the cerebellum. Folia were small, with thinning of the granular and molecular layers, and there was marked
reduction in Purkinje cell numbers (note that the microscopic changes were not detected until around 1 month of
age). Occasional necrotic Purkinje cells had nuclear pyknosis and cytoplasmic eosinophilia. These changes were
most prominent in the dorsal vermis and flocculus. Swollen, eosinophilic Purkinje cell dendrites were present in
the molecular layer, associated with Purkinje cell necrosis and depletion. There were increased numbers of
astrocytes with large nuclei throughout the molecular layer. The granule cell layer was hypocellular, particularly in
areas of Purkinje cell loss. Histological examination of a skin sample revealed uneven distribution of
macromelanosomes within hair shafts. Pedigree analysis suggested an autosomal recessive mode of inheritance.
This is the first description of a genetic syndrome affecting the CNS and associated with coat color dilution in
dogs. While the molecular basis for this condition is unknown at this time, present evidence supports the
hypothesis of a single gene mutation with pleiotropic effects [27].
Cerebellar Cortical Abiotrophy in Coton de Tuléar Dogs

A neonatal ataxia syndrome has been described in Coton de Tuléar puppies [225] with signs very similar to those
seen in the Rhodesian Ridgeback puppies, with most of the affected pups being unable to stand and having a
propulsive "swimming" form of gait. They frequently would fall to lateral recumbency with subsequent
decerebellate posturing and paddling. Ocular motor abnormalities included fine vertical tremors at rest and
saccadic dysmetria. The condition was nonprogressive at least until 4 months of age. No specific abnormalities
were identified in blood, urine, CSF cellularity/protein (although a mild increase in protein concentration was
observed in one dog), CSF organic and amino acid concentrations, brain imaging (MRI/CT), and electrodiagnostic
testing (brain stem auditory-evoked potentials, EMG, nerve conduction studies). Microscopic lesions were not
seen in the CNS or musclcle/nerves using light microscopy or immunocytochemical techniques, although
ultrastructural studies of the cerebellum showed synaptic abnormalities, including loss of presynaptic terminals
and organelles associated with parallel fiber varicosities within the molecular layer and increased numbers of
lamellar bodies in Purkinje cells. An autosomal recessive trait affecting development of the cerebellum is
suspected. Remarkably, an unusual form of cerebellar granuloprival degeneration has also been in three male
Coton de Tuléar puppies between 12 and 14 weeks of age showing progressive cerebellar signs beginning at 8
weeks after birth. Signs included generalized ataxia with hypermetria, tendency to fall, intention tremor and
abnormal menace response. Grossly, the cerebellum appeared shrunken. Histopathologically the granular cells
were diminished or almost completely absent. However, with the exception of some swollen Purkinje cell axons
("torpedos") in the granular layer, Purkinje cells did not appear to be reduced in number and did not show
degenerative changes. There was a marked gliosis in the molecular layer, and occasionally small inflammatory
foci were present in the cerebellar cortex. A marked diffuse T cell infiltration (CD3(+) cells) occurred in the lesions
(B cells were not seen). CD18 staining showed an upregulation of microglial cells at the lesion site. The lesions
resembled some forms of paraneoplastic syndromes in people believed to be caused by an autoimmune
mediated T cell reaction [227]. The authors state that this congenital condition in the Coton de Tuléar dog breed
could be based on a genetically defined immune defect leading to autoimmune destruction of the granular cells.
Cerebellar Cortical Abiotrophy in Beagles
A degenerative cerebellar disease has been reported in Japan involving three Beagle puppies from a litter of eight
[14]. Clinical signs began at 3 weeks of age and were characterized by frequent falling. Signs were progressive.
The cerebellum appeared smaller than normal. Lesions were confined to the cerebellum and were characterized
by thin folia and widened sulci, extensive degeneration and loss of Purkinje cells, thinning of molecular and
granule cell layers, and granule cell depletion. Axonal torpedoes (a non-specific sign of Purkinje cell
degeneration) were seen in the granule layer. The cerebellar hemispheres were most severely involved followed
by rostral parts of the culmen and declive of the vermis. The genetic status of this condition remains to be
confirmed. A similar, early onset disorder reported in a Beagle puppy in the USA was considered to be inherited
as an autosomal recessive trait [28].
Cerebellar Cortical Abiotrophy in Miniature Poodles

This degenerative condition is described under multisystem neuronal abiotrophy.
Cerebellar Cortical Abiotrophy in Brittany Spaniels

This late-onset cerebellar disorder has been observed in older, usually spayed, Brittany Spaniels [29,30]. Onset of
signs occurs between 7 and 14 years of age. Clinical signs are slowly progressive, sometimes extending over a 4-
year course. Subtle limb spasticity and hypermetria eventually leads to truncal ataxia, head tremor, "lurching" gait,
"saluting" movements in the thoracic limbs, frequent falling, and inability to stand. Terminally, dogs crawl in a
crouched thoracic posture with neck extension. Results of all diagnostic testing, including CSF analysis, are
normal. The cerebellum is grossly normal. Microscopic lesions are confined to cerebellum, medulla oblongata and
spinal cord. The most severe lesion is diffuse Purkinje cell loss (approximately 20%) throughout the cerebellar
lobules, particularly in the vermis, with massive neurofilament accumulation in degenerating cells.
Neurofilamentous accumulation in Purkinje cells and their processes appears to precede necrosis. Axonal
spheroids are scattered in granular and deep molecular layers. There is some bilateral neuronal degeneration in
the dorsal horns of the spinal cord and in the gracilis and cuneate nuclei. There is bilateral sporadic axonal
degeneration in the dorsal columns and lateral and ventromedial areas of the spinal cord. The genetic status of
this condition remains to be confirmed.
An unusual cerebellar abiotrophy characterized by granular cell loss has been reported in an intact, male Brittany
Spaniel (3 years old), with a history of ataxia and head tremors of more than 6 months duration [31]. Grossly, the
cerebellum was symmetrically smaller than normal and represented < 6% of the total brain weight (normal is 10%).
Histological examination showed an unusual form of cerebellar abiotrophy characterized by marked and diffuse
depletion of the granular and molecular layers of the cerebellum with normal morphology and numbers of Purkinje
cells. The marked loss of neurons in the granular layer was thought to be due to an innate metabolic error of
granule cells and that concomitant decreased thickness of the molecular layer might be expected because of the
decreased excitatory input from granule cell parallel fibers. It was reasoned that the slight changes in Purkinje
cells was expected because the major excitatory input comes from brainstem nuclei, with only minor excitation
evoked from granule neuron synapses.
Cerebellar Cortical Abiotrophy in a Schnauzer-Beagle Dog

Late-onset cerebellar degeneration has been reported in a 6 year old male Schnauzer-Beagle dog with clinical
signs similar to those seen in Brittany Spaniels [32]. The condition progressed slowly over a 5-year period to a
point where the dog was unable to walk, eat or drink without assistance. Cerebellar biopsy revealed reduction in
size of the cerebellar hemispheres and vermis, loss of Purkinje cells and granule cells, Purkinje cell degeneration,
and thinning of the molecular layer. Some Purkinje cells were displaced into the granule cell layer.
Cerebellar Cortical Abiotrophy in Portuguese Podencos

Cerebellar cortical abiotrophy has been reported in two Portuguese Podenco littermates [33]. Clinical signs had
an early onset around 2 to 3 weeks of age and were characterized by progressive cerebellar ataxia. Lesions were
confined to the cerebellar hemispheres and characterized by extensive loss, degeneration, and necrosis of
Purkinje cells. An autosomal recessive pattern of inheritance was suspected.
Cerebellar Cortical Abiotrophy in Old English Sheepdogs

A slowly progressing, late-onset form of cerebellar degeneration characterized by progressive gait abnormality
has been reported in Old English Sheepdogs, with an apparent autosomal recessive mode of inheritance [34].
Clinical signs began when dogs were from 6 to 40 months of age and were characterized by wide-based stance in
hind limbs, hypermetric forelimb gait, and inconsistent menace deficit. As the disease progressed, truncal ataxia
progressively worsened, often with dragging of the toes, and ambulation became increasingly difficult, with
frequent falling and difficulty rising from a recumbent position. Some dogs developed a fine head tremor. The
course of the disease developed slowly over many months to several years. The cerebellum appeared grossly
normal. Microscopically, there was localized loss of Purkinje cells with gliosis, thinning of the granule cell layer,
and increased cellularity of the molecular layer. These changes were restricted to the folia of the paravermal and
vermal cerebellar cortex. There was also a marked increase in glial cell numbers in the cerebellar nuclei.
Interestingly, 4 of 22 dogs in this study had no histological cerebellar changes but had clinical signs of cerebellar
degeneration.
Cerebellar Cortical Abiotrophy in Bernese Mountain Dogs

An unusual disorder has been reported in Bernese Mountain Dogs characterized by progressive cerebellar and
hepatic disease [35]. Clinically, stiffness in the hind limbs, mild incoordination, and a slight head tremor were first
noticeable when pups were 4 to 6 weeks old. As the condition progressed, pups assume a wide-based stance.
Other signs included head bobbing, spontaneous nystagmus, and, finally, paresis. Hematologic findings included
leukocytosis with a left shift; normocytic, normochromic anemia; hypoproteinemia, low serum creatinine, and urea
nitrogen concentrations; excessive fasting plasma ammonia concentration; and an increase in concentration of
serum bile acids. Portal venography performed on 1 dog revealed a small liver and extensive extrahepatic
varicosities. Necropsy revealed cerebellar hypoplasia, nodular liver, extensive abdominal varicosities, and ascites.
Histologically, degeneration and depletion of Purkinje's cells and vacuolation, degeneration, and nodular
regeneration of hepatic tissues were evident. Preliminary analysis of the pedigree suggested an autosomal
recessive pattern of inheritance.
Cerebellar Cortical Abiotrophy in American Staffordshire Terriers

A disorder has been recently recognized in American Staffordshire Terriers in the United States (Dr. Natasha
Olby, personal communication, 2001) and in Europe [217,220] with adult onset, slowly progressive cerebellar
signs. Clinical signs develop between 2.5 and 6 years of age and include ataxia, spontaneous nystagmus and
falling over. Neurological examination reveals ataxia in all limbs with normal conscious proprioception and, as the
signs progress, worsening hypermetria and truncal ataxia. Strength is normal. Dogs ambulate well on flat straight
surfaces, but tend to trip, stagger, or fall over as soon as they attempt to turn quickly, negotiate a door, or go
down steps. Affected dogs often fall over when they shake their heads. In some instances, dogs assume an
opisthotonic posture after falling. Spontaneous nystagmus (horizontal, rotary and vertical) is easily elicited by
sudden movements. Menace reaction may be absent in severely affected dogs. To date, CSF analysis, and
metabolic screening have been normal. Imaging studies have revealed asymmetrical lateral ventricular dilatation
(CT scans) and symmetrical cerebellar atrophy (MRI scans) [220]. Histopathological findings include complete
absence of Purkinje cells in cerebellar cortex, increased density of Bergmann glia in the Purkinje layer, and
thinning of molecular and granular layers. Pedigree analysis is compatible with an autosomal recessive
inheritance.
Cerebellar Cortical Abiotrophy in English Bulldogs

Clinical signs characterized by wide-based stance, generalized intention tremors, hypermetria in all limbs,
decreased menace response and slight proprioceptive deficits have been described in 3 young English Bulldogs
(between 5 and 8 months of age) born from the same parents [223]. Onset of signs was around 2 months of age.
A CT scan on one dog was normal. No gross abnormalities were noted in the CNS. Histopatholgy was limited to
the cerebellum and included severe Purkinje cell loss and marked gliosis in Purkinje and granule cell layers.
Occasional Purkinje cells were located in molecular and granule cell layers. The condition is believed to be
inherited.
Cerebellar Cortical Abiotrophy in Other Canine Breeds

Cerebellar degenerations, usually involving Purkinje cells, have been reported in families of Samoyeds (with
swollen axons of Purkinje neurons in the granule cell layer), Airedale Terriers, Finnish Harriers, and Bern Running
Dogs [36]. A genetic basis has been suggested. A similar disorder has been observed in single litters of Akitas,
Clumber Spaniels, Golden Retrievers, Cocker Spaniels, Cairn Terriers, Fox Terriers, Great Danes, and mixed-
breed dogs [36]. Cerebellar cortical abiotrophy has recently been reported in a Scottish terrier using magnetic
resonance imaging [230]. At Auburn University, we have observed isolated cases of Purkinje cell degeneration
and loss in German Shepherd, English Springer Spaniel, Miniature Poodle, and Pit Bull Terrier puppies aged
between 6 and 16 weeks. Clinical signs are characterized by the typical cerebellar syndrome.
Cerebellar Cortical Abiotrophy in Cats

Cerebellar cortical abiotrophy-degeneration is considered rare in cats [10]; however, late onset cerebellar
degeneration was diagnosed in a one-and-a- half year old Siamese cat [37]. The cat presented with mild ataxia
involving all four limbs. Over the following two years, the signs gradually progressed to severe incoordination, a
frequent tendency to fall, and a head tremor. Profound and diffuse Purkinje cell loss and evidence of brainstem
Wallerian degeneration were found on histopathological examination, but no etiological agent was detected. A
similar clinical history was noted in a 4 year old male Domestic Shorthair cat with signs of symmetrical
hypermetria and spasticity, whole body tremor, intention tremors of the head, positional vertical nystagmus, and
loss of balance [191]. In addition, the cat had bilaterally absent menace response and widely dilated pupils with
diminished pupillary light repsonse. Fundoscopic exam revealed end-stage retinal degeneration, pale optic disks
and retinal vessel attenuation. Grossly, the cerebellum was approximately two-thirds the normal size. Microscopic
lesions were restricted to the cerebellum and included marked reduction/loss of Purkinje cells in all folia and
‘empty baskets’, along with diminished molecular layer and increased numbers of Bergmann’s glia. Photoreceptor
degeneration was observed in retinal sections associated with pronounced reduction in rod/cone numbers. This
case was considered to be analagous to spinocerebellar ataxia type 7 (SCA7) in humans, an autosomal dominant
form of cerebellar ataxia with retinal degeneration [192] associated with accumulation of expanded polyglutamine
proteins resulting from an expanded CAG (cytosine-adenosine-guanine) sequence [193,194].
There have been recent reports of cats with hereditary cerebellar degeneration, transmitted as an autosomal
recessive trait [38,39]. Cats developed cerebellar signs around 7 weeks of age characterized by intention tremor,
especially of the head and neck, during eating and drinking, wide-based stance when standing, and ataxia-
dysmetria with staggering gait and frequent falling. The clinical course was progressive. The cerebellum was
atrophic. Microscopic findings included pronounced loss of Purkinje cells with an increase in Bergmann's glia in
the cerebellar hemispheres, preservation of some Purkinje cells in the vermis and moderate neuronal depletion of
the olivary nucleus. Cerebellar and pontine nuclei were normal, as were other areas of the brain, spinal cord and
peripheral nerves. Electron microscopic examination revealed swelling of the distal dendrites of Purkinje cells in
the less-affected nodule of the vermis, and clusters of presynaptic boutons without any synaptic contact in the
severely affected folia. Presence of presynapses in the molecular and Purkinje cell layers was confirmed by
positive immunoreactivity to anti-synaptophysin. Quantitativeultrastructural analysis revealed an increase in the
density and mean size of presynapses in the molecular layer of the severely affected folia. These findings
suggested that degeneration of Purkinje cells began at the most distal part of the dendrite, and that presynapses,
axon terminals of the granular cells and basket cells may remain for a long time even after complete degeneration
of the Purkinje cells [39]. These cats were considered to represent a novel animal model of human
spinocerebellar degeneration.
Several other variants of this condition have been reported. An olivopontocerebellar atrophy has been observed in
2 adult feral cats with signs of head and limb dyssynergia and microscopic lesions characterized by loss of
cerebellar cortical neurons (Purkinje cells, Golgi and basket cells and granule cells), loss of myelin in vermis and
lobules, reduction in pontine nuclei and transverse fibers, and neuronal loss /gliosis in the inferior olivary complex
[222]. Cerebellar degeneration involving only Purkinje cells (characterized by cell loss and degeneration including
dendritic vacuolization and axonal spheroids) with normal inferior olive and pontine nuclei, has been described
from Belgium in two 4 month old female kittens from the same litter with characteristic cerebellar signs [224]. MRI
in one kitten was normal. The cerebellum was grossly normal. A similar condition has been reported from the U.K.
in two domestic shorthair littermate kittens with signs occurring around 7 - 8 weeks of age [228]. Cerebellar
abiotrophy has also been reported in cats with neuraxonal dystrophy.
Dalmatian Leukodystrophy
A progressive neurological disorder, transmitted by autosomal recessive inheritance, was described in male and
female Dalmatian dogs [40]. Clinical signs were noted between 3 and 6 months of age and were characterized by
visual deficiency and progressive ataxia, initially in the hind limbs, then involving all limbs, sometimes progressing
to the point where the dog could no longer stand. Results of routine hematology, urinalysis, and CSF analysis
were within normal limits. Gross pathological findings included brain atrophy, dilatation of lateral ventricles, and
cavitation of the central white matter of the cerebral hemispheres, primarily involving the centrum semiovale. The
subcortical arcuate fibers (U-fibers) of the cerebral white matter appeared to be spared. The occipital lobes were
usually more severely involved than more rostral areas of the brain. Bilaterally symmetrical grayish and somewhat
depressed areas, and occasional foci of softening, were also found in the corpus callosum. Microscopic lesions
occurred in internal and external capsules, caudate nucleus and claustrum (sometimes with microscopic cavities
in these basal ganglia), optic nerve, and less frequently, the spinal cord where lesions were mainly confined to the
ventral horns and adjacent white matter in thoracic cord segments. A few cases had vacuoles within the spinal
cord white matter adjacent to the gray matter and beneath the meninges. Within affected areas of white matter,
there was a diffuse loss of myelin, widespread vacuolation, edema, presence of numerous, lipid-filled
macrophages, and reactive astrocytosis. Axons appeared to remain intact, at least initially. Vacuolation was seen
in myelin sheaths as a result of lamella splitting. Spinal roots and peripheral nerves were unaffected. Prognosis
was poor. There is no treatment. To my knowledge, there have been no additional reports of this disease during
the past 15 years; however, very similar clinicopathological findings have been reported in 2 related Labrador
Retriever puppies [237].
Degenerative Myelopathy
This degenerative disease may have an inherited basis in dogs [41] and it may represent an abiotrophy [1]. It is
most often observed in German Shepherd dogs over 5 years of age; however, a similar clinical and pathological
condition has been reported in young German Shepherd dogs [42], other breeds of dogs [43-46], and cats [47].
The onset of the disease is insidious. Initial signs include pelvic limb ataxia and paresis. Ataxia, in the form of
hypermetria or excessive circumduction of the limb, crossing of the legs when walking with one limb catching
behind the other, is greater than paresis, seen as dragging the toes and flexing the stifles when weight-bearing
[45]. The signs progress slowly to truncal ataxia and severe pelvic limb paresis. Knuckling of paws of pelvic limbs
is commonly observed, with wearing of the nails of the affected pelvic limb(s). The cutaneous trunci reflex is
usually intact. Deep pain perception is unimpaired. Some dogs have a depressed patellar reflex. Sphincter
function remains normal. The disease usually is slowly progressive over 6 to 36 months, although fluctuations in
clinical signs may be seen [48].
Grossly, spinal ganglia, dorsal and ventral roots and rootlets are normal. Histopathologically, white matter
changes are found throughout the length of the spinal cord, with the most severe lesions being present in the
thoracic cord. Lesions are characterized by degeneration of white matter, especially in dorsolateral and
ventromedial funiculi, along with degenerating dystrophic axons, swollen myelin sheaths, often with macrophages,
astrocytosis, and gliosis. Axons may fragment and disappear. The lesions are bilateral but not necessarily
symmetrical, are not restricted to particular fiber tracts, and on longitudinal studies, appear not to be continuous
[41]. Lesions typically do not extend into the brainstem [46]. However, at variance with all previous reports, a
recent study documented chromatolysis, gliosis and neuronal loss in various brain neurons, including the red
nucleus, lateral vestibular nucleus and, occasionally, in the dentate nucleus [49]. The significance of these
changes is uncertain, especially since the authors found similar lesions in dogs with spinal injuries.
Leptomeningeal thickening and fibrosis has been noted [46]. Dorsal root involvement and loss of neurons in
dorsal gray horns (Clarke’s column) of spinal cord have been observed in some German Shepherds [45,46],
although this may be an age-related effect [50]. Ventral roots are unaffected. Occasional dorsal root ganglion cells
show minor central chromatolysis [45]. No significant changes are seen in brain, peripheral nerves or muscles,
including end-plates and spindles [41,45,46].
The pathogenesis of this disease is unknown. It is unrelated to intervertebral disk degeneration, spondylosis
deformans or osseous metaplasia of dura mater. Trauma and vascular disease have been suggested as possible
causes [46], but have not been substantiated. Some affected dogs have an associated enteropathy characterized
by biochemical changes in peroral jejunal biopsies and accompanied by overgrowth of bacteria in duodenal juice,
and decreased serum levels of tocopherol (vitamin E) and cobalamin (vitamin B12) [51-53]. The significance of
these findings remains unclear and a recent study refutes vitamin E involvement [49] (See vitamin E deficiency, in
Nutritional Disorders). The clinical course of the disease in dogs with low levels of vitamin B12 has not been
reversed by parenteral administration of cobalamin [52]. Morphologic and morphometric data [41] do not support
the hypothesis that this disease represents a "dying back" neuropathy [45]; although this theory involving distal
involvement of motor and sensory fibers is still favored by some [49]. Another theory is that degenerative
myelopathy is an immune-mediated neurodegenerative disease [54]. Depression of cell-mediated immune
responses (to conconavalin A, phytohemagglutinin P and pokeweed mitogens reportedly occurs secondary to a
progressive increase in the number of circulating suppressor cells [55,56]. Affected dogs have 3 to 10 times more
circulating immune complexes than normal dogs, including a possible protein-specific antigen with a molecular
weight of 85 kD, and plasma cell infiltrates are reportedly found in several organs, including kidneys and intestinal
tracts [48]. Furthermore, an immunohistochemical study on German Shepherd dogs with degenerative
myelopathy reports focal staining for immunoglobulin G (IgG) and the third component of complement (C3) in
spinal nerve tracts characteristically affected in degenerative myelopathy [57]. Deposition of IgG and C3 is also
found with large and small blood vessels and in other areas independent of visible lesions, suggesting that IgG
and C3 deposition may precede histological evidence of spinal cord damage. Degenerative myelopathy may well
be a genetic, late-onset neurodegenerative disease [45,49]. Griffiths and co-workers are searching for candidate
genes [49]. A study aimed at characterizing the histopathology, antemortem diagnostics (myelography/MRI and
electrophysiology), excitotoxicity/oxidative stress in CSF (glutamate, methionine, prostanoids) and genetic factors
is currently being undertaken at Texas A and M University with Dr. Joan Coates as the senior investigator.
Diagnosis is based on clinical syndrome, breed, and age. Hematology, blood chemistries, urinalysis, and CSF
analysis are normal (although an elevation in protein in CSF samples from the lumbar cistern have been reported
in some dogs [48]), as are spinal radiographic-myelographic studies, which help distinguish degenerative
myelopathy from other degenerative conditions, such as pachymeningitis, disk protrusion, diskospondylitis, and
spinal neoplasia. It has been reported that spinal cord evoked potentials recorded at the level of the cisterna
magna, after stimulation of the sciatic nerve, are abnormal and that magnetic resonance imaging may reveal
lesions throughout the spinal cord [58]. Despite the claims for immune-mediated disease (see above), repeated
mitogen response assays in some dogs with confirmed degenerative myelopathy are negative [59]. Prognosis is
guarded.
Recommended treatment involves a combination of exercise, vitamin supplementation, and administration of
aminocaproic acid (EACA) (Amicar®, Lederle), at 500 mg, PO, tid [60]. This is the only drug that has been shown
to alter the course of the disease, perhaps by blocking the final common pathway of tissue inflammation. It has
been stated that EACA does not cure degenerative myelopathy but may slow its progression by as much as 50%,
and that clinical improvement will usually be seen within 2 months of initiation of treatment [58]. Approximately
15 - 20% of affected dogs have no further deterioration, some improve, and others have survived for more than 4
years. The main disadvantage of this drug is its expense-it may cost from $ 80 to $100 per month. As an
alternative, the generic injectable form of the drug (250 mg/ml) can be given as an oral solution by mixing 192 ml
of EACA with 96 ml of a hematinic compound, e.g., Lixotinic. This combination provides 500 mg of EACA in 3 ml
of the mixture. The dose of EACA in this form is 500 mg, tid. It is recommended that corticosteroids be reserved
for acute exacerbations (e.g., prednisone, at 1 mg/kg/day, in three divided doses for 3 days before reducing to
0.33 mg/kg every 12 hours for 2 days, and continuing at maintenance levels of 0.5 mg/kg, every other day). High
doses of vitamin E (2000 IU /day) and B complex vitamins (e.g., stress tablets, twice daily) can be given with the
EACA. For pain, acetaminophen (i.e., Tylenol®) may be given at 5 mg/kg (not to exceed 20 mg/kg/day) [48].
Drugs that have no benefit include dimethyl sulfoxide, cobra venom, and immunosuppressive agents, such as
cyclophosphamide and azathioprine. In conjunction with treatment, affected dogs should be placed on an
increasing exercise program, including walking and swimming.
Encephalomyelopathy in Young Cats

In a retrospective study, Palmer and Cavanagh have described a neurodegenerative disorder that primarily
occurred in cat colonies (both conventional and specific pathogen-free) in the United Kingdom between 1969 and
1980 [61]. In some colonies, over 40 per cent of litters were affected. In this report, 19 cats aged 3 to 16 months
developed neurological signs including hind limb ataxia that progressed to paraparesis, paraplegia, and in some
instances, tetraparesis, along with urinary and fecal incontinence and muscle atrophy over the hindquarters.
Other signs included visual deficits, dilated pupils, sluggish pupillary light reflexes, head shaking, head tremor,
nystagmus, seizures ("fits"), and proprioceptive deficits. Spinal reflexes appeared intact, although the cutaneous
trunci reflex was absent in some cats. Pain perception was also absent in one cat. Hematology and serum
chemistries were normal. Serological testing for picorna virus, feline rhinotracheitis, feline pneumonitis,
panleukopenia virus, and toxoplasmosis were negative. Transmission studies (animal and culture) were also
negative. Plasma and red blood cell cobalamin levels were normal. Treatment of some cats with vitamin B12, at
0.25 mg/day for 6 weeks reportedly led to clinical improvement, although complete remission of signs did not
occur.
Histopathological changes were confined to the CNS and characterized by Wallerian degeneration (degeneration
of axons and myelin with myelophages often seen within remnants of the fiber) affecting long tracts in the spinal
cord and variously in the brainstem, cerebral white matter, and optic pathways. There was an accompanying mild
status spongiosis, increased numbers of astrocytes and microglial cells, and occasionally, swollen axons.
Inflammatory changes were not a feature. Most severe lesions occurred in the spinal cord, especially involving
larger diameter fibers (e.g., spinocerebellar and ventral tracts). There was no evidence of a distal dying back
distribution to the lesions. All areas of the spinal cord were affected except the dorsal columns. In the brainstem,
Wallerian degeneration was noted in the external arcuate fibers and caudal cerebellar peduncles, and less
commonly in middle and rostral cerebellar peduncles, medial lemniscus, pyramidal tracts, spinal trigeminal tracts,
pontine decussation, medial longitudinal fasciculus, and cerebral peduncles. In 7 cats there was loss of Purkinje
cells in the cerebellum and in 8 there was neuronal degeneration-loss in the spinal cord, especially in the
intermediate cell columns, either at the base of the dorsal columns or in the region of Clarke’s column. Larger
ventral horn cells and larger neurons in the brainstem were usually not affected. No changes were found in
peripheral nerves, spinal ganglia, or skeletal muscle.
The cause of this condition remains unknown. Genetic studies were inconclusive and nutritional and dietary toxins
were ruled out. Despite the absence of inflammatory changes and the fact that no viral agent was isolated, the
authors suggested the condition might have an infectious cause. Purkinje cell loss as well as spinal cord myelin
degeneration and neuronal degeneration have been reported in young cats with feline panleukopenia virus [62]
and the condition has some similarities to idiopathic feline polioencephalomyelitis. Another degenerative
myelopathy with changes similar to those seen in the colony cats has recently been reported as a complication of
chronic feline leukemia virus infection [63].
Encephalomyelopathy and Organic Acidopathies

Several inherited diseases in people involve abnormal metabolism of organic and amino acids leading to
neurologic dysfunction [195]. These conditions are rarely recognized in dogs and cats; however, methylmalonic
and malonic aciduria has been reported in a young dog with progressive encephalomyelopathy (see cobalamin
deficiency).
Two distinct autosomal recessive encephalopathic disorders with elevated urinary excretion of 2-hydroxyglutaric
acid are recognized in infants and children: L-2-hydroxyglutaric aciduria and D-2-hydroxyglutaric aciduria [203-
205]. Recently, a third variant has been reported associated with both isomeric forms of 2-hydroxyglutaric acid
[206]. L-2-hydroxyglutaric aciduria is characterized by moderate to severe mental deficiency, often with cerebellar
dysfunction, and epilepsy [203,207]. Magnetic resonance imaging typically reveals subcortical
leukoencephalopathy, cerebellar atrophy, and signal changes in the putamina and dentate nuclei [203,208].
Increased levels of L-2-hydroxyglutaric acid also occur in blood and CSF. Patients may also have hyperlysinemia
in plasma and CSF [203,209]. Patients with D-2-hydroxyglutaric aciduria have somewhat different clinical features
(severe and mild phenotypes have been recognized), including dysmorphic facies, developmental delay,
generalized hypotonia, myoclonic seizures, cortical blindness, and dilated cardiomyopathy [205,210]. The most
consistent MRI finding is enlargement of the lateral ventricles (especially occipital); early MRI may demonstrate
subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white-
matter abnormalities [211]. In addition, there lesions have been reported in the substantia nigra, the
periaqueductal area, the medial part of the thalamus, the hypothalamus, the caudate nucleus, putamen and
globus pallidus [212]. Patients typically have elevated levels of D-2-hydroxyglutaric acid in plasma and CSF,
along with increased CSF levels of gamma-aminobutyric acid [213].
L-2-hydroxyglutaric aciduria has recently been reported in six Staffordshire Bull Terriers from 4 months to 7 years
of age with clinical signs of seizures, ataxia, or dementia [214]. Cerebral MRI findings revealed a diffuse
polioencephalopathy with hyperintensity on T2-weighted images of the cerebral, cerebellar, thalamic and
brainstem gray matter. L-2-hydroxyglutaric acid levels were increased in urine, plasma and CSF. In all dogs
tested, CSF lysine levels were also increased. One dog had increased urinary excretion of methylamalonic acid.
CSF cytology/protein content was normal. Electrodiagnostic testing on muscle and nerve was normal as were
muscle biopsies. While serum total and free carnitine concentrations were within the normal range, the
concentrations of muscle total and free carnitine were reportedly low. Histopathology of the CNS has yet to be
reported in affected dogs. The authors state that treatment strategies, pedigree analysis, and studies aimed at
identifying the underlying biochemical defect are underway.
D-2-hydroxyglutaric aciduria has also been reported in an adult dog with a 2-year history of progressive lethargy
and muscle weakness [215]. A neuromuscular componenet to this disease was suggested by abnormal
spontaneous activity, including myotonic discharges (on EMG studies) and observation of scattered atrophic
angular myofibers with increased lipid content in a muscle biopsy. Interestingly, muscle biopsy in one human
patient with D-2-hydroxyglutaric aciduria demonstrated excessive glycogen histochemically and subsarcolemmal
cylindrical spirals with normal mitochondria ultrastructurally [210].
Fibrinoid Leukodystrophy
Fibrinoid leukodystrophy (synonyms include Alexander's disease and fibrinoid encephalomyelopathy) is a rare
degenerative disorder that has been reported in two 8 month old male littermate black Labrador Retriever dogs, a
9 month old male Scottish Terrier, a 6 month old female Miniature Poodle, and a 13 week old Bernese Mountain
dog [64-68]. Clinical signs are noted from 2 to 6 months of age and include pelvic limb paresis, progressive ataxia,
wide-based stance, generalized weakness, exercise intolerance, reluctance to go up and down stairs, and
sometimes tremors, falling, and personality changes, ranging from depression, agitation, and growling. In the
Scottish Terrier, head tilt, seizure-like activity characterized by thoracic limb extension and opisthotonus,
abduction of all limbs, and progressive tetraparesis were seen. At 9 months of age, the elbow and stifle joints of
this dog were maintained in a flexed position with abnormally short range of motion, and attempts to ambulate
resulted in a "swimming" motion [69].
Hematology, blood chemistries, urinalysis, and CSF analysis are normal. In the Scottish Terrier, an abnormal
electroencephalogram was recorded, consisting of 50 to 75 v, 2 to 5 Hz wave forms [69]. Gross changes include
gray pallor of cerebral subcortical white matter and sometimes, enlargement of the lateral ventricles.
Histopathological changes include diffuse pallor with vacuolation of subcortical white matter with increased
vascularity in which vessels are accentuated by thick cuffs of Rosenthal fibers, and mild to moderate gemistocytic
astrocytic gliosis. There may be considerable myelin loss in some affected dogs [67], and neuronal loss may be
evident in the cerebral cortex and subcortical gray structures [65]. The Rosenthal fibers are round, club-shaped,
or elongated eosinophilic refractile bodies (up to 50 m in diameter) that are also found in astrocytes located in
subependymal and subpial areas of the brain and spinal cord. These bodies are common in pontine and midbrain
regions. In one immunohistological report, the Rosenthal fibers were positive for glial fibrillary acidic protein and
-crystallin [67]. Ultrastructurally, the refractile bodies consist of non-membrane bound granular osmiophilic
aggregates within the cytoplasm of astrocytic processes adjacent to vessels. The aggregates are surrounded by
bundles of glial filaments ranging in diameter from 7 to 10-nm, a size and morphology similar to that of glial
fibrillary acid protein [66]. Scattered peripheral nerve fiber degeneration and demyelination were reported in one
affected dog [68]. In skeletal muscle from this dog, multiple subsarcolemmal masses were noted in many muscle
fibers and were basophilic on hematoxylin and eosin staining, bright red with Modified Gomori’s Trichrome, black
with NADH-TR, weakly periodic acid-Schiff positive, and brown with osmium tetroxide.
The histological, immunohistochemical, and ultrastructural findings in affected dogs appear identical with those in
human cases [67]. The cause of this disease is not known, although the bodies may represent an overproduction
of astrocytic fibers, and genetic or congenital disease has been postulated. In people, the condition is thought to
represent an inborn error in astrocyte metabolism that leads to global dysmyelination or demyelination of the CNS
[4]. The origin of the myelin loss is also unclear, but may be due to secondary damage to oligodendrocytes.
Prognosis is poor. There is no treatment.
Hereditary Ataxia
Hereditary ataxia is an autosomal recessive disorder in Smooth-Haired Fox Terriers in Sweden that has been
reported as a clinical entity since 1941 [70,71]. A similar condition has been described in Britain and in Germany
in Jack Russell Terriers, a short-legged variety of the Smooth-Haired Terrier breed [72,73]. In the German study,
certain families of Jack Russell Terriers were predisposed to the disease [73]. Clinical signs in both breeds occur
between 2 and 6 months of age when pelvic limb swaying and incoordination are observed. The incoordination
progresses to involve all limbs and a prancing or dancing type of gait is observed, especially affecting the hind
limbs. There is over protraction of the forelimbs. Animals appear to be unable to gauge the extent of a movement,
which is unpredictable in direction. Severely affected animals frequently fall and are unable to rise again to their
feet. Animals have difficulty in climbing stairs and jumping. There is no skeletal muscle atrophy. The head may
show a rotational intention tremor, while hearing appears unimpaired. Approximately one third of the German
cases have seizures and some dogs develop respiratory distress (Dr. Andrea Tipold, personal communication,
2001). Clinical signs may stabilize after several months and some affected animals are able to carry on a
relatively normal life, in spite of the abnormal movements. In no case has the disease, per se, proved to be fatal
[71].
Pathologically, a symmetrical bilateral myelopathy is found in the dorsolateral and ventromedial white matter of
cervical, thoracic, and lumbar spinal cord [70]. There is myelin pallor reflecting Wallerian degeneration of the
white matter, which has a spongy vacuolar appearance, accompanied by a mild subpial astrocytosis [10]. The
dorsolateral spinal cord lesions appear to involve the spinocerebellar pathways [70]. In the Jack Russell Terriers,
similar lesions are seen in the spinal cord but tend to be most severe in cervical segments (Dr. Andrea Tipold,
personal communication, 2001). In addition, moderate diffuse gliosis, marked loss of myelinated nerve fibers, and
argyrophilic axonal spheroids are found in central auditory pathways, including superior olivary nuclei, cochlear
nuclei, connecting nerve fibers between these nuclei and the trapezoid body, and the lateral lemniscus [72].
Massive ballooning of myelin sheaths, with an apparently intact axon, was found in dorsal and ventral nerve roots
and sciatic nerves, often accompanied by endoneurial edema and fibrosis and axonal swelling. In addition,
marked nerve fiber loss and variable numbers of macrophages are found in the sciatic nerves [72].
Routine hematology and blood chemistries, urinalysis, CSF analysis, radiography, myelography, and spinal
computed tomography are normal [70,73]. An abnormal measurement of brainstem auditory-evoked potentials
(only waves I and II being detected) has been found in some affected Jack Russell Terriers [73]. There is no
treatment. Control measures should focus on preventing further breeding of affected animals or their parents.
Preliminary pedigree studies suggest a polygenic model of inheritance in Jack Russell Terriers [216].
Hereditary Polioencephalomyelopathy of Australian Cattle Dogs

A vacuolar degeneration affecting primarily the gray matter in the CNS of young Australian Cattle Dogs has been
described [74]. Male and female dogs were affected and clinical signs were noted within the first year of life. An
initial presentation of psychomotor seizures (episodes of running in circles, vocalizing and urinating) was followed
within approximately 6 to 12 months by progressive fatigue and thoracic limb stiffness, and eventual spastic
tetraparesis over an ensuing period of several months. Dogs in lateral recumbency could move their neck and
trunk but thoracic limbs were rigidly extended in a tetanic posture with persistent contraction of extensor muscles.
Dogs remained bright and alert. Patellar reflexes were depressed or absent in 2 dogs, but nociception and
withdrawal reflexes were normal. In thoracic limbs, dogs felt a noxious stimulus applied but were unable to
withdraw these limbs. While normal vestibular nystagmus was difficult to elicit, a brief positional nystagmus could
be induced. Remaining cranial nerve function was normal. Routine blood cell count and serum biochemistry were
normal. CSF analysis was normal in one dog but a mild increase in protein (29 mg/dl) and mild mononuclear
pleocytosis (13 cells/ml) comprising leukocytes and macrophages, a few of which contained myelin fragments,
was found in another dog. EMG studies showed evidence of continual muscle fasciculations in proximal thoracic
limbs muscles, rhythmic contraction of carpal flexors, and denervation potentials in numerous thoracic limb
muscles.
Bilateral and symmetrical foci of malacia were seen grossly in the nuclei of the cerebellum and brainstem (caudal
colliculi, lateral vestibular nuclei, lateral cuneate nuclei, and lateral reticular nuclei) and the gray matter of the
spinal cord associated with cervical and lumbosacral intumescences. Additional, focal lesions were noted in the
interposital nucleus of the cerebellum and spinal nuclei of the trigeminal nerve. Bilateral atrophy of thoracic limb
muscles was also found, being most severe in the scapular musculature. Microscopically, vacuolation of glial cells,
dilation of the myelin sheaths and reactive astrocytosis characterized mild CNS changes and were seen in
oculomotor, abducent, lateral cerebellar and hypoglossal nuclei, and the reticular formation. Dissolution of the
neuropil, prominent vacuolation of reactive astrocytes, numerous glial fibrillary acidic protein-positive coiled
astrocytic processes, neuronal vacuolation and loss with relative sparing of large neurons were observed in more
advanced lesions. This change was most severe in the C7 - T1 region where tissue loss involved up to 80% of the
spinal cord with relative sparing of only the central canal and a thin subpial band of white matter and substantia
gelatinosa. The innermost area of the affected cord segments was characterized by advanced rarefaction. The
next zone was filled with macrophages followed by a cribriform vacuolar zone and finally, the outer unaffected
zone of white matter. Ultrastructurally marked mitochondrial accumulation and swelling were seen in astrocytes.
Scattered Wallerian degeneration was found in ventral roots and peripheral nerves. In the appendicular muscles,
changes interpreted as long-term denervation atrophy accompanied by widespread expression of the neonatal
isoform of myosin were observed. The character of the neurological signs and the nature and distribution of the
lesions within the CNS appear to be novel in veterinary neurology. A biochemical defect, possibly mitochondrial,
affecting several cell populations within the CNS was proposed, with a more pronounced effect on glial cells than
neurons. Genetic analysis suggested an autosomal recessive mode of inheritance.
Hound Ataxia
A degenerative myelopathy has been recognized in Britain and Ireland in adult Foxhounds, Harrier Hounds and
Beagles, of either sex [75-78]. In some packs, up to 75% of animals have been affected [77]. Age of onset varies
from 2 to 7 years. Initial signs are pelvic limb weakness, ataxia and exaggerated elevation of these limbs when
retracted at a gallop. Occasionally the pelvic limbs are dragged. The cutaneous trunci reflex is usually absent at
levels caudal to T13 - L2 vertebrae. Muscle atrophy is not observed and spinal reflexes are normal. Affected
animals usually become unworkable due to increasing pelvic limb incoordination within 6 to 18 months from the
onset of symptoms. Animals remain bright and alert and thoracic limb function and cranial nerves are normal. In
some affected dogs, clinical signs are not progressive. In one report, consanguinity was not established between
affected dogs [78].
No gross lesions are observed. Histologically, severe Wallerian degeneration is found in the spinal cord involving
all tracts except dorsal columns. Lateral columns are also unaffected in the cervical cord region. The
degeneration, characterized by severe myelin ballooning with intramyelinic macrophages, is diffusely distributed
within funiculi, varying in intensity from slight to severe. Axonal spheroids are rarely seen. The pathological
severity seems unrelated to clinical neurological deficiency. Degeneration in lumbar cord is not as marked as in
more rostral levels. In some animals, changes are most severe in the thoracic cord region. Typically, changes are
not seen in gray matter of the cord, although chromatolysis was seen in neurons of the thoracic cord segments in
one 2.5 tear-old female Foxhound accompanied by astrocytosis and gliosis [77]. Tract degeneration extends into
the brainstem, including the external arcuate fibers, inferior cerebellar peduncles, spinothalamic tract, medial
longitudinal fasciculus, and tectospinal tract. At midbrain level, Wallerian degeneration is seen in the medial
lemniscus, medial longitudinal fasciculus, decussation of the superior cerebellar peduncles, and rarely, the lateral
lemniscus. With the exception of chromatolysis affecting neurons of the lateral vestibular nucleus in one
Foxhound, there is no evidence of nerve cell damage or loss. No lesions are found in skeletal muscles, nerve
roots or dorsal root ganglia, but in occasional animals, degenerative changes (possibly sensory) are found in
sciatic nerves [77]. In one ultrastructural report, degenerate fibers were accompanied by astrocytic proliferation,
and changes suggestive of a primary myelinopathy included vacuolated myelin sheaths around apparently intact
axons, degenerative changes in inner oligodendrocyte tongues, large numbers of remyelinated axons with
disproportionately thin myelin sheaths, and the occurrence of myelin lamellae around glial cells [78].
The etiology of this condition remains unknown although a dietary factor may be involved, since outbreaks
typically occur in animals kept under hunt condition where they are fed a diet consisting of paunch or tripe (the
four stomachs of cattle and sheep), which has questionable nutritive value. Sheahan and colleagues suggest that
the condition is associated with methionine deficiency and altered methionine synthetase activity [78] (see
cobalamin deficiency). One outbreak in Beagles was attributed to pitch poisoning (dogs were eating the pitched
lining of the kennels) [79], however, it is likely that this is another condition since the onset of signs was rapid, one
affected dog was only 3 months of age, and in at least 2 cases, there was gradual recovery. Furthermore, no
dogs were available for necropsy studies.
Results of hematological, radiographic, myelographic, and CSF testing are within normal limits. Serum copper
levels are normal. In one report, mean serum methionine levels were significantly lower and mean liver
methionine synthetase levels were significantly greater in affected dogs restored to a balanced diet than in age-
matched controls maintained on the balanced diet [78]. However, methionine synthetase levels in spinal cord from
affected animals were normal, as were liver folate concentrations [78]. To date, there is no specific treatment;
however, the condition has been eliminated in kennels after the diet is changed to one containing a high
proportion of meat [78,80].
Hypomyelination
Over the past two decades, CNS hypomyelination has been reported in several breeds of dogs, some of which
are known to be inherited. The condition has also been reported in cats.
Hypomyelination in Chow Chows

Hypomyelination of the CNS in Chow Chow dogs is believed to be hereditary [81,82]. Animals show clinical signs
at 2 to 4 weeks of age-wide-based stance, "rocking horse" motion of the entire body when attempting to walk,
hypermetria, intention tremors of head and limbs, and often, a bunny-hopping gait. Tremors decrease or cease
completely when affected animals lie quietly or are asleep. Menace response is depressed bilaterally, however,
vision and pupillary reflexes are normal. Clinical signs plateau from 6 to 12 months, followed by gradual
improvement to the point where only a slight intention tremor is noted in some dogs, with other dogs appearing
normal [82].
In these dogs, a severe myelin deficiency is found throughout the CNS, especially in subcortical white matter and
foliate white matter of the cerebellum, as seen with myelin stains (e.g., Luxol fast blue). The outer half of the
lateral and ventral columns of the spinal cord, the ventral half of the cerebral peduncles, parts of the optic tracts
and several brainstem tracts such as spinothalamic and vestibular fibers are virtually devoid of myelin, with only a
few single, widely separated myelinated fibers seen [81]. Axons appear normal and have thin or uncompacted
myelin sheaths. Most axons in poorly myelinated areas are naked. Cell processes in contact with these axons
appear to be derived from fibrous astrocytes and from large cells with abundant granular electron-dense
cytoplasm, typical of oligodendrocytes, and containing astrocytic-type fibrils, a few profiles of rough endoplasmic
reticulum, mitochondria, and many free ribosomes. No lesions are found in the gray matter. Peripheral and cranial
nerves are myelinated normally. The myelin deficiency in absence of degenerative changes indicates a disorder
of myelin formation rather than breakdown. Follow-up studies on older Chows revealed that myelination
progressed with age but was still deficient at the age of 3 years [82]. Axons had thin or uncompacted myelin
sheaths, separated by massive astrocytosis, and bizarre myelin formations. Conventional numbers of
morphologically normal oligodendrocytes were found in the myelin-deficient areas. These results suggested that
the condition in Chows dogs involved retarded myelination possibly due to a dysfunction or delay in
oligodendroglial maturation [82].
Hypomyelination in Lurcher Hounds

A similar tremor syndrome and hypomyelinogenesis has been reported in two 4 week old, male, crossbred
Lurcher Hound puppies [83]. Signs were first seen at 2 weeks of age and were characterized by pelvic limb
bouncing or dancing while standing, along with fine tremors of the limbs and trunk, which sometimes involved the
head. Tremors became more pronounced with excitement, abated with rest, and disappeared during sleep.
Hypermetria was seen in the forelimbs in one puppy. Cranial nerve function, spinal reflexes, and postural
reactions were normal. Clinical signs regressed completely in one puppy by 16 weeks of age.
Hypomyelination (based on pallor of myelin staining and abnormal myelin sheath:axon relationships) was present
in spinal cord sections with numerous axons surrounded by inappropriately thin myelin sheaths, especially in the
peripheral areas of the lateral funiculi of the cervical spinal cord. Some axons were naked. Small myelin figures
were found in axons within oligodendrocytic and astrocytic processes. Demyelination was not seen.
Oligodendrocytes and astrocytes appeared normal and there was no evidence of demyelination, lipophages, or
inflammatory cells. Nerve roots and peripheral nerves were normal.
Hypomyelination in Springer Spaniels

A myelin disorder that has an X-linked recessive mode of inheritance has been reported between 2 and 4 weeks
of age in male Springer Spaniels [84,85]. Tremors in Springer Spaniels ("shaking pups") are much more severe
than those in Chow Chows or Lurcher Hounds. Animals have great difficulty standing, performing useful
coordinated movements, and cannot feed without assistance. A pendular nystagmus may be seen. Affected dogs
are approximately half the size and weight of normal littermates. Seizures may occur as dogs mature. Most
animals are euthanized as a result of progressive morbidity. Some heterozygous female puppies have shown a
tremor at 12 - 14 days of age, which is not as severe as the affected males and which may disappear by 1 month
[85].
Hypomyelination occurs throughout the CNS and it is more marked in the cerebrum and optic nerves than in the
spinal cord. There is marked pallor of the white matter on gross examination of the CNS. Axons are either naked
or surrounded by a disproportionately thin layer of myelin. Myelinated internodes tend to be short and heminodes
are frequent. Vacuoles are present adjacent to axons or within glia but there is no evidence of demyelination. At
the light microscopic level, many oligodendroglial and astrocytic nuclei are seen. Peripheral, cranial and
autonomic nerves are myelinated normally. A marked transition from normal Schwann cell myelin to the
amyelinated-hypomyelinated area of oligodendroglial territory is seen in dorsal and ventral nerve root entry zones.
Ultrastructurally, there is marked distension of the rough endoplasmic reticulum reticulum (suggesting an
abnormality of protein synthesis or transport) and perinuclear envelope in oligodendrocytes. Myelinated and non-
myelinated zones are often found on a single axon. Many myelin sheaths appear poorly compacted and often
show paranodal or internodal abnormalities suggestive of immaturity. Abnormal inter-relationships of
oligodendrocytes and astrocytes are present at many paranodes [86] suggesting that astrocytic processes may
interfere with oligodendrocyte-axon interactions [87]. A morphometric study revealed a marked reduction of
oligodendrocytes in the affected pups [88]. Oligodendrocyte death was not noticeable. Astrocyte numbers were
similar in both normal and affected pups. Axonal diameters were not reduced in the affected pups and there was
no apparent correlation between myelination and axonal size in these animals. Total myelin volume and thickness
were greatly reduced in the "shaking pups". Myelination appears to increase with age. Impaired stem cell division
together with metabolic disturbance of oligodendrocytes was considered to be the main causes of the
hypomyelination in this mutant [88]. Freeze-fracture studies indicated some abnormal contacts between
oligodendrocytes and axons [89]. Biochemical studies have shown a reduction in various myelin proteins (myelin
basic protein, myelin-associated glycoprotein, and 2' 3'-cyclic nucleotide phosphodiesterase, as well as proteolipid
protein and the related DM-20 protein) and an immature form of myelin (the amount of the 21 kDa MBP compared
to the 18 kDa MBP was relatively increased) in affected dogs [90,91]. Affected Springer Spaniel puppies carry
mutations in proteolipid protein and DM-20, the major protein constituents of CNS myelin. These mutations
reportedly hinder oligodendrocyte differentiation [92]. It has been reported that Schwann cells in shaking pups
may penetrate the glia limitans and invade spinal cord, brainstem, and cerebellum and that this process increases
with age [93].
Female heterozygotes of the shaking pup show myelin mosaicism of the optic nerve and spinal cord that is
characterized by patches of normal central myelination interspersed between areas of amyelination or
hypomyelination [85]. Abnormal oligodendrocytes with distended rough endoplasmic reticulum are found in the
abnormal patches and are a marker of the trait.
Hypomyelination in Samoyeds
This possibly inherited condition has been seen in puppies around 3 weeks of age [94]. Signs included
generalized tremors (involving the head, eyes, trunk, and limbs), inability to stand, nystagmus (rapid spontaneous
vertical or horizontal), and absent menace response. Tremors disappeared at rest or during sleep. Postural
reactions, spinal reflexes, and nociception were normal. There was severe lack of myelin throughout the CNS,
usually associated with reactive astrocytosis and diffuse staining for glial fibrillary acidic protein. The glia limitans
appeared dense and thick with coarse astrocytic processes, especially in subpial and peripheral areas of the
spinal cord. Staining for myelin basic protein was markedly diminished in hypomyelinated areas. Ultrastructurally,
most axons were devoid of myelin, but occasional fibers were encircled by several poorly compacted lamellae,
sometimes with accompanying astrocytic processes. Many naked axons were abutted by multiple astrocytic
processes containing microtubules and intermediate filament bundles. Oligodendrocytes were greatly reduced in
number (representing 13% of all glia counted compared to 57% in control pups). Furthermore, the
oligodendrocytes were of the immature light or medium type and contained distended cisternae of endoplasmic
reticulum and nuclear envelopes, similar to that seen in the shaking Springer Spaniels [88]. Lack of mature dark
cells (these cells were present in the shaking Spaniels) suggested disruption in oligodendrocyte differentiation
and maturation, as has been reported in the shaking Spaniels [88,92]. There were increased numbers of
astrocytes and microglial cells (type III glial cells). Peripheral nerves were myelinated normally.
Hypomyelination in Weimaraners
American Weimaraner puppies of either sex affected by hypomyelination develop generalized body tremors and
dysmetria about 3 weeks of age [95]. Mental status, gait, postural reactions, vision, and cranial nerve and spinal
reflexes are normal. Signs appear to ameliorate with age, so that dogs may be clinically normal by one year of
age.
Many axons throughout the brain and spinal cord are either hypomyelinated or amyelinated relative to controls.
Hypomyelination is especially prominent in peripheral subpial regions of the spinal cord, particularly of the ventral
and lateral funiculi. In contrast, dorsal columns appear normally myelinated. Myelin is normal in nerve roots and
peripheral nerves. In hypomyelinated areas, astrocytes outnumbered oligodendrocytes that have features typical
of medium or dark cell types. Ultrastructurally, some myelin sheaths are uncompacted while many axons are
being actively myelinated. There is no evidence of oligodendrocyte necrosis. Neuronal cell bodies are normal. A
reversible defect in glial differentiation is considered responsible for the hypomyelination.
A condition has been reported in the UK in an 8 week old Weimaraner puppy with signs of incoordination, pelvic
limb weakness and ataxia, bunny-hopping gait when attempting to move quickly, and abnormal frog-like sitting
posture [96]. A tremor was not seen. There was no muscle atrophy in the limbs. There was subpial depletion of
myelin throughout the spinal cord, involving all funiculi. Pial thickening and vacuolated degeneration of the
sensory neurons in the dorsal horns and of neurons in the lateral cuneate nucleus and in the lateral caudal part of
the reticular formation in the medulla accompanied this change. Dystrophic axons were present in the spinal cord,
granular layer of the cerebellar vermis, and internal capsule. While focal vacuolation was seen in the cerebellar
white matter, there was no myelin depletion found in the brainstem, cerebellum or cerebral hemispheres. No
abnormalities were seen in nerve roots, dorsal root ganglia or in peripheral nerves. Despite the clinical and
pathological differences, the condition in this puppy may be a variant of the disorder described above in the
American Weimaraners.
Hypomyelination in Bernese Mountain Dogs

Clinical signs of central hypomyelination appear in Bernese Mountain Dog puppies of either sex from 2 to 8 weeks
of age [97] and are manifested as a fine tremor of the limbs and head which becomes more intense with
excitement or stress and which disappears with sleep. Other signs are weakness, imbalance, a high tail carriage,
and a stiff action of the pelvic limbs. Signs appear to gradually diminish with age but tremors may reappear when
animals are frightened or excited. Hypomyelination, characterized by presence of thinly myelinated axons, is
observed throughout the spinal cord but not in the brain. There is astrocytosis and an increased number of
astrocytic processes. Oligodendrocytes appeared normal, except for a small number (approximately 5%), which
contained abnormal dilated membrane systems, membranous whorls and osmiophilic structures. Peripheral
nerves are myelinated normally. Preliminary breeding data suggest an autosomal recessive mode of inheritance.
Hypomyelination in Dalmatians
Cerebrospinal hypomyelinogenesis has been reported in a 5 week old Dalmatian puppy [98]. Generalized body
tremors were present at birth. The puppy could not walk voluntarily and horizontal pendular nystagmus was
observed. The tremors disappeared at rest and during sleep. Spinal reflexes were normal. Grossly, on frontal
sectioning of the brain and spinal cord, poor demarcation between the gray and white matter was noted.
Microscopically, myelin was not found anywhere in the CNS, although normal axons were demonstrated with
silver stains. Disseminated spongy vacuolation was found in the white matter of the spinal cord. There was no
evidence of active white matter degeneration. Ultrastructurally, there was prominent astrocytic gliosis throughout
the white matter. Cells, with features typical of oligodendrocytes, appeared reduced in number. Most nerve fibers
were entirely devoid of myelin, but occasional larger axons were covered by a thin irregular layer of 2 or 3 myelin
lamellae. Abnormal myelin inclusion figures were noted in some oligodendrocytic processes. Limited axonal
necrosis was found throughout the white matter. The peripheral nerves were myelinated normally. A failure of
myelin synthesis was considered the primary cause of this disorder.
Hypomyelination in Cats
Hypomyelination of the CNS has been reported in two Siamese kitten littermates [99]. Signs began at 4 weeks of
age and were characterized by a history of progressively intensive whole body intention tremors accompanied by
episodes of frenzied behavior with indiscriminate biting. The kittens assumed a quiet (normal) state at rest, but
with activity, the above-mentioned signs returned. Microscopic examination of spinal cord revealed marked
hypomyelination, as suggested by pallor of white matter of the lateral and ventral funiculi, without apparent
rostrocaudal gradation in severity. The dorsal columns appeared normal, as did nerve roots and spinal ganglia.
Silver staining showed morphologically normal axons. The brainstem, cerebellum, and cerebral cortex appeared
normal. Glial fibrillary acidic protein staining confirmed a mild astrogliosis, including an increased prominence of
the glia limitans in the hypomyelinated areas, with astroglial processes often assuming a radial orientation.
Ultrastructurally, there was a preponderance of nonmyelinated axons and the few myelinated sheaths that were
present appeared thin and frequently loosely compacted. Astrocytic processes often had condensed intermediate
filaments. Immunocytochemically, the intensity of staining for myelin basic protein, myelin-associated glycoprotein,
and proteolipid protein was decreased in the hypomyelinated areas, reflecting the increased numbers of hypo- or
amyelinated axons.
Note that frenzied behavior and biting is unusual for hypomyelination and may represent paresthesia evoked by
inappropriate excitation of noninsulated portions of sensory pathways [99].
Miscellaneous Hypomyelination
Note that various forms of CNS hypomyelination have been reported in several lysosomal storage diseases,
including globoid leukodystrophy in dogs and mannosidosis in cats.
Idiopathic Vascular Calcification

A novel degenerative disease has recently been reported in a 3 month old Labrador Retriever puppy [196].
Clinical signs included progressive lethargy, weakness, and reluctance to move over a three day period.
Examination revealed generalized muscle atrophy and palpably hard muscles. Joints were enlarged and painful
and there was restricted range of joint and spinal movement. The dog showed slight ventroflexion of the head,
neck stiffness, and was tetraparetic with proprioceptive deficits in pelvic limbs. All spinal reflexes were diminished.
Radiographic studies showed multifocal mineralization throughout the body including intervertebral disks,
cartilage of spinous processes, intersternebral and costal cartilages, growth plates, articular/periarticular soft
tissues (joint capsules, muscle/tendon insertions), menisci, and thyroid, cricoid and extrathoracic tracheal
cartilages. In addition, mineralization was noted in the common carotid arteries, tongue and kidney vessels, and
vessels in the popliteal region. Sonography confirmed mineralization of neck and kidney arteries. EMG studies
indicated presence of fibrillation potentials in paraspinal and limb muscles while nerve conduction was slow in the
peroneal nerve. Grossly, carotid and coronary arteries were extremely hard and thicked by mineral deposition.
Microscopic changes included marked mineral deposition in the tunica intima and tunica media of of blood
vessels in several organs, as well as in carotid and coronary arteries. The mineralization in periarticular tissue and
joint capsules was accompanied by a granulomatous reaction with numerous multinucleated giant cells. In
cervical and thoracic spinal cord segments, a myelopathy characterized by fragmentation and loss of axons and
myelin ballooning/macrophage phagocytosis was found in all white matter funiculi. Multifocal subdural
calcifications were seen at all levels of the spinal cord. Swollen axons and partial myelin loss was found in the
peroneal nerve while calcification s were noted in perineurial vessels of the radial nerve. Atrophy and hypertrophy
were present in skeletal muscle. No histological abnormalities were observed in the brain. The cause of the
calcifications was not determined. Additional diagnostic testing revealed that serum parathormone, vitamin A, 25-
hydroxycholecalciferol (25-OH-VitD), and 1,25-dihydroxycholecalciferol (1,25-OH-VitD) were normal. In addition,
screening for mucopolysaccharidoses did not indicate storage disease. The authors suggested that this unusual
condition had similarities to idiopathic arterial calcification of infancy seen in children, a rare disorder
characterized by extensive arterial calcification and stenoses of large and medium-sized arteries with
complications including severe systemic hypertension and cardiomyopathy [197].
Kooiker Dog Myelopathy

A degenerative myelopathy has been reported in young Kooiker dogs (Dutch decoy dogs), of either sex, with
signs beginning from 3 to 12 months of age [11,100]. Clinical signs include mild to severe hind limb paresis and
ataxia. In some dogs, forelimbs are similarly affected and there may be proprioceptive deficits, exaggerated spinal
reflexes, and urinary incontinence. Many dogs are euthanized by 12 months of age. Routine hematology, blood
chemistries, radiography, and myelography are normal. Grossly, lesions are found at all levels of the spinal cord,
and are seen as transparent areas associated with malacia and loss of myelin and axons. Lesions appear most
severe in the last cervical and first thoracic cord segments, being localized primarily in ventral and dorsal columns.
The ventral malacic areas extend to involve lateral columns in some cervical and thoracic segments. In severely
affected dogs, all white matter may be involved in some thoracic segments. There is reactive vascular
proliferation, numerous macrophages, and variable numbers of gemistocytic astrocytes in the malacic areas. At
the border of the necrotic areas, axons appear intact. Wallerian degeneration occurs in spinal cord segments
caudal to the ventral and lateral malacic areas, and rostral to the dorsal areas of malacia. Spinal cord neurons
and nerve roots are not affected. Wallerian degeneration in the dorsal funiculus sometimes extended to the
gracile and cuneate nuclei. Severe neuronal degeneration may occur in trapezoid body, while vacuolation is
sometimes seen in the olivary nuclei. Pedigree studies suggest this disease has a simple autosomal recessive
mode of inheritance. This condition is quite similar clinically and pathologically to Afghan hound myelopathy
except for the reported axonal involvement in the Kooiker dogs [2].
Labrador Retriever Axonopathy

A degenerative disorder has been reported in Labrador Retriever puppies characterized by an ataxic-dysmetric
gait when they first begin to walk [10]. The hind limbs move in a crouched, short-strided, adducted manner while
the forelimbs are hypermetric. Animals may fall frequently. Forelimbs become progressively more spastic and
abducted. By 3 to 5 months of age, most puppies are unable to stand or walk without assistance. Signs may
remain static after this time. Head tremor occurs late in the course of the disease. Hematology, blood chemistries,
and CSF analysis are normal.
Grossly, all affected puppies have aplasia or hypoplasia of the corpus callosum. Spina bifida at C7 has been
found in two puppies. Microscopically, there is extensive bilaterally symmetrical degeneration of the spinal cord
white matter, particularly in the superficial dorsal areas of the lateral funiculi, the fasciculus gracilis of each dorsal
funiculus, and the ventral funiculus adjacent to the ventral median fissure. The degenerative changes are most
severe in the thoracic cord segments, with decreasing intensity in the lumbar and cervical segments.
Degenerative changes of partial or complete axonal and myelin loss and associated gliosis are found throughout
the medulla oblongata, caudal cerebellar peduncles, and cerebellum. Ultrastructural studies indicate a more
extensive loss of larger caliber axons with preservation of smaller processes. There is multifocal presence of
swollen axonal spheroids that contain neurofilaments, vesicular structures, mitochondria, and Golgi apparatus.
The spheroids appear most numerous in the dorsal funiculus of the cord at all spinal levels, on the lateral surface
of the medulla, and in focal areas of the granular layer of the cerebellar cortex. They occur with less frequency in
the foliate and central cerebellar white matter, transverse fibers of the pons and middle cerebellar peduncles,
optic tracts, internal capsule, and corona radiata of the cerebrum. There is extensive neuronal loss in spinal
ganglia and spinal cord gray matter. Degenerative changes are found in each olivary nucleus characterized by
neuronal chromatolysis and scattered large spheroids. In some dogs, there is complete loss of cell bodies in
these nuclei with astrocytic replacement. This degenerative disorder is presumed to have an inherited recessive
mode of inheritance [10].
Lafora's Disease
A progressive, degenerative neurological disorder associated with a complex glycoprotein accumulating within
neurons and glial cells or lying free in the neuropil has been recognized sporadically in dogs for several decades.
The condition is considered analogous to Lafora's disease in people in whom it is clinically characterized by
progressive myoclonic epilepsy. Most reports involve older Beagles and Basset Hounds. Clinical signs are
variable, including depression and somnolence [101]; however, seizures (e.g., myoclonic epilepsy, see Epilepsy)
are often reported in advanced stages of the disease, and have been noted in affected dogs from 5 months to 7
years of age [102-107].
Seizures can be precipitated by external stimuli, especially a change in noise or light in the surroundings
[103,107]. Electroencephalographic studies may reveal slow, rhythmic activity with showers of myoclonic type
seizure patterns [107]. In a 10 year old female Corgi, clinical signs progressed from abnormal, jerky head
movements to generalized muscle fasciculations with severe myoclonic contractions of the head and neck
muscles [102]. Almost identical signs (body tremors, twitching, and/or abnormal jerky head movements) have
been observed in Miniature Wirehaired Dachshunds in the United Kingdom [198] and in South Africa [199]. The
myoclonic jerks occurred spontaneously or in repsonse to visual or auditory stimuli, or sudden movement, but did
not appear to affect consciousness. In one study, generalized seizures and hypnic jerks were also reported [198].
Apart from these signs, neurological examination was normal in these dogs, as were hematology and serum
chemistries (except for mild increase in CK and lactate dehydrogenase levels in some instances), CSF analysis,
and cranial magnetic resonance imaging. EMG studies may be normal [198] or show evidence of moderate
amounts of fibrillation potentials and positive sharp wave activity [199]. Muscle biopsy may reveal presence of an
amorphous bubbly subsarcolemmal material consisting of periodic acid-Schiff positive, diastase resistant
inclusions (polyglucosan bodies) [105,198,199]. The inclusions also stain positively with Grocott’s methenamine
silver nitrate. Similar inclusions may be found in peripheral nerves [198]. The ultrastructural characteristics are
similar to those inclusions found in the CNS (see below).
In most reports to date, variably sized, basophilic inclusions have been observed in perikarya and processes of
neurons throughout the brain and spinal cord, and are often especially numerous in neurons within the cerebrum,
cerebellum, thalamus, and midbrain [101-104,106,107]. The inclusions are strongly positive for carbohydrate
stains, weakly metachromatic, and lipid negative [101,103]. The histological, immunohistochemical, and
ultrastructural features of polyglucosan bodies in humans and Lafora bodies in dogs are similar [108]. Lafora
bodies in dogs stain with concanavalin A indicating they contain mannose and glucose residues and suggest a
derivation from rough endoplasmic reticulum and Golgi [109]. Occasionally, they are also seen in retina,
peripheral nerves, liver, spleen, and lymph nodes. In skeletal muscle, inclusions that stain dark blue with
hematoxylin and eosin, and red with periodic acid-Schiff (PAS), may be seen lying between myofibers or beneath
the sarcolemma [103,105]. Based on differences in internal structure and staining characteristics, three types of
Lafora bodies are recognized [104]:
1. Type I - Small (3 to 10 m in diameter), fine, evenly stained granules. This is the most common type and
is usually found in middle and deep layers of the cerebral cortex and in glial cells of the cerebellum.
Ultrastructurally, these bodies consist of branching fibrillar structures without a limiting membrane. The
branching filaments measure about 8 - 10-nm in diameter [110].
2. Type II - These larger bodies (13 to 30 m in diameter) have a strongly PAS-positive homogeneous core
with a more faintly staining radiating periphery. This form is commonly found in Purkinje cells of the
cerebellum and in the midbrain. Electron microscopy reveals osmiophilic granules in a central core
surrounded by fibrillar material. Rough endoplasmic reticulum in affected neurons may be dilated with
increased numbers of coarse ribosomes free in the cytoplasm. Such changes suggest abnormalities in
protein synthesis.
3. Type III - These bodies range from 5 to 20 m in diameter and are occasionally found in the midbrain.
These structures exhibit a dense peripheral ring of PAS-positive material.
The relationship between seizures and these Lafora bodies is enigmatic since similar inclusions have been
observed in the CNS of older dogs (e.g., over 8 years of age) of various breeds with no signs of seizures
[101,110-112]. These bodies may also be found in the retina of clinically normal dogs and cats [113]. Furthermore,
in a recent study of epilepsy-prone beagles only 6 of 68 dogs (8.8%) had Lafora-like inclusion bodies [114].
Lafora bodies have also been found in cats. In a recent report, Lafora bodies were identified in the brain of a
young adult cat with neurological signs characterized by intermittent but progressively worsening head and body
tremors [115]. The cerebellar cortex was the most severely affected area of the brain and the deposits were
identified within Purkinje cell bodies and processes and throughout the neuropil. More commonly, Lafora bodies
occur in the CNS of aging cats, without signs of seizures, as incidental lesions [116]. In one feline study, most of
the bodies were situated in the neuronal processes and disseminated throughout the brain, especially in the
cerebral cortex, midbrain, cerebellum and medulla oblongata [117]. In the spinal cord of older cats and dogs,
caudal lumbar and the coccygeal regions are reportedly predilection sites for Lafora bodies, being prominent in
the ventral column and intermediate substance and preferentially located in neuronal processes, but only rarely in
astrocytes. [118].
Prognosis is somewhat guarded in animals with Lafora’s disease because of the tendency for signs to become
progressively worse; however, this may not be the case for at least some affected Miniature Wirehaired
Dachshunds [198]. In people, Lafora's disease is an autosomal recessive, progressive myoclonus epilepsy with
characteristic inclusions (polyglucosan bodies) caused by mutations in the EPM2A gene, which codes for laforin,
a cell membrane and endoplasmic reticulum-associated protein, tyrosine phosphatase, that may play a role in the
prevention of polyglucosan accumulation in healthy neurons [200,201].
Miniature Poodle Demyelination

A rare, possibly inherited, neurodegenerative disorder has been reported in Miniature Poodles [119-121]. Clinical
signs first appear between 2 and 4 months of age with some puppies showing signs of ataxia-dysmetria with
constant shifting of the hind limbs and difficulty standing. Puppies may fall frequently trying to reach their food
bowl. Within 1 to 2 weeks, puppies develop a spastic paraplegia followed rapidly by a tetraplegia [119,120] and
tend to lay on their sides with all limbs extended, sometimes with the forelimbs held in a clasped position [120].
Placing and hopping reactions are absent, while spinal reflexes are usually intact, cranial nerve function is normal,
and puppies remain alert. Hand feeding may be necessary and some puppies appear to have impaired tongue
function. In one report, grinding of the teeth was a constant signs [121]. Loss of sensation to pinprick caudal to the
scapula was noted in another affected dog [119]. Hematology, blood chemistries, urinalysis, and radiography are
within normal limits. CSF analysis is usually normal, although a mild protein increase was noted in one dog [121].
Microscopically, large areas of malacia occur in the midbrain and the cervical cord [119]. In the midbrain, there is
a symmetrical loss of myelin in the tegmentum. Areas of malacia also occur bilaterally in medial and lateral
lemniscus, inferior colliculus, cerebral peduncles, posterior commissure, corpus callosum, middle cerebellar
peduncle, roof of the cerebellum, descending vestibular tract, and pyramids [119]. In the cord, the most severe
lesions occur in dorsal and ventral white columns of cervical and thoracic segments [121]. Loss of myelin may be
almost complete at C7 with only the fasciculus proprius being spared, while there is some preservation at C2 and
T5, and only slight loss at the lumbar intumescence [119]. The dominant lesion appears to be distinct myelin
degeneration and loss. In the center of the malacic lesions, nerve cells are preserved, although some show
evidence of chromatolysis. There is some hyperplasia of small vessels with endothelial swelling, a microglial
reaction, and variable astrocytosis. In some areas, lipid macrophages are common. A status spongiosis is found
at the periphery of the malacic lesions with myelin ballooning. Silver stains reveal loss and degeneration of axons
in some areas, but with some degree of axonal integrity in others [121]. Gray matter in the spinal cord is
preserved, as are dorsal and ventral nerve roots. Prognosis is poor. There is no treatment. To my knowledge,
there have been no additional reports of this disease during the past 20 years. Summers and colleagues reported
that 2 cases had been seen at Cornell over the course of 30 years [3].
Mitochondrial Encephalomyelopathy
A progressive encephalomyelopathy of insidious onset has been reported in a 16- month-old female English
Springer Spaniel [122]. Clinically, the dog showed evidence of ataxia-dysmetria that was exacerbated by
excitement, occasionally stumbled into objects, and had mild behavioral abnormalities, including moments of
disorientation and being easily excitable. A vertical positional nystagmus could be elicited and postural reactions
were delayed and spastic in all limbs. Patellar reflexes were brisk and there was no evidence of muscle atrophy.
Routine laboratory findings, including CSF analysis, were normal.
Grossly, bilateral and symmetrical depressed gray foci were observed in the dorsal accessory olivary nuclei. Light
microscopic findings included profound Wallerian degeneration (diffuse axonal and myelin loss) and astrogliosis
of the optic pathways (bilaterally), loss of Purkinje neurons along with Bergmann’s gliosis, granular cell layer
torpedoes, and axonal spheroids and gliosis in cerebellar nuclei (bilaterally), focal bilateral and symmetrical
brainstem spongiosis (olivary nuclei and substantia nigra) and diffuse neuraxial astrogliosis with swollen and
abnormally shaped nuclei in the above-mentioned sites as well as in the lateral geniculate nuclei. The majority of
neurons in the brain and spinal cord appeared normal. Variable, scattered Wallerian degeneration was found in all
white matter funiculi of the spinal cord and peripheral nerves, especially the sciatic. Ultrastructurally, there were
giant (up to 10 times normal size) and bizarre mitochondria (e.g., increase or loss of mitochondrial cristae,
membrane blebbing, and internal compartments) within neuronal perikarya and axons as well as diffuse loosening
of the cerebral and cerebellar neuropil associated with myelin sheath ballooning and/or astrocytic intracellular
edema. It was suggested that the neuropathological findings in this dog resembled the mitochondrial
encephalomyopathies of man.
Motor Neuron Diseases

Motor neuron diseases are neurodegenerative disorders in which there is premature degeneration and death of
various neuronal cell populations in the spinal cord and/or brainstem, and as such, can be classified among the
degenerative abiotrophies [1]. In small animals, most of the conditions involve the spinal cord lower motor
neurons and, based on comparative studies, have also been termed spinal muscular atrophies. Most of these
degenerative conditions occur within the first 3 to 6 months of life. Motor neuron diseases have been reported in
several breeds of dogs, in which they have a familial or genetic basis, but are only rarely seen in cats. Clinical
signs usually are progressive and tend to be dominated by neuropathies in pelvic and thoracic limbs as a
consequence of lower motor neuron (LMN) involvement. Prognosis is guarded to poor, and there is no treatment.
Motor Neuron Disease in Giant-Breed Crosses

This rare degenerative condition, also known as Stockard's paralysis, was produced in 1936 by crossbreeding
Great Danes with Bloodhounds and St. Bernards [123]. Clinical signs occur around 3 months of age and are
characterized by sudden onset of paresis and posterior paralysis, priapism, and atrophy of pelvic limb
appendicular muscles. There is no involvement of head, neck, or trunk. No additional reports have appeared in
the literature since 1936. Pathological findings include chromatolysis, degeneration, and depletion of motor and
preganglionic sympathetic neurons in ventral and intermediolateral horns of lumbar spinal cord. The disease is
transmitted through an inheritable, multiple factor involving at least three dominant genes.
Motor Neuron Disease in Swedish Lapland Dogs

An autosomal recessive disease has been reported in Swedish Lapland dogs [124] that has been compared to
infantile spinal muscular atrophy (Werdnig-Hoffman disease) in children [124]. I have listed this condition with the
multisystem neuronal abiotrophies.
Motor Neuron Disease in English Pointers

A LMN degenerative disorder has been described in young English Pointer dogs in Japan [125] that appears to
have an autosomal recessive mode of inheritance [126]. Clinical signs of pelvic limb trembling (an initial sign),
weakness, dysphonia, and diminished tendon reflexes are observed in affected dogs at about 5 months of age.
Progressive muscular atrophy occurs in all limbs and trunk, particularly in the shoulder region. Animals eventually
become tetraplegic, with superficial muscle fasciculations seen and eventually, joint contractures.
Electromyographically, fibrillation potentials and positive sharp waves are noted in epaxial, proximal, and distal
appendicular muscles, but are first seen in distal muscles [127]. The clinical course of this progressive disease is
3 to 4 months. Routine hematology and radiography are normal.
Axonal degeneration is found in peripheral nerves and chronic neurogenic atrophy and endomysial fibrosis occur
in skeletal muscle. While the number of ventral horn cells in the spinal cord seem to be normal, numerous
accumulated lipid-like granules, 1 to 3 m in diameter, are present in ventral horn cells and in hypoglossal and
spinal accessory nuclei of the brainstem. These granules stain with Nile blue sulfate, Sudan black B, Luxol fast
blue, Alcian blue, and periodic acid-Schiff on paraffin sections, suggesting the granules are composed of a
compound lipid. The granules have no autofluorescence. Ultrastructurally, granules appear as multilamellar
structures, arranged concentrically or in parallel, resembling membranous cytoplasmic bodies or zebra bodies.
This finding suggests that a hereditary abnormality of lipid metabolism may underlie the LMN disease in these
dogs [125].
Motor Neuron Disease in German Shepherds

A focal form of spinal muscular atrophy has been reported in two German Shepherd puppies [128]. Signs were
seen 2 weeks after birth and were characterized by unilateral or bilateral thoracic limb weakness and atrophy,
carpal valgus deformity, and carpal flexion due to contracted, atrophic flexor muscles. In one puppy, signs
progressed rapidly over the ensuing 5 weeks to the point he was unable to stand or walk using the thoracic limbs.
Electromyographic studies revealed fibrillation potentials and complex high frequency activity in shoulder, forearm
and interosseous muscles, bilaterally. Microscopic changes included asymmetric loss and degeneration of motor
neurons in the cervical spinal cord intumescence (from C5 to T1), especially in the lateral region of the ventral
horn of C7 - 8. Degenerating neurons appeared vacuolated or chromatolytic. Glial nodules, neuronophagia, and
axonal spheroids were seen occasionally. Degenerative changes, including axonal loss and multifocal presence
of Bungner’s bands (denervated Schwann cells), were observed in ventral rootlets and in thoracic limb peripheral
nerves, and neurogenic atrophy was seen in muscle. Ultrastructurally, numerous denervated Schwann cells were
seen together with dispersion and loss of ribosomes, and variable cisternal dilation in some degenerating neurons.
The peripheral chromatolysis resulted from dispersion and loss of the free and attached ribosomes that normally
form Nissl bodies. Prognosis is guarded. Surgical tenotomy and carpal splinting were effective in the second dog,
which was clinically less affected. At 15 months of age, thoracic limb atrophy was not seen in this dog, although
slight weakness was sometimes observed. This canine condition is thought to resemble the asymmetric and
unilateral, benign spinal muscular atrophies found in people.
Motor Neuron Disease in Doberman Pinchers

Motor neuron degeneration has been documented in 2 male Doberman puppies from a litter of eight [10]. Signs of
pelvic limb weakness were seen around 4 weeks of age and progressed to tetraparesis and muscle atrophy in all
limbs. Microscopic changes showed degeneration of neurons in spinal cord and various brainstem nuclei,
including vestibular and reticular nuclei. The neurons were chromatolytic or vacuolar, the latter change apparently
being derived from rough endoplasmic reticulum.
Motor Neuron Disease in Griffon Briquet Vendéens

Motor neuron disease characterized by progressive weakness, hind limb paresis and eventually tetraparesis
(extensor paralysis in hind limbs, flexor paralysis in forelimbs) was documented in two 2 month old Griffon Briquet
Vendéen dogs from a litter of six [202]. Muscle atrophy was prominent in all limbs, with diminished spinal reflexes
and loss of superficial and deep pain sensation. Mental status and cranial nerve function were normal.
Microscopic lesions included marked neuronal loss in ventral horns cells of the spinal cord, Wallerian
degeneration of ventral spinal roots and peripheral nerves, and neurogenic muscle atrophy. Axonal swelling was
noted adjacent to neuronal cell bodies. In addition, a severe loss of motor neurons was observed in the red nuclei
and in lateral and medial vestibular nuclei accompanied by astrogliosis.
Motor Neuron Disease in Salukis

A motor neuron abiotrophy was reported in a 9 week old Saluki puppy presented for progressive generalized
weakness and bilaterally symmetrical deformities of the carpi associated with limb contracture [236]. Histological
lesions included diffuse, symmetrical, degenerative lower motor neuronopathy of the ventral horn of the spinal
cord characterized by neuronal swelling, chromatolysis, swollen dendritic processes and enlarged axons.
Degenerative changes were present in ventral nerve roots. No lesions were seen in spinal ganglia or brainstem
nuclei. Similar clinical signs were noted in a sibling.
Motor Neuron Disease in Other Canine Breeds

A LMN disease has been reported in New Zealand in 9 dogs (6 rural collie sheep dogs, a Pug, a Dachshund, and
a Fox Terrier. Seven of the dogs were 3 to 9 months of age) [129]. Clinical signs included acute onset of posterior
paresis that typically progressed rapidly (over 2 to 4 weeks) to posterior flaccid paralysis and, in 3 dogs, to
tetraplegia. Severe muscular atrophy occurred in pelvic limbs and, in a few animals, in all four limbs. Microscopic
lesions were found in thoracic and lumbar cord segments in dogs with pelvic limb signs and were also present in
cervical cord segments in tetraplegic dogs. Lesions were characterized by mild to marked loss of motor neurons
in lateral and ventrolateral regions of the ventral horn of the spinal cord (often seen as empty spaces), and often
accompanied by diffuse microgliosis and several small glial scars in areas of missing motor neurons, and
presence of Wallerian degeneration in ventral spinal roots and spinal nerves. The peripheral nerve changes
appeared more severe in distal levels. Minimal changes were seen in dorsal roots or dorsal root ganglia. The
cause of the LMN disease was not established.
Motor Neuron Diseases with Neurofibrillary Accumulation

Several motor neuron disorders have been described in which there is accumulation of neurofilaments in neurons.
The best studied is hereditary canine spinal muscular atrophy (HCSMA), a dominantly inherited, LMN disease in
Brittany Spaniels that does not appear to be sex linked [130-132] and which has certain clinical and pathological
features in common with familial amyotrophic lateral sclerosis in people [133]. Three forms of the disease have
been recognized-accelerated, intermediate, and chronic [134]. The accelerated disease appears in puppies that
are homozygous for the trait; whereas, heterozygous animals express intermediate and chronic phenotypes [132].
a. Early Onset or Accelerated Disease - This form of the disease is similar to spinal muscular atrophy of
infants (spinal muscular atrophy type I or Werdnig-Hoffman disease [135]). Puppies first show clinical
signs by 6 to 8 weeks of age. Affected puppies are usually thinner than littermates, develop weakness
associated with paraspinal and proximal pelvic limb muscular atrophy, and often have a slow tremor of
the head. There is weakness of muscles of mastication and the tongue, which makes feeding difficult, and
the gag reflex may be depressed. Affected dogs become tetraparetic or tetraplegic and are unable to lift
their heads by 3 to 4 months of age. They lose about 30% of their body weight due to neurogenic muscle
atrophy. Pathological findings occur in motor neurons of the ventral horns of the spinal cord and certain
brainstem nuclei, especially the hypoglossal, and include chromatolysis, variable dendritic enlargement,
and swollen axons in gray matter of spinal cord, and sometimes, in proximal portions of the ventral root
exit zone or proximal ventral roots. Proximal axons are filled with massive accumulations of 10-nm
maloriented intermediate neurofilaments, an abnormality similar to that which occurs early in the course of
human amyotrophic lateral sclerosis [130,133]. Many myelin sheaths around distended axons are
attenuated.
b. Intermediate Disease - This is the most common form of the disease [2] and is similar to juvenile spinal
muscular atrophy of children (spinal muscular atrophy type III or Kugelberg-Welander syndrome [135]).
Clinical signs develop by 6 to 12 months of age, and are characterized by weakness in proximal muscles
of limb girdles and trunk. Animals walk in a waddling fashion. Progressive atrophy ensues in proximal
muscles of pelvic limbs and lumbar paraspinal muscles. Intercostal muscle involvement may lead to
respiratory distress. Affected dogs are usually unable to walk by 2 to 3 years of age. Microscopic findings
reveal loss of motor neurons late in the disease, fewer axonal swellings than those seen in the
accelerated disease, and neuronophagia in ventral horn neurons. Ultrastructurally, there may be electron-
dense, membrane-bound, intracytoplasmic vacuoles in both dendrites and neurons. Occasional neurons
contain tubulo-fibrillar material. Wallerian-like degeneration may be present in ventral horn, intramedullary
ventral root exit zone, and proximal ventral roots. Distal axons are atrophic.
c. Chronic Disease - This form is characterized by slowly progressive disease, with dogs surviving well into
adult life. Clinical signs are usually mild, except for overall thinness. One dog has reportedly survived for
more than 7 years without marked motor involvement. Microscopically, motor neurons tend to be intact
and only few axonal swellings are observed.
Electromyography reveals sporadic fibrillation potentials and positive sharp waves. Nerve conduction studies are
normal. Degenerative changes in peripheral nerves result in neurogenic atrophy, particularly in more proximal
appendicular and paraspinal muscles.
The pathogenesis of HCSMA remains unclear. The neurofilamentous swellings of proximal axons, atrophy of
distal axons, and degeneration of motor neurons are believed to be associated with impaired axonal transport of
the neurofilament triplet proteins and a maldistribution of phosphorylated neurofilaments [133]. Cyclin-dependent
kinase 5, an enzyme that phosphorylates neurofilaments and regulates neurofilament dynamics, is markedly
increased in young HCSMA homozygotes prior to the development of significant neurofilament pathology [136]. In
the accelerated and intermediate phenotypes, there is a reduction in axonal size in ventral roots, primarily in large
axons, and the frequency of small-caliber axons is increased; however, the density of fibers in motor nerves is
increased, suggesting that the changes in axonal size in motor nerves are associated with both growth arrest and
axonal atrophy [137]. Results of recent studies suggest that motor unit failure is due to failure of neuromuscular
synaptic transmission that precedes nerve or muscle degeneration [231]. Immunocytochemical and morphometric
studies on dogs with intermediate and chronic phenotypes indicate that HCSMA cholinergic motor neurons are
smaller, with fewer neurons expressing choline acetyltransferase, compared with controls [138]. Acidic excitatory
amino acids may also play a role in the pathogenesis. There are significant reductions in the levels of
endogenous aspartate, glutamate, N-acetylaspartate (NAA), and the neuropeptide N-acetyl-aspartyl-glutamate
(NAAG) in the spinal cord in homozygous but not heterozygous HCSMA [139]. In contrast, the activity of N-
acetylated-alpha-linked-amino dipeptidase, an enzyme that cleaves NAAG into NAA and glutamate, is
significantly increased. None of these parameters is affected in the motor cortex or occipital cortex. Other studies
on colony dogs have revealed low serum vitamin E concentrations in affected dogs, especially puppies, but no
mutations in a major cytosolic antioxidant enzyme, Cu/Zn superoxide dismutase (SOD1) [232,233].
Prognosis is favorable only for Brittany Spaniels with the chronic form of the disease. At this time, there is no
treatment.
A LMN disease associated with spinal muscular atrophy has been reported in young Rottweiler puppies [140-
142]. Signs were seen at 4 weeks of age and included pelvic limb ataxia that rapidly progressed to tetraparesis
and tetraplegia over the ensuing 2 to 4 weeks. Additionally, spinal reflexes were diminished or absent (except for
flexor and perineal reflexes), and there was slight intention tremor, limb tremor after exercise, depressed postural
reactions, megaesophagus with regurgitation, inability to hold up the head, generalized muscle atrophy, and
development of pelvic limb extensor rigidity. Analysis of CSF was normal. Microscopic findings were
characterized by central chromatolysis and swelling of many neurons in ventral horns of the spinal cord and in
several brainstem nuclei, including red, oculomotor, trigeminal motor, and ambiguus nuclei. Wallerian-like
degeneration was prominent in neuropil of spinal cord and in peripheral nerve. Affected neurons contained
prominent Golgi complexes and numerous neurofilaments.
De Lahunta has described a young Rottweiler puppy with some clinical and pathological variations [1].
Tetraparesis was evident without significant muscle atrophy. The swollen chromatolytic motor neurons contained
widely dispersed endoplasmic reticulum but few neurofilaments, and degenerative changes were found (in
addition to those neuronal populations described in the Rottweilers above) in neurons of the spinal ganglia and
various medullary sensory neurons, including vestibular, cochlear and cerebellar nuclei.
Neurofibrillary accumulation has also been reported in a 12 week old Collie puppy with signs of progressive
neurological disease [143]. The puppy was weak, had difficulty rising from a sitting position, and would frequently
collapse when walking. Patellar reflexes were diminished. Cranial nerve function appeared normal except for
absence of menace response and presence of widely dilated and unresponsive pupils. A diffuse neuronal
abnormality was observed microscopically. An intracytoplasmic slate-gray material that appeared fibrillar and
often arranged in whorls distended the cell body and displaced the nucleus and Nissl substance peripherally.
Lower motor neurons of the ventral gray column were affected in the first cervical spinal cord segment, as well as
neurons in various brainstem nuclei, including vestibular nuclei, spinal nucleus of the trigeminal nerve, ventral
nucleus of the trapezoid body, central tegmental nucleus, oculomotor nuclei, mesencephalic nucleus of the
trigeminal nerve, a few neurons in the rostral colliculi, and many thalamic and hypothalamic neurons. A few
Purkinje cells were affected as were occasional large pyramidal neuron in layer V of the cerebral cortex.
Ultrastructurally, there was abnormal proliferation of 12-nm neurofilaments arranged in whorls and linear arrays.
There are only a few reports of cats with motor neuron disease. A LMN disease with accumulation of
neurofilaments has been described in a 10 week old female, Domestic Shorthair cat with clinical signs of
tetraparesis that progressed to tetraplegia within a few weeks [144]. There was diffuse atrophy of appendicular
musculature. Spinal reflexes were absent. Mentation and cranial nerve function were normal. Abnormal
spontaneous fibrillation potentials were detected in limb muscles with EMG. CSF analysis was normal.
Microscopically, widespread degeneration was seen in the large motor neurons of the lateral parts of the ventral
horns in the cervical and lumbar intumescences of the spinal cord. Nissl substance was missing in some cells,
while nuclear destruction accompanied by advanced chromatolysis resulted in formation of ghost cells. Glial
nodules were seen in areas of lost neurons. A diffuse argentophilia with indistinct whorls was seen after silver
impregnation of the affected neurons. Wallerian degeneration was found in ventral spinal nerve roots and
peripheral nerves of the affected spinal cord segments. No other lesions were found in the spinal cord, brainstem,
cerebellum, or cerebrum. Ultrastructurally, the degeneration of nerve cells was characterized by abnormal
proliferation of neurofilaments, which were also seen in dendritic spines but not in axons. The fibrillary material
had a diameter of about 10-nm.
Summers and colleagues described a LMN disorder in 2 older cats with signs of crouched gait, severe muscle
atrophy, and tongue fasciculations [10]. Signs were present in one cat for 3 years and for 1 year in the second cat.
Profound loss of motor neurons in the ventral horns were observed in cervical, thoracic and lumbar cord
segments, accompanied by mild astrocytosis and numerous macrophages in the ventral horns. Extensive loss of
axons was noted in the ventral roots. While very few motor neurons were available for study, occasional swollen
axons distended with filamentous accumulations were found in the ventral horns. In the brainstem, vacuolated
neurons or occasional ghost cell were found in oculomotor and facial nuclei. The authors make the caveat that
they were unsure if the cats had the same disorder or if the condition was inherited or acquired.
Multisystem Neuronal Abiotrophies

Several familial neurodegenerative disorders occur in young dogs that are characterized by progressive
degeneration and loss of neurons in multiple neuronal systems. These entities are considered to represent
system degenerations and have been termed multisystem neuronal abiotrophies [1,10].
Multisystem Neuronal Abiotrophy in Swedish Lapland Dogs

An autosomal recessive neurodegenerative disease has been reported in Swedish Lapland dogs [145] that has
been compared to infantile spinal muscular atrophy (Werdnig-Hoffman disease) [124]. Signs appear in affected
puppies at 5 to 7 weeks of age. The onset is marked by thoracic or pelvic limb weakness that progresses rapidly
to tetraparesis and tetraplegia. In 7 to 14 days after onset, puppies are in sternal recumbency and unable to stand.
The carpi become fixed in a flexed position and pelvic limbs become extended with extreme flexion of the stifles.
Subsequent muscle wasting and deformity are most pronounced in distal portions of the limbs. Spinal reflexes are
reduced or absent, and electromyographic examination reveals denervation potentials. Microscopically, central
and peripheral neuronal chromatolysis along with neuronal degeneration and loss are observed in the lateral parts
of the ventral horns in cervical and lumbar intumescences, and in dorsal root ganglia. While no degenerative
changes are found in any of the motor nuclei of the brainstem, other affected neurons include those in the dorsal
gray column of the spinal cord, trigeminal ganglia, and the trigeminal mesencephalic nucleus. Degeneration of
Purkinje cells is pronounced and associated with chromatolysis and ischemic cell change, with prominent axonal
degeneration in the cerebellar foliate white matter and cerebellar roof nuclei. The neuronal changes are
accompanied by diffuse axonal degeneration in the dorsal roots, dorsal funiculus of the spinal cord, and
spinocerebellar tracts, as well as in the trigeminal, optic, and vestibulocochlear nerves. It is suggested that the
pathologic process is initially manifest as degeneration in the terminal portion of the axon and then proceeds
toward the cell body as a "dying back" phenomenon. Prognosis is poor and there is no treatment.
Multisystem Neuronal Abiotrophy in Cocker Spaniels

This is a slowly progressive neurological disease that has been reported in 4 red-haired Cocker Spaniels (1
female and 3 males), aged between 10 and 14 months [146]. The dogs had a common male ancestor. Clinical
signs began in all dogs several months before presentation and included behavioral changes such as apathy, loss
of house training, loss of recognition of persons and objects, hyperactivity, hypersexuality, and aggression. All
dogs appeared excessively anxious and were easily startled. Menace response was absent in all dogs. One dog
had a slight head tilt, and another had fixed miotic pupils. Hypermetria, intention tremors, ataxia, and wide-based
stance were noted in three dogs. Other variable signs included periodic falling, bumping into objects, pacing, and
circling. Delayed knuckling reactions occurred in one dog. Spinal reflexes were normal. CSF analysis and skull
radiography were unremarkable. Pathological findings included bilaterally symmetrical lesions in gray and white
matter. There was diffuse nerve cell loss, gliosis, and occasional dystrophic axons throughout subcortical and
brainstem nuclei, including septal nuclei, globus pallidus, subthalamic nuclei, substantia nigra, tectum, medial
geniculate bodies, and cerebellar and vestibular nuclei. White matter changes, which were considered to be
secondary to the neuronal loss, included gliosis, moderate numbers of axonal spheroids, perivascular
macrophages, and myelin loss. The white matter changes were most pronounced in central cerebellar areas,
corpus callosum, thalamic striae, subcortical white matter, and in fimbriae of the fornix. No lesions were noted in
the one spinal cord examined.
The etiopathogenesis of this unique condition is presently unknown. Pedigree studies suggest a possible
autosomal recessive mode of inheritance. Prognosis appears to be poor. Corticosteroid therapy in two dogs was
ineffective.
Multisystem Neuronal Abiotrophy in Cairn Terriers

This neurodegenerative condition in young Cairn Terriers of either sex has been termed "progressive
neuronopathy" [147] and "multisystemic chromatolytic neuronal degeneration" [148]. It has been seen in the USA,
Australia, Holland, and the UK [148-150]. Clinical signs begin around 5 months of age and are characterized by
pelvic limb weakness that progresses to tetraparesis, depressed spinal reflexes and diminished proprioception,
incoordination, hypermetria, and head tremor. Microscopic findings include central and/or peripheral
chromatolysis in medial aspects of dorsal and ventral horns (including Clarke's column) of the spinal cord as well
as various brainstem nuclear groups-cuneate nucleus, glossopharyngeal and vagus nuclei, lateral vestibular
nucleus, reticular nuclei of the medulla, cerebellar roof nuclei, red nucleus, and mesencephalic nucleus of the
trigeminal nerve. Typically, neuronal loss is not a feature of this disorder. Moderate white matter changes
(including axonal degeneration and considered to be secondary to the neuronal changes) are seen in lateral and
ventral columns of the spinal cord, brainstem, dorsal and ventral nerve roots, and in peripheral nerves.
A range of clinical and pathological variations may occur in this condition. In one report of a 4 month old female
Cairn Terrier with mild episodic paraparesis, clinical signs were apparent at 4 months of age and were confined to
the pelvic limbs [148]. In addition, chromatolytic degeneration of varying pattern (e.g., central, peripheral, or
patchy) was observed in neurons of the cerebral cortex, in spinal, autonomic and myenteric ganglia, as well as in
brainstem and spinal cord neuronal populations mentioned above. In another case report involving an 11 week
old Cairn Terrier [151], pelvic limb weakness was noted initially. Signs rapidly progressed to include head tremors,
inability to stand, uncoordinated movements involving the head, trunk and limbs, positional nystagmus, absent
patellar reflexes, and absent menace response. Muscle atrophy was not evident. This dog also manifested
episodic cataplectic attacks, characterized by generalized hypotonia or atonia that were responsive to imipramine
(see narcolepsy). In this dog, a symmetrical thoracolumbar myelomalacia was found in dorsal horns and adjacent
funicular white matter. Ultrastructural studies in these two case reports revealed dispersion and loss of ribosomes
in chromatolytic neurons, often accompanied by numerous mitochondria [148,151]. More recently, the condition
has been reported in two older Cairn Terrier littermates, an 18 months old male and an 11 month old female [150].
The initial clinical signs were characterized by hind limb weakness and ataxia, which deteriorated with exercise.
These signs progressed over several months to tetraparesis.
Multisystem Neuronal Abiotrophy in Miniature Poodles

This degenerative condition has been described in two male puppies from a litter of three [152]. Clinical signs
appear at 3 to 4 weeks of age and were characterized by rolling from side to side, inability to stand or right into
sternal position, periodic opisthotonus, intention tremors involving head and sometimes, trunk and limbs, and
absent menace response. Abnormal vertical nystagmus could be elicited. Microscopically, degeneration was
present in the cerebral cortex and cerebellum. Cerebellar cortical atrophy was characterized by extreme loss and
degeneration of Purkinje cells which appeared either pale, swollen and vacuolated or shrunken and
hyperchromatic associated with eosinophilia and nuclear pyknosis [2]. In addition, there was granule cell loss,
gliosis in the molecular layer, and axonal degeneration in foliate white matter. Vacuolar degeneration was present
in the lateral (dentate) cerebellar nuclei. Diffuse degenerative (hyperchromatic) and vacuolar changes were also
present in neurons throughout the cerebral cortex. Ultrastructural studies indicate that vacuolar neuronal
degeneration was associated with marked dilation of endoplasmic reticulum and loss of ribosomes. Shrunken
Purkinje cells had decreased numbers of Nissl bodies and there were accumulations of mitochondria and lamellar
bodies. The latter, stacked derivatives of endoplasmic reticulum, were not seen in shrunken cerebral perikarya.
Lamellar bodies reached giant proportions in the dendritic stems of degenerating Purkinje neurons. In Purkinje
axons, however, honeycombed aggregates of axoplasmic tubules usually predominated. The cytological changes
in these Poodle pups were notably different from those reported in ultrastructural studies of canine inherited
cerebellar degenerations. The genetic status of this condition remains to be confirmed.
Nervous System Degeneration in Ibizan Hounds

A neurodegenerative condition has been described in Ibizan Hounds characterized by a gait abnormality that
occurs around the time puppies first begin to walk [10]. Puppies manifest an ataxic-dysmetric gait that affects the
hind limbs initially and then progresses to the forelimbs. The gait has a bouncy, dancing character associated with
awkward strides, truncal swaying, and frequent falling. Patellar reflexes are absent, but without evidence of
muscle atrophy. No gross lesions are seen in the CNS. Microscopic changes include bilaterally symmetrical
degeneration of ascending and descending white matter tracts throughout all levels of the spinal cord and
involving all funiculi. Changes appear more severe in the thoracic cord, and especially involve the lateral areas of
the dorsal funiculus, the superficial and dorsal portion of the lateral funiculus, and superficial regions of the ventral
funiculus. Numerous large spheroids are found in the cochlear neurons of the trapezoid body. The dorsal nucleus
of the trapezoid body appears gliotic. Degenerative changes, including myelin and axonal degeneration and
macrophage infiltration are seen in spinal roots, especially ventral roots, and in peripheral nerves. An autosomal
recessive mode of inheritance is suggested by pedigree analysis. The condition is considered to have clinical and
pathological similarities to hereditary ataxia in Smooth-haired Fox Terriers and Jack Russell Terriers.
Neuroaxonal Dystrophy
Neuroaxonal dystrophy (NAD) is a degenerative neurological disease that has been reported in cats and dogs.
NAD is transmitted as an autosomal recessive trait in Tri-Colored cats and is familial or believed to be inherited in
a similar fashion in dogs. The disease is characterized by membrane-filled swellings ("spheroids") of preterminal
regions of axons and in synaptic terminals within the CNS [10]. The pathogenic mechanisms underlying the
development of this type of axonal abnormality are not well understood, although it is believed that the
degeneration starts in the distal axon and progresses proximally, resulting in eventual death of the neuronal cell
body [153]. Neuroaxonal dystrophies are considered further examples of abiotrophic processes in animals [1]. In
humans, NAD can be separated into 3 types [153]:
a. physiological NAD: a normal part of brain aging;

b. primary NAD: diseases in which the main pathology is neuroaxonal dystrophy; and
c. secondary NAD, occurring as a "reactive" process in another condition.
A similar morphological classification seems to exist in animals. In general, clinical signs of cerebellar-like disease
develop in young animals with primary NAD and signs are typically progressive. Ancillary laboratory tests, such as
CSF analysis and electrodiagnostics are usually normal. There is no treatment. Prognosis is guarded due to the
progressive nature of the disease.
Neuroaxonal Dystrophy in Rottweilers

A recessive mode of inheritance is suspected in Rottweiler dogs with NAD [154-156]. Clinical signs are
characterized by slowly progressive ataxia, hypermetria, and wide-based stance beginning in the first year of life,
and in some cases, as early as 10 weeks of age [157], although in one report, 3 dogs were normal in the first year
of life, while a fourth dog only showed poor coordination and clumsiness during the first year [158]. Some dogs
stand with legs crossed or on three legs with one elevated. Mild proprioceptive deficits have been reported [157].
As the neurological deficit progresses, sometimes over several years [155], head intention tremors, postural and
spontaneous nystagmus (positional and then continuous), and menace deficit with preservation of vision and
pupillary light reflexes, may be noted. In advanced cases, dogs are unable to climb or ascend stairs. Some
Rottweilers have been observed with the disorder for more than 6 years. Muscle bulk, tone and strength appear to
be preserved [154]. Hematology and blood chemistries are normal, as are plasma and urine amino acid levels
and serum vitamin E levels. Analysis of CSF is usually normal, although a mild protein increase has been
reported in one affected dog [158]. Nerve conduction studies are normal, while EMG studies may reveal the
presence of fibrillation potentials and positive sharp waves in interosseous muscles [154,158].
Histological changes are progressive and tend to mirror the clinical signs [10]. Grossly, the cerebellum is normal
or mildly atrophic [158]. Microscopic studies reveal the presence of massive numbers of axonal spheroids in gray
matter of many regions of the neuraxis, especially in sensory axon terminals, e.g., the dorsal horn of the spinal
cord, nuclei gracilis and cuneatus, accessory cuneate nucleus, sensory nucleus of the trigeminal nerve, nucleus
of the dorsal spinocerebellar tract, granular layer of the cerebellum, vestibular nucleus, and lateral and medial
geniculate bodies. The spheroids (up to 100 m in diameter) are often eosinophilic and either smooth or granular.
Some may be palely vacuolated with central cores of swirling filaments or granules that are often argyrophilic. The
central cores may stain with Luxol fast blue and periodic acid-Schiff. Some spheroids retain portions of the myelin
sheath, while in others, the sheath is attenuated and frequently absent. In some dogs, a marked loss of cerebellar
Purkinje cells has been reported, especially in the vermal lobules and floccules [154]. Ultrastructurally, spheroids
are filled with accumulations of smooth membrane-bound vesicles, membranous lamellae, dense bodies,
tubulovesicular arrays, and neurofilaments [158]. The pathogenesis of this condition remains uncertain, although
pertubations of axonal transport have been suggested [158], a theory supported by findings of accumulated
synaptic proteins (including synaptophysin, synapsin-I, synaptosomal-associated protein of 25 kDa (SNAP-25),
Rab 3a, and alpha-synuclein) in dystrophic axons [235]. Prognosis is poor because of the slow progression of the
disease although affected dogs may be acceptable pets for a long time.
An unusual case of neuroaxonal dystrophy has been described in Australia in a 15 week old female Rottweiler
puppy presenting with an acute onset of coughing and severe inspiratory stridor [159]. The dog was surgically
treated for vocal cord paralysis. A few weeks post- surgery, the dog developed a bunny-hopping hind limb gait
when running. Soon after, the owners reported that the dog collapsed while exercising and at rest. On
reexamination, the dog had a severe inspiratory dyspnea, pronounced inspiratory stridor, was cyanotic and weak.
Proprioceptive deficits developed soon after. Microscopic findings included vacuolation, hemorrhage, and
chromatolysis of neurons in the medial vestibular nuclei. Additionally, there was vacuolation of the inferior
cerebellar peduncle, and vacuolation and axonal swelling with macrophage infiltration in the spinothalamic tract at
the same level. In the midbrain, there was vacuolation of the corticospinal tracts, the medial longitudinal fasciculus
and gliosis of the rostral colliculus. Gliosis and neuronal vacuolation was found in the nodular lobule of the
cerebellar vermis and inferior olivary nucleus. In the spinal cord, axonal swelling and vacuolation were present in
various white matter tracts, including the ventral and dorsal spinocerebellar pathways, the fasciculus cuneatus,
and the ventral corticospinal tract. Focal hemorrhages were present in the gray columns. This atypical
neuroaxonal dystrophic condition has clinical and histopathological similarities to progressive tetraparesis and
laryngeal paralysis in young Rottweilers with neuronal vacuolation and axonal degeneration [160] (see spongy
degeneration in gray matter).
Neuroaxonal Dystrophy in Collie Sheep Dogs

A cerebellar neuroaxonal dystrophy in Collie Sheep dogs has been reported in New Zealand and Australia [161].
Clinical signs developed from 2 to 4 months of age and gradually increased in severity. Signs included
hypermetria, wide-based stance, difficulty in maintaining balance, intention tremor, and ataxia. Body growth,
learning ability and social behavior with other dogs were normal. Microscopically, numerous spheroids, appearing
as round or oval eosinophilic and moderately argyrophilic bodies ranging from 4 to 36 m in diameter, were found
in cerebellar roof nuclei and lateral vestibular nuclei, and in the central cerebellar, adjacent peduncular, and folia
white matter, where they were associated with mild Wallerian degeneration. Purkinje cells were normal.
Spheroids were also seen in molecular layer of the cerebellum, nucleus gracilis, substantia nigra nuclei, rostral
colliculus, cerebral cortex, and gray matter of the spinal cord. The spheroids were accompanied by moderate
diffuse gliosis. The history of several affected puppies in litters from successive mating of the same sire and dam
suggested an autosomal recessive mode of inheritance.
Neuroaxonal Dystrophy in Chihuahuas

A degenerative neuroaxonal dystrophy has been reported in 2 female Chihuahua littermates [162]. At 7 weeks of
age, there was sudden onset of tremor and exaggerated gait. Grossly, a moderate dilatation of the lateral
ventricles was noted. The main histopathological change was presence of spheroids throughout the white matter
of the brain and were especially prominent in internal capsule, cerebellum, lateral geniculate body, anterodorsal
nucleus of the thalamus, acoustic tubercule, superior and inferior olives, and corticospinal and spinothalamic
tracts. Spheroids were also present in the lateral cuneate nucleus, and gray matter of the thalamus, but
infrequently in the cerebral cortex. Minimal changes were found in the spinal cord. Ultrastructurally, the major
accumulated organelle was a membrane-bound body with containing numerous mitochondria and dense bodies.
In the gray matter many of the spheroids had synaptic clefts indicating that in these sites the spheroids were
presynaptic.
Neuroaxonal Dystrophy in Papillons

Neuroaxonal dystrophy has been reported in a litter of five 14 week old Papillon puppies [163]. Clinical
examination revealed signs of ataxia, hypermetria and depressed postural reflexes affecting all four limbs. The
severity of these signs varied between members of the litter. The condition became progressively worse and by
19 weeks of age all but the least severely affected pup (the single male of the litter) had deteriorated to the point
that euthanasia was indicated on humane grounds. Pathological examination revealed widespread changes in
both white and gray matter of the neuraxis caudal to the forebrain, particularly involving the dorsolateral white
matter of the spinal cord, characterized by axonal swellings typical of neuroaxonal dystrophy.
Neuroaxonal Dystrophy in a Jack Russell Terrier

A 9 week old Jack Russell terrier with progressive ataxia had histopathological lesions consistent with
neuroaxonal dystrophy [164]. Gross observation revealed absence of the septum pellucidum, hypoplasia of the
corpus callosum and marked bilateral hydrocephalus. Light microscopy of the CNS showed extensive axonal
swellings principally in the gray matter of the brainstem where the sensory nuclei were most affected, especially
medullary proprioceptive and vestibular nuclei, and in diencephalic nuclei [2]. Spheroids were also seen
throughout the spinal cord gray matter with a few also present in the dorsal funiculi. Ultrastructurally, spheroids
were identified as axonal terminals and dystrophic boutons and characterized by accumulations of membrane
bound bodies. Clinical and morphological findings were similar to those identified in human infantile neuroaxonal
dystrophy (Seitelberger's disease).
Feline Neuroaxonal Dystrophy

Neuroaxonal dystrophy has been reported in Domestic Tri-Colored cats as an autosomal recessive condition
[165] and has been termed feline hereditary neuroaxonal dystrophy (FHND). Clinical signs occurred in kittens
around 5 - 6 weeks of age, at which time head tremors and head shaking were observed. Signs progressed to
marked incoordination of gait and hypermetria. Affected kittens had a lilac color that darkened with age.
Unaffected littermates were black. There was gross atrophy of the cerebellar vermis. Microscopically, axonal
spheroids were found principally in the inferior olivary nucleus and lateral cuneate nucleus. Spheroids were noted
also in the brainstem tegmentum, nucleus ventralis and ventralis anterior of the thalamus, and the cerebellar
vermis. The spheroids had a finely granular homogenous quality, sometimes with a periodic acid-Schiff-positive
central dark core. The spheroids were seen with and without ballooned cell processes. The latter type was found
in the previously mentioned areas but also in medial lemniscus, medial longitudinal fasciculus, region of the
central tegmental tract, and in dorsal roots of the spinal cord. These changes were accompanied by loss of
neurons, including Purkinje and granule cells of the cerebellar vermis, and glial proliferation that was prominent in
the molecular layers of the cerebellar vermis. Spheroids were present in the spiral ganglia of the inner ear, along
with neuronal depletion. Ultrastructurally, most spheroids had a myelin sheath. Spheroidal morphology was
variable and included large membrane-bound vacuoles with a homogeneous electron-opaque interior, numerous
small mitochondria and osmiophilic dense bodies, sometimes within membrane-bound vesicles, and variable
neurofilaments that were often separated by multilaminated membranous structures.
Neuroaxonal dystrophy (multifocal swollen axons in brainstem, medulla, and spinal cord; swollen myelin sheaths
in spinal cord) with cerebellar abiotrophy (characterized by multifocal Purkinje cell loss and displacement of
remaining Purkinje cells into the granular layer of the cerebellum with molecular layer gliosis) has recently been
reported in 2 littermate Domestic Shorthair cats with dilute gray coat color [218]. Progressive cerebellar signs,
stunted growth, muscle atrophy, and apparent blindness (absent menace response, miotoc pupils and unusual
green irises) began a few weeks after birth.
A syndrome resembling (FHND) has been studied in siblings from several litters of Domestic Shorthair cats born
to the same queen [166]. The disorder was characterized by a sudden onset of hind limb ataxia, from 6 to 9
months of age, that slowly progressed to hind limb paresis with crouched standing or dragging-rolling gait, and
eventual paralysis. Hematology, biochemistries, urinalysis, and electrodiagnostic testing were normal.
Histologically, there was marked ballooning of axonal processes, with spheroid formation and vacuolation in
specific regions of the brain and spinal cord. Some dystrophic axons contained a central periodic acid- Schiff
positive core. Neuronal loss and gliosis were seen in certain brainstem nuclei (most severe in the lateral and
medial cuneate nuclei and nucleus gracilis), the thoracic nucleus (dorsal nucleus or Clarke’s column) in the gray
matter of the spinal cord, and the cerebellum (especially in the cerebellar nuclei and granular layer of the
cerebellar vermis, with associated degeneration and loss of Purkinje cells). Degenerative changes in white matter
were seen in ascending and descending tracts of the spinal cord and were most severe in the fasciculus gracilis
in the cervical cord. The spheroids ranged in size from 25 to 100 m with similar microscopic and ultrastructural
features to those described above in FHND. The syndrome in this report differed from FHND in Domestic Tri-
Colored cats in that no inner ear involvement was seen, onset of clinical signs occurred at a later age, and there
was involvement of cerebellar nuclei and spinal cord. In addition, although some of the affected cats did have
diluted coat colors, abnormal coat color was not always associated with clinical disease.
Neuroaxonal dystrophy has also been reported in two 5 week old (male and female) Siamese kittens with
progressive neurological signs including head tremor, hypermetria, proprioceptive deficits (all limbs), hind leg
ataxia and paralysis. Signs were initially noted at 2 weeks of age [167]. The kittens had heightened
responsiveness to touch and noise. Coat color in the kittens was normal. Grossly, the cerebellum was slightly
smaller than normal in both cats. Microscopically, the most prominent changes were found in the brainstem and
characterized by ballooning of cell processes, axonal spheroids, and neuronal depletion, principally in the lateral
cuneate nucleus. Many spheroids had a dense, central eosinophilic core. Degeneration and loss of Purkinje cells
were also observed, especially in the cerebellar vermis. In addition, vacuolation was seen locally around Purkinje
cells and in the granular layer, as well as in the white matter of the cerebellum and spinal cord. The condition was
believed to be hereditary.
Rottweiler Leukoencephalomyelopathy
This neurodegenerative disorder has been recognized in the USA, Netherlands, UK, and Australia affecting young
Rottweiler dogs of either sex from about 1.5 to 4 years of age [168-171]. The etiopathogenesis is unknown,
although the disease is considered to be inherited and transmitted as an autosomal recessive trait [171]. Clinical
signs include ataxia, tetraparesis, hypermetria, proprioceptive loss, and normal or exaggerated spinal reflexes
with increased muscle tone. Signs are often first seen in thoracic limbs [169-171]. The disease progresses over a
6 to 12 month period to the point where animals have difficulty in rising and standing, and there is frequent
stumbling, scuffing of the paws, and falling [170]. There is no muscle atrophy, extensor tone is often increased,
and pain sensation may be decreased [171]. Cranial nerves, vision, pupillary reflexes, and menace responses are
unaffected. All diagnostic studies including hematology, blood chemistries, CSF analysis, electrodiagnostics
(EMG and NCVs), plain radiography, and myelography are normal.
Bilateral, symmetrical lesions may be seen throughout the spinal cord, but are most severe in dorsal and lateral
funiculi of the cervical cord segments. In transverse sections of fixed specimens, these lesions appear grossly as
areas of increased pallor and opacity. In the brainstem, lesions tend to be bilaterally symmetrical and may be
found in the spinal tracts of the trigeminal nerve, caudal cerebellar peduncles, deep cerebellar white matter,
subventricular rostral medullary tracts, pyramidal tracts, and the medial lemniscus. Optic nerves and tracts may
also be affected (but not to the point of causing visual deficits) [171]. Occasionally, diffuse or patchy lesions occur
in the corona radiata [171]. Cranial nerves and autonomic ganglia are normal. Histopathological changes include
rarefaction and polymicrocavitation of the white matter associated with demyelination, edema, diminished myelin
staining, dissociation of myelin sheaths, gemistocytic astrocytosis, fibrillary gliosis, and macrophage infiltration
[170]. In the severe cervical cord lesions, a narrow rim of normal white matter is seen between the edge of the
lesion and the pial surface [169]. Wallerian degeneration is not a feature of this condition [171], and therefore, not
surprisingly, axonal degeneration is mild, although a few swollen degenerating axons are seen occasionally.
There is minimal inflammation or endothelial cell proliferation. Axonal spheroids are variably present, but in one
dog, these structures were found in accessory cuneate nucleus, nucleus gracilis, nucleus cuneatus, and the
nucleus of the dorsospinocerebellar tract, but were not associated with neuronal loss [169]. Ultrastructurally,
myelin splitting, thinly myelinated axons and naked axon sheaths separated by broad astroglial processes, are
seen [169,170]. There is little evidence of axonal swelling or neurofilament aggregation. Slocombe and colleagues
found evidence of scattered swollen and vacuolated nerve sheaths within hind limb peripheral nerves in all of their
affected dogs [170].
Possible storage disease has been ruled out in affected Rottweilers by the demonstration of a battery of normal
lysosomal enzyme activities in peripheral blood leukocytes [170]. Presently, there is no treatment. Prognosis is
poor.
This condition needs to be differentiated from neuroaxonal dystrophy in Rottweilers, which is often seen before 1
year of age, and is slowly progressive over several years. Clinical signs include hypermetria, head tremors, and
nystagmus, but typically, there is no paresis [155,171]. Young adult Rottweilers (18 to 20 months of age) with
cervical spondylomyelopathy and signs of progressive proprioceptive loss and ataxia may also be confused
clinically with Rottweiler leukoencephalomyelopathy [168].
Spongy Degeneration of the CNS

Spongy degeneration of the CNS in children has been termed Canavan’s syndrome (van Bogaert-Bertrand type
of spongy degeneration) and is characterized by accumulation of vacuoles in a variety of cells, particularly
astrocytes [4], which also contain abnormally structured elongated mitochondria [172]. The vacuoles result from
excessive fluid accumulation, seemingly from metabolic disturbances that produce dysmyelination. Studies
suggest biochemical heterogeneity in the pathogenesis of infantile spongy degeneration, including deficient
activity of aspartoacylase (antemortem diagnosis can be made using cultured fibroblasts) and astrocytic
mitochondria with reduced levels of adenosine triphosphate [4,173,174]. Increased amounts of N-acetylaspartic
acid are found in urine and plasma [175]. In this condition, demyelination can be prominent but axons and
oligodendroglia are not extensively affected [4]. Familial and hereditary forms of spongy degeneration have been
recognized sporadically in young dogs and cats and the changes may be predominant in either white or gray
matter.
Spongy Degeneration in White Matter

Spongy degeneration has been observed in 2 young female Labrador Retriever littermates [176]. Clinical signs
were noted between 4 and 6 months of age and were characterized by progressive ataxia-dysmetria of head,
trunk, and limbs, wide-based stance, hyperreflexia with clonus, muscle atrophy, and episodes of exaggerated
rigidity and opisthotonus. Excitement increased the frequency of the episodes. In one dog, signs included periodic
extension of the forelimbs, dorsiflexion of the head, and falling over backwards. In the second dog, one spell of
marked extensor rigidity and opisthotonus lasted for 2 hours. Cranial nerve function (apart from possible auditory
deficits in one dog and a visual placing deficit in the second dog) and proprioception appeared normal, and dogs
retained bowel and bladder control. At 11 months of age, one dog became very weak and dysmetric and all
muscle groups were atrophic. This dog could take no more than 2 or 3 steps without falling or collapsing. Routine
hematology, blood chemistries, urinalysis and CSF tests were all within normal limits. Distal tibial nerve
conduction velocities were considered slow in the 11 month old dog and EEG studies revealed normal
background activity with occasional spiking in the left frontal region. Microscopically, spongy degeneration of the
white matter of the CNS and PNS was found, with most prominent lesions in cerebellar peduncles, deep
cerebellar white matter, and in the subcortical and deep white matter of all lobes of the cerebrum [177]. Similar
lesions were found in the tracts of some cranial nerves, in the thalamic area, midbrain and brainstem, and in the
white matter of the spinal cord. These areas were associated with hypertrophied cell bodies, processes, and
perivascular footplates of fibrous astrocytes. Myelin loss was described, but axons were normal and there was no
evidence of myelin breakdown or inflammation. Ultrastructural studies indicated that the vacuolation was caused
by myelin separation at intraperiod lines between major dense lines. The hypertrophic astrocytes had dilated
cytocavitary systems, membrane-bound crystalline inclusions, abundant intermediate filaments, and degenerated
mitochondria. The clinical, histological, and ultrastructural findings resembled those reported for the juvenile form
of Canavan's disease (van Bogaert and Bertrand type) in children. The cause of this condition remains uncertain,
but a biochemical lesion involving a membrane-associated adenosine triphosphatase ion transport system in
astrocytes has been proposed [177]. Prognosis of dogs with this disorder appears to be poor. Treatment with
acepromazine (0.25 mg/kg, IM) decreased the frequency of the episodes of extensor rigidity but resulted in
marked weakness. Diazepam (15 mg, IV) did not improve the extensor rigidity-opisthotonus.
A progressive neurological disorder has been reported recently in several related litters of Shetland Sheepdogs
[178]. Clinical signs, beginning at 7 days to 3 weeks of age, included seizures with increasingly frequency and
severity, mental depression, inability to assume sternal recumbency from a lateral position, whole body
hyperesthesia, intention tremors of head and neck, inability to ambulate, extensor and flexor rigidity and spasticity
of all 4 limbs. Patellar and sciatic reflexes were hypertonic. Affected puppies tended to remain in an opisthotonic
position at rest. Serum biochemistry profile, hematology, urinalysis, and CSF studies were normal. CT scans
revealed diffuse hypomyelination of white matter in one affected pup, along with dilation of the lateral and 4th
ventricles. Electrodiagnostic studies (EMG and NCVs) were normal. In puppies euthanized, no gross lesions were
noted. Microscopic studies revealed severe, diffuse, patchy vacuolation of the white matter of the brain and spinal
cord that did not appear to worsen with age. Spongiosis was most severe in the cerebellar medulla and folial
white matter and the corona radiata. Vacuolation was moderate and patchy in the cerebral white matter and mild
in the optic tracts and brainstem, although the caudal colliculi and ventrolateral pons were often involved. The
corpus callosum was minimally affected. In the spinal cord, all white matter tracts were affected, especially those
in the dorsal funiculi. The CNS vacuolation was not accompanied by glial cell response and there was no
evidence of swollen, degenerating axons or axonal debris. In a few puppies, cerebellar Purkinje cells had subtle
changes including intracytoplasmic vacuolation, swollen dendrites and axons, and some cells appeared to be
undergoing degeneration. Ultrastructurally, the vacuoles were associated with interlamellar splitting of myelin
sheaths. Cytoplasmic vacuolation of Purkinje cells corresponded to dilation of the endoplasmic reticulum.
Vacuolation was seen occasionally in nerve roots, although peripheral nerves were normal. The disorder was
compared to Canavan’s disease, although diminished aspartocyclase enzyme activity in tissue or N-acetylaspartic
aciduria was not found. In addition, biochemical screening for known human organic acid or aminoacid
abnormalities (such as maple syrup urine disease, phenylketonuria, hyperglycinuria, and homocyteinuria) were
negative. The mode of inheritance of this familial condition was not determined, although the authors considered
an autosomal recessive inheritance unlikely due to the large number of puppies affected.
Spongy degeneration has also been described in Samoyed puppies [179]. Pelvic limb tremors were observed at
12 days of age, progressing to generalized tremors over the next 5 days. Microscopically, a generalized
vacuolation of white matter was seen throughout the CNS. Changes were most severe in the cerebellum and
spinal cord, and less severe in the cerebrum. No degenerative or inflammatory changes were found and dorsal
and ventral spinal nerve roots were normal. There was no evidence of myelin breakdown. Axons appeared
normal. Ultrastructurally, vacuolations arose from splitting and distension of the myelin sheaths, usually as a
"blowout" to one side of the axon rather than encircling them. There was no evidence of astrocytic change or of
expanded extracellular space. The cause was no determined.
A degenerative spongiform disorder has been reported in 3 Silky Terrier puppies from a litter of five [180].
Clinical signs were noted at birth and consisted of head nodding, approximately twice per second, and
uncontrolled intermittent contractures of the vertebral column, especially muscles of the thoracolumbar region, at
intervals of approximately 2 per second. Occasionally the pelvic limbs were lifted off the ground during these
contractures. The episodes were intensified with excitement and decreased markedly after a period of enclosure
in a confined space. Low intensity contractions continued during sleep. Signs did not appear to be progressive. A
spongy state, along with pallor of myelin staining, was found throughout the cerebral white matter, especially in
the corpus callosum, optic tracts, and subcortical cerebral and cerebellar white matter. A large number of
Alzheimer type II protoplasmic astrocytes were found in severely affected areas. Axons were normal.
Spongy degeneration has been reported in two female littermate kittens of the Egyptian Mau breed of cat (a
small breed derived from the Siamese cat) [181]. Clinical signs, first noticed in kittens at 7 weeks of age, were
characterized by pelvic limb ataxia and hypermetria. At 4 months of age, signs included a fixed, vacant stare, slow
deliberate movements, and intermittent periods of severe depression and reduced activity, with frequent flicking
movements of distal pelvic limbs when at full flexion. Blink, righting, and withdrawal reflexes were severely
reduced. The condition improved with age in one kitten, although occasional episodes occurred. At 20 months of
age, this cat was well grown, could jump and run, but had slight residual posterior ataxia. Another littermate (a
male) was reported with hind limb ataxia that was first noticed by the owner at 10 months of age. Microscopically,
there was widespread vacuolation throughout the brain and spinal cord. The intensity of this vacuolation varied,
but was most severe in cerebral subcortical and sub-ependymal white matter, cerebellar foliar white matter, and
the midbrain and brainstem. No neuronal abnormalities were seen and axons appeared to be unaffected. A
paucity of myelin occurred in the vacuolar areas. Cerebrocortical and spinal cord gray matter also contained
vacuoles, but were much less severely affected than the white matter. Ultrastructural studies revealed
intramyelinic vacuolation, resulting from splitting of the intra-period line of the myelin lamellae. There was no
evidence of myelin breakdown, and no neuronal, axonal, or glial changes, although a few small myelin figures
were noted in the cytoplasm of astrocytic foot processes.
Spongy Degeneration in Gray Matter

There are several forms of spongy degeneration characterized by their predominant involvement of gray matter.
One of these, believed to be an autosomal recessive disease, occurs in Bull Mastiff puppies [182,190], of either
sex, usually between 6 and 9 weeks of age, although in one affected dog, signs were initially noted at 7 months of
age [182]. Clinical signs included ataxia, most obvious in pelvic limbs, hypermetria, proprioceptive deficits, and
head tremor that was accentuated as animals attempted to eat. To date, all affected animals have had visual
deficits and slowed menace reflexes. Less constant signs included hysterical behavior, compulsive forward
movements, backing compulsively when called, lifting a fore limb while eating, circling, and an intermittent
nystagmus (seen in the oldest dog). Some dogs appeared dull, disinterested in their surroundings, and difficult to
train. Ancillary aids such as hematology, blood biochemistry and CSF analysis were within normal limits.
Venticulography revealed enlarged lateral ventricles, but unassociated with obstruction of CSF flow since the
contrast passed from lateral ventricles to fourth ventricles and into the spinal subarachnoid space without
hindrance. There was no evidence of megaesophagus and esophageal motility was normal. Magnetic resonance
imaging in one report demonstrated symmetric hydrocephalus and two focal areas of increased signal intensity
within the central nuclei of the cerebellum [190]. Macroscopic findings were characterized by moderate to severe
communicating hydrocephalus with dilatation of all ventricles and the cerebral aqueduct. In addition, a yellow-
brown discoloration of the cerebellar nuclei was seen. Microscopically, bilaterally symmetrical spongy lesions
occurred in the three deep cerebellar nuclei (dentate, interpositus, and fastigial), where the lesions were most
severe, in the lateral vestibular nucleus, and at the base of the inferior colliculus. The cerebellar lesions consisted
of vacuolation, gliosis (increase in both microglia and astrocytes, many of which were hypertrophic), and frequent
axonal spheroids. The neurons appeared normal but were often in close proximity to vacuoles and spheroids. No
cerebellar cortical atrophy was observed despite the presence of occasional torpedoes in the granule cell layer.
Many of the vacuoles were surrounded (partially or completely) by attenuated myelin. The vacuoles often
contained myelin remnants and occasional axons. Degenerating axons were found within affected nuclei, the
white matter of cerebellar folia, and the granule cell layer. Some swollen axons contained increased numbers of
axoplasmic organelles, while others had dark, granular axoplasm. It was also reported that oligodendrocytes were
degenerating. The basis for this vacuolar change remains unclear. Prognosis is guarded. There is no treatment.
A similar spongiform disorder has been seen in young Saluki dogs with signs of seizures and behavioral changes,
sleeping deeply, disinterest in their surroundings, aimless running, circling and back flips [2,183]. Skull
radiography and CSF analysis were normal. EEG showed generalized low voltage activity in all leads.
Microscopically, a pronounced spongiosis was present diffusely in the cerebrum (involving the deep laminae),
brainstem and cerebellum. The spongiosis predominated in the gray matter, being especially severe in neuropil of
olivary and cerebellar nuclei [2], but was also found in the thalamus, ventral internal capsule, tegmentum of the
pons, nuclear areas of the medulla and optic nerve, usually accompanied by marked astrocytosis [183]. The
lesions extended into white matter in some areas, such as at the junction of the lentiform nucleus with the internal
capsule [2]. Lesions were not found in the spinal cord. A mild spongiform degeneration was noted in two clinically
normal puppies. The condition was considered to be recessively inherited with variable expression.
Familial spongy degeneration has recently been reported in three Cocker Spaniel puppies out of a litter of six,
from a mating of the mother with her father [184]. Clinical signs began around 3 to 4 weeks of age and included
episodic behavioral changes, aimless running, and autonomic signs (salivation, urination, and defecation) that
may reflect psychomotor seizures [184]. Bilateral pelvic limb proprioceptive deficits, forelimb hypermetria, bunny
hopping, and absent menace response have also been noted. Results of hematology, blood chemistry, urinalysis,
thyroid function, serum bile acids, blood ammonia levels, CSF analysis, and CT scans were all normal.
Microscopic changes were characterized by spongy degeneration and associated diffuse gliosis mainly found in
the gray matter, and were especially evident in the pons and cerebellar nuclei. Lesion intensity was less severe in
other brainstem nuclei such as the dorsal and ventral thalamic nuclei and dorsal nuclei of the lateral geniculate
body, as well as in the cerebral cortex and cerebellar cortex. Lesions were multifocal and always bilaterally
symmetrical. Many spheroids were found in spongy areas as well as in normal neuropil. Demyelination (based on
Luxol-fast blue staining) was found in internal capsule, thalamic tracts, cerebellar peduncles, cerebellar
rubrothalamic tract, facial tract, and the trigeminal spinal tract. Axonal changes were mild. Immunohistochemical
staining for canine distemper virus was negative. No lesions were found in the spinal cord.
Spongy degeneration of the CNS has been reported in two Malinois Shepherd crossbreed puppies [185].
Coarse tremors involving the head, limbs and trunk were observed at 3 weeks of age. The tremors were
accentuated by excitement or voluntary movement but disappeared at rest and sleep. Other signs included wide-
based stance, difficulty in maintaining balance, a tendency to move backwards or to the side while attempting to
walk, and stilted, hypermetric gait. A fine oscillating tremor was observed in the eyes. Oculocephalic reflexes were
delayed and postural reactions were slightly hypermetric. Spinal reflexes were normal. Hematology and blood
chemistries were normal. Microscopic findings were characterized by a bilaterally symmetrical spongy state
throughout the brain and spinal cord, with predominant involvement of the gray matter. All layers of the cerebral
cortex were affected. Gray matter lesions were noted in basal nuclei, brainstem nuclei, cerebellar nuclei, and in
lumbar and cervical intumescences of the spinal cord gray matter. White matter was relatively uninvolved, except
for a spongy state and myelin loss in the cerebellar folia and some vacuolation in the cerebral cortical U-fiber
region. The neuropil vacuoles were located adjacent to neurons, blood vessels, and glial cells. Neurons were not
involved. There was no sign of necrosis, demyelination, or hypomyelination. Gliosis and marked astrocytic
hypertrophy (shown by glial fibrillary acid protein staining) were evident. Axons appeared normal. Prognosis was
considered to be poor.
A spongiform neurodegenerative disease has been recently reported in young Rottweiler dogs, of either sex,
from North America, Europe, and Australia [160,186,187,219]. The condition is characterized by progressive
signs of ataxia-dysmetria, especially apparent in the pelvic limbs, initially seen in puppies from 6 to 16 weeks of
age, and progressing (sometimes over several months) to tetraparesis. Inspiratory stridor, associated with
bilateral laryngeal paralysis, has been noted in several reports [160,186]. Absence of a gag reflex has also been
reported [219]. Tendon reflexes are normal and there is no muscle atrophy in the limbs. In some affected dogs,
opthalmoscopy reveals persistent pupillary membranes on both irises and bilateral cataracts, and nystagmoid
movements [160]. Behavioral changes, including aggression, absent-mindedness, and difficulty in training, have
been noted in some dogs [186]. Analysis of CSF is normal, as are cervical radiography and myelography, ruling
out vertebral malformation or injury. Thoracic radiographs show no evidence of megaesophagus.
Electromyography may show abnormal spontaneous activity from the intrinsic musculature of the larynx,
suggestive of denervation. At necropsy there is no gross abnormalities of the nervous system but atrophy of the
dorsal cricoarytenoid muscles of the larynx has been noted in dogs with signs of laryngeal paralysis. Widespread
histological abnormalities have been reported throughout the nervous system, including neuronal vacuolation
(especially prominent in cerebellar roof nuclei and the nucleus of the spinal tract of the trigeminal nerve, but also
in nuclei of the extrapyramidal system, thalamic nuclei, nucleus of the caudal colliculus, vestibular nuclei, medial
cuneate nuclei, neurons of the spinal gray matter, dorsal root ganglia, and visceral ganglia), spongiform and
microvesicular intra-axonal changes in the neuropil (in lateral vestibular nuclei, red nuclei, anterior colliculi, and
dorsal root ganglia), and axonal degeneration which is most prominent in the spinal cord, especially severe in the
thoracic segments, and most concentrated in the dorsolateral and ventromedial funiculi [160]. Wallerian
degeneration in the spinocerebellar tracts may extend into the caudal brainstem, and in the central cerebellar gray
and white matter. There is focally extensive degeneration and loss of Purkinje cells, Bergmann’s gliosis, and
presence of axonal torpedoes in the granule cell layer. The dorsal cricoarytenoid muscles of the larynx show
evidence of neurogenic atrophy, and nerve fascicles associated with this muscle (presumably from the recurrent
laryngeal nerves) may have reduced numbers of axons. In one report, there was no sign of neuronal
degeneration or loss in the nucleus ambiguus [160]. Wallerian-type degeneration has also been reported in sciatic
nerves [186]. Ultrastructurally, the neuronal vacuoles are bound by a single membrane and are empty or contain
granular material and sometimes membranous profiles [186,187,219]. Axosomatic and axodendritic synapses in
affected neurons are intact both ultrastructurally and with synaptophysin immunostaining [187]. The cause of this
condition remains unknown, although it is not considered to be a prion disease: immunoblotting and
immunocytochemical staining of the brain for protease-resistant scrapie prion protein are negative [186,187,219].
A very similar (if not the same) condition has been described as an atypical form of neuroaxonal dystrophy in a 15
week old female Rottweiler with laryngeal paralysis [159].
A progressive spongiform neurodegenerative condition of the CNS has been reported in 5 related Birman kittens,
of either sex [188]. All affected kittens were normal at birth. Clinical signs of progressive hind limb paresis and
ataxia were first noted in animals from 2 to 6 months of age. The breeder noted that affected kittens had a very
light coat color when born, were smaller in size than unaffected kittens, had smaller heads, and "closer-set" eyes,
and a higher pitched meow. Kittens were bright and alert and 4 had bilateral cataracts. When walking, the hind
limbs were excessively abducted with knuckling over on to the dorsal surface of the hind paws. Postural reactions
were absent in the hind limbs and spinal reflexes were exaggerated. One cat had posterior paralysis and an
absent menace response and gag reflex. Spinal reflexes and postural reactions were usually normal in the
forelimbs, except in one cat with abnormal postural reactions on the right forelimb. This cat also had an inspiratory
stridor and abnormal high-pitched meow. Hematology and blood chemistries were usually normal (2 cats had
peripheral eosinophilia), as were CSF analysis (pressure, cell count, and protein levels), radiography, and motor
nerve conduction velocity studies (performed in one cat). Microscopically, brains of all cats showed several large
bilaterally symmetrical, disseminated foci of spongy change. These were often located in the gray matter of the
cerebral cortex, and were especially marked in the piriform lobe where extensive vacuolation of the molecular
layer extended into the pyramidal cell layer. Less severe foci were present in the inferior collicular nuclei of the
midbrain. Vacuolation was also seen in the thalamus, cerebellar peduncles, oculomotor nucleus, and medulla
oblongata. Vacuoles (from 10 to 50 m) were spherical or ovoid and typically present in clusters in the neuropil.
Wallerian degeneration was observed in sensory and motor white matter tracts in the spinal cord. Ultrastructurally,
the spongy change was associated with intramyelinic edema. Vacuoles were bound by one or more lamellae.
Most were empty but a few contained loose whorled myelin figures. Peripheral nerves were normal. All kittens
were inbred and an inherited etiology was suspected [188].
Myopathic Disorders
C. H. Vite
• Bouvier des Flandres Myopathy

• Familial Dysphagia
- Central Core Myopathy
• Devon Rex Cat Hereditary Myopathy
• Exertional Myopathy
• Fibrotic Myopathy
• Glycogenosis
• Hepatozoon Myositis
• Hyperadrenocortical (Cushing's) Myopathy
• Hyperkalemic Myopathy
• Hypernatremic Myopathy
• Hypokalemic Myopathy
• Hypothyroid Myopathy
• Hypotrophic Myopathy
• Immobilization Myopathy
• Ischemic Neuromyopathy
• Labrador Retriever Hereditary Myopathy
• Limber Tail
• Malignant Hyperthermia
- Canine Stress Syndrome
• Megaesophagus
• Mitochondrial Myopathy
• Clumber and Sussex Spaniel
- Old English Sheepdog
- Jack Russell Terrier
- Labrador Retriever
- Lipid Storage Myopathy
• Muscular Dystrophy
- Canine Muscular Dystrophy
- Dystrophinopathies
- Females
- Distal Myopathies
- Feline Muscular Dystrophy
- Congenital Muscular Dystrophy
• Myasthenia Gravis *
- Acquired Myasthenia Gravis
- Congenital Myasthenia Gravis
• Myositis
- Masticatory Myositis
- Atrophic Myopathy/myositis
- Polymyositis
- Extraocular Myositis
- Dermatomyositis
- Myositis Ossificans
- Laryngeal Myositis
- Infectious Myositis
- Paraneoplastic Myositis
- Drug-induced Myositis
• Myotonic Myopathy
- Myotonia Congenita
- Adult-onset Myotonic Myopathy
- Secondary Myotonia
• Nemaline Myopathy
• Polyglucosan Myopathy
• Toxic Myopathy
• Vitamin E / Selenium-responsive Myopathy
* I have included a review of myasthenia gravis in this chapter. While this condition represents a junctionopathy,
its inclusion here seems appropriate due to its clinical similarities with some myopathic disorders.
Abbreviations -
ADH (adrenal-dependent hyperadrenocorticism); ALT (SGPT) alanine aminotransferase; AST (SGOT) aspartate
aminotransferase; ATPase (myofibrillar adenosine triphosphatase); CK (creatine kinase); CSF (cerebrospinal
fluid); CT (computed tomography); EMG (electromyography); HAC (hyperadrenocorticism); MRI (magnetic
resonance imaging); NADH-TR (reduced nicotinamide adenine dinucleotide tetrazolium reductase); NCV (nerve
conduction velocity); PAS (periodic acid-Schiff); PDH (pituitary-dependent hyperadrenocorticism).
Bouvier des Flandres Myopathy

A degenerative myopathy has been reported in two female Bouvier des Flandres dogs [1]. Clinical signs were
observed when dogs were about 2 years of age. Signs included regurgitation, exercise intolerance, generalized
muscle atrophy, weakness, and a peculiar paddling gait characterized by overextension of the paws when walking.
Cranial nerve function, postural reaction testing, and segmental spinal reflexes were normal. Contrast studies
reveal megaesophagus. Serum creatine kinase (CK) levels were markedly elevated. Other hematological and
blood chemistry values were normal. Electrodiagnostic testing demonstrated bizarre, high-frequency discharges
in skeletal muscles. Motor nerve conduction velocities were normal. Muscle changes were characterized by
moderate to pronounced fiber size variation associated with atrophic and hypertrophic fibers of both histochemical
types (types 1 and 2), occasional giant-sized fibers with a whorled internal architecture and clefts, numerous
internalized nuclei, multifocal necrosis, variable phagocytosis, basophilia, and marked increase in perimysial and
endomysial fibrosis. These changes were seen in both limb and esophageal muscle samples. Peripheral and
intramuscular nerves were normal. Muscle biopsy samples taken from two clinically normal related dogs showed
similar but less severe histopathological changes.
Prognosis is guarded to poor since the disease appears to progress rapidly. Corticosteroids given to one dog had
no clinical effect. The clinical signs, elevated CK levels, and muscle pathology are similar to those seen in some
dogs with muscular dystrophy.
A familial dysphagia, associated with megaesophagus, has been reported in Bouviers [2,3] mainly adults (age
range: 6 months to 9 years), with histopathological findings in pharyngeal and/or esophageal muscle very similar
to those described above, but without clinical signs of generalized weakness or exercise intolerance. In some
Bouviers with megaesophagus, similar lesions were also observed in the masseter and temporalis muscles and in
the intrinsic laryngeal muscles [2]. The EMG showed myopathic changes in oral/ pharyngeal/esophageal muscles.
In 13 of 24 dogs, CK levels were elevated. This condition was considered to have similarities to oculopharyngeal
muscular dystrophy in people, an autosomal dominant disorder characterized by progressive ptosis and
dysphagia [4].
Central Core Myopathy

A myopathy has been recognized in young Great Danes beginning around 6 months of age. Clinical signs of
generalized weakness exacerbated by moderate exercise [5,6]. In one report, exercise or excitement associated
with feeding would induce an episode of general body tremor and collapse into sternal recumbency, with rapid
recovery after a few minutes rest [6]. Clinical weakness progressed in affected dogs, so that around 15 to 18
months of age, exercise intolerance was severe, with one dog unable to walk more than a few feet before
collapsing. Elevated serum levels of CK, aspartate aminotransferase, and alanine aminotransferase have been
reported. The condition is unresponsive to intravenous edrophonium chloride (Tensilon). EMG abnormalities
include presence of positive sharp waves and fibrillation potentials in all muscles examined, including proximal
and distal limb and trunk muscles. At necropsy, moderate atrophy of proximal limb and paraspinal muscles were
noted in one dog [5]. Approximately 50% of muscle fibers contained a central core that occupied from 20 to 80%
of the fiber. The cores appeared dark staining with hematoxylin and eosin stains, lacked cross-striations, and
some contained vacuoles and nuclei. The cores were found in both type 1 and type 2 fibers. In longitudinal
sections, the cores sometimes extended from 50 to 150 um along the fibers. The core structure varied from
homogenous to finely granular or fibrillar. In Gomori trichome stains, scattered rod-shaped bodies were seen.
Scattered necrotic and regenerating (characterized by small basophilic fibers with subsarcolemmal nuclear
chains) fibers were also observed. Ultrastructurally, the cores consisted of numerous mitochondria, glycogen
granules and disarrayed, irregular filament bundles attached to thickened Z-lines. No abnormalities were seen in
spinal cord, peripheral nerves, or intramuscular nerve branches. The condition has some similarities to certain
congenital myopathies in people, including central core disease, an autosomal dominantly inherited disorder,
although in humans there is an absence of oxidative enzyme activity in the cores, which consistently affect type 1
fibers [7]. Note that the cores resemble target fibers seen in denervating muscle [8], however unlike targets, cores
extend along the length of the fiber [9]. In one dog, some clinical improvement occurred following oral
prednisolone therapy, although signs quickly returned upon cessation of treatment [5]. Prognosis appears to be
guarded to poor. The etiology of this myopathy is uncertain, although a possible genetic disorder involved with
oxidative metabolism has been suggested [6].
Devon Rex Cat Hereditary Myopathy

A degenerative, congenital myopathy, often called "spasticity" (albeit, erroneously), occurs in Devon rex cats and
is believed to be inherited as an autosomal recessive trait [10-13]. Male and female cats are susceptible and
signs may be seen in young cats around 4 to 7 weeks of age but may be delayed until 12 to 14 weeks. The most
consistent clinical feature is passive ventroflexion of the head and neck, which is especially noticeable during
locomotion, urination or defecation [12]. In severe cases, the chin is tucked into the sternum. Affected cats show a
high-stepping forelimb gait, head bobbing, and with shoulder blades held high and the neck arched downwards.
There is exercise intolerance often accompanied by progressive shortening of the stride and tremor. A "dog-
begging" position is commonly observed. Some affected cats appear to have difficulty prehending and swallowing
food, which may lead to upper airway obstruction. Regurgitation may be observed. Some cats have partial trismus.
Clinical signs may be accentuated by concurrent illness, stress, or cold ambient temperature [12]. Apart from
variable muscle atrophy seen in some cats, neurological testing is normal. Routine hematology and blood
chemistries are normal, including serum CK levels. Radiographic and imaging studies reveal presence of
megaesophagus and esophageal hypomotility, sometimes with gastroesophageal reflux [12]. EMG changes are
mild and include variable presence of fibrillation potentials and positive sharp waves in muscles, particularly in
triceps brachii and dorsal cervical muscles. No gross changes are seen in skeletal muscles. Microscopic changes
in muscle include fiber size variation associated with hypertrophic and round/angular atrophic fibers, occasional
fiber degeneration/regeneration, and variable presence of internal nuclei. In muscle samples from young cats, the
muscle lesions tend to be mild and variable, but become more prominent with age and/or clinical severity [12].
There is no evidence of myositis or fiber type grouping. Dystrophin staining is normal. No abnormalities are seen
in peripheral nerves, spinal cord, or brain. Mitochondrial enzyme assays in muscle are normal.
The condition seems to stabilize around 9 months of age and affected cats may learn to cope with eating and
drinking over time (feeding from a raised platform may be beneficial). Contractures do not occur. With adequate
care, cats can thrive, although they may continue to tire easily [10]. In some cats, prognosis may be guarded due
to propensity to asphyxiation and laryngospasms associated with obstruction of the larynx/pharynx with food.
Exertional Myopathy
Exertional myopathy, or exertional rhabdomyolysis (ER), is a disease that affects many animal species, including
man [14]. It is an important complication commonly arising in newly captured wild animals and, in domestic
animals, is most frequently encountered in horses, in whom the condition has been variously termed azoturia and
paralytic myoglobinuria. The condition appears to be rare in cats. In dogs, exertional myopathy probably occurs
most frequently in racing Greyhounds [15-18], although it is also common in sled dogs [19,20]. It has also been
reported sporadically in dogs as a complication of prolonged convulsive seizures (and extreme muscle exertion)
[21,533], babesiosis [22], malignant hyperthermia [23], and monensin-contaminated diets [24]. Rhabdomyolysis
has been reported in dogs following experimental potassium and magnesium deficiency [25,26]. Rhabdomyolysis
is occasionally seen in humans with lipid storage myopathies and defects of fatty acid oxidation [7]. The
pathogenesis of ER is poorly understood since intensity and duration of muscle contraction are not the entire
explanation [27]. Humidity and temperature may be factors in Greyhounds in Australia, and highly strung dogs
that bark excessively and are overexcited at the track appear to be susceptible to developing rhabdomyolysis [15].
Results of a study performed during the 1998 Iditarod sled race showed no association between pre-race plasma
vitamin E or total antioxidant status levels and risk of development of ER [19]. It has been suggested that
mechanisms other than oxidative damage to muscles, such as repetitive trauma during eccentric exercise (e.g.,
running downhill), may be involved in initiating muscle damage and subsequent development of ER in sled
dogs[19]. Energy for muscle metabolism is derived from blood glucose, muscle glycogen, and fatty acids (plasma
free fatty acids, esterified fatty acids, and ketone bodies), while contributions from branched chain fatty acids and
amino acids may increase with prolonged exercise [28]. Intense muscle exertion requires an adequate supply of
glycogen (via glycolysis) and once depleted, the adenosinetriphosphate of muscle decreases leading to muscle
cramps and muscle fiber necrosis. Sufficient muscle injury will lead to release of myoglobin (the red pigment
responsible for the color of muscle) into the circulation and filtration through the renal glomerulus resulting in red-
brown urine pigmentation and possibly, acute renal failure [29].
In racing greyhounds, severe lactic acidosis leading to muscle cell swelling, local ischemia, muscle cell necrosis
and myoglobinuria with nephropathy has been proposed as a likely sequence of events in the pathogenesis of ER
[15-17]. The nephropathy is considered to result from a mechanical obstruction of tubules by precipitated
myoglobin [27]. Some Greyhounds have relapsing rhabdomyolysis without secondary renal involvement [18].
Clinical signs may occur during or within 24 - 48 hours of a race or trial and are characterized by extreme distress,
hyperpnea, and generalized muscle pain, especially over the back and hindquarters, which may appear swollen
and firm. Limbs may be rigidly tonic and affected dogs may have a "hunch-back" appearance and refuse to walk
[15,17]. Myoglobinuria and death within 48 hours are common in severe, acute cases. There may be increased
serum activities CK, aspartate aminotransferase (formerly SGOT), alanine aminotransferase (formerly SGPT),
and lactate dehydrogenase; all of which may remain elevated for more than a week following an attack [15,17]. In
one report on racing Greyhounds, presence of increased serum CK activities suggested possible subclinical
muscle injury [30]. In the Iditarod study, blood CK activity was used to identify dogs withdrawn with exertional
rhabdomyolysis (reference CK levels above which dogs were identified as having ER were > 10,000 IU/L,
although some dogs had values > 400,000 IU/L) [19]. Interestingly, sled dogs prone to ER seem to develop the
disorder early in the Iditarod race (e.g., within the first 500 miles) [19,20] and electrolyte disorders, such as
hyponatremia (perhaps related to the high renal solute load associated with large energy intake) have been noted
[19,20]. Hyponatremia (possibly from renal damage) and hyperkalemia have been reported in a Greyhound with
ER [17]. Pathological findings in muscle include multifocal hemorrhage and myonecrosis that may involve 50 -
70% of muscle fibers [21]. Older lesions (several days) may show mineralization of necrotic muscle fibers,
inflammatory infiltration by neutrophils, and sarcolemmal cell proliferation [14].
Prognosis depends on the severity of clinical signs. Dogs with hyperacute signs usually die within 48 hours from
renal failure. Mortality rate is low in less severe cases that are treated with intravenous fluids, bicarbonate,
anabolic steroids, antibiotics, body cooling, and rest [31]. Note that exertional rhabodomyolysis has certain
features in common with stress-related malignant hyperthermia.
Fibrotic Myopathy
This acquired, non-painful disorder associated with a fibrous band within a muscle has been reported sporadically
in dogs - most commonly in German Shepherds, usually male, with an age range from 8 months to 9 years [32-
38]. Other breeds include Doberman Pinscher, Rottweiler, Bobtail, St. Bernard, Boxer, and Old English Sheepdog.
Fibrotic myopathy has recently been called gracilis or semitendinosis myopathy [37]. The etiopathogenesis of this
condition is unclear. In humans, fibrotic myopathy may be congenital, although intramuscular injections have been
implicated in some patients [39-41]. Active dogs seem to be susceptible to this disorder [32], and recent studies in
dogs suggest that fibrotic myopathy may be related to muscle injury from excessive activity, including jumping and
sprinting that can lead to muscle strain [38], with a suggested sequence of inflammation, edema, localized
hemorrhage, and eventually fibrosis. Increased angulation (flexion) at the stifle in normal German Shepherds may
predispose these dogs to increased hamstring stress during physical activity [38]. While onset in some dogs is
acute (compatible with grade 2 or 3 muscle injury), the lameness appears to be insidious in most dogs
(compatible with chronic or grade 1 muscle strain) [38]. Apart from semitendinosis and gracilis muscles, fibrous
bands may occur in quadriceps muscles, biceps femoris, and semimembranosus in hind limbs [32,38], as well as
in supraspinatus and infraspinatus muscles in dogs [33,34]. A palpable band has also been found in the teres
minor muscle (see below) . Duration of signs may range from weeks or several years [38].
Fibrotic myopathy of the semitendinosus muscle is associated with a palpable thickened fibrous band that may
extend from the tuber ischii to the tibia within the belly of the semitendinosus muscle. Tight fibrous cords are also
palpable in affected gracilis muscles extending from the midline of the pelvis to the caudomedial aspect of the
stifle. In dogs with gracilis and/or semitendinosus muscle involvement, the hind-limb gait is characterized by a
shortened stride with a rapid, elastic medial rotation of the paw, external rotation of the hock, and internal rotation
of the stifle during the mid-to-late swing phase of the stride [35,37]. Kinematic analysis indicate that the range of
motion of the stifle is reduced [42]. The gait anomaly results from restricted abduction of the coxofemoral joint and
reduced extension of the stifle and hock. Note that the lameness is best appreciated at the trot. Bilateral
involvement (of the gracilis or semitendinosus muscle) is commonly encountered, with reports varying from 39%
to 61% of affected dogs [37,38], while both muscles may be involved ipsilaterally or contralaterally [35,36].
Histologically, the band consists of an abundance of dense collagenous connective tissue, with a distinct interface
between connective tissue and muscle bundles. Morphological studies in our laboratory or in others have not
identified primary muscle or peripheral nerve disease, although variable myofiber degeneration around the
periphery of the fibrotic band has been seen occasionally, sometimes associated with mild mononuclear cell
inflammation and focal hemorrhage [37].
The replacement of muscle fibers with dense collagenous connective tissue results in a mechanical lameness
resulting from failure to fully extend the limb. Neurological examination is usually normal; however, pressure
applied to the affected muscle, abduction of the coxofemoral joints of affected limbs, and extension of
stifle/talocrural joints in affected limbs may elicit pain [37]. Serum CK levels may be normal or moderately
elevated in some animals [35,43]. Absence of myoelectrical activity in the band during EMG evaluation is
consistent with total replacement of muscle fibers by dense connective tissue [35,43]; however, spontaneous
EMG activity in the vicinity of the band suggests recent muscle damage [38]. In occasional dogs, fibrillation
potentials and rare myotonic discharges have been recorded [35,36]. Imaging techniques have been used to
identify the intramuscular fibrous cords in people [44]. Soft-tissue swellings associated with the myotendinous
areas of affected muscles may be detected on radiographs, and two-dimensional ultrasonography in one dog
revealed increased size and reduced homogeneity of the gracilis muscle, with an enlarged tendon of insertion
compared to the normal muscle [37]. Prognosis is guarded to poor since the condition in dogs tends to recur
within several months following surgical resection of the fibrous band, or transection, partial excision, or complete
resection of the affected muscle [37]. Non-surgical treatment (e.g., corticosteroids, non-steroidal inflammatory
drugs, acupuncture) is usually ineffective. Non-surgical rehabilitation, including therapeutic ultrasound and cross-
fiber friction massage, resulted in mild improvement in several dogs (slight increase in range of motion of the stifle
and less crossing over of pelvic limbs) [38]. If fibrotic myopathy is causally related to muscle strain, appropriate
preventive measures might include stretching, warm up exercises, and gradual build up to more intensive
activities [38]. Inability to maintain the affected leg in extension during healing might contribute to recurrences [38].
The suggestion that oxygen-free radicals cause pericytic necrosis and fibroblastic proliferation in some forms of
human fibrotic disorders may offer therapeutic possibilities [45].
Post-traumatic fibrotic myopathy has also been reported in an 18 month old female Dalmatian together with
myositis ossificans [46]. Clinically, there was markedly reduced range of motion of hip extension and stifle flexion,
and a firm mass beneath the sartorius muscle in the region of the rectus femoris muscle. Surgical studies
revealed replacement of the rectus femoris muscle by a white fibrous band that was histologically characterized
by dense fibroblastic connective tissue. A firm calcified mass was found on the iliac shaft. Immediately upon
resection of the fibrous band, the coxofemoral and stifle joints were returned to a normal range of motion. No
recurrence of lameness was seen after 6 months.
More recently, teres minor myopathy causing sudden onset left forelimb lameness of 8 month’s duration was
reported in a 5 year old working Labrador Retriever [47]. Minimal circumduction was present in the left forelimb
and the left suprascapular muscles were atrophied. A painful palpable band-like structure was found in the region
of the teres minor muscle. Ultrasonography revealed an area of increased echogenicity within this band. EMG
studies were normal. Exploratory surgery identified the band to be the teres minor muscle, which was adhered to
the joint capsule and infraspinatus/deltoid muscles. Histological examination revealed focal areas of inflammation
with mononuclear cells, floccular degeneration of contractile elements, patchy regeneration, but surprisingly,
without significant fibrosis. Following excision of the teres minor muscle, there was complete resolution of the
lameness with no apparent adverse affects on joint function. The etiology of this condition was not determined
although trauma was suspected to be the initiating factor.
A comparable condition involving the semitendinosus muscle was reported in a mature castrated male Himalayan
cat [43] in which the lameness was characterized by marked flexion of the hip, stifle, and hock as the limb was
advanced. Since the limb could not be fully extended, the paw was placed abruptly, sometimes with knuckling. A
single injection of methylprednisolone acetate (10 mg, IM) had no discernible effect. Surgical exploration indicated
that the semitendinosus muscle was firm, white, and cord-like. Tenorrhaphy produced a favorable long-term
response (1 year after surgery, the cat's gait remained abnormal but had little effect on ambulation).
Glycogenosis
Several glycogen storage diseases may result in weakness and muscle changes, including type II, III, IV, and VII
glycogenoses (see glycogenosis).
Hepatozoon Myositis
This disease is caused by Hepatozoon canis, a protozoan organism that infects dogs [48-51], and rarely, cats [52].
It is transmitted primarily by the tick Rhipicephalus sanguineus. The disease has a world-wide distribution [53-56],
although the North American strain of H. canis, seems clinically distinct from those in other parts of the world in
which signs tend to be subclinical [57,58]. Indeed, the North American strain has recently been identified as
Hepatozoon americanum, a species of the apicomplexan protozoan parasite [59,532]. The definitive host for H.
americanum is believed to be the tick Amblyomma maculatum [60,61]. In the U.S., most cases are reported from
the Gulf Coast region of Texas and Louisiana, and Oklahoma, but recent reports extend the range to Georgia and
Alabama [62]. Infection occurs by ingestion of an infected tick [58]. Sporozoites are released in the intestine of the
dog, penetrate the intestine and spread via the blood or lymph to various tissues where they undergo schizogony.
Merozoites are released from schizonts. Merozoites that enter leukocytes become gametocytes. Infection of
blood-sucking ticks occurs by ingestion of infected leukocytes. Vertical transmission has been reported in puppies
[63].
Commonly reported clinical signs of H. americanum include fever (unresponsive to antibiotics), lethargy, weight
loss, anorexia, depression, muscular hyperesthesia (especially over paraspinal areas), paraparesis or paralysis,
bloody diarrhea, mild anemia and purulent ocular and nasal discharges. Glossitis, pharyngitis, and skin lesions
have also been reported. Hyperesthetic animals may be reluctant to move and often assume a sitting posture with
rigidity of the trunk and neck ("master's voice" posture) [58]. Temporal muscle atrophy may be present.
Concurrent infection or immunosuppression may facilitate infection and accelerate development of clinical signs.
Young dogs (< 6 months of age) appear most susceptible to infection. The clinical course may be prolonged with
spontaneous remissions and intermittent periods of fever and pain.
Laboratory findings include neutrophilic leukocytosis (ranging from 20,000 to more than 200,000 cells/ul),
occasional eosinophilia and basophilia, mild regenerative anemia, low serum glucose (probably an artifact
associated with the extreme neutrophilia [58]) and albumin levels, increased serum alkaline phosphatase and
increased inorganic phosphorus concentrations [62]. Analysis of CSF from affected dogs may reveal neutrophilic
pleocytosis (e.g., > 300 WBCs /ul) and increased protein levels (e.g., > 100 mg/dl) [64]. Radiography may
demonstrate pronounced periosteal bone proliferation and/or smooth laminar thickening of the periosteum
affecting any bone except the skull, although the diaphysis of the more proximal long bones of the limbs is
commonly involved [65]. EMG studies reveal abnormal spontaneous potentials.
Muscle biopsy is often useful in establishing a diagnosis [50,62,66] - changes include myositis and
pyogranulomas composed of macrophages, neutrophils, and occasionally eosinophils, sometimes adjacent to
large, thin-walled cysts (schizonts) approximately 250 - 500 um in diameter (pain, fever, and periosteal bone
proliferation may be a consequence of the polymyositis). The nuclei of the cysts are surrounded by host-derived
bluish, mucinous mucopolysaccharide material associated with fine lamellar membranes [66,67]. Some cysts
contain numerous small, round, basophilic bodies considered to be micromerozoites. Tissue stages of H.
americanum may be identified in tissue sections using immunohistochemical techniques [68]. Organisms can be
seen within neutrophils and monocytes in Romanovsky-stained peripheral blood smears [49,57,58]. At necropsy,
gross visible pyogranulomas may be seen in cardiac and skeletal muscles (including extraocular muscles),
smooth muscle, liver, skin, lymph nodes, lung, and kidney [57]. Glomerulonephritis, amyloidosis, and the
nephrotic syndrome are commonly found [57]. An indirect enzyme-linked immunosorbent assay (ELISA) has
recently been reported to be a reliable tool for diagnosing American canine hepatozoonosis [69].
Until recently, no antiprotozoal agents consistently caused long-term remission of signs, and most infected dogs
could be expected to die within 2 years of clinical diagnosis [58]. Temporary remission of signs for several months
had been achieved by administering trimethoprim sulfadiazine (15 mg/kg PO bid), clindamycin (10 mg/kg PO tid),
and pyrimethamine (0.25 mg/kg PO sid) (TCP) for 2 weeks [62]. Aspirin given at 5 mg/kg PO bid for several days
was helpful in reducing the fever. Temporary remissions had also been achieved using toltrazuril at 5 mg/kg PO
bid for 5 days [62], a drug no longer available for clinical use in the United States. The initial favorable response to
TCP is typically followed by periodic relapses that subsequently result in chronic debilitation leading to renal
failure, death, or euthanasia. Corticosteroids frequently exacerbate clinical signs or induce a recurrence of signs.
However, in a recent study, treatment of affected dogs with TCP for 2 weeks followed by long-term administration
of decoquinate, a quinoline anticoccidial agent at 10 to 20 mg/kg, every 12 hours mixed in food (the drug is
available from feed stores in 50-lb bags, and the dosage is 0.5 to 1.0 teaspoon/10 kg, mixed in food, twice daily)
has increased survival time (> 33 months) without any deleterious side-effects [70]. Continuous treatment with
decoquinate for 2 years is being recommended. Note that decoquinate is ineffective in dogs with advanced
disease/glomerulonephropathy at the time treatment is begun. Control of ticks by routine dipping of dogs from
infected areas will help to limit spread of the disease and reinfestation of susceptible hosts [51]. Hepatozoonosis
does not appear to be an important public health concern.
Hyperadrenocortical (Cushing's) Myopathy

An acquired degenerative myopathy has been reported in dogs in association with hyperadrenocorticism
(Cushing's disease) [71-75]. Several forms of hyperadrenocorticism (HAC) exist and are listed below, all of which
are characterized by chronic high serum cortisol (glucocorticoid) concentrations [76]:
1. Pituitary-dependent HAC (PDH) - Often accompanied by tumors of the adenohypophysis that produce
ACTH or a similar acting hormone. Eighty percent or more of cases of pituitary Cushing's disease are
reportedly associated with a pituitary tumor. These tumors may stem from the pars distalis (80%) or the
pars intermedia (20%), since both regions contain cells that are capable of producing
adrenocorticotropic hormone (ACTH). This form of HAC is most frequently associated with bilateral
adrenocortical hyperplasia. If the hypothalamus is disrupted by the tumor, signs of a hypothalamic
syndrome may accompany signs of HAC (see pituitary tumor). Approximately 75% of dogs with PDH
weigh < 20 kg and Poodles, Beagles, German Shepherds, Dachshunds, and Terrier breeds appear
overrepresented [76,77].
2. Adrenal-dependent HAC (ADH) - Usually associated with primary adrenocortical neoplasia (adenoma or
carcinoma) with contralateral adrenocortical atrophy, and which occurs in approximately 10 to 20% of
dogs with HAC [77]. Occasionally, tumors may involve both adrenal glands. Poodles, German
Shepherds, Dachshunds, Terrier breeds, and Labrador Retrievers appear overrepresented in dogs with
adrenal tumors and approximately 50% of dogs weigh > 20 kg [76,77].
3. Iatrogenic HAC - Associated with excessive/prolonged corticosteroid administration, especially fluorinated
agents such as triamcinalone, betamethasone, and dexamethasone [78]. It is usually associated with
bilateral adrenocortical atrophy. Interestingly, a presumed glucocorticoid-induced myopathy was
reported in a dog receiving ophthalmic corticosteroid therapy that was associated with adrenal
suppression [79].
Clinical signs of HAC include panting, polydypsia, polyuria (due to a reversible form of central diabetes insipidus),
bilaterally symmetrical alopecia, pendulous abdomen, hyperpigmentation, comedones, and hepatomegaly [76].
Myopathic signs may include gradual development of a stiff, stilted gait, weakness, stumbling, and generalized
muscle atrophy that is often marked in epaxial, temporal, and masseter muscles [71-75]. Proximal limb muscles
may appear enlarged and bulging in some dogs [72]. Pelvic limb rigidity, especially in middle-aged and older dogs,
especially Poodles, is not unusual. Some hyperadrenocorticoid dogs have a form of myotonia with signs of
muscle dimpling and myotonic-like discharges seen on EMG (see below), generalized increase in muscle tone,
rigid epaxial muscles, arching of the back, ears drawn back, and tongue protrusion [71,72,75]. Feldman states
that myotonic-like stiffness occurred in only 5 of 800 dogs with Cushing’s syndrome in his practice [80]. Tendon
reflexes are usually normal. Gastrocnemius muscle rupture, believed to be associated with the underlying
myopathy, was reported in a 6 year old spayed female Shetland Sheepdogdog with iatrogenic HAC [81]. Note that
one potential complication of HAC is thromboembolism, possibly related to coagulation protein loss in urine [76],
and signs of pelvic limb weakness, pain and collapse as a result of occlusion of the distal aorta and/or the iliac
arteries [82]. Electromyographic studies of proximal and distal limb muscles and paraspinal muscles may reveal
evidence of bizarre high frequency discharges, often producing a "dive-bomber" sound. The discharges may wax
and wane in amplitude and frequency suggesting they represent myotonic potentials [75], although in most dogs
with hyperadrenocorticoid myopathy, the discharges do not wax and wane and are termed pseudomyotonic
potentials (See Electrodiagnostics). It has been suggested that pseudomyotonia in French Poodles is not a simple
consequence of HAC but a separate, possibly genetic, disease [524]. In one recent study of 30 dogs with HAC,
complex-repetitive discharges were recorded that were more prominent in proximal appendicular muscles while
fibrillation potentials and positive sharp waves were found in 60% of affected dogs and localized in the distal limb
muscles [525]. Myotonic discharges were not found in this study. Nerve conduction studies may be normal or
slowed (see hyperadrenocortical neuropathy).
Diagnosis of hyperadrenocortical myopathy is based on laboratory data, signalment (mature, female Poodles may
be predisposed to the myopathy), clinical and electrodiagnostic findings, and muscle biopsy. Laboratory findings
include "stress" blood count (lymphopenia, eosinopenia, neutrophili, and monocytosis), increased serum alkaline
phosphatase (in dogs), hyperglycemia (usually lower than renal threshold in dogs), hypercholesterolemia and
lipemia from the glucocorticoid-induced lipolysis, and reversible (usually) hypertension in dogs [76,83]. Serum CK
activity may be elevated [72,75]. Histological findings include mild degenerative changes associated with fiber
size variation, presence of subsarcolemmal masses, focal necrosis and fiber splitting, target fibres or fibres with
"central areas", and fiber atrophy, especially of type 2 fibers [71,73]. Fiber grouping may be present, and in some
dogs, we have seen demyelination/remyelination in peripheral nerves (see hyperadrenocortical neuropathy).
Ultrastructural changes in muscle include splitting and disorientation of myofibrils, disruption of mitochondrial
cristae, subsarcolemal and intermyofibrillar aggregates of mitochondria, presence of large bizarre-shaped
mitochondria, increased numbers of intermyofibrillar vacuoles, small increase in sarcoplasmic glycogen
deposition, and variable dilatation of the sarcotubular system [73,84].
The pathophysiologic basis for hyperadrenocortical myopathy is unknown, although the changes probably result
from excessive circulating glucocorticoids and muscle protein catabolism, since identical muscle changes are
observed in dogs and cats receiving corticosteroids [72,73,84,85]. Muscle weakness and atrophy are believed to
be mediated by the glucocorticoid induction of the enzyme glutamine synthetase [86,87], and the increased
glutamine synthetase activity may be reduced by growth hormone or insulin-like growth factor [87]. It was
proposed that selective muscle atrophy (i.e. type 2 fibers) may result from differences in myofiber glucocorticoid
sensitivity [88], although density of glucocorticoid receptors appears to be comparable in different muscle fiber
types [89]. In people with Cushing’s disease, ACTH excess may also be directly myopathic [90]. Specific findings
for the different forms of HAC are as follows [77,91].
1. Pituitary-dependent HAC (PDH) - Normal or high baseline plasma cortisol and ACTH levels; exaggerated
cortisol response to ACTH stimulation; and suppression of plasma cortisol with high-dose (but not low-
dose) dexamethasone. Approximately 20 - 30% of dogs with this form of HAC are resistant to
dexamethasone suppression.
2. Adrenal-dependent HAC (ADH) - Normal or high baseline plasma cortisol; normal or exaggerated cortisol
response to ACTH stimulation; failure to suppress plasma cortisol with any dose of dexamethasone;
and undetectable plasma ACTH concentration.
3. Iatrogenic HAC - Normal or low baseline plasma cortisol; little or no cortisol response to exogenous
ACTH; and undetectable plasma ACTH concentration [76,92].
In one review, the most sensitive tests in distinguishing dogs with pituitary-dependent HAC from dogs with
adrenocortical tumors were the plasma endogenous ACTH concentrations, abdominal radiography, and
abdominal ultrasonography, although none of the tests alone were completely reliable [77]. Recently, however, a
single determination of endogenous plasma ACTH levels and adrenal ultrasonography were considered to be
discriminatory in a prospective study to differentiate between PDH and ADH and more accurate than
dexamethasone suppression testing [93]. Ultrasonography appears to be a reliable test for functional
adrenocortical tumors [94]. The number of PDH dogs with macroadenomas is probably higher than the literature
suggests [95]; however, on the basis of endocrine test results, dogs with PDH and large pituitary tumors cannot
be adequately distinguished from dogs with PDH and microscopic pituitary tumors prior to onset of clinical signs
[95]. Nevertheless, it has been suggested that inadequate serum cortisol suppression during high-dose
dexamethasone suppression testing in dogs with PDH, may be a prognostic indicator for subsequent
development of an invasive pituitary tumor [96]. It should be noted that pituitary and adrenal tumors can coexist in
dogs with HAC, leading to a confusion of test results and complicating diagnosis and treatment [97]. Note also
that diabetes mellitus can be a complication of HAC, especially in cats, and that dogs with a reduced beta cell
mass prior to development of HAC are more likely to develop concurrent diabetes or to develop diabetes with
glucocorticoid administration (Dr. Richard Nelson, University of California-Davis, personal communications, 2002).
Myopathic signs may abate following surgical or medical management of the hyperadrenocorticism [76,98-101].
Several treatments used in the medical management of PDH and ADH in dogs include mitotane (a potent
adrenocorticolytic drug that causes necrosis of the zona fasciculata and reticularis, and thus effects "medical
adrenalectomy"), and ketoconazole (a drug that inhibits steroid biosynthesis and suppresses cortisol secretion
with minimal effects on mineralocorticoid production) [101]. L- deprenyl (Anipryl) thought to control Cushing’s by
downregulating ACTH via enhanced brain dopamine levels [76], is not recommended as the sole treatment for
canine PDH [102]. Other clinicians do not recommend it at all [76]. Another potentially useful drug for treating
dogs with PDH or ADH is trilostane, which interferes with adrenal steroid biosynthesis [103].
Note that withdrawing or reducing the dose of the glucocorticoid is the primary method of treating steroid
myopathy, or using non-fluorinated steroids since steroid myopathy is most often associated with fluorinated
steroids (e.g., triamcinalone, betamethasone, and dexamethasone) [104,105].
Prognosis is guarded in dogs with HAC if contractures and severe muscle atrophy are present in pelvic limbs.
Myotonic signs may progress despite effective mitotane therapy, in which case procainamide administration (e.g.,
at 12.5 mg/kg PO bid) may reduce the myotonic stiffness [75]. Exercise programs and physical therapy may
assist recovery and probably should be encouraged in any animals receiving glucocorticoids.
Hyperkalemic Myopathy
Increased serum potassium values may occur in association with adrenocortical insufficiency, diabetes mellitus,
acute renal failure, or severe acidosis (see feline muscular dystrophy). In conjunction with the characteristic signs
of these diseases, animals may manifest episodic weakness, loss of strength and tendon reflexes due to
increased intracellular positivity (with hyperkalemia, the chemical gradient for potassium efflux is decreased) to
the point that resting membrane potential falls below the threshold potential with subsequent minimal
depolarization and less excitable membranes [106,107]. Muscle weakness with hyperkalemia typically occurs with
serum potassium levels > 8 mEq/l [535]. Diagnostic aids include serum potassium and sodium, plasma cortisol,
ACTH response testing, blood glucose, blood urea nitrogen, urinalysis, creatinine, and blood pH values.
Hyperkalemic periodic paralysis (HPP) is a rare disorder in dogs that is characterized by episodic weakness, limp
neck, protruding tongue, collapse and paralysis and may be precipitated by exercise and/or excitement [108].
Attacks lasted10 to 15 seconds after which the animal appeared drowsy but quickly resume normal behavior.
Attacks were also precipitated by oral potassium administration. No changes in serum glucose or lactate levels
were found. In humans, the pathogenesis of this disorder is associated with a sodium channelopathy, an inherited
disorder resulting in reduced inactivation of the sodium channel, leading to increased muscle cell permeability to
sodium and muscle membrane hypoexcitability, and episodic weakness [109,110]. The sodium current, through
noninactivating channels, may cause the skeletal muscle weakness in HPP by depolarizing the cell, thereby
inactivating normal sodium channels, which are then unable to generate an action potential. In addition, myotonic
potentials may occur as a result of a small depolarization and repetitive excitation (see also, myotonic myopathy)
[110]. Thus, the hyperkalemia appears to be the consequence rather than the cause of the periodic paralysis [9].
A very similar condition occurs in horses as an autosomal codominant genetic disease [111]. Attacks are usually
associated with increased plasma potassium levels. Focal necrosis and variable vacuolar changes may be seen
in skeletal muscle fibers. EMG abnormalities may be detected, including prolonged insertional activity, complex
repetitive discharges, spontaneous activity and myotonic discharges [112]. Treatment with acetazolamide, 2
mg/kg, bid, PO, was beneficial in treating the 7 month old Pit Bull with HPP [108]. Acetazolamide is a thiazide
derivative and carbonic anhydrase inhibitor that promotes renal loss of sodium and potassium. In humans with
HPP, thiazide diuretics are effective [9].
Hypernatremic Myopathy
Episodic weakness and signs of depression were reported in a 7 month old Domestic Shorthaired cat with
episodic hypernatremia (serum Na concentration ranging from 182 to 215 mEq/L; normal is 148 to 161 mEq/L)
secondary to hypodipsia (failure to drink water) [113]. This rare condition was accompanied by hyperosmolality
(ranging from 381 to 431 mOsm/L) and evidence of hypopituitarism (adrenocorticotrophic and growth hormone
deficiencies, along with blunted thyroxine response to thyroid-stimulating hormone). The most prominent clinical
sign was ventroflexion of the neck. No other neurological abnormalities were detected. Electromyographic testing
revealed prolonged insertional activity, fibrillation potentials, positive sharp waves, and bizarre high-frequency
discharges. Nerve conduction velocities were normal. These abnormalities were more severe during episodes of
hypernatremia. Serum creatine kinase activity was increased, while CSF analysis was normal. Examination of
several muscle biopsies were normal. Contrast-enhanced computed tomographic studies of the brain
demonstrated marked hydrocephalus, although no hypothalamic or pituitary lesions were detected. The episodic
weakness might have been associated with muscle membrane alterations associated with displacement of
intracellular potassium by high levels of extracellular sodium. Interestingly, the clinical signs, serum CK levels,
electrodiagnostic data, and muscle biopsy findings were very similar to those seen in cats with hypokalemic
myopathy. Forced water intake and dietary sodium restriction (using a low-salt feline diet) corrected the
hypernatremia and signs of muscle dysfunction. After restoration of eunatraemia, secretion of pituitary hormones
became normal. It was suggested that hypothalamic dysfunction, possibly related to hydrocephalus, induced both
hypodipsia and transient hypopituitarism [113].
Hypokalemic Myopathy
Hypokalemic myopathy is a metabolic disorder of older cats that has been linked with chronic renal disease and
excessive urinary potassium loss [114-116], although a similar, if not identical disease, was reported in 1984 [117].
Synonyms are feline kaliopenic polymyopathy-nephropathy syndrome, and sporadic feline hypokalemic
polymyopathy. Low dietary potassium intake secondary to inadequate potassium levels in certain commercial
rations has been associated with episodic hypokalemic myopathy [114,118]. Additionally, potassium urinary loss
may be exacerbated by some diets that are acidified to reduce development of crystalluria and urolithiasis. It has
been suggested that increased potassium loss induced by renal dysfunction may represent a phenomenon
peculiar to cats [115]. Furthermore, chronic potassium depletion (e.g., from deficient rations) may lead to
progressive renal disease (associated with renal ischemia, increased renal ammoniagenesis, activation of the
alternate complement pathway, and tubulointerstitial injury) as well as sudden changes in muscle membrane
sodium permeability [114]. Decreased extracellular potassium levels will produce an increase in resting
membrane potential, resulting in a greater difference between resting and threshold potential necessary for
muscle contraction [119]. This lessened state of electrical excitability underlies the muscle weakness [107].
Additionally, hypokalemia may negatively affect insulin release and end-organ sensitivity to insulin [106]. Other
causes of hypokalemia include gastrointestinal loss of potassium, post-obstructive diuresis following relief of
urethral obstruction in cats, administration of loop or thiazide diuretics, and rarely, mineralocorticoid excess [535].
Clinical signs are characterized by acute onset of a stiff-stilted gait, reluctance to walk, exercise intolerance,
ventroflexion of the neck (especially in cats), and muscle pain. Spinal reflexes may be depressed. Serum CK
levels are moderately to markedly elevated, while serum potassium values are low (e.g., < 4.0 mEq/L). Serum
creatinine levels may be markedly increased. In the hypokalemic cats fed a high protein vegetarian diet, plasma
taurine concentrations decreased and glutamic acid increased markedly [118]. Mild, diffuse electromyographic
changes (e.g., presence of positive sharp waves) have been recorded in various skeletal muscles. Light
microscopic evaluation of muscle samples is usually normal, although myofiber vacuolation and mild myonecrosis
may occasionally be observed. Ultrastructural changes in people indicate that the vacuoles are membrane-bound
and reveal the frequent presence of tubular aggregates that selectively involve type 2 fibers [120].
Rhabdomyolysis in severe hypokalemia might be related to osmotic expansion of cells due to increased
intracellular sodium and chloride levels or reflect ischemic myonecrosis due to decreased muscle blood flow
associated with impaired potassium metabolism during muscle contraction/exercise [106,114].
Prognosis is guarded to favorable and may depend upon the severity of the underlying renal disease, if present.
Most cats reportedly show significant improvement in muscle strength within 2 to 3 days of initiation of treatment.
tm
Oral potassium supplementation (e.g., potassium gluconate - Tumil-K , Daniels Pharmaceuticals), at 5 to 10
mEq/ cat /day, divided bid, is recommended for severely hypokalemic cats. For less severely affected animals, 2
to 4 mEq/day is usually adequate. Permanent daily supplementation with regular re-evaluation of serum
potassium, serum creatinine, and urinary potassium loss is recommended, since cats that are not supplemented
have a tendency to become hypokalemic again.
Severe hypokalemia and generalized flaccid paralysis has been reported in a 6 year old female Miniature Poodle
after furosemide administration for suspected congestive heart failure [121]. In this case, hypokalemia presumably
resulted from an increased flow rate in the distal tubules and increased secretion of aldosterone secondary to
volume depletion caused by the thiazide diuretic. Muscle biopsies showed severe myonecrosis, phagocytosis,
fiber splitting, internalized nuclei, and atrophy/hypertrophy. Peripheral nerve biopsy was normal. After treatment of
the hypokalemia (intravenous fluids and potassium supplementation), the dog was clinically normal within 16 days
of complete paralysis, while muscle biopsies were normal within 30 days.
Note that hypokalemia may also result from various metabolic and endocrine disorders [122]. In one report,
hypokalemic myopathy occurred in 9 cats as a result of severe diabetic ketoacidosis and its therapy (e.g.,
hypokalemic may result from the attendant osmotic diuresis, correction of the acidosis, or insulin-mediated cell
uptake) [123]. In this study, normokalemia and the myopathy resolved within a few days of potassium
supplementation. Acute onset of muscular weakness and ventroflexion of the neck have been reported in several
hyperthyroid cats in association with hypokalemia, the cause of which was not determined [13,119,124]. Cats
responded quickly to potassium supplementation or following resolution of the hyperthyroidism. In humans,
nonfamilial hypokalemic thyrotoxic periodic paralysis is commonly seen among Asians [125,126]. It has been
reported that sudden paralysis occurring while at rest after a large carbohydrate meal or strenuous exercise is a
common presentation and that intracellular shifts of potassium triggered or facilitated by hyperthyroidism and
hyperinsulinemia are the biochemical features [126,127]. Correction of the hyperthyroidism is the definitive
treatment in people. A periodic myopathy characterized by muscle stiffness, weakness, and pain secondary to
persistent hypokalemia and metabolic alkalosis has been reported in a German Shepherd with an hepatic
neuroendocrine carcinoma, thought to be a primary hepatic carcinoid [128]. Ectopic adrenocorticotrophin
hormone secretion was suspected as the cause of hypercortisolism and hypokalemia (possibly associated with
cortisol inactivation overload). Note that in most dogs with hyperadrenocorticism, hypokalemia is either not seen
or is mild and clinically insignificant [76]. Hypokalemia secondary to an aldosterone producing tumor of the
adrenal gland (Conn’s syndrome) has been observed in cats [13]. Aldosterone normally regulates electrolyte/fluid
balance by facilitating sodium retention and potassium excretion. Clinical signs included intermittent muscle
weakness and collapse that became progressively more severe. Blood biochemical studies revealed elevated
aldosterone levels and high serum creatine kinase levels. Temporary improvement resulted from administration of
spironolactone at 10 - 100 mg PO daily.
A second type of hypokalemic myopathy has been reported in young Burmese kittens, 2 to 6 months of age [129-
131], although the disorder has also been reported in a 2 year old Burmese cat [132]. This condition is considered
to be a homozygote recessive hereditary disease and is characterized by periodic muscle weakness and
ventroflexion of the neck associated with intermittent hypokalemia (e.g., < 3.0 mE/L) and increased serum
creatine kinase values, sometimes reaching very high values, e.g., > 50,000 - 90,000 IU/L [129,131]. The
condition has also been termed periodic hypokalemic myopathy [132]. Attacks occur suddenly and are transient
and may be precipitated by stress or vigorous exercise. The variable clinical course is characterized by
improvement followed by relapse, and there may be weeks between episodes. A head tremor is seen in some
cats. Cats are reluctant to walk and tire easily, have a stiff, stilted gait with thoracic limb hypermetria, and a wide-
based stance in the hind limbs. Carpal knuckling can be a distinctive clinical feature and some cats sink on their
hocks [129]. There are only minor electromyographic and histopathologic changes seen in muscle. Neither
decreased potassium intake nor increased renal potassium loss have been found in affected Burmese cats.
Continued dietary supplementation of oral potassium usually produces a favorable response (e.g., potassium
gluconate solution at 2 to 4 mEq or mmol/cat PO daily, until serum potassium levels are stable) [133]. Some
kittens improve without treatment. The periodic hypokalemic attacks in these cats are similar to those seen in
humans with hypokalemic periodic paralysis, an inherited calcium channelopathy disorder associated with
abnormal muscle membrane excitability and influx of potassium into the muscle fiber that causes muscle fiber
depolarization and inexcitability [9]. Patients have an increased sensitivity to insulin moving potassium into cells.
Hypothyroid Myopathy
Myopathies have been reported infrequently in mature dogs with primary hypothyroidism [134]. Clinical signs of
bilaterally symmetrical flank alopecia and obesity are often associated with the hypothyroidism. Presence of
lethargy, weakness, and reduced exercise tolerance in some dogs with chronic hypothyroidism may reflect the
underlying myopathy [135]. A polymyopathy has been seen in several dogs with megaesophagus and myasthenia
gravis [136]. We have seen myotonic-like discharges in muscles of some hypothyroid dogs on EMG studies [137].
In people, skeletal muscle changes may precede clinical and laboratory evidence of hypothyroidism [138]. The
etiopathogenesis of this endocrine myopathy is unknown. A disturbance in carbohydrate metabolism has been
proposed to explain the preferential type 2 fiber atrophy which occurs in human and canine muscle [139]. In
hypothyroid people, phosphorus magnetic resonance spectroscopy studies suggested a defect of the high energy
phosphate metabolism (lower phosphocreatine recovery rate) reflecting probable mitochondrial metabolism
impairment [140]. Muscle glycogenolysis is impaired that may result in fasting hypoglycemia in human patients,
and there is net protein catabolism [105]. Atrophic type II fibers are oval or angular in outline and are distributed
throughout all muscle fascicles. A deficiency of type II fibers has also been noted in some dogs. Variable fiber
hypertrophy may be present and nemaline rod inclusions may be observed in some muscle fibers, especially in
type I fibers. No cellular response or myodegeneration is seen and intramuscular and peripheral nerves are
normal. In people, internal nuclei may be increased, along with glycogen and mitochondrial aggregates, dilated
sarcoplasmic reticulum, proliferating T-system profiles, and focal myofibrillar loss [120]. More recently, muscle
fiber cores have been found in needle biopsies in people [141]. Reversal of the myopathy may follow thyroid
hormone replacement, although animals with severe neuromuscular signs may have slow or incomplete
resolution of signs [142]. The few cases I have seen appear to have been primary myopathies, with no qualitative
or quantitative (morphometric) evidence of peripheral nerve changes [134]. This is interesting given the fact that
hypothyroid neuropathies comprise a significant proportion of cases seen in my peripheral nerve laboratory (see
hypothyroid neuropathy). Some reports of dogs with hypothyroidism and unilateral forelimb lameness along with
widespread electrodiagnostic changes in muscles (positive sharp waves, fibrillation potentials) that are not
reflected clinically, may be examples of hypothyroid myopathy [143].
Hypotrophic Myopathy
A subclinical myopathy has been reported in pectineus muscles of German Shepherd dogs that is characterized
by a retardation in muscle fiber growth particularly of type 2 fibers [144]. It has been suggested that hypotrophy of
the pectineus muscle may potentially influence the development of the coxofemoral joint; however, the
relationship between pectineal myopathy and subsequent development of hip dysplasia has not been
substantiated. Indeed, hip dysplasia can still develop in dogs in which the pectineus muscle has been exercised.
Immobilization Myopathy
A syndrome characterized by pelvic limb hyperextension, generalized muscle atrophy in the affected limb,
abducted gait, and a limited range of stifle joint range of motion has been reported in five dogs, four of which were
immature [145]. Distal femoral fractures, of traumatic origin, were found in all dogs; four dogs were subjected to
limb immobilization in extension for three to seven weeks. Lesions in muscle biopsies included fiber size
variability associated with multifocal/diffuse presence of small atrophic fibers, increased prominence of
subsarcolemmal nuclei, increased perimysial fibrosis and focal necrosis. These changes were most severe in the
vastus lateralis, with less severe changes seen in the biceps femoris and gastrocnemius muscles. Histochemical
and morphometric studies demonstrated a significant type 1 fiber atrophy and loss in the vastus lateralis muscles
in the limbs with femoral fractures treated by hyperextension. The shortest time period between onset of fracture
and the presence of type I fiber atrophy was seven weeks (there was no correlation between the extent of type 1
fiber atrophy and duration of limb immobilization). The pathogenesis of this condition, termed "stiff-stifle
syndrome", is not well understood, although immobilization of muscle induces muscle atrophy and this change is
especially influenced by the degree of stretch in which the muscle is held. In animals with limb immobilization in
extension, the quadriceps muscle group, held in a shortened state, undergoes selective and progressive atrophy.
Additionally, joint stiffness may be exacerbated by fibrous adhesions in and around the stifle joint while it is
maintained in an extended position. A similar condition occurs in people [146-148]. Experimental studies indicate
an increase in numbers of glucocorticoid receptors in immobilized muscles [88]. Prognosis is guarded, as all dogs
in our study failed to show clinical improvement after removal of the immobilization device. Breakdown and
removal of adhesions by surgical management may result in a return of function of the femorotibial joint. In
experimental studies in dogs, a reversible type I fiber atrophy occurred in most restricted muscles and early type II
fiber atrophy was seen in a few muscles after trauma and splinting [149]. Multifocal fiber necrosis was the only
irreversible change seen after 3 weeks of splinting with or without concurrent muscle trauma. Relative fiber
percentages did not change appreciably during splinting or recovery. In this study, the limited joint motion
appeared to be related to shortening of the extensor mechanism of the femorotibial joint. Clinical signs similar to
the stiff-stifle syndrome are seen in dogs with congenital limb contractures [150]. Interestingly, we did not observe
muscle lesions in a dog with a proximal tibial fracture followed by a 3 week period of immobilization.
Ischemic Neuromyopathy
This is a disorder that occurs not infrequently in cats caused by thromboemboli usually associated with
cardiomyopathy [151]. While hypertrophic cardiomyopathy has now become the most important cardiac disorder
in cats following the discovery of the role of taurine deficiency in dilated cardiomyopathy [152-155], in one review
aortic thromboembolism reportedly occurred in approximately 50% of cats with hypertrophic cardiomyopathy, 25%
of cats with dilated cardiomyopathy, and 25% of cats with restrictive cardiomyopathy [151]. It has also been seen
in a small percentage of cats with cardiomyopathy associated with excessive moderator bands [156]. In one
report on 100 cats with distal aortic thromboembolism [157], the average age was 7.7 years, with the neutered
male being overrepresented. Evidence of preexisting cardiac disease was found in 11% of the cases, with
murmur or arrhythmia noted in > 50 % of the cases on presentation, and the most frequent underlying disease
was hypertrophic feline cardiomyopathy. Cardiovascular disease (cardiomyopathy and thromboembolism)
associated with taurine depletion was an unexpected finding in 3 of 6 healthy adult cats during a potassium -
depletion study [158].
The cause of the disease and emboli formation in the heart are uncertain, although recent studies suggest a
possible role for vitamin B12 and arginine in cardiomyopathy and arterial thromboembolism [159]. Predisposing
factors to thrombus formation may include exposed vascular subendothelial tissue, abnormal circulation patterns
and heightened platelet activity, and increased blood coagulability [151]. The origin of the embolus is a thrombus,
an aggregate of fibrin and platelets attached to an endocardial surface, usually within the left atrium. An embolus
breaks loose from the cardiac thrombus and occludes one or more branches of the aorta. The emboli may be
carried to any site within the arterial circulation. The most common site of occlusion is the aortic trifurcation.
Embolic occlusion at this site obstructs internal and external iliac arteries and the median sacral artery. Emboli
which extend into the iliac arteries have been termed "saddle thrombi". A less common embolic site is the brachial
artery [160]. Vasoactive substances released from embolic platelet products, such as serotonin, thromboxane A2,
prostaglandins and 5-hydroxytryptamine may impair collateral circulation [161]. Cats of the Persian breed may be
at risk for ischemic neuromyopathy [162], although this has been disputed[163].
Clinical signs are acute in onset and usually include pelvic limb pain during the first 24 hours, plantigrade stance,
and paraparesis or paralysis. Signs may be unilateral or bilateral. Femoral pulse may be weak or absent, the
cranial tibial and gastrocnemius muscles are firm and often painful, and the limb(s) are cool. Distal limb muscles
below the stifle are particularly affected. Flexion and extension of both hip and stifle joints and the patellar reflex
are usually present, although initially, limb(s) may be held rigidly extended because of ischemic muscle
contracture [151]. Pain sensation to noxious stimuli is typically absent in the distal limbs. The nail bed of pelvic
limbs is cyanotic. Left forelimb paralysis is seen with brachial artery embolization.
Electrodiagnostic studies reveal an absence of or markedly reduced evoked potentials from interosseous and
cranial tibial muscles. Nerve conduction velocities are frequently reduced. Chest radiography may indicate
cardiopulmonary disease (pulmonary edema, biventricular failure), and electrocardiographic/echocardiographic
abnormalities are common (e.g., increased septal and/or left ventricular free wall thickness) [157,163]. Diagnosis
of occlusive vascular disease can be confirmed from an aortogram. Pathologically, changes occur in skeletal
muscle and peripheral nerve [164]. Lesions in peripheral nerves begin in the mid-thigh region, with the central
fibers in a fascicle being more susceptible than peripheral fibers. The majority of fibers show changes of axonal
degeneration, while others have evidence of paranodal/segmental demyelination. In skeletal muscle, ischemic
myopathy characterized by focal necrosis, myophagia, internalized nuclei, and occasional mononuclear cell
infiltrates, contributes to the clinical signs.
Improvement in nerve conduction velocities and evoked potentials correlates well with return of limb function.
Femoral pulses frequently return within 1 to 2 weeks. At present there are no results that show that any treatment
of the aortic thromboembolism produces a significantly better recovery than no therapy. Surgical embolectomy
does not appear to be warranted; besides, cats with unstabilized cardiomyopathy are definite surgical risks. Use
of thrombolytic agents to dissolve the emboli awaits clinical trials. For animals that are in pain, movement should
be restricted. Morphine sulfate, at 0.1 mg/kg, subcutaneously, will produce analgesia (without excitement) for 4
hours [151]. This can be repeated every 4 to 6 hours for 2 days. In an attempt to prevent future episodes, affected
cats should receive aspirin, at 25 mg/kg PO, every third day, for life. Aspirin inhibits platelet aggregation and
preserves collateral circulation. While aspirin might prevent recurrences, it will have little effect on the underlying
cardiomyopathy. It has been reported that there is no difference in survival time or rate of recurrence with warfarin
vs. aspirin, and that low-dose aspirin (5 mg PO q3d) is an inexpensive option for thromboprophylaxis that seems
to be as effective as high-dose aspirin (40 - 162 mg PO q 2 - 4 d) and warfarin [517]. Supportive care for initial
cardiac decompensation includes administration of oxygen, diuretics, fluid therapy, glucocorticoids, and external
heat [151].
Although the collateral circulation does return in the majority of cases with return of function to varying degrees
(some cats with extensive limb necrosis do not recover; others retain dropped hocks) within 6 weeks to 6 months
(an increase in nerve conduction studies and evoked potentials may correlate with return of limb function [164]),
the long-term prognosis is guarded to poor because of the potential of further thromboembolism. Other potential
complications are associated with reperfusion of ischemic tissues and include release of toxic factors such as
lactic acid, potassium, and myocardial depressant factor [151]. Thus, the severity of the cardiac disease usually
determines prognosis. Limb complications may include necrosis requiring amputation or wound management, and
limb contracture [517]. In one retrospective study of idiopathic feline hypertrophic cardiomyopathy, analysis of
survival revealed that all cats with thromboembolism were dead 6 months after diagnosis [163]. In another study
involving cats with distal aortic thromboembolism, the average, long-term survival in the 37% of cases that
survived the initial thromboembolic episode was approximately 12 months, while the remaining cases either died
(28%) or were euthanized (35%) [157]. Long-term survival time is reportedly significantly shorter in cats with
congestive heart failure during the initial episode [517]. Hypothermia has been associated with poor outcome
[517].
Ischemic neuromyopathy secondary to aortic foreign body obstruction have occasionally been reported in cats
[165,166]. In one case, in addition to muscle and nerve damage similar to that described above in
thromboembolic disease, spinal cord infarction was present in lumbosacral spinal cord gray matter resulting in
clinical signs of a lumbosacral syndrome (absent anal tone, bladder incontinence, megacolon, pelvic limb paresis,
and flaccid analgesic tail) [165]. Removal of the foreign body by aortotomy was successful in another cat that
recovered almost completely within one year after the surgery (external coaptation splints facilitated return of
function of the pelvic limbs)[166]. Post-surgical therapy included heparin (100 U/kg IV q4h for 3 days), aspirin (25
mg/kg PO every 3 days for a total of 4 treatments), cefazolin (20 mg/kg IV q6h for 4 days), and
methylprednisolone sodium succinate (20 mg/kg IV immediately after surgery and again 6 hours later).
Thromboembolic disease is not common in dogs but may be seen associated with hypercoagulable states,
bacterial endocarditis, dirofilariasis, hyperadrenocorticism, neoplasia, cardiac disease (although
thromboembolism secondary to cardiomyopathy has not been reported in dogs) [82,151,167-169]. Yet curiously,
aortic thromboembolism in dogs has been reported infrequently [82,170-172]. In one report of 36 dogs with aortic
thromboembolism, 4 had severe atherosclerosis associated with thyroid disease [170]. Thrombotic occlusion of
the distal aorta and/or the iliac arteries in dogs results in signs of pelvic limb weakness, pain and collapse.
Diagnosis is based on clinical signs, angiography and ultrasonography. In one report, dogs that survived the
acute episode received aspirin in an attempt to prevent recurrence of thrombosis and all regained pelvic limb
function [82]. For dogs that survived longer than one month after the acute episode, repeat thrombosis was
uncommon. Aortic thromboembolism in dogs carries a more favorable prognosis than feline aortic
thromboembolism.
A possible genetic predisposition to femoral artery occlusion occurs in Cavalier King Charles Spaniels [173]. The
condition is usually subclinical due to sufficient collateral circulation (femoral pulse may be undetectable
unilaterally or bilaterally).
Labrador Retriever Hereditary Myopathyies

A degenerative myopathy that is inherited as an autosomal recessive trait has been reported in Labrador
Retriever dogs in the United States and United Kingdom, and has been seen in Continental Europe and Australia
[174-180,520,541]. The condition has been called Labrador Retriever hereditary myopathy (LRHM), centronuclear
myopathy (CNM), Labrador Retriever myopathy, type 2 muscle fiber deficiency and muscular dystrophy. The
disorder affects male and female dogs and has been seen in animals with both black and yellow coat color. The
age at onset and the severity of clinical signs may be variable. Some puppies have clinical signs at 6 to 8 weeks
of age. In others, a later onset at 6 to 7 months has been observed. Cases of both early (8 weeks) and late (6
months) onset have been observed within the same litter. In typical cases, clinical signs become obvious at 3 to 4
months of age and include muscle weakness, abnormalities of gait and posture, and decreased exercise
tolerance. Severely affected puppies may have a low head posture, with ventroflexion of the neck. The back is
arched, and the gait is characterized by short, stilted strides in which the hind legs are often advanced
simultaneously in a synchronous, bunny hopping fashion. Clinical signs become more accentuated as the animal
tires, and, if encouraged to continue, the puppy may collapse forward with the head and neck to one side. There
is no loss of consciousness or cyanosis. Exercise tolerance may be reduced to 20 yards in severely affected
animals. Severe tetraparesis, inability to walk, hyporeflexia, and elevated serum CK levels have been seen in two
4 month old littermates [178]. However, mildly affected dogs may be presented because they seem to be "slow"
puppies that are less playful than their littermates and less willing to exercise. These dogs may not collapse
unless forcibly exercised, at speed, for several minutes. Rest results in some improvement, but the clinical signs
rapidly recur on resumption of exercise. Joint posture is often abnormal, with affected dogs having carpal
overextension, carpal valgus, splaying of the digits, and a "cow-hocked" stance. As the condition progresses,
generalized atrophy of skeletal muscles develops. The proximal muscles of the limbs and the muscles of the head
are particularly affected, but in milder cases, the atrophy may not be dramatic. Signs may be exacerbated by
excitement or stress and particularly by exposure to cold weather. After exposure to cold, an affected dog may be
unable to stand or to lift its head. Moving the animal to a warm kennel usually results in improvement within a few
hours. A less common complication observed in adult dogs (some of whom have been pregnant) is the
development of a transient megaesophagus. Other sporadic complications that have been observed include the
presence of a luxating patella and clinical and radiographic evidence of degenerative joint disease in the hip of
one affected dog that was obese. Affected dogs are bright and alert, although often poorly muscled when
compared with their normal littermates. Temporal muscle atrophy is often a feature, but cranial nerve functions
are otherwise normal. Muscle tone may be normal or reduced. There is no muscle pain on palpation nor dimpling
on percussion. Severely affected puppies are obviously weak and may have difficulty wheelbarrowing or hopping,
although in less affected puppies, postural testing may indicate no abnormalities. Proprioceptive function is
normal, and no sensory deficits have been observed. Tendon reflexes are generally reduced or absent, even in
mildly affected dogs with little muscle atrophy. There is no impairment of bladder function and no signs of
autonomic nervous system dysfunction.
Serum CK levels may be within normal limits or moderately elevated. Levels may increase following exacerbation
of signs after exposure to cold weather but do not reach the levels reported in other degenerative muscle
diseases, such as the inherited muscular dystrophy described in Golden Retrievers (see muscular dystrophy).
Other routine hematological and blood biochemical parameters are within normal limits. Motor nerve conduction
velocities are within the normal range in affected dogs, and there is no decremental response to repetitive nerve
stimulation. On EMG examination, there frequently is spontaneous activity, particularly in the proximal limb
muscles, musculature of the head, and the thoracolumbar paraspinal muscles. The most commonly recorded
abnormalities are fibrillation potentials, positive sharp waves, and bizarre high-frequency discharges [181].
Myotonic-like discharges and fasciculation potentials are recorded infrequently. EMG changes may be less
pronounced in mildly affected dogs and may be difficult to detect in very young dogs. Results of
electrocardiographic examination of affected adults and puppies have indicated no cardiac involvement. Despite
the abnormal joint posture seen in many affected dogs, there have been no abnormalities on radiography of
hocks, carpi, and the vertebral column. In some cases, however, changes consistent with hip dysplasia have
been present.
A wide range of morphological features may be observed in muscle biopsies from affected dogs. The changes
reported include small and large group atrophy, small fibers of both fiber types that tend to have a round rather
than angular appearance, occasional fiber type grouping, large numbers of internal nuclei, disturbances in
myofiber architecture, necrosis, regeneration, and replacement of muscle fibers with fat and fibrous tissue.
Alterations in fiber type percentages are a common finding. In most muscles there is a reduction in the proportion
of type 2 fibers (except for the cranial tibial muscle in which an increase in the percentage of type 2 fibers has
been noted) [182]. These changes in fiber type proportions appear to become more accentuated as the disease
progresses. No abnormalities have been found in brain, spinal cord, or peripheral nerves. Note that similar
histological findings have been observed in clinically normal Labrador Retrievers closely related to those with
LRHM [520. It has been suggested that an additional gene or an environmental factor is responsible for
expression of the subclinical form of the disease [520].
The underlying pathophysiological mechanisms involved in this disease are still unclear, although the myopathy
has genetic, clinical, pathological, and histochemical similarities to the limb-girdle form of muscular dystrophy in
people [183]. Myofiber dystrophin staining is normal. However, immunocytochemical and Western blot studies
reveal that sarcoglycans, alpha-actinin, dysferlin, and calpain 3 are present in affected dogs [184]. These
sarcolemmal and Z-disc (alpha-actinin) proteins have been incriminated in various limb-girdle muscular
dystrophies in people [185-187]. Muscle biochemical studies indicate significantly elevated concentrations of
sodium, calcium, zinc, copper, and chloride and reduced levels of potassium and magnesium in muscles from
affected adult Labrador Retrievers [182]. There is a significant increase in the intracellular water and sodium
levels and a concomitant reduction of intracellular potassium content [188]. In addition, a significant decrease in
muscle-specific proteins has been identified in the biceps femoris muscle of affected dogs [189]. Also, lipid fluidity
of erythrocyte membranes is significantly different in affected Labrador Retrievers [190]. Results of other studies
have not supported the hypothesis of a possible vascular defect [ 191].
Recent molecular studies have confirmed recessively inherited canine centronuclear-like myopathy and Labrador
Retriever hereditary myopathy (LRHM) are the same disease. Affected dogs are homozygous for a mutation in
the gene PTPLA (542; personal communication L. Tiret). The function of the gene product is current being
investigated. The identification of the mutation allows for the definitive diagnosis of affected animals and a
molecular test is now available (http://www.labradorcnm.com).
Diagnosis is based on signalment, clinical signs, muscle biopsy data, and molecular testing. Prognosis is
generally favorable for longevity. In most cases, the clinical signs stabilize between 6 months and 1 year of age.
There may be some improvement in ability to exercise, particularly in those dogs with the mildest signs. The
atrophy of skeletal muscles persists, however, and although affected dogs may be acceptable house pets, they
are not suitable for work. Owners of affected dogs should be warned that stress, including exposure to low
temperatures, can result in a dramatic worsening of clinical signs, even in clinically stable adults. The life span of
affected dogs does not appear to be directly affected by the condition, although the prognosis for dogs with
megaesophagus should be more guarded because of the risk of developing inhalation pneumonia.
There is no definitive treatment for this condition, although various forms of medication have been used.
Diazepam , given orally at a dose of 10 mg twice daily, may have some ameliorating effect. Diphenylhydantoin
has little effect, and edrophonium chloride may worsen clinical signs. Anabolic steroids have apparently been
beneficial in some cases; however, the evidence for this in anecdotal. Low muscle carnitine levels have been
found in a few dogs tested suggesting that administration of L-carnitine (at 50 mg/kg PO bid) might be beneficial
[192].
There has been a recent preliminary report of a condition termed "canine centronuclear-like myopathy" in
Labrador Retrievers in which onset, clinical signs, pathology (including centrally-placed myofiber nuclei) and
histochemistry are virtually identical to those seen in LRHM [521]. The authors report that the gene for this
condition (CNM gene) is localized on canine chromosome CFA2 and suggest that the disorder is a homologue of
the human autosomal centronuclear myopathy. The relationship of this disorder to LRHM, if any, remains to be
seen.
Limber Tail
A condition colloquially referred to as "limber tail", "limp tail", and "cold tail" is familiar to people working with
hunting dogs, primarily Pointers and Labrador Retrievers [193-198]. The typical case consists of an adult dog that
suddenly develops a flaccid tail. The tail either hangs down from the tail base or is held out horizontally for several
inches from the tail base and then hangs straight down or at some degree below horizontal. Initially, the hair on
the dorsal aspect of the proximal tail may be raised and dogs may resent palpation of the area 3 - 4 inches from
the tail base. Affected Pointers almost always have a history of prolonged cage transport, a hard workout the
previous day, or exposure to cold or wet weather. Pain may be noted in acute stages of the condition. In cases
where people are not familiar with this disease, other conditions such as a fracture, spinal cord disease, impacted
anal glands, or prostatic disease have been incorrectly diagnosed. Results of a recent study [193] in 4 affected
Pointers showed evidence of coccygeal muscle damage, which included mild serum elevation of CK early after
onset of clinical signs, needle electromyographic examination showing abnormal spontaneous discharges (e.g.,
positive sharp waves and/or fibrillation potentials) restricted to the coccygeal muscles several days after onset,
and histopathologic evidence of muscle fiber damage (fiber size variation associated with multifocal fiber
hypertrophy and scattered round/angular fibers many of which were basophilic, internal nuclei, fiber splitting, and
mild fat infiltration, and in some instances, diffuse fiber atrophy). Specific muscle groups, namely the laterally
positioned intertransversarius ventralis caudalis muscles, were affected most severely. Intramuscular nerves
appeared normal. Infrared thermography revealed increased temperatures of the sacrococcygeal area and the
entire tail in acute cases, indicative of reduced blood flow possibly associated with local edema, swelling and
vascular stasis. Radionuclide perfusion imaging indicated uniform vascular perfusion over the lumbosacral area
and tail of one affected dog, however, an area of increased radioactivity (indicative of increased vascularity or
perfusion) was seen in the proximal tail caudal to the anus in another dog. No significant abnormalities were seen
in the lumbosacral or coccygeal regions using imaging techniques (MRI, CT). The authors suggested the
condition may be related to acute compartment syndrome (a condition in people associated with muscle ischemia,
pain, pallor, pulselessness, paresthesia, and paralysis [199,200]) caused by tail injury, perhaps from damage
associated with eccentric muscle contractions from tails being whipped from side to side. Treatment strategies
include rest to allow healing of the muscle damage and short-term administration of anti-inflammatory drugs
during the acute stages (anecdotal reports suggest that anti-inflammatory drugs administered within 24 hours of
onset hasten recovery) [38]. Prevention is aimed at minimizing predisposing factors, including instituting regular
training programs so as to avoid overexertion in unconditioned dogs, and regular stops with exercise when
travelling long distances [38]. Prognosis is usually favorable with most dogs recovering spontaneously within a
few days to weeks. Less than one half of affected dogs experience a recurrence.
Malignant Hyperthermia
Malignant hyperthermia (MH) is a life-threatening hypermetabolic and contractile condition that is triggered in
humans, pigs, dogs and cats by certain anesthetic agents (e.g., halothane and succinylcholine). The underlying
defect in calcium (Ca) homeostasis occurs at the level of the skeletal muscle sarcoplasmic reticulum where there
is hypersensitive and heightened ligand-gating of the Ca-release channel [201]. The Ca channel is readily opened
by certain drugs, such as caffeine and halothane. Caffeine- or halothane-induced muscle contracture develops as
a result of sustained increase in cytoplasmic Ca levels and subsequent activation of the actin-myosin contractile
proteins. In addition, calcium uptake is reduced. The continuous contraction results in depletion of glycogen
stores, hypoxemia, and accumulation of heat, hyperkalemia, lactic acid, and metabolic and respiratory acidosis. In
people, as a consequence of severe muscle necrosis, CK levels may rise 100-fold and myoglobinuria and
disseminated intravascular coagulation may occasionally occur, which may lead to renal failure [9]. Recent
reports indicate that canine malignant hyperthermia is caused by a mutation in the gene encoding the skeletal
muscle calcium release channel (RYR1) [23], similar to that found in pigs and humans.
Malignant hyperthermia has been reported in various breeds of immature and mature dogs: St. Bernard, Border
Collie, Labrador Retriever, Pointer, Spaniel, Greyhound and animals crossbred with Doberman Pinscher [202-
207]. MH in some colony-bred dogs is inherited as an autosomal dominant trait [23,204]. Dogs susceptible to MH
may be nervous and difficult to handle. Their muscles may be hypertrophic with greater than normal muscle tone
and strength. Resting body temperature may be high normal or slightly above and serum CK and aspartate
transaminase levels may be mildly elevated. While Greyhounds are often reported with MH, some studies indicate
they may not be specifically MH susceptible [208]. MH has been reported only sporadically in cats [209].
Reports of MH in dogs and cats are most often associated with halothane anesthesia. It should be noted that this
disorder does not always occur during the first exposure to halothane anesthesia. Clinical signs can include
hyperthermia, tachycardia, tachypnea, severe limb rigidity, and trismus, followed by respiratory and cardiac arrest.
In some animals, extreme trismus and generalized muscle rigidity occur immediately after death. Succinylcholine
and enflurane, but not methoxyflurane, have also been implicated as triggers of MH in the dog. A MH-like episode
was reported in a 5 year old Greyhound anesthetized with thiamylal sodium and also given lidocaine for
premature ventricular contractions [210]. In another adult Greyhound, two episodes of malignant hyperthermia
occurred at 20 and 44 hours post-surgery following anesthesia with fentanyl-droperidol and sodium pentobarbital
[206].
Histopathologic features in skeletal muscle tend to be fairly non-specific and include fiber size variation, fiber
hypertrophy, and increased numbers of internal nuclei in muscle cells [203]. Occasional perivascular infiltrates of
lymphocytes with infrequent perimysial and epimysial neutrophils have also been noted [209]. In some patients,
muscle biopsies are normal. Ultrastructurally, there may be loss of mitochondria, presence of moth-eaten fibers,
cores, and Z-line streaming. Cardiac histomorphometric parameters are normal in MH-susceptible dogs [211].
Diagnosis of fulminating MH can be suggested by historical data relating to breed or colony susceptibility, and by
development of characteristic clinical signs while under or following (see above) anesthesia. Signs may occur
after 30 to 300 minutes of halothane exposure.
Prognosis is guarded. Removal of triggering agents and symptomatic treatment (total body cooling,
corticosteroids, sodium bicarbonate, intravenous fluids) usually are ineffectual in reversing MH episodes, although
hyperventilation with 100% oxygen, stomach lavage with iced water, body surface cooling, and IV administration
of cold isotonic saline solution was successful in one report [202]. Dantrolene is the drug of choice for treating
affected animals [212]. It can prevent a malignant hyperthermia crisis or reverse anesthetic-induced MH if given
early in the development of the syndrome [213]. A recommended intravenous dosage is 3 to 5 mg/kg. Injectable
dantrolene may also be prepared from an oral preparation [214].
In instances where MH is suspected, susceptible animals can safely undergo anesthesia if triggering agents are
avoided. Screening tests for animals susceptible to MH include caffeine/halothane-contracture tests (CCT),
erythrocyte osmotic fragility test (EOFT), lymphocyte Ca test, and biochemical tests for defective Ca-transport in
sarcoplasmic reticulum isolated from skeletal muscle [203,215,216]. Several reports have noted that the initial
sign of a MH episode was a rapid increase in end tidal partial pressure of carbon dioxide before any increase in
rectal temperature or muscle tone [204,213].
It is now established that the Ca channel may also be triggered by stressors such as excitement, fighting for
dominance, and sudden increase in ambient temperature in pigs, and by exercise, in dogs. This exercise-induced
hyperthermia has been termed "canine stress syndrome" [203,217] and has been reported in several breeds
including an English Springer Spaniel and a Greyhound [218,219]. In susceptible dogs, the stress of moderate
exercise can cause a reversible MH-like syndrome characterized by hyperthermia (e.g., 42°C), muscle cr amping,
dyspnea (labored stertorous breathing), panting (e.g., respiratory rate > 200 breaths/minute), hemoconcentration,
hyperlactemia, respiratory alkalosis, and raised levels of muscle enzymes. Similar findings have been reported in
Labrador Retrievers following strenuous exercise [220]. Dogs with the exercise-induced hyperthermia are
clinically normal but reportedly have a hyperactive temperament [218,219]. Absence of myoglobinuria rules out a
diagnosis of exertional rhabdomyolysis. Hypercontracted myofibers have been observed in muscle biopsies [219].
Recovery can be relatively rapid (e.g., within 30 minutes of rest) and this condition may represent "mild aborted
malignant hyperthermia" [219]. A suggested diagnostic protocol for animals with canine-stress syndrome includes
exercise/challenge testing, EOFT, and serum CK levels [219]. In susceptible animals, CCT and EOFT are not
always positive [218]. The halothane-challenge test is likely risk prohibitive. Note that in dogs with exercise-
induced hyperthermia, administration of dantrolene prior to exercise may not prevent the stress syndrome
occurring [219].
Megaesophagus
This condition refers to esophageal dilatation with absence of effective esophageal peristalsis. Megaesophagus
has been termed esophageal achalasia, esophageal dilatation, esophageal hypomotility, and esophageal
neuromuscular disease. Both congenital idiopathic (CIM) and acquired forms of megaesophagus occur.
Congenital megaesophagus has been reported in Great Danes, German Shepherds, Irish Setters,
Newfoundlands, Shar Peis, and Greyhounds. The condition occurs as an inherited disease in Wire-Haired Fox
Terriers (autosomal recessive) and Miniature Schnauzers (autosomal dominant or 60% penetrance autosomal
recessive). A suspected hereditary form has been reported in Bouvier des Flandres dogs (see Bouvier des
Flandres myopathy) [2]. Idiopathic megaesophagus is also reported in cats [221-223], with a predisposition noted
in Siamese and Siamese-related breeds [222]. The congenital form is usually apparent in animals around the time
of weaning. Less commonly, adult-onset idiopathic megaesophagus may be detected [224]. Readers should refer
to other texts for more information on megaesophagus associated with obstructive esophageal disease such as
neoplasia, granulomas, vascular rings, strictures, periesophageal masses, and foreign bodies.
Acquired megaesophagus may occur in dogs or cats at any age, although in one study, older (mean = 8 years),
heavier dogs were at risk, including German Shepherds, Golden Retrievers and Irish Setters [225]. In many cases,
the cause is unknown; however, the condition has been observed in association with certain systemic
neuromuscular disorders such as myasthenia gravis, botulism, hypoadrenocorticism (associated with
glucocorticoid deficiency with or without concurrent mineralocorticoid deficiency), polymyositis, dermatomyositis,
myotonic myopathy, nemaline myopathy, polyradiculoneuritis, distemper, giant axonal neuropathy (German
Shepherds), tick paralysis, lead toxicosis, thallium toxicosis, canine and feline muscular dystrophies and
dystrophy-like conditions, laryngeal paralysis-polyneuropathy complex, dysautonomia, glycogen storage disorders,
feline mannosidosis, sensory ganglioradiculitis, and spinal muscular atrophy [136,225-231]. In acquired
myasthenia gravis in dogs, megaesophagus may be the only clinical sign. It has also been reported sporadically
in canine pituitary dwarfs, dogs with tetanus, and Labrador Retriever puppies with familial reflex myoclonus [227].
In one report, megaesophagus was noted in English Springer Spaniels with a polysystemic disorder comprising
dyserythropoiesis, polymyopathy, and cardiac disease [232]. Megaesophagus may also occur with bilateral vagal
nerve damage due to surgery, trauma, or neoplasia as well as with various brainstem lesions - neoplasia,
distemper encephalitis, granulomatous meningitis/meningoencephalomyelitis, trauma, and infarction [233]. It has
also been observed in dogs secondary to tiger snake envenomation [536]. It has been stated that the relationship
between hypothyroidism and megaesophagus has yet to be established [225,539]. In one report, megaesophagus
was found in 5 dogs with hypothyroidism and myasthenia gravis [136].
The pathogenesis remains elusive. Megaesophagus may result from lesions involving the esophageal muscle, or
afferent/efferent pathways controlling esophageal motility [226,234]. Afferent pathways include esophageal
sensory receptors, afferent fibers in the vagus nerve and its branches (e.g., cranial laryngeal nerve), and the
solitary tract/nucleus complex. The efferent limb of the reflex comprises the vagus nerves (including special
visceral efferent axons from the nucleus ambiguous and general visceral efferent fibers from the parasympathetic
vagal nucleus), neuromuscular junction, and esophageal muscle (primarily skeletal, with less involvement of
smooth muscle) [234,235]. Electrolytic lesions of the nucleus ambiguous in dogs and of the parasympathetic
nucleus of the vagus in cats produce esophageal dysfunction similar to the clinical syndrome [236]. A reduction of
the normal number of neuronal cell bodies in the nucleus ambiguous has been recorded in clinically affected dogs,
but not in affected cats [237,238]. These neuroanatomical differences between dogs and cats with
megaesophagus probably relate to differences in proportion of striated and smooth esophageal muscle between
the two species [226,235]. In one study in 12 week old Chinese Shar Peis with CIM, no histological lesions were
found in the nucleus ambiguous or parasympathetic nucleus of the vagus, or in ganglion cells of the myenteric
plexus [239]. CIM appears to be associated with loss of peristaltic function in the esophagus due to
developmental immaturity of innervation and/or musculature [240]. Based upon studies of upper and lower
esophageal responses to intraesophageal balloon distension, CIM was considered to be at least partly due to a
faulty afferent component of the reflex neural pathway that controls swallowing [241]. Seemingly consistent with
this finding, more recent studies on dogs with CIM showed no electrophysiological evidence for segmental
demyelination or axonal degeneration in cervical vagal motor fibres innervating striated muscle of the thoracic
esophagus portion and no EMG abnormalities indicative of esophageal muscle denervation or primary myopathy
[242]. Additionally, demonstration of a normal Hering-Breuer lung inflation reflex is consistent with an organ
specific, selective vagal afferent dysfunction in dogs with CIM [538]. Note that few cases of megaesophagus
appear to be related to disturbances of gastroesophageal sphincter function [226]. In one study, resting caudal
esophageal sphincter pressure was similar in clinically normal dogs and in dogs with congenital or acquired
idiopathic megaesophagus [243].
Clinically, megaesophagus is characterized by postprandial regurgitation of undigested food, with radiographic
evidence of megaesophagus, usually to the level of the diaphragm. Abnormal esophageal motility may be
demonstrated by contrast radiography/fluoroscopy. In some dogs, respiratory signs such as cough, dyspnea
and/or abnormal secretions may be the only signs observed.
Prognosis of congenital megaesophagus in young dogs is guarded. Some animals appear normal by the time
they mature, based on radiographic, manometric, and clinical examination, while others show no clinical
improvement with time. Acquired, idiopathic megaesophagus generally has a poor prognosis for recovery [226],
although transient megaesophagus followed by spontaneous recovery has been reported occasionally in dogs
[178,224]. The prognosis for secondary megaesophagus varies with the underlying cause, for example, cats with
megaesophagus and dysautonomia have a poor prognosis, while clinical improvement has been noted in dogs
following treatment of the primary disease process, e.g., myasthenia gravis, hypoadrenocorticism, hypothyroidism,
botulism, tetanus, and lead poisoning [226,231,244-246,537]. Cachexia becomes an important complication and
death is a common consequence of inhalation pneumonia. Recommended management includes elevated
feeding and/or gastrostomy tube feeding of high caloric diets [227,240]. Surgical treatment remains controversial.
Pharmacological management, using drugs that relax the gastroesophageal sphincter or increase strength of
esophageal contractions, has been disappointing [226], although sildenafil, a phosphodiesterase-5 inhibitor, is
reported to have profound effects on esophageal motility in cats by modifying propagation and amplitude of
esophageal contractions [247]. Nifedipine, a calcium channel blocker, resulted in temporary clinical improvement
(2 months) in an adult German Shepherd with megaesophagus [248].
Mitochondrial Myopathies
A myopathy has been reported in young Clumber and Sussex Spaniel puppies (male and female) in which clinical
signs are usually seen with the introduction of lead training - about 3 months of age [249-253]. Animals tire easily,
pull back on the leash, and collapse in sternal recumbency. Animals attempt to rise only after 10 to 15 minutes.
During this time, excessive panting and tachycardia are noted. Animals appear thirsty and remain depressed for
about an hour after each episode. Tensilon testing for myasthenia gravis is normal. Serum CK levels, along with
EMG studies and nerve conduction velocities are normal [253]. Blood biochemical studies reveal a metabolic
acidosis (nonhypoxic) in arterial blood samples due to elevated levels in lactate and pyruvate (resting levels are
higher than normal and both increase dramatically above the levels expected following exercise), presumably
leading to clinical weakness and muscle cramping. This metabolic disorder is believed to be associated with
abnormal mitochondrial function. Biochemical studies showed that muscle mitochondria were unable to oxidize
pyruvate (via the tricarboxylic acid cycle/Krebs cycle) due to a deficiency of pyruvate dehydrogenase (PDH)
[249,251]. Recent studies have confirmed PDH deficiency in cultured fibroblasts from one affected Clumber
Spaniel [253]. In this report, lactic acidemia with a lactate to pyruvate ratio < 10 was considered diagnostic for
PDH deficiency. The etiology remains unknown, although the condition appears to be inherited (note that
interbreeding between Clumber and Sussex Spaniels has occurred in the past). Treatment should be aimed at
reversing the acidosis. More recently, a suggested treatment protocol includes a high fat and low carbohydrate
dietary regimen, in conjunction with L-carnitine (50 mg/kg PO bid) and thiamine (100 mg daily) may improve
exercise tolerance [253]. Prognosis appears guarded as dogs may die suddenly following exercise from cardiac
arrest (presumably related to the metabolic acidosis).
A similar condition has been reported in two male Old English Sheepdog littermates (presented at 1 year of age
and 2.5 - years of age, respectively) with a history of clumsiness since 3 months of age [254]. Other signs
included reluctance to play rigorously, and progressive exercise intolerance. Muscle biopsy data revealed
scattered myonecrosis, ragged red fibers characterized by reddish-purple subsarcolemmal stain using modified
Gomori’s staining and dark blue subsarcolemmal deposits using the oxidative stain NADH-TR, empty
sarcolemmal tubes, fibrosis, vacuolated fibers, and marked increase in numbers of internalized nuclei.
Ultrastructural findings included scattered myofibrillar disruption, increased numbers of mitochondria, and
increased myofibrillar glycogen. Electromyographic studies revealed increased insertional activity and complex
repetitive discharges. Nerve conduction velocities were normal. Arterial blood analysis immediately after exercise
showed a high anion gap metabolic acidosis associated with lactic acidosis and increased pyruvate levels,
elevated lactate/pyruvate ratio, along with dramatic increase in serum CK, alanine aminotransferase, and
aspartate aminotransferase activity. A subsequent biochemical study using fibroblasts and skeletal muscle from
one of the affected dogs demonstrated a partial deficiency in cytochrome oxidase [255], suggesting that the
exercise intolerance and elevated lactic acidosis resulted from impaired mitochondrial oxidative phosphorylation
and reduced pyruvate usage. In skeletal muscle from the affected dog, reduced activity of two additional
mitochondrial inner membrane enzymes (i.e., ATPase and NADH-ferricyanide reductase) was also found.
Empirical treatment with vitamin C (at 10 mg/kg, daily), a drug considered to be useful in people with
mitochondrial myopathy caused by complex III deficiency, had little effect in either dog.
More recently, similar clinical and pathological findings were reported in a 4 month old Jack Russell Terrier [256].
In this dog, exercise intolerance was progressive so that by 10 months of age, it could walk for only about 30
meters before collapsing. The dog was able to resume walking after a short rest (30 seconds). The muscle
changes were worse at 10 months of age (increased numbers of ragged red fibers and increased fiber size
variation associated with marked muscle fiber atrophy). While serum CK values were slightly increased, serum
biochemical studies revealed a lactic acidosis before and after feeding, along with increased fasting level of
pyruvate and a marked increase in the post - feeding lactate/pyruvate ratio (the pyruvate levels decreased to
normal range after feeding). While mitochondria in this dog appear to be structurally normal, the authors regarded
the blood biochemical findings to be consistent with a defect in the electron transport involved in oxidative
phosphorylation, or in the enzyme pyruvate decarboxylase. Electrophysiological studies (nerve conduction
velocities, EMG) in this dog were normal.
Exercise intolerance leading to ataxia and collapse within 15 minutes of strenuous activities is encountered in
some working young-adult Labrador Retrievers [257] suggesting possible abnormal muscle oxidative metabolism.
In a controlled study using healthy Labrador Retrievers, only brief periods of strenuous exercise were required to
produce a marked increase in rectal temperatures, significant increase in arterial blood pH and oxygen partial
pressure, significant decrease in arterial blood bicarbonate levels and carbon dioxide partial pressure, and
marked increase in plasma lactate and pyruvate levels (the lactate/pyruvate ratio, however, remained normal)
[220]. In this study, the metabolic acidosis were unassociated with clinical weakness or collapse. Similar
metabolic changes have been noted in healthy racing Greyhounds [258-260]. The condition in the Labradors may
be another example of exercise-induced hyperthermia (see Canine Stress Syndrome).
A lipid storage myopathy characterized by abnormal accumulations of lipid droplets (using lipid stains such as oil
red O or Sudan black), localized predominantly in type 1 fibers, have been reported in male and female dogs of
various breeds and ages with signs of myalgia, weakness, and muscle atrophy [261,262]. The occurrence of lactic
acidemia, hyperalaninemia, lactic and pyruvic aciduria, variably increased urinary excretion of carnitine esters,
and muscle carnitine deficiency suggested a metabolic block in mitochondrial oxidative metabolism.
Recommended treatment for affected dogs includes L-carnitine (50 mg/kg, PO bid), coenzyme Q (100 mg PO
daily), and riboflavin (100 mg PO daily) [262].
Note that mitochondrial dysfunction is considered to play a role in other myopathies, including hypothyroid
myopathy and hyperadrenocortical (Cushing's) myopathy. Mitochondrial abnormalities (ultrastructural and
abnormal biochemical respiration characteristics) were found in Irish Terrier puppies with possible X-linked
inherited myopathy characterized by stiff gait, lumbar kyphosis, and dysphagia [263] and in older Golden
Retrievers with muscular dystrophy [264] (see muscular dystrophy). Abnormal mitochondrial within neuronal
perikarya and axons are a feature of mitochondrial encephalomyelopathy in dogs [265]. In people, mitochondrial
myopathies are a complex and heterogeneous group seen in most diseases of oxidative phosphorylation [266].
The mitochondrial abnormalities are due to defects in the respiratory chain enzymes associated with
mitochondrial DNA deletions [7]. Ultrastructural abnormalities in mitochondria may involve the number, size, or
shape of mitochondria, and there may be changes in the patterns of the cristae and/or presence of crystalline or
osmiophilic inclusions [120].
Muscular Dystrophy
The muscular dystrophies are hereditary, degenerative dystrophinopathies and disorders of dystrophin-associated
proteins. Dystrophinopathies are those muscular dystrophies in which there is a defect in the dystrophin gene (the
cause of Duchene muscular dystrophy) [4]. Dystrophin binds to a complex of proteins and glycoproteins called
dystrophin-associated proteins and dystrophin-associated glycoproteins. Muscle dystrophin occurs on the plasma
membrane surface in skeletal muscle fibers, on plasma membrane and transverse tubule surfaces of cardiac
muscles, and on smooth muscle membranes. This membrane-associated protein is thought to help maintain
membrane integrity. Dystrophin is a member of the spectrin superfamily of proteins. Dystrophin itself is closely
related to three proteins that constitute a family of dystrophin-related proteins (DRP): utrophin, DRP2, and
dystrobrevin [267]. There are several subcomplexes that form the glycoprotein complex involved with dystrophin
[4,268]:
a. The dystroglycan complex that consists of α- and β- dystroglycans and forms the dystrophin-axis. The
basal membrane of each muscle fiber contains several components including laminin, a subunit of
which, merosin (also called laminin α2), is bound to α-dystroglycan, which binds to the cysteine-rich and
carboxyl-terminus domains of dystrophin. Merosin is also found in the basement membrane of Schwann
cells of peripheral nerves (see congenital muscular dystrophy, below). The N-terminus domain of
dystrophin is bound to actin filaments forming the cytoskeleton of the subsarcolemma. The dystrophin
homologue, utrophin, is believed to bind to actin and the dystroglycan complex.
b. The sarcoglycan complex that appears to be fixed to dystrophin axis in skeletal and cardiac muscles.
There are four of these transmembrane glycoproteins: α-sarcoglycan (also called 50DAG, A2, and
adhalin), β-sarcoglycan (43DAG, A3b), γ--sarcoglycan (35DAG, A4), and δ--sarcoglycan.
c. The syntrophin complex α, β1, and β2 that binds to the distal part of the carboxy-terminal domain of
dystrophin.
Perturbations in these proteins and glycoproteins result in several types of muscular dystrophy in people, as well
as in dogs and cats.
Canine Muscular Dystrophy

Dystrophinopathies as exemplified by Golden Retriever muscular dystrophy have received considerable
comparative interest because of their similarities to Duchenne muscular dystrophy (DMD) in people [269-272].
Molecular biology studies have shown that the Golden Retriever canine model is genetically homologous to DMD
and its molecular basis has been described [273]. This degenerative myopathy in dogs, which has received the
most attention of the canine "models" of human disease so far, has an X-linked inheritance (in which the disease
is expressed in males and carried by females) and has been termed canine X-linked muscular dystrophy (CXMD).
The genetic symbol xmd was proposed for this canine mutation [272]. Mutations in the DMD gene lead to
disturbances in dystrophin expression, and this protein also is lacking in skeletal and cardiac muscle of affected
dogs. Dystrophic muscle has also been shown to exhibit abnormal sarcolemmal expression of utrophin [274], but
not of laminin [275]. Histopathological studies of skeletal muscle from affected Golden Retrievers reveal
pronounced fiber size variation associated with atrophy and hypertrophy, endomysial and perimysial fibrosis,
internalization of nuclei, marked hypercontraction, and segmental necrosis of muscle fibers with phagocytosis and
regeneration (basophilic fibers), and increased levels of intracytoplasmic calcium [264,271]. Fibrosis may be be
mediated by fibrogenic cytokines, particularly transforming growth factor-beta1 [528]. Differential skeletal muscle
involvement has been noted [276,277] while studies of postnatal muscle changes have shown that muscle
damage occurs before completion of muscle maturation in dystrophic dogs, that necrosis and hypercontraction
appear stable in adults but fiber regeneration declines, and that muscle fibrosis does not increase with age
[278,527]. In CXMD dogs, there is a selective loss of fibers expressing fast myosin and persistence of immature
developmental fibers [279]. Histochemical studies indicate a predominance of type I fibers in many muscles, and
occasional fiber type grouping [264]. Ultrastructurally, there is dilatation of the sarcoplasmic reticulum, focal
subsarcolemmal areas of degeneration, Z-band streaming and duplication, mitochondrial accumulation, and
presence of nemaline rods (especially in older dogs) [264]. No abnormalities have been found in the central or
peripheral nervous systems [276].
Clinical signs are first observed in affected male dogs from 6 to 9 weeks of age. These include stunting,
weakness and gait abnormalities (e.g., stiff, stilted shuffling gait with abduction of elbows and bunny hopping in
pelvic limbs), exercise intolerance, marked muscle atrophy of temporal, truncal, and limb muscles, fibrosis, and
contractures by 6 months of age (semimembranosus and semitendinosus muscles may be hypertrophied). Other
signs may include plantigrade stance, inability to fully open the jaw, progressive enlargement of the base of the
tongue, signs of pharyngeal and esophageal dysfunction and excessive salivation, and weak bark. Skeletal
deformities including variable lumbar kyphosis that may develop into lordosis by 1 year of age and curvature of
the costal arch may also be seen, along with various muscle/limb conjectures [280,281]. Spinal reflexes may be
diminished later in the disease. Clinical signs slowly progress during the first 6 months of life and then tend to
stabilize [280]. Signs of inhalation pneumonia and congestive heart failure have been noted in older dogs and a
lethal neonatal form has been recognized in some puppies [280].
Serum CK levels are markedly elevated and affected puppies can be identified by 1 week of age. CK levels
reportedly peak at 6 to 8 weeks of age, just before onset of overt clinical signs [280]. After this time, CK levels
plateau at approximately 100 times normal values. Serum CK levels do not show a clear correlation with clinical
severity. Serum levels of muscle enzymes (CK and aspartate aminotransferase), as well as alanine
aminotransferase activity, are increased after exercise [282], suggesting that in the absence of dystrophin,
exercise-induced muscle injury may play a role in the dystrophic process [283]. Electrodiagnostic testing reveals
pseudomyotonic discharges, especially in dogs over 10 weeks of age. Myotonic discharges may also be present
but are less frequent. Positive sharp waves and fibrillation potentials are not commonly noted. Flash
electroretinographic abnormalities have been recently detected [284,529] that suggest a dysfunction in the rod
signaling pathway. Prognosis is guarded to poor. At present, there is no effective treatment; however, potential
strategies for gene therapy (including chimeraplast-mediated gene repair for dystrophin mutations) and bone
marrow transplantation are being pursued at several institutions with variable success [267,285-288,526,530].
Treatment by nitric oxide donors (argenine and molsidomine) failed to modify the evolution of the disease in one
study [523]. Molecular testing now provides rapid, accurate diagnosis of carrier and affected Golden Retrievers
[289,290].
Females with the X-linked muscular dystrophy (produced from carrier female x dystrophic male breedings)
manifest milder clinical signs compared to the males, but with similar CK levels and comparable histological
lesions [264,281]. Results of breeding studies indicate that obligate female carriers of CXMD usually have no
clinical evidence of disease although CK levels may be mildly elevated [280]. In skeletal muscle of carrier animals,
dystrophin is expressed in a mosaic pattern with normal dystrophin-staining fibers muscle interspersed with
severely affected fascicles and negatively-staining fibers, but as animals mature, dystrophin staining becomes
more homogeneous and the number of negative-staining fibers declines [291]. In a recent developmental study,
calcium- and albumin- positive fibers observed in carrier dogs, always expressed dystrophin abnormally [278],
while utrophin was absent from muscle fiber surfaces in 2 day old animals, present between 15 and 30 days, and
disappeared by 60 days [279]. Variable loss of dystrophin, dystrophin-associated proteins, or laminin α2
deficiency has also been identified in female purebred and mixed-breed dogs in whom variable clinical signs were
seen (including generalized weakness, exercise intolerance, muscle hypertrophy/atrophy, and limb deformities)
along with variable CK levels (ranging from normal to high values) [292]. Histological changes included fiber size
variability, degeneration/regeneration, and fibrosis.
Similar muscular dystrophies/dystrophinopathies have been reported in several canine breeds, including
Rottweiler [293], German Shorthaired Pointer [294], Irish Terrier [295], Belgian Groenendaeler Shepherds [296],
Samoyed [297], Miniature Schnauzer [298], Brittany Spaniel [299], Rat Terrier [300], and Labrador Retrievers
[301,522]. We have seen similar pathological findings in a 4.5 month old, male, Welsh Corgi presented with
stiffness, apparent muscle enlargement, and extremely high CK levels. Electromyography revealed diffuse,
pseudomyotonic, bizarre high-frequency discharges in skeletal muscles. Prominent muscle changes were
characterized by moderate/pronounced fiber size variation associated with atrophic (round, some angular) and
hypertrophic fibers, scattered as well as in groups, multifocal necrosis, macrophage infiltration (positive acid
phosphatase staining), multifocal fibers with internal nuclei, multifocal mineralization, fiber splitting, basophilia,
and fibrosis. Histochemical staining showed involvement of both type 1 and type 2 fibers, although there
appeared to be a type 2 fiber loss in some fascicles. There was also fiber type grouping. Immunocytochemical
staining revealed an absence of dystrophin staining in myofiber sarcolemmal membranes. Spectrin staining was
normal. An attenuated form of canine dystrophinopathy has also been reported in Japanese Spitz dogs in which
staining was absent against the rod domain of dystrophin but not against the carboxy terminus, suggesting
possible similarities to Becker’s muscular dystrophy in people [302]. Labrador Retriever Hereditary Myopathy has
genetic, clinical, pathological, and histochemical similarities to the limb-girdle form of muscular dystrophy in
people, although a recent study [184] demonstrated that the canine disease was not due to a deficiency of alpha-
actinin (a Z-disc protein that may be implicated in some forms of autosomal dominant limb-girdle muscular
dystrophy in people), or any of the known autosomal recessive limb-girdle muscular dystrophy proteins identified
in people, namely the sarcoglycans, dysferlin and calpain 3 [187]. A muscular dystrophic-like condition has also
been reported in Bouvier des Flandres (see Familial Dysphagia) and in three related young English Springer
Spaniel dogs with regurgitation from an early age [232] associated with slowly progressive temporal muscle
atrophy with partial trismus, and generalized skeletal muscle atrophy. All dogs exhibited moderate
dyserythropoietic anemia, polymyopathy (histological evidence of muscle fiber size variation and internalized
nuclei without regeneration/inflammation) with megaesophagus, and varying degrees of cardiomegaly. The cause
of this condition was not determined. In the English Springer Spaniels, EMG changes (fibrillation potentials) were
patchy and there was no increase in serum CK levels.
Distal myopathies are a form of muscular dystrophy that occur rarely in people and are characterized by
progressive muscular weakness and atrophy that starts in the hands or feet . Several types have been identified:
late adult onset type 1 (autosomal dominant); late adult onset type 2 (autosomal dominant); early adult onset type
1 (autosomal recessive); early adult onset type 2 (autosomal recessive); and early adult onset type 3 [303].
Dysferlin, a sarcolemmal-associated protein, is absent in the early adult onset type 2 form (Miyoshi myopathy)
although dystrophin and other dystrophin-associated proteins are normal in these patients [304]. Serum CK levels
may be very high while nerve conductions are normal. A distal myopathy (termed juvenile-onset distal myopathy)
has recently been reported in young Rottweilers (male and female) from three different litters in California (2 of
the puppies were littermates) presented for decreased activity and various postural abnormalities, including
plantigrade and palmigrade stance and splayed forepaw digits [305]. These clinical signs were seen in some
puppies as early as 3 weeks of age. Neurological examination was normal. EMG studies revealed rare fibrillation
potentials and positive sharp waves. While motor nerve conduction velocities were normal, compound muscle
action potentials from the interosseous muscles were decreased. Serum CK levels were normal or mildly
increased. Histopathologic changes (more prominent in distal muscles) included myofiber atrophy with mild
myonecrosis, endomysial fibrosis and replacement of muscle with fatty tissue. While plasma and muscle carnitine
concentrations (total and free) were low in most puppies, the significance of this finding is uncertain but may be
related to the degenerative process (metabolic testing did not reveal abnormalities in any intermediary
metabolites). Dystrophin immunocytochemistry was normal. The condition in these dogs is considered to be
inherited.
Feline Muscular Dystrophy

Muscular dystrophy-like disorders in cats have been reported in the Netherlands, Germany, and the US [306-309].
To date, all cats have been male, suggesting an X-linked inheritance. Clinical signs may be first seen in cats
about 5 to 6 months of age and include generalized skeletal muscle hypertrophy, excessive salivation, reduced
exercise tolerance, stiff gait and bunny-hopping when running, difficulty in jumping, adducted hocks, cervical
rigidity, vomiting/regurgitation, and partial protrusion of the tongue. Multifocal lingual calcification (submucosal),
hepatosplenomegaly, and megaesophagus have been noted in some cats [308]. Based on the clinical features,
including the extensive muscle hypertrophy, the term "hypertrophic feline muscular dystrophy" has been proposed
for this condition [308]. Serum CK levels may be markedly increased, often accompanied by variably elevated
levels of aspartate aminotransferase and alanine aminotransferase. Atrial and ventricular dilatation, left ventricular
wall thickening, and papillary muscle hypertrophy have been detected in echocardiographic studies. Notching of R
waves has been noted with electrocardiographic testing. Electromyographic studies of skeletal muscles reveal
bizarre high frequency discharges (also called complex repetitive discharges), sometimes interspersed with
positive sharp waves [309,310]. Motor nerve conduction velocities are normal. Necropsy examination has shown
severe hypertrophy of the diaphragmatic musculature, and enlargement of muscles of the tongue and larynx.
Pathological findings are similar to those described for dystrophic dogs and include muscle fiber hypertrophy
(involving both type 1 and type 2 fibers), fiber splitting, accumulation of calcium deposits within muscle,
myonecrosis and phagocytosis (mononuclear cell infiltrates may be seen), hypercontracted fibers, numerous
internalized nuclei, and occasional fiber type grouping. Aging studies have shown a significant decrease in the
number of type 2A myofibers and increase in numbers of type 2X fibers in younger dystrophin-deficient cats [311],
with an apparent loss of type 1 fibers in older cats [312]. Endomysial or perimysial fibrosis is not a feature in axial
or appendicular muscles. Immunoblotting and immunofluorescent studies have shown marked dystrophin
deficiency in skeletal muscles [307-309], although, a small percentage of fibers may stain positive [311].
Molecular studies have demonstrated deletion of the dystrophin muscle promoter in affected cats [313]. No
histological lesions are seen in carrier females despite presence of a mosaic staining pattern for dystrophin in
skeletal muscle (irregular staining in most myofibers or absent staining in rare fibers) [311]. Mineralization, fibrosis,
and myodegeneration have been seen in cardiac muscle of some affected cats. Ultrastructural changes in
skeletal muscle include distention of the sarcoplasmic reticulum and the T system, swollen mitochondria, and Z-
band streaming.
Prognosis is guarded in cats because of the development of diaphragmatic and lingual hypertrophy which
potentially leads to megaesophagus, insufficient water intake, dehydration, hyperosmolar syndrome (see
hypernatremia), and acute renal failure [308]. Another potential complication is rhabdomyolysis, possibly
associated with increased sensitivity of the dystrophin-deficient sarcolemmal membrane to volatile anaesthetic
agents, stress, or intense muscular activity. In one report, 3 dystrophin-deficient cats developed peracute, lethal
rhabdomyolysis following either isoflurane anesthesia or manual restraint for a procedure) [312]. Serum
chemistries revealed severe hyperkalemia, hyperphosphatemia, hypocalcemia, massive increases in CK,
aspartate aminotransferase, and alanine aminotransferase concentrations, and high ion gap metabolic acidosis.
Skeletal muscle changes included severe acute hyaline necrosis and endomysial edema without infiltration of
inflammatory cells.
Congenital Muscular Dystrophy - A novel muscular dystrophy has recently been reported in cats associated with
deficiency of merosin (laminin α2) [314]. Laminins are large glycoproteins found in the basement membrane of a
variety of tissues, including skeletal muscle fibers and Schwann cells of peripheral nerves. Clinical signs in the
cats beginning around 6 months of age included progressive muscle weakness, muscle atrophy, and
extraordinary muscle contractures resulting in rigidity and extension of the pelvic limbs in one cat. The second cat
was non-ambulatory and hypotonic/hyporeflexive in all limbs. Serum CK levels were markedly elevated.
Histological muscle changes were characterized by marked endomysial fibrosis, myofiber necrosis, variability of
fiber size, and perimysial lipid accumulation. In both cats, immunohistochemical labeling showed complete
absence or marked reduction in staining against laminin α 2. However, staining for dystrophin and all the
components of the dystrophin-associated glycoprotein complex were present and normal. In one cat studied,
motor nerve conduction velocity was decreased, and demyelination and vacuolar Schwann cell degeneration
were observed in peripheral nerves. No abnormalities were seen in the CNS and there was no evidence of
cardiomyopathy. The disease was considered similar to primary or secondary merosin (laminin α 2)-deficient
congenital muscular dystrophy in people.
Myositis
The incidence of myositis appears to be increasing in dogs and cats. Although several forms of myositis have
been described in animals, a precise classification has not yet been established. One proposed scheme is to
separate these myopathies into generalized and focal forms [540]. Generalized inflammatory myopathis include
immune-mediated polymyositis, polymyositis due to infections agents including protozoa, rickettsia, and bacteria,
and paraneoplastic polymyositis [315-317, 540]. Focal inflammatory myopathies include masticatory myositis and
extraocular myositis. These myopathies share common histological features including presence of inflammatory
cell infiltrates (the hallmark of myositis/polymyositis) and various degenerative changes in the muscle fibers. Note
that inflammatory cells are also sometimes seen in muscles of animals with muscular dystrophy. Also note the
caveat that "… absence of any inflammatory infiltrates in a biopsy does not exclude an inflammatory myopathy"
[120].
In a retrospective study of 200 dogs with inflammatory myopathies the mean age for dogs was 4.88 +/- 2.8 years
with an overrepresentation of Boxers and Newfoundlands. 140 were identified with generalized inflammatory
myopathy: 63% immune-mediated; 28.5% infectious; 8.5% preneoplastic; 1.5% dermatomyositis [540]. 45 cases
of masticatory myositis and 2 cases of extraocular myositis were identified.
Masticatory Myositis
This inflammatory myopathy (synonym is eosinophilic myositis) is one of the most common forms of myositis in
dogs and is particularly common in adult, larger-breed dogs [318-322]. Results of one retrospective study
indicated that most dogs were under 4 years of age with no gender or breed predilection [321]. This disease is
characterized by recurrent inflammation of muscles, especially those of mastication (masseteric, temporalis, and
pterygoid muscles), sometimes in association with peripheral blood eosinophilia. In most instances, the condition
is restricted to muscles of mastication. This is an autoimmune disease in which B-lymphocyte-mediated
antibodies are directed against type 2 M fibers in masticatory muscles. Type 2 M fibers are the dominant fiber
type in masticatory muscles [323,324]. Biochemical studies have shown that masticatory muscles contain a
unique myosin isoform, unique myosin light chains, and unique myosin heavy chains [325]. In one study of dogs
with masticatory myositis, 86% of cases had autoantibodies fixed to type 2 M fibers of the temporalis muscle [326].
Incubation of normal muscle with sera from affected dogs resulted in labeling of 82% of type II M fibers.
Immunocytochemical studies suggest that transforming growth factor-beta (TGF-beta) and latent transforming
growth factor-beta binding protein (LTBP) may play a role in muscle tissue repair, inflammation and fibrogenesis
in masticatory myositis [327].
Lesions consist of myonecrosis, hemorrhage, edema and multifocal or diffuse cellular infiltrates including
macrophages, lymphocytes, plasma cells, occasional neutrophils, and rarely, eosinophils. Skeletal muscle fiber
atrophy involving all fiber types may be pronounced, sometimes with foci of small round fibers comprising entire
muscle bundles [321]. Fiber hypertrophy is usually not a feature. Perimysial and endomysial fibrosis is usually
marked. Regeneration of muscle fibers, characterized by vesicular nuclear changes and fiber basophilia is
frequently found.
Clinical signs are characterized by acute onset of painful, swollen, masticatory muscles. The jaw is held partially
open (pseudotrismus) and passive manipulation is painful. Unilateral or bilateral exophthalmos may also be
present [319], which in some cases may cause optic nerve compression or stretching resulting in blindness [321].
Dogs are often febrile, and tonsils and mandibular lymph nodes may be swollen. The acute phase may last 2 to 3
weeks, with signs reaching a peak by 10 to 14 days. Serum CK levels are elevated early in the disease and
gamma globulin levels may be increased.
Diagnosis is based on signalment, clinical, and muscle biopsy data, although histological demonstration of
antibodies against type 2M fibers is also a sensitive index (the antibody titer may be reduced if corticosteroids
have been administered previously). Prognosis is usually favorable. In most cases, the acute disease responds to
corticosteroids, e.g., prednisone 1.0 to 2.0 mg/kg PO bid. The dose is reduced after remission of signs, and
gradually withdrawn using alternate day therapy. Note that the lowest alternate-day dosage may be required for
up to 6 months [317]. Repeated clinical episodes are not uncommon, which usually result in muscle atrophy. In
one study, better clinical responses were noted in dogs receiving prednisone early in the course of the disease,
for at least one month, and with the dosage tapered gradually from the initial immunosuppressive dosage [321].
Other immunosuppressive drugs such as azathioprine (at 0.6 mg/kg PO every one to three days) may also be
used in conjunction with prednisone, with a steroid-sparing effect, or alone, to maintain remission. There is no
apparent correlation between response to treatment and the extent/severity of the muscle lesions. Note that
manual manipulation of the jaw carries an inherent risk of mandibular luxations/fractures [321]. In some severely
affected dogs, there may be a permanent inability to adequately open the jaw, necessitating blending of the food
for intake/ingestion [317].
Recently, a masticatory myositis has been reported in dogs with leishmaniasis (Leishmania infantum) [328] (see
infectious myositis).
I have observed masticatory myositis in several cats and an autoimmune process is suspected. Note that many
tissue samples received in our laboratory from dogs with suspected masticatory myositis have evidence of
neurogenic atrophy with little or no sign of inflammation. These cases probably represent idiopathic trigeminal
neuritis.
Atrophic Masticatory Myopathy/myositis

This is a chronic degenerative myopathy that is characterized by atrophy of muscles of mastication which can
occur in dogs of any breed [329,330]. It has also been termed atrophic myositis and cranial myodegeneration.
The pathogenesis of this condition is uncertain. It may be a stage of masticatory myositis or it might represent
neurogenic atrophy secondary to idiopathic trigeminal neuritis associated with severe axonal degeneration. In
some dogs with leishmaniasis, severe masticatory muscle atrophy may be present [331] (see infectious myositis).
Atrophic masticatory myopathy may also be prominent in younger dogs with dermatomyositis. There is no
peripheral or local eosinophilia present. The atrophy is accompanied by a state of trismus (lock-jaw) which may
not be reduced, even under general anesthesia, and which may interfere with eating (although this is not a feature
seen in dogs with leishmaniasis). Pathological studies reveal large numbers of atrophic fibers and increased
perimysial connective tissue. Focal areas of lymphoplasmacytic infiltrates may be seen occasionally in
masticatory and other skeletal muscles.
Prognosis of this form may be guarded because of the severe trismus. However, in most dogs jaw function
returns to normal. Some animals appear to respond to corticosteroids. Note that bilateral masticatory muscle
atrophy may be seen in some cats with nemaline myopathy.
Polymyositis
Polymyositis is a relatively common myopathic disorder in dogs, but less common in cats. It has been suggested
that polymyositis, masticatory myositis and other clinical variations, such as pharyngeal-esophageal and focal
appendicular myositis, may represent different clinical and pathological expressions of a single primary muscle
inflammatory disease [332]. The cause of polymyositis in dogs is not always known, although the responsiveness
of the disease to immunosuppressive therapy suggests that the pathogenesis is immune-mediated. In people with
polymyositis, the pathogenesis appear to involve cell-mediated immune mechanisms, with the inflammatory cells
being mainly CD8+ T cells [333]. Polymyositis has been reported in dogs with specific autoimmune diseases,
including systemic lupus erythematosus [334], primary lymphocytic thyroiditis, and immune-mediated polyarthritis
(see below). Furthermore, it has been seen as an autoimmune paraneoplastic complication of thymoma, usually
accompanied by myasthenia gravis [335,336]. Polymyositis and myasthenia gravis have also been reported in a
dog following fetal liver transplant (see myasthenia gravis) and immunological mechanisms were considered to be
involved [337]. Polymyositis is also a feature of dermatomyositis in Collie dogs and Shelties, another suspected
immunological disease (see dermatomyositis).
Clinical signs are variable and are usually observed in larger breed, mature adults of either gender; however,
there are reports in younger animals, including two 7 month old littermates [338]. Onset of signs may be acute or
chronic. Signs may include acute vomiting and excessive salivation, weakness of gait with rapid fatigue,
megaesophagus, dysphagia, shifting lameness and/or stiffness of gait, muscle swelling and/or pain, pyrexia,
muscle atrophy, voice change and depression. Some dogs show signs of cervical ventroflexion [317].
Neurological examination is usually normal. Early in the disease, serum levels of CK, aspartate aminotransferase,
alanine aminotransferase may be elevated but may not reflect the severity of clinical signs or the underlying
muscle pathology (see below). Total serum protein may be elevated associated with increased β- and γ--globulin
fractions. Some animals have positive antinuclear antibodies and circulating antimuscle antibodies.
Electrodiagnostic changes include polyphasic motor unit potentials, positive sharp waves, and fibrillation
potentials. Motor and sensory nerve conduction velocities are normal. Histopathological findings in skeletal
muscle (appendicular and masticatory) are focal/multifocal or diffuse myonecrosis, phagocytosis and
lymphoplasmacytic cellular infiltrates, endomysial/perimysial fibrosis, considerable fiber size variation, and areas
of fiber regeneration. Rarely, eosinophilic cells may predominate [339]. Deposition of immunoglobulin G (but not
C3 component) on sarcolemmal membranes has been demonstrated [340]. In dogs with polymyositis associated
with leishmaniasis, IgG immune complexes are detected in muscle samples [328].
Diagnosis is based on clinical signs, increased serum levels of muscle enzymes, electromyographic abnormalities,
and histopathological evidence of muscle necrosis and inflammatory cell infiltrates. Not all of these criteria may be
found in any one animal. Diagnosis is definite if all criteria are present, probable if three are present, and possible
if two are found [229]. Muscle enzyme activity is an unreliable index of polymyositis.
Prognosis is usually favorable for animals with polymyositis, provided inhalation pneumonia is not a complication,
and severe damage has not occurred in esophageal and laryngeal muscles. The disease is usually responsive to
corticosteroids, e.g., prednisolone at 1 to 3 mg/kg PO sid or bid. The dose is reduced after remission and
gradually withdrawn using alternate day therapy. In some instances, long-term therapy for 12 months or longer
may be required. Azathioprine may also be used in combination with corticosteroids and has a steroid-sparing
effect [341]. Repeated clinical episodes are not uncommon. A fentanyl patch (25 - 50 ug/h) for pain relief during
the first 2 to 3 days has been recommended [317]. Prognosis is guarded in animals with thymoma because of the
potential for malignancy and occurrence of other non-thymic tumors.
A connective tissue disorder characterized by non-erosive polyarthritis and polymyositis has been reported in 6
young adult dogs [518]. Clinical signs included stiffness, joint swelling, joint pain, muscle atrophy, muscle pain
and contracture and the presence of chronic active inflammation (lymphocytes, neutrophils, macrophages, and
plasma cells) in biopsies of muscle and synovium. There was no muscle fiber immunofluorescence. Systemic
lupus erythematosus was excluded by the absence of circulating antinuclear antibody. 5 of the dogs were of
Spaniel breeds. Prognosis was poor with only 2 dogs recovering after treatment with cyclophosphamide (2 mg/kg
on 4 days each week) and prednisolone (1 mg/kg/day) for 2 months. In another report, however, 2 dogs with this
condition (signs included lethargy, exophthalmos, muscle pain, and atrophy of masticatory/appendicular muscles)
responded favorably to immunsuppressive corticosteroid therapy [519].
Polymyositis occurs sporadically in cats [342], sometimes in association with thymoma [343]. The inflammatory
infiltrates are predominantly mononuclear, with small lymphocytes and macrophages. Neutrophils are seen
infrequently. Eosinophils are rare. A polymyositis has also been observed in cats usually over 1 year of age,
without breed or sex predisposition [117], and while the cause was not defined, many affected cats were
hypokalemic (see hypokalemic myopathy). Pathological findings included myonecrosis, lymphocytic cellular
infiltrates, internal nuclei and fiber regeneration. Clinical signs were characterized by a persistent ventroflexion of
the neck, appendicular weakness especially in the thoracic limbs, painful muscles and exercise intolerance.
Serum levels of CK and aldolase were elevated. Electromyography revealed fibrillation potentials, positive sharp
waves and bizarre high-frequency waves. Prognosis was guarded. Some cats recovered spontaneously while
others appeared to respond to corticosteroids. Recurrences were observed.
We have seen suspected immune-mediated, mononuclear polymyositis in muscles of several cats, including
samples from one cat with myasthenia gravis and thymoma. In muscle samples from another cat with myositis,
numerous muscle fibers
stained positively with staphylococcal protein A-horseradish peroxidase.
Extraocular Myositis
This is condition has been reported in dogs aged between 6 months and 3 years [344-346]. It appears to be more
often reported in Golden Retrievers, but other breeds include Doberman Pinscher, German Shepherd and mixed-
breed dogs. Male and female dogs may be affected. The dominant clinical sign is acute bilateral exophthalmos,
although unilateral involvement has been noted. Extraocular muscle myositis and restrictive strabismus (unilateral
or bilateral) has been reported in 11 dogs of different breeds [346,347]. Clinically, abnormalities are restricted to
the extraocular muscles with sparing of the masticatory muscles and limb muscles. An immune mechanism
directed against specific muscle fiber antigens in the extraocular muscles is suspected. Direct and indirect
pupillary reflexes and fundic examination are normal. Visual impairment may be present and intraocular pressure
may be elevated [344]. Swelling of extraocular (extrinsic) muscles may be detected using ultrasonography or
computer tomography [346]. EMG studies reveal presence of fibrillation potentials and positive sharp waves. Fine
needle aspirate biopsies can be diagnostic. In one study, macroscopic findings were confined to the extraocular
muscles, the central zones of which appeared swollen and pallid, while microscopically, there was severe
lymphocytic inflammation with variable, mild plasmacytic, neutrophilic and eosinophilic infiltrates, multifocal
necrosis, phagocytosis, basophilia, internalized nuclei, slight fibrosis, and occasional foci of hemorrhage [344]. No
abnormalities were seen in blood vessels or nerves.
Oral corticosteroid therapy for two weeks usually results in complete resolution of signs. Relapses may occur but
usually respond well to a second treatment. No dogs exhibit clinical signs of hypothyroidism. Surgical correction
may restore eye position and vision in dogs with restrictive strabismus [347].
Dermatomyositis
Dermatomyositis or familial canine dermatomyositis is a well documented disease of Collie dogs, of all coat colors
and both coat lengths. Dermatomyositis has also been reported in the Shetland Sheepdog (Shelty), Beauceron
Shepherd, Pembroke Welsh Corgi, Australian Cattle dog, Lakeland Terrier, Chow Chow, German Shepherd, and
Kuvasz [348-355]. The condition is considered to be inherited as a dominant trait with variable expressivity in
Collies and in Shetland Sheepdogs [355,356]. Cutaneous lesions involving the face, lips, ears, and skin over bony
prominences of the limbs, feet, sternum, and tip of the tail are noted usually between 2 and 6 months of age. Male
and females can be affected. Other clinical signs range from generalized weakness and exercise intolerance, to
difficulty in lapping water, chewing and swallowing. Megaesophagus may lead to inhalation pneumonia.
Generalized or localized muscle atrophy may be noted, especially of muscles of mastication and distal limbs.
Cutaneous pain is often seen in Beaucerons.
Dermatomyositis is an inflammatory disease of muscle and skin, and sometimes blood vessels. The cutaneous
lesions consist of pustules, ulcers, and vesicles which may progress rapidly to crusted or alopecic areas. Myositis
develops several months later and principally involves muscles of mastication and muscles of the extremities
below the elbow and stifle. The muscle lesions appear to correlated with the severity of the skin lesions. Muscle
lesions consist of multifocal muscle fiber necrosis, internalization of muscle nuclei, atrophy, fibrosis, and
regeneration, and mild to severe interstitial and perivascular inflammatory cell infiltrates (lymphocytes, neutrophils,
plasma cells, and macrophages). Small intrafascicular nerves may be surrounded by inflammatory cells.
Vasculitis is seen in skin, muscle, and occasionally in other tissues. Necrotizing vasculitis of small venules and
arterioles is characterized by fibrinoid thickening of the vessel wall, pyknosis and karyorrhexis of endothelial cell
nuclei, and neutrophilic inflammation [357]. In many cases, the lesions spontaneously regress by 6 to 8 months of
age, although severely affected dogs may have dermatitis throughout their lives. Differential diagnosis of the skin
lesions includes demodicosis, dermatophytosis, staphylococcal folliculitis, epidermolysis bullosa simplex, and
discoid lupus erythematosus [355].
This condition is believed to be immune-mediated, although some clinicians favor an infectious etiology [358].
Other have suggested it is a subset of lupus erythematosus [359]. A type III hypersensitivity reaction may be
involved in the pathogenesis [357]. Autoantibodies to muscle or skin have not been demonstrated, and a
antinuclear antibody titers and lupus erythematosus cell testing are negative. Coombs' test may be positive. There
is a dramatic increase in serum concentrations of IgG and circulating immune complexes, which may be detected
before clinical signs and which show a positive correlation with disease severity, and which decline as animals
enter remission [357]. There is no deficiency of complement (C3, C2, C4, or CH50) [360]. In people with
dermatomyositis, the capillary lining is thought to be the target of the circulating immune complexes, and
perifascicular muscle atrophy may be a consequence of ischemic changes secondary to endomysial vasculopathy
[333].Non-regenerative anemia due to chronic inflammation may occur in severely affected dogs. CK levels are
usually normal but may be increased. Cerebrospinal fluid analysis and nerve conduction studies are normal. The
presence of fibrillation potentials, positive sharp waves, and bizarre high frequency discharges has been
demonstrated electromyographically.
The cyclic and self-limiting nature of this disease complicates treatment evaluation. Rarely, affected adult dogs
may die from acute renal failure as a result of severe secondary amyloidosis [361]. Hypoallergenic shampoos are
beneficial. Prognosis tends to be guarded, especially in severely affected dogs. Prednisolone, at 1 to 2 mg/kg PO
bid, may be effective in some animals [355]. If improvement is seen, the dosage should be tapered to alternate
day therapy. Vitamin E (200 - 800 U daily PO) or marine lipid supplements may be useful in refractory cases.
Pentoxifylline may be included as a corticosteroid-sparing drug (at 200 - 400 mg q24 - 48h). Dogs with disease
remission by 1 year of age tend to have a good prognosis [357]. Note that muscle disease may progress as skin
lesions regress leading to severe muscle atrophy in some older dogs, and with potential problems in eating and
drinking due to masticatory muscle atrophy.
Myositis Ossificans
Myositis ossificans or ossifying myopathy, perhaps a misnomer (see below), is an uncommon myopathic disorder
of animals that is characterized by heterotopic ossification of skeletal muscle. Local and generalized forms of this
disease have been reported in dogs and cats [46,362-364]. The etiopathogenesis is uncertain. Trauma may be
associated with localized, ossifying myopathy [46,365], but it is not a prerequisite. Focal masses have been
reported adjacent to the zygomatic arch and near the coxofemoral joint in dogs. The generalized form in people is
suggested to be congenital or hereditary in nature.
Histopathological lesions of focal myositis ossificans in animals vary from mild interstitial fibrosis, to complete
replacement of muscle by fibrous tissue and heterotopic bone. In one report, the mass was well circumscribed
with fibrous tissue around the periphery, then cartilage, and cancellous bone with bone marrow/fibrous tissue
centrally [366] (this may have been a case of heterotopic osteochondrofibromatosis). Focal masses need to be
differentiated from extraskeletal osteosarcomas [367]. The generalized form is characterized by fibrosis, muscle
fiber degeneration, mononuclear myositis, muscle atrophy, dystrophic calcification, and ossification [363]. Clinical
signs of the focal form are usually associated with lameness. In one dog with a focal mass near the zygomatic
arch, the jaw could not be opened more than 3 cm. In the generalized form, signs are variable and may include
progressive weakness, swollen muscles, muscle pain, stiffness, and palpable firm enlargements in affected
muscles. We have seen generalized myositis and calcification in muscle samples from a 4 year old female
Domestic Shorthaired cat with a history of relapsing weakness. Muscles were firm, serum CK levels were very
high, and myoglobinuria was noted. Electromyographic testing revealed diffuse abnormal potentials that were
more severe in proximal muscles. Muscle lesions were characterized by diffuse mineralization (calcium deposits
that stained positively with Alizarin Red), disseminated necrosis and phagocytosis, mononuclear cell infiltration,
and fibrosis. At necropsy, multifocal white areas were observed in most skeletal muscles. The cause of this
apparent generalized myositis ossificans was not determined.
Radiographic studies of myositis ossificans may reveal focal or multiple soft tissue radiopacities of irregular linear
calcification, along with variable periosteal reactions [363,368]. Prognosis is guarded in animals with generalized
myositis ossificans; however, surgical excision of focal masses has been performed successfully [366,368]. In
some cases, focal lesions may regress. In people, the more generalized form of myositis ossificans may be seen
as a complication of dermatomyositis in childhood [7].
As mentioned above, the term "myositis ossificans" may be too simple, or even incorrect, in some reported cases
in animals. For example, another condition seen occasionally in cats, termed fibrodysplasia ossificans, differs
from myositis ossificans in that it does not primarily involve muscle, is multicentric, often symmetrical, and
unrelated to trauma [369-371], and Valentine and colleagues [372] have included the above-mentioned cases of
generalized myositis ossificans, progressive ossifying myositis, and fibrodysplasia ossificans under the category
of fibrodysplasia ossificans progressiva (FOP). Absence of muscle fiber lesions and lack of abnormal EMG
findings in some animals are more commensurate with a primary connective tissue disorder associated with
fibrovascular proliferation, chondroid and osseous metaplasia in epimysium, tendons/ligaments, or fasciae, than a
primary defect of skeletal muscle (any muscle changes present may be secondary to the connective tissue
disease) [372]. In people, FOP is an extremely rare hereditary disorder (autosomal dominant) of connective tissue
characterized by progressive heterotopic ossification of the tendons, ligaments, fasciae, and striated muscles
[373]. Other forms of heterotopic calcification in dogs occur with calcinosis circumscripta/tumoral calcinosis.
Recently, bilateral cervical heterotopic ossification associated with a thoracic limb lameness, was reported in an
adult German shepherd dog [374]. Hard, non-painful masses were palpable under the cranial border of the
scapula in both forelimbs. Radiographs revealed two mineralized densities ventrolateral to the lateral processes of
the 6th cervical vertebra. These lesions appeared to be adjacent to the tendons of insertion of the longissimus
cervicis muscles that attach to the lateral processes of the 6th cervical vertebra. The lameness resolved following
surgical removal of one of the masses. The lesion was classified morphologically as fibrodysplasia ossificans, and
it was postulated that the heterotopic ossification resulted from the metaplastic change of calcinosis circumscripta
lesions.
Laryngeal Myositis
I have seen myositis in laryngeal muscles of several dogs (a 7 year old male Boykin Spaniel; a 10 year old male
Malamute; and a 3 year old Bouvier des Flandres) presented with signs of chronic laryngeal paralysis and
dysphagia. Laryngeal muscle changes included multifocal myonecrosis, phagocytosis, mononuclear cell infiltrates,
and variable fibrosis. Intramuscular nerve bundles appeared normal although there was mild evidence of
neurogenic atrophy in laryngeal muscles of all three dogs. Electromyographic studies on laryngeal and/or
esophageal muscles revealed fibrillation potentials, positive sharp waves, and high frequency, bizarre discharges.
With the exception of mild, focal inflammation seen in temporalis muscle from one dog, pathological and
electrodiagnostic changes were restricted to laryngeal / pharyngeal muscles. Laboratory tests were normal in all
dogs. The etiopathogenesis, treatment and prognosis of this condition remain to be determined. Prognosis is
guarded to favorable: one dog was euthanized because of respiratory distress, a castellated laryngoplasty was
performed on one dog, and the third dog that was marginally hypothyroid, responded to thyroid hormone
replacement and corticosteroids.
Infectious Myositis
Infectious myositis is most commonly seen in dogs with several protozoon diseases, including hepatozoonosis
and toxoplasmosis and neosporosis. Myositis also occurs with trypanosomiasis. More recently, myositis has been
reported with leishmaniasis, an endemic protozoan disease in Mediterranean countries and Portugal that is
caused by Leishmania infantum [328,331]. The disease usually occurs in older dogs (with a range from 1.5 to 10
years) and affects dogs of either gender and of various breeds. Clinical signs include skin lesions (e.g., exfoliative
dermatitis and skin ulcerations) and atrophy of the masticatory muscles. In some dogs, there is also appendicular
muscle atrophy. The masticatory atrophy tends to be insidious, slowly progressive, usually unassociated with
trismus. Exercise intolerance, megaesophagus, or gait disturbances are not seen. In some dogs, the myositis is
subclinical. Serum CK levels are often elevated, especially in those dogs with severe muscle atrophy. EMG
studies reveal positive sharp waves, fibrillation potentials, and bizarre, high frequency discharges. Nerve
conduction studies are normal. Histological changes in muscle include myofiber necrosis, degeneration,
regeneration, with varying degrees of atrophy, along with fibrosis, interstitial and/or perivascular mononuclear cell
infiltration (macrophages, lymphocytes, occasional plasma cells), and neutrophilic vasculitis, sometimes with mild
to severe thrombosis. Leishmanial amastigotes are frequently seen within macrophages and skeletal muscle cells.
IgG complexes are found within myofibers and also on the sarcolemma, and circulating antimuscle antibodies are
found in serum. While the exact pathogenesis of the muscle lesions remains uncertain, the immunological
findings suggest at least partial immune-mediated pathology. Other muscle changes might be related to ischemia
secondary to vasculitis/thrombosis. The vasculitis is considered to be the result of a type III hypersensitivity
reaction.
Prognosis is guarded. Note the zoonotic potential for leishmaniasis. Treatment is complicated due to resistance to
therapy of Leishmania organisms; however, allopurinol (at 7 - 15 mg/kg PO bid for 26 weeks) has been
recommended, although complete recovery is rarely achieved [375].
Bacterial myositis is reported sporadically in dogs and cats. Normal muscle in people is resistant to bacterial
infection and suppurative myositis is rarely seen [376]. Polymyositis associated with Leptospira australis infection
was documented in a 10 year old male greyhound [377]. Signs included fever, severe back pain, arched back and
semiflexed limbs, and reluctance to stand. Neurological examination was normal. Electromyography revealed
generalized abnormal spontaneous potentials. Serum CK levels were markedly elevated. Other findings included
red colored urine (attributed to the presence of myoglobin), neutrophilia, and positive titer for L. australis. Clinical
signs abated somewhat with non-steroidal inflammatory anti - inflammatory medication and amoxicillin.
Polymyositis has also been seen with Leptospira icterohaemorrhagiae [378]. There are several reports of
clostridial myositis (e.g., associated with C. chauvoei and C. septicum infection) in dogs and cats, often in
association with muscle wounds/injuries, or surgical procedures [379-385]. Pain, swelling, and lameness may be
seen with limb involvement. Grossly, crepitant swelling, subcutaneous edema and black, emphysematous
muscles are often found. Histologically, hemorrhages, congested vessels, myofiber necrosis, and variable
neutrophilic infiltration is seen in affected muscles [381].
Treatment usually requires radical surgical aeration, along with appropriate antibiosis, e.g., clavulanate
potentiated amoxicillin at 22 mg/kg PO bid for 5 - 7 days, in combination with metronidazole, at 10 mg/kg PO bid
or tid (dog) (or 62.5 mg, PO bid for cats) for 5 - 7 days, and allowing healing by secondary intention [379]. Less
frequently, myositis may occur with migrating parasites and rickettsial disease (also see rickettsial
meningoencephalitis) [386,387]. Trichinosis myositis associated with Trichinella spiralis has been observed in a 6
year old female Fox Terrier used for badger hunting with signs of acute onset weakness [388].
Viral myositis appears to be rare in dogs and cats; however, an inflammatory myopathy was experimentally-
induced in adult cats using feline immunodeficiency virus [389]. The predominant histologic abnormalities
consisted of perivascular and pericapillary lymphocytic infiltration (CD8+ lymphocytes), myofiber necrosis,
phagocytosis, and regeneration.
Paraneoplastic Myositis
Low-grade myositis is seen sporadically in dogs with malignant tumors, such as bronchogenic carcinoma, myeloid
leukemia, and tonsilar carcinoma [378,390] and it is thought to represent a paraneoplastic complication (see
paraneoplastic syndromes).
Drug-induced Myositis
A polymyositis reportedly occurred in several Doberman Pinschers as part of a multisystem allergic drug reaction
(type III hypersensitivity) following treatment with sulfadiazine [391]; although supporting evidence from
electrodiagnostic studies or muscle biopsies were not provided.
Myotonic Myopathy
Myotonia refers to a state in which active contraction of a muscle persists after cessation of voluntary effort or
mechanical/electrical stimulation. This condition is characterized by muscle spasm (stiffness) and by temporary
inability to initiate movement. Myotonia may be clinically observed, noted during EMG studies, or both. Reduced
muscle membrane chloride conductance leading to membrane hyperexcitability, after-depolarization and
repetitive firing, is the underlying mechanism responsible for congenital myotonia in children (including both the
autosomal dominant Thomsen’s disease and autosomal recessive Becker’s disease) [9,392]. A similar chloride
channelopathy occurs in goats with Thomsen's disease [393,394]. Paramyotonia congenita (autosomal recessive)
is one of several recently classified sodium channelopathies in people [395,396]. In contrast, dystrophic myotonia
(myotonic dystrophy or Steinert’s disease) is an adult-onset, non-channelopathy, autosomal dominant,
multisystem degenerative disease occurring in people characterized by myotonia, progressive muscular
weakness, gonadal atrophy, cataracts, and cardiac dysrythmias [4]. Myotonia is also sometimes seen in human
patients with hyperkalemic periodic paralysis (see hyperkalemic myopathy) associated with a sodium
channelopathy [9]. Congenital and acquired forms of myotonia have been reported in dogs, and congenital
myotonia has been seen in cats. Congenital myotonic myopathy (myotonia congenita) has been reported in male
and female Chow Chows, Staffordshire Terriers, Great Danes, and Miniature Schnauzers [397-407]. These
conditions are considered to be inherited (probable autosomal recessive in Chows and Staffordshire Terriers),
although results of breeding trials await confirmation. Spontaneous mutations are likely in the sporadic cases
reported. However, in the Miniature Schnauzer puppies, the myotonia congenita is autosomal recessive and
caused by a mutation in the skeletal muscle voltage-dependent chloride channel, CIC-1 [407,408]. A multisystem
membrane defect associated with low serum cholesterol was suggested in Chow Chows [400]. Congenital
myotonia has also been reported in male and female kittens [409-411]. The condition in cats is thought to be
inherited and the disease is currently being investigated.
Clinical signs in puppies may be seen as early as 2 to 3 months of age. Signs include stiffness in the first
movements after a period of rest, splaying of thoracic limbs, and a bunny hopping pelvic limb gait. Dogs will
remain in rigid hyperextension in lateral recumbency for up to 30 seconds if they are suddenly rotated onto their
sides. Affected dogs may not be able to climb stairs or mount raised platforms. Some dogs may manifest
dysphagia and respiratory difficulty from stenosis of the glottis. Laryngeal paralysis was noted in the Miniature
Schnauzers. Stiffness and weakness largely disappear with exercise. Most skeletal muscles can be hypertrophied,
especially proximal limb muscles, neck muscles and tongue. Signs are worse in cold weather. In older animals,
an increasing period of exercise is necessary for muscle relaxation to occur. Percussion of muscles results in
formation of dimples. This reaction is elicited in conscious and anesthetized dogs, and in those administered
neuromuscular blocking agents.
In kittens, the gait is also stiff and stilted (limbs tend to be abducted), especially in the hind limbs, and signs are
also worse in cold weather and improve with exercise [410,411]. There may be marked non - painful enlargement
of proximal appendicular muscles. When startled, all four limbs become extended and kittens fall into lateral
recumbency. Other signs seen on being startled include third eyelid prolapse, spasm of the orbicularis oculi
muscle, lip retraction, and ear flattening. Masticatory muscle spasms may result in trismus, which may lead to
dysphagia. Dysphonia and inspiratory stridor (sometimes with cyanosis) is seen occasionally. Some kittens have
a coarse meow.
Electromyographic studies in dogs and cats are characterized by trains of repetitive discharges which wax and
wane in frequency, producing an audible "dive-bomber" or motorcycle sound. These myotonic discharges are
independent of neural control and persist even under general anesthesia [412]. A regional curare test for
evaluating muscle discharges without subjecting animals to general anesthesia has been reported [413]. Motor
and sensory nerve conduction velocities are normal. Myopathic changes are mild and typically non-specific with
occasional fiber hypertrophy, centralized nuclei, and focal necrosis. Histochemical stains and dystrophin
immunocytochemistry are normal in dogs and cats. A deficiency in type I fibers has been reported in Staffordshire
Terriers [399]. Mild dilatation of transverse tubules have been seen in affected kitten muscle by electron
microscopy [410]. No abnormalities are seen in peripheral nerves. Serum creatine kinase levels are normal or
slightly elevated. Hypocholesterolemia has been reported in one affected Chow Chow [400], while serum
cholesterol levels were normal in kittens [411].
Diagnosis is based on signalment, clinical and electrodiagnostic data. Prognosis is guarded, although myotonia
congenita does not appear to be progressive. Membrane stabilizing agents including procainamide (at 40 mg/kg
PO qid) and mexiletine (at 8.3 mg/kg PO tid) , as well as quinidine and phenytoin, may result in significant
improvement in clinical signs [406]. These drugs act by blocking voltage-dependent sodium channels thereby
decreasing membrane excitability (drugs acting on the chloride channel are not presently available). Note that
these membrane stabilizing drugs have a high risk of side-effects in cats [411]. To date, no treatment has been
necessary in the affected kittens (close supervision is advised, however). Anesthesia may also be a risk in
affected animals due to difficulty in endotracheal intubation associated with an inability to open the mouth to a
wide angle, enlargement of the tongue and pharyngeal muscles, or narrowing of the glottis due to muscle spasm
or paralysis [400,406,410,411]. Potassium bromide may be contraindicated in dogs with myotonia congenita [414].
Adult-onset myotonic myopathy has been reported as an idiopathic condition in several dogs, including a 3 year
old Rhodesian Ridgeback dog [415], a 3 year old Boxer [416], and 11 and 13 year old female Poodles [417].
Clinical signs and electrodiagnostic findings are similar to those seen in dogs with myotonia congenita. Serum CK
levels are elevated. Histopathological changes tend to be much more obvious, and these may include fiber size
variation, fiber splitting, occasional myonecrosis, many fibers with internalized nuclei, and type I fiber deficiency.
Note that similar changes have been noted in adult dogs with myotonia congenita. Immunohistochemical staining
is positive for dystrophin [416]. No changes are seen in peripheral nerves. Clinical (e.g., weakness, stiff gait with
short stride, tonic extension of all limbs and falling, palpably firm skeletal muscles and myotonic dimpling) and
electromyographic evidence of myotonia has been observed in dogs exposed to herbicides containing 2,4-
dichlorophenoxyacetic acid (2,4-D) or 2-methoxy-3,6-dichlorobenzoic acid (dicamba or MCPA), and serum CK
levels may be markedly elevated [418-421].
Secondary myotonia occurs in several other myopathic disorders in dogs, including hyperadrenocortical
(Cushing's) myopathy, hypothyroid myopathy, Labrador Retriever hereditary myopathy, and the
dystrophinopathies in dogs and cats (see muscular dystrophy). In these conditions, electrophysiological evidence
of myotonic-like discharges may be seen and heard [72,75,137,174,181,263,295,309,398,412,413,422]. However,
since these discharges typically do not wax and wane, they have been termed "pseudomyotonic" or "bizarre high
frequency discharges" [412]. An overlap of true myotonic and pseudomyotonic discharges may occur in some
instances. For example, Duncan and colleagues reported that of 5 dogs with Cushing’s disease, waxing and
waning discharges were recorded in four dogs, and pseudomyotonic potential in one dog [71]. Curiously,
myotonic discharges that waxed and waned were noted in one study of dogs with fibrotic myopathy [36]. Note that
clinical myotonia may occur secondary to Cushing’s disease in some dogs, with signs including stiffness, muscle
hypertrophy, muscle dimpling, rigid epaxial muscles, arching of the back, ears drawn back, and tongue protrusion
[71,72,75,417].
Nemaline Myopathy
In people, nemaline myopathy is a disorder characterized morphologically by the presence of rods (nemaline
bodies) in muscle cells. Various forms of the disease have been reported, including congenital, childhood-onset
and adult-onset, and both autosomal dominant and autosomal recessive cases have been documented [423].
Three genetic mutations have been identified as the cause of nemaline myopathy: the gene for slow alpha-
tropomyosin 3, the nebulin gene, and the actin gene . Nemaline myopathy appears to be most commonly
associated with the autosomal recessive form caused by mutations in the nebulin gene [424]. The pathogenesis
of nemaline myopathy is still unclear although recent molecular genetic studies suggest that rod formation is
secondary to contractile dysfunction [425]. The main component of the nemaline bodies is α-actinin [426].
Nemaline myopathy has been infrequently reported in animals. In 1986, Cooper and associates reported on
nemaline myopathy in 5 cats, of either gender, derived from 4 litters from the same mother, thus suggesting
possible autosomal recessive mode of inheritance [427]. Clinical signs were observed in cats (a specific breed
was not reported) between 6 months and 1.5 years of age. Cats appeared extremely apprehensive. Signs
included mild weakness, reluctance to move, and a crouched, jerky hypermetric gait when prompted to move.
Following a short period of movement, some cats appeared fatigued and panted. In some animals there was skin
twitching and muscle atrophy (especially in scapular and gluteal muscles, and occasionally, in masticatory
muscles). Patellar reflexes were consistently depressed or absent. Other spinal reflexes, along with sensation,
were normal. Electrodiagnostic studies and cerebrospinal fluid analyses were normal, although mild increase in
serum CK and lactate dehydrogenase levels were seen in some cats. Prognosis was poor. Clinical signs
persisted for up to a year after signs first began, but did not appear to progress. However, muscle atrophy did
progress, and cats became inappetent, lost condition, and were eventually euthanized.
Pathological findings were characterized by presence of large numbers of nemaline rods in skeletal muscle fibers
(while all muscles examined were abnormal, the changes were most apparent in the proximal forelimb muscles),
marked fiber size variation, atrophy of type 1 and type 2A fibers, internalized nuclei, and fiber splitting. In some
muscles, core-like lesions were seen characterized by disorganization of the internal structure producing a
swirling pattern and particularly evident on NADH-TR-stained myofibers. Rods stained red with trichrome stain
and were aligned along the long axis of muscle fibers (in some instances measuring up to 5.7 um in length). Rod
numbers varied from a few to many (that filled some fibers) and were in subsarcolemmal or central locations.
Rods were most common in atrophic type 1 and type 2A fibers. Predominance of type 1 fibers, typically a feature
of the human disease [428,429], was not observed. Ultrastructurally, there was myofibrillar disarray. Rods were
electron-dense and showed bi-directional periodicity (approximately 17 nm along the axis and 8 nm transversely)
in longitudinal sections, and a lattice-like arrangement in cross-sections. Rods appeared to arise from Z-bands
and the smallest rods consisted of localized expansions of the Z-band. No lesions were seen in extraneural
tissues, brain, spinal cord, or peripheral nerves. Nemaline rods have been experimentally-induced in cats by
tenotomy [425].
Congenital and adult-onset nemaline myopathies have also been reported in several dogs, including a 12 week
old female Silky Terrier [230], a 10 month old Border Collie, an 11 year old Schipperke with a 5 year history of gait
abnormalities [430]. Clinical signs are somewhat variable but may include exercise intolerance and limb tremors,
stiff-stilted gait (in hind limbs or in all four limbs), and spasmodic limb jerking. In some instances, a plantigrade
stance has been noted in the thoracic limbs, there may be generalized muscle hypertrophy, and sometimes
absence of patellar reflexes along with decreased withdrawal reflexes. In one affected dog, there was a history of
dysphagia/choking, the tongue was protruded, and the dog assumed a "begging" position after mild exercise [230].
EMG changes in these young dogs were usually mild (occasional fibrillation potentials and positive sharp waves),
and nerve conduction velocities were normal. Muscle changes in affected dogs include presence of numerous
rods, especially in atrophic type 1 fibers. Type 1 fiber predominance was reported in one dog with most fibers
having a lobulated appearance [430]. Ultrastructural findings are similar to those seen in cats.
As in people, rods are not exclusive to nemaline myopathy and have been seen in normal canine muscle in fibers
adjacent to thick fibrous septa/tendinous insertions [431], occasionally in adult dogs associated with
hypothyroidism [137,432] and Cushing's syndrome [430] (although concurrent hypothyroidism may have
complicated the Cushing’s syndrome in this report), and in older Golden Retrievers with muscular dystrophy [264].
The significance of the rods in these various other canine myopathies remains to be determined.
Polyglucosan Myopathy
A myopathy may be found in some dogs with progressive myoclonic epilepsy (see Lafora’s disease that is
characterized by presence of periodic acid-Schiff positive polyglucosan inclusions in a variety of tissues including
skeletal muscle, peripheral nerve, and CNS.
Toxic Myopathy
There have been sporadic reports of a severe myopathy in dogs associated with ingestion of dog food
contaminated with monensin, a coccidiostat and feed additive used for chickens and cattle [24,433]. In one report
in which 17 dogs were exposed, 14 died [24]. Clinical signs included polydipsia, polyuria, dark urine, vomiting,
lethargy/weakness, anorexia, dehydration, and diarrhea. In cases we have seen, morphological changes are
characterized by acute necrosis, muscle fiber degeneration, fiber atrophy, regeneration, and fibrosis.
Organophosphates have been incriminated in skeletal muscle necrosis in dogs (see organophosphate/carbamate
toxicity).
Vitamin E Myopathy
Vitamin E (alpha tocopherol) myopathies (variously termed white muscle disease, nutritional myopathy, and
nutritional myodegeneration) have been reported in sheep, cattle, pigs, horses, and poultry (often in conjunction
with selenium deficiency), but only rarely in dogs or cats [434-438]. This myopathy is associated with low dietary
levels of vitamin E , although similar clinical signs and pathology occur in dogs with experimental vitamin E and
selenium deficiency [439]. Selenium is an integral part of glutathione peroxidase and its function is closely
involved with that of vitamin E. Clinical signs include of vitamin E (vitamin E/selenium) myopathy include
weakness, dysphagia, sialosis, dysphonia, stiff stilted gait, difficulty in rising from a recumbent position, and
inability to raise heads. Sudden death is reported in newborn puppies. Signs may be exacerbated with exercise.
Serum muscle enzymes are often elevated, especially CK levels [440]. Skeletal muscle lesions tend to be
bilaterally symmetrical and may affect individual or several muscle groups. Grossly, the affected muscle is paler
than normal and distinct chalky longitudinal striations may be visible. Pathological findings are characterized by
necrosis, phagocytosis, proliferation of sarcolemmal nuclei, loss of striations, and fiber regeneration.
Mineralization may be seen in necrotic muscle fibers. Myocardial necrosis is also a feature of vitamin E/selenium
deficiency [434,435,439,441].Diagnosis is based on historical, clinical, and histopathological data. Animals usually
recover rapidly after selenium and/or vitamin E replacement therapy.
A confirmed case of a myopathy due to a deficiency of vitamin E has been reported in a 2 year old female cat that
was fed a diet consisting almost entirely of boiled Norwegian coley [442]. Muscles in the pelvic limbs were swollen,
hot and very painful on palpation. Histological muscle changes were similar to those reported in dogs. Complete
clinical recovery occurred within 14 days following correct dietary management and multivitamin supplementation
(especially vitamin E additives). Recent studies [19] suggest that vitamin E does not appear to play a role in sled
dogs developing exertional rhabdomyolysis. For more information on vitamin E and the CNS, see vitamin E
deficiency.
Myasthenia Gravis
Myasthenia gravis (MG) is a disorder of the neuromuscular junction and both acquired and congenital forms of the
disease are recognized in animals and in humans.
Acquired MG is now recognized as a common condition in dogs [443-448] (although it is less commonly reported
in cats) characterized by failure of neuromuscular transmission due to reduction in number of functional nicotinic
acetylcholine receptors (AChR) on the post-synaptic membrane of the neuromuscular junction [449-451]. This
deficiency of receptors reduces the sensitivity of the postsynaptic membrane to the transmitter, acetylcholine.
Acquired canine MG is an immune-mediated disease caused by production of antibodies (predominantly IgG)
directed against acetylcholine receptors (AChR-ab) of the neuromuscular junction [452]. Reactive antibodies are
usually demonstrable in the sera of dogs (approximately 98%) with acquired MG [443] and in most affected cats
[453-457]. Antibodies reactive with muscle striations and other autoantibodies (see below) may coexist with a high
titer of AChR-ab. Based on experimental and human clinical studies, MG involves both B and T cells (T cells and
complement are involved in persistent B cell stimulation and in cell-mediated postsynaptic destruction of the
neuromuscular junction, and there is antibody-induced blockade of the function of the remaining AChR molecules)
[458,459]. In people, the thymus (either hyperplastic or neoplastic) appears to play an important role in the
pathogenesis of MG [459,460,531]; thymic dysfunction may occur in 75% of human patients with MG [461].
Acquired MG in dogs and cats also occurs in association with thymic dysfunction, including thymomas
[451,456,462-473], other thymic abnormalities such as thymic cysts [457,474,534], or non-neoplastic thymic
disease [474]. Some cysts (thymic or brachial cleft cysts) have apparent T-cell infiltration [534]. The reported
incidence of thymoma is approximately 3% in dogs [448] but is much higher in cats, with an incidence ranging
from 19 to 25% [444,475]. In these animals, the pathogenesis of the autoimmune response of acquired MG
remains unclear but may it may be paraneoplastic and related to the recognized antigenic similarity between
myoid cells of the thymus and receptor-bearing muscle cells at the neuromuscular junction. One theory is that
disruption of the thymic lymphocytes or muscle cells may lead to an autoimmune attack against acetylcholine
receptors and other skeletal muscle components [476,477].
Human patients with thymoma-associated MG may also produce autoantibodies to a variety of neuromuscular
antigens, including the muscle protein titin, skeletal muscle calcium release channel (ryanodine receptor, RyR),
and voltage-gated potassium channels [478,531]. Titin and RyR antibodies have been recently detected in dogs
with thymoma-related MG, as well as in dogs with other forms of MG [451]. The presence of circulating RyR
antibodies seems to be associated with a severe form of thymoma associated myasthenia gravis in human and
canine patients [443,479]. Occasionally, MG may develop in dogs and cats after removal of the thymoma
[468,480]. In dogs, acquired MG has also been reported in association with other tumors including
cholangiocellular carcinoma [481], osteogenic sarcoma [482], anal sac adenocarcinoma [475], and non-
epitheliotropic cutaneous lymphoma [483]. Acquired MG and polymyositis developed in one dog following fetal
hematopoietic cell transplantation, along with presence of AChR-ab and immune complexes reactive with
myoneural junctions [484]. Acquired MG has also been reported in dogs with hypothyroidism [485], and in
hyperthyroid cats receiving tapazole (methimazole) therapy [486], a drug known to exacerbate MG in people [487].
Shelton states that she has identified MG in dogs with hypoadrenocorticism, thrombocytopenia, and hemolytic
anemia [443].
Acquired MG has been observed in adult dogs of all sizes, but more commonly in medium-to-large breeds, and
particularly in German Shepherds, Golden Retrievers, and Labrador Retrievers [448,452,463]. In one report, the
relative risk of acquired MG in different breeds of dogs was highest in Akitas [448]. Newfoundlands may also be
predisposed to acquired MG [488]. A bimodal age of onset (<5 years and >7 years) has also been reported in
affected dogs [452], and spayed female dogs may have heightened risk [448] (a bimodal incidence peak is also
seen in people: second and third decades in women, and fifth and sixth decades in men [459]). In one review of
cats with acquired MG, Abyssinians and a close relative, Somalis, usually > 3 years of age, seemed to be
overrepresented (gender was not a risk factor) [444]. A spectrum of clinical signs occurs in animals with MG,
along with some variations between cats and dogs. Signs in dogs are often characterized by generalized muscle
weakness/fatigability that is exacerbated by exercise. Additional signs may be lameness, collapse, regurgitation,
drooling, ventroflexion of the head, and tremors. Megaesophagus is also commonly seen (presumably associated
with the presence of striated muscle along the entire length of the esophagus in dogs), being as high as 88% in
one survey [448]. Note that apart from fatigue/skeletal muscle weakness, neurological deficits may be minimal in
some affected dogs [471]. In one study involving 1154 dogs, generalized MG was reported in 57% of cases [448].
Focal forms of MG have also been recognized in dogs, with an incidence ranging from 26% to 43% of all cases of
MG [447,448,489]. Focal signs may include megaesophagus, pharyngeal paralysis and/or decreased palpebral
reflexes, but without evidence of appendicular weakness [470,489-491]. Facial and laryngeal muscle weakness
may also be observed. Focal MG in dogs may occur with thymoma [470]. Approximately 25% of dogs presented
with idiopathic megaesophagus have increased serum titers of AChR-ab [489,492]. Idiopathic cardiac conduction
disturbances (e.g., 3rd degree heart block) have been reported in some dogs with MG (with and without
thymomas and with generalized and focal MG) [469].
A severe, fulminating form of MG has also been recognized in dogs clinically characterized by frequent
regurgitation of large quantities of fluid associated with megaesophagus, rapid loss of muscle strength leading to
recumbency that is not abated by rest, and marked respiratory distress [447,493]. Several of these dogs have had
thymoma [493]. In a recent report involving 5 dogs with fulminating MG, titin and RyR antibodies were found [451].
In cats, signs often include progressive lameness, weakness, drooling and ventroflexion of the head
[454,456,494]. Other signs may include head and body trembling (which may be related to exercise in some cats,
but in others, it may be seen at rest), crouching posture, dysphagia, regurgitation, weight loss, and voice change.
Megaesophagus/esophageal motility dysfunction may be present [454,495]. In a recent review of 105 cats with
MG (diagnosis based on positive AChR-ab in serum samples), clinical data indicated that signs of generalized
weakness without megaesophagus occurred in approximately 30% of cats, generalized weakness and
megaesophagus/dysphagia occurred in 20%, generalized weakness associated with thymoma occurred in
approximately 26%, while focal forms of MG, including megaesophagus and dysphagia, without signs of
generalized weakness, occurred in approximately 15% of cats [444]. Some cats manifest stiff, choppy movements
in all limbs, and after a few steps, they crouch to sternal recumbency and rest their heads on their forepaws.
Many cats have facial weakness and are unable to close their eyelids (accompanied by lack of menace and
absent palpebral reflex). Third eyelids may be protruded. Neurological examination may reveal normal sensation,
intact tendon reflexes but diminished withdrawal reflexes, poor postural reactions, and proprioceptive deficits
[455,457].
In human patients, MG has been classified into 4 grades: ocular disease (grade I), generalized weakness of mild
(grade IIa) or moderate intensity (grade IIb), severe generalized disease (grade III), and fulminating
disease/myasthenic crisis with respiratory failure (grade IV) [459].
Pathological findings (at the light microscopic level) in muscle are minimal but in our laboratory we have seen
scattered angular, atrophic fibers in several muscle samples from dogs and cats with MG, sometimes with small,
focal aggregations of lymphocytic cells (lymphorrhages). Lymphocytic myositis has been reported/suspected in
some affected dogs and cats with thymomas [456,466,469,496-498]. No changes are found in peripheral nerves.
Immunocytochemical methods (e.g., staphylococcal protein A-horseradish peroxidase) may reveal presence of
immune complexes localized at neuromuscular junctions [449]. Ultrastructural studies in human cases of MG
indicate decreased number of acetylcholine receptors, widening of the synaptic space, and flattening of the
regular undulations in the muscle cell membrane at the motor end-plate [460,461]. A significant reduction in
muscle acetylcholine receptors has been shown biochemically in dogs with acquired MG [450].
Diagnosis is based on clinical signs, EDX evidence of decremental response of the compound muscle action
potentials after repeated nerve stimulation (consistent with a postsynaptic transmission defect), serological testing
for autoantibodies, and amelioration of signs following administration of the short-acting anticholinesterase
edrophonium chloride (Tensilon), using a dosage of 0.1 - 0.2 mg/kg, IV in dogs and 0.25 - 0.5 mg IV in cats, total
dose (anticholinesterase drugs inhibit the enzymatic elimination of acetylcholine, thereby increasing its
concentration at the postsynaptic membrane). Neostigmine methylsulfate (Prostigmin) at 40 ug/kg, IM or 20 ug/kg
IV) may also be used in dogs. Following injection, an animal that has been previously recumbent may be restored
immediately to normal activity, which will last for a few minutes before muscle weakness gradually returns.
However, some dogs with MG may not respond, while dogs with other neuromuscular disorders may be
responsive. It has been reported that the Tensilon test has not proven useful in the diagnosis of focal MG [489].
Note also that a decremental response to nerve stimulation is not always detected in dogs and cats with acquired
MG [456,467]. Chest radiography, ultrasonography, or specialized imaging techniques (CT, MRI) may
demonstrate a mediastinal thymic mass. EMG testing is normal, as is hematology, blood biochemistry, urinalysis
and CSF analysis. Definitive diagnosis can be made using radioimmunoassays for detection of serum
acetylcholine receptor antibodies that appear to be specific for acquired MG in dogs [475]. This test (a positive
antibody titer in dogs is > 0.6 nmol/L; and > 0.3 nmol/L in cats) will detect nearly all cases of generalized MG
[443]; lower serum titers reportedly occur in animals with the focal form of MG [489]. High serum AChR-ab titers
were reported in dogs with acute fulminating MG [493]. It should be noted that the assay is not necessarily
correlated to the severity of clinical signs in any affected animal, results may be negative in a small percentage of
animals with generalized (<2%) or focal forms, and serum titers are decreased by immunosuppressive therapy
>7 - 10 days [475,489]. Clinical improvement of signs may be associated with decreasing AChR-ab titers, and
remission of signs may occur when titers reach < 0.6 nmol/L [489]. Recently, molecular cloning of the canine
nicotinic acetylcholine receptor alpha- subunit gene has been reported along with development of an ELISA assay
to facilitate diagnosis of MG in dogs [499].
In people, nearly all cases of MG can be diagnosed using a combination of tests, including ACHR-ab titers,
repetitive nerve stimulation studies, and single fiber EMG demonstration of increased "jitter" [459].
Prognosis is guarded, especially in dogs with thymoma [471]. Also, dogs with the acute fulminating form of MG
appear to have a very guarded prognosis associated with propensity for developing aspiration pneumonia [493].
The presence of circulating RyR antibodies in dogs with various forms of MG may have negative prognostic
significance (see above) [451]. Medical treatment usually entails a trial and error approach to the drug(s) used,
dosage, frequency, or combination. Long-acting anticholinesterase drugs such as pyridostigmine bromide
(Mestinon) may result in clinical control. Dosages range from 30 to 60 mg, PO, two or three times a day in dogs.
Dosage depends on the severity of signs and on the size of the dog. In cats, oral pyridostigmine bromide syrup,
starting at 2.5 mg bid, has been successful. Overdose in animals can produce a cholinergic crisis with signs of
muscarinic (hypersalivation, lacrimation, urination, defecation, pupillary constriction, bradycardia respiratory
paralysis), nicotinic (muscle fasciculations, tremors, stiff gait), or CNS (anxiety, hyperactivity, anorexia,
generalized seizures) stimulation. Administration of atropine (at 0.2 - 0.4 mg/kg IV, slowly over 5 minutes) will
reduce the muscarinic signs. Some animals with acquired MG may become refractory to anticholinesterase
therapy after a period of successful treatment. However, Shelton and associates have recently reported
spontaneous clinical and immunologic remission in 47 of 53 dogs treated only with anticholinesterase therapy (no
immunosuppressive drugs were used) within an average of 6.4 months [475]. Interestingly, various neoplasms
developed in the 6 remaining dogs that did not go into remission.
It has been stated that anticholinesterases provide only symptomatic relief and have no effect on the underlying
immunological dysfunction [500]. Accordingly, some cats have been treated aggressively with
immunosuppressive doses of corticosteroids, e.g., prednisolone, 2 mg/kg, bid, for several months, followed by
gradual reduction every 2 months over a 12 to 16 month period, has resulted in complete remission of signs and
withdrawal of all therapy [455]. In some dogs and cats, combination of corticosteroids and anticholinesterases has
been necessary [456,467]. In a report of acquired MG in a cat, successful management involved thymectomy in
conjunction with long-term immunosuppressive corticosteroid therapy [457]. The efficacy of the corticosteroid
treatment is probably related to both suppression of the immune response and to a direct facilitatory presynaptic
action. One caveat is that corticosteroids may initially worsen clinical signs in some instances and steroid induced
polydipsia can exacerbate the problem of regurgitation [471,475]. Azathioprine, alone or with pyridostigmine, has
been used successfully to treat dogs with MG [501]. Another dog was successfully treated using plasmapheresis
and corticosteroids [502]. In one report, surgical removal of a thymoma in a 10 year old mixed breed dog resulted
in rapid remission of signs; however, the thymoma recurred 6 months post-operatively [470].
Treatment strategies in people with MG including anticholinesterase inhibitors (typically pyridostigmine),
thymectomy, corticosteroids, cytotoxic agents (azathioprine, cyclosporine), plasma exchange, and intravenous
pooled immune globulins have led to a low mortality rate and favorable prognosis for most patients (although
lifelong immunomodulating therapy may be needed) [459].
It is recommended that the following drugs be avoided in animals with MG (acquired or congenital) since they
may further impair neuromuscular transmission [443]: aminoglycosides, phenothiazines, methoxyflurane,
magnesium, and anti-arrhythmic agents.
Congenital MG in animals may occur as a postsynaptic or a presynaptic disorder. It has been described as a
postsynaptic disorder in young dogs of several breeds: Jack Russell terrier [503,504], Springer Spaniel [505], and
Smooth haired Fox terrier [506], usually appearing between the ages of 6 and 9 weeks, and with multiple cases
occurring in a single litter. This form of congenital MG has also been reported in several cats, including a Siamese
(5 month of age) and Domestic Shorthair cats (4 and 7 months of age) [453,507,508]. Congenital MG is inherited
as an autosomal recessive trait in Jack Russell and Smooth haired Fox terriers [509,510]. The physiological basis
of this form of congenital MG is the same as that of acquired MG; however anti-acetylcholine receptor antibodies
are not demonstrable in serum or muscle in congenital MG. Ultrastructurally, there appears to be increased
postsynaptic membrane density and shorter fold depths (possibly associated with abnormal trophic influences
during synaptogenesis) [511]. Palmer and colleagues demonstrated a marked reduction in acetylcholine receptors
(AChR) in skeletal muscle samples from Jack Russell terriers and Springer Spaniels with congenital MG
[504,512]. In a related study, the low junctional membrane density of AChR in canine congenital MG was
considered to represent a low insertion rate of AChR in the postsynaptic membrane rather than a primary inability
of muscle to synthesize AChR, or an accelerated degradation of AChR in the postsynaptic membrane [513].
Clinical signs and electrophysiological findings of animals with postsynaptic congenital MG are similar to those
described for acquired MG; however, signs of episodic weakness are often relentlessly progressive, ultimately
leading to generalized weakness, muscle wasting and inability to ambulate, in spite of treatment. Megaesophagus
has been observed only in the Smooth haired Fox terriers. Diagnosis is based on response to Tensilon
(pyridostigmine bromide), using a dosage of 0.1 to 0.5 mg, IV. Mestinon (pyridostigmine bromide) is used for
treatment at a dosage of 7.5 to 30 mg, PO, once daily. Clinical response to this drug is often erratic, with frequent
relapses and animals may become refractory to treatment [504]. Accordingly, prognosis is guarded to poor in
affected dogs. The prognosis of affected cats is uncertain because of insufficient numbers of reported cases;
however, long-term treatment with pyridostigmine bromide syrup (1.5 mg, PO, bid) was beneficial in one cat [507].
Another congenital myasthenic disorder has been identified in Miniature Dachshund puppies around 5 - 6 weeks
of age that is responsive to anticholinesterase therapy and resolves with maturation [443].
Presynaptic congenital MG has been reported in 12 to 16 week-old Gammel Dansk Hønsehund dogs, with
autosomal recessive inheritance [514]. Signs are characterized by exercise-induced weakness, short strides with
flexed limbs, head drooping, occasional falling, and crawling movements. Muscle tone and reflexes are normal
during attacks, there is no facial weakness, no swallowing defect, no megaesophagus, and no change in voice.
The condition is not progressive and some dogs have been followed for 6 years. No antibodies to acetylcholine
receptors are found. Anticholinesterase treatment has no effect on muscle weakness or electrophysiological
changes. The underlying defect is considered to be presynaptic and may be due to a defect in the synthesis of
acetylcholine, impaired release of acetylcholine, abnormality of acetylcholine-induced ion channels, or deficiency
of end-plate acetylcholinesterase. Specific electrophysiological patterns may be used to identify heterozygotes as
well as myasthenic dogs [515].
In humans, congenital MG is relatively rare and has been classified as presynaptic, synaptic (with end-plate
acetylcholinesterase deficiency), or postsynaptic (consisting of abnormal function or numbers of acetylcholine
receptors [516]. Inherited cases are usually associated with autosomal recessive inheritance.
Neuropathic Disorders
K. G. Braund
Neuropathic Disorders
The peripheral nervous system (PNS) comprises the cranial nerves, spinal nerve roots, dorsal root ganglia, the
peripheral nerve trunks (motor and sensory nerves), the terminal branchings of motor nerves as they innervate
skeletal muscle, and the peripheral autonomic system [1]. Disorders of the parent cell bodies located in the spinal
cord (and/or brainstem) are discussed under motor neuron diseases. In people, dorsal root ganglion
degenerations are described as sensory neuropathies, while in animals such disorders are sometimes called
ganglionopathies or sensory neuronopathies. In the chapter on Localization, I have arbitrarily classified small
animal neuropathies into hereditary/degenerative and developmental disorders, and acquired toxic, traumatic,
metabolic, inflammatory/infectious, neoplastic/paraneoplastic, and vascular disorders (see neuropathic syndrome).
Peripheral nerve disorders are common and usually well-recognized in dogs and cats, although in some instances
problems may arise in distinguishing neuropathies from diffuse muscle disease, certain CNS disorders, or skeletal
problems. In general, most acquired neuropathies are seen in both dogs and cats, although hereditary disorders
are more commonly reported in dogs. Both sophisticated electrodiagnostic testing and qualitative/quantitative
pathological studies have further defined peripheral nerve disease in small animals. Despite these advances, the
etiology of many neuropathies in dogs and cats continues to be uncertain, in contrast with the situation in people,
in whom approximately 10 to 15% of neuropathies remain cryptogenic [2].
The following neuropathic disorders will be described in this chapter and have been listed alphabetically:
Alaskan Malamute Polyneuropathy Polyradiculoneuritis

Birman Cat Distal Polyneuropathy Coonhound Paralysis
Brachial Plexus Avulsion Idiopathic Polyradiculoneuritis
Brachial Plexus Neuropathy-neuritis Cauda Equina Polyradiculoneuritis
Congenital Hypomyelination Neuropathy Chronic Inflammatory Demyelinating
Dancing Doberman Disease Polyneuropathy
Deafness Infectious Polyradiculoneuritis
Congenital Sensorineural Deafness Postvaccinal Polyradiculoneuritis
Acquired Sensorineural Deafness Trigeminal Neuritis
Normal Aging Rottweiler Distal Sensorimotor Polyneuropathy
Diabetic Neuropathy Sensory Neuropathies
Distal Denervating Disease Sensory Ganglioradiculitis
Distal Symmetrical Polyneuropathy Progressive Axonopathy in Boxers
Dysautonomia Sensory Neuropathy in Longhaired Dachshunds
Facial Paralysis Sensory Neuropathy in English Pointers
Familial German Shepherd Neuropathy Sensory Trigeminal Neuropathy
Giant Axonal Neuropathy Idiopathic Self-mutilation
Hyperadrenocortical (Cushing's) Neuropathy Storage Disease Neuropathies
Hyperlipidemia Toxic Neuropathies
Hyperoxaluria Traumatic Neuropathy
Hypertrophic Neuropathy Vascular Neuropathy
Hypoglycemic Neuropathy Vestibular Disease
Hypothyroid Neuropathy Peripheral Vestibular Disease
Laryngeal Paralysis - Idiopathic Vestibular Disease
Laryngeal Paralysis Polyneuropathy - Otitis Media-interna
Complex Cholesteatoma
Optic Neuritis - Congenital Vestibular Disease
Paraneoplastic Neuropathy - Miscellaneous Causes of Peripheral Vestibular
Peripheral Nerve Tumors Disease
Inflammatory Polyps
Central Vestibular Disease
Abbreviations -
ADH (adrenal-dependent hyperadrenocorticism); ATPase (myofibrillar adenosine triphosphatase); BAER
(brainstem auditory evoked response); CK (creatine kinase); CMAP (compound muscle action potential); CSF
(cerebrospinal fluid); CNS (central nervous system); CT (computed tomography); EDX (electrodiagnostic); EMG
(electromyography); HAC (hyperadrenocorticism); HSMN (hereditary sensory and motor neuropathy); MRI
(magnetic resonance imaging); NADH-TR (reduced nicotinamide adenine dinucleotide tetrazolium reductase);
NCV (nerve conduction velocity); PAS (periodic acid-Schiff); PDH (pituitary-dependent hyperadrenocorticism);
PNS (peripheral nervous system); SSN (subacute sensory neuropathy)
Alaskan Malamute Polyneuropathy

A progressive polyneuropathy has been reported in young mature Alaskan Malamutes [3]. Male and female dogs
were affected and the mean age of onset of clinical signs was 14.6 + 3.1 months (range 10 to 18 months). Clinical
signs included progressive paraparesis slowly progressing to thoracic limb weakness, incoordination with
stumbling or toe-dragging, synchronous pelvic limb gait when running, exercise intolerance and collapse, inability
to walk up stairs, inability to jump, difficulty standing, paraspinal (especially lumbar) or appendicular hyperesthesia,
hyporeflexia, muscle atrophy (especially in distal limb muscles), proprioceptive deficits, and, in some cases,
tetraplegia. A hoarse bark and /or inspiratory stridor were noted in 2 dogs. Electromyographic (EDX) testing
revealed diffuse fibrillation potentials and positive sharp waves in limb muscles, especially in muscles below the
elbow and stifle. Motor nerve conduction velocities were either normal or low-normal (50 to 60 m/sec) or slow (28
to 47 m/sec). Sensory NCV was normal in one dog tested. No decremental response to repetitive nerve
stimulation was seen in one dog tested. Results of routine hematologic and blood biochemical analyses and
thyrotropin response testing, blood lead concentration, serum cholinesterase activity, and immunologic function
were normal. Ophthalmoscopy, spinal radiography, urinalysis, edrophonium testing were negative. Pathological
findings in skeletal muscles included neurogenic muscle atrophy characterized by fiber size variation with
atrophic/hypertrophic fibers, more frequent type 2 angular fiber atrophy, and fiber type grouping, without evidence
of inflammation or antimuscle antibodies. In peripheral nerves, microscopic changes included focal or diffuse loss
of myelinated nerve fibres, myelinoaxonal necrosis, increased endoneurial fibrosis, occasional infiltrating
macrophages, and variable demyelination or remyelination. Axonal degeneration and nerve fiber loss were more
prominent in distal parts of the nerves. Axonal degeneration was also noted in the sensory saphenous nerve.
Ultrastructural changes included loss of myelinated fibers, axonal degeneration, presence of numerous Büngner
bands, denervated Schwann cell subunits, collagen pockets, and occasional regenerating clusters. No onion-bulb
formation was seen. Myelin debris, membranous bodies, and prominent organelles, especially mitochondria were
observed in axons and Schwann cell cytoplasm. Macrophages were occasionally seen within Schwann cell
cytoplasm of myelinated fibers containing degenerating axons. Some axons had a watery appearance with
apparent loss of normal cytoskeletal components. There was no evidence of axonal neurofilamentous
accumulation or tubovesicular aggregates. The nature and distribution of abnormal electrophysiological and
pathological findings were suggestive of a distal sensorimotor polyneuropathy. Prognosis is guarded to poor since
the disorder appears to be progressive in most dogs. Response to corticosteroids and azathioprine have been
unsatisfactory. However, less clinically affected dogs may have a favorable prognosis and lead a reasonably
normal life style (several dogs that we have followed are alive at 8 years of age). The cause of this condition
remains obscure, although recessive inheritance is suspected. In a recent report from Germany, EDX and
histopathological abnormalities were detected in clinically normal relatives of affected dogs [4]. Interestingly,
abnormal vocalization was also noted in some affected dogs.
Note that the signalment, age of onset, and clinical course of this disease are similar to those reported in
Norwegian Alaskan Malamutes, a hereditary (autosomal recessive) polyneuropathy that was believed to have
been eradicated in Norway in 1982 [5,6]. The Norwegian dogs had evidence of coughing, regurgitation, and
megaesophagus, proximal and distal abnormalities on electrodiagnostic testing, atrophy of laryngeal muscles,
primarily demyelinative changes in nerves at all levels (Dr. L. Moe, personal communication, 1997), and a
guarded to favorable prognosis, often with clinical recurrences. It seems likely that these two conditions are
manifestations of the same disorder, although we had initially suggested the term "idiopathic polyneuropathy of
Alaskan Malamutes" to distinguish the present condition from the hereditary neuropathy of the Norwegian dogs [3].
Future studies should help clarify if these neuropathies are different expressions of the same disorder.
Birman Cat Distal Polyneuropathy

A degenerative polyneuropathy has recently been reported in several litters of Birman cats bred from the same
parents. A recessive mode of inheritance is suspected [7]. Pathologically, the central nervous system (CNS)
lesions were most prominent in the lateral pyramidal tracts of the lumbar spinal cord, the fasciculi gracili of the
dorsal column in the cervical spinal cord, and the cerebellar vermian white matter. Lesions were characterized by
diffuse loss of myelinated fibers and fibrillary astrocytosis. Inflammatory changes were not seen. Neurons of the
cerebral cortex, cerebellum, and brainstem were normal. In the PNS, numerous degenerating nerve fibers were
observed in the sciatic nerves but not in the spinal nerve roots. No changes were found in the cauda equina,
dorsal root ganglia, or ventral horn cells. Ultrastructurally, degenerating ovoids consisting of myelin debris and
disrupted axons were frequently observed. Selective involvement of distal portions of the CNS and PNS
suggested that this disorder is a distal central-peripheral axonopathy (dying-back disease). Clinical signs were
first noted in cats 8 to 10 weeks of age. Affected cats fell frequently and had a tendency to stand and walk on their
hocks which were held in an adducted fashion. The gait was characterized by slight hypermetria in all limbs and
there was progressive pelvic limb ataxia. Analysis of blood and CSF was normal. Nerve conduction velocity
studies were normal; however, EMG revealed presence of fibrillation potentials and positive sharp waves in pelvic
limbs. Prognosis is poor. Presently, there is no treatment. Future breeding trials should confirm that this condition
is caused by a genetic defect and help characterize the exact mode of inheritance.
Brachial Plexus Avulsion

The brachial plexus consists of the large nerve plexus which gives rise to the nerves which supply the thoracic
limb. It is formed by the ventral branches of the 6th, 7th and 8th cervical and the 1st and 2nd thoracic spinal
nerves [8-11]. Traumatic injury to the brachial plexus is often encountered clinically in animals, especially dogs, in
which there is traction of the thoracic limb or severe abduction of the scapula. Typically, it is the nerve roots, not
the plexus itself, that bear the brunt of traumatic avulsive injury because of the lower resistance of nerve roots to
stretch (due to lack of a perineurium). The ventral roots are more susceptible to traumatic stretch than the dorsal
roots. Avulsion is usually intradural and the lesion in dogs is diffuse rather than circumscribed with involvement of
fibers at many different levels [12,13].
Degenerative changes in dorsal and ventral nerve roots and ventral branches of spinal nerves are characterized
by axonal necrosis, myelin fragmentation, and loss of myelinated fibers. Many fibers are damaged where they
penetrate the leptomeninges, resulting in neuroma formation. Retrograde changes are observed in the ventral
horn cells, characterized by chromatolysis, cell swelling and neuronal depletion. Retraction balls may be seen.
Dorsal column degeneration occurs only with lesions central to the dorsal root ganglion.
Clinical signs reflect the distribution of damage to nerve roots, branches, and plexal cords rather than direct
peripheral nerve involvement. Signs may vary from weakness of single muscle groups, without sensory loss, to
paralysis of all thoracic limb muscle groups with accompanying sensory loss (e.g., with a lesion from C6 to T1 - 2).
A lesion that involves spinal cord segments C8 - T1 may produce ipsilateral loss of the panniculus reflex; while
involvement of the T1 - 3 roots, which contains preganglionic sympathetic fibers, frequently results in partial
Horner's syndrome (characterized by anisocoria). Patterns of cutaneous anesthesia associated with brachial
plexus avulsions have been described in the dog [14]. Conscious pain presentation is usually impaired to a
variable degree in all dogs with brachial plexus avulsion. In general, desensitized areas of skin may be detected
on lateral, medial, dorsal, and palmar surfaces of the affected thoracic limb. Brachial plexus avulsion may be
confused with radial paralysis since the clinical signs of avulsion are predominantly those of radial nerve paralysis
at the level of the shoulder [15]. Table 1 outlines some differentiating features between these conditions.
Table 1. Radial Nerve Paralysis Versus Brachial Plexus Avulsion.
Radial Nerve (C6 - T2) Brachial Plexus ( C6 - T2)
Level of injury Radial nerve Brachial plexus
Muscle atrophy Triceps, carpal extensors Any forelimb muscle
Sensory loss Craniolateral forearm, dorsal

Any forelimb skin zone
(skin) paw
Panniculus reflex Present + absent ipsilaterally
Horner's + yes (often partial if

No
syndrome present)
Modified from Braund KG. Clinical syndromes in veterinary neurology. St. Louis: Mosby, 1994 [16].
Diagnosis is most commonly based on historical and clinical data [17]. Electrodiagnostic (EDX) testing is useful
for detecting muscle denervation, especially minor degrees which cannot be uncovered by routine neurological
examination. This information may be helpful in those cases where muscle-tendon transposition is being
considered for surgical management. Myelography may occasionally demonstrate a contrast-outlined diverticulum
at the level of the cervicothoracic junction. More recent studies suggest a diagnostic and prognostic role for CT-
myelography [18]. It has been reported that exploration of the brachial plexus is not productive since the extent of
the lesion cannot be determined at that level [19]. In general, the prognosis is guarded to poor. EDX testing will
detect early changes in reinnervation and recovery. Some fibers, following acute injury, may show a temporary
conduction block, from which they will recover within a few days. Since the roots of the radial nerve are commonly
injured in brachial plexus avulsion, an electrodiagnostic evaluation of the radial nerve may provide early
prognostic information: prognosis being poor in animals with initial, decreased radial nerve conduction velocity
[19,509]. If this situation remains unchanged after 4 weeks, with concurrent severe EMG changes in the triceps
muscle, there is virtually no chance of spontaneous recovery. In a recent study of prognostic factors in dogs with
brachial plexus avulsion, the best predictor of complete recovery was pain perception, with 5 of 7 dogs with
normal sensation recovering completely [509]. Muscle tendon transpositions have been successful in some dogs
with partial avulsion. Carpal fusion may be useful in animals with adequate triceps muscle function that have a
tendency to knuckle over on their paws [20]. Amputation of the affected limb may be necessary if the limb is
severely excoriated from dragging or self-mutilation. Experimental studies in dogs suggest that ventral root
reimplantation can successfully promote reinnervation [21,22]. Successful bypass coaptation procedures for
cervical nerve root avulsion have been reported in people [23].
Brachial Plexus Neuropathy-Neuritis

This is a rare, bilaterally symmetrical, neurological condition reported in dogs and cats that involves the nerves of
the brachial plexus [24,25]. It has been suggested that this canine disorder may be the result of an allergic or
hypersensitivity reaction similar to serum neuritis in man following prophylactic inoculations such as tetanus
antiserum. The proposed pathogenesis is that the allergic condition produces spinal nerve swelling and
subsequent compression at the level of the intervertebral foramina. In people, acute brachial plexus neuritis is an
uncommon disorder characterized by severe shoulder and upper arm pain followed by marked upper arm
weakness [26]. At least some forms are considered to represent an immuno-allergic mechanism [27,28]. Brachial
plexus neuritis has also been recently reported in a man associated with herpes zoster [29].
Clinical signs described in a 9 month old Great Dane were characterized by acute onset of thoracic limb paresis
with depressed or absent reflexes and hypotonia, facial paresis and neurogenic atrophy in all thoracic limb
muscles. Pain perception appeared diminished over antebrachial regions. EMG studies revealed denervation
potentials and absence of evoked muscle action potentials in the thoracic limbs. CSF evaluation was normal.
Axonal degeneration was observed in a biopsy of a sensory branch of the radial nerve. This dog manifested two
allergic episodes with facial edema and generalized urticaria over a 48 hour period prior to development of
neurological signs. Immunological testing indicated that these signs were related to an all horse-meat diet. Three
weeks prior to onset of signs the dog had been vaccinated with modified-live rabies virus. No improvement was
noted in this dog 49 days after onset of clinical signs even with glucocorticoid therapy. Pathological findings
include severe, asymmetrical axonal and myelin degeneration (characteristic of Wallerian degeneration) of
peripheral nerves of the brachial plexus. The changes were most severe in the proximal ventral roots where there
was axonal loss, variable axonal regenerating clusters, increased endoneurial fibrosis, many lipid-containing
macrophages, and many endoneurial mast cells. Retrograde chromatolytic lesions were seen in the ventral horns
cells of the cervical intumescence as well as in dorsal root ganglion cells. In a 1.5 year old Doberman Pinscher
with brachial plexus neuropathy characterized by axonal degeneration, slight improvement was reported 4 months
after signs first developed. No treatment was given. A milder form of brachial plexus neuropathy has been
reported in several dogs presented with shifting thoracic limb lameness and diffuse EMG changes typical of
denervation [20]. Myelography and CSF analysis were normal. Some of these dogs were steroid-responsive,
while others clinically improved when fed poultry-based diets that contained no beef or horse products.
Brachial plexus neuropathy has been reported in a cat with clinical signs similar to those in the dog [30]. Reflexes
in thoracic limbs were depressed and nerve conduction velocity was markedly reduced in the median nerve;
however, EMG studies in thoracic limbs were normal. The cat recovered spontaneously over a three-week period.
The neuropathy was thought to be causally related to vaccination with modified live rabies virus.
Congenital Hypomyelination Neuropathy

In contrast with CNS hypomyelination, hypomyelination of the peripheral nerves is rare, but has been reported in
two Golden Retriever littermates [31,32]. Both dogs were presented for pelvic limb ataxia at 7 week of age. Both
had a crouched stance, mild pelvic limb atrophy, and weakness. Circumduction was evident in pelvic limbs when
walking, and a bunny hop gait was present when running. Segmental spinal reflexes were depressed or absent in
all limbs. Motor nerve conduction velocities were markedly reduced in sciatic-tibial and ulnar nerves. Needle EMG
studies were normal except for rare denervation potentials in a few muscle groups. Teased nerve fibers were
difficult to see because of lightness of myelin staining. Light and electron microscopic findings included reduced
number of myelinated axons, presence of myelinated sheaths inappropriately thin for the calibre of the fiber, poor
myelin compaction, increased numbers of Schwann cell nuclei, increased concentration of neurofilaments in
myelinated axons, many Schwann cells with voluminous cytoplasm, and increased perineurial collagen. Onion
bulb formation was not seen and there was no evidence of demyelination. In contrast to controls, a poor
correlation was seen between numbers of myelin lamellae (ML) and axonal circumference (AC). The frequency
distribution of ML ranged from 5 to 55 lamellae in affected animals (mean, 28 lamellae) compared to 20 to 140
lamellae in controls (mean, 66 lamellae). The ML/AC ratio was reduced in nerves of affected dogs. Morphometric
results indicated that fibres of all calibres were hypomyelinated. Axons appeared normal. Possible Schwann cell
defect or abnormal axon-Schwann cell signaling were suggested to account for the hypomyelination [31]. The
defect appears to be reversible since both dogs clinically improved. Repeat nerve biopsies around 2 years of age
showed that myelination had increased, although it was still less than normal. Motor nerve conduction velocity
studies also showed improvement, but were only about half normal values. Both affected dogs were able to live a
normal life span.
The condition appears similar to the rare congenital hypomyelination neuropathy (CHN) in children [33]. CNN is a
member of a heterogeneous group of hereditary demyelinating/dysmyelinating peripheral neuropathies that
includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot - Marie - Tooth disease (CMT),
and Dejerine-Sottas syndrome (DSS), all of which may represent a spectrum of related "myelinopathies" due to
an underlying defect in myelination [34]. Some forms of CHN are associated with missense point mutations of
PMP22 (peripheral myelin protein 22) leading to possible disruption of Schwann cell growth and differentiation
[35,36]. CHN has also been identified in people with a mutation in the gene for protein zero (P0) [37].
Note that hypomyelination may also occur in various storage disorders. Using ultrastructural morphometric
studies of G-ratios, we have recently identified universal hypomyelination in cats with alpha-mannosidosis [38]
and in dogs with globoid leukodystrophy [39].
Dancing Doberman Disease

Dancing Doberman disease (DDD) is a term given to a chronic, slowly progressive, neuromuscular disease that,
to date, has only been described in Doberman Pinschers [40,41]. Recent studies suggest the condition is
inherited as an autosomal recessive trait (Dr. Janet Steiss, Tuskegee University, unpublished data, 2002). DDD
was originally regarded as being either a behavioral disorder or a sensory neuropathy [40], and later as a possible
distal polyneuropathy [42]. Dogs of either gender, from 6 months to 7 years of age, initially manifest flexion of one
pelvic limb when standing. Similar signs may be noted in the opposite pelvic limb several months later, and
affected dogs begin to alternately flex and extend each pelvic limb in a dancing motion and prefer to sit rather
than stand. The condition progresses insidiously over several years. There is apparent pelvic limb weakness,
proprioceptive deficits, and gradual atrophy of pelvic limb musculature, especially the gastrocnemius muscles.
Pelvic reflexes are normal or hyperactive. Affected dogs do not appear to be in pain based on subjective
examination, including manipulation or palpation of the affected limb(s) or spine. Mild numbers of positive sharp
waves and fibrillation potentials have been detected on EMG testing in some animals, primarily involving the
gastrocnemius muscle(s). Bizarre high frequency discharges may develop after several years. Sensory and motor
nerve conduction velocities are normal. Results of hematology, blood chemistries, serum creatine kinase levels,
thyroid function testing, CSF analysis, and joint fluid examinations are within normal limits. Histopathologic
changes in most muscles are minimal. However, changes are seen in the gastrocnemius muscle(s) including
multifocal atrophy and hypertrophy, numerous fibers with internal nuclei, focal necrosis, endomysial/perimysial
fibrosis, and sometimes, histochemical fiber type grouping. These changes resemble findings seen in adult canine
myotonic myopathy. Reported nerve changes in older dogs are variable, but including demyelination and
remyelination, and occasional axonal necrosis [41]. In samples from one 9 year old Doberman examined in my
laboratory, the nature and incidence of neurogenic changes in several peripheral nerves and nerve roots were
similar between left and right pelvic limbs and between proximal and distal samples, thus ruling against a distal
neuropathy in this case. The incidence of changes was considered to be higher than those associated with
normal aging. In another nerve biopsy examined in our laboratory from a 1 year old Doberman with clinical signs
of Dancing Doberman disease, severe degenerative changes were seen that were dominated by axonal necrosis.
In a recent study of DDD conducted at Scott-Ritchey Research Center, Auburn University College of Veterinary
Medicine (Dr. Janet Steiss, Tuskegee University, unpublished data), degenerative changes were found in mixed,
sensory, and sympathetic nerves suggesting either a sensorimotor autonomic neuropathy or possibly a sensory
autonomic neuropathy. In this study, ultrastructural changes included myelinoaxonal necrosis and scattered
presence of denervated Schwann cells involving myelinated and unmyelinated fibers. The proprioceptive deficits
and mild or absent EMG changes in most muscles (with the exception of the gastrocnemius muscle) might
suggest that DDD is a sensory neuropathy, with similarities to the rare hereditary sensory and autonomic
neuropathies in humans (HSAN) [43]. In these conditions, there is selective involvement of the peripheral sensory
and autonomic neurons, with axonal degeneration. The symptoms are related to which population of neurons is
affected. In some types of HSAN, patients are afflicted with the abnormal sensation of burning soles or other
forms of dysesthesia. Similar discomfort associated with pressure on the feet could account for the constant lifting
of the feet in dogs with DDD. The changes in the gastrocnemius muscles from DDD dogs remain enigmatic and
do not appear to be neurogenic, although there are instances in which myopathic-appearing lesions (e.g.,
rounded atrophic/hypertrophic with central nuclei, fiber splitting, increased endomysial fibrosis, whorled, and fiber
degeneration/regeneration) occur in primary neuropathies, e.g., Charcot - Marie - Tooth disease type 2, a form of
hereditary sensory and motor neuropathy in people [44]. Perhaps the muscle changes reflect some form of reflex
sympathetic dystrophy, a syndrome characterized by a triad of autonomic, motor, and sensory symptoms
associated with abnormally increased sympathetic tone [45]. The presence of abnormal thermographic patterns
seen in some affected dogs might be compatible with an imbalance between activity of sympathetic
vascoconstrictor nerves supplying arteries and those supplying veins, potentially leading to muscle
necrosis/atrophy [46]. Further studies should help clarify this confusing disorder.
At present, there is no treatment. Therapeutic trials using diazepam and primidone have not been effective. The
long-term prognosis for a pain-free, acceptable pet is good [41]. To date, there have been no reports of
spontaneous clinical improvement or resolution of signs in any affected dogs.
Deafness
Deafness or hearing loss may be conductive, sensorineural, or central. In animals, as in humans, the most
common type of deafness is sensorineural hearing loss associated with a lesion in the cochlear or eighth cranial
nerve (see below). Conductive deafness stems from problems within the external or middle ear cavities so that
sound is not conducted into the inner ear. The most common cause of conductive deafness is chronic otitis
externa-media, sometimes in association with cholesteatomas [47]. Other causes include external ear canal
occlusion or ablation, atresia of the external acoustic meatus, rigidity or rupture of the tympanic membrane,
damage to the ossicular chain (stapes, malleus and incus), or fluid within the middle ear [48,49]. Congenital
palatine defects in dogs and cats may predispose to middle ear disease and hearing loss [50]. Conduction
deafness has been noted in Scottish fold osteodystrophy [51]. Central hearing loss resulting from damage to CNS
auditory pathways is rare in people and in animals. Central deafness has been noted in Labrador retrievers with
spongy degeneration of the CNS [52]. In one study of deaf Dalmatian puppies, morphological abnormalities were
found in the temporal lobes, medial geniculate bodies, acoustic tracts of the tectal surface, caudal colliculi, pons,
medulla oblongata and trapezoid bodies, indicative of retarded development of the CNS (with a 40% reduction in
the area of the acoustic cortex) [53].
Sensorineural deafness resulting from cochlear abnormalities may be congenital or hereditary, acquired due to
ototoxic drugs or inflammatory diseases, or associated with normal aging.
Congenital sensorineural deafness is usually present from birth, or within a few weeks post-natally, and it is
permanent. Some animals are affected unilaterally. The etiology of congenital deafness is unclear. Maternal
exposure to ototoxic drugs, such as streptomycin, or viral infection has been suggested as a cause in some
instances of congenital deafness [54]; however, the incidence of deafness from these causes is considered to be
low [55]. Autosomal recessive disorders have been reported in Bull Terriers [56], Doberman Pinschers [57], and in
colony Pointers selectively bred for excessive nervous behavior [58], and have been cited for Rottweilers and
Pointers [55]. Congenital deafness is frequently associated with pigmentation disorders such as a white coat color
and blue eyes [55,59-62]. Coat color abnormalities have been linked with the "merle" color gene. In heterozygotes,
this dominant gene will increase the amount of white in the animal's coat, cause dappling in the pigmented
portions of the coat, and also alter the pigment in the tapetum and iris. In the homozygous state the gene
commonly produces a nearly all white animal that is deaf and blind. Congenital/hereditary deafness is frequently
seen in blue-eyed white cats (transmitted as an autosomal dominant trait), Dalmatians, Australian Heelers,
English Setters, Catahoulas, and Australian Shepherds. The Dalmatian reportedly has the highest prevalence of
deafness of all canine breeds, with an overall incidence from 15 to 30% [54,63-65]. The condition in Dalmatians is
consistent with an autosomal recessive, multifactorial gene with incomplete penetrance [66]. The deafness may
be unilateral (most common) or bilateral. In a recent study involving > 3000 Dalmatians, an increased prevalence
of deafness was found in females, especially in those with two blue eyes [67]. In this study, there was no
difference in the prevalence of hearing loss between offspring of deaf mothers and the offspring of deaf sires.
Congenital deafness has been noted in numerous canine breeds (Old English Sheepdogs, Norwegian
Dunkerhound, dappled Dachshund, Harlequin Great Dane, Shetland Sheepdog, Samoyed, Great Pyrenees,
Sealyham Terrier, Greyhound, Beagle, Maltese Terrier, Bulldog, Boxer, Akita, American Staffordshire Terrier, Fox
Terrier, Miniature Poodle, Papillon, Ibizan Hound, Kuvasz, Saint Bernard, Rhodesian Ridgeback, Scottish Terrier,
West Highland White Terriers, Cocker Spaniels, Border Collies, Scotch Collies, Boston Terriers, Walker American
Foxhounds, and Shropshire Terriers [55,68], but the mode of inheritance remains to be defined.
In animals with congenital deafness, pathological findings consist of total or partial agenesis of the organ of Corti,
the spiral ganglion, and the cochlear nuclei [69-72]. Additionally, in congenitally deaf Collie and Dalmatian
puppies, partial collapse of the saccule, atrophy of the saccular nerve and obliteration of the cochlear duct have
been described [73]. Some forms of hereditary deafness are thought to be associated with cochleosaccular
degeneration in which the stria vascularis is atrophic due to absence of normal pigment cells [55,72]. This leads to
secondary degeneration of the organ of Corti, and collapse of the saccule. In a study of congenital deafness and
vestibular disease in young Doberman Pinscher puppies, histopathologic studies revealed that all affected
puppies had a non-inflammatory neuroepithelial degeneration of the cochlea with a progressive loss of the
auditory sensory hair cells, resulting in almost complete loss of the organ of Corti by 11 weeks of age [57].
Acquired sensorineural deafness can result from various ototoxic agents [74,75]:
1. Aminoglycoside antibiotics are the most common ototoxic drugs. These drugs concentrate in perilymph
and endolymph, thus exposing the cochlear hair cells to high concentrations of the drugs (note that
cochlear hair cell activity is dependent on endolymph fluid production by the stria vascularis). While all
aminoglycoside antibiotics can damage auditory and vestibular receptors, streptomycin and gentomycin
have their greatest effects on the vestibular system, whereas, neomycin, kanamycin, tobramycin, and
amikacin sulfate produce more damage to the auditory peripheral receptors. The toxic effects of these
drugs is believed to be heightened if the tympanic membrane is perforated. Experimental studies suggest
enhanced ototoxicity with nutritional deficiency [76].
2. Other ototoxic antibiotics - topical polymixin B and chloramphenicol.
3. Antiseptic solutions - ethanol, iodine, iodophors, chlorhexidine, benzalkonium chloride, benzethonium
chloride, and cetrimide. Chlorhexidine combined with cetrimide is especially toxic in dogs and cats.
Interestingly, the use of 0.2% chlorhexidine acetate is reportedly safe when instilled into the external ear
canals of normal dogs for a period of 3 weeks (and no signs of ototoxicity occurred in dogs with surgically
perforated tympanic membranes) [77].
4. Diuretics - ethacrynic acid, bumetanide, and furosemide. These agents induce changes in the stria
vascularis of the cochlear.
5. Antineoplastic agents - cisplastin, which acts on the hair cells in similar fashion to the aminoglycoside
antibiotics.
6. Miscellaneous agents used in otic preparation - propylene glycol, ceruminolytic agents and detergents,
especially if the tympanic membrane is ruptured.
7. Overdosage with closantel, a salicylanilide derivative, produced a reversible hearing loss in a dog [78].
Neuroepithelial degeneration, in which the organ of Corti is primarily affected, reportedly occurs mainly with
acquired deafness [55]. Acquired sensorineural deafness occurred in a 3 year old Collie dog with disseminated
protothecosis, in which Prototheca organisms disrupted the tectorial membrane and destroyed the organ of Corti
[79]. Other causes of acquired sensorineural hearing loss in people include toxin exposure (e.g., high dose
aspirin), Ménière’s disease (paroxysmal symptoms of tinnitus, fluctuating hearing, monaural fullness, and episodic
vertigo), and noise [80].
Normal Aging - Hearing impairment is also commonly noted in dogs with normal aging. The loss of ability to
perceive or discriminate sounds associated with aging in people is termed "presbyacusis". In one study, hearing
loss in older dogs was associated with atrophy and loss of spiral ganglion neurons of the cochlea [81]. This loss of
neurons and nerve fibers in the osseous spiral lamina was thought to be secondary to loss of hair cells and
supporting cells in the organ of Corti. Similar changes have been previously reported in a 20 year old dog and in a
19 year old cat with progressive hearing loss [82].
While hearing is very difficult to assess accurately using response to sounds such as clapping, electrodiagnostic
testing using the brainstem auditory evoked response (BAER) method (also known as auditory brainstem
response) can provide early diagnosis of deafness, allowing breeders and owners to avoid propagating further
affected litters [64,83-85]. The BAER is the only reliable method of identifying animals with unilateral hearing loss
[86]. Bone conduction thresholds, using a bone vibrator against the head (e.g., mastoid process, mandible or
zygomatic arch), can also be used to confirm conductive hearing impairment in the dog in the same way as in
humans [87,88]. The ear canals open between 12 and 14 days in dogs and at 5 days after birth in cats. Mature
hearing patterns are established by 30 to 40 days of age in dogs (e.g., 67Hz to 45kHz) and by 20 to 30 days in
cats (e.g., 45Hz to > 64kHz) [55]. Deaf animals can be difficult to arouse from sleep, may be more aggressive
than normal littermates, and may be very vocal. There is no treatment.
Deafness also has been reported in young dogs and cats accompanied by signs of peripheral vestibular disease.
It has been seen in colony Beagles, Akita and Doberman Pinscher puppies, and Siamese kittens [89]. Clinical
signs, which usually begin at 3 - 12 weeks of age, include head tilt, circling, and ataxia. Nystagmus is not a
feature of this disorder, but there is a deficit in normal eye movements. With the exception of the Doberman
Pinscher puppies in which severe degenerative lesions were found (see above), histopathologic lesions have not
been reported. The vestibular signs are generally not progressive, and improvement is usually seen over a period
of weeks or months. This is probably due to visual and somatosensory compensation rather than resolution of the
problem. Deafness in these animals is usually permanent. In affected Doberman Pinschers (in which the disease
is inherited as an autosomal recessive trait), hearing was absent in all puppies three weeks of age or older.
Prognosis in animals with hearing loss will vary according to the cause. Treatments are mainly focused on
preventing further damage, e.g., avoidance of ototoxic medications in animals with mild sensorineurial damage.
Correction of causes of conductive deafness may be ameliorative. Hearing aids seem to work best in human
patients with conductive deafness [80]. At this time, comprehensive trials evaluating hearing aids are lacking in
dogs and cats with hearing loss. There is a recent report on surgical placement of a bone-anchored hearing aid in
a dog with conductive deafness [90].
Diabetic Neuropathy
Spontaneous diabetes mellitus is a well-recognized metabolic disorder in dogs and cats associated with impaired
utilization of carbohydrates and enhanced lipid and protein use. Central nervous system effects of this metabolic
condition relate to two hyperglycemic syndromes: diabetic ketoacidosis and nonketotic hyperosmolar
hyperglycemia (see diabetes mellitus). Diabetes mellitus may also be associated with peripheral nerve disease,
with sporadic cases of spontaneous diabetic neuropathy reported in adult dogs and cats [91-98]. Recently, a
retrospective study encompassed 19 cats with spontaneously-occuring diabetes neuropathy [519].
Clinical signs of diabetic neuropathy are extremely variable ranging from an insidious subclinical condition to one
with an acute or chronic onset of weakness, progressive paraparesis, proprioceptive deficits, muscle atrophy and
depressed spinal reflexes. Cats often assume a plantigrade posture in pelvic limbs. Lumbosacral hyperesthesia
has been noted in affected dogs and cats [93,94,96]. Diabetic cataracts may be present. Hypotension has been
documented in a dog with diabetic neuropathy [94].
Electrodiagnostic (EDX) testing has revealed fibrillation potentials, positive sharp waves and fasciculation
potentials in muscles, decreased motor and sensory nerve conduction velocities, and decreased amplitudes of
evoked compound muscle action potentials (CMAPs). Temporal dispersion/diminished amplitude of CMAPs
evoked by stimulation at the hip, as compared with potentials evoked by stimulation at the hock [94,99], suggest
conduction block. Rarely, bizarre-high frequency discharges (myotonic-like) have been recorded in dogs with
clinical/subclinical diabetic neuropathy [94,99]. In the cat retrospective study, EMG abnormalities were mainly
restricted to the most severely affected cases [519]. Pathological findings reported in dogs and cats range from
active axonal degeneration to demyelination-remyelination and axonal regeneration, along with neurogenic
skeletal muscle fiber atrophy [91,93,96,100]. In a 8 year old female Doberman Pinscher with diabetic neuropathy,
axonal degeneration was the dominant finding (involving approximately 35 to 40% of teased nerve fibers) in
biopsies of lateral and medial plantar nerves [93]. In one teased nerve fiber study involving diabetic dogs without
signs of clinical neuropathy, the dominant lesions were demyelination, remyelination, and less prominent axonal
degeneration and teased nerve fibers with evidence of axonal regeneration [91]. Semi-thin sections revealed
scattered thinly myelinated fibers and regenerating clusters of myelinated fibers. Early onion-bulb formation was
seen ultrastructurally. Morphometric analysis revealed that the changes occurred in larger-caliber fibers from
distal plantar nerves but not in more proximal tibial nerves. The results of this study, and the EDX testing of these
dogs [99], suggest that some forms of diabetic neuropathy in dogs (and cats?) reflect a distal polyneuropathy that
involves motor and sensory nerves.
Diagnosis is based on laboratory evidence of diabetes mellitus (hyperglycemia, glycosuria, insulin assays) and
clinical, neurological, electrophysiological, and nerve biopsy data. EDX testing is a useful non-invasive technique
for detecting animals with subclinical diabetic neuropathy [99]. Prognosis is guarded; however, partial or full
recovery can occur with good diabetic control from insulin therapy [93,94,96]. A high fibre diet has been shown to
significantly improve glycemic control and quality of life in dogs with diabetes mellitus [528]. Preliminary studies
suggest that sulindac (a substituted indene acetic acid) may ameliorate some histological abnormalities in
experimental diabetic dogs [527].
We have observed a polyneuropathy (dominated by axonal degeneration) in a diabetic 4 month old Chow Chow
puppy with pancreatic islet cell hypoplasia in which there was absence of delta cells, and diminished numbers of
alpha and beta cells [101]. We have also seen degenerative changes in nerves from young Keeshonds with
inherited diabetes mellitus (K.G. Braund and J.W. Kramer JW, unpublished data). Prognosis is guarded. At
present, there is no effective treatment for the diabetic neuropathy; however adequate and long-term dietary and
insulin control of the hyperglycemia can result in marked clinical improvement [93,102].
In people, a variety of PNS disorders may be seen with diabetes, including focal disorders (focal myopathies and
mononeuropathies, often associated with injections and entrapment/compression/infarction, respectively),
segmental disorders such as diabetic polyradiculoneuropathy, and generalized neuropathies such as diabetic
distal symmetrical sensorimotor polyneuropathy (DDSPN) and diabetic autonomic neuropathy [103]. Diabetic
autonomic neuropathy often occurs as a continuum of the symmetrical polyneuropathy [104]. DDSPN is the most
common form and its glove-stocking distribution of paresthesia and numbness, the distal to proximal gradient of
EDX abnormalities, and predominantly axonal involvement (especially of large myelinated fibers) are consistent
with a dying-back neuropathy [105], while autonomic involvement leads to a various dysautonomic signs,
including hypotension, pupillary miosis, and constipation. One characteristic pathological feature of diabetic
nerves is hyalinization of endoneurial microvessels, typically associated with reduplication and thickening of
microvascular basement membranes, and perineurial cells may have a thickened basal lamina [106,107]. Recent
studies have also demonstrated significant abnormalities of the perineurium in the spontaneously diabetic dog
(total perineurial sheath thickness, mean perineurial lamellar width, total interlamellar space, and perineurial cell
basement membrane thickness [108]). Endoneurial capillary basement membrane area was significantly
increased in experimentally-induced (alloxan/streptozotocin) diabetic dogs [527], similar to that found in diabetic
people. In this report, there was no loss of capillaries.
The pathogenesis of diabetic neuropathy remains unknown, although interaction of multiple factors is considered
likely [109-111], including interactions between vascular factors (decreased nerve perfusion/endoneurial hypoxia,
changes in endoneurial microvasculature) and metabolic factors (hyperglycemia, enhanced glycation end product
formation, intraneural polyol pathway activation, protein C activation, and omega-6 essential fatty acid
dysmetabolism) [112,113]. One study in diabetic cats demonstrated evidence of polyol pathway activity (marked
increases in nerve fructose without appreciable sorbitol accumulation) [519]. Deficiency of several neurotrophic
factors, namely nerve growth factor, neurotrophin-3, and insulin-like growth factors have also been implicated in
diabetic neuropathy [114,115]. Preliminary clinical trials have demonstrated improvement in signs and symptoms
of sensory neuropathy in human patients with lower extremity vascular occlusive disease after intramuscular
injection of naked DNA encoding vascular endothelial growth factor [116], although it is uncertain if these positive
effects result from an angiogenic activity (formation of new blood vessels) or a direct neurotrophic effect [117].
Inflammatory cell infiltrates in nerves of diabetic people (particularly in those with diabetic autonomic neuropathy)
also suggests that inflammatory or immune mechanisms may be involved [110]. While axonal degeneration
appear to be the dominant pathology in patients with DDSPN, it remains to be determined if the myelin changes
are secondary to an axonopathy or develop from a primary schwannopathy [105]. Note that insulin deficiency is
probably not related to the diabetic neuropathy since nerves (just as the CNS) are not dependent on insulin for
glucose uptake/energy utilization [118].
Distal Denervating Disease
This degenerative neuropathy is reportedly the most common canine polyneuropathy in the United Kingdom
[119,120], but has not been reported elsewhere. In this disorder there is no breed, sex, or age predisposition. The
etiology and pathogenesis are presently unknown. Affected animals have had no history of exposure to toxins.
The rate of onset of clinical signs is variable from 1 week to greater than 1 month. The main presenting sign
reported is tetraparesis. In some dogs, the head and neck cannot be supported and there is loss of voice.
Mastication, swallowing, respiration and bladder function are unimpaired. Pain sensation is preserved. Muscle
atrophy may be prominent, especially involving proximal extensor muscles. There is hypotonia and depressed or
absent patellar reflexes. Facial nerve dysfunction has been observed. Moderate to marked spontaneous
potentials (fibrillations and positive sharp waves) are present in limb, paraspinal, masticatory muscles, and tongue.
Motor nerve conduction velocities are in the low-normal range. The amplitude of evoked potentials is reduced.
Sensory nerve potentials are normal. Pathologically, there is degeneration of the distal intramuscular axons with
collateral sprouting. Skeletal muscle changes are typical of neurogenic atrophy. Proximal and middle portions of
peripheral nerves are normal, and there is no evidence of sensory nerve damage. The prognosis for full recovery
is good, with appropriate nursing care. Most dogs recover spontaneously within 4 to 6 weeks of onset of clinical
signs. Recurrence has not been reported. The condition is clinically similar to Coonhound paralysis and idiopathic
polyradiculoneuritis, although the later diseases tend to run a more acute course.
Distal Symmetrical Polyneuropathy

A distal symmetric sensorimotor polyneuropathy has been reported in young adult Great Danes (1.5 to 5 years)
[121,122]. The cause and pathogenesis are not known; however, an inherited dying-back process of peripheral
axonopathy has been suggested. Clinical signs include chronic pelvic limb paresis that progresses to involve
thoracic limbs, and bilateral atrophy of head (masticatory) and distal limb muscles. A reduced response to painful
stimuli has been observed. Electrodiagnostic studies reveal fibrillation potentials, positive sharp waves in distal
limb muscles (below stifle and elbow), and absence of evoked muscle action potentials. Diagnosis is based on
clinical, electrodiagnostic, and nerve biopsy data. Prognosis is poor. Affected dogs have shown no response to
corticosteroids or thyroid hormone supplementation. Results of pathological and morphometric studies of
peripheral nerves reveal myelinated nerve fiber degeneration and loss, especially of larger-caliber fibers, which
are accentuated in distal parts of appendicular and laryngeal nerves. Varying degrees of demyelination and
remyelination may also be present. Sensory and autonomic nerves are affected to a lesser degree. No lesions are
found in the CNS.
In a 3 year old, male Setter-cross, an almost identical polyneuropathy was noted after canine heartworm disease
therapy (thiacetarsamide), which was complicated by disseminated intravascular coagulation [123]. Indeed, it now
seems that this polyneuropathy is not specific for Great Danes, since we have seen similar clinical signs and
pathology in several other large-breed dogs, including Chesapeake Bay Retriever, St. Bernard, Newfoundland,
Collie, Labrador Retriever, and Rottweiler (see Rottweiler Sensorimotor Polyneuropathy). Treatment, including
corticosteroids, has been disappointing in dogs with distal symmetrical polyneuropathies; however, results of a
recent therapeutic trial using prosaptide TX14(A), a homologue of a neurotrophic peptide sequence within the
lysosomal protein sapsonin C, indicated promising beneficial clinical and pathological effects in some dogs [512].
Dysautonomia
This disease has been frequently reported in cats [124-134] and dogs [129,135-142]. It was first reported in cats
by Key and Gaskell [124] in the United Kingdom, where it is still mainly restricted, although it now appears to have
a world-wide distribution [143]. It is much less common in the United Kingdom today than it was in the 1980's,
although there have been recent outbreaks in closed cat colonies [144,145]. The etiopathogenesis of this disease
is unknown. Immunological studies in affected cats have revealed no abnormalities [146]. In one study, there was
no consistent factor identified when management, vaccinal status, and drug therapy were examined [147].
Attempts to transmit the disease have been unsuccessful. However, recent demonstration of antibodies against
the nicotinic ganglion acetylcholine receptor in some dogs with dysautonomia (as also found in human patients
[513]) suggests a possible autoimmune basis for this disease [514].
The condition has been reported in cats from 6 weeks to 11 years of age. In the majority of cases, clinical signs
develop in less than 48 hours, but may take up to 7 days. Historically, cats begin vomiting/retching and become
depressed and anorexic. The third eyelid protrudes, pupils are dilated and poorly responsive to light stimulation
(but usually responsive to pilocarpine), and lacrimation is reduced. Cats may be febrile, emaciated, constipated
(sometimes with fecal impaction) and dehydrated. Urinary and fecal incontinence may develop. Sneezing may
occur and the nose is often dry. Dried exudate may block the external nares. Occasionally, very mild posterior
ataxia or more generalized paresis, depressed proprioception, and absent anal reflex have been detected. Many
cats have bradycardia of less than 120 beats/minute. Some animals manifest transient syncopal episodes. A
clinical grading system has been proposed [148]. Megaesophagus is often present and is usually associated with
regurgitation. The putative role of the parasympathetic system in the development of the megaesophagus
appears somewhat complicated. This sign usually occurs with damage to the special visceral efferent system
emanating from the solitary tract/nucleus [149]. The parasympathetic vagal nucleus gives rise to the general
visceral efferent (GVE) axons that innervate the smooth muscle of the digestive system, and while experimental
lesions of the parasympathetic nucleus reportedly cause esophageal paralysis in cats, it has been suggested that
the GVE vagal neurons are not critical for direct initiation of smooth muscle activity in the digestive tract since
intestinal peristalsis and colonic mass movement are maintained by intrinsic neural mechanisms [149].
Dysautonomia in dogs is common in parts of the United States [142], especially around SW Missouri, NE
Oklahoma, and Eastern Kansas. More than 50 canine cases have been confirmed at the University of Missouri
(Dr. Dennis O'Brien, University of Missouri; personal communication, 2000). Recently, the condition was
diagnosed in a family of German Shorthaired Pointers (the dam and 4 of 5 puppies) [150]. In dogs, signs may be
non-specific [151]: lethargy, depression, anorexia, retching, regurgitation, vomiting, salivation, constipation, or
more commonly, diarrhea. Other signs include dry crusty nose, dry oral mucous membranes, subnormal Schirmer
tear tests, dilated or anisocoric pupils (poorly responsive to light), prolapsed nictitating membranes,
megaesophagus, decreased anal tone, and distended incontinent urinary bladder. Heart rate is often < 120
beats/minute (even after exercise), and neurological abnormalities such as twitching jaw muscles, cervical
hyperesthesia, dilated anal sphincter, and decreased patellar reflexes have been observed sporadically. Affected
dogs of different breeds have ranged in age from 4 weeks to 5 years.
Diagnosis may be facilitated by ocular pharmacological testing to confirm post-ganglionic sympathetic and
parasympathetic dysfunction [127,131,142,148]. For example, rapid pupillary constriction following instillation of
0.1 to 0.05 % pilocarpine into the eyes of affected animals is suggestive of denervation hypersensitivity [127].
Decreased urinary catecholamine measurements (e.g., catecholamines and catecholamine metabolites,
metanephrine and vanillylmandelic acid) are indicative of sympathetic failure and may be another useful
diagnostic tool [127,152]. The bradycardia typically is unaffected by administration of anticholinergic drugs, such
as atropine.
While many of the clinical signs (e.g., dry mucous membranes, mydriasis, regurgitation/constipation) suggest
involvement of the parasympathetic nervous system (although bradycardia reflects sympathetic involvement)
[153], the pathology primarily involves neuronal perikarya especially of autonomic ganglia, both sympathetic and
parasympathetic [125,126,153,154]. Note that some signs, such as proprioceptive deficits and anal sphincter
dysfunction, are non-autonomic. Lesions are characterized by chromatolytic changes in autonomic neurons (with
loss of Nissl substance and eccentric/pyknotic nuclei), neuronal degeneration and loss, neuronophagia, and
occasionally mild mononuclear perivascular cuffing (in one report, the majority of mononuclear cells were T
lymphocytes [140]). In another report, 2 of the least affected cats had evidence of eosinophilic polymorphonuclear
cells in several autonomic ganglia [144]. Ultrastructurally, there are dilated cisternae of rough endoplasmic
reticulum, loss of Golgi complex, and large stacks of smooth parallel membranes which suggest possible
disruption of neuronal glycoprotein biosynthesis [155,156]. In a dog with dysautonomia, numerous multilamellated
bodies and myelin figures were seen in neuronal cytoplasm [137]. Degeneration has been found in many
autonomic nerves with variable changes in myelinated and unmyelinated axons, including increased numbers of
microtubules, which can be misaligned, vesicles, and branched vesiculotubular arrays of smooth endoplasmic
reticulum. Changes are also frequently present in dorsal nucleus of the vagus and motor nuclei of cranial nerves
III, V, VI, VII, and XII, ventral horn cells, and intermediolateral gray matter of spinal cord [140]. Note that
degenerative changes (axonal degeneration, demyelination) may also be found in peripheral somatic nerves (e.g.,
common peroneal nerve) of dogs and cats. In cats, enteric neurons are also affected based on reported depletion
of immunoreactivity for vasoactive intestinal polypeptide, metenkephalin, and substance P in peptidergic neurons
throughout the gastrointestinal tract [148]. Sensory ganglia (e.g., dorsal root ganglia and ganglia of cranial nerves)
are affected to a much lesser degree. The pathology has features in common with grass sickness of horses.
No specific treatment is available but supportive therapy is indicated and can be successful [132,157]. One review
recommends correction of hypovolemia, hypothermia, hypoglycemia, and other electrolyte abnormalities;
metoclopramide for vomiting and enhanced gastrointestinal motility; bladder evacuation (e.g., manually and/or
with bethanechol); enemas for constipation; and total parenteral nutrition or tube gastrostomy for long-term
alimentation [148,158]. Ophthalmic administration of parasympathomimetic drugs (e.g., 0.25 to 1.0 % pilocarpine)
may stimulate lacrimal and oral secretions [157]; however, repetitious vomiting/regurgitation may become a
complication [127]. Prognosis in dogs and cats is guarded to poor [158], especially in animals that suffer from
persistent regurgitation/vomiting with heightened risk of inhalation pneumonia [148,151]. In one study, 28 of 40
cats did not survive the illness [154]. Cats that begin to produce secretions and eat and drink have the best
prognosis. Clinical recovery make take up to 12 months. In affected dogs, mortality may exceed 90% [142,158].
In people, autonomic nervous system disorders may be associated with (a) diffuse autonomic failure
(pandysautonomia), subcategorized into preganglionic, ganglionic/postganglionic, and peripheral
neuropathies/neuronopathies with autonomic failure, and (b) those related to pure cholinergic or adrenergic
disorders [159].
Facial Paralysis
Idiopathic facial nerve paralysis of acute onset has been reported in mature dogs and cats (e.g., > 5 years). There
is an apparent predisposition for Cocker Spaniels, Pembroke Welsh Corgis, Boxers, English Setters, and
Domestic Longhair cats [160,161]. The cause of this condition is unknown. The facial paralysis is unrelated to
otitis media. In one study of 95 dogs and cats with facial paralysis, the condition was considered to be idiopathic
in 75% of dogs and 25% of cats [161].
Clinical signs are characterized by ear drooping, lip commissural paralysis, sialosis, deviation of the nose away
from the affected side, and collection of food on the paralyzed side of the mouth. Menace response testing and
palpebral reflexes are absent. Facial paralysis may be bilateral in some animals. There is no evidence of Horner's
syndrome in animals with idiopathic facial paralysis. Electrodiagnostic testing may reveal spontaneous
denervation potentials (e.g., fibrillations potentials and positive sharp waves) in superficial facial muscles.
Stimulation of the facial nerve external to the stylomastoid foramen may fail to evoke muscle action potentials.
Skull radiographic/imaging studies are usually non-contributory. Pathological studies of facial nerve biopsies may
reveal active degeneration of large- and small-caliber myelinated fibers [160,162]. Inflammation has not been
reported. Ultrastructurally, numerous macrophages may be present along with ovoids, Schwann cell proliferation,
collateral sprouting, and various stages of remyelination. Prognosis is guarded. Improvement may take place in a
few weeks or months, or may never occur. Chronic lip paralysis may result in permanent contracture, and the
inability to close the eyelids often leads to corneal lesions due to lack of lacrimal lubrication. In one study, dogs
with facial paralysis were ten times more likely to develop keratoconjunctivitis sicca, possibly as a result of
damage to the parasympathetic preganglionic neurons within the facial nerve that pass to the lacrimal gland [161]
(note that these parasympathetic fibers leave the facial nerve at the level of the inner ear, so decreased tear
secretion will indicate a facial nerve lesion between the medulla and the middle ear [149]). Artificial tears may
assist with corneal dryness. In a recent report of idiopathic facial paralysis of 35 days duration in a 7 year old
female Yorkshire Terrier, acupuncture treatments (every other day for the first week, then once a week for the
next 3 weeks) resulted in complete facial symmetry, normal ear movement and sensation, and voluntary closure
of the eyelids [163].
In people, up to 75% of all cases of facial paralysis are also of unknown etiology and are called Bell’s palsy [164].
High risk patients include those with diabetes mellitus or multiple sclerosis, and pregnant women [165]. Present
knowledge suggests that Bell’s palsy is most likely caused by herpes simplex infection and administration of
acyclovir and corticosteroids facilitates recovery in most patients [166].
Acquired unilateral or bilateral facial paresis or paralysis in animals has also been seen in association with myriad
disorders including polyradiculoneuritis (e.g., Coonhound paralysis), hypothyroidism, insulinomas, laryngeal
paralysis-polyneuropathy complex, myasthenia gravis, botulism, middle ear infection/neoplasia, paraneoplastia,
borreliosis, trauma external to the stylomastoid foramen (e.g., compression of the superficial branches of the
facial nerve in anesthetized animals that have been lying in lateral recumbency for prolonged periods of time),
extracranial tumors, or in conjunction with petrosal bone fracture [149,167-175]. Peripheral and /or central facial
paralysis may be seen with brainstem inflammation or neoplasia (including pituitary tumors), and cerebral
ischemia associated with parasitic migration [149,176-179]. It may occur secondary to surgical ablation of the
external ear canal or bulla osteotomy for chronic otitis externa-media [180-185]. Intermittent facial spasms have
been seen in dogs with idiopathic facial paralysis [161] and chronic otitis media [186], and may occur in animals
with central brainstem lesions [187], presumably associated with increased irritability of the facial nerve or facial
nucleus. Facial twitching was seen in a cat with a pancreatic endocrine tumor (insulinoma), removal of which
resulted in clinical remission [188]. Idiopathic paradoxic lacrimation ("crocodile tears") reported in a cat may have
resulted from prior facial nerve paralysis affecting autonomic innervation [189]. In people, this condition (also
known as Bogorad’s syndrome) may follow facial palsy and is thought to result from aberrant migration of
regenerating preganglionic parasympathetic fibers to the pterygopalatine ganglion rather than to the
submandibular ganglion. Consequently during meals, stimulus for salivation results in stimulation of the lacrimal
gland and increased tearing [165].
Familial German Shepherd Neuropathy

A familial neuropathy has been reported in three older (10 years of age) German Shepherd dogs (one male, two
females) that were littermates [190]. Progressive clinical signs, beginning around 9 years of age, included
unsteady hind limb gait, tetraparesis, marked hind limb muscle atrophy, and depressed reflexes. Serological
studies showed marked elevation in total lipids, CK levels, lactic dehydrogenase, and moderate decrease in
aspartate aminotransferase concentration. Grossly, the sciatic nerves appeared swollen and fibrotic in two of the
dogs. Microscopic changes in nerves included marked endoneurial fibrosis, loss of myelinated fibers,
regenerating clusters, and numerous thinly myelinated axons. Active axonal degeneration was also seen, along
with evidence of segmental demyelination/remyelination. No lesions were found in trigeminal and
vagosympathetic nerves. Neurogenic muscle atrophy was observed in skeletal muscles (especially hind limb and
paraspinal muscles) characterized by muscle atrophy/hypertrophy, endomysial fibrosis, fatty infiltration, mild
regeneration, and histochemical fiber type grouping. Collateral ramifications/sprouting and multiple terminal
arborizations were noted in terminal axons entering muscle. Based on these findings, the disorder was
considered to represent an axonopathy with a dying-back pattern. Absence of onion-bulbs and the axonal lesions
in these older dogs also suggested similarities to HSMN type II neuropathy in people, a usually dominant
(sporadic and recessive cases are less commonly seen), distal axonopathy characterized by diffuse loss of larger-
caliber myelinated fibers, little or no active degeneration, and prominent cluster formation [105].
The familial nature of this late-onset German Shepherd disorder is enhanced by the reported involvement of two
other littermates (with less severe clinical signs), and the history that similar signs occurred in the mother and
grandmother.
Giant Axonal Neuropathy
Giant axonal neuropathy (GAN) is a rare inherited (autosomal recessive) neurological disease of German
Shepherd dogs [191,192]. The pathogenesis of GAN is unknown, however it may represent a genetic defect in
slow axonal transport affecting a wide variety of intermediate filaments [120], or altered neurofilament
configuration [193,194]. An inborn error of metabolism of enzyme-linked sulfhydryl containing proteins, leading to
impaired production of energy needed for normal organization of intermediate filaments has been proposed in
human patients with GAN [195]. The neurofilaments in dogs with GAN have a normal polypeptide composition
[196] and are morphologically similar to those seen in human GAN.
In dogs, neurological signs are noted around 14 to 16 months of age, are more obvious in pelvic limbs, and are
progressive. Signs are characterized by paresis, proprioceptive loss, diminished patellar reflexes, and pelvic limb
hypotonia with atrophy of muscles below the stifles. Conscious perception of pain is gradually reduced in pelvic
limbs. Bark may be lost or diminished and there may be fecal incontinence. Megaesophagus develops around 18
months resulting in regurgitation and occasional inhalation pneumonia. By 18 to 24 months of age, tetraparesis is
pronounced. Note that affected dogs often have a very tight curl of their hair coats [193] (kinky/curly hair is a
characteristic finding in children with GAN). Electrophysiologically, amplitudes of evoked compound muscle action
potentials are decreased several months prior to clinical evidence of neuropathy [192,193]. This decrease is
progressive. Denervation potentials are demonstrated by EMG in distal muscles of pelvic and thoracic limbs by 18
months of age.
Pathologically, the disease is characterized by loss of myelinated nerve fibers and presence of giant axons in
myelinated and unmyelinated fibers [197-199]. Myenteric and distal vagal axons are also affected. The swollen
axons contain masses of disordered 10 nm neurofilaments in both nodal and paranodal locations. Axonal
collections of paracrystalline structures may also be seen in canine and human GAN nerves [194]. Similar
morphological changes are found in the CNS with axonal swellings found in the distal portions of the spinal long
tracts (e.g., caudal lumbar segments and rostral cervical segments) and their terminations in the cerebellar vermis,
in the distal optic pathways, nuclei of the habenulo - interpeduncular tract, various thalamic relay nuclei, and the
cerebral cortex [191,198,199]. Other organelles that may accumulate include mitochondria, membranous bodies,
glycogen bodies, amorphous electron dense material, and occasionally, smooth endoplasmic reticulum [199].
Adjacent astrocytic processes may be enlarged with excessive whorling of the glial filaments. Attenuation of the
myelin sheath over the swellings is seen in the PNS and CNS. The predominance of lesions in both PNS and
CNS at the distal ends of large motor and sensory nerve fibers suggests that the disease represents a central-
peripheral, distal axonopathy [191,192,198]. Similar lesions are seen in experimental studies of various
neurotoxins, including acrylamide, IDPN, n-hexane, and methyl-n-butyl ketone [200]; however, the axonal
neurofilamentous accumulations in human and canine GAN differ from those seen with 2,5-hexanedione
neuropathy [194].
Diagnosis is based on signalment, clinical, electrodiagnostic, and pathological (nerve biopsy) data. Prognosis is
poor. There is no treatment.
Hyperadrenocortical (Cushing's) Neuropathy

In our laboratory, we have found evidence of a peripheral neuropathy in several dogs with hyperadrenocorticism.
Changes have included demyelination, remyelination, occasional axonal degeneration, and neurogenic atrophy in
muscle, sometimes accompanied by signs of reinnervation (fiber type grouping). These changes have been
observed in dogs with and without histopathological evidence of hyperadrenocortical (Cushing’s) myopathy.
Electrodiagnostic changes may include fibrillation potentials and positive sharp waves, along with significantly
slowed nerve conduction velocities [515].
Hyperlipidemia
Hyperlipidemia is defined as an excess of blood lipids, and as most lipids in blood are incorporated into
lipoproteins and transported by these particles, the condition is also called hyperlipoproteinemia [201].
Lipoproteins may be separated into four major classes: chylomicrons, very low-density lipoproteins, low-density
lipoproteins, and high-density lipoproteins [201-203]. Chylomicrons and very low-density lipoproteins are involved
primarily in triglyceride transport, while low-density lipoproteins and high-density lipoproteins are involved with
cholesterol transport [204]. Chylomicrons are composed predominantly of triglyceride and are cleared from the
plasma by lipoprotein lipase and its cofactor, apoprotein C-II (apo C-II). Removal of triglyceride from the core of
the chylomicron leaves a cholesterol-rich remnant particle that is removed from the circulation by the liver
[201,202,205]. Lipid disorders infrequently involve the nervous system in dogs and cats, with the notable
exception of hyperchylomicronemia, a familial condition in cats that is characterized by fasting
hyperchylomicronemia. This lipid disorder appears to have a world-wide distribution, with reports from New
Zealand, United States, and Europe [206-209]. Various breeds of cats have been documented including Domestic
Shorthair, Himalayan, European, Persian, Siamese, and Domestic Longhair [205,208]. The underlying
biochemical lesion is associated with a reduction in lipoprotein lipase activity. Subsequent biochemical studies
indicate that the lipoprotein lipase (LPL) is produced in an inactive form similar to the class III type defect
characterized in human LPL deficiency, and that heterozygous cats have intermediate LPL activity [210,211]. A
mutation in the lipoprotein lipase gene is the molecular basis of chylomicronemia [212]. The condition is inherited
as an autosomal recessive trait [205,208]. Pathologically, hyperchylomicronemia is characterized by presence of
xanthomata (lipid granulomas) within many organs, including skin, liver, spleen, lymph nodes, kidney, adrenal
glands, heart, and peripheral nerves [209]. These masses are distinguished by the presence of many large
macrophages with vacuolated cytoplasm ("foam cells") within a coagulum of blood, degenerating blood
components, fibrin, serum, and lipids. Ceroid, lipofuscin, hemosiderin, and crystal of triglycerides and cholesterol
may also be seen. The xanthomata may be smooth, are often lobulated, and may be up to 5 cm in diameter. They
are thought to arise either from frank hemorrhage or from the leakage of lipid-rich plasma perivascularly. Trauma
is thought to predispose to xanthomata formation in peripheral nerves [205]. Nerve involvement is most noticeable
at sites such as the spinal foramina and over bony prominences, where they are susceptible to stretching and
compression associated with normal vertebral movement. Nerve bundles closely associated with the xanthomata
show compression of fascicles (the masses typically are located outside the perineurium) which leads to
secondary axonal degeneration and nerve fiber loss.
Clinical signs reflect involvement of various peripheral neuropathies:
a. Horner's syndrome (ptosis, miosis, enophthalmos and prolapse of the third eyelid)
b. Facial nerve paralysis (absence of corneal and palpebral reflexes)
c. Tibial nerve paralysis (overflexion of the tarsus)
d. Femoral nerve paralysis (atrophy of quadriceps muscles and absence of patellar reflex)
e. Trigeminal nerve paralysis (temporal muscle atrophy, inability to prehend and chew food)
f. Radial nerve paralysis (inability to extend digits)
g. Recurrent laryngeal nerve paralysis (dyspnea and cyanosis due to impaired abduction of vocal cords).
Neuropathic signs are usually not seen until cats are at least eight months of age; however, paraplegia reportedly
due to thrombotic occlusion of the aorta has been seen in an affected four week old Siamese kitten [208].
Recurrent pancreatitis and/or hepatosplenomegaly are rarely seen in affected cats [205].
Blood samples from affected cats have the appearance of "cream of tomato soup". Funduscopic examination may
reveal the presence of lipemia retinalis. Serum lipoprotein studies show a significant increase in chylomicrons and
a smaller increase in very low density lipoproteins. Cholesterol and triglyceride serum values are increased and
there is a significant reduction in lipoprotein lipase activity. Other serum chemistry findings are within normal limits,
including serum thyroxine levels. Prognosis is usually favorable, since all of the clinical manifestations of
hyperchylomicronemia are reversible provided that the plasma triglyceride levels are reduced [205]. Peripheral
neuropathies in affected cats resolve after 2 to 3 months on a low fat (e.g., as little as 10 g/day), high fiber diet.
Gene replacement therapies are in progress [213]. A transient hyperlipidemia and anemia has been reported in
kittens with significantly lower LPL activity (apo C-II function was normal) but without the above-mentioned LPL
gene mutation [204]. None of these cats subsequently (as adults) developed xanthomata affecting nerve roots.
Idiopathic hyperlipoproteinemia is commonly seen in Miniature Schnauzers and Beagles with defective lipid
metabolism characterized by hypertriglyceridemia and moderate cholesterol elevation [203]. The pathogenesis of
this condition remains uncertain but may be associated with decreased activity of LPL. Abnormalities in
lipoproteins include increased serum levels of low-density/very low-density lipoproteins with or without
hyperchylomicronemia [201]. Affected animals have signs of abdominal distress, seizures, and occasionally,
pancreatitis [214,215].
Secondary hyperlipidemia may occur in dogs and cats with various metabolic disorders including hypothyroidism,
acute pancreatitis, diabetes mellitus, hyperadrenocorticism, and renal disease, and cholestatic hepatic disorders
[201,216].
Hyperoxaluria
Hyperoxaluria, primary or secondary, is occasionally seen in dogs and cats. Primary hyperoxaluria is considered
to be an autosomal recessive disorder associated with renal failure from oxalate nephropathy and neurological
signs in young Domestic Shorthair cats of either gender, resulting in death before one year of age [217-219]. This
condition was initially observed in a closed cat colony in 1984. Affected cats develop acute renal failure between 5
and 9 months of age due to deposition of oxalate crystals within the kidney tubules. Signs include anorexia,
dehydration, marked weakness, and depression. Kidneys are often enlarged and seem to be painful when
palpated. Affected cats develop a crouching, cow-hocked stance, and are reluctant to stand or walk. Neurological
examination reveals deficiencies in postural reaction testing, depressed patellar and withdrawal reflexes, absent
cutaneous trunci reflex, and a reduced response to pain. Abnormal spontaneous potentials (positive sharp waves,
fibrillation potentials, and high frequency discharges) are detected on EMG testing. Clinical signs in cats often
deteriorate to the point that euthanasia is necessary. There is progressive increase in blood urea nitrogen and
creatinine values, as well as increased serum levels of glucose, phosphate, and potassium. Urine contains
increased oxalate and L-glycerate levels. Biochemical studies in affected cats have revealed deficient liver
enzymatic activities of D-glycerate dehydrogenase and glyoxylate reductase, which are the deficient enzyme
activities in human primary hyperoxaluria type 2 (PH2) [220]. Heterozygote cats appear to have intermediate liver
levels of these enzymes.
Histopathological examination of kidneys reveal presence of numerous birefringent crystals within the tubules,
interstitial fibrosis, and occasionally, periglomerular fibrosis. In the spinal cord, large swellings with a
homogeneous appearance are observed in proximal axons of ventral horn cells. Ultrastructural examination
shows that the swellings are due to accumulation of neurofilaments. Swollen axons are also seen in ventral roots,
intramuscular nerves, and in dorsal root ganglia. Oxalate crystals are not observed within axons. Muscle changes
are considered to represent neurogenic atrophy. Diagnosis may be made in affected cats before they develop
clinical signs by identifying L-glycerate in urine. This metabolite is not present in urine of normal cats. Prognosis is
grave. There is no treatment.
This inherited feline condition is now considered to be analogous to PH2 (L-glyceric aciduria) in people, an
inherited condition characterized by recurring calcium oxalate kidney stones. The pathogenetic mechanisms
associated with the lesions in the nervous system of the cats are not clear. Note that liver levels of the enzyme
serine:pyruvate/alanine:glyoxylate aminotransferase, functional deficiency of which causes primary hyperoxaluria
type 1 (PH1) in people and in Tibetan Spaniels [221,222], are normal in these cats. Peripheral nerve trunk
involvement, as well as sensory and sympathetic ganglia, has been reported in people (but not in dogs) with PH1
with deposition of oxalate crystal within axons and in the walls of perineurial arterioles, leading to axonal
degeneration, and demyelination [223,224]. Multiple calcium oxalate crystals are also seen in muscle surrounded
by inflammatory infiltrates. In some patients with primary hyperoxaluria and renal failure, chronic hemodialysis
may favor the development of neuropathy [225]. PH1 in people is an autosomal recessive disease. D-glycerate
dehydrogenase/glyoxylate reductase levels are normal in people and affected dogs [222].
Secondary hyperoxaluria may also occur in cats and dogs following ingestion of the antifreeze ethylene glycol,
which is metabolized to glycolic acid, glyoxalate, and oxalate. Oxalate nephrosis and renal sclerosis has been
reported in a cat following renal transplantation [226]. There was no evidence of primary type 2 hyperoxaluria in
this cat.
Hypertrophic Neuropathy
Hypertrophic neuropathy is an autosomal recessive neurological disease that has been reported in Tibetan Mastiff
dogs [227-230]. This disease is also known as canine inherited hypertrophic neuropathy. Clinical signs appear in
animals from 7 to 10 weeks of age and consist of rapidly developing generalized weakness, hyporeflexia/areflexia,
muscle hypotonia, and dysphonia. No other cranial nerve signs are reported. Severely affected puppies may
become totally recumbent within 3 weeks of onset with subsequent development of sternal compression and limb
contractures. Some puppies may regain the ability to stand and walk, but remain weak. Mild muscle wasting
occurs and ambulatory puppies have a shuffling, plantigrade gait. Pain perception is normal.
Electrodiagnostic studies reveal progressive, moderate to severe reduction in nerve conduction velocities.
Transient EMG abnormalities (positive sharp waves, fibrillation potentials, and high frequency potentials) may be
seen early in the course of the disease but tend to disappear 2 or more months after onset of signs. Temporal
dispersion of evoked muscle action potentials is reported in chronically affected dogs. There is variable elevation
in CSF protein.
Pathologically, this disease results in a reduced density of myelinated fibers in peripheral nerves and nerve roots,
widespread demyelination, and primitive onion-bulb formation with relatively little axonal degeneration. There is
no inflammation. A constant feature is accumulation of actin-like filaments (6 to 7 nm in diameter) in Schwann cell
cytoplasm, either in an adaxonal location or in cytoplasmic compartments within the myelin sheath. Experimental
nerve transplantation studies point to a Schwann cell defect, possibly involving the cytoskeleton [231].
Ultrastructurally, some degenerating and remyelinating axons are surrounded by concentric layers of Schwann
cell cytoplasm. Macrophages often invade the degenerating myelin sheaths. Morphological evidence of axonal
injury is unusual, although ovoids and Büngner's bands are occasionally seen.
Diagnosis is based on signalment, clinical, electrodiagnostic, and nerve biopsy data. Prognosis is guarded. There
is no treatment. This canine hypertrophic demyelinating neuropathy has similarities to hereditary sensory and
motor neuropathy (HSMN) type I, also known as Charcot-Marie-Tooth disease (CMT) type I, and HSMN type III
(also known as Dejerine-Sottas disease, a variant of CMT) [43].
A condition that has some similarities to inherited hypertrophic neuropathy in the Tibetan Mastiff dog has been
reported in two unrelated cats around 1 year of age with signs of intention tremor, mild sensory abnormalities,
depressed reflexes, and urinary-fecal incontinence [232]. Grossly, peripheral nerves (motor/sensory and
autonomic) appeared thickened. Microscopic studies of peripheral and autonomic nerves revealed demyelination
and onion-bulb formation, endoneurial fibrosis, and presence of inner perineurial mucoid masses. Axonal
degeneration was not a feature. The condition was considered to resemble HSMN type I in people. Summers and
colleagues also reported a hypertrophic neuropathy in a 1 year old male Domestic cat with generalized tremors,
plantigrade gait, proprioceptive deficits, forelimb spasticity/hypermetria, progressive ataxia, and depressed
nociception over paws, face and nasal vestibule [200]. Signs began around 7 months of age. Myelin sheaths of
larger axons appeared thinly myelinated or demyelinated and there was onion-bulb formation. Ultrastructural
changes revealed presence of filaments and accumulation of granular material within Schwann cell cytoplasm
similar to that seen in Tibetan Mastiffs. Again, axonal changes were minimal. However, in their cat, degenerative
changes (demyelination, spheroid formation, Wallerian degeneration, and astrocytic scarring) were observed in
dorsal, lateral, and ventral funiculi of the spinal cord. Axonal degeneration extended to the medulla oblongata,
caudal cerebellar peduncles, and accessory cuneate nucleus.
Pathological findings with some similarities to those seen in Tibetan Mastiffs have been observed in Beagle-
Basset puppies (around 14 weeks of age), with widespread demyelinating radiculoneuropathy [200]. These
puppies had megaesophagus, aspiration pneumonia, generalized weakness, diffuse muscle atrophy (especially
proximally), absent patellar reflexes, and EDX findings of widespread denervation potentials (including facial and
masticatory muscles) and decreased motor NCV.
Hypoglycemic Neuropathy
Severe hypoglycemia (e.g., 18 to 45 mg/dl; normal = 80 - 120 mg/dL) in dogs and cats (less frequently) is most
commonly associated with insulinomas with CNS signs of neuroglycopenia (generalized seizures, weakness,
ataxia, collapse, lethargy, transient blindness, and abnormal behavior, e.g., hysteria) and sympathoadrenal
stimulation (muscle tremors, nervousness, restlessness, and hunger) seemingly relating to the dependence of the
CNS on glucose [103] (see hypoglycemia). An infrequently encountered complication of insulinoma-associated
hypoglycemia in dogs is polyneuropathy [233-239]. Onset and clinical course may be acute to sub-acute (several
days) or insidious/chronic (weeks to months). Clinical signs range from paraparesis to tetraplegia, facial
paresis/paralysis, hyporeflexia/areflexia (e.g., myotatic and cutaneous trunci reflexes), hypotonia, and muscle
atrophy (e.g., appendicular/masticatory/facial), sometimes in conjunction with seizures. In one report involving 3
severely-affected dogs, seizures or other signs of CNS dysfunction were not observed [238]. In another dog,
seizures were seen approximately 16 months after initial signs of tetraparesis [239]. There is also a report of an
affected dog with a history of recurring episodes of hind limb weakness, each episode lasting about 30 minutes,
and with the dog appearing normal between episodes (seizures were not seen in this dog) [234]. Sensory nerve
involvement is suggested by presence of a lick granuloma in some dogs [233,234]. A subclinical polyneuropathy
has also been reported in dogs [235].
Electrodiagnostic (EDX) testing has shown presence of abnormal spontaneous potentials (positive sharp waves,
fibrillation potentials), and slowed motor nerve conduction velocities [235]. In several dogs, EDX data point to a
distal distribution of the neuropathy (distal axonopathy), including presence of fibrillation potentials/positive sharp
waves below the elbow and stifle [234,235]. CSF studies have been normal [239]. Histopathological findings in
motor and sensory nerves from affected dogs include moderate to severe axonal necrosis, nerve fiber loss
(affecting medium- and large-caliber myelinated fibers), and variable demyelination-remyelination [235,239,240].
Muscle changes reflect neurogenic atrophy, e.g., fiber size variation associated with scattered angular atrophic
fibers and hypertrophic fibers (both type 1 and type 2A fibers, especially the latter). Diagnosis of insulinoma is
based on the demonstration of high serum insulin level in the presence of fasting hypoglycemia (see
hypoglycemia). The peripheral neuropathy diagnosis is suggested by clinical signs, and confirmed by EDX testing
and nerve biopsy.
Treatment strategies have yet to be determined in dogs. Since most of the pancreatic tumors tend to be malignant
(unlike the situation in people), prognosis is guarded to poor in dogs with insulinomas regardless of the presence
of a polyneuropathy or not. In one report, oral treatment with prednisolone or prednisone at 1 mg/kg daily for 10
days and then every other day was successful in almost completely reversing all neurological signs for several
months before the dog was euthanized because of occurrence of uncontrollable seizures [239]. Interestingly,
there was no correlation between the blood glucose levels and clinical recovery (glucose levels remained low
while insulin levels remained high when the dog was almost completely normal). Similarly, normalization of serum
glucose levels using intravenous dextrose failed to improve clinical signs in one report involving 3 dogs with
insulinoma-related neuropathies [238]. There is a report of clinical recovery in an ambulatory, hypoglycemic 7
year old female German Shepherd (with seizures, reduced exercise tolerance and dysphonia) following surgical
removal of the insulinoma [241]. Streptozocin reportedly resulted in rapid reversal of the peripheral neuropathy in
2 dogs with pancreatic islet cell tumors [520]. The streptozocin was administered at a dosage of 500 mg/m2, IV,
every 3 weeks and combined with a protocol for induction of diuresis.
In people, hypoglycemia-induced peripheral neuropathy due to insulinoma is uncommon, with only 34 patients
being reported through 2000 [242]. The pathogenesis of the neuropathy remains unknown [110]. In people, the
condition may be seen after several episodes of prolonged hypoglycemia, usually with obvious cerebral signs,
and the neuropathy is typically symmetrical, predominantly distal, and usually sensorimotor [242]. A less severe
polyneuropathy (predominantly sensory) occurred in schizophrenic patients treated with insulin shock therapy
[243]. Experimental studies suggest that severe and mild hypoglycemia causes a distal axonopathy, with motor
axons appearing more vulnerable than sensory axons [242,244-247]. Further, experimental studies indicate that
nerve damage may result from the hypoglycemia due to disruption of fast anterograde axonal transport [248].
Both duration and severity of hypoglycemia (e.g., blood glucose < 1.5 mmol/L or 27 mg/dL and > 12 hours)
appear to be risk factors for axonal degeneration [249] which, in one experimental study, occurred mainly in
central fascicular regions of distal peripheral nerves, suggesting deficiency of energy substrate due to poor
perfusion in watershed zones [250]. Impaired motor nerve conduction velocities and axonal atrophy have also
been reported [251]. There is also the possibility that the hypoglycemia-induced peripheral neuropathy due to
insulinoma represents a paraneoplastic neuropathy [236,239,247,252]. Paraneoplastic syndromes in humans are
thought to be immunologically mediated since some patients have circulating antibodies that recognize antigens
shared by neural elements and tumor cells [253]. The remarkable clinical response to corticosteroids in the canine
case reported by van Ham and associates [239] certainly suggests possible immune-mediated pathogenetic
mechanisms. Although a sensorimotor, symmetric, and predominantly distal neuropathy may be seen in human
patients with paraneoplastic neuropathies (including insulinomas), no tumor-related immunologic alteration has
yet been identified similar to the circulating antineuronal antibodies found in patients with paraneoplastic subacute
sensory neuropathy (usually occurring in association with small cell lung cancer) [254]. In people, other possible
causes of the neuropathy have included toxic factors produced by the tumor, metabolic causes (e.g., the tumor
competing with the host for essential metabolites), vitamin/nutritional deficiency, vascular causes (e.g., vasculitis),
and viral infections causes; however, definitive proof is lacking for each of these [252,255].
Hypothyroid Neuropathy
Hypothryroidism is common in dogs but rare in cats and most cases of acquired canine hypothyroidism are
associated with immune-mediated lymphocytic thyroiditis/idiopathic thyroid atrophy [256,257]. A hypothyroid-
associated neuropathy commonly occurs in mature to middle-aged dogs, usually of the large-breed variety. The
few cases reported in the literature [258-261] do not reflect the prevalence of this metabolic neuropathy, based on
muscle and nerve biopsy material that we have examined (both at the Scott-Ritchey neuromuscular laboratory at
Auburn University and at my peripheral nerve laboratory) from numerous hypothyroid dogs. Sub-clinical cases
have been recognized [534]. Clinical signs may include exercise intolerance, progressive weakness (e.g.,
paraparesis, tetraparesis), muscle atrophy (mainly appendicular) and depressed spinal reflexes. Other signs may
include pelvic limb proprioceptive deficits, unilateral/bilateral facial nerve paresis/paralysis, ventrolateral
strabismus, and decreased corneal/facial sensitivity. Intermittent forelimb lameness is less commonly reported
[533]. In one comprehensive study of the neurological manifestations of hypothyroidism in 29 dogs, lower motor
neuron signs were seen in 11 dogs, 9 dogs had peripheral vestibular deficits, 4 had megaesophagus, and 5 had
laryngeal paralysis [260]. Peripheral neuropathy has been seen in several hypothyroid dogs with megaesophagus
and myasthenia gravis [261]. Electrodiagnostic studies in appendicular muscles have revealed multifocal patterns
of fibrillation potentials, positive sharp waves, decreased motor and sensory nerve conduction velocities, and
complex repetitive discharges. Similar changes may be found in facial muscles. In some instances, there is a lack
of correlation between the degree of EMG abnormalities and the severity of the clinical weakness [258]. Dogs with
vestibular deficits may have abnormal brainstem auditory-evoked responses [260]. CSF analysis usually reveals
normal cellularity with normal or mild/moderate protein increase (25 - 110 mg/dL) [259,260]. Serum cholesterol
levels are usually increased. Muscle changes reflect varying degrees of neurogenic atrophy (angular atrophy of
muscle fibers, especially type 2 fibers; compensatory hypertrophy) while teased nerve fiber studies and semithin
sections are typically characterized by mixed pathology involving demyelination/remyelination and axonal
necrosis. The underlying pathology appears to be a sensorimotor polyneuropathy and, based on my experiences,
at least some of these cases have a distal distribution (i.e., distal sensorimotor polyneuropathy).
Diagnosis is based on serological evidence of hypothyroidism (low serum T4 concentration and inadequate
response to thyroid-stimulating hormone administration) [260]. Prognosis is often favorable. In one study involving
29 dogs, most dogs recovered within 2 to 3 months of thyroid hormone supplementation (20 g/kg of L-thyroxine
PO bid). Dogs with megaesophagus improved over 4 months, while dogs with laryngeal paralysis showed partial
improvement after 5 months. One caveat is that we have encountered a number of dogs in which there is less
dramatic or no clinical response to long-term thyroid hormone supplementation.
Note that affected dogs may also have generalized signs of hypothyroidism, including thinning of the haircoat,
alopecia, dry skin with epidermal scales and flaking, etc.
The pathophysiology surrounding hypothyroid neuropathy remains unexplained [262]. In people with
hypothyroidism, a mild peripheral neuropathy is relatively common and may include facial mononeuropathy,
sensorineural hearing loss, distal sensory neuropathy, and sensorimotor polyneuropathy [103,263]. One study
reported changes in nerves consistent with a dying back process and possible underlying slow axonal transport
[264]. There may be preferential loss of larger caliber myelinated fibers [265]. Carpal tunnel syndrome (median
nerve mononeuropathy at the wrist) is the most common mononeuropathy encountered [103]. As we have seen in
dogs, the relative proportions of axonal degeneration (secondary to disturbance of neuronal metabolism?) and
demyelination (primary Schwann cell involvement?) varies from case to case [264,266,267]. Onion bulb
formations are infrequently found. Ultrastructural changes in affected human nerves include prominent cluster
formations and excessive glycogen deposition in Schwann cells, myelinated and unmyelinated axons, endothelial
cells, and perineurial cells [265,268].
Laryngeal Paralysis
Innervation of three of the four intrinsic laryngeal muscles (dorsal and lateral cricoarytenoid muscles and
thyroarytenoid muscle) comes from the special visceral efferent axons of the recurrent laryngeal nerves. The
fourth muscle (cricothyroid muscle) is supplied by the motor branch of the cranial laryngeal nerve [269]. The
recurrent laryngeal nerve on each side is derived from the vagus nerve which in turn originates from the nucleus
ambiguus in the brainstem [149]; so theoretically, a lesion in any of these anatomic locations might lead to
laryngeal dysfunction. The efferent axons to the larynx are categorized as special visceral efferent fibers [149].
Laryngeal paralysis (LP) classically results from unilateral or more commonly, bilateral denervation of the
laryngeal abductor muscles (dorsal cricoarytenoid muscles), which leads to impaired abduction of the vocal fold(s),
glottic obstruction, and dyspnea [269-271].
Hereditary, idiopathic, and acquired forms of this potentially fatal disorder have been reported in dogs and cats. A
hereditary form (autosomal dominant) has been documented in Bouvier des Flandres dogs either as unilateral or
bilateral disease [270,272,273]. A inherited or presumed hereditary form has been reported in young Siberian
Huskies, Husky cross-breeds, Bull Terriers, Dalmatians, Rottweilers, white-coated German Shepherds, and
Pyrenean Mountain dogs [172,271,274-277,531]. Affected Huskies share a phenotype of blue eyes, and white
freckled face. LP has also been recently reported in young Rottweiler puppies in association with neuroaxonal
dystrophy [278] and spongy degeneration of the CNS [279]. The idiopathic form has been reported mostly in
middle-aged and older large and giant breed dogs, such as St. Bernard, Chesapeake Bay Retriever, Irish Setter,
Afghan Hound, Labrador Retriever and Rottweiler, but medium and small/toy breeds also may be affected
[269,280-282]. Male dogs, particularly if castrated, were more frequently affected than females in one reported
survey [280]. In another study, the severity of the laryngeal paralysis was correlated with increasing age in larger
breed dogs [283]. Acquired LP is sporadically reported in dogs. Bilateral LP resulted from entrapment of both
recurrent laryngeal nerves by fibrous tissue surrounding a peritracheal abscess (thought to be caused by a
foreign body penetrating the wall of the esophagus) in an 8 month old Cocker Spaniel [284]. LP has also been
seen in dogs as a surgical complication in the treatment of carotid body tumors [285] and thyroid carcinomas
[286]. Trypanosomiasis was considered to be the cause of LP in a 12 year old Labrador Retriever [287].
Laryngeal paralysis may be one of several signs seen in animals with rabies. LP in some older dogs has also
been linked with hypothyroidism (see hypothyroid neuropathy) [260,280,281,288,532]. LP has also been reported
in two older dogs as a possible complication of paraneoplastic neuropathy (both dogs were also hypothyroid)
[289]. Dysphonia/LP may also be observed in animals with coonhound paralysis/idiopathic polyradiculoneuritis,
chronic inflammatory demyelinating polyneuropathy, in German Shepherd dogs with giant axonal neuropathy, and
in some dogs with sensory ganglioradiculitis.
In cats, congenital and idiopathic forms of LP have been reported sporadically and earlier reports favored
castrated males [290-292]; however in a more recent study, no gender or breed predilection was noted, although
7/8 male cats were neutered and all females were spayed [293]. Acquired LP in cats has been reported as a
result of trauma to the neck [294], lymphomatous infiltration of the vagus nerve [295], cystic thyroid adenoma
[296], adenocarcinoma of the tympanic bulla and damage to the recurrent laryngeal nerve [297], and seen as a
complication of lead poisoning [298], percutaneous ethanol injection for the treatment of hyperthyroidism [299],
surgical repair of intrathoracic tracheal avulsion [300], surgical thyroidectomy [301], and other neck/mediastinal
surgeries (e.g., removing a thyroid adenoma, ligation of a patent ductus arteriosus, thymectomy) [302,303].
Onset of clinical signs in the congenital/hereditary forms of LP in dogs is from 4 to 6 months of age. The acquired
and idiopathic forms usually develop in older animals from 1 to 13 years of age. Clinical signs reflect respiratory,
primarily inspiratory, distress and are characterized by increasing loss of endurance, progressive laryngeal stridor
(especially on exertion), voice changes (dysphonia), dyspnea, cyanosis during episodes of severe dyspnea, and
collapse with complete airway obstruction. Clinical signs are usually of several months duration. In cats,
excessive head shaking and abnormal purring may also be noted. Megaesophagus is usually not a clinical feature
of LP in cats, although it has been confirmed radiographically in occasional cats [293]. Note that unilateral
paralysis (also termed laryngeal hemiplegia) in dogs may be subclinical [269,270], although in working dogs, such
as racing Greyhounds and Siberian Husky sled dogs, unilateral paralysis can result in obstructive dyspnea and
interfere with racing function [269]. In cats, unilateral LP can be subclinical [294] or result in mild clinical signs.
Unilateral congenital and idiopathic forms tends to affect the left side of the larynx in dogs and cats [270,293].
Diagnosis of LP is based on clinical signs, laryngoscopy showing impaired abductor dysfunction, and EMG
evidence of denervation potentials in the intrinsic laryngeal muscles. Ultrasound (echolaryngography) may also be
a useful diagnostic technique [304]. There is histological evidence of neurogenic atrophy in laryngeal muscles. In
the Bouviers, lesions found in the recurrent laryngeal nerves (e.g., axon fragmentation, digestion chambers,
endoneurial fibrosis) were found at all levels of the nerves and were considered to be secondary to lesions
involving the nucleus ambiguus [270]. Gliosis and neuronal atrophy of the vagal nuclei were reported in an
affected Husky Cross puppy [271]. Degenerative changes, including axon and myelin degeneration, axonal loss,
and endoneurial fibrosis have been noted in recurrent laryngeal nerve samples from older dogs with idiopathic LP
[269].
Laryngeal paralysis has also been noted in dogs with clinical, electrodiagnostic (EDX), and pathological evidence
of a more generalized polyneuropathy [281], which has been termed laryngeal paralysis polyneuropathy complex
(LPPC) [172]. This condition has now been seen in young Dalmatians, Rottweilers, and Pyrenean Mountain dogs
[172,276,277]. In addition to the clinical signs described above, other neurological abnormalities associated with
the laryngeal paralysis included spinal hyporeflexia, limb muscle atrophy or fasciculations, limb hyperextension,
facial/lingual paralysis, and hypermetria. Megaesophagus was a common feature in affected Dalmatians and
Pyrenean Mountain dogs (megaesophagus was found in one affected Rottweiler, while regurgitation was
associated with hiatal hernia/gastroesophageal intussusception in another puppy). Four of the five Rottweiler
puppies had bilateral lenticular cataracts. Bilateral paralysis of the vocal folds (arytenoid cartilages) was noted in
all dogs (although not always symmetrical) under light sedation. EMG abnormalities included fibrillation potentials
and positive sharp waves in a variety of muscles including laryngeal, esophageal, facial, masticatory, and distal
appendicular muscles. Nerve conduction velocities (NCVs) may be normal or mildly decreased. Direct evoked
compound muscle action potentials have shown low amplitude without evidence of dispersion (polyphasic waves),
suggestive of axonal degeneration. Congenital deafness has been demonstrated in several dogs using BAER
testing. Neurogenic atrophy was observed in intrinsic laryngeal and appendicular muscles. Changes in cranial
and appendicular nerves (motor and sensory, as well as in autonomic nerves) were dominated by axonal necrosis
and loss of medium sized and larger-caliber myelinated fibers, with the intensity of the changes being more
severe in distal parts of nerves (e.g., recurrent laryngeal nerve). Ultrastructural changes included loss of
myelinated fibers, variable ovoid presence, marked increase in endoneurial collagen, numerous Büngner bands
(denervated Schwann cells), and evidence of unmyelinated fiber involvement (e.g., collagen pockets, flattened
axons, empty Schwann cell subunits). To date, no lesions have been found in the nucleus ambiguus of the brain
stem. Morphological, morphometric, and/or EXD studies suggest that LP in Dalmatians, Rottweilers, and
Pyrenean Mountain dogs represents a distal axonopathy (or dying-back disease).
While O’Brien and colleagues stated that no clinical evidence of central or peripheral nerve deficits were found in
their cases of idiopathic LP in older, larger breed dogs (although they reported Wallerian degeneration in sciatic
nerve from one affected dog) [269], paresis and foot drop due to denervation of the cranial tibial muscle have
been occasionally observed in affected young Bouviers [270]. Furthermore, signs of pelvic limb weakness are
sometimes seen in older dogs with idiopathic LP [280,281]. In these animals, pelvic limb reflexes may be
diminished and there may be evidence of abnormal spontaneous potentials (fibrillation potentials and positive
sharp waves) on EMG studies, along with slowed motor NCVs. Muscle/nerve biopsies may show neurogenic
muscle atrophy, (e.g., scattered angular atrophic fibers, small fiber group atrophy), demyelination, and variable
axonal degeneration [281]. A more generalized neurological disorder has also been observed in two cats with
laryngeal paralysis that were eventually euthanized because of progressive neuromuscular signs [292]. In
summary, it appears that hereditary and idiopathic forms of LP in dogs and cats often may be related to a more
generalized polyneuropathy.
Serum cholinesterase activity, thyroid testing, serum antinuclear antibody and rheumatoid factor titers, Coombs
testing, and serum anti-acetylcholine receptor antibody levels are normal in dogs with LPPC, and there is no
evidence of lead toxicity.
Prognosis in dogs with congenital/hereditary LP is guarded to poor, especially if megaesophagus is present due
to the high risk of inhalation pneumonia. Feeding of a liquid gruel from an elevated platform may be beneficial in
dogs with megaesophagus. Laryngeal tie-back surgical procedures may provide dramatic relief of the dyspnea,
but multiple surgeries may be required during the first 12 months. Additional complications in dogs are joint
contractures (especially the carpus), which may be surgically managed by arthrodesis. Conversely, idiopathic
paralysis in older dogs may have a favorable prognosis since megaesophagus is typically not a feature of the
disorder, clinical signs of more generalized peripheral nerve disease appear to milder, and the dominant
pathology in nerves is more likely to be demyelination rather than axonal degeneration. Harvey and colleagues
reported that thyroid hormone supplementation resulted in marked clinical improvement in their older hypothyroid
dogs with LP [288]. Surgical management, such as arytenoidectomy and vocal fold removal, arytenoid
lateralization, cricoarytenoid laryngoplasty, and castellated laryngofissure may be very effective [292,305-308]. In
one experimental study, bilateral arytenoid cartilage lateralization produced more consistent clinical improvement,
a wider rima glottidis, increased inspiratory air flow, and a significant increase in post-operative arterial oxygen
tension when compared to castellated laryngofissure [309]. Thyroarytenoid lateralization also requires less
surgical time to perform than cricoarytenoid laryngoplasty [307]. Despite favorable reports, it should be noted that
surgical repair of idiopathic/acquired forms of laryngeal paralysis may be associated with high postoperative
complications (particularly aspiration pneumonia) and mortality rates [532]. (These complications were more
commonly associated with bilateral arytenoid lateralization and partial laryngectomy techniques). Surgical
intervention is also beneficial in cats with idiopathic LP [293,302], although prognosis is guarded to poor in
suspected congenital/idiopathic cases developing progressive neuromuscular disease [292]. Prognosis for cats
with mild signs (e.g., in those with traumatically-induced unilateral LP) may be favorable with conservative
treatment, such as moving cats indoors, avoiding excitement, and restricting exercise [293]. Prognosis for animals
with acquired LP will usually depend on the underlying cause. In cats with subclinical traumatic laryngeal
hemiplegia, resolution of the impaired arytenoid cartilage abduction occurred spontaneously over several months
[294]. Prevention of the inherited form by breeding control is indicated.
Note that LP may also be a component of the hereditary Alaskan Malamute polyneuropathy that was thought to
be eradicated in Norway in 1982 [6]. Dysphonia has been observed in some Alaskan Malamutes with a similar if
not identical condition that has been reported recently in the United States and Germany [3,4].
Optic Neuritis
Optic neuritis is an inflammatory condition of the optic nerve(s) that results in loss of vision. It may be associated
with primary ocular disease or can occur secondary to systemic inflammatory disease. In most animals, the
underlying cause is not determined. The condition is not uncommon, affecting dogs [310,311] more frequently
than cats [312,313]. There is no apparent breed or gender predisposition, however, most affected dogs are older
than 3 years of age.
In dogs, diagnostic considerations include canine distemper, ocular form of granulomatous
meningoencephalomyelitis, systemic mycosis (e.g., cryptococcosis, blastomycosis), toxoplasmosis, neoplasia,
trauma, and acute toxicity (e.g., lead, chlorinated hydrocarbon, or clioquinol toxicity, and closantel intoxication)
[78,314-327]. Optic neuritis may also be seen as a complication of uveodermatologic syndrome, a disorder
characterized by bilateral panuveitis and skin and hair depigmentation that is similar to human Vogt-Koyanagi-
Harada syndrome in people [328], although the associated meningitis in the human disease has not been
reported in dogs.
An apparently healthy animal may present with a history of unilateral or bilateral blindness of sudden onset. Pupils
usually are unilaterally or bilaterally dilated and unresponsive to light stimulation. The disorder may be associated
with orbital pain or pain with ocular movement [329]. Ophthalmoscopic examination may or may not be helpful.
Ophtalmoscopic abnormalities may include an edematous, elevated optic disk and engorged retinal vessels.
Focal hemorrhage may be present. Active or inactive chorioretinitis may accompany the optic neuritis. Atrophy of
the optic nerve frequently follows repeated episodes of acute optic neuritis. Optic neuritis is distinguished from
papilledema in that vision is preserved in the latter condition. Optic neuritis is termed "intrabulbar" if fundic
changes are seen ophthalmoscopically or "retrobulbar" if no changes are seen (note that acute optic neuritis is
often retrobulbar) [329]. Neurological exam is frequently normal.
The first line of treatment should be directed at the primary disease process that initiated the optic neuritis.
However, since the cause is frequently undetermined, the animal may be treated symptomatically with retrobulbar
corticosteroids (e.g., betamethasone, 2.5 mg) in conjunction with oral corticosteroid administration (e.g.,
prednisolone, at 2 mg/kg daily, divided bid, for 10 to 14 days, followed by half this dosage for two more weeks,
and gradual reduction to maintenance therapy every other day for up to one year). Prognosis is guarded. Clinical
response to treatment can be difficult to assess and the course is unpredictable. Some animals have a return of
vision within 1 or 2 days, while others may show only gradual improvement over several months. Clinical
exacerbations may occur if treatment is prematurely stopped. In some animals, the disease process may
progress, resulting in permanent structural changes and irreversible blindness.
Optic nerves were involved in a subclinical, inflammatory demyelinating CNS disorder in cats characterized by
infiltrating lymphocytes, plasma cells and macrophages, and intracytoplasmic inclusions consisting of tubular
structures with similarities to paramyxovirus nucleocapsids [330,331].
Paraneoplastic Neuropathy
The frequency of peripheral neuropathy in human patients with cancer (see also paraneoplastic disorders) varies
with the screening technique employed. The clinical incidence of some forms of paraneoplastic neuropathy has
been estimated to be 5 to 16% [254]. This figure increases to more than 40% if quantitative sensory testing or
electrophysiological / pathological evaluation are performed, reflecting the high incidence of subclinical
neuropathy [252,332-334]. As stated by Mcleod [255], the actual frequency of peripheral neuropathy in
malignancy is difficult to ascertain since it "…depends on the pathological type and site of tumor, the stage and
duration of the illness, the diligence with which it is sought, the techniques of investigation employed, and the
criteria for diagnosis". Several paraneoplastic neuropathies have been recognized in human cancer patients
[252,254,255,332]: subacute sensory neuropathy, sensorimotor neuropathy (including mild terminal neuropathy,
severe rapidly evolving or relapsing sensorimotor neuropathies, microvasculitic neuropathy, and sensorimotor
neuropathies associated with malignant monoclonal gammopathies), Guillain-Barré syndrome that is sometimes
seen in association with Hodgkin’s disease, and brachial plexitis. Paraneoplastic autonomic dysfunction may
occur, usually accompanying other paraneoplastic syndromes. Pathological findings vary with the particular
paraneoplastic neuropathy [254,255]. In subacute sensory neuropathy (SSN), there is loss of neurons in spinal
ganglia along with focal inflammatory infiltrates, and dorsal column degeneration. In paraneoplastic sensorimotor
neuropathies, axonal or demyelinating changes, either inflammatory or non-inflammatory, may be observed. The
pathogenesis of some forms of paraneoplastic neuropathies appears to be related to molecular mimicry in which
antibodies produced against the tumor cross-react with neural antigens, e.g., SSN is associated with circulating
(serum and CSF) antineuronal antibodies (anti-Hu) expressing specificity for neuronal nuclear antigens [335,336].
In most instances, the malignancy is small cell lung cancer. In contrast to SSN, the underlying pathogenesis of
paraneoplastic sensorimotor neuropathies (much more common than SSN) remains unclear but appears
unassociated with immunological mimicry (no tumor-specific antibodies have been recognized) or tumor toxin
[255]. The malignancy often involves the lung, but carcinomas have been found in a variety of organs (e.g.,
pancreas, stomach, rectum, uterus, breast, colon, cervix, kidney, prostate, and testis) [255]. Some forms of
paraneoplastic sensorimotor neuropathies may represent dying-back axonopathies [254]. In some instances,
paraneoplastic neuropathies may be obscured by neurotoxic chemotherapeutic agents, metabolic disorders, and
inactivity [252].
The clinical or subclinical incidence of PNS paraneoplasia in animals is presently unknown; however, peripheral
nerve lesions may be facilitated by presence of certain types of cancer in animals, as in people. In one
prospective qualitative and quantitative study on the effects of cancer on the PNS in dogs, the highest percentage
of abnormalities in teased nerve fibers from dogs with malignancies were found in bronchogenic carcinoma (59%),
mammary adenocarcinoma (59%), malignant melanoma (48%), insulinoma (47%), osteosarcoma (39%), thyroid
adenocarcinoma (35.5%) and mast cell tumor (32%) [236]. The major histopathological findings in this study
included paranodal-segmental demyelination, remyelination, axonal degeneration, and myelin globules. Overall,
16 of 21 dogs (76%) had a significantly greater number of lesions in peripheral nerves than age-matched controls.
It is interesting to note that two of the tumor cases in our prospective study (those with the highest number of
abnormalities) were bronchogenic carcinomas. Such tumors have long been recognized for their intimate
association with paraneoplastic neuropathies in people [337,338]. It was also evident that different types of
malignancies (mammary adenocarcinoma, malignant melanoma, insulinoma, osteosarcoma, etc.) resulted in a
differing incidence of neuropathy, a finding also well-recognized in human cancer patients. In addition, the
severity of the neuropathy sometimes varied markedly with tumors of the same type, probably reflecting
differences in the stage and duration of the illness. Of all the malignant tumors in our study, lymphosarcoma
appeared to have the least neuropathic effect. The neuropathies in dogs of this study were mainly subclinical.
Clinical hallmarks of the neuropathic syndrome are reduced or absent spinal/cranial reflexes, flaccid weakness,
reduced muscle tone, paralysis of limb or head muscles, and after 1 to 2 weeks, neurogenic muscle atrophy.
Dysphonia may also be detected. Clinical neuropathies have been seen sporadically in dogs with malignant
tumors, including bronchogenic carcinoma, insulinoma, lymphosarcoma, fibrosarcoma, leiomyosarcoma,
hemangiosarcoma, and undifferentiated sarcoma [170,234,235,289,339-341]. In two of these reports, the
neuropathies had a distal distribution based on electrodiagnostic (EDX) and pathological studies [235,289].
Abnormal EDX findings include fibrillation potentials, positive sharp waves, and slowed motor nerve conduction
velocities. In my peripheral nerve laboratory, I have examined nerve samples from dogs with synovial cell
sarcoma and adrenal adenocarcinoma that were accompanied by clinical neuropathies.
In contrast with people [342], malignant monoclonal gammopathies (dysproteinemic neuropathies) rarely seem to
involve the peripheral nerves in dogs or cats [343,344]; however, a polyneuropathy (based on EMG findings) was
reported in a 12 year old German Shepherd with multiple myeloma and monoclonal hypergammaglobulinemia
[345]. In people, dysproteinemic neuropathy or NAP (neuropathy associated with paraproteinemia) are relatively
common and the paraproteins (circulating immunoglobulins, or M-Proteins) may be IgM, IgG, or IgA, consisting of
the whole immunoglobulin molecule or only the heavy or light chain [342]. Diseases associated with NAP include
monoclonal gammopathies of unknown significance (MGUS), multiple myeloma, Waldenstrom’s
macroglobulinemia, osteosclerotic myeloma/POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,
M-protein, and skin changes), primary amyloidosis, lymphoproliferative diseases (lymphoma, leukemia), heavy
chain disease, and cryoglobulinemia [342,346]. The majority of NAP cases appear to be IgM with myelin sheath
anti-MAG (myelin-associated glycoprotein) activity and characteristic widely-spaced myelin lamellae (associated
with separation of the intraperiod line), along with evidence of a distal sensorimotor symmetrical neuropathy
characterized by demyelinating changes (active myelin breakdown, denuded axons, thinly myelinated fibers, and
onion-bulb formations) [342,347]. Axonal degeneration and loss of myelinated fibers may also be present,
especially in chronic cases.
Too few cases have been documented to evaluate treatment strategies of paraneoplastic neuropathies in dogs
and cats. In a recent report, antineuronal antibodies were not found in 120 dogs with extraneural tumors
suggesting that screening for ANNA may not be useful for detecting dogs with paraneoplastic neuropathies [516].
Prognosis is guarded to poor in cases that have been reported, although recovery occurred in one dog following
surgical removal [341] and in another with multiple myeloma treated with melphalan and prednisolone [345].
Peripheral Nerve Tumors

Readers are referred to chapter 2 and Neoplasia of the Nervous System for a review of neoplasms involving
peripheral nerves (see peripheral nerve tumors).
Polyradiculoneuritis
By definition, polyradiculoneuritis is an inflammatory condition primarily involving multiple nerve roots. It may be
one of the more commonly observed and least understood conditions in dogs and cats. It is becoming evident that
there are a number of nerve root disorders (polyradiculoneuritides or polyradiculoneuropathies) that are
characterized clinically by sudden onset of paresis, paralysis, or tetraplegia. Cranial nerve involvement may be
prominent and there may be a relapsing clinical course. Differentiation of these conditions from pure primary
peripheral nerve disorders (those without nerve root involvement) or junctionopathies can be difficult but may be
facilitated by electrodiagnostic (EDX) testing [86,348]. With nerve root lesions, there may be abnormal latencies in
F-waves (small compound muscle action potentials [CMAPs] resulting from antidromic excitation of motor
neurons) or H-waves (small CMAPs that occur following nerve stimulation resulting from impulses in sensory
nerve fibers that monosynaptically excite ventral horn cells). The latency of the H-wave is about the same as the
F-wave but requires functional dorsal roots, in addition to ventral roots and proximal peripheral nerve). Additional
EDX testing includes determination of compound action potential amplitudes, F-ratios, F-wave amplitudes, and
electromyography [349]. There may be increased levels of CSF protein without pleocytosis (albuminocytologic
dissociation), and nerve root biopsy may show evidence of inflammatory cell infiltration. It is likely that many
cases of polyneuritis are actually polyradiculoneuritides. A tentative classification of polyradiculoneuritis in dogs
and cats follows. Readers should note that Coonhound paralysis and Idiopathic polyradiculoneuritis described
below have been termed "acute canine polyradiculoneuritis" by some authors [433].
Coonhound Paralysis -
Coonhound paralysis (CHP) is a sporadically-occurring neurological disease of dogs, occurring especially in
raccoon-hunting breeds [350-353]. The pathogenesis is unknown. A raccoon bite has been a consistent
antecedent in CHP. The condition has been reproduced experimentally by injection of raccoon saliva into a dog
that had recovered from two earlier spontaneous attacks [354]. Results of this work suggested that raccoon saliva
contains the etiologic factor for CHP and that only specifically susceptible dogs are at risk of developing CHP
when exposed to this factor.
Interest has focused on CHP due to its resemblance to Guillain-Barre syndrome (GBS) in people and its potential
as an elucidating model. Like the human syndrome, CHP may have an immunological pathogenesis, although
results of one study of CHP did not conform with the evidence presented in GBS for an obligatory role of
macrophages in initiating myelin damage [355]. However, the observed changes do resemble those reported in
immunological-mediated experimental allergic neuritis [356].
Pathological findings are associated with a polyradiculoneuritis, with both segmental demyelination and
concurrent degeneration of myelin and axons. Leukocytic infiltration, consisting mostly of cells of the monocyte-
macrophage series, and scattered aggregates of lymphocytes and plasma cells also are observed. Changes
occur in peripheral nerves and nerve roots, especially in the latter and more consistently in ventral roots than
dorsal roots. In one comprehensive study, lumbosacral roots and spinal nerves were more involved than thoracic
and cervical roots and spinal nerves [357]. Neutrophils may be present early in severely affected dogs.
Chromatolytic changes in spinal motoneurons may occur secondary to severe axonal degeneration in peripheral
nerves and nerve roots.
The disease affects dogs of any breed, both sexes, and usually of adult age. Clinical signs frequently appear 7 to
11 days after an encounter with a raccoon. Onset is marked by weakness and pelvic limb hyporeflexia, although
thoracic limb involvement may sometimes be the initial and dominant clinical sign. Paralysis progresses rapidly,
resulting in a flaccid symmetric tetraplegia; however, milder forms without paralysis can occur. The duration of
paralysis varies from several weeks to 2 or 3 months. Motor impairment is more pronounced than sensory
changes, although many dogs appear to be hyperesthetic to sensory stimuli. Bladder and rectal paralysis are not
usually observed. In severely affected animals, there may be complete absence of spinal reflexes, facial
weakness, loss of voice, inability to lift the head, and labored respiration. Motor nerve conduction velocities may
be markedly reduced and EMG studies reveal widespread denervation 6 to 7 days after the onset [355]. F-waves
can be altered (e.g., prolonged F-wave latencies and F-wave dispersion, decreased F-wave amplitudes),
depending on the clinical signs and duration of disease [358]. In addition, increased F-ratios, and decreased
CMAPs may be helpful EDX features [349]. Note that in some cases, the EDX changes appear to have a distal
distribution. Similar findings occur in people with GBS and it has been explained by the preferential involvement of
longer nerves associated with their greater chance of being affected by a multifocal demyelinating process [524].
Elevated protein with normal cell counts in CSF has been reported, especially in samples obtained from lumbar
puncture [353]. This protein is predominantly albumin and its origin is thought to be more consistent with protein
transudation rather than intrathecal immunoglobulin production [511]. Presence of circulating antibodies against
raccoon saliva has been demonstrated using ELISA assays [358].
Prognosis is usually favorable, but dogs with severe axonal degeneration may die from respiratory paralysis or
may have protracted, incomplete recoveries, and some animals may not show any clinical improvement.
Protection from future attacks is short-lived or nonexistent. Affected dogs may have a greater chance of
redeveloping paralysis on subsequent encounters with raccoons [353]. Treatment is symptomatic. Corticosteroids
in our experience have not been effective in expediting recovery. Good nursing care is essential, including
physiotherapeutic rehabilitation.
In people, GBS (or acute inflammatory demyelinating polyradiculoneuropathy) appears to be an autoimmune
disease, involving both cell-mediated and humoral factors (e.g., IgG and IgM antibodies) resulting from aberrant
immune responses against various components of peripheral nerve fibers (the myelin sheath is the specific target
structure) and is characterized by presence of inflammatory lesions (lymphocytes and macrophages) and
localized demyelination throughout the PNS [347]. Axonal lesions also occur but are usually less severe than the
demyelinating lesions. However, two forms of axonal-GBS are recognized: acute motor-sensory axonal
neuropathy and acute motor axonal neuropathy [359,360]. Some forms of GBS appear to be related to
Campylobacter jejuni infection (especially the axonal forms), while other antecedent events (or "triggers") include
viral and spirochete infection, surgery, and vaccination (including some strains of rabies) [347]. While the
existence of a primary axonal neuropathy in a small percentage of human patients having a poor prognosis has
been reported [361,362], we found that the intensity and type of lesion in 13 GBS patients with severe clinical
disease (all bed-ridden in an intensive care unit and most requiring assisted ventilation) had no predictive value
for eventual clinical recovery, but was correlated with length of clinical course (axonal lesions dominated in 23%
of patients, while axonal lesions in presence of the more classical demyelinating form of GBS was seen in a
further 23% of patients) [363]. In people, supportive care is the cornerstone of treatment as the majority of
patients recover once the acute stage is passed, while specific treatment includes plasmapheresis and
intravenous immunoglobulins [347]. Corticosteroids are usually ineffective.
Idiopathic Polyradiculoneuritis -
A condition that appears to be identical to Coonhound paralysis with respect to onset, clinical signs, clinical
course, EDX findings, and pathology occurs in dogs that have had no possible exposure to raccoons [364,365].
This condition has a world-wide distribution, occurs in countries where raccoon do not exist [366] and may have
an incidence much higher than the literature suggests [367-369]. Mature dogs are typically affected; however, a
suspected polyradiculoneuritis has also been reported in a 14 week old Rottweiler puppy in the UK [370]. Note
that mild forms of polyradiculoneuritis may occur in dogs in which flaccid paralysis does not develop fully in any
muscle group and animals maintain ambulatory function [368]. As with Coonhound paralysis, some dogs with
idiopathic polyradiculoneuritis may require ventilatory support [367]. In my experience, pathological findings in
peripheral nerve biopsy samples (e.g., common peroneal nerve) reflect the clinical course of idiopathic
polyradiculoneuritis: minimal changes are seen within the first 7 to 10 days of clinical signs. In chronic cases, the
incidence of changes increases, usually reflecting a mixture of axonal degeneration, demyelination, and
remyelination. Idiopathic polyradiculoneuritis is clinically, but not pathologically, similar to distal denervating
disease, reportedly the most common canine polyneuropathy in the UK. In a recent study examining the
relationship between acute polyradiculoneuritis and prior infection or exposure to various infectious agents,
affected dogs had significantly higher serum IgG titers against Toxoplasma gondii than controls, although a
causal relationship was not established [510].
Despite the clinical prevalence of polyradiculoneuritis, demonstration of inflammatory cell infiltrates in peripheral
nerve biopsies (e.g., common peroneal nerve or tibial nerve sampled at the level of the stifle) seems to be very
uncommon, as least in my experience. Undoubtedly, inflammation would be more frequently observed in nerve
root biopsy samples.
Idiopathic polyradiculoneuritis occurs infrequently in cats. As with dogs, demonstration of inflammatory cells in
peripheral nerve biopsy samples from cats with clinical evidence of acute polyradiculoneuritis is unusual. Of all
the feline peripheral nerves processed in my laboratory, I have seen only one case of polyneuritis in a cat with
clinical signs suggestive of a polyradiculoneuritis. A severe, acute polyneuritis associated with anemia and
transient icterus and fever was reported in a four year old neutered female cat [371]. Pathological findings were
largely restricted to peripheral nerves and axons and consisted of extensive destruction of myelin and axons and
macrophage infiltration. The variable presence of perivascular cuffs of lymphocytes and plasma cells was
commensurate with an inflammatory disease and suggested a possible viral and/or immune-mediated etiology.
Clinical signs included tetraparesis progressing to tetraplegia, lack of placing and tendon reflexes, depressed
flexor reflexes, and hyperesthesia. Cranial nerves, perineal reflex and tail function were normal, as was mental
status. Severe muscle wasting was present in all limbs after two weeks. EDX data were not available. Brain,
spinal cord and nerve roots were not examined.
Cauda Equina Polyradiculoneuritis -

A polyradiculoneuritis has been reported in two dogs - a 9 year old female Labrador Retriever and an 8 month old
female Yorkshire Terrier - that were presented with a lumbosacral syndrome (pelvic limb paraparesis, muscle
hypotonia and atrophy, loss of patellar reflexes, and proprioceptive loss) [372]. Pain sensation, bladder function,
and anal reflex were intact. Motor nerve conduction velocity was decreased in the sciatic-tibial nerves. Latency of
F-waves was markedly increased following stimulation at the level of the greater trochanter and at the hock.
Pathologically, lesions in both dogs were located in the lumbosacral nerve roots that comprise the cauda equina.
Dorsal and ventral nerve roots, as well as dorsal root ganglia were involved. There was marked interstitial and
perivascular infiltration of mononuclear cells (lymphocytes, plasma cells, and macrophages), axonal degeneration,
demyelination, and remyelinating clusters. Milder changes were seen in nerve roots throughout the spinal cord, as
well as in roots of the trigeminal nerve. Muscle changes reflected neurogenic atrophy. Intraneural injection of
serum from an affected dog failed to induce demyelination in normal rat nerve. Serum levels of the myelin-specific
protein, P2, were not elevated in either dog. Protein level in CSF was increased in one dog.
Chronic Inflammatory Demyelinating Polyneuropathy -

Over the past several years, we have accumulated data on a spontaneous demyelinating peripheral neuropathy
that we have called chronic inflammatory demyelinating polyneuropathy (CIDP) [373]. Based on surveys of
biopsies received from the Scott-Ritchey neuromuscular laboratory at Auburn University and from my private
peripheral nerve laboratory, CIDP is one of the more common neuropathies seen in dogs and cats. This disorder
occurs in dogs and cats of either gender and does not appear breed-related. Mature animals of any age may be
affected (from 1 to 14 years). Onset of signs is usually insidious and the course is typically chronic, often
relapsing, and frequently slowly progressive. Clinical signs are usually first noticed in the pelvic limbs and, in most
animals, progress to involve the thoracic limbs. Clinical signs include tetraparesis, sometimes progressing to
tetraplegia, stumbling gait, and hyporeflexia. Less commonly observed signs are muscle trembling (dogs),
intermittent shifting limb lameness characterized by a plantigrade stance (cat), and ventroflexion of the head and
neck (cat). Facial nerve paralysis or laryngeal paralysis are seen occasionally in dogs, while
megaesophagus/regurgitation is found in some cats. Serological testing is normal, although one cat had an IgG
monoclonal gammopathy. CSF analysis is usually normal, although occasional animals may show a moderate
protein increase. Motor nerve conduction velocities (NCVs) are decreased, along with temporal dispersion,
decreased amplitudes and prolonged latencies of the compound muscle action potentials. Slow sensory NCVs
have also been noted. EMG studies in this report were either normal or revealed mild, patchy pattern of fibrillation
potentials and positive sharp waves. Pathologically, changes in teased single fibers from peripheral nerves are
dominated by multifocal paranodal demyelination, and sometimes segmental demyelination. Other changes
include remyelination and variable numbers of fibers with internodal globules. Axonal degeneration is infrequently
observed. Scattered, thinly myelinated fibers are seen on semithin sections. Severe changes may include
presence of onion-bulbs and rarefaction of myelinated fibers. Ultrastructural studies reveal macrophages within
myelinated fibers stripping the myelin sheaths, naked and remyelinating axons, and focal/multifocal endoneurial
mononuclear cells, including lymphocytes, rare plasma cells, macrophages with myelin debris, and vacuolated
fibroblasts. Indirect immunofluorescence revealed positive IgG staining in peripheral nerve myelin sheaths from
two dogs. No fluorescence was seen using anti-dog or anti-cat C3 (positive immunofluorescence to anti-human
IgM and C3d was observed in control dog and cat nerve sections incubated with serum from a human patient with
an IgM monoclonal gammopathy [374]). In skeletal muscle, minimal lesions are seen , apart from mild fiber size
variation in some cases. Diagnosis is based on clinical signs, relapsing clinical history, and nerve biopsy studies.
Prognosis is often favorable with treatment. The majority of dogs and cats (approximately 90%) were initially
steroid-responsive (e.g., prednisolone at 1 - 2 mg/kg PO bid for at least a week followed by alternate day, reduced
dosage for several weeks or several months), with many animals showing a return to normalcy following
treatment. In some cases, the response to steroids is incomplete. Signs may relapse when treatment ceases
(requiring addition treatment cycles) or upon reduction of the dose of steroids. Uncommonly, some animals with
relapsing signs that are steroid-responsive may become steroid-resistant and deteriorate clinically.
The course of the disease, clinical signs, electrophysiology, and pathology have similarities to chronic
inflammatory demyelinating polyneuropathy in people in whom weakness has a proximal distribution [262]. Most
human patients with CIDP respond to corticosteroids and other immunosuppressive agents (e.g., azathioprine
and cyclophosphamide), plasma exchange, and intravenous immunoglobulin (therapies aimed at treating
immune-mediated disorders) [347].
Sporadic case reports of chronic relapsing polyradiculoneuritis in a dog [375] and a cat [376], chronic relapsing
polyneuropathy in a cat [377], and prednisolone-responsive neuropathy in a cat [378], also appear very similar to
CIDP.
Infectious Polyradiculoneuritis -
A severe polyradiculoneuritis and/or polymyositis associated with either Toxoplasma gondii or Neospora caninum
occurs commonly in dogs, especially those less than one year of age (see toxoplasmosis). In one dog with
diskospondylitis due to Aspergillus terreus, multiple granulomas with fungal elements were found in the
subarachnoid space associated with the nerve roots of the cauda equina [379].
Postvaccinal Polyradiculoneuritis
Post-vaccinal polyradiculoneuritis (e.g., multivalent vaccine, inactivated rabies vaccine) has been reported only
sporadically in dogs [380-382] with signs and clinical course similar to those in dogs with Coonhound paralysis.
The condition, also known as postvaccinal inflammatory neuropathy (IPN), occurs rarely in people and is believed
to be an autoimmune reaction triggered by the vaccine against some myelin, axonal or neuronal component [526].
Trigeminal Neuritis -
Trigeminal neuritis, or idiopathic trigeminal neuropathy, occurs commonly in dogs and sporadically in cats and is
typically characterized by acute onset of jaw paralysis, inability to close the mouth, drooling, and difficulty eating
and drinking [383-385]. Older animals are usually affected, although the condition may occur at any age. There is
no apparent breed, sex, or seasonal predisposition, although in one retrospective study of 29 cases, Golden
Retrievers were overrepresented [518]. In this study, trigeminal sensory deficits were found in 9 of 26 dogs (35%).
Horner’s syndrome (due to damage of postganglionic sympathetic fibers incorporated in segments of the
trigeminal nerve and its ophthalmic branch) has been observed in several cases [149,518,525], as well as
occasional facial nerve involvement [518]. EMG studies usually reflect abnormalities in muscles of mastication
and CSF studies may be abnormal (usually characterized by a mild mononuclear pleocytosis, often with normal or
mildy elevated protein content) [518]. Pathologically, a bilateral non-suppurative neuritis has been found in motor
branches of the trigeminal nerve and ganglion, associated with demyelination and occasional fiber degeneration,
and accompanied by inflammatory infiltrates consisting predominantly of macrophages and B and T lymphocytes
[149,525]. Masticatory muscle changes may reflect variable neurogenic atrophy, usually without evidence of
inflammatory cell infiltrates. The disease appears to be self limiting and recovery usually occurs in 3 to 4 weeks,
but some cases may take several months to resolve. Corticosteroid administration appears not to affect the
clinical course of the disease [518]. Supportive fluid and nutrient intake may be necessary. Definitive antemortem
diagnosis of trigeminal neuritis is complicated by the fact that biopsy of the trigeminal nerve is difficult.
The severity of muscle atrophy, the clinical course, and clinical recovery may depend upon the extent of axonal
degeneration present. If it is the dominant lesion, then prognosis can be guarded. Note that some animals with
rabies may present with signs of trigeminal neuritis.
Definitive classification of this disorder awaits more detailed pathologic studies on a greater number of cases,
although the few cases examined histologically are suggestive of immune-mediated disease [525]. I think that it is
also possible that trigeminal neuritis in some instances may represent a focal manifestation of a more diffuse
polyradiculoneuritis. Note that bilateral trigeminal neuropathy in a dog has been reported in association with
lymphosarcoma [386], and an invasive intracranial juvenile parameningeal rhabdomyosarcoma that destroyed the
trigeminal nerve causing unilateral denervation atrophy of masticatory muscles was reported in a 23 month old
dog [530]. When I was at the Neuromuscular Diagnostic Laboratory at Auburn University, many of the muscle
samples that we received from dogs with suspected masticatory myositis (and some dogs with clinical evidence of
trismus!) showed non-inflammatory neurogenic atrophy compatible with idiopathic trigeminal neuritis/neuropathy.
Rottweiler Distal Sensorimotor Polyneuropathy

A polyneuropathy has been reported in mature Rottweiler dogs in the US [387]. Clinical signs are characterized
by paraparesis that progresses to tetraparesis, spinal hyporeflexia and hypotonia, and appendicular muscle
atrophy. While signs may appear acutely, the course tends to be gradually progressive (up to 12 months or longer
in some dogs) and may be relapsing. Nerve and muscle biopsies were examined from eight affected Rottweilers,
six male and two female, aged between 1.5 and 4 years. Pronounced neurogenic atrophy was present in skeletal
muscle samples and there was no evidence of necrosis, phagocytosis or inflammation. Changes in sensory and
motor peripheral nerves included loss of myelinated nerve fibers, axonal necrosis, and variable numbers of fibers
with inappropriately thin myelin sheaths. Demyelination and remyelination were more apparent in dogs with a
chronic clinical course. Regenerating clusters were not common. Ultrastructural findings included occasional
myelinated fibers showing myelinoaxonal necrosis, demyelinated fibers often associated with macrophage
infiltration, many axons with myelin-like membranous profiles, increased endoneurial collagen, occasional axonal
atrophy, and numerous Büngner bands. Many axons had a watery appearance with loss of neurofilaments and
microtubules, but no evidence of neurofilamentous accumulation. Onion-bulb formation was rare. Lesions in
unmyelinated fibers included increased numbers of Schwann cell profiles and loss of axons in Schwann cell
subunits. Morphological and morphometric studies indicated preferential loss of medium- (5.5 to 8 m) and large-
caliber (8.5 to 12.5 m) fibers which was more severe in distal parts of nerves compared to more proximal
regions and nerve roots. Mean nerve fiber diameters for proximal and distal segments were 4.95 + 2.75 m and
2.41 + 0.71 m, respectively. Numerous positive sharp waves and fibrillation potentials were detected in
appendicular muscles by EMG, especially in muscles distal to the elbow and stifle. Few abnormal potentials were
noted in proximal limb/paraspinal muscles. Motor and sensory nerve conduction velocities were reduced in some
dogs. Hematology, blood chemistries, spinal radiography/ myelography were normal. With the exception of one
dog that was serologically positive for Valley Fever and Ehrlichia canis (1:80), and another dog that was
antinuclear antibody positive (1:160), testing has been negative for immunological disorders (e.g., lupus
erythematosus cell preparation, rheumatoid factor, Coombs' test), endocrine dysfunction (e.g., diabetes mellitus,
hypothyroidism, hyperadrenocorticism), toxicity (e.g., lead, cholinesterase levels), and infectious disease (e.g.,
Rocky Mountain Spotted Fever, Borreliosis, ehrlichiosis). CSF protein was marginally elevated in one dog.
Pathological findings suggest this condition is a dying-back, distal sensorimotor polyneuropathy. Prognosis
appears guarded to poor; despite the fact that some dogs showed a temporary response to corticosteroid therapy.
This disorder has morphological and morphometric similarities to hereditary sensory and motor neuropathy
(HSMN) type II (or CMT II) in people, a distal axonal neuropathy with normal or near normal nerve conduction
velocities with reduced amplitudes, indicating loss of axons [43,225].
Note that this condition appears similar to other distal symmetrical polyneuropathy seen in large-breed dogs.
Sensory Neuropathies
Several sensory neuropathies have been observed in small animals, primarily in dogs. In people, sensory
neuropathies may affect one or more sensory modalities - pain, proprioception, touch, and temperature. In
animals, only the first two sensory modalities can be determined with any degree of accuracy [388]. Sensory
neuropathies in dogs may also be characterized by self-mutilation. In general, paresis and muscle atrophy are not
present, and no abnormal spontaneous potentials are detected on electromyographic testing. Nerve conduction
studies may demonstrate slowed velocities in sensory but not motor nerves. Spinal cord dorsum potentials (a type
of spinal cord evoked potential) can also be used to accurately assess functional severity and distribution of
abnormalities in proximal sensory nerves, dorsal nerve roots, and spinal cord dorsal horns in dogs with suspected
neuropathy, radiculopathy, or myelopathy involving the brachial or lumbosacral intumescences [86,389].
Electrodiagnostic (EDX) evaluation of H-reflexes (H-waves) provides additional information on dorsal nerve root
integrity/function [388].
Sensory Ganglioradiculitis -
A sensory disorder has been reported in adult dogs (with an age range from 1.5 to 9 years) of different breeds
and of either gender [353,390-394]. I have also seen the condition in a 2.5 year old Scotch Collie. The terms
sensory neuronopathy, sensory polyganglioradiculoneuritis, and ganglionitis have also been used to describe this
condition because of involvement of craniospinal sensory ganglia. Pathologically, the disease is characterized by
pronounced degeneration and loss of neurons in dorsal root ganglion cells and in cranial sensory ganglia (such as
trigeminal and nodose ganglia), usually accompanied by inflammatory lymphoplasmacytic and macrophage
infiltration. The infiltrating cells are primarily T lymphocytes and immunoglobulins are not present on the cell
membranes of affected neuron [522]. A marked loss of larger-diameter myelinated fibers has been observed in
dorsal roots and in sensory nerves, and there may be selective loss of myelinated fibers in the dorsal columns of
the spinal cord (grossly, the dorsal columns may appear white/opaque), indicative of degeneration secondary to
ganglion dysfunction [200,392]. Similar degenerative changes may occur in sensory pathways of cranial nerves,
such as the spinal tract of the trigeminal nerve and the solitary tract (containing visceral afferent fibers of facial,
glossopharyngeal and vagus nerves). In one case I have seen, axonal necrosis present in multiple nerves was
more severe distally. Ventral roots are usually spared or only mildly affected. Denervated Schwann cells of
myelinated and unmyelinated fibers are found in the dorsal roots.
The clinical course is usually insidiously progressive over several months or years. Clinical signs are variable and
include proprioceptive deficits, generalized ataxia with preservation of muscle strength, depression or absence of
tendon reflexes, such the patellar reflex, facial hypalgesia/paresthesia, megaesophagus, head tilt, loss of voice,
hearing loss, anisocoria, difficulty in prehending food, dysphagia, stiff gait often with hypermetria, and
occasionally, self-mutilation. Muscle atrophy is usually not a feature; however, atrophy of masticatory muscles
may be seen in some dogs, attributed to inflammatory involvement of fibers from the motor root of the trigeminal
nerve as they course through the trigeminal ganglion [390]. Hematological values, CSF analysis and radiographic
studies are within normal limits; however, a mild increase in CSF cellularity and total protein may be present.
EMG findings are usually normal. Sensory nerve conduction velocites (NCVs) are slowed or absent, while motor
NCVs are normal. Prognosis is guarded to poor. To date, corticosteroids (e.g., prednisone) and procarbazine
have been ineffective.
The pathogenesis of ganglioradiculitis remains to be established, but the evidence points to a cell-mediated
immune mechanism [522]. A possible toxic etiology was considered in a 4 year old Labrador Retriever with
pathology localized to sensory nerves, dorsal root ganglia and the dorsal columns of the spinal cord [393]. In this
dog, liver mercury levels were elevated above normal, although below the range normally associated with
mercury poisoning.
Progressive Axonopathy in Boxers -

This putative sensory neuropathy is an inherited autosomal recessive neuropathy of Boxer dogs [395-402].
Pathological findings are seen in nerve roots, peripheral nerves, and in the CNS. Large axonal swellings
(spheroids) are found in various brainstem nuclei, especially cuneate and superior olivary nuclei. Spheroids and
degenerating fibers are seen in spinal cord white matter, particularly in lateral and ventral funiculi. Minimal
changes occur in the dorsal columns. The optic pathways are also involved. In the PNS, small axonal swellings
develop at proximal paranodal areas in dorsal and ventral nerve roots as well as in proximal nerves. Axonal
swellings are due to accumulation of both disorganized neurofilaments and membranous organelles, mainly
vesicles and vesiculo-tubular profiles. Myelin over such swellings is often attenuated. Myelin changes
predominate in the nerve roots, whereas axonal degeneration and regeneration are encountered in more distal
nerves. In contrast, regenerating axonal clusters are common in cervical ventral roots, throughout the course of
the disease. Axonal degeneration in the spinal cord shows no obvious tract or proximal/distal selectivity [397].
Most early axonal spheroids are surrounded by a myelin-associated glycoprotein (MAG)-positive zone but in the
larger swellings and longer duration cases this was sometimes absent; however, distorted Schmidt-Lanterman
incisures, a feature of the advanced disease, tend to be strongly MAG-positive. [402]. It has been hypothesized
that failure of slow axonal transport may occur in roots leading to axonal swellings and secondary hypoplasia of
more distal, larger-diameter fibers. Myelin/Schwann cell alterations might occur in response to the axonal
changes [399,400]. Immunocytochemical studies revealed that the major axonal cytoskeletal proteins in nerve
roots and in spinal cord are markedly disturbed: many spheroids contain increased amounts of actin, and
sometimes deficient tubulin in the periphery of the neurofilament accumulations, while the distribution of axonal
fodrin in CNS and PNS appears unaltered [401]. In addition, the perikarya of many motor neurons in the spinal
cord and brain stem contained phosphorylated 200 kD neurofilaments (phosphorylated neurofilaments are
normally localized in the axon rather than the cell bodies).
Onset of clinical signs occurs about 2 months of age. There is a progressive ataxia and weakness, initially in
pelvic limbs, but later involving thoracic limbs. Proprioceptive function, muscle tone and tendon reflexes are
diminished or absent, while pedal reflexes and pain sensation are preserved. Absent patellar reflexes can be
detected at 1 month of age. Muscle atrophy is minimal. Signs slowly progress until animals are 12 to 18 months of
age, and then tend to stabilize. Mild cerebellar signs may be evident late in the course of the disease. EDX
studies reveal little spontaneous activity in muscle but reduced motor and sensory nerve conduction velocities
and reduced evoked muscle action potential amplitudes after about 4 months of age. Eventually, sensory nerves
cease to conduct impulses. F-wave latency is increased.
Diagnosis is suggested by signalment, clinical, and electrodiagnostic data, and confirmed by nerve biopsy or
pathological evaluation of the CNS. Prognosis is poor. There is no treatment.
A disorder with similar clinical signs, clinical course, and pathological features has been reported in a young
Rottweiler puppy (2 affected puppies out of a litter of 11) [200]. Distribution and nature of lesions observed in a 5
month old Pyrenean Mountain dog were also considered similar to those in the Boxers [403], although the
characteristic axonal neurofilamentous accumulation was not described.
Sensory Neuropathy in Long-Haired Dachshunds -

This is a neurological disease reported in Long-Haired Dachshund puppies thought to be inherited as an
autosomal recessive trait [120,404]. The pathogenesis is unknown. Pathological findings occur in distal sensory
nerves affecting both larger caliber myelinated fibers and unmyelinated fibers (UF). Changes include myelinated
nerve fiber loss, axonal degeneration, many bands of Büngner, marked increased numbers of axonal organelles
(mitochondria, smooth endoplasmic reticulum, and glycogen), prominent endoneurial fibrosis, occasional
evidence of small regenerating clusters, and rarely, onion bulb formations. While UF density appeared normal,
abnormalities in UFs were frequently seen in distal nerves including increased numbers of intra-axonal
neurotubules and/or tubulo-vesicular elements, stacks of lamellar profiles, collections of dense granular material,
along with accumulation of mitochondria, smooth endoplasmic reticulum and glycogen, darkening of the axoplasm,
empty Schwann cell subunits, Büngner bands, and collagen pocket formations. Paranodal demyelination seen on
teased nerve preparations is considered to be secondary to axonal changes. Degenerative changes are noted in
the vagus nerve. Less severe, but similar changes occur in mixed nerves. Sensory neurons in the spinal ganglia
are normal and dorsal roots appear normal. In the CNS, distal degeneration has been observed in the fasciculus
gracilis, suggesting this condition is a distal central-peripheral axonopathy.
Clinical signs are noted in dogs as early as 8 to 12 weeks of age, and are characterized by subtle ataxia, loss of
proprioception and placing reactions, especially in pelvic limbs, reduction or loss of pain sensation ("nociception")
over the whole body in response to superficial and deep pain stimulation, and dribbling of urine. Self-mutilation of
the penis and intermittent vomiting have been noted. Pelvic limbs may splay-out when dogs are lying in sternal
recumbency. There is no evidence of paresis or muscular atrophy and patellar reflexes are normal or slightly
reduced. EMG studies and motor NCVs are normal. Sensory NCVs are reduced or absent.
Diagnosis is based on signalment, clinical, electromyographic and pathological (nerve biopsy) data. Provided that
complications do not occur from vomiting or from self-mutilation (which may necessitate muzzling), it has been
stated that most affected dogs live normally [388]. There is no treatment. This canine disorder was considered to
have some similarities to human hereditary sensory neuropathy type II (now re-classified as hereditary sensory
and autonomic neuropathy type II, an autosomal recessive disorder).
A sensory neuropathy having similar clinical (loss of proprioception and generalized loss of superficial pain
sensation, except over the lips and inside the nostrils where pain sensation was blunted but present, and urinary
incontinence) and pathological features has been reported in a 2 month old Border Collie puppy [405]. Sensory
nerve action potentials were absent.
Another condition that appears similar to that in the Dachshunds has been reported in a 6 year old, male Jack
Russell Terrier presented with a chronic history of abnormal pelvic limb posture and a tendency to repeatedly bite
its right pelvic limb [406]. At rest, the dog stood with one pelvic limb flexed and the other extended. Neurological
examination revealed proprioceptive deficits in pelvic limbs and in one thoracic limb. Postural reaction testing was
clumsy in pelvic limbs. The dog continued to dribble urine following micturition. Pain perception was diminished in
the distal pelvic limbs up to the level of each stifle. Patellar reflexes were brisk bilaterally and there was no
evidence of paresis or muscle atrophy. Electrodiagnostic data were not included in this report. Examination of a
sensory nerve biopsy (lateral branch of the superficial peroneal nerve) revealed absence of myelinated fibers,
preservation of unmyelinated fibers, abundant endoneurial and epineurial connective tissue, and small numbers
of denervated Schwann cells. Future studies are needed to determine if there is involvement of sensory ganglia,
and if the condition is inherited.
Sensory Neuropathy in English Pointers -

This sensory neuropathic disease, inherited as an autosomal recessive trait, has been reported in English Pointer
dogs [407-409]. An apparently similar, recessively inherited entity has been reported in Czechoslovakian
Shorthair Pointer dogs in Europe and has been called toe necrosis, hereditary neurotrophic osteopathy, and
ulcero-mutilating acropathy [410].
Changes in the primary sensory neurons are observed pathologically, including presence of small spinal ganglia
with reduced numbers of cell bodies (from 20 - 50%), a disproportionately large population of small sensory cell
bodies, degeneration of unmyelinated and myelinated fibers in the dorsal roots and peripheral nerves, and
reduced fiber density and myelin staining in the dorsolateral fasciculus (Lissauer’s tract) of the spinal cord in
which pain and temperature fibers travel. Ultrastructurally, there is evidence of bands of Büngner, denervated
Schwann cell subunits, collagen pockets, lysis of neurotubules and filaments in unmyelinated fibers, and little
evidence of axonal regeneration of myelinated or unmyelinated fibers [407].
The pathogenesis of this disease is presently unclear; however a deficiency in growth and/or differentiation of
primary sensory neurons may be involved. The loss of primary sensory neurons is associated with a notable
reduction in staining of substance P, an excitatory agent that mediates nociception (i.e., pain sensation) [411].
This loss is most apparent in the dorsolateral fasciculus and superficial laminae of the spinal dorsal horns. In older
dogs, a loss of P substance was also found in the spinal nucleus of the trigeminal nerve. This finding, in addition
to appearance of scattered fiber degeneration in the dorsal columns of the mature Pointer, suggested that fiber
degeneration may progress slowly with age to include sensory systems not affected in early postnatal life [411].
Clinical signs are characterized by nociceptive (pain) loss and acral mutilation. This nociceptive loss is more
apparent in distal parts of limbs, so that acral analgesia is replaced by hypalgesia proximal to the carpus and
tarsus. No nociceptive loss is found about the face. Although blunting of digital pain has been detected prior to
weaning, clinical signs usually become apparent at 3 to 8 months when affected dogs suddenly begin to lick and
bite their paws. Acral changes include swollen reddened paws, ulcerations, lacerations, paronychia, painless
fractures, and autoamputations.
There is no evidence of proprioceptive loss, ataxia, or depressed tendon reflexes. EMG studies and sensory and
motor nerve conduction studies are normal. Diagnosis is based on signalment and clinical data, and normal
electrodiagnostic results. Histopathological evaluation of nerve or spinal ganglia biopsy samples may support the
clinical diagnosis. Prognosis is poor because of high potential for osteomyelitis secondary to autoamputation.
There is no treatment for the underlying sensory neuropathy.
This sensory neuropathy appears to have clinical and pathological similarities to several of the hereditary sensory
and autonomic neuropathies (types I through V) described in people [43,412].
Sensory Trigeminal Neuropathy -

Sensory trigeminal neuropathy has been reported in a 2 year old, female Rough Coated Collie dog [413]. The
cause was not determined. Pathological lesions included marked loss of nerve fibers in the trigeminal nerves and
their spinal tracts. Motor fibers of the mandibular nerves were unaffected. These changes were not associated
with inflammation and were considered to be secondary to loss of neurons in the trigeminal ganglion (Gasserian
ganglion). The motor nucleus of the fifth nerve was normal. Clinical signs of acute onset of excessive salivation,
coughing and dysphagia were believed to be associated with bilateral loss or absence of tactile sensation and
deep pain from the face, tongue and oral mucosa. The condition in this dog remained relatively unchanged over
an 18 month period.
Idiopathic self-mutilation -
Idiopathic self-mutilation or behavioral self-mutilation has been seen in both dogs and cats. Affected animals are
often of nervous or high-strung breeds such as Siamese, Burmese, Himalayan or Abyssinian cats, and Doberman
Pinscher, German Shepherd, Great Dane, and Irish Setter dogs [414]. In dogs, this self-mutilation may manifest
itself as continued licking, biting or scratching of one or more areas usually near the carpus or hock, and has been
termed acral lick dermatitis (ALD), lick granuloma, acral pruritic nodule, neurodermatitis, and canine
obsessive/compulsive disorder (also see Behavioral disorders). EDX studies have provided evidence of both mild
sensory axonal polyneuropathy in some affected dogs [415], as well as apparent motor ventral root involvement in
9 of 16 dogs with lick granuloma [416] The tricyclic antidepressant drug, clomipramine (Anafranil ®), dosed at 1 to
3 mg/kg PO daily, results in significant improvement in the dogs' licking behavior [417-419]. Other effective drugs
against ALD include citalopram, fluoxetine, and naltrexone [420-422].
A feline orofacial pain syndrome has been described in cats (the majority of cases are in Burmese cats)
characterized by acute onset of exaggerated licking and chewing movements with pawing at the mouth
sometimes leading to severe self-mutilation [517]. Signs may be seen in kittens around 14 weeks of age
(associated with vaccination and mouth ulceration), in kittens around 5 months of age (associated with teething),
or in older cats (from 1 to 16 years of age), sometimes associated with stress or dental disease. The attacks can
be episodic (eg, lasting between 5 minutes and 2 hours) or continuous (necessitating paw bandaging or an
Elizabethan collar to prevent mutilation). Some cats show spontaneous remissions and recurrences. The
syndrome may be similar to trigeminal neuralgia and glossodynia (burning or painful tongue) in people. Treatment
using anti-epileptic drugs (diazepam or phenobarbitone) are effective in many cases.
I have seen degenerative changes in sensory and in mixed nerves (perhaps affecting only the sensory portion)
from 2 dogs (an 8 month old male Spitz and a 6.5 year old male Miniature Doberman Pinscher) presented for
bilateral self-mutilation of the digits in the pelvic limbs. Axonal necrosis was dominant in the Spitz, whereas,
demyelination and remyelination were the main features seen in the Miniature Doberman. Mild dorsal column
pallor (fasciculus gracilis) was observed in the Spitz (suggesting this condition might have been a form of sensory
ganglioradiculitis), but no inflammation was present in dorsal roots or ganglia in which there was mild loss of
neurons. No spinal cord or ganglia changes were noted in the Miniature Doberman. Neurological examination and
EMG testing were normal in both dogs, while sensory but not motor nerve conduction velocity was markedly
reduced in the Miniature Doberman.
Self-mutilation has also been noted in animals with nerve injury, e.g., lumbosacral stenosis and trauma [423,424],
and auto-mutilation was observed in an epizootic of tibial and peroneal neuropathy in a kennel of Walker Hound
puppies thought to be toxin-induced (see toxic neuropathies) [425].
Storage Disease Neuropathies

Readers are referred to Chapter 2 and Storage Diseases for neuropathies associated with different storage
disorders, including gangliosidosis, fucosidosis, globoid leukodystrophy, glycogenosis type IV, mannosidosis, and
sphingomyelinosis (phenotypic variant of Niemann-Pick disease type A).
Toxic Neuropathies
Clinically-related, drug-induced neuropathies are not well defined in dogs and cats. Vincristine-associated
peripheral neuropathy was reported in a 12 year old, female, Golden Retriever that received 16 weekly doses of
vincristine (0.5 mg/m2) as part of a regimen for treatment of mycosis fungoides [426]. The dog was presented for
sudden onset of a shuffling pelvic limb gait, intermittent collapse, and difficulty negotiating turns and stairs.
Neurological examination revealed mild ataxia in the pelvic limbs, depressed pelvic limb postural reactions, and
depressed patellar and pelvic limb withdrawal reflexes. EMG testing revealed fibrillation potentials and positive
sharp waves consistent with denervation. Sciatic motor NCV was decreased. Evoked muscle potentials were
polyphasic and had reduced amplitude and prolonged duration. Severe nerve fiber degeneration, nerve fiber loss
(both small- and large-caliber fibers), and marked endoneurial fibrosis were seen in a nerve biopsy sample. The
neuropathy improved after vincristine was discontinued. Results of a repeat nerve biopsy taken 10 weeks after
cessation of vincristine administration showed fewer degenerating nerve fibers and presence of demyelination-
remyelination. The dog appeared neurologically normal at this time. In experimental studies in cats, focal axonal
swellings (giant axon formations) due to distorted accumulations of neurofilaments and secondary paranodal
demyelination were found primarily in the proximal portions of peripheral nerves, with only a few giant axon
formations seen distally along with variable axonal degeneration [427]. In people, a neuropathy typically occurs in
all patients receiving vincristine for a sufficient period and signs/EDX testing suggest a symmetrical distal
sensorimotor polyneuropathy [105]. Loss of myelinated fibers and axonal degeneration in unmyelinated fibers
have been observed [428]. In people, itraconazole may aggravate vincristine-induced neurotoxicity [429,430]. Cis-
platinum, another antineoplastic agent, has been implicated in peripheral neuropathies in human patients, usually
resulting in large fiber sensory neuropathy and axonal degeneration/demyelination [431,432]. The neurotoxicity is
dose-limiting and cumulative. Neurological signs (ataxia, lower motor neuron paresis in pelvic limbs) have been
noted in some dogs following use of this drug, although a distinction between toxic neuropathy and paraneoplastic
neuropathy was not made [433].
As chemotherapeutic treatment of tumors becomes more aggressive, there is a real possibility that clinicians will
be presented with further cases of drug-induced neuropathies. There is also a risk of neuropathies being induced
by tumor irradiation (see radiation therapy). In an experimental study of intraoperative radiation therapy,
peripheral neuropathy resulting from direct effects of irradiation on nerve and secondary effects on nerve
vasculature was apparent clinically (e.g., hind limb paresis associated with significant loss of large-caliber nerve
fibers and endoneurial/perineurial/epineurial fibrosis) 1 to 19 months following irradiation [434,435]. This toxicity
appears to be dose-limiting, with intraoperative doses < 15 Gy not resulting in clinically significant peripheral
nerve injury [436,437]. The nerve toxicity appears to be enhanced by hyperthermia [438].
Thallium poisoning, from ingestion of thalium-containing rodenticides or insecticides, may produce degenerative
changes in peripheral nerves (distended myelin sheaths with swelling and fragmentation of axons) and
ganglionitis, with clinical signs of trembling, muscle spasms, paresis or paralysis of hind limbs, severe pain, and
megaesophagus [439]. Experimental studies in cats indicate that thallium induces a central-peripheral sensory
distal axonopathy [440]. Thallium in rodenticides has been banned in the US since 1965; however, sporadic
cases of acute and chronic thallium poisoning continue to be reported [441,442] (see thallium). Experimental
neuropathies (resulting in dying-back disorders) have been induced in cats using a variety of neurotoxic
hexacarbons and acrylamide [443]; however, these neuropathic toxicities are rarely encountered in clinical
practice. Neurotoxic organophosphates may induce a delayed peripheral neuropathy in cats (16 - 18 days after
injection) associated with focal, distal but not terminal axonal degeneration [444] (see
organophosphate/carbamate toxicity). Experimental administration of beta, beta'-iminodipropionitrile (IDPN) to
cats induces neurofilament-filled axonal swellings in proximal and distal regions of peripheral nerves [445]. Lead
intoxication does not appear to produce a toxic neuropathy in dogs [446] (see lead poisoning). Experimental
pyridoxine (vitamin B6) intoxication in dogs results in degeneration of primary sensory neurons (affecting
peripheral nerves, dorsal roots, dorsal funiculus, and spinal tract of the trigeminal nerve) and clinical signs of
ataxia-dysmetria and proprioceptive deficits [447-449]. Iatrogenic peripheral vestibular disease and/or deafness
may result from use of various antibiotics and chemical agents that cause degeneration of vestibular and auditory
peripheral receptors (see deafness and vestibular disease).
An epizootic of peroneal and tibial neuropathy was reported in a kennel of Walker hounds in eastern North
Carolina [425]. Approximately 40 puppies were involved. Signs of pelvic limb monoparesis, areflexia, muscle
atrophy, and deficient postural reactions, were first seen in 2 week old puppies. Signs progressed to severe
paresis and self-mutilation of digits. Limb analgesia was also noted. Histopathological findings were largely
restricted to distal tibial and peroneal nerves and included nerve fiber loss, especially the larger-caliber fibers, and
occasional scattered demyelinating fibers. Ultrastructurally, axonal neurofilaments were often whorled and denser
than normal. Dilated granular endoplasmic reticulum were prominent in Schwann cell cytoplasm. The cause was
not determined; however, a toxic-induced neuropathy secondary to a contaminant in the well water was
suspected.
Traumatic Neuropathy
Trauma to peripheral nerves is a common cause of neuropathies in animals [450]. Nerve injuries may result from
mechanical blows, gunshot wounds, fractures, pressure, and stretching (see brachial plexus avulsion). Sciatic
nerve injury in dogs and cats often follows fracture of the ileal body or acetabulum, or from sacroiliac fracture-
dislocation with cranial displacement of the ilium [424,451-453]. Facial nerve injury may occur during total ear
canal ablation and lateral bulla osteotomy in the dog [454]. Bilateral mandibular nerve injury has been reported in
dogs thought to result from carrying large objects in the mouth (probably from mandibular nerve neuropraxia, see
below) [455]. A transient facial nerve paralysis (presumably resulting from nerve compression) was reported in a
50 kg Doberman Pinscher x Great Dane dog following prolonged anesthesia [168]. Neck trauma in cats may lead
to Horner’s syndrome and subclinical ipsilateral laryngeal hemiplegia by damage to the vagosympathetic trunk
[294]. Sciatic nerve entrapment by muscle or fibrous tissue has been reported in small animals following femoral
fracture, ischial or acetabular fracture, and femoral head and neck excision [452,456-458]. Bilateral entrapment
was found in a dog with hip dysplasia [457]. Note that nerve root entrapment and compression commonly occur in
dogs with cauda equina syndrome (see lumbosacral stenosis). Another common cause of nerve compression
and/or entrapment is peripheral nerve neoplasia (see peripheral nerve tumors). In cats with hyperlipidemia,
peripheral nerve fascicles are subjected to compression by xanthomata which leads to secondary axonal
degeneration and nerve fiber loss. Nerve root injury and spinal cord hemorrhage has been reported in a dog in
association with tearing of the dura mater following an episode of violent struggling [459].
Additional iatrogenic causes of nerve injury include crushing, cutting, compression by casts or splints, and
injecting agents into, or adjacent to the nerve. In one study involving 57 dogs and 26 cats with femoral fractures
that were fixed with intramedullary pins, 12 (14.5%) exhibited signs of sciatic nerve entrapment [460].
Normograde intramedullary pinning of the femur is less likely to induce sciatic nerve injury, particularly in midshaft
and distal fractures [461]. In an experimental study evaluating the effects of injection of various agents normally
administered intramuscularly, the degree of nerve injury varied with [462,463]:
a. The agent injected; e.g., iron-dextran, meperidine, and cephalothin induced minimal damage, while
maximal nerve injury followed injection of penicillin, diazepam, chlorpromazine, and steroid agents
(especially hydrocortisone and triamcinalone, while minimal damage was seen with dexamethasone)
[462].
b. The site of injection, e.g. severe injury followed intrafascicular injection but there was minimal injury
following extrafascicular injection.
c. The quantity of drug injected.
d. The caliber of the fibers, e.g., large, heavily myelinated fibers were more susceptible to injection injury
than smaller, thinly myelinated nerve fibers.
The mechanism of injury appears to be a direct neurotoxic effect on both axons and Schwann cells, with
disruption of the blood-nerve barrier and with changes occurring in nerves within 30 minutes of injection [464,465].
Nerve damage may be defined in terms of structural damage. Neurotmesis is complete severance of all structures
of the nerve with Wallerian degeneration (axonal necrosis and myelin fragmentation) of the distal stump.
Axonotmesis consists of damage to the nerve fibers resulting in degeneration; however, the endoneurial and
Schwann cell sheaths remain intact and provide a framework for axonal regeneration. Neuropraxia is an
interruption in the function and conduction of a nerve without structural damage.
The regenerative ability of a nerve is directly proportional to the degree of continuity of connective tissue
structures within the nerve. In neuropraxic and axonotmesic lesions where the endoneurial connective tissue and
Schwann cells remain intact, the potential for axonal regeneration is good. In neurotmesis, axonal regeneration is
usually frustrated by lack of connective tissue scaffold or growth tubes. Also, scar tissue tends to interfere with
sprouting axons, resulting in neuroma formation. Once an axon has grown past the point of injury and penetrates
a Schwann tube in the distal nerve stump, remyelination occurs. Axonal regeneration occurs at a rate of 1 to 4
mm per day. Clinical signs of spinal nerve dysfunction are outlined in Table 2.
Table 2. Clinical Signs of Spinal Peripheral Nerve Trauma

Spinal
Nerve Cord Muscles Innervated Clinical Signs of Dysfunction
Origin
Loss of shoulder extension;
Supraspinatus
Suprascapular C6 - C7 muscle atrophy with prominent
Infraspinatus
spine of scapula
Reduced shoulder flexion;
Deltoideus
deltoid atrophy; reduced
Axillary C7 - C8 Teres major
sensation over lateral surface of
Teres minor
shoulder
Reduced elbow flexion; loss of
Biceps brachii
bicipital reflex; reduced
Musculo - cutaneous C6 - T1 Brachialis
sensation over medial surface of
Coracobrachialis
forearm
Reduced extension of elbow,
carpus, and digits; loss of
Triceps brachii extensor postural thrust and limb
Extensor carpi radialis support (with radial nerve
Radial C6 - T2 Ulnaris lateralis damage above the elbow); loss
Lateral digital extensor of triceps reflex; reduced
Common digital extensor sensation over dorsal surface of
paw and craniolateral surface of
forearm
Reduced flexion of carpus and
Flexor carpi radialis
Median C7 - T2 digits; reduced sensation over
Superficial digital flexor
palmar surface of paw
Reduced flexion of carpus and
Flexor carpi ulnaris
Ulnar C8 - T2 digits; reduced sensation over
Deep digital flexor
caudal surface of forearm
Inability to extend stifle or bear
weight on affected limb; loss of
Iliopsoas
patellar reflex; reduced
Femoral L4 - L6 Quadriceps
sensation over medial surface of
Sartorius
paw, hock, stifle, and thigh (via
sensory saphenous nerve)
External obturator Inability to adduct hip or thigh
Obturator L5 - L6 Pectineus (animal "does the splits" on a
Gracilis smooth surface)
Inability to flex stifle; loss of
Biceps femoris flexor reflex (for other
Sciatic L6 - S1 Semimembranosus dysfunction see branches of
Semitendinosus sciatic nerve - tibial and common
peroneal nerves)
Gastrocnemius Inability to extend hock or flex
Popliteus digits; reduced sensation over
a) Tibial (L6) L7 - S1
Deep digital flexor plantar surface of paw; loss of
Superficial digital flexor gastrocnemius reflex
Inability to flex hock or extend
Peroneus longus
digits; knuckling of dorsal paw;
Lateral digital extensor
b) Common Peroneal L6 - L7 (S1) reduced sensation over
Long digital extensor
craniodorsal surface of paw,
Cranial tibial
hock, and stifle
Loss of anal reflex and
External anal sphincter bulbocavernosus reflex (males
Pudendal S1 - S3
Striated urethral muscle only); reduced sensation of
perineum
Pelvic (parasympathetic) S1 - S3 Smooth muscle of bladder and rectum Urinary incontinence
Modified from Braund KG. Clinical syndromes in veterinary neurology. St Louis: Mosby, 1994 [16].
Diagnosis of traumatic neuropathy is usually based on history and clinical signs. EDX data may be helpful in
evaluating nerve integrity, severity of damage, and in monitoring progress/regeneration. Approximately 5 to 7
days post-injury are required before increased insertional activity and spontaneous potentials (e.g., positive sharp
waves and fibrillation potentials) are detected. Nerve integrity may be easily assessed by nerve stimulation
proximal and distal to the site of the lesion. Exploratory surgery is another method for direct evaluation of
peripheral nerve damage.
Treatment may involve surgical anastomosis (neurorrhaphy) or neurolysis (freeing of a nerve from inflammatory
adhesions). Experimental studies in dogs suggest that too early mobilization following neurorrhaphy will impede
nerve regeneration by delaying revascularization and enhancing scar formation [466]. In those instances where
nerve damage is chronic, high, or severe, muscle relocation and muscle tendon transfers are recommended,
including arthrodesis of the tibiotarsal joint in pelvic fracture cases where the lumbosacral joint or sciatic nerve is
severed [424,456,467].
Prognosis is guarded with peripheral nerve injury. Lesions characterized by neuropraxia and axonotmesis have a
better prognosis than those of neurotmesis. Also, the closer the nerve injury is to the muscle it must reinnervate,
the better the prognosis. Self-mutilation that results from abnormal sensation in an affected area produced by
regeneration of sensory nerves can be a major complication and a poor prognostic sign. In one study involving 34
dogs and cats with nerve injury associated with fracture-dislocation of the pelvis, 81% had good/excellent limb
function 16 weeks after the injury, and the outcome was the same for animals with or without surgery [424]. The
authors of this report suggested that surgery be performed on animals with signs of severe pain or moderate to
severe nerve injury so as to relieve the nerve entrapment, avoid further nerve damage, and assess prognosis
(e.g., the affected nerve may be severely attenuated, frayed, stretched, lacerated or transected). Loss of limb
function or self-mutilation occurred in 15% of animals in this study. A poor prognosis is given if limb function has
not improved in 3 to 4 months in animals with lumbosacral trunk/high sciatic nerve injury [424]. Physical therapy,
such as a whirlpool bath, may help to overcome circulation problems and delay muscle atrophy (see
rehabilitation).
Vascular Neuropathy
Readers are referred to chapter 2 and Myopathic Disorders for a review of vascular neuropathy (see ischemic
neuromyopathy).
Vestibular Disease
Various forms of vestibular disease have been identified in dogs and cats, and they may involve peripheral
receptors within the inner ear or the centrally located nuclei and tracts within the brainstem.
A. Peripheral Vestibular Disease may be congenital, idiopathic, or associated with otitis media-interna. There are
also several miscellaneous causes of peripheral vestibular disease.
Idiopathic Vestibular Disease - This is an acute peripheral vestibular syndrome, without evidence of inflammatory
lesions, that is seen in cats of all ages and in older dogs [468,469]. In one study of 75 affected cats, 80% were
diagnosed in the months of July and August [468]. Both dogs and cats have signs of peripheral vestibular
involvement including head tilt, asymmetrical ataxia, and horizontal or rotatory nystagmus. More severe signs of
falling, rolling, and vomiting (especially in dogs) are seen occasionally. The signs appear suddenly, often causing
severe incapacitation. In a few days, the affected animal tends to stabilize and improves gradually over several
weeks. Residual deficits, such as a mild head tilt, may be seen.
It is important to exclude an infection as the cause since the idiopathic syndrome and acute labyrinthitis (see
below) have identical clinical signs; however, facial nerve dysfunction and Horner's syndrome are never seen in
animals with idiopathic disease. In the idiopathic disease, the external, middle, and inner ear are grossly normal.
Otoscopic and radiographic examinations are normal. The canine disease must also be differentiated from brain
stem disease (e.g., central vestibular disease). The syndrome has also been mistaken for an acute vascular
accident (i.e. infarction or hemorrhage) of the brain stem. The signs of the idiopathic syndrome are only those of
peripheral vestibular dysfunction. Postural reactions and other cranial nerves are not affected. In the early stages,
postural reactions may be very difficult to test and the peripheral nature of the syndrome may not be obvious until
the second or third day.
The peracute onset of clinical signs and absence of otitis media/interna, based on otoscopic and or radiographic
examinations, suggest a diagnosis of idiopathic vestibular disease. Analysis of CSF is normal. The etiology
remains uncertain. No microscopic lesions have been documented in the labyrinth, vestibular nerve and ganglion,
or within the brainstem.
Prognosis for spontaneous remission is good; however, recovery may take 2 or 3 weeks. Recurrences may be
noted, especially in dogs. A variety of treatments have been tried, including antibiotics, anti-inflammatory agents,
anti-motion sickness drugs, and others. There is no evidence that any treatment alters the course of the disease.
If infection cannot be absolutely excluded, antibiotics are recommended, but aminoglycosides should be avoided.
Otitis Media-interna refers to an inflammation of the middle and inner ears and is a common cause of peripheral
vestibular dysfunction in dogs and cats [468]. The most common route of infection to the middle and inner ears is
from the external ear canal with attendant otitis externa and subsequent rupture of the tympanic membrane. The
nasopharynx is also a source of retrograde infection by way of the eustachian tubes. A third source of infection of
the middle-inner ear structures is hematogenous spread. Most infections are caused by bacteria including
Staphylococcus sp., Streptococcus sp., Proteus sp., Pseudomonas sp., Enterococcus sp., and Escherichia coli.
Foreign bodies such as grass awns may initiate inflammation and predispose to secondary microbial infection.
Yeast (e.g., Candida sp. and Malassezia canis) and fungal infection (e.g., aspergillosis, cryptococcosis) [470,471]
are observed infrequently. Animals predisposed to chronic otitis externa and chronic ear mite infestations would
appear to have an increased risk of developing otitis media-interna; however, in one survey, no breed was
disproportionately represented, compared to the hospital population examined [468]. Nevertheless, the psoroptid
mite Otodectes cynotis reportedly can damage the tympanic membrane and invade the middle and inner ears,
especially in cats, resulting in secondary infection of these structures [472]. Occasionally, middle ear infection
occurs secondary to trauma (e.g., traumatically ruptured tympanic membrane associated with petrosal bone
fracture), inflammatory polyps, granulomas (e.g., cryptococcal), and tumors (see below).
Varying degrees of vestibular disturbance reflect otitis media-interna. Signs may range from ipsilateral head tilt,
nystagmus (frequently rotatory), positional strabismus (ventral or ventrolateral), and ataxia of trunk and limbs,
such as torticollis, circling, falling, and rolling. These dramatic signs may become less pronounced within 2 - 3
days. Postural reactions, preservation of strength, and initiation of voluntary movement are similar to those
described for idiopathic vestibular disease. Mild hypertonia and hyperreflexia may occur in limbs on the side of the
body opposite the vestibular lesion. Pain may be noted around the external ear and when the animal opens its
mouth. An aural discharge, sometimes bloody, head shaking, and pawing or rubbing of the ears may be noted.
Frequent yawning has been observed and affected animals may be lethargic, anorexic and febrile. Attendant
middle ear inflammation may disturb function of the facial and sympathetic nerves which course through the
middle ear, resulting in ipsilateral facial paresis/paralysis and Horner's syndrome, respectively. During the course
of the disease, irritation of the sympathetic fibers may induce mydriasis. Since the facial nerve contains the
parasympathetic preganglionic neurons that modulate lacrimal gland secretion, animals with otitis media-interna
may have decreased tear production and develop ipsilateral keratitis sicca. Facial nerve dysfunction may be seen
in approximately 50% of animals with otitis media/interna [473]. Ipsilateral hemifacial spasms have been reported
in dogs with otitis media [186] and signs, including blepharospasm, elevation of the ear, and deviation of the nose,
are probably due to facial nerve irritation. Another structure that may be involved in otitis media-interna is the
cochlear nerve, dysfunction of which results in deafness.
Occasionally, otitis media-interna is bilateral and affected animals may assume a wide-based stance with head
close to the ground and swinging from side to side, or alternatively, assume a crouched posture on the ground
with limbs spread apart [89]. Nystagmus is not present and the oculocephalic response (normal vestibular
nystagmus) is absent in bilateral disease. Such animals may also be deaf and show bilateral facial paralysis.
The diagnosis of otitis media-interna is based on clinical signs, otoscopic examination, radiography/imaging, and
surgical exploration [474]. Examination of the pharynx (visually or using a retroflexed pediatric gastroscope) may
reveal inflammation that may have spread to the middle ear via the auditory tube [472], polyps originating from the
auditory tube or tympanic cavity [475], or granulomas protruding from the choanae [470]. Cats with tumors of the
middle and inner ear often have signs of pain when opening the mouth [182]. Otoscopy may reveal an otitis
externa and evidence of erosion or rupture of the tympanic membrane. Fluid in the middle ear produces outward
bulging of the tympanic membrane which may appear opaque and hyperemic. Fluid behind the membrane may
appear clear or discolored. Fluid and/ or inflammatory exudate should be sampled for culture, cytology, and
sensitivity testing from the external and middle ear by aspiration if the tympanic membrane has ruptured, by
myringotomy (surgical incision of the tympanic membrane performed caudal to the malleus in the posteroinferior
quadrant of the tympanic membrane [472]), or by exploratory surgery. Radiographic examination (recommended
skull radiographic views include oblique lateral, open-mouth and ventrodorsal projections [472] of the petrous
temporal bones may reveal middle ear inflammation as suggested by fluid density and sclerosis of the bulla.
Normal detail of the bony labyrinth may be lost. The presence of a nasopharyngeal mass on lateral radiographic
views is suggestive of inflammatory polyps in cats [182]. Lysis or active periosteal reaction involving the bulla or
petrous part of the temporal bone is usually associated with neoplasia. In some instances, radiographs may be
normal, despite significant middle ear inflammation [474] and special imaging techniques, e.g., CT and MRI may
be more sensitive in detection of fluid in the middle ear disease [476]. Soft tissue changes in the early stages of
the disease may be detected better with MRI [477]. Positive contrast ear canalography is considered to be a more
sensitive method for detecting tympanic membrane rupture and otitis media than either otoscopy or survey
radiography [478].
Prognosis is usually favorable with prolonged oral and topical antibiotics chosen from positive culture and
sensitivity studies. When culture and sensitivity are not available, chloramphenicol (25 - 50 mg/kg PO tid in dogs
and bid in cats), cephalexin (22 mg/kg PO tid); cefadroxil (22 mg/kg PO bid) or trimethoprim-sulfadiazine (15
mg/kg, PO or SC bid) can be used, over a 4 to 6 week period. For cases of cryptococcal peripheral vestibular
disease (e.g., Cryptococcus neoformans), itraconazole at 50 to 100 mg PO every 24 hours for several months
has been beneficial in cats [470]. Artificial tears can be used for animals with keratitis sicca. Because of potential
ototoxicity, especially in cases where the tympanic membrane has been damaged, topical agents (e.g., iodophors,
aminoglycosides, cetrimide, iodine, chloramphenicol and chlorhexidine) should be used with caution. Indeed,
topical antibiotics are considered insufficient for the treatment of otitis media-interna [476]. Drainage of the middle
ear using a bulla osteotomy (e.g., from a ventral approach) may be required in the event of fluid buildup in the
tympanic bulla. Note that the tympanic bulla in cats consists of dorsolateral and a ventromedial cavities divided by
an incomplete bony septum, and both compartments should be surgically drained [479]. In more chronic cases
refractory to treatment, surgical debridement and total ear canal ablation-lateral bulla osteotomy or ventral
osteotomy (especially used for disease processes confined to the middle and inner ear) can be successfully
performed [181,182,480]. Short-term complications may include Horner’s syndrome, facial nerve paralysis, and
otitis interna [182]. In some animals, neurological signs may recur, while in other patients, minor residual
neurological deficits (e.g., head tilt or ataxia) may persist. Ventral bulla osteotomy and curettage, along with
removal of retained epithelium and debris, can successfully treat cases of recurrent otitis media that develop after
total ear canal ablation and lateral bulla osteotomy [481]. Removal of nasopharyngeal polyps by traction and/or
bulla osteotomy is usually successful [475]. Treatment of middle ear tumors may involve surgical resection,
radiation or chemotherapy. Prognosis is guarded to poor [182,482].
Additional potential complications include development of osteomyelitis of the osseous bulla and petrous temporal
bone, extension of infection to the meninges or brain parenchyma leading to meningoencephalitis [89] or to
pontine and cerebellomedullary abscesses [483], complications that occurs more often in cats [484], and
cholesteatoma formation. A cholesteatoma is a form of epidermoid cyst that is lined by stratified squamous
keratinizing epithelium. It appears as a laminated structure composed of layers of keratin, and rests on a fibrous
stroma of inflammatory granulation tissue. In one study of otitis media, 7 of 42 dogs had an accompanying
cholesteatoma within the middle ear [47]. In this study, the masses appeared to be formed from pockets of the
tympanic membrane which became adherent to the inflamed middle ear mucosa. Clinical signs in some affected
dogs included head tilt, poor balance, deafness, and difficulty and pain when eating or yawning. None of the dogs
had Horner's syndrome or facial nerve disorder. Radiographically, the cholesteatomas were sometimes
responsible for extensive resorption and remodeling of adjacent bone, including the temporomandibular joint and
retroglenoid process. Treatment is by surgical resection (e.g., via osteotomy).
Congenital Vestibular Disease - Signs of peripheral vestibular disease without deafness have been observed in
several breeds of puppies [89,485,486] including English Cocker Spaniels, German Shepherds, Tibetan Terriers,
and in Burmese kittens. Signs may be noted from birth to 3 or 4 months of age, and typically include a
pronounced head tilt, circling, and often falling and/or rolling. Nystagmus is not a feature in these young animals.
The cause of this disorder is unknown. Pathological studies have failed to produce any evidence of either
inflammation, degeneration or malformation. Prognosis is guarded since clinical signs may regress completely,
recur, or remain static. There is no treatment.
A congenital condition, characterized by early onset of deafness and vestibular disease, has been reported in
Doberman Pinscher puppies [57]. Twenty-one dogs from ten different litters were examined for signs of vestibular
disease, at ages between birth and 10 weeks. Signs included rolling or falling, head tilt, circling, and inaccurate
control of head movements with occasional bumping against objects. Vision was normal and no head tremors
were observed. As the puppies grew older, signs usually became less pronounced and affected animals showed
only mild head tilt and a tendency to circle when excited; however, relapses occasionally occurred. Vestibular
testing (such as rotational and post-rotational nystagmus, and caloric stimulation) was abnormal in all dogs,
bilaterally. Righting reflexes were poor in young dogs, but improved with age. Hearing, as assessed by the
brainstem auditory evoked response (BAER) method, was absent in all puppies 3 weeks of age or older.
Otoscopic and radiographic studies indicated that the tympanic membranes and tympanic bullae were normal.
Histopathologic studies revealed that all affected dogs had a non-inflammatory neuroepithelial degeneration of the
cochlea with a progressive loss of the auditory sensory hair cells, resulting in almost complete loss of the organ of
Corti by 11 weeks of age. Microscopic examination of the vestibular system from several affected dogs showed
either absence of otoconia or some degree of otoconial abnormality in one or more maculae. Pedigree analysis
indicated that this vestibular/hearing disorder in Doberman Pinschers had an autosomal recessive mode of
inheritance.
Diagnosis is usually straightforward and the prognosis for clinical improvement of the vestibular disease is good.
This improvement may result from central compensation due to sensory and visual input. However, the deafness
is severe, bilateral, and permanent. While hearing is very difficult to assess accurately using response to sounds,
such as clapping, BAER testing can provide early diagnosis of deafness, allowing breeders and owners to identify
affected parents and avoid further breeding.
A similar condition has been seen in Beagle and Akita puppies and in Siamese kittens [89]. Almost identical
clinical signs have been reported in two related litters of Doberman Pinscher puppies with congenital peripheral
vestibular disease attributed to lymphocytic labyrinthitis [487]. Multiple lymphocytic aggregates were found in the
lamina propria beneath the ciliated columnar epithelium of the middle ear. No lesions were found in the brain.
Analysis of CSF was normal. Signs of unilateral or bilateral vestibular disease developed when puppies were
between 3 and 12 weeks of age. Several of the puppies were deaf and some showed thoracic limb hypermetria.
Vestibular signs improved in some dogs but persisted unchanged in others.
Congenital nystagmus, without vestibular disease, occurs sporadically in puppies. The nystagmus is usually
pendular and spontaneously resolves. It has also been seen in Belgium Sheepdogs with incomplete development
of the optic chiasm [488]. Nystagmus may also be observed in some Siamese cats and it may persist for life [89].
It has also been seen in some cats with Chediak-Higashi syndrome in which it is associated with congenital
cataracts, photophobia, pale irises, and albinotic or depigmented fundi [489].
Miscellaneous Causes of Peripheral Vestibular Disease - Neoplasia is an infrequent cause of peripheral vestibular
disease, however, older cats and dogs appear at risk for tumors involving the middle or inner ear [182]. While a
variety of tumors, including anaplastic carcinoma, lymphoblastic lymphosarcoma, osteosarcoma, fibrosarcoma,
chondrosarcoma, squamous cell carcinoma, basal cell tumors, sebaceous adenocarcinoma, papillary adenoma,
and ceruminous gland adenoma and adenocarcinoma have been reported in dogs and cats (involving bony or
soft tissue structures), squamous cell carcinoma and ceruminous gland adenocarcinoma may be the most
common tumor of the middle ear in cats [490,491]. In dogs, however, papillary adenomas and extension of
adnexal or ceruminous gland tumors originating in the external ear appear to be more common in this location
[492]. Rarely, middle ear tumors may directly extend into the brainstem [482]. Neurofibromas involving the
vestibulocochlear nerve are very rare. Prognosis is poor. Iatrogenic peripheral vestibular disease may result from
use of aminoglycoside antibiotics, which can cause degeneration of vestibular and auditory peripheral receptors
(see deafness). Cats are especially susceptible to the vestibular effects of streptomycin. Cranial trauma may
cause signs of peripheral vestibular disease secondary to fractures in the petrous temporal bone or tympanic
bulla. Signs of peripheral vestibular disease accompanied by facial paresis/paralysis, but without otitis media,
occur sporadically in dogs, a few of which have had hypothyroidism and pituitary chromophobe adenoma [89].
Thyroid hormone replacement therapy has been ineffective in these cases.
Inflammatory Polyps are another cause of peripheral vestibular disease. Polyps are smooth, non-neoplastic
masses that arise from the lining of the tympanic cavity, auditory tube, or nasopharynx [490,493]. They are
typically pedunculated and fixed by a thin stalk to their point of origin. The polyps are often associated with
obstructive disease and may cause rupture of the tympanic membrane. Inflammatory polyps are commonly
associated with otitis media [475]. They are thought to occur as a result of chronic middle ear infection or from
ascending infection from the nasopharynx. Polyps tend to be single masses and are especially common in young
adult to middle-aged cats, with no apparent gender or breed predisposition. They are infrequently observed in
dogs [494]. Clinical signs include head shaking, aural discharge, head tilt, facial paralysis, vestibular dysfunction,
Horner’s syndrome, and sometimes, presence of a mass in the external ear canal. Masses in the nasopharynx
may cause dysphagia and stertorous respiration, respiratory distress, and phonation change [490,495]. Polyps
are composed of fibrous connective tissue stroma containing numerous capillaries and inflammatory cells,
including macrophages, neutrophils, lymphocytes and plasma cells, covered by pseudostratified columnar ciliated
or non-ciliated respiratory epithelium. This epithelium is continuous with the tympanic cavity, eustachian tube and
nasopharynx. Some polyps are covered by squamous epithelium if lesions originate from deeper portions of
external ear canal. Focal mucosal ulceration may be seen. They are differentiated from neoplastic masses by
direct visualization, cytology and histopathology. Skull radiographs may indicate changes similar to those seen in
otitis media. They may also be seen as soft tissue masses in the pharyngeal region and within the tympanic bulla.
Imaging (e.g., CT) can also be used to define the regional extent of the polyp [496]. Treatment is usually
uncomplicated and involves simple traction-avulsion of the mass through the external meatus (sometimes
necessitating lateral ear canal resection) or from the nasopharynx (retraction of the soft palate or incision may be
required to visualize the eustachian tube). Bulla osteotomy facilitates polyp removal from the tympanic bulla.
Prognosis is usually good, although a temporary Horner’s syndrome was commonly observed in one study
following bulla osteotomy [475]. Less frequently, self-limiting facial and hypoglossal neuropathies may also
develop following surgery [521]. Recurrences can occur. In one study, recurrence rate following removal by
traction-avulsion was approximately 40% and was more likely in cats with aural polyps and in those with more
severe aural signs. Interestingly, none of the cats treated with prednisolone after traction-avulsion suffered a
recurrence. Results of another study suggest that traction-avulsion is a reasonable treatment for inflammatory
polyps if the bullae are radiographically normal [523].
B. Central Vestibular Disease - Signs of central vestibular disease in animals are similar to those seen with
peripheral vestibular disease. However, in central disease, there may be evidence of other cranial nerve
dysfunction due to involvement of various brainstem nuclei (e.g., trigeminal or abducent), altered mental status,
vertical or positional nystagmus, cerebellar signs, and evidence of paresis and/or proprioceptive deficits resulting
from brainstem involvement of descending and ascending long tracts. Also, animals with central vestibular
disease have a tendency to roll in one direction [89]. Central signs do not include Horner's syndrome but facial
paresis/paralysis, secondary to involvement of the facial nucleus, may be observed. Unilateral lesions in the
brainstem usually produce an ipsilateral hemiparesis and postural reaction deficiencies (associated with lesions in
the general proprioceptive and/or upper motor neuron systems). However, central lesions occasionally result in a
"paradoxical" vestibular syndrome in dogs in which the lesion is located on the opposite side to that expected
from the clinical signs (head tilt, strabismus, body tilt). The lesion, typically a space-occupying one in the area of
the cerebellopontine angle, such as tumor or granulomatous mass, is considered to be located on the same side
of the body in which proprioceptive/postural reaction deficits are detected [89,497-499,529]. Presumably,
presence of unilateral deficits of other cranial nerves would be another indicator of the side on which a lesion is
located. This syndrome may occur if vestibular pathways in either the caudal cerebellar peduncle (particularly the
supramedullary juxtarestiform body) or the flocculonodular lobe of the cerebellum are involved [89,498]. The
paradoxical vestibular syndrome occurs less frequently in cats [500,501].
Causes of central vestibular disease include inflammatory diseases, such as distemper and granulomatous
meningoencephalomyelitis (GME), bacterial meningitis/meningoencephalitis [502] and rickettsial
meningoencephalitis (e.g., Rocky Mountain spotted fever) [503], feline infectious peritonitis [504], toxoplasmosis
and neosporosis, migrating parasites, such as Cuterebra larvae in cats [89], and mycotic
meningoencephalomyelitis (e.g., cryptococcosis and Acremonium sp. [505], along with vascular disease, thiamine
deficiency (especially cats), storage diseases [506], trauma, drug toxicity (e.g. metronidazole in dogs and cats)
and tumors, particularly those located at the cerebellopontine angle. Surface tumors may include meningioma,
choroid plexus papilloma, medulloblastoma, neurofibroma, trigeminal neurofibrosarcoma/schwannoma, and
lymphosarcoma [89,529]. Dogs may be at risk for meningiomas and choroid plexus papillomas, while in cats,
meningiomas and lymphomas are common [89,476]. Parenchymal tumors that may cause central vestibular
dysfunction include the focal/neoplastic form of GME, gliomas, or metastatic tumors [89,507]. Forebrain tumors
may result in central vestibular disease secondary to caudal transtentorial herniation [476].
Diagnostic aids in evaluating central vestibular disease include otoscopy, CSF analysis for inflammatory diseases
(including cellularity, protein, antibodies, protein electrophoresis, etc.), advanced imaging studies (e.g. CT or MRI)
for tumors, skull radiographs for skull fractures and tympanic bulla evaluation, BAER studies to evaluate hearing
and integrity of central brainstem pathways, and surgical biopsy/resection (intracranial, ear canal, or bulla
osteotomy) [473,476,508]. Specific treatments are based on the underlying cause of the vestibular disorder, for
example antimicrobial therapy for infectious agents, surgical removal/resection, radiation therapy and
chemotherapy for tumors, and thiamine administration for thiamine deficiency.
Endogenous Metabolic Disorders
K. G. Braund
Endogenous metabolic disorders in small animals that impact the central nervous system (CNS) encompass
myriad conditions, including electrolyte abnormalities, endocrine disorders, and organ failure. These conditions
have sometimes been referred to as metabolic encephalopathies because of functional CNS perturbations arising
from altered energy metabolism, destabilization of neural membranes, hypoxia, endogenous toxin formation, or
osmolality shifts.
Diabetes Mellitus
Hepatic Encephalopathy
Hypernatremia
Hypocalcemia
Hypoglycemia
Hyponatremia
Central Pontine Myelinolysis
Hypothyroidism
Myxedema Coma
Uremic Encephalopathy
Miscellaneous Metabolic Disorders
Acidosis
Alkalosis
Hyperthyroidism
Hypophosphatemia
Hypercalcemia
Potassium Disorders
Diabetes Mellitus
This chronic disorder is associated with impaired utilization of carbohydrates and enhanced lipid and protein use.
Neurological signs attributable to the CNS have been associated with two hyperglycemic syndromes: diabetic
ketoacidosis (DKA) and nonketotic hyperosmolar hyperglycemia (NKHH). Hyperglycemia results in
hyperosmolality and this may lead to cerebral dehydration, with a pathogenesis similar to that of hypernatremia.
Insulin deficiency (either relative or absolute) is the problem in patients with DKA and is related to the
hyperglycemia associated with increased gluconeogenesis, enhanced glycogenolysis, and reduced glucose
clearance [1], associated with increased levels of diabetogeneic hormones (epinephrine, glucagon, cortisol, and
growth hormone) which promote insulin resistance [2-4]. Furthermore, there is increased fatty acid mobilization
and fatty acid oxidation (from increased glucagon:insulin ratio), and as a result, elevated serum ketone bodies
(e.g., acetoacetic acid and beta-hydroxybutyric acid) from lipolysis. Glycosuria ensues once renal threshold is
exceeded, e.g., > 180 - 220 mg/dl in dogs and > 200 - 320 mg/dl in cats [3], leading to osmotic diuresis, polyuria
and compensatory polydipsia. Increasing serum levels of ketones will also eventually exceed renal tubular
threshold and spill into the urine exacerbating the already existing osmotic diuresis and water loss from
hyperglycemia, and potentiate loss of sodium, potassium and magnesium in urine. In summary, the
consequences of DKA are severe metabolic acidosis, hyperosmolality, osmotic diuresis, dehydration, and severe
electrolytic derangement [2,5,6]. In patients with NKHH, sufficient insulin is produced to prevent lipolysis and
ketone body formation, although insufficient to prevent hyperglycemia. This syndrome is seen when blood
glucose > 600 mg/dl (sometimes > 1000 mg/dl) and with hyperosmolality > 330 - 350 mOsm/kg [4,5].
Compromised renal function (from primary renal disease or from the hypovolemia) with decreased glomerular
filtration and decreased excretion of glucose may be associated with the extreme hyperglycemia and
hyperosmolality [3,5,7]. Neurological signs for both DKA and NKHH are essentially the same as those seen in
patients with hypernatremia. In addition, DKA animals are dehydrated and may have a fruity acetone breath odor
from the ketosis. In people, seizures are commonly observed in patients with NKHH [8-10], possibly related to
excessive activation of glutamate receptors ("excitotoxicity"), including N-methyl-D-aspartate receptor-operated
channels [11]. Diagnosis is based on biochemistry panels, serum osmolality, anion gap determination, and blood
gas studies [5,12]. Demonstration of both hyperglycemia and glucosuria is an important diagnostic finding, and
most dogs and cats with DKA have evidence of hyponatremia [3]. Treatment consists of administration of the
following [3,5]:
a. 9% saline solution at 60 - 100 mL/kg/24h. In addition, provide 80% of fluid deficits (% dehydration x kg
body weight = fluid deficit in liters) and also adjust for any ongoing fluid losses (e.g., vomiting and
diarrhea) to correct cellular dehydration and hypovolemia. For initial fluid replacement, isotonic saline
administration at a moderate rate is recommended over hypotonic fluids given rapidly since a rapid
decrease in serum osmolality may lead to cerebral edema (especially in patients in whom the serum
concentration of sodium fails to rise as that of glucose declines) [4,13]. In one human study, failure of the
serum sodium concentration to rise as glucose concentration declined was considered to be a marker for
excessive administration of free water [14]. In this report, repair fluid containing an average of 125 mEq/L
sodium early in therapy usually prevented a downward trend in the concentration of sodium in serum
thereby avoiding a rapid decline in effective serum osmolality [14]. Rehydration over 48 hours was shown
to be a safe strategy in people with moderate or severe DKA [15]. After 12 to 24 hours, fluids can be
changed to 0.45% saline if hypernatremia or hyperchloremia are present [5].
b. Potassium or phosphate supplementation if required (if unknown, add 20 mEq KCl and 20 mEq KPO4 to
each liter of fluids). During therapy for DKA, serum potassium levels decline in most animals due to
rehydration (dilution effect), correction of acidosis (hydrogen moves out of cells in exchange for
potassium), insulin-induced cellular uptake of potassium, and continuing urinary losses [16]. Hypokalemia
may lead to muscle weakness, cardiac arrhythmias and respiratory failure. Hypophosphatemia
occasionally occurs in animals with DKA and has been reported in association with osmotic diuresis and
urinary losses. It can lead to muscle weakness, hemolysis, rhabdomyolysis, seizures, cardiac dysfunction
and respiratory failure [17]. When serum phosphate levels < 1.0 mg/dl, potassium phosphate at 0.01 -
0.03 mmol phosphate/kg/h should be administered for 6 hours [5,18].
c. Bicarbonate supplementation if serum bicarbonate < 12 mEq/L or total venous CO2 < 12. Amount of
bicarbonate (mEq) = body wt (kg) x 0.4 x (12 - patient’s serum bicarbonate level). Note that improved
renal perfusion will facilitate urinary loss of ketoacids while insulin treatment will decrease the production
of ketoacids.
d. Insulin therapy, e.g., regular crystalline insulin at 0.2 U/kg, IM followed by 0.1 U/kg IM hourly until blood
glucose level < 250mg/dL, then use SC regular insulin at 0.1 - 0.4 U/kg every 6 - 8 hours. Note that
resolution of ketoacidosis requires insulin therapy.
e. Dextrose supplementation using 5% dextrose (e.g., add 100 ml of 50% dextrose to each liter of fluids)
once blood glucose level falls below 250 mg/dl to avoid hypoglycemia.
Note - For more detailed information on therapeutic management of animals with severe diabetic ketoacidosis,
readers are referred to the recent publication by Nelson [3]. The overall aim should be to return to normal all
abnormal parameters slowly over 36 to 48 hours. Too-rapid correction might lead to cerebral edema [2]. Since
DKA usually coexists in dogs and cats with other conditions (e.g., pancreatitis, congestive heart failure, infection,
gastroenteritis, renal failure, or insulin antagonistic disorders such as hyperadrenocorticism), treatment should
also be directed at these disorders [3,16,18].
For animals with NKHH, primary treatment is aimed at rehydration (e.g., using 0.9% saline at 20 - 30 ml/kg IV as
an initial bolus, and then 0.45% saline at 60 ml/kg/day), followed by insulin therapy (see above), and correcting
any underlying illnesses including cardiac abnormalities, renal disease, or hyperthyroidism [4]. It is recommended
that approximately one-half of the estimated body fluid deficits be corrected over the first 24 hours and the
remainder over the ensuing 24 hours [5]. It has been stated that insulin should not be initiated until the patient has
received hypotonic fluids for approximately 6 hours to avoid inducing cerebral edema (from rapid decrease in
serum glucose) and hypokalemia (insulin induces movement of potassium from the extracellular space to the
intracellular space) [5]. Finally, seizures associated with hyperglycemia (usually in NKHH patients) are resistant to
anticonvulsant treatment and respond best to insulin and rehydration [1].
Note that besides the two hyperglycemic syndromes, a third diabetic emergency may occur in dogs and cats,
namely insulin overdose, resulting in hypoglycemia. The clinical and neurological signs may be similar in all three
instances [4]. In people, diabetes also increases the risk of stroke associated with large, medium, and small
vessel atheroma formation, as well as arteriolar and capillary microangiopathy [1].
Hepatic Encephalopathy
Hepatic encephalopathy (HE) in dogs and cats is a complex metabolic disturbance of the CNS that may result
from diminished hepatic function, urea cycle enzyme deficiency, or shunting of portal blood around the liver. As a
result, the metabolic and detoxification functions of the liver are impaired and/or bypassed and the unaltered
constituents of the portal blood go directly into the systemic circulation. Many "toxic" substances derived from
intestinal degradation, including ammonia, amino acids (especially the aromatic amino acids phenylalanine,
tyrosine, and tryptophan), short-chain fatty acids, mercaptan and various biogenic amines, indoles and skatoles,
have been incriminated in causing HE [19,20]. Ammonia, metabolized by astrocytes to glutamine (catalyzed by an
astroglia-specific enzyme, glutamine synthetase [21]), has been one of the most studied toxins and is considered
to play an integral role in the pathogenesis of HE [1]. Increased intracellular osmolality from too-rapid glutamine
accumulation may result in cerebral edema, which also may play a role in development of cerebral hyperemia and
increased intracranial pressure in experimental studies of fulminant hepatic failure [22]. Low-grade cerebral
edema has been reported in humans with hepatic cirrhosis [23]. Glutamine, short-chain fatty acids, aromatic
amino acids, and mercaptans are sodium/potassium ATPase inhibitors [1,24]. Other theories pertaining to the
pathogenesis of HE include perturbed monoamine neurotransmission as a result of altered plasma amino acid
metabolism; an imbalance between excitatory amino acid neurotransmission mediated by glutamate, and
inhibitory amino acid neurotransmission mediated by gamma -aminobutyric acid; and increased cerebral
concentration of an endogenous benzodiazepine-like substance [25-27]. It has been stated that there is no
evidence that increased levels of "false" neurotransmitters (e.g., octopamine and phenylethanolamine), potentially
leading to reduced neuronal excitation and increased neural inhibition, are responsible for the encephalopathy [1].
HE can occur with the conditions listed below.
1. Acute liver failure. Acute hepatic failure may occur in animals of any age. Causes may include toxic injury,
metabolic disturbance (e.g., lipidosis in cats), trauma, heatstroke, vascular compromise (e.g., vena cava
syndrome or liver lobe infarction), and infectious disease (e.g., infectious canis hepatitis) [28]. The onset
of signs is rapid with a fulminant course. Non-specific signs may include depression, anorexia and
vomiting.
2. Chronic liver insufficiency (e.g., chronic hepatitis, cirrhosis, hepatobiliary neoplasia, etc.) and acquired
portal systemic shunting. Dogs with encephalopathy associated with chronic liver disease are typically
middle-aged or older. Weight loss, depression, anorexia, gastrointestinal signs, polydipsia and polyuria
may be observed. In these cases, acquired shunts may develop as a compensatory response to portal
hypertension and appear as multiple tortuous vessels that usually communicate with the caudal vena
cava. Rarely, multiple acquired extrahepatic shunts may develop as a consequence of portal
hypertension associated with intrahepatic arterioportal fistulae in young dogs [29]. A syndrome
resembling idiopathic noncirrhotic portal hypertension has been reported in 4 young Doberman Pinschers
[30]. This hepatopathy, in which there is no intrahepatic arteriovenous fistulae, portal vein atresia or
intrahepatic fibrosis, results in portal hypertension, development of portosystemic collateral vessels and
HE. Abdominal ultrasonography disclosed a small liver and portosystemic collateral vessels.
Radiographic imaging studies confirmed hepatofugal portal circulation. Histopathological features
included increased cross-sectional views of hepatic arterioles, hepatic lobular atrophy, mild increase in
connective tissue around some large portal triads, with absence of inflammation, disturbed lobular
architecture, bile duct proliferation, or intrahepatic cholestasis. Acquired portosystemic shunting is
uncommon in cats [240].
3. Congenital portosystemic anomalies (usually single shunts that may be intrahepatic or extrahepatic and
usually not associated with portal hypertension) that shunt portal blood around the liver, allowing
mesenteric blood to directly enter the central venous system, most frequently the caudal vena cava or
azygous vein [31,32]. The congenital extrahepatic shunts usually involve the portal vein or one of its
tributaries, such as the left gastric vein, splenic vein, cranial or caudal mesenteric veins, or
gastroduodenal vein [31]. It has been reported that intrahepatic portosystemic venous anomalies are
diagnosed relatively infrequently in dogs [33]. These shunts occur when the fetal ductus venosus remains
patent or when another portal-to-hepatic-vein communication exists. Shunts tend to be extrahepatic in
small breeds, while a single intrahepatic shunt is most common in medium-to-large breeds [34,35].
Congenital portosystemic anomalies usually occur in young dogs less than 1 year of age [36]. There are
reports of breed predilection for congenital portosystemic anomalies, including Miniature Schnauzers,
Yorkshire Terriers, Cairn Terriers, Australian Cattledogs, Old English Sheepdogs, and Maltese Terriers
[19,32,34,37,38]. Affected animals are often stunted and in poor nutritional condition. Clinical signs are
intermittent, varying from one day to the next, and are frequently seen a few hours after eating a high
protein meal. Signs may include anorexia, depression, weight loss, polydipsia/polyuria, jaundice, and
ascites [32]. There may be intolerance to certain drugs, such as tranquilizers or anesthetics. Neurological
signs (see below) reportedly occur in approximately 95% of cases with shunts [39]. In animals with
congenital shunts the liver is grossly small and often mottled in appearance, while microscopic findings
include small hepatic acini with few portal venous branches and arteriolar hyperplasia [32,40]. Marked
irregular thickening of the glomerular capillary wall has been observed in dogs with congenital shunts [41].
It has been reported that almost all Irish Wolfhound pups without signs of HE have moderate
hyperammonemia and that approximately 2 - 3% of these dogs have inherited portosystemic shunts
associated with high venous ammonia concentrations ( >125 g/dl) and signs of HE [42].
4. Hepatic urea cycle enzyme deficiency. Affected dogs are usually less than 1 year of age and the HE is
associated with hyperammonemia without any evidence of hepatocellular destruction or portosystemic
shunting [19].
Irrespective of the cause, the neurological signs of HE are similar and are especially related to the
prosencephalon (forebrain). Moderately severe cases can be characterized by alterations in behavior or
personality, including staring into space, inappropriate vocalizing, aggression, and agitation. More severe
changes can induce ataxia, circling, aimless wandering, and head pressing. Advanced neurological alterations
can cause depression, blindness, myoclonus, stupor, coma, or seizures.
There are no gross CNS changes in animals with HE. Histopathological findings typically consist of diffuse
polymicrocavitation of myelin (status spongiosus) at various levels of the brain, especially in the cerebral cortex
(usually involving the peripheral fibers of the corona radiata at the junction of the gray matter), but cerebellum
(e.g., cerebellar medulla and peduncles) and brainstem may also be involved, including the internal capsule,
thalamus, and hypothalamus, pons, and medulla oblongata). The distribution tends to be bilaterally symmetrical
and myelinated bundles of fibers interspersed with gray matter are typically prominent [40]. In the spinal cord,
vacuolation occurs in the fasciculus proprius along gray and white matter borders [43]. Ischemic neuronal
degeneration of the cerebral cortex has also been reported [44]. The vacuolation is considered to be cytotoxic
edema [40] and may be associated with the hyperammonemia since the vacuoles tends to regress when blood
ammonia concentration returns to normal (see comments on ammonia and cerebral edema, above) [45].
Experimentally, the vacuoles appear to represent ballooning of myelin sheaths which have split at the intraperiod
line [46]. Another morphological feature of HE is presence of Alzheimer type II astrocytes which are most
numerous in the neocortex, basal nuclei, and hippocampus. These cells, thought to be derived from protoplasmic
astrocytes and characterized by their large, vesicular nuclei, may be in close association with neurons or isolated
in the neuropil [40]. Glial fibrillary acidic protein (GFAP) staining is weak or negative, but S-100 expression is
retained suggesting that HE results in selective loss of GFAP filaments [40,47]. Polyneuropathy has sometimes
been reported in humans with HE [48], some cases of which are associated with alcoholism [49]. Note that
polyneuropathies (in people) can develop secondary to liver disease-related vitamin E deficiency [50].
Acute hepatic failure is characterized by marked elevations in alanine aminotransferase (ALT) and total bilirubin,
with variable levels of serum alkaline phosphatase (SAP). Chronic liver disease or cirrhosis is typified by variable
levels of ALT and total bilirubin, with marked elevations in SAP. Liver enzyme levels can be normal or mildly
elevated in animals with congenital shunts. Hypoproteinemia, hypoalbuminemia, hypoglycemia,
hypocholesterolemia, and prolonged clotting times can be found in animals with impaired hepatic function,
regardless of etiology [32]. Sulfobromophthalein (BSP) retention is often increased, blood urea nitrogen may be
abnormally low (due to the inability of the liver to convert ammonia to urea), blood ammonia levels are often
increased (approximately 90% of HE patients have an elevated fasting blood ammonia level, e.g. > 95 g/dl [19]),
which may result in the presence of ammonium biurate crystals in the urine sediment from 50 to 100% of affected
dogs [34,51]. Fasting (e.g., 12-hour) and post-prandial (e.g., 2-hour) total serum bile acid (TSBA) values are
sensitive indicators of hepatic dysfunction, including occult liver disease such as portosystemic venous anomalies
or hepatic cirrhosis [52-54]. Results of one study in dogs with suspected liver disease showed that fasting TSBA
levels > 20 m/L and post-prandial TSBA values > 25 m/L were 100% specific for liver disease [55]. While
TSBA levels do not indicate the severity of the hepatic disease or suggest a prognosis [53], comparison of fasting
and post-prandial TSBAs may help to discriminate between some hepatobiliary diseases (e.g., animals with
significant extrahepatic or intrahepatic shunting often have normal or mildly elevated fasting TSBAs) [56]. Another
diagnostic aid regarded as being equal in sensitivity to postprandial SBA in dogs with shunts is the ammonia
tolerance test [52]. Increased free cortisol levels have been reported in dogs with portosystemic shunts and HE
[57]. In order to confirm the type of liver pathology present, hepatic biopsy is necessary. Clinicopathological
features reported in young dogs with a syndrome resembling idiopathic noncirrhotic portal hypertension included
erythrocyte microcytosis, normal to mildly increased liver enzyme activities, increased concentrations of TSBAs,
reduced plasma indocyanine green clearance, and normal total bilirubin concentration [30].
Electroencephalography in dogs with HE reveals a predominance of generalized slow wave activity with
increased amplitude [19]. Results of a CSF study from dogs with congenital shunts showed significantly increased
levels of glutamate (e.g., 2 to 3-fold increase), glutamine (6-fold increase) and aromatic amino acids
(phenylalanine, tyrosine and tryptophan) compared to CSF of control dogs, while concentrations of GABA and
branched chain amino acids (valine, leucine, isoleucine) were within normal limits [58]. It is possible that high
concentrations of quinolinic acid and other tryptophan metabolites (e.g., 5-hydroxyindoleacetic acid) in the CNS
may contribute to neurologic abnormalities found in dogs with PSS and hepatic encephalopathy [242]. In humans,
ammonia metabolites alpha-ketoglutarate and glutamine levels in CSF are elevated and glutamine may be one
parameter that is related to the degree of HE [59-61].
Diagnosis of HE may be facilitated by use of radiographic imaging techniques, such as positive contrast
portography (considered to be the procedure of choice), computed tomography [62], and transcolonic portal
scintigraphy, to demonstrate presence of a small liver and/or anomalous portal vein(s) and large kidneys in dogs
with congenital shunts [32,63,64]. Diagnostic gray-scale ultrasonography is another useful technique [65,66].
Experienced surgeons may elect to perform exploratory abdominal surgery. In human medicine, proton magnetic
resonance spectroscopy has been used to detect specific metabolic abnormalities (including cerebral increase in
glutamine compounds) in the brain (especially in the globus pallidus) in patients with chronic HE [67]. In a recent
MRI study in humans with acute HE, cortical lesions resembled those of hypoxic brain damage and were
interpreted as acute toxic cortical laminar necrosis [68].
The principal objectives in the specific therapy of HE are listed below.
1. Dietary management. This is aimed at decreasing foods rich in protein, such as meat and egg proteins.
Cottage cheese, at 2 g/kg body weight, daily, supplemented with easily digestible carbohydrates (e.g.,
rice or pasta), can be used to provide most of the caloric needs, along with good quality vitamin (including
B vitamins and vitamin A, C, D, E, and K) supplements [28,34]. Note that vitamin K deficiency may
develop during liver disease and vitamin K-dependent factors (II, VII, IX, X, and protein C) may be
inactivated leading to coagulation abnormalities [56]. Prescription diets (e.g., u/d, k/d; Hill's Pet Products,
Topeka, KS) are available to provide protein restricted rations at 1.75 to 2.5 g of protein /kg/day for dogs
and 3 to 3.5 g/kg/day for cats [39].
2. Administration of lactulose, a non-absorbable synthetic disaccharide. A recommended dose in dogs is 10
to 40 ml of a 3.35 gm/5 ml solution by gastric tube, three times daily (alternatively, 2.5 to 15 ml for dogs or
1 to 3 ml for cats by mouth, every 8 hours). Dosage can be manipulated so as to produce passage of 2 to
3 soft stools each day. Lactulose results in a marked reduction in the pH of the colonic contents. This, in
turn, significantly reduces the formation and absorption of ammonia and other nitrogenous toxins into the
portal circulation. Also, the pH gradient causes movement of ammonia into the colon. Dietary
supplementation with soluble fiber (psyllium) at 1 - 3 teaspoons daily may also be beneficial [32]. Sodium
benzoate is reported to be a safe, cheaper, and effective alternative to lactulose in the treatment of acute
portosystemic HE in humans [69].
3. Removal of toxic agents, e.g., bowel cleansing using enemas and/or cathartics; and intestinal antibiotics
such as neomycin (20 mg/kg PO bid or tid) or metronidazole (8 mg/kg PO bid). The antibiotics kill colonic
bacteria and thereby reduce levels of bacterial nitrogen content and the synthesis of urea.
4. Supportive therapy, e.g., maintaining fluid, electrolyte and acid-base balance).
5. Prevention/control of precipitating factors such as ammonia-producing processes such as GI bleeding
(e.g., administration of H2 receptor antagonists), constipation, and azotemia. In humans with
portosystemic encephalopathy, other precipitants include infection, hypokalemia, hypoglycemia, hypoxia,
and certain medications (e.g., sedatives and analgesics) [1].
Surgical closure of a portosystemic shunt helps to reverse hepatic atrophy, results in an increased hepatic mass,
and corrects imbalances in carbohydrate, lipid, and protein metabolism that are not affected by medical
management [70]. Today, total surgical ligation of a single portosystemic shunt is the preferred method of choice
[32], although partial ligation/surgical attenuation may be indicated in many cases because of the risk of portal
hypertension [71,72], which is characterized by abdominal distension and pain, bloody diarrhea, ileus, endotoxic
shock, and peracute cardiovascular collapse [32]. For treatment of single, extrahepatic, portosystemic shunts, this
complication may be overcome by gradual vascular occlusion (over 30 to 60 days) using a specialized ameroid
constrictor device [73]. Alternatively, the use of transvenous coil embolization and cellophane banding for gradual
occlusion of intrahepatic and extrahepatic shunts have been described [74,75]. Use of a portocaval venograft and
ameroid ring for the occlusion of intrahepatic portocaval shunts in dogs also shows promising short-term results
[76]. Note that following surgical correction of shunts, TSBA levels may not return to normal, even in clinically
normal dogs [77]. Transcolonic portal scintigraphy, as well as ultrasound-guided injection of (99M)Tc-
macroaggregates into a splenic vein, have been used to evaluate immediate and long-term changes in shunt
blood flow after partial ligation of single extrahepatic portosystemic shunts [78,79]. If shunting persists, complete
surgical ligation or ameroid constrictor placement is indicated [32].
The prognosis for animals with HE is guarded; however, successful long-term medical and surgical treatment
have been reported in young and old dogs with portosystemic shunts [34,37,80,81]. In one study, the outcome of
surgical management of intrahepatic portosystemic shunts in dogs was graded as excellent in 75% and grave in
25% [33]. In contrast, a recent study reported that animals with intrahepatic shunts had a significantly lower
probability of survival than animals with extrahepatic portocaval or portoazygos shunts [72]. Prognosis appears to
be better in dogs with complete surgical ligation [82,83]. Seizures, including status epilepticus, may occur in dogs,
especially in older dogs (e.g., >18 months of age) following ligation of portosystemic shunts [84,85,241]. The
recommended antiepileptic drug therapy for these dogs is potassium bromide at 100 mg/kg PO qid for 24 hours,
followed by maintenance therapy at 30 mg/kg daily [86]. Benzodiazepine therapy should be avoided. Another
complication following ligation, usually with a grave prognosis, is portal vein thrombosis [87]. Acute pancreatitis,
cardiac arrhythmias, hemorrhage, pulmonary edema, fever and positive blood cultures, as well as intraoperative
hypothermia and hypoglycemia are other perioperative complications [33,88,89]. Coagulopathies (including
disseminated intravascular coagulation, which can be related to release of thromboplastin and defective
clearance of activated clotting factors by the liver) can also be a complication of hepatic necrosis [90].
Primary congenital portosystemic shunts are also an important cause of HE in cats [91,92] and the majority are
single extrahepatic shunts [32,93]. Most cats are of mixed breeding, although Persians and Himalayans may be at
risk. In contrast to dogs, affected cats present with intermittent clinical and neurological signs, e.g., stunted growth,
seizures, ataxia, visual disturbance, tremors or twitching, pupillary dilatation, and behavioral changes, usually
accompanied or preceded by ptyalism. Other signs including poor condition, diarrhea, ascites, and
polydipsia/polyuria are uncommon [32]. Many affected cats have golden or copper-colored irises [36]. Clinical
signs are often first noted in kittens around 10 to 12 weeks of age; however, signs may be first seen in well grown,
adult cats. Note that portosystemic shunts can occur in cats without signs of HE but with a history of vague
gastrointestinal signs [94]. In one survey of 52 cats with congenital shunts, common biochemical findings were
hyperammonemia, increased BSP retention, and high fasting and postprandial TSBA concentrations [95]. In
contrast to dogs, only a small percentage of cats have ammonium biurate crystalluria. There appears to be no
advantage in performing an ammonium chloride tolerance test in cats that have unequivocal fasting
hyperammonemia [96,97]. Surgery appears to be the treatment of choice, and prognosis may be favorable,
providing recanalization of the shunt does not occur [96-98], although the outcome of surgical ligation of
portosystemic shunts is cats is considered to be less favorable than in dogs [99,100]. Neurological dysfunction
occurred in one cat following attenuation of an intrahepatic portosystemic shunt [241]. In a report of per rectal
portal scintigraphy in cats, it was concluded that this imaging technique was useful in the diagnosis of congenital
portosystemic shunts, facilitated a quantitative assessment of the effects of surgical ligation of the shunting vessel,
and might be a more accurate indicator of the degree of shunting after surgery than blood ammonia and TSBA
levels [63].
Hypernatremia
Sodium (Na) is the major extracellular ion (osmole) in the body, including the CNS. Blood sodium levels reflect the
ratio of Na to water in the extracellular fluid and account for most of the osmotically active particles in serum.
Serum osmolality is defined as the concentration of a solution expressed in osmoles of solute particles per
kilogram of solvent. Serum osmolality (normally 290 - 310 mOsm/L) can be calculated by the following formula
[101]:
2 x ([Na] + [K]) + glucose/18 + BUN/2.8
Hypernatremia occurs when serum Na levels exceed the normal range (>156 mEq/L in dogs and >161 mEq/L in
cats) [101,102]. It is indicative of a relative increase in total body Na relative to total body water. Causes of
hypernatremia include [101-107]:
a. Excess water loss, e.g., diabetes insipidus (central or nephrogenic), burns, fever, osmotic diuresis
(acute/chronic renal failure, diabetes mellitus, diuretics, or IV solute administration such as mannitol,
glucose or urea), osmotic diarrhea (lactulose therapy, malabsorption syndromes, infectious enteritides)
and hot weather.
b. Excess salt intake, e.g., salt poisoning [107], administration of IV hypertonic solutions (NaCl), sodium
bicarbonate, or saline emetics. Water loss and salt gain may occur with hyperaldosteronism and
hyperadrenocorticism.
c. Insufficient water intake, e.g., lack of access, inability to drink (mechanical inability to prehend or swallow
is a potentially serious complication of hypertrophic feline muscular dystrophy), or CNS disease resulting
in primary adipsia (absence of thirst), or mental depression, or congenital adipsia. Essential
hypernatremia due to failure of the hypothalamic osmoreceptors to respond appropriately to an increase
in serum osmolality is rare in small animals [101]. Note that in normal animals stimulation of thirst and
antidiuretic hormone (ADH) release by increasing serum osmolarity is the physiologic protection against
development of hypernatremia and hyperosmolality. The ADH results in increased renal water
reabsorption and increase in urine osmolality.
As with hyponatremia, hypernatremia may be further classified into hypovolemic, normovolemic, and
hypervolemic forms [7]. Hypernatremia represents hyperosmolality, and as a consequence, an osmotic gradient is
created that results in water movement out of cells into the extracellular fluid. Mild to moderate hypernatremia
usually causes minimal clinical signs; however, marked hypernatremia may induce cerebral signs, such as
depression, weakness, irritability, uncharacteristic aggression, confusion, propulsive circling, dementia, seizures,
coma, and death in dogs and cats as a result of cellular dehydration of neurons [102,106]. Additionally, in people
and in experimental animals, shrinkage of brain tissue may cause tearing of vessels, leading to intracranial
hemorrhage (e.g., subarachnoid, subdural, intraparenchymal), infarction, venous thrombi, and cerebral edema
[108-110]. Neurological signs might not occur until serum Na levels exceed 170 - 175 mEq/l (>350 mOsm/kg)
[101,103]. The effects of rising serum osmolality on the nervous system was demonstrated in experimental
studies (rabbits) in which predictable signs occurred: lip licking, restlessness, and heightened response to touch
were noted with serum osmolality between 350 - 375 mOsm/kg; nystagmus, ataxia, and trunk/limb trembling
appeared when osmolalities were in the 375 - 400 range; and finally, when osmolality exceeded 400 mOsm/kg,
synchronous/asynchronous jerking movements, limb spasm, reduced responsiveness and death occurred [111].
The severity of the neurological signs is not only dependent on the degree of hyperosmolality but especially on its
rate of increase, with signs being most severe in animals with rapidly developing hyperosmolality [102,105]. If the
serum is chronically hyperosmolar, the brain compensates by increasing intracellular osmolality by movement of
Na, potassium, chloride, and glucose into cells and by production of solutes called osmolytes or idiogenic
osmoles (these include amino acids such as glutamine, glutamate, aspartate, creatine, and taurine, as well as
myo-inositol and glycerophosphoryl-choline) which help normalize brain water content [112-115].
Pathological studies of brain lesions associated with hypernatremia are somewhat sparse. In one case involving
hypernatremia and adipsia in a 4.5 month old female Dalmatian puppy with diabetes insipidus associated with
inadequate ADH secretion, a nuclear scan of the cranial vault was normal, as were skull radiographs and CSF
analysis [106]. Pathological studies revealed extensive dysplastic malformation involving midline structures of the
frontal lobes and rostral diencephalon. These included absence/reduction of the corpus callosum at rostral/caudal
levels, frontal lobe fusion in the median plane ventrally including caudate nuclei and prorean gyri (both of which
blended caudally with the rostral hypothalamus), and absence of rostral part of the fornix, its columns, septum
pellucidum, and septal nuclei. The pituitary gland was normal. The dysplasia was considered to involve the nuclei
normally related to thirst regulation and ADH formation. In a 7 month old female Miniature Schnauzer with
seizures, hypernatremia and adipsia associated with defective osmoreceptor function, suggesting this was a case
of essential hypernatremia (the dog did not have diabetes insipidus), astrogliosis and neuronal degeneration were
detected in thalamic and hypothalamic regions but were considered to be nonspecific lesions related to the
seizures [116]. The authors of this report added an addendum that they had seen two additional young female
Miniature Schnauzers with thirst deficiency and neurological signs associated with hypernatremia. In one of these
dogs necropsied, no pathological changes were found in the thalamic/hypothalamic region. In a further canine
case characterized by seizures and hypodipsic hypernatremia associated with defective osmoregulation of ADH,
pathological changes including hydrocephalus, atrophy of the septum pellucidum, and neuroaxonal dystrophy of
the cuneate nuclei were observed at necropsy [117]. Pressure atrophy of osmoreceptors in the hypothalamus
secondary to hydrocephalus was postulated. The underlying cause of the pathological changes was not
determined. Adypsia/hypernatremia in a 7 year old Doberman was thought to be the result of destruction of
hypothalamic osmoreceptors by a focal granulomatous meningoencephalitis [250]. In a report of a fatal
hypernatremia from salt ingestion in a 8 year old male Airedale Terrier, CNS lesions included intracranial
hemorrhage, thrombosis, and vascular stasis with engorgement of vessels, along with diffuse white matter
vacuolation [107]. The authors considered that the cerebral edema might have followed prolonged seizural activity
or was due to isotonic water intoxication (Plasma-Lyte was administered initially followed by 5% dextrose solution).
For treatment, a solution of 5% dextrose can be administered intravenously for acute hypernatremia [12]; however,
oral administration of fluids is recommended for treating chronic hypernatremia since rapid correction may lead to
cerebral edema (water intoxication), seizures, and death because of the accumulated intracellular idiogenic
osmoles [105,118] (see also the pathophysiology associated with too-rapid correction of hyponatremia). A caveat
is that excessive ingestion of water mixed with food may result in hyponatremia and neurological deterioration
associated with cerebral edema [238]. The water deficit may be calculated [12,105] using the following formula:
Water deficit (L) = 0.6 x lean body weight (kg) x (patient’s Na/normal
Na -1)
For animals with acute-onset symptomatic hypernatremia, a decline of serum Na around 1 mEq/L per hour can be
safely performed; however the rate of decline in animals with chronic hypernatremia should not exceed 0.5 mEq/L
per hour [101]. Of course, therapy for hypernatremia should also be directed at the underlying cause. Prognosis
for acute hypernatremia is guarded. Adipsic animals may be maintained for several years by combining water with
food [106,116,238]. Diuretics (e.g., furosemide) are recommended for animals with hypernatremia caused by
excessive salt intake to prevent development of pulmonary edema during fluid therapy [103,107].
Hypernatremic Myopathy - Episodic weakness and signs of depression were reported in a 7 month old Domestic
Shorthaired cat with episodic hypernatremia (serum Na concentration ranging from 182 to 215 mEq/L; normal is
148 to 161 mEq/L) secondary to hypodipsia (failure to drink water) [119]. This rare condition was accompanied by
hyperosmolality (ranging from 381 to 431 mOsm/L) and evidence of hypopituitarism (adrenocorticotrophic and
growth hormone deficiencies, along with blunted thyroxine response to thyroid-stimulating hormone). The most
prominent clinical sign was ventral flexion of the neck. No other neurological abnormalities were detected.
Electromyographic testing revealed prolonged insertional activity, fibrillation potentials, positive sharp waves, and
bizarre high-frequency discharges. Nerve conduction velocities were normal. These abnormalities were more
severe during episodes of hypernatremia. Serum creatine kinase activity was increased, while CSF analysis was
normal. Examination of several muscle biopsies were normal. Contrast-enhanced computed tomographic studies
of the brain demonstrated marked hydrocephalus, although no hypothalamic or pituitary lesions were detected.
The episodic weakness might have been associated with muscle membrane alterations associated with
displacement of intracellular potassium by high levels of extracellular sodium. Interestingly, the clinical signs,
serum CK levels, electrodiagnostic data, and muscle biopsy findings were very similar to those seen in cats with
hypokalemic myopathy. Forced water intake and dietary sodium restriction (using a low-salt feline diet) corrected
the hypernatremia and signs of muscle dysfunction. After restoration of eunatremia, secretion of pituitary
hormones became normal. It was suggested that hypothalamic dysfunction, possibly related to hydrocephalus,
induced both hypodipsia and transient hypopituitarism [119].
Hypocalcemia
Ionized calcium is important for presynaptic neurotransmitter release from synaptic vesicles and stabilization of
nerve and muscle membranes [1]. As a result of reduction in extracellular fluid concentration of calcium ions, and
since divalent cations have a stabilizing effect on nerve and muscle membranes [120], the nervous system
becomes increasingly excitable due to increased neuronal membrane permeability to sodium. Nerve fibers
discharge spontaneously resulting in skeletal muscle contraction and tetany.
Total serum calcium is approximately 50% ionized, 40% protein bound (especially to albumin), and 10%
complexed with anions such as citrate or phosphate [121]. Only ionized calcium is biologically active in bone
formation, neuromuscular activity, blood coagulation, and cellular biochemical processes. The proportion of
ionized calcium is affected by acid-base balance: ionized calcium levels are decreased by alkalosis and increased
by acidosis. Total serum calcium and protein-bound calcium are decreased in hypoproteinemia, but ionized
calcium levels remain normal. Accordingly, clinical signs of hypocalcemia do not occur in hypoalbuminemic
conditions. The correction formula based on serum albumin concentration is [122]:
Corrected total calcium level (mg/dl) = measured calcium (mg/dl) - albumin (g/dl) +
3.5
(Note that assessment of ionized calcium levels are preferable to such formulas and today are readily available in
commercial laboratories and are inexpensive).
Serum calcium levels usually represent a balance between bone formation and bone resorption which is
regulated by parathyroid hormone (PTH), 1,25-dihydroxycholecalciferol, and calcitonin. Except for acid-base
imbalance and hypoalbuminemia, hypocalcemia usually indicates hormonal imbalance [121]. Dietary intake of
calcium rarely affects serum levels directly.
Hypocalcemia may be seen with:
1. Hypoparathyroidism. In normal animals, an inverse linear relationship exists between parathyroid

hormone (PTH) and serum calcium levels, e.g., a fall of serum calcium levels below 10.5 mg/dl stimulates
PTH secretion, while calcium levels > 10.5 mg/dl result in suppression of PTH secretion [122]. With
hypoparathyroidism, there is a decrease in serum calcium concentration and an increase in plasma
phosphate levels (associated with loss of PTH actions on mobilizing calcium and phosphate from bone
and retention of calcium and enhancing phosphate secretion by the kidneys). Primary hypoparathyroidism
results from absolute or relative deficiency of parathormone and is infrequently seen in dogs and cats
[123-131]. Hypocalcemia has also been seen with secondary hypoparathyroidism attributable to
hypomagnesemia [243]. Animals have been classified as having ‘idiopathic hypoparathyroidism’ in the
absence of trauma, malignant or surgical destruction, or other obvious damage to the neck or parathyroid
glands [122,132,133]. The histological interpretation is lymphocytic parathyroiditis since the glands are
microscopically atrophied with infiltration/replacement by lymphocytes, plasma cells, fibrous connective
tissue and capillary proliferation. Commonly reported canine breeds include Poodles, Miniature
Schnauzers, Retrievers, German Shepherds and Terriers [122].
2. Nutritional hyperparathyroidism (typically a disease of young growing animals) occurs secondary to
dietary calcium deficiency, hypovitaminosis D, or dietary phosphate excess. This is an uncommon
condition, especially in cats, due to the wide availability of commercial balanced diets, that usually results
from animals fed foods such as beef heart or liver that have low calcium-to-phosphorus ratios (note that
all-meat diets are extremely low in calcium and have a low phosphorus concentration resulting in a low
calcium:phosphorus ratio [134]). In an attempt to maintain mineral homeostasis, the low dietary calcium
results in a transient decrease in serum calcium, inducing increased PTH release which leads to
accelerated bone resorption and reduction in bone mass as calcium is removed from bone, increased
renal calcium reabsorption and phosphorus excretion, increased renal synthesis of active vitamin D
(calcitriol), and eventually the development of skeletal disorders including osteopenia (marked decrease
in bone opacity), vertebral lordosis/kyphosis, bone pain, and pathologic fractures, including the vertebrae.
Note that affected animals usually have normal serum levels of calcium and phosphorus [122], although
in one recent report, 4 of 6 affected young cats were hypocalcemic [134]. In this study, serum PTH levels
were markedly elevated, 1,25(OH)2-vitamin D3 (calcitriol) levels were mildly increased, while 25(OH)-
vitamin D3 concentration was mildly decreased [134].
3. Renal disease (acute and chronic) - associated with decreased renal hydroxylation of vitamin D, soft-
tissue calcification, reciprocal decrease in calcium serum levels secondary to hyperphosphatemia, and
skeletal resistance to the effects of parathormone [121]. Note that uremic acidosis results in an increased
proportion of ionized calcium in serum that may prevent signs of tetany in a hypocalcemic animal [122].
4. Acute pancreatitis in which ionized calcium may be bound to free fatty acids in necrotic fat [121,122,135].
The hypocalcemia is usually mild and subclinical in dogs with pancreatitis and any co-existing acidosis
(frequently present in acute pancreatitis) will increase the levels of ionized calcium [122].
5. Post-parturient eclampsia (most common in small dogs; less common in cats and large dogs)
[121,122,136].
6. Ethylene glycol toxicity in dogs and cats [122,137].
7. Intestinal malabsorption in dogs [121,122].
8. Commercial phosphate-containing enemas (resulting from acute, severe hyperphosphatemia following
colonic absorption of the enema solution) [138].
9. Miscellaneous causes include trauma to the parathyroid glands, thyroid medullary carcinoma, various
primary and metastatic bone tumors, and some forms of chemotherapy [122]. There has been a report of
acute hypocalcemia in 2 dogs associated with infarction of parathyroid gland adenomas that were
previously responsible for causing persistent hypercalcemia. [139]. In experimental studies in which
gnotobiotic dogs were infected by canine distemper virus, some infected dogs had low serum calcium
concentrations associated with ultrastructural evidence of parathyroid gland inactivity, degeneration, and
viral inclusions [140]. Hypocalcemia has also been seen following administration of sodium bicarbonate
for salicylate intoxication in a cat [141].
In dogs and cats, hypocalcemic tetany may occur when serum calcium levels are less than 6 mg/dl, or when
ionized calcium levels are less than 2.5 mg/dl [121]. Clinical signs of hypocalcemia are characterized by abrupt
onset of intermittent neurological or neuromuscular disturbances. Signs include nervousness, panting, pacing,
muscle spasm and cramping, often seen in leg muscles, focal muscle twitching, trembling, stiff-stilted gait, intense
facial rubbing with the paws or on the ground, ataxia, tonic-clonic spasms, episodic rigidity and falling,
tetraparesis, and sometimes seizures and status epilepticus. In a recent report on nutritional secondary
hyperparathyroidism, 4 of 6 cats were presented for evaluation and treatment of seizures (3 of these cats were
hypocalcemic) [134]. Hypocalcemic animals are frequently febrile. Nictitating membranes may be raised in cats.
Some animals manifest mental dullness and appear disoriented. Typical electrocardiographic findings include
deep, wide T waves, prolonged Q-T intervals, and bradycardia [122]. Diagnosis of hypocalcemia is based on
clinical signs and serum ionized calcium levels.
Hypocalcemic tetany requires prompt and immediate replacement of calcium, e.g., calcium gluconate as a 10%
solution at 1 - 1.5 ml/kg or 5 - 15 mg/kg, IV, slowly over a 10 to 30 minute period [122]. Following control of the
tetany, the same dose can be given subcutaneously (diluted in an equal volume of saline) every 6 to 8 hours
while waiting for oral vitamin D and calcium supplementation to take effect (this usually requires a period of 24 to
96 hours). Once serum calcium levels are stable, the subcutaneous injections can be gradually tapered (serum
calcium levels should be maintained above 8 mg/dl). Oral calcium supplements should be given to animals initially
with primary hypoparathyroidism, e.g., calcium carbonate tablets at 0.5 - 1 g/day (cats) and 1 - 4 g/day (dogs) in
divided doses, for several weeks or months, according to serum calcium levels. After this period calcium in
balanced diets is usually sufficient. Vitamin D therapy, however, is usually permanent for animals with primary
hypoparathyroidism. Vitamin D increases serum calcium by promoting intestinal absorption.
Suggested dosages are [122]:

- Vitamin D2 (ergocalciferol) at 4000 - 6000 U/kg/day initially for several weeks, followed by a maintenance dose
of 1000 - 2000 U/kg once daily to once weekly, depending on monitored serum calcium levels; or
- Dihydrotachysterol at 0.02 - 0.03 mg/kg/day initially for several weeks, followed by a maintenance dose of 0.01 -
0.02 mg/kg q24 - 48h. This preparation raises serum calcium levels faster than vitamin D2 and its effects
dissipate quicker once administration is stopped.
Treatment of animals with nutritional secondary hyperparathyroidism entails short- term parenteral calcium
gluconate injections as clinically indicated, a balanced diet, and cage rest [122,134].
Prognosis will depend upon the underlying cause of the hypocalcemia. Correct dosage and owner compliance
may result in excellent prognosis for animals with uncomplicated primary hypoparathyroidism; however, animals
with spinal fractures have a guarded prognosis [134]. Note that uncontrolled motor activity as a result of seizures
and/or excessive muscle jerking in animals with vertebral osteopenia will place these animals at high risk for
spinal cord damage secondary to spinal fracture [134]. Iatrogenic hypoparathyroidism in cats resulting from neck
surgery is often transient and lifelong treatment is not always necessary [122]. The prognosis for uncomplicated
cases of nutritional secondary hyperparathyroidism is good [134].
Hypoglycemia
Glucose is the major nutritive carbohydrate substrate of the brain which requires about 100g glucose/day for
normal functions [1,86]. This dependence on glucose, along with the brain’s limited glycogen stores, results in
rapid CNS dysfunction when hypoglycemia is present and permanent neurological sequela if the condition is
prolonged [1]. Counterregulatory (i.e. glucose-raising) hormones (in particular, epinephrine and glucagon, but also
norepinephrine, growth hormone, and cortisol) are released once blood glucose reach critical levels, e.g., < 40
mg/dl with induction of gluconeogenesis [142-144]. If the glucose levels decline slowly, the CNS is able to utilize
alternative non-glucose organic substrates, such as ketoacids, intermediaries of glucose metabolism, and certain
amino acids [1,145,146]. In people, neuronal damage consecutive to severe and prolonged hypoglycemia occurs
mainly in the cerebral cortex, hippocampus and caudate-putamen as a result of active extracellular release of
excitatory amino acids [147-149]. Neuropathological studies have been limited in dogs, although early signs of
acute neuronal necrosis were reported exclusively in the superficial layers of the cerebral cortex, in addition to
spongy changes in the dentate gyrus of the hippocampus in a 5 year old female Collie dog with hypoglycemia
[150]. In another dog, there was extensive bilateral polioencephalomalacia observed in the cerebral cortex and
basal nuclei [151]. Hypoglycemic Toy-breed puppies with hepatic steatosis (fatty liver) have ischemic neuronal
changes in the cerebral neocortex [152]. The apparent selective vulnerability of certain neurons to hypoglycemia
mimics that seen in hypoxic-ischemic conditions (e.g., cardiac arrest) and seizures [153]. Curiously, it has been
reported that cats appear to have high resistance to brain injury caused by hypoglycemia [154]. Hypoglycemia
plus hypoxia has been equated with tissue ischemia [40].
A common cause of hypoglycemia in dogs is a functional islet cell tumor (synonyms are hyperinsulinism, beta cell
tumor, and insulinoma) [155]. These tumors occur in middle-aged to older dogs, of either gender, and are
associated with increased insulin or proinsulin secretion by functional, neoplastic beta ells ("islet" cells) of the
pancreas, independent of the negative feedback effects caused by hypoglycemia [156-160]. While a wide variety
of breeds may be affected, Labrador Retriever, German Shepherds, Irish Setters, Standard Poodles, Collies,
Boxers, and Fox Terriers may have a higher incidence than other breeds. Insulinomas occur less frequently in
cats [161-164]. Clinical signs of hypoglycemia may reflect both neuroglycopenia (generalized seizures, weakness,
ataxia, collapse, lethargy, transient blindness, and abnormal behavior, e.g., hysteria) and sympathoadrenal
stimulation (muscle tremors, nervousness, restlessness, and hunger) [6]. The adrenergic signs precede
neurobehavioral signs in humans and thus function as an early warning system [165]. Signs are often intermittent
initially but become more frequent as the disease progresses. There is a strong correlation between onset of
clinical signs of hypoglycemia and fasting, excitement, exercise, or eating [6,166]. Food consumption may
stimulate excessive insulin secretion by the tumor resulting in postprandial hypoglycemia 2 to 6 hours later [6].
Polyneuropathy may be another complication of insulinoma in dogs [157,167-173]. Clinical signs range from
paraparesis to tetraplegia, facial paresis/paralysis, hyporeflexia, hypotonia, and muscle atrophy, usually in
conjunction with seizures, etc. Histopathological findings in nerves from affected dogs include severe axonal
necrosis, nerve fiber loss, and variable demyelination. Muscle changes reflect neurogenic atrophy.
Results of CBC and urinalysis are usually normal. Hypoglycemia is the only consistent abnormality identified in
serum biochemical profiles in animals with insulin-secreting tumors [6]. In one study involving 71 dogs with
insulinomas, the mean initial blood glucose concentration was 46 mg/dl [6]. A serum insulin concentration > 20
U/ml in a dog with a blood glucose level < 60 mg/dl is strong evidence for the diagnosis of an insulinoma. Some
dogs may be euglycemic, necessitating hourly evaluations of blood glucose concentrations during a 4- to 12-hour
fast. In one study, a fast of 8 hours was successful in demonstrating hypoglycemia in 26 of 28 trials in 25 dogs
with insulinomas [174]. Some researchers no longer recommend use of insulin:glucose ratios because of false-
negative and false-positive results [6,175,176]. Abdominal radiographic studies are usually normal. Since tumor
metastasis to the lungs is extremely rare [6], thoracic radiographs are of limited help in evaluating metastatic
disease. Abdominal ultrasonography may sometimes identify a pancreatic, peripancreatic, or hepatic mass
[6,177]. Ultrasound may also detect biliary obstruction caused by the tumor [177]. Scintigraphy has been used to
identify tumors and metastases (often to liver and mesenteric lymph node) in dogs [178,179]. In one report,
somatostatin receptor scintigraphy using indium In-111 pentetreotide was performed [178].
Definitive diagnosis is obtained by surgical exploration, biopsy and histopathological examination of the tumor.
Insulin-secreting tumors can often be visualized or palpated by the surgeon [6]. As islet cell tumors in dogs and
cats are frequently malignant with metastasis occurring early in the course of the disease, usually to regional
lymphatics and lymph nodes (e.g., duodenal, mesenteric, hepatic and splenic nodes), liver, mesentery, and
omentum [6], careful inspection of these sites is imperative. Surgical removal is the treatment of choice [6,180].
Immunohistochemical studies of 20 islet cell tumors in dogs revealed that 8 of the 20 tumors had positive
immunoreactivity for insulin, 9 for glucagon, 14 for somatostatin, and one for gastrin [159]. Three tumors were
pure insulinomas, but no pure somatostatinomas, glucagonomas, or gastrinomas were identified. Most tumors
and metastases had mixed positive immunoreactivity; one neoplastic cell type predominated with lesser numbers
of other cell types. The authors noted that the tumor staining pattern did not correlate consistently with function,
as determined by blood glucose and serum insulin assays. Positive immunoreactivity has also been shown for
insulin, somatostatin, and islet amyloid polypeptide in an islet cell tumor in a cat [162].
With inoperable cases (e.g., animals with extensive local tumor spread or metastatic disease, older animals, or
animals that are anesthetic risks) medical therapy for chronic hypoglycemia evolves around frequent feedings of
diets high in proteins, fats, and complex carbohydrates, in conjunction with prednisone at 0.25 - 0.5 mg/kg/day,
PO, in two divided doses (dogs), and/or diazoxide, from 10 to 60 mg/kg, divided into 2 doses daily (not to exceed
60 mg/kg/day for dogs) [6,181,182]. Prednisone antagonizes the effects of insulin at the cellular level and
promotes gluconeogenesis, while diazoxide inhibits the release of insulin, inhibits tissue use of glucose, enhances
epinephrine-induced glycogenolysis, and increases the rate of mobilization of free fatty acids. Neither drug has
any effect on tumor growth or metastasis. In a dog with an insulinoma-related peripheral polyneuropathy, frequent
feeding and treatment with corticosteroids resulted in recovery from a non-ambulatory to an almost completely
normal clinical state, despite the persistence of hypoglycemia and hyperinsulinism [183]. Frequent feedings and
prednisone (5 mg, sid or bid, PO) have been used in successfully treating a cat with chronic hypoglycemia
associated with insulin-secreting pancreatic islet cell carcinoma [163]. Variable results have been obtained with
the long-acting somatostatin analogue, octreotide acetate (SMS 201 - 995; Sandostatin®) in dogs with insulinoma
[184].
The long-term prognosis for animals with islet cell tumors is guarded to poor. In canine surgical cases, a mean
post-operative survival time is reported to be 12 to 14 months [6,174]. In dogs treated only medically, the mean
survival times drop to around 90 days, with few dogs surviving a year [6]. One surgically-treated cat survived 7
months [162], while a medically managed cat survived 18 months [163]. Postoperative complications can include
acute pancreatitis and diabetes mellitus (which may develop as a result of chronic beta cell suppression by the
excessive insulin levels). Sometimes the diabetes persists, necessitating a low-carbohydrate diet and/or insulin
administration. Dogs that remain hypoglycemic after surgical removal are considered to have functional
metastases [6].
Miscellaneous Causes of Hypoglycemia - Hypoglycemia has been reported in association with various non-islet
cell tumors in dogs, including hepatocellular carcinoma, hepatoma, hemangiosarcoma, hepatic leiomyosarcoma,
splenic hemangiosarcoma, salivary gland adenocarcinoma, metastatic oral melanoma, metastatic mammary
carcinoma, primary pulmonary adenocarcinoma, and lymphatic leukemia [185-187]. In the dog, non-islet cell
tumor hypoglycemia has been attributed to excess production of IGF-II (insulin-like growth factor II) circulating in a
molecular form that can easily cross the capillary wall to exert its insulin-like effects on target tissues [188].
Removal of the tumor can result in return of normal blood glucose levels and remission of clinical signs [186].
Transient, juvenile hypoglycemia may occur in neonatal puppies and in toy and miniature-breed puppies less than
3 months of age as a result of cold, starvation, or gastrointestinal disease. It may also be seen with liver
insufficiency (e.g., portal shunt). These disorders usually respond to a dietary carbohydrate source. Feeding
puppies and the bitch with a protein-rich diet reportedly prevented the juvenile hypoglycemia seen in the
Yorkshire Terrier breed and other toy breeds [189]. A 50% dextrose solution, at a dose of 0.5 to 1.0 ml/kg
administered slowly over 10 minutes, IV, may be given for temporary control of seizures in animals with a
hypoglycemic crisis [190]. The cause of transient hypoglycemia is unknown but it may be related to enzyme
immaturity leading to depletion of primary energy sources, such as ketones or glucose [191]. Another cause of
juvenile hypoglycemia is glycogen storage disease (see glycogenoses).
Hypoglycemia can result from excessive insulin administration to animals with diabetes mellitus [4], and cats may
be at greater risk of insulin overdose than dogs, especially if the cats are obese and receiving insulin doses > 6
U/injection, administered once or twice daily [192]. Interestingly, in some affected diabetic dogs and cats,
sympathoadrenal signs were either not seen or not recognized [192]. Treatment of such cases includes
administration of a slow bolus of 50% dextrose at 0.5 g/kg, diluted 1:4, followed by a continuous infusion of 5%
dextrose to maintain normal blood glucose levels, and the animal fed as soon as it is able to eat unassisted [4]. In
adult dogs, hypoglycemia may also occur with severe hypoadrenocorticism, liver disease (e.g., impaired glucose
production and glycogen storage), sepsis, glycogenoses, and as a complication of pregnancy accompanied by
ketonuria [6,193]. Spontaneous hypoglycemia has been reported in a 9 year old cat with chronic renal failure
[194]. Hypoglycemia in highly nervous hunting dogs is also well recognized. Attacks are characterized by
apparent disorientation, weakness and generalized seizures. Recovery is rapid; however the affected animal's
hunting ability is compromised. Frequent feedings with protein-rich foods and/or candy bars may prevent the
attacks. The cause has not been determined.
Hyponatremia
Hyponatremia is a metabolic state in which serum sodium (Na) levels are < 146 mEq/L in dogs and < 151 mEq/L
in cats [102]. True hyponatremia is associated with serum hypoosmolality (< 290 mOsm/L) which suggests total
body water in excess of Na [1,101]. Hyponatremia generally results from retention of ingested or administered
water and usually indicates a defect in renal water excretion (e.g., inappropriate reabsorption of water in
proportion to Na, or failure to reabsorb sodium by the kidney) and with urine specific gravity > 1.003 [102].
Electrolyte loss in excess of water may cause hyponatremia but this is uncommon. Hyponatremia with normal or
increased serum osmolality is termed pseudohyponatremia. Hyperosmolar pseudohyponatremia may be
associated with administration of hypertonic mannitol or parenteral hyperglycemia [195], urea nitrogen, or toxins
that attract water into the intravascular space and dilute serum Na concentration. Differential diagnosis might
include diabetes mellitus, ethylene glycol toxicity, and renal failure [101]. Isoosmolar pseudohyponatremia is often
seen with hyperlipidemia and hyperproteinemia [102]. True hypoosmolar hyponatremia can be further subdivided,
based on extracellular fluid volume, into [1,102]:
a. Hypervolemic (e.g., congestive heart failure, liver failure, nephrotic syndrome, hypoalbuminemic states
b. Normovolemic (e.g., syndrome of inappropriate antidiuretic hormone secretion, primary polydipsia, water
intoxication, hypothyroidism, adrenal insufficiency [196], or renal failure;
c. Hypovolemic (e.g., renal or extrarenal disease, such as gastrointestinal, third space or cutaneous losses).
Neurological signs of hyponatremia are related to the rapidity of onset of the hyponatremia [12,105]. In acute
hyponatremia, water flows down the its concentration gradient and enters brain cells producing cerebral edema
and increased intracranial pressure [1]. Signs range from generalized weakness and mental depression to stupor,
coma, seizures, and dementia [197]. Treatment is aimed at increasing serum Na levels and treating the
underlying cause of the hyponatremia. Administration of hypertonic saline (e.g., 3 - 5%) should be given to
animals in which serum Na is < 115 mEq/L. The Na deficit may be calculated using the following formula [101]:
Na deficit (mEq/L) = (140 - measured Na) x body weight (kg) x

0.3
The replacement fluid should be given slowly over 12 to 24 hours. Normal isotonic saline can be given to
hypovolemic animals, while water restriction (i.e. limiting water intake to less than urine output) can be performed
for animals with normovolemia or hypervolemia associated with excessive water intake or renal retention. In
instances where severe neurological signs are seen associated with normal or excessive intravascular fluid,
furosemide (at 2 - 4 mg/kg IV) can be used to promote renal water excretion [101].
Treatment of chronic cases of hyponatremia may present a different challenge. Paradoxically, the neurological
condition of some patients with severe hyponatremia may actually deteriorate as their electrolytes get better. In
hyponatremic people in whom correction of the hyponatremia occurs too rapidly (e.g., correction of hyponatremia
by more than 12 mEq/L per day), a demyelinating condition termed central pontine myelinolysis is well recognized
in which nerve cells and axons are spared but there is loss of oligodendrocytes [197,198]. This disorder is
characterized by symmetrical myelinolytic foci in the pons and sometimes (in approximately 10% of cases) in
extrapontine areas such as thalamus, subthalamic nucleus, striatum, internal capsule, amygdaloid nuclei, lateral
geniculate body, white matter of cerebellum foliae, and deep layers of the cerebral cortex and adjacent white
matter [199]. Results of an immunohistochemical study of central pontine myelinolysis in people indicated
reduced immunoreactivity of myelin basic protein, myelin- associated glycoprotein, transferrin, and carbonic
anhydrase C, and dystrophic astrocytic alterations based on labeling of glial fibrillary acidic protein and S-100
protein [200]. The exact pathogenesis of this myelinolysis still has not been determined but is certainly appears to
be associated with the electrolyte derangement [201]. One hypothesis is that chronic hyponatremia (e.g., 2 - 3
days) may allow the brain to compensate for the imbalance in the osmotic gradient by active extrusion of
intracellular electrolytes (sodium, potassium, and chloride) followed by organic osmolytes ("idiogenic osmoles"),
including amino acids glutamine, glutamate and taurine, as well as myoinositol, phosphocreatine/creatine, and
glycerophophorylcholine [114,202], and thereby reduce the brain edema. Although the adaptive solute loss from
the brain helps protect against cerebral edema in severe hyponatremia, it also places the brain at risk to
dehydration when serum sodium levels are returned to normal, since with rapid correction of chronic
hyponatremia, compensatory influx of electrolytes is not matched by the slower moving organic osmolytes as
serum becomes hypertonic relative to the CNS [203]. This sudden new osmotic gradient can lead to cellular
dehydration, including possible axonal shrinkage away from myelin sheaths and other events leading to
subsequent demyelination [203]. Results of an experimental study indicated that following rapid correction of
chronic hyponatremia, a topographic correlation occurred between demyelination lesions and delayed
accumulation of organic osmolytes [204]. There have been a few reports of a similar pathophysiological event
occurring in dogs following rapid correction of naturally occurring hyponatremia using 0.9% saline (the rate of
correction in two dogs ranged from 16 to 22 mEq/L/day, while in the third dog, the rate was 17mEq/L in 9 hours)
[205,206]. Interestingly, the cause of the hyponatremia was heavy whipworm (Trichuris vulpis) infestation in all
cases. Neurological signs were seen several days after saline infusion and included ataxia, weakness,
hypermetria, visual deficits, depressed menace responses with normal pupillary light reflexes, deficient postural
reactions, trismus, exaggerated licking movements, episodic myoclonus, episodic whole-body spasms,
obtundation and tetraparesis. In experimentally induced hyponatremia in dogs, several were stuporous or
comatose [197]. Cerebrospinal fluid evaluation in two clinically-affected dogs tested was normal. T2-weighted
magnetic resonance imaging in two clinically-affected dogs revealed symmetrically increased signal intensity in
the area of the central thalamic nuclei, which in one dog progressed to a marked increase in signal intensity with
ring-like effects [205]. In one dog necropsied, macroscopic tan-colored foci were seen in the central lateral
thalamus bilaterally (the more prominent being approximately 4x5x3 mm in size). Microscopic lesions were found
in the thalamus as well as in the rostral commissures. Lesions were characterized by myelin loss, apparent
decrease in numbers of oligodendrocytes and increased numbers of astrocytes, and degenerating
oligodendrocytes, some of which appeared to have pyknotic nuclei and vacuolated cytoplasm. Axons and nerve
cell bodies appeared normal. Myelin splitting was observed intrastructurally, and cells considered to be
oligodendrocytes had electron-lucent cytoplasm containing numerous, dilated membrane-bound vacuoles. The
authors stated that the myelin loss appeared to be secondary to acute degeneration and probable loss of
oligodendrocytes and other glia [205]. In experimental studies using dogs in which hyponatremia was rapidly
corrected using 3% saline (at a correction rate of 15 mEq/L/day), symmetrical lesions primarily involving myelin
and oligodendrocytes were seen in the thalamus and other areas including the central pons, lateral aspects of the
thalamus and adjacent internal capsules, caudate nucleus, putamen, red nuclei, deep layers of cerebral cortex
and subjacent white matter, and cerebellum [197]. The histological lesions were almost identical to the naturally
occurring lesions, although some loss of axons and neurons were found at the center of the lesions. Also,
Purkinje cells loss was noted in areas of severe white matter involvement, and fibrillary gliosis was present in
chronic lesions [197]. The cause(s) of this regional vulnerability in animals and people remains undetermined. The
prognosis of dogs with hyponatremia-related myelinolysis is guarded to favorable. While one affected dog was
euthanized, two others slowly recovered completely without medication over the ensuing 4 - 7 weeks [205,206].
In summary, in order to avoid rapid normalization of severe, sustained hyponatremia, recommended rates of
correction for animals with chronic hyponatremia are 10 - 12 mEq/L per day or approximately 0.5 mEq/L per hour
[205,206].
Hypothyroidism
Hypothyroidism results from decreased production of thyroxine (T4) and triiodothyronine (T3) by the thyroid gland.
Thyroid hormones have myriad functions, for example, they increase metabolic rate and oxygen consumption of
most tissues, have positive inotropic and chronotropic cardiac effects, increase the number/affinity of beta-
adrenergic receptors, enhance response to catecholamines, have catabolic effects on muscle and adipose tissue,
stimulate erythropoiesis, regulate cholesterol synthesis/degradation, and are essential for normal development of
nervous and skeletal systems [207]. Hypothryoidism is common in dogs but rare in cats and most cases of
acquired canine hypothyroidism are associated with immune-mediated lymphocytic thyroiditis/idiopathic thyroid
atrophy [208,209]. An association between hypothyroidism and acquired myasthenia gravis has been suggested
in dogs [239]. A recent study of a closed colony of Beagles showed that dogs with hypothyroidism associated with
lymphocytic thyroiditis had an increased risk for thyroid follicular epithelial neoplasia [210]. Hypothyroidism is
more common in certain breeds, such as Doberman Pinscher and Golden Retrievers, especially in neutered
animals [211]. Common clinical findings include obesity, seborrhea, alopecia, weakness, lethargy, bradycardia,
and pyoderma [211]. Impaired ventricular function, along with decreased amplitude of the P and R waves, has
been shown in echocardiographic and electrocardiographic studies [212]. Clinicopathologic abnormalities may
include hypercholesterolemia, non-regenerative anemia, high serum alkaline phosphatase activity, and high
serum creatine kinase activity [207,211].
Myxedema coma is an extremely rare form of decompensated hypothyroidism [213] in which patients may
manifest bradycardia, hypothermia, and stupor/coma, along with hypoventilation, hypoxia, and hypotension [214-
216]. The hypothermia in affected dogs tends to be characterized by absence of shivering [214,217]. The
pathogenesis of the coma remains enigmatic [1], although it has been stated that the hypothyroidism is often
profound and associated with an inciting event such as respiratory depressant drugs, infectious diseases
(especially respiratory), heart failure, decreased blood volume (e.g., diuretics), or other stressors such as
exposure to cold environment or surgery [1,217,218]. In affected dogs, the more classical signs of hypothyroidism
(see above) will also be present [217].
Diagnosis of hypothyroidism is suggested by low resting free T4 levels and confirmed by performing a thyroid
stimulating hormone (TSH) response test. A diagnosis is likely if both the pre- and post-TSH serum total T4 levels
< 1.5 g/dl [207]. Treatment involves administration of synthetic L-thyroxine at 0.02 mg/kg PO, bid for several
weeks , according to results of therapeutic monitoring. Maintenance dosage is at 0.02 mg/kg PO daily, once
clinical signs have resolved and total T4 levels are normalized [207]. Recommended dosage of L-thyroxine for
animals in myxedema coma is 5 g/kg every 12 hours, intravenously, along with fluid therapy, warming and
ventilatory support [207]. Administration of glucocorticosteroids and broad-spectrum antibiotics has also been
suggested [217]. If possible, the diagnosis of myxedema coma should be suspected based on the clinical
presentation, and treatment should not be delayed while awaiting confirmatory laboratory data [217]. Prognosis is
guarded for animals with myxedema coma. In a recent report involving a 7 year old male English Coonhound with
suspected myxedema coma (the dog was comatose and cold to the touch, had bilateral rotary nystagmus,
bradycardia and irregular cardiac rhythm, a non-detectable peripheral pulse, and showed bilaterally symmetrical
alopecia of the base of the ears and caudal aspects of the thighs) [216], successful treatment involved a
combination of active external and core rewarming techniques (e.g., recirculating water heating pads placed over
and under the dog), intravenous (1.0 g/kg, q 12h) and oral (4.0 g/kg, q 12h) administration of L-thyroxine,
supplemental oxygen, and administration of warmed fluids (Lactated Ringer’s solution and 0.9% saline at 20
ml/kg).
Signs of CNS disease may also occur in dogs with hypothyroidism and atherosclerosis (see infarction), while
secondary hypothyroidism can be caused by pituitary tumors (see neoplasia). Signs of peripheral nerve disease
are commonly encountered in animals with hypothyroid neuropathy.
Uremic Encephalopathy
Uremic encephalopathy (UE) is an ill-defined condition that has been infrequently reported in young and old dogs
with renal failure [40,219,220]. Clinical signs include depression or stupor, generalized seizures, muscle
fasciculations (especially in facial muscles), myoclonic head bobbing movements, and weakness. In one
retrospective report involving 29 dogs, dementia was more common in dogs with chronic renal disease, while
seizures were more commonly associated with acute renal failure [220]. Laboratory studies reveal increased
levels of blood urea nitrogen and creatinine. Renal lesions that have been reported include nephrosclerosis,
nephrocalcinosis, peritubular fibrosis, tubular degeneration, pyelonephritis, renal infarction, and hydronephrosis
[219,249]. In this report, parathyroid hyperplasia was present in one dog, while no gross or microscopic lesions
were seen in the brain of 2 dogs euthanized [219]. The cause of uremic encephalopathy is presently unknown.
Suggested mechanisms include depressed cerebral oxygen consumption, cerebral hypoxia, increased brain
calcium levels, and increased blood levels of parathyroid hormone (PTH). In experimental uremia in dogs,
increased brain calcium levels have been associated with an increase in the serum PTH levels, while
administration of PTH to normal dogs produced EEG changes similar to those seen in uremic animals [221]. The
EEG abnormalities, as well as the increased brain calcium , could be prevented by performing a
parathyroidectomy before the induction of uremia. Serum calcitriol levels (1,25-dihydroxyvitamin D) are reduced in
animals with renal failure [222]. The accumulation of toxic organic acids as a possible mechanism of UE is not
supported by findings of normal acid-base balance in the CSF, blood, brain, and skeletal muscle of uremic dogs
[223]. Water, osmolality, and electrolyte abnormalities do not appear to play a role in the development of UE in
people [1]. Furthermore, clinical signs in dogs are probably not related to hypocalcemia and hypocalcemic tetany
due to renal failure, since the metabolic acidosis of uremia tends to maintain the ionized calcium fraction at
normal or increased levels [219] (see Hypocalcemia). A recent study suggests that several guanidine compounds
(GCs) may play an important role in the etiology of uremic encephalopathy in people, including creatinine,
guanidine, guanidinosuccinic acid, and methylguanidine [224]. The excitatory effects of uremic GCs on the central
nervous system may be explained by the activation of N-methyl-D-aspartate (NMDA) receptors and concomitant
inhibition of GABA-A receptors, and other depolarizing effects. Prognosis for animals in renal failure would appear
to be guarded, although earlier research studies indicate that calcitriol, at 1.5 to 3.4 ng/kg/day PO, lowers serum
levels of PTH, reverses neurological depression in dogs and cats with chronic uremia, and has a salutary effects
on the dog's or cat's sense of well being, appetite, activity, strength, and lifespan [225,226]. Low doses of calcitriol
are most effective when started early in uremia before the advanced stages of renal secondary
hyperparathyroidism. Serum phosphate levels must be normalized before initiating calcitriol therapy because
hyperphosphatemia enhances the tendency for calcitriol to promote renal mineralization and injury [222]. Other
treatments should be aimed at the causes of the acute or chronic renal failure, such as correction of
hypercalcemia, administration of antibiotics/antimycotics to eliminate bacterial/mycotic infections, removal of
lesions (e.g., tumors, uroliths) causing obstructive uropathy, and correction of abnormal renal perfusion that has
caused ischemic renal lesions [222]. Hemodialysis, peritoneal dialysis, and renal transplantation are also
available treatment strategies. Note that rapid hemodialysis of uremic animals may induce a syndrome
characterized by increased CSF pressure, grand mal seizures, and EEG abnormalities [223]. There is a fall in pH
and bicarbonate concentration in CSF, and brain osmolality exceeds that of plasma, resulting in a net movement
of water into the brain (cerebral edema). This syndrome has been called experimental dialysis disequilibrium
syndrome.
Miscellaneous Metabolic Disorders
Acidosis - Acidosis secondary to respiratory or metabolic disorders may lead to cerebral vasodilation, increased
cerebral blood flow, and sometimes increased intracranial pressure. Neurological signs of CSF acidosis including
altered mentation, delirium, and coma [12], and usually result from increased blood levels of CO2, which readily
crosses the blood-brain-barrier leading to CO2 narcosis, rather than from metabolic acidosis [1]. In patients with
metabolic acidosis, CSF pH decreases slowly and usually does not reach blood pH levels [227]. Treatment should
be directed at the underlying cause of the acidosis. A transient paradoxical CSF acidosis may follow
administration of bicarbonate [16,227].
Alkalosis - Hyperventilation can lead to hypocapnea, respiratory alkalosis, cerebral vasoconstriction, decreased
cerebral blood flow, reduced availability of oxygen, a reduction in ionized serum calcium levels, and
hypophosphatemia [1,227]. Signs may include confusion and disorientation [12]. Metabolic alkalosis commonly
accompanies hypokalemia as a result of translocation of hydrogen ions: as intracellular potassium moves out of
cells down the concentration gradient, hydrogen ions (and sodium) shift into cells, causing extracellular alkalosis.
Hyperthyroidism - Hypothyroidism in cats may be associated with hyperactivity (hyperkinesis) characterized by
pacing, circling, or restlessness, and variable personality changes including anxiety, confusion, and aggression
[228-231]. Focal and generalized seizures may also be seen [230]. Neuromuscular signs attributable to
hyperthyroidism include weakness, neck ventroflexion, decreased ability to jump, fatigue after physical activity,
muscle tremors, nonspecific gait disturbances, and collapse [230]. Some or all of these neuromuscular signs
might be related to hypokalemia [232](see hypokalemic myopathy). The pathophysiology of these manifestations
is presently unknown, although perturbations in central and peripheral beta adrenergic tone may play a role [1].
Weight loss, increased heart rate, and hyperactivity has been reported in an adult dog with hyperthyroidism and a
thyroid neoplasm [244].
Hypophosphatemia - Severe hypophosphatemia (i.e., serum inorganic phosphate concentration < 1 mg/dl)
occurs infrequently in animals [17,233,234]. It is most often associated with diabetic ketoacidosis (DKA) (see
above) in small animals, especially in cats [16]. Hypophosphatemia results from urinary loss of phosphate
associated with the osmotic diuresis and replacement fluid therapy in animals with DKA and from insulin-induced
movement of phosphate into cells (note that phosphate shifts between the intracellular and extracellular
compartments in a similar manner as potassium)[5]. In addition, phosphate depletion may be caused by
decreased intake from anorexia and vomiting, and translocation following alkali administration [16]. Other
conditions associated with hypophosphatemia in small animals include hyperadrenocorticism,
hyperparathyroidism (primary and pseudo), and hypothermia [233]. Respiratory alkalosis associated with
hyperventilation will also cause phosphate to move into the intracellular space resulting in hypophosphatemia
[233]. Phosphate is necessary for the production of 2,3 diphosphoglycerate (2,3-DPG) and adenosine
triphosphate (ATP); both are important for normal cellular metabolism. When serum inorganic phosphate levels
fall below 1 mg/dl, high energy demanding body cells such as red blood cells, muscle cells (skeletal muscle and
cardiac), and brain cells may be preferentially affected with subsequent development of hemolytic anemia,
seizures, altered mentation, cardiomyopathy, and skeletal muscle weakness/rhabdomyolysis [16,233]. Note that
severe hypophosphatemia may be clinically silent [3].
Treatment in most cases usually involves correction of the underlying cause of the hypophosphatemia; however,
in severe cases (e.g. when serum inorganic phosphate levels < 1 mg/dl), parenteral phosphate therapy (e.g.,
sodium or potassium phosphate solutions) is recommended at a dosage of 0.01 to 0.03 mmol phosphate/kg/h for
six hours, before rechecking serum inorganic phosphate levels [5]. A caveat of phosphate therapy is potential risk
of deposition of insoluble calcium phosphate into soft tissues and hypocalcemia [5,16,234].
Hypercalcemia - Hypercalcemia occurs when serum calcium (from bone resorption or from gastrointestinal
absorption) exceeds calciuresis [1]. Physiological hypercalcemia refers to ionized calcium levels increased above
their normal range (e.g., > 5mg/dL). Myriad clinical signs associated with hypercalcemia include heart failure,
unexplained shock, gastrointestinal disturbances (e.g., vomiting, constipation), renal failure, abdominal pain,
tachypnea, restlessness, weakness, hyporeflexia, listlessness, depression, obtundation, and coma [227,235].
Causes of hypercalcemia include primary hyperparathyroidism, hypercalcemia of malignancy, neoplastic bony
metastases, vitamin D toxicity, hypoadrenocorticism, and renal failure (acute or chronic) [236]. Paraneoplastic
hypercalcemia has been seen with a variety of tumors in dogs and cats including lymphosarcoma/T-cell
lymphomas, lymphocytic leukemia, myeloproliferative diseases, and myeloma, as well as solid tumors with
metastasis to bone (e.g., nasal, pancreatic, pulmonary carcinomas) and without bony metastases (anal sac
apocrine gland adenocarcinoma, malignant melanoma, squamous cell carcinoma, thyroid adenocarcinoma,
pulmonary carcinoma, pancreatic adenocarcinoma, and fibrosarcoma [236,245-248]. Treatment should be aimed
at the underlying cause of the hypercalcemia, e.g., platinum chemotherapy in canine apocrine gland carcinoma
[245]. Calciuresis is promoted with intravenous fluid therapy (e.g., using 0.9% saline at 10 ml/kg bolus over 15
minutes ) and furosemide (1 mg/kg/hour) [227,235,236]. Lowering serum ionized calcium using sodium
bicarbonate or sodium phosphate should be avoided due to calcium precipitation into soft tissue and potentially
compromising major organs [235].
Potassium Disorders - Hypokalemia and hyperkalemia in animals and people are usually not associated with
metabolic encephalopathies [1,12]. These disorders are more typically associated with neuromuscular disorders
(see hyperkalemic myopathy and hypokalemic myopathy). The major complication of hyperkalemic (usually with
serum levels > 7 mEq/L) is cardiac toxicity with irregularities in the EKG, arrhythmias, and/or cardiac arrest [237].
Neurotoxic Disorders
K. G. Braund
Introduction
Neurotoxicity in dogs and cats may result from myriad agents, including metals, pesticides, solvents and other
chemicals, and bacterial, animal, and plant-derived toxins, as well as therapeutic agents [1]. Drug-induced toxicity
may be caused by overdosage, undesirable side effects, or accidental exposure, usually ingestion. In one study
[2], the most commonly reported toxins were: lindane-based insecticides (HCB, hexachlorocyclohexane, Isotox,
Lintox); pyrethrin and pyrethroid insecticides (permethrin, fenvalerate/DEET); chlorpyrifos, strychnine, lead,
metaldehyde (in metaldehyde-based molluscicides), and caffeine (e.g., ingestion of caffeine-based stimulants or
chocolate which contains caffeine and theobromine). In general, signs of neurotoxicity may include excitation,
depression, tremors, clonic-tonic seizures, hyperactivity, ataxia, circling, salivation, hyperthermia, and coma.
Treatment involves decontamination where indicated (e.g., bathing/shampooing), inducing emesis (e.g.
apomorphine), correction of any fluid and electrolyte imbalances, repeated administration of activated charcoal
with a saline cathartic (sodium sulfate is more efficient than magnesium sulfate) or performing gastric lavage to
decrease the amount the animal absorbs, and providing demulscents (milk, kaolin-pectin) for any gastrointestinal
irritation [3].
Neurotoxic agents have been arbitrarily grouped as follows:
Metals
Lead
Mercury
Automotive products Animal
Ethylene glycol Tick Paralysis
Solvents/cleansing agents Toad Toxicity
Alcohols Therapeutic agents/drugs
Chlorhexidine Aminoglycosides
Hexachlorophene Barbiturates
Rodenticides Caffeine and other Methylxanthines
Anticoagulant Rodenticides Bromide
Bromethalin Closantel
Strychnine Griseofulvin
Thallium Ivermectin
Insecticides, Molluscicides, Repellents Levamisole
Amitraz Methionine
Chlorinated Hydrocarbons Metoclopramide
Metaldehyde Metronidazole
Organophosphates/Carbamates Pemoline
Pyrethrins and Pyrethroids Toluene/Dichlorophen
Herbicides Tricyclic Antidepressants
(2-methyl-4-chloro) Phenoxyacetic Acid Vincristine
Plants Zolpidem
Cyanogenic 5-Fluorouracil
Cycad Palms 5-Hydroxytryptophan
Bacterial
Botulism
Tetanus
Alcohols
Widespread utilization of short-chain alcohols in solvents and alcoholic beverages provides small animals with
numerous opportunities for exposure [4]. Toxicosis most commonly occurs following ingestion but may also arise
from inhalation and/or dermal absorption. The actions of short-chain alcohols are believed to result from
nonspecific interactions with biomembranes altering the function of membrane-bound proteins, including the
GABA-A receptor. Onset of signs typically occurs within an hour of exposure and may last for 24 hours. Clinical
signs include behavioral changes such as excitability, vocalizing, and incontinence, ataxia, drowsiness,
unconsciousness, loss of reflexes, respiratory compromise, respiratory and cardiac arrest, and death. Therefore,
general measures for resuscitation should be followed in the initial treatment of severe alcohol toxicosis, including
endotracheal intubation, mechanical ventilation, correction of acid base imbalance with bicarbonate (metabolism
of alcohols alters the redox state in the liver, leading to hypoglycemia and lactic acidosis in some cases).
Activated charcoal (2 g/kg PO) should be given within 3 hours of an alcohol ingestion and skin should be
decontaminated.
Aminoglycosides
Aminoglycoside antibiotics can adversely affect auditory and vestibular mechanisms, especially after prolonged
administration of large amounts of the drugs [5]. These drugs concentrate in perilymph and endolymph, thus
exposing the cochlear hair cells to high concentrations of the antibiotic agents. While all aminoglycoside
antibiotics can damage auditory and vestibular receptors, streptomycin and gentomycin have their greatest effects
on the vestibular system, whereas, neomycin, kanamycin, tobramycin, and amikacin sulfate produce more
damage to the auditory peripheral receptors [6]. The toxic effects of these drugs are heightened if the tympanic
membrane is perforated. However, in one experimental study, gentamicin sulfate did not induce detectable
alteration of cochlear or vestibular function in dogs with intact tympanic membranes or after experimental bilateral
myringotomy [7]. In other experimental studies, ototoxicity of aminoglycosides may be enhanced by loop diuretics
[8], while the severity of ototoxic side-effects can be influenced by nutritional factors [9].
Amitraz
Amitraz, an alpha-adrenergic agonist and a weak monoamine oxidase inhibitor, may induce sedation, depression,
ataxia, and muscle weakness in dogs following excessive exposure, such as application to the skin for Demodex
control and ingestion of tick collars [10]. Other signs may include hypertension, mydriasis, hypothermia,
bradycardia, hyperglycemia, hypoperistalsis, vasoconstriction, vomiting, and diarrhea [11-13]. I have also seen
brief, generalized seizures in our own Welsh Corgi following treatment for demodicosis. Nerve conduction studies
are normal [13]. Treatment with yohimbine at 0.1 mg/kg IV normally reverses the signs. It has been reported that
signs can be reversed by low doses of atipamezole (50 g/kg, IM), a potent alpha 2-antagonist, within 10 minutes
after injection [12].
Anticoagulant Rodenticides
A variety of anticoagulant rodenticies are available with one of the best known being warfarin. These agents
interfere with vitamin K1 hydroquinone recycling in the liver leading to impaired synthesis of functional forms of
clotting factors II, VII, IX, and X, and development of coagulopathies/bleeding [220]. Intrathecal or intrameningeal
hemorrhage may lead to ataxia, stiffness, or seizures. Diagnosis may be made using common coagulation tests
(bleeding time, blood clotting time, activated clotting time, prothrombin time, and activated partial thromboplastin
time). The PIVKA test may also be useful in identifying a vitamin K1-responsive coagulopathy. Treatment may
involve use of fresh frozen plasma (at 9 mL/kg) or whole blood (at 20 mL/kg) followed by oral vitamin K1 at a rate
of 2.5 mg/kg sid for 2 to 4 weeks.
Barbiturates
Barbiturates inhibit calcium accumulation in neural tissues and thereby inhibit the release of neurotransmitters [1].
Barbiturate anesthetics produce profound respiratory and CNS depression, general anesthesia, hypothermia,
hypotension, shock, cyanosis, and coma [1]. Phenobarbital may have several side-effects that include sedation,
nystagmus, ataxia, behavioral changes, hyperexcitability, polydipsia, polyuria, and polyphagia [10]. Signs may
disappear after several weeks of treatment as animals adapt to the dosage. The hyperexcitability may be difficult
to manage and may be the limiting factor in the use of phenobarbital [10]. Treatment of barbiturate poisoning
involves use of emetics, activated charcoal, gastric lavage, ventilation support, and fluid therapy.
Botulism
Botulism is a disease resulting from the ingestion of spoiled food or carrion containing a preformed exotoxin
produced by spores of Clostridium botulinum. The neurotoxin associated with canine disease has been reported
to be type C [14-21]. Botulism is an uncommon disease in dogs and naturally occurring disease has not been
reported in cats [22], although type C botulism has been reported in dairy cattle from feed contaminated with a
dead cat [23]. Most cases in dogs appear to result from eating carrion or contaminated raw meat (botulinum toxin
is destroyed by heating at 100ºC for 10 minutes). The toxin is absorbed from the stomach and upper intestine,
circulates in lymphatics and finds it way to the neuromuscular junction of cholinergic nerves where it blocks pre-
synaptic release of acetylcholine [24] leading to generalized motor neuron disease and parasympathetic
dysfunction [22]. Clinical signs may occur within hours to several days following ingestion of toxin. Clinical signs
reflect a progressive, symmetrical disorder, ranging from mild weakness to severe flaccid tetraplegia with absent
spinal reflexes and evidence of weakness in muscles of the face, jaw, pharynx, and esophagus resulting in
dysphonia, dysphagia, facial paralysis, and megaesophagus. Mydriasis may be present. Early in the course of the
disease, or in mildly affected animals, the gait may be stiff and pelvic limbs may be used in a synchronous, bunny
hopping fashion. Presence of keratoconjunctivitis sicca in some dogs suggests autonomic dysfunction. Pain
perception remains normal and muscle atrophy is not seen. There is no hyperesthesia [22].
Hematological and biochemical parameters are unaffected. Electrodiagnostic studies may reveal a low amplitude
of the evoked muscle action potential, decrease in amplitude of the compound muscle action potential with slow
repetitive stimulation, slowing of motor and sensory nerve conduction velocities, and sometimes, fibrillation
potentials and positive sharp waves, especially in distal limb muscles [25]. These latter changes indicate
peripheral nerve dysfunction through some as yet unknown action of the botulinum toxin. Nerve conduction
velocity and amplitude can return to normal as clinical improvement occurs.
Diagnosis is suggested by historical, clinical, and electrodiagnostic data. It is confirmed by identification of the
toxin in the material ingested or in serum, feces, or vomitus of an affected animal with type-specific antitoxin using
the neutralization test in mice [22,26]. ELISA has also been used [27]. Serum should be collected early in the
course of the disease [21]. In one report, Clostridium botulinum type C was still present in feces and a low toxin
titer persisted for 114 days after ingestion of a contaminated duck carcass [20].
The prognosis is usually favorable in dogs, with recovery occurring within 1 to 3 weeks [22], although some
affected dogs are euthanized due to other clinical complications [28]. Treatment is primarily supportive. Severely
affected animals should be monitored closely to avoid the potential complications of inhalation pneumonia,
respiratory paralysis, and urinary tract infections. Padding should be used for recumbent animals, along with
assistance with drinking and eating. Penicillin or metronidazole may be used to reduce intestinal clostridial
numbers. The use of botulinum antitoxin is controversial [22]. Note that the history, clinical signs, and pattern of
onset of lasalocid-induced toxicosis in dogs are similar to those reported for botulism [29].
Bromethalin
Bromethalin toxicosis (e.g., in bromethalin-containing rodenticides) in dogs induces a variety of neurological signs.
Dogs given a single oral dose of bromethalin at 6.25 mg/kg developed a toxic syndrome characterized by
hyperexcitability, tremors, focal motor and generalized seizures, depression, and death within 15 - 63 hours after
bromethalin administration. Clinical signs were dose-dependent, with signs of hind limb ataxia, and/or paresis,
and/or CNS depression noted following lower doses. CSF pressure may be increased. Predominant abnormal
EEG changes included spike and spike-and-wave EEG patterns, high voltage slow wave (50 - 150 microV, 1 - 6
Hz) activity, photoconvulsive or photoparoxysmal irritative responses, and marked voltage depression (dominant
activity less than 10 microV) in all leads [30]. Gross lesions included mild cerebral edema and mild pulmonary
congestion. Histologic lesions included diffuse white matter spongiosis, mild microgliosis, optic nerve vacuolation,
mild thickening of Bowman's capsule, and occasional splenic megakaryocytes. Ultramicroscopic examination of
midbrain stem revealed occasional swollen axons, intramyelinic vacuolization, and myelin splitting at the
intraperiod line. Bromethalin was detected in kidney, liver, fat, and brain tissues, using gas chromatography with
electron capture detection. Photodegradation of extracted bromethalin may limit accurate quantification of tissue
residues. In experimental trials, repeated oral administration (e.g. 3 times daily) of a superactivated
charcoal/sorbitol product (Superchar-Vet Liquid®) is reportedly an effective therapy [31,32]. In addition,
dexamethasone at 2 mg/kg IV every 6 hours, or prednisolone at 2 to 6 mg/kg, PO, daily, and mannitol solution at
500 mg/kg, IV, every 6 hours to reduce cerebral edema, is recommended [11]. Bromethalin-based rodenticides
are also highly neurotoxic to cats. Signs include tetraparesis/paralysis with extensor rigidity, depression, coma,
focal motor seizures, anisocoria, positional nystagmus, and opisthotonus [33].
Bromide
Potassium bromide (BR) is a commonly used antiepileptic drug. The recommended oral dosage for BR is 20 - 40
(60) mg/kg /day (one daily dosage). The therapeutic range of BR in dogs is 100 - 200 mg/dl when potassium
bromide is used as an add-on drug and 250 - 300 mg/dl when used as monotherapy (see Epilepsy). A variety of
neurological signs have been reported in dogs attributable to bromide toxicosis (bromism) including anisocoria,
muscle pain, hyporeflexia, hind limb weakness, ataxia, disorientation, depression, recumbency, and stupor.
Presumably toxicosis might be expected in some dogs when serum levels exceed therapeutic BR concentrations
[215,218]. Toxicosis has also been reported in an epileptic dog with renal insufficiency receiving potassium
bromide at a dosage of 29 mg/kg /day [219].
Caffeine
Caffeine is a methylxanthine compound (other related compounds are theophylline, aminophylline, and
theobromine) and a CNS stimulant [34]. Methylxanthines enhance catecholamine release and increase calcium
entry into cells, and inhibit phosphodiesterase, an enzyme that degrades cyclic AMP (cAMP) [2]. Cardiac
acceleration occurs with the increase of cAMP [34]. Intoxication in animals most commonly occurs within several
hours following ingestion of chocolate, caffeine-based tablets, or elixirs [1]. One ounce of chocolate contains 5 -
10 mg of caffeine and 35 - 50 mg of theobromine, while baking chocolate is approximately 10 times more toxic [2].
Signs of toxicity in dogs and cats may include vomiting, restlessness, hyperactivity, ataxia, muscle tremors,
tachycardia, cardiac arrhythmias, seizures, hyperthemia, polydipsia/polyuria, cyanosis, and coma [1,35,209].
There are usually no histological lesions found in the CNS [2]. Treatment is symptomatic and supportive, including
anticonvulsants, antiarrythmic agents, activated charcoal, and fluids.
Chlorhexidine
Chlorhexidine is commonly used as an antiseptic and disinfectant. There have been reports of vestibular
dysfunction following use of chlorhexidine (0.5%) or chlorhexidine (1.5%)/cetrimide (15%) in treating otitis externa
in dogs and cats with perforated tympanic membranes [36]. Pathological findings included loss of sensory
epithelium and fibrosis, and degeneration of afferent nerve terminals and the hair cells in the organ of Corti [1,36].
There is no specific treatment for this toxicosis although immediate flushing of the middle ear with saline may be
beneficial [36]. Interestingly, a solution containing 0.2% chlorhexidine did not induce vestibular or cochlear
neurotoxicity following installation (over a 3-week period) into the external ear canals of dogs with intact and
surgically perforated tympanic membranes [37].
Chlorinated Hydrocarbon Toxicity

Chlorinated hydrocarbon compounds (e.g., endrin, aldrin, dieldrin, heptachlor, lindane, DDT) are used for
prevention and control of insect infestations around farms, homes, and on animals, although regulatory agencies
have banned the use of may of these insecticides because of accumulating tissue residues and environmental
persistence [11]. Dogs and cats may be poisoned by ingestion, inhalation, or absorption through the skin when
the insecticide is applied topically [38]. Endosulfan is presently used for garden or farm use and is highly toxic to
cats and has been used maliciously to kill dogs [11]. Chlorinated hydrocarbon insecticides are considered to be
non-specific stimulants of the central nervous system [38]. Clinical signs can include anxiety, hysteria, facial
muscular spasms, jaw champing, spastic gait, ataxia, mydriasis, salivation, and severe generalized seizures.
External stimuli may precipitate seizures. Body temperature will usually increase significantly as a result of the
seizures. Death may occur within minutes or hours, after several days, or not at all. Neuropathological changes
are usually absent [39].
A presumptive diagnosis is based on historical data of recent exposure to the toxin and clinical signs. Prognosis is
guarded. Signs of acute toxicosis usually abate in 1 to 2 days. Complete recovery may take weeks. Treatment is
symptomatic since there is no known antidote. Seizures may be controlled using intravenous anesthetic
barbiturates, given to effect. Purgatives and/or gastric lavage will help remove residual toxin ingested, but
maximum benefit is to be expected only during the initial 2 hours after exposure. Soap and water scrubs are
indicated for animals exposed by the dermal route. Hyperthermic animals may be bathed in cool water. Forced
diuresis with 5% mannitol in 0.9% sodium chloride can enhance urinary excretion.
Closantel
Closantel, a salicylanide derivative and potent uncoupler of mitochondrial oxidative phosphorylation, is primarily
used as an anthelmintic against nematodes, trematodes and some arthropods in ruminants. It has also been used
in treating dogs infected with demodectic mange and ancylostoma caninum. Acute closantel intoxication has been
reported in a 13 month old dog that accidentally received 6 times the normal recommended dosage (normal
dosage is 5 mg/kg subcutanously followed by 2.5 mg/kg every week until cessation of clinical signs) [210]. Clinical
signs of intoxication included depression, blindness, bilateral mydriatic pupils unresponsive to light stimulation,
hearing deficit, pelvic limb weakness, hypotonicity, hypersalivation, emesis, diarrhea, and polydipsia/polyuria.
Fundic exam revealed markedly swollen optic disks, small papillary/peripapillary hemorrhages, and tapetal
hyperreflectivity. Biochemical serum studies revealed marked increase in liver enzymes, muscle CK, and total
bilirubin, but decrease in total protein and albumin. The results of clinical and diagnostic findings suggested optic
neuritis, myopathy, retinal degeneration, and hepatotoxicosis. Initial supportive treatment included fluid therapy,
forced feeding a semifluid diet (Canine/Feline a/d ®, Hills), and prednisolone 2 mg/kg PO bid (followed by
alternate day therapy for 1 week and progressive reduction over the ensuing 2 weeks) for the optic neuritis. In
order to bind any free closantel (the toxic fraction, since most closantel is bound to plasma proteins, and almost
exclusively to albumin), a daily intravenous infusion of 20% albumin was administered (1 ml/kg/day). The dog
responded over several weeks and biochemical values returned to normal. Three months after intoxication, the
dog appeared clinically normal, although blindness persisted. The histopathology associated with closantel
poisoning in dogs is uncertain; however, in sheep with closantel intoxication, spongiform changes are commonly
found in the brain, including optic tracts/fasciculi, and neuronal loss in the ganglion cell layer and outer layer of the
retina. The chances of chronic toxicity developing in dogs receiving closantel over several months appears to be
quite low.
Cyanogenic Plants
Seizures and semicoma, accompanied by bradycardia, pale and cyanotic mucous membranes, pulmonary
congestion, vomiting, and frequent defecation were observed in an 11-week-old puppy after consumption of
leaves and stems from the cyanogenic shrub, heavenly bamboo (Nandina domestica) [40]. Treatment was
supportive, including intubation and oxygenation, epinephrine (1:10,000, IM), prednisolone sodium succinate (100
mg, IV), furosemide (12.5 mg, IV), and ampicillin trihydrate (50 mg, SC). The following morning, the puppy
appeared normal.
Cycad Palms
Cycad palms occur in dry sandy soils of tropical and subtropical regions. Ingestion of cycads (also known as sago
palms) can result in toxicosis in animals. In a recent survey of 60 dogs with evidence of cycad ingestion,
approximately 90% of the dogs were from the southern United States, 39% ingested seeds, 95% developed liver
and gastrointestinal tract problems, and 53% had abnormal neurologic signs, including weakness, ataxia,
depression, proprioceptive deficits, coma, or seizures [41]. It is not known if the neurological signs were
secondary to liver damage or to neurotoxins. High serum bilirubin concentration and alkaline phosphatase and
alanine aminotransferase activities were the most common serum biochemical abnormalities. Although clinical
signs were observed within 1 day, laboratory values did not change for 24 to 48 hours after cycad ingestion.
Mortality rate was 32%, with the remaining dogs responding well to treatment and supportive care such as,
emesis, repeated doses of activated charcoal, fluid therapy (e.g., 5% dextrose IV), and seizure control. Sucralfate
at 0.5 - 1.0 g, PO, tid, may be used if vomiting is severe or if GI ulceration develops. Dogs ingesting seeds were
likely to develop more serious problems.
Ethylene Glycol Toxicity

Ethylene glycol (EG) is a commercial antifreeze automotive product with limited toxicity, but its metabolites,
including glycolic acid are extremely toxic to dogs and cats. In a recent report from the ASPCA National Animal
Poison Control Center, exposures were commonly (57%) from container spill, engine flush, or engine leak and
were in or around the home (66%) [42]. Interestingly, among cases with a known final outcome, 59% did not show
clinical signs and death/euthanasia was reported in 28%. In an earlier study, a mortality rate of 43% was reported
in dogs and cats [43]. As little as 1 tablespoonful of 50:50 radiator fluid can be lethal in cats, while 4.5 ounces may
be lethal in a 20-pound dog [11]. Signs of depression, vomiting, knuckling, ataxia, seizures, and coma may be
observed within a few hours of exposure. Affected animals may be hypothermic. The condition is associated with
severe metabolic acidosis, serum hyperosmolality, and eventually, renal failure with polydipsia, polyuria, calcium
oxalate monohydrate and dihydrate crystalluria, and isosthenuria [44]. Glycolic acid is metabolized to formic acid,
oxalic acid and oxalate. The oxalate combines with calcium to form oxalate crystals in renal tubules (especially
proximal), urine, and within the lumen or perivascular space of cerebral capillaries [39]. Microscopically, the
crystals appear pale yellow and there is evidence of nephrosis with attenuated epithelial cells and dilated tubules
[39]. The birefringent crystals may be found in urine after 3 hours in cats and after 5 hours in dogs. Anion gaps >
40 - 50 mEq/L may be diagnostic. A moderate hypocalcemia may be found in serum. Ultrasonographic changes
vary from mild to marked increases in renal cortical echogenicity [45]. Ethylene glycol colorimetric spot tests are
available for use with urine and serum. A test for rapid (10 min) analysis of biological fluids for EG and glycolic
acid also has recently been reported [46].
Treatment consists of administration of activated charcoal and sodium sulfate, correction of dehydration and
acidosis, and maintaining fluid therapy. Fomepizole (4-methylpyrazole), an alcohol dehydrogenase inhibitor, is
considered safe and effective for dogs if started within 8 hours of exposure [44,47]. The dose is 20 mg/kg, IV,
initially as a loading dose, followed by doses of 15, 15, and 5.0 mg/kg at 12, 24, and 36 hours. This drug is not
recommended for cats [48]. Instead, 20% ethanol (also an inhibitor of EG metabolism) is given at 5 mL/kg in
saline IV, and 5% sodium bicarbonate at 6 mL/kg IV every 6 hours for 5 treatments, then every 8 hours for 4
treatments [11]. For dogs, the ethanol dosage is 5.5 mL/kg in saline IV, together with 8 mL/kg of 5% sodium
bicarbonate, IP, each given every 4 hours for 5 treatments, then every 6 hours for 4 treatments. In cases of
severe renal failure, peritoneal dialysis and hemodialysis may be options to ameliorate the azotemia, fluid,
electrolyte, and acid-base abnormalities [49,50]. Prognosis is guarded. In one study in which EG intoxication was
confirmed in 37 dogs, 21 were azotemic or became azotemic within 18 hours after admission, and only 1 of the 21
survived [47]. However, dogs treated with Fomepizole within 8 hours of EG ingestion had a good prognosis. Note
that ultrasonographic detection of the "halo" sign (a pattern of greater than normal cortical and medullary
echogenicity with persistence of areas of lesser echo intensity at the corticomedullary junction and central
medullary regions) in anuric animals with EG intoxication was considered to warrant a grave prognosis.
5-Fluorouracil
5-Fluorouracil (5-FU) is a pyrimidine analog and an antimetabolite. It destroys rapidly dividing cells and is used to
treat many neoplastic conditions. 5-FU creams and solutions are used for topical treatment of solar and actinic
keratoses and some skin tumors in people [1,51]. In a report of 26 cases of accidental 5-FU ingestions by dogs
reviewed from phone calls to the Illinois Animal Poison Information Center from January 1, 1987 to December 31,
1988, 12 were classified as "toxicosis", 13 as "suspected toxicosis", and one as "exposure" [51]. Dogs were the
only species involved in 5-FU cases received during this time. Ingestion of more than 20 mg/kg of 5-FU was
associated with the development of toxicosis. None of the 12 dogs that ingested oral doses in excess of 43 mg/kg
(estimated) survived. Clinical signs associated with 5-FU poisoning in the dog were death, seizures, vomiting
(with and without blood), tremors, diarrhea (with and without blood), ataxia, and depression. Cardiac arrhythmias,
and respiratory depression have also been noted [51]. Clinical signs generally developed within 45 to 60 minutes
after exposure, and deaths occurred 6 to 16 h after ingestion. Hyperesthesia, hyperexcitability, nervousness,
muscle tremors, and cerebellar ataxia have also been reported in dogs and cats following intravenous 5-FU
treatment or accidental ingestion [1]. Treatment should include dermal decontamination, GI tract
decontamination/protection (e.g., sucralfate 0.5 - 1.0 gm, PO, tid), fluid therapy, anticonvulsants (e.g.,
pentobarbital sodium 3 - 15 mg/kg IV slowly to effect, or phenobarbital 3 - 30 mg/kg IV slowly to effect), and GI
protectants. It is recommended that induction of emesis or administration of activated charcoal be delayed until
seizures are controlled and the airway protected so as to avoid aspiration [51].
Griseofulvin
Griseofulvin treatment of ringworm in pregnant cats has resulted in multiple congenital malformations in kittens
[52]. Malformations of the brain included exencephaly, malformed prosencephalon, caudal displacement, and
hydrocephalus. Skeletal malformations included cranium bifidium, spina bifida (C1 through C4, and sacral),
abnormal atlantooccipital articulation, cleft palate, absence of maxillae, and lack of tail vertebrae. Cyclopia and
anophthalmia with absence of optic nerves and rudimentary optic tracts were also observed. Atresia ani, atresia
coli, lack of atrioventricular valves in the heart, and absence of external nares and soft palate were other
abnormalities present.
Hexachlorophene Toxicity
Hexachlorophene (pHisoHex ®) is used as a germicide in soaps, shampoos and disinfectant solutions. Dogs and
cats may be exposed by percutaneous absorption of hexachlorophene following skin application, or dogs may eat
soap containing hexachlorophene [53-57]. Nursing puppies have been poisoned following hexachlorophene
application to the mammary glands of the bitch [55]. Clinical signs in dogs are usually characterized by acute
onset of tremors, especially of the head, that can increase with excitement. Tremors may disappear during
inactivity or sleep. Neuromuscular twitchings, spasms, opisthotonus, severe seizures, and death have been
reported in some affected animals [56]. Irreversible visual impairment and permanent mydriasis were reported in
Beagles following dermal application of an ointment containing 3% and 10% hexachlorophene over a 12-week
period [58]. In cats, dilated pupils, vomiting, weakness, ataxia and spastic or flaccid paralysis, along with signs of
hypovolemic shock (hypothermia, pale mucous membranes, tachycardia, tachypnea, and dyspnea) have been
reported [53,59]. Significant elevations in cerebrospinal fluid pressure have been recorded in cats following
experimental hexachlorophene toxicity [59].
Grossly, mild brain edema has been reported associated with flattening of the cerebral gyri and prolapse of a
portion of the cerebellum through the foramen magnum [54,56]. Microscopically, the toxin produces spongiform
changes, seen as a vacuolar myelinopathy, in the white matter of the brain, cerebellum and spinal cord, along
with astrocytosis and microgliosis [53,56]. Comparative studies have shown that the vacuoles are associated with
intramyelinic edema with splitting of myelin sheaths at the intraperiod line [60,62]. Neuronal cell bodies appear to
be unaffected. Vacuolar lesions may also be seen in peripheral nerves [39,63]. Lesions in the CNS may regress
after exposure to hexachlorophene is stopped [63].
Prognosis is guarded. Some animals recover spontaneously within a few weeks following removal of the
exposure to hexachlorophene [55]. Paralyzed cats that have not reached the stage of severe central nervous
system depression usually recover if exposure is stopped; however, clinical recovery may take 4 to 6 weeks.
Gastric lavage or saline cathartic treatment may help animals that have ingested the toxin. In experimental
studies with cats, hexachlorophene toxicosis has been reversed by slow intravenous injection of 30% urea (2
gm/kg) in a 10% aqueous glucose solution [59]. Cats are especially sensitive to phenol intoxication because of
their inability to conjugate glucuronic acid with phenolic compounds. Since hexachlorophene is a polychlorinated
biphenol, its use in cats should be contraindicated [53]. Barbiturates reportedly are ineffective in controlling
seizures in dogs with experimental hexachlorophene toxicity [56].
5-Hydroxytryptophan
5-Hydroxytryptophan (5-HTP) is sold as an over-the-counter dietary supplement. Within target cells of the CNS,
cardiovascular system, GI tract and respiratory tract, 5-HTP is rapidly converted to serotonin. In a recent survey
involving 21 dogs with evidence of accidental 5-HTP ingestion, clinical signs of toxicosis, resembling serotonin
syndrome in humans, developed in 19 of 21 (90%) dogs. Neurologic signs included seizures, depression, tremors,
hyperesthesia, and ataxia. Gastrointestinal tract signs included vomiting or diarrhea, signs of abdominal pain, and
hypersalivation. Other clinical signs were hyperthermia and transient blindness. Three dogs died. No important
clinical laboratory or necropsy findings were reported. The doses of 5-HTP ingested ranged from 2.5 to 573 mg/kg
of body weight; the minimum toxic dose reported was 23.6 mg/kg, and the minimum lethal dose was 128 mg/kg.
Onset of signs ranged from 10 minutes to 4 hours after ingestion, and signs lasted up to 36 hours. Of 17 dogs
with clinical signs of toxicosis that received prompt and aggressive treatment, 16 recovered. Treatment consisted
of decontamination, seizure control, thermoregulation, fluid therapy, and supportive care. Cyproheptadine, a
serotonin antagonist, is also recommended at 1.1 mg/kg, PO or rectally, every 1 to 4 hours until signs resolve
[64,65].
Ivermectin
Ivermectin, approved for the prevention of canine heartworm infection (at 6 g/kg, monthly), and believed to be a
gamma-aminobutyric acid (GABA) agonist, can produce severe CNS dysfunction in some dogs. In mammals,
GABA acts as an inhibitory neurotransmitter at pre- and postsynaptic neurons within the CNS. Signs include
depression/disorientation, muscle fasciculations, ataxia, dilated pupils, drooling, rarely seizures, and coma.
Mydriasis, depressed menace response, and apparent blindness (reversible with time) may also be observed,
along with vomiting, diarrhea, hyperthermia, bradycardia, and sinus arrhythmia [1]. Collies appear idiosyncratically
sensitive to the drug [66-68], although toxicosis has been seen in other breeds [69], perhaps associated with the
blood-brain barrier acting as an ineffective ivermectin barrier [1]. Treatment is supportive, including activated
charcoal and a saline cathartic, fluids, shock doses of corticosteroids (in severely affected dogs), and picrotoxin
and physostigmine only in comatose dogs [1]. It has been reported that ivermectin and milbemycin commercial
formulations have similar margins of safety and that milbemycin toxicosis appears to be dose-dependent in
Collies with a demonstrated sensitivity to ivermectin [70].
Lead Poisoning
Accidental lead poisoning is one of the more common intoxications of dogs and cats [71-80]. It may occur from
many sources including linoleum, putty, roofing felt, golf balls, old car batteries, lead weights, ingestion of
contaminated soil, improperly glazed ceramic water bowls, and toys; however, lead-based paints are the most
frequent source of poisoning [78,81]. Lead is believed to inhibit sulfhydryl groups of essential enzymes of cellular
metabolism. One important consequence of this is inhibition of heme synthesis resulting in the circulation of
immature erythrocytes [82]. Dietary factors, such as high-fat- low-calcium diets, may facilitate absorption of lead
from the alimentary tract [83]. The majority of absorbed lead is deposited in bones, followed by liver and kidney,
brain and spinal cord [84]. Lead can disrupt the blood-brain barrier by damaging capillary endothelial cells with
resultant cerebral edema and hemorrhage. In the brain, morphological changes range from diffuse capillary
proliferation to status spongiosus and cerebral cortical necrosis. In studies of experimental lead toxicosis of dogs,
microscopic lesions were present in up to 89% of the lead-treated dogs [85,86]. Cerebrocortical lesions
comprising spongiosis, vascular hypertrophy and gliosis predominated. These lesions were bilateral, had a
predilection for gyri and were located mainly in the parietal and frontal cortex. There were bilaterally symmetrical
spongiform changes in the brain stem. The cerebellum had spongiform changes in the roof nuclei and in the
lingula there was spongiosis of the Purkinje cell layer and vacuolation of Purkinje cells. Axonal degeneration was
evident in a sciatic nerve of only one dog. While peripheral neuropathy may occur sporadically with spontaneous
lead poisoning, the inability to experimentally produce a polyneuropathy in dogs given chronic oral low level lead
in another study [87], further suggests that dogs may be resistant to the toxic neuropathic effects of lead.
Lead poisoning is more commonly reported in dogs than cats [77]. Affected animals may be of any age (e.g., from
8 weeks to 16 years). In case reports of lead toxicoses from 2 major animal poison control centers in Europe and
North America, 60% of dogs were less than 2 years old [81]. The incidence is reportedly higher in summer and
early fall [81]. Clinical signs of central nervous system dysfunction usually are preceded or accompanied by
gastrointestinal malfunction [74,78]. Signs may be acute or chronic. The most common gastrointestinal signs in
dogs and cats are vomiting, anorexia, diarrhea, and in some animals, abdominal pain. Common neurological
signs in dogs and cats include depression, generalized seizures, hysteria (barking and/or whining continuously,
aimless running and snapping at objects), ataxia, blindness, head pressing, and jaw champing. Abdominal pain
and hysteria may be more common in animals less than 1 year of age. Megaesophagus and partial laryngeal
paralysis, believed to be due to lead-associated neuropathy, have been seen in a cat [88]. Megaesophagus may
also be observed in dogs with lead poisoning. In some cats, clinical signs may be non-specific (e.g., weight loss).
Low-level lead intake in young dogs can cause an early increase in blood pressure [89].
Diagnosis is suggested by finding rubricytosis and numerous nucleated erythrocytes in a stained blood smear [90].
The presence of basophilic stippling in red blood cells, anemia, increased packed cell volume, presence of diffuse
radiopaque material in the gastrointestinal tract, and radiopaque bands in x-rays of long bone metaphyses of
young dogs [84], also supports the diagnosis (chronic low dose lead intoxication results in bone storage and
altered normal bone physiology [91]). Elevated urinary levels of delta aminolevulinic acid has been reported to
have limited value as a diagnostic aid in canine lead poisoning [75,92]. Furthermore, recent studies suggest that
theta-aminolevulinic acid dehydratase and zinc protoporphyrin were of poor predictive diagnostic value as
markers of lead intoxication in dogs [93,94]. In some animals, leukocytosis, elevated liver enzyme levels, and
increased serum concentrations of glucose and cholesterol may be found. Levels of 40 g or more of lead/100 ml
of whole blood is considered definitively diagnostic of lead poisoning [71,77]. There is no direct correlation
between severity of clinical signs and blood level content. Electroencephalographic changes reported in
nonsedated dogs were marked by intermittent high-amplitude slow wave activity [95].
Treatment with the chelating agent, calcium disodium ethylene diamine tetraacetate (EDTA), using a dose of 25
mg/kg IV, qid for 2 to 5 days, often results in rapid recovery within 36 to 48 hours. Oral administration (same
dosage) has also been effective [96]. Alternatively, oral penicillamine may be given in a dose of 100 mg/kg, daily,
for 1 to 2 weeks. Treatment is repeated over another 5-day period if signs persist. The prognosis is favorable in
the majority of lead poisoning cases treated with chelating agents [78,97]. Recent studies in dogs with naturally
acquired lead poisoning indicated that succimer (meso-2,3-dimercaptosuccinic acid), administered orally for 10
days (10 mg/kg of body weight, PO, q 8 h), also effectively reduced blood lead concentrations and eliminated
clinical signs of lead poisoning [98]. Succimer is also effective in cats [214]. Succimer may also be given rectally
as a solution in patients that are vomiting.
Levamisole
Levamisole is used as an anthelmintic, microfilaricide, and immunostimulant [1,99,100]. Clinical signs of toxicity
may be seen at approximately 4 times the normal therapeutic dose (which is 10 to 11 mg/kg), although toxicity
has been reported following a single oral dose of levamisole hydrochloride given at the rate of 12 mg/kg [101].
Levamisole is a nicotine-like ganglionic stimulant producing both muscarinic and nicotinic effects at cholinergic
receptors [1]. Clinical signs and lesions of levamisole toxicosis include: nausea, vomiting, increased salivation,
frequent urination and defecation, colic, dizziness, headache, muscle tremors, ataxia, anxiety, hyperesthesia with
irritability, clonic convulsions, depression, rapid respiration, dyspnea, cardiac arrhythmias, prostration, collapse,
hemorrhages in the subepicardium and thalamus, enteritis, hepatic degeneration and necrosis, and splenic
congestion. Most of these signs and lesions are similar to those observed in nicotine poisoning [102]. Levamisole
causes an electroencephalographic arousal and multiple foci of EEG irritation [101,102]. Treatment is largely
supportive, including GI tract decontamination, seizure control, fluid therapy, and ventilation support [1].
Mercury Poisoning
Dogs and cats are susceptible to mercury poisoning [39,103-105] a condition that has been termed Minamata
disease (methyl mercury poisoning) in people. Elemental mercury is transported in blood plasma, proteins and
hemoglobin, and may be incorporated rapidly into the brain [106]. While rarely seen in clinical practice,
methylmercury (MM) poisoning or methylmercurialism usually occurs after consumption of contaminated fish,
especially in cats [107-109] although it has also been reported in dogs [110]. Neurologic signs in dogs and cats
following oral exposure have included abnormal symmetrical use of pelvic limbs, hypermetria, ataxia, paresis,
abducted pelvic limbs, loss of postural reactions, proprioceptive impairment, blindness, opisthotonus, grand mal
convulsions and terminal recumbency [111]. Serum biochemical findings were limited to hypercholesterolemia in
dogs. Significant species difference in susceptibility to MM-induced neuronal lesions was the relative resistance of
the feline spinal cord, canine cerebellar cortex and canine peripheral nervous system. Subacute exposure
produced marked cerebral cortical involvement in dogs and cats, marked cerebellar cortical lesions, marked CNS
perivascular inflammatory cell cuffing in cats, marked leptomeningitis in dogs and moderate lesions in the brain
stem and cerebellar roof nuclei in both species. Chronic exposure of a dog to 120.4 g Hg/kg/day for 55 weeks
produced a marked loss of neurons and reactive astrocytosis in the cerebral cortex in the absence of clinical signs
of toxicity. Twice weekly exposure to 0.64 mg Hg/kg as MM for 6 to 9 weeks in 5 dogs produced milder clinical
signs, hypercholesterolemia, lipoproteinemia, and hydrocephalus. Neuronal loss and gliosis were most severe in
the cerebral cortex with minimal involvement of the brain stem. Cerebellar lesions observed in cats include focal
atrophy of the granular layer, focal spongiosus of the molecular layer and degeneration and loss of Purkinje cells
in the cerebellum [112]. Demyelination in the fiber tracts of the dorsal funiculus, mainly the fasciculus cuneatus
and in the lateral and ventral corticospinal tracts were also noted [112]. Terminal blood MM levels were in excess
of 18 g/ml, while brain methylmercury levels ranged from 21.0 to 28.4 g/g. The liver and kidney contained the
highest total levels of mercury of 50 to 80 g/g, of which 23 to 37% was inorganic [112]. Increased levels of
mercury in the brain does not necessarily result in behavior abnormalities or pathology [113]. In acute exposure to
ingested mercury salts, oral administration of milk and eggs to bind mercury to protein has been recommended
[11].
Metaldehyde
Metaldehyde toxicosis usually follows ingestion of metaldehyde-based molluscicides [2]. The incidence of
toxicosis is more common in coastal and low-lying areas. Metaldehyde is degraded to various aldehydes in the
stomach which may give a formaldehyde odor to the contents [114]. Signs include tachycardia, salivation, tremors,
vomiting, hyperesthesia, nystagmus (especially in cats), ataxia, opisthotonus and seizures, hyperthermia,
diarrhea, and depression. Death from respiratory failure may follow from 4 to 24 hours after ingestion. Delayed
deaths may follow liver failure (after 3 to 4 days). Stomach contents should be submitted in suspected poisonings.
Treatment includes activated charcoal, anticonvulsants, and fluid therapy with sodium lactate to correct the
severe acidosis that develops in poisoned animals [11].
Methionine
Methionine is an essential amino acid and nutrient, a lipotrope, and a urine acidifier [65]. It has been used as a
nutritional supplement in food animals. Accidental ingestion may lead to neurotoxicity and metabolic acidosis. The
toxicity of methionine is partially related to its metabolism to ammonia and to increased production of mercaptan-
like compounds. Toxicity is especially apparent in dogs with pre-existing liver disease. Signs include excessive
salivation and vomiting, ataxia, depression, lethargy, circling, head pressing, aimless pacing, aggression,
somnolence, blindness, seizures, stupor and coma [1]. In experimental studies, cats given DL-methionine (0.5 to
1 g/kg of body weight/day) developed severe hemolytic anemia and excessive oxidation of hemoglobin leading to
a marked increase of methemoglobin concentration and Heinz-body formation [115]. Treatment is supportive,
including emetics, activated charcoal, saline cathartic, and fluids containing bicarbonate [1].
(2-Methyl-4-chloro) Phenoxyacetic Acid
Ten hours following ingestion of an accidentally spilled herbicide that contained an octanoic acid ester of
bromoxynil (3,5-dibromo-4-hydroxybenzonitrile) and an isooctyl ester of (2-methyl-4-chloro) phenoxyacetic acid
(MCPA), an 8 year old Golden Retriever showed signs of vomiting, abdominal pain on palpation, ataxia, anorexia,
and generalized weakness [116]. Appendicular muscles were firm on palpation and persistent muscle contraction
(myotonia > 1 minute duration) was found on muscle percussion, using a reflex hammer. Electrical activity
indicative of myotonia was identified on EMG evaluation. With supportive treatment, the dog eventually recovered
from suspected MCPA toxicosis.
Metoclopramide
Metoclopramide, a derivative of para-aminobenzoic acid, has GI stimulatory and antiemetic properties, and has
been employed clinically for gastric stasis disorders, gastroesophageal reflux, vomiting, nausea, and to allow
intubation of the small intestine [117]. In the CNS, metoclopramide antagonizes dopamine at receptor sites and
also sensitizes tissues to the effects of acetylcholine. Neurotoxicity may occur at therapeutic levels with dogs and
cats showing signs of movement disorders such as slow to rapid twisting movements of the face, neck, trunk or
limbs, as well as CNS depression, nervousness, restlessness, or frenzied behavior (especially in cats) [1]. Signs
usually resolve within a few days after terminating metoclopramide medication. Diphenhydramine (2 - 4 mg/kg PO,
IM, or IV, tid) may reduce the movement disorders. Most of the sign dissapear in 2 - 3 days after stopping
medication [10].
Metronidazole
Metronidazole is used in small animals for treating giardiasis, trichomoniasis, and certain anaerobic infections. It
appears that most neurotoxicoses in dogs and cats result from long term administration, and usually at high dose
rates (e.g., exceeding 66 mg/kg/day, in dogs) [1]. In one report, five dogs receiving metronidazole at doses
ranging from 67 to 129 mg/kg of body weight per day, for 3 to 14 days, showed signs of acute neurological
dysfunction severe generalized ataxia and vertical, positional nystagmus, usually preceded by anorexia and
intermittent vomiting [118]. Increased levels of protein were noted in 2 of 3 dogs from which CSF was collected.
Two dogs were euthanatized because of severe neurological dysfunction. Three dogs slowly improved and
eventually recovered completely after several months. Axonal degeneration was seen in vestibular tracts of one
dog, while bilateral leukomalacia was found in another dog near the radix of the vestibular nerve. It was
concluded that currently recommended dosages of metronidazole for dogs were excessive, and a total daily
dosage of 30 mg/kg was recommended [118]. In another report involving a 2 year old Plott Hound-cross dog
(receiving metronidazole at 89.5 mg/kg/day for 5 weeks) with progressive ataxia, nystagmus and knuckling, who
was disoriented, had intermittent excitatory episodes, consisting of paddling, muscle spasms and vocalization,
with involuntary urination during defecation, neurological abnormalities were reversed within 2 weeks after
discontinuation of metronidazole therapy [119]. Interestingly, in a recent report from Sweden, adverse CNS signs
were associated mainly with metronidazole administration to Collies [120]. In one retrospective study involving 20
dogs with metronidazole toxicosis (ranging from 60 - 65 mg/kg over 37 - 45 days), recovery was enhanced by
administration of diazepam (the average intravenous/oral dosage was 0.43 mg/kg tid for 3 days) [212]. It was
postulated that this positive effect might result from diazepam competitively displacing metronidazole from GABA
receptors. In cats, receiving metronidazole from 58 to 222 mg/kg, daily, for up to 6 months, neurological
abnormalities seen include disorientation, ataxia, seizures, and blindness [121,122]. The neurological signs in all
cats resolved within days of initiating supportive therapy and withdrawal of the drug.
Organophosphate/Carbamate Toxicity
Organophosphate and carbamate compounds are widely employed for control of external parasites in dogs and
cats and for control of insects in the home and garden. Cats are relatively susceptible to acute toxicosis by the
organophosphate compound chlorpyrifos [123]. Toxicosis may develop following ingestion of liquid concentrates
or granules of these compounds or from excessive skin/hair coat dusting or painting [63]. Organophosphates and
carbamates are acetylcholine esterase (ChE) enzyme inhibitors: -organophosphates are irreversible inhibitors of
the enzyme, whereas carbamates are reversible inhibitors of ChE. This results in an accumulation of the
neurotransmitter acetylcholine, causing:
a. overstimulation of the parasympathetic nervous system and subsequent development of muscarinic signs,
e.g., salivation, lacrimation, urination, and defecation (SLUD), as well as pronounced gastrointestinal
sounds, bradycardia, and pupillary constriction,
b. nicotinic signs associated with skeletal muscle stimulation, e.g., muscle fasciculations, tremors, twitching,
spasms that may result in a stiff gait or rigid stance, and eventually weakness and paralysis, and
c. variable involvement of the central nervous system due to central cholinergic overstimulation (anxiety,
restlessness, hyperactivity, anorexia, and generalized seizures).
The role of various serum and liver esterases in the pathogenesis of acute organophosphate toxicosis remains to
be determined [63]. Death from asphyxia may result from severe central respiratory depression, bronchial fluid
accumulation and bronchoconstriction. Clinical signs occur usually within minutes or hours. It has been reported
that toxicity by the organophosphate compound, fenthion (Spotton®, Prospot®) usually results in a predominance
of nicotinic signs (with no muscarinic signs), including muscle tremors, muscle weakness (particularly the neck
muscles), and collapse after exercise [124]. In experimental intoxication with dichlorvos, muscle hemorrhage and
necrosis was noted and was believed to be secondary to continual muscle fasciculations/contractions and
possibly to the metabolic disturbances (metabolic acidosis and tissue hypoxia) produced in muscle as a result of
ChE inhibition [125]. The myopathy associated with organophosphate toxicosis seems to be associated with
excessive entry of calcium ions into muscle cells [126]. In a clinical report, acute polymyopathy in a 7 year old
German Shepherd dog was attributed to the muscular hypertonia, tremors and seizures which developed during
the acute phase of carbamate poisoning [127]. After two days of generalized muscular rigidity, the dog adopted a
characteristic fetal position thought to be explained by the imbalance between the injuries to the extensor and
flexor muscles. The polymyopathy, the diagnosis of which was based on EMG findings, myoglobinuria, and
elevated serum muscle enzymes (muscle biopsy was normal), resolved gradually over the course of a week. A
delayed neurotoxicity may occur in cats days or weeks after minimal exposure to organophosphates. In an
experimental study, cats developed clinical signs of delayed neurotoxicity 16 to 18 days after di-
isopropylfluorophosphate injection [128]. A histologic survey of the central and peripheral nervous systems
revealed that the topographic distribution of axonal degeneration was characteristic of a dying-back neuropathy.
In teased- fiber preparations from the left recurrent laryngeal nerve, the axonal degeneration that was initially
focal and nonterminal subsequently spread in a somatofugal direction to involve the entire distal axon. Nerve fiber
varicosities and paranodal demyelination preceded the axonal degeneration. The varicosities were associated
ultrastructurally with intra-axonal and/or intramyelinic vacuoles, along with accumulations of axonal agranular
reticulum [129]. Neurotoxic esterase is considered to be the target enzyme in the production of
organophosphorus-induced delayed neurotoxicity (OPIDN) [130,131]. Affected animals manifest signs of a
neuropathic syndrome. Dogs appear to be relatively resistant to delayed neurotoxicity [132]. Clinical signs
associated with carbamate toxicity are likely to be less severe and shorter in duration [63]. ChE activity in
domestic animals has been recommended as a potential biomonitor for nerve agent and other organophosphate
exposure [133]. In this regard, it should be noted that physostigmine is a reversible ChE inhibitor and has a short
duration of action. It crosses the blood-brain barrier readily; hence, it is a centrally acting carbamate. Pretreatment
with physostigmine rapidly improves the incapacitating effects of organophosphate intoxication in various animal
species [134]. Physostigmine carbamylates to a portion of ChE enzyme and thus protects the enzyme from
irreversible binding with organophosphate.
Diagnosis is suggested by historical data, clinical signs and response to therapy. Whole blood cholinesterase
levels can be determined using several substrates, including acetyl-, butyryl- and propionylthiocholine [217]. Red
blood cell ChE levels reduced by 25% or more will confirm exposure [11]. At post mortem examination, brain
tissue submitted for ChE activity is the most definitive diagnostic measure available for lethal organophosphate
toxicosis [123]. Atropine, a muscarinic cholinolytic agent, at a dosage of 0.2 to 0.4 mg/kg body weight, IV, slowly
over 5 minutes, usually results in a dramatic cessation of muscarinic signs within 3 to 5 minutes. Repeated
administration of atropine, SC or IV, at lower dosages is often required, especially in cats. Atropine blocks the
effects of accumulated acetylcholine at muscarinic parasympathetic nerve endings. However, it does not affect
the skeletal muscle (nicotinic) signs. Repeated doses of atropine can be given using one-half the initial dose.
Overatropinization can cause tacchyarrhythmias, pyrexia, behavioral excitation and signs of delirium. Additionally,
a ChE-reactivating oxime, such as pralidoxime chloride (2-PAM, Protopam Chloride) may be used to counter the
nicotinic cholinergic signs. This compound acts by forming a relatively non-toxic complex with the
organophosphate compound that can be excreted in urine, and also reactivates acetylcholine esterase. 2-PAM
works best in the presence of atropine, the dose of which may be reduced when 2-PAM is used (e.g., 0.04 to 0.4
mg/kg once, or as needed). The dose of 2-PAM (given as a 10% solution) is 10 to 20 mg/kg for cats and 40 mg/kg
for dogs, given IV slowly, or with fluids over a 30 minute period [11]. Signs of muscle weakness and fasciculations
usually disappear within 30 minutes. If signs remain, repeat the dosage within an hour and then give every 8
hours, for 24 to 48 hours, or until recovery. Treatment with 2-PAM should begin within 24 to 48 hours and this
agent may be especially beneficial in animals exposed to fenthion and chlorpyrifos with their slow rate of
elimination [11]. The dose can be reduced in animals that are severely depressed, weak and anorectic one or
more days after exposure. Oximes are of not benefit in treating carbamate toxicosis and may worsen the animal's
condition. Orally administered activated charcoal in cats and dogs (0.5 to 4.0 gm/kg), in combination with a saline
cathartic (e.g., 70% sorbitol), will help reduce absorption following ingestion of organophosphate/carbamate
compounds. Seizures in cats and dogs may be controlled using diazepam (2.5 to 5.0 mg/kg IV as needed) or a
barbiturate such as phenobarbital (10 to 20 mg/kg IV as needed). Supportive care is very important, especially in
cats, and includes monitoring for hypo- and hyperthermia, oral or parenteral potassium supplementation if
hypokalemia is detected, and parenteral fluid, electrolyte and nutritional support (e.g., hand-feeding, tube-feeding,
or use of pharyngostomy tubes) [123]. Such care may extend over several weeks.
Diphenhydramine (Benadryl®) may be effective in treating organophosphate-induced neuromuscular weakness in
dogs and cats, that is refractory to other forms of therapy [135,136]. Initial treatment should be initiated IV or IM
(IM only in cats) at 4 mg/kg every 4 to 6 hours until clinical improvement occurs, followed by oral treatment at 4
mg/kg, tid. Diphenhydramine blocks the nicotinic and muscarinic effects of compounds such as fenthion
(Spotton®). Experimental studies have shown that early and prolonged treatment using a high-dose regimen of
methylprednisolone prevented the development of OPIDN in cats [137].
Variations in clinical presentations may occur with organophosphate compounds. In one report, two cats with
chronic exposure (3 weeks) to chlorpyrifos (Dursban®), an organophosphate available as a soil insecticide and a
parasiticide for use on cattle, presented with paraparesis, generalized hyperesthesia, anorexia, depressed
postural reactions and bilaterally dilated pupils that were partially responsive to light stimulation [138]. It was
considered that both cats lacked muscarinic signs but showed evidence of nicotinic and central nervous system
stimulation. Serum ChE activity was low in both cats and electromyographic studies revealed presence of
fibrillation potentials and high frequency discharges, especially in more distal muscles of the pelvic limbs.
Administration of 2-PAM, 20 mg/kg, IV, bid, for 5 or 6 treatments, as well as atropine sulfate, 0.05 mg/kg, SC,
every 6 hours for 2 days, resulted in complete clinical recovery. Interestingly, diazepam induced signs of acute
organophosphate toxicity (miotic pupils, hypersalivation, generalized muscle fasciculations, and depression) in
both cats - the mechanism of action was not determined.
Pemoline
Extreme agitation, hyperactivity, and vomiting that began within 24 hours after ingestion of approximately 750 mg
of pemoline, a CNS stimulant used in humans for treating attention deficit-hyperactivity disorder in adolescents,
was reported in a 3 year old German Shorthaired Pointer [139]. The dog was tachycardic, hyper-responsive,
pyrectic, disoriented, and had mydriasis. These signs were consistent with excessive stimulation of the CNS and
sympathomimetic effects resulting from pemoline toxicosis. Plasma pemoline concentration was markedly
elevated (32 hours after ingestion the plasma concentration was 368 g/ml, compared with a therapeutic
concentration of 1.7 to 7.0 g/ml reported for children). Several sedatives were administered intravenously to
alleviate clinical signs and to allow administration of activated charcoal and fluids. Clinical signs resolved
approximately 72 hours after ingestion of pemoline.
Pyrethrin and Pyrethroid Insecticides

These compounds are used as parasiticides and formulated for use in dogs and cats as shampoos and dips.
Pyrethrins are natural insecticides while pyrethroids (e.g., permethrin and fenvalerate) are synthetic compounds
and classified as type I (no alpha cyano-3-phenoxybenzyl group) or type II (with alpha cyano-3-phenoxybenzyl
group) [2,140]. These insecticides are thought to interfere with sodium channels (type I pyrethroids and
pyrethrins), enhance sodium ion conductance, and block post-synaptic GABA-A receptor-chloride ionophore
complexes (type II pyrethroids). Cats may be more susceptible to pyrethrin/pyrethroid poisoning than dogs [11].
Signs of toxicosis may occur within hours of exposure (but may be delayed) and include tremors, salivation,
ataxia, vomiting, depression, hyperexcitability, hyperactivity, seizures, dyspnea, and death [2]. Treatment is
symptomatic and supportive, including dermal decontamination, emesis induction within 1 hour (e.g.,
apomorphine at 0.03 mg/kg IV or 0.04 mg/kg IM), activated charcoal (2 g/kg, qid), magnesium sulfate or sodium
sulfate (0.5 g/kg PO as a 10% solution in water), anticonvulsants, oxygenation (if necessary), and fluid therapy.
The syndrome is generally reversible, with most animals recovering within 72 hours [33].
Strychnine Poisoning
Strychnine is a rodenticide poison used for "control" of squirrels, gophers, rabbits and other wild carnivora [63].
Dogs, and infrequently cats, become poisoned when they eat strychnine baits, especially in rural areas, although
dogs also may be poisoned maliciously in rural and urban areas [63,141-144]. In one report on 261 cases of
strychnine poisoning in dogs in Canada [145], strychnine poisoning occurred more often in younger dogs, with
61% of the cases being in animals less than 2 years old. Large breeds of dogs and male dogs were affected more
often. In this study, the German Shepherd was the most common breed of dog affected.
Strychnine acts at the brainstem and spinal cord level by stereochemically and competitively blocking the motor
inhibitory neurotransmitter, glycine. Some supraspinal signs may also be associated with strychnine inhibition of
gamma-aminobutyric acid (GABA). Clinical signs of poisoning are induced by uncontrolled impulses reaching
skeletal muscles and are characterized by retraction of the corners of the mouth, drawing together of the ears,
stiffness of muscles of the neck, chest and abdomen, stiffness of gait and assumption of a "sawhorse" stance
followed by tonic extension of the limbs, opisthotonus, vocalization, and difficult respiration. Affected animals are
hypersensitive to auditory, visual (e.g., bright light), and tactile stimuli [11]. Consciousness is not lost during initial
"seizural" attacks. After several minutes, the attack(s) may subside only to be followed by further episodes.
Eventually, the respiratory muscles may be unable to function. Apnea can lead to cerebral anoxia, loss of
consciousness and death. The entire course may last from 30 minutes to 1 to 2 hours, if the animal is untreated.
Atypical signs, including absence of seizures or tetanic spasms, and time course (e.g., 10 hours) have been
reported in dogs [216].
A presumptive diagnosis is based on a history of ingestion and characteristic clinical signs. In one report,
chemical analysis of tissues and ingesta containing strychnine indicated that the highest concentrations were in
stomach contents, followed by the liver, and the kidney [145]. Vomitus and urine can also be screened. The
dimethoxy derivative of strychnine, brucine (2,3-dimethoxystrychnidin-10-one), may be detected in serum [216].
Prognosis is guarded, depending on the amount of poison ingested and/or promptness of treatment. The main
objectives of treatment are to keep the muscles relaxed and to prevent asphyxia. The drug of choice in dogs has
been pentobarbital, at 30 mg/kg, IV (or via intraperitoneal or intrathoracic routes if the animal is difficult to manage
or is having seizures). Thiobarbiturates, such as thiopental sodium or thiamylal sodium, given IV to effect, are
recommended for cats. Muscle relaxants recommended include glyceryl guaiacolate ether given in an intravenous
dose of 110 mg/kg in either a 5 or 33 1/3% solution [146]. This drug controls "seizures" for up to 60 minutes. It
can be safely repeated as needed. Methocarbamol (Robaxin®) also can be used, at a dose of 150 mg/kg IV, and
repeated as needed. Supportive treatment includes prompt gastric or enterogastric lavage using 1 to 2% tannic
acid or 1:2000 potassium permanganate and enemas, followed by administration of activated charcoal. Forced
diuresis with 5% mannitol in isotonic saline and acidification of urine with 150 mg/kg body weight of ammonium
chloride PO, will enhance urinary elimination of strychnine.
If the animal survives 24 hours, prognosis for complete recovery is very good. The clinical signs and necropsy
findings closely resemble plastic explosive type 4 (PE4 containing cyclonite) toxicity [147]. Roquefortine (a
diketopiperazine alkaloidal tremorgenic mycotoxin) and strychnine poisoning may be difficult to differentiate
clinically [148].
Tetanus
Tetanus is a bacterial disease caused by Clostridium tetani that can affect all domestic animals and people.
Disease occurs as a result of localization of tetanus spores in an anaerobic environment, such as a necrotic
wound with suppuration, with conversion to a vegetative, toxin-producing form. Infection most frequently occurs
following an injury, but may also develop after surgical procedures, such as ovariohysterectomy [149-152].
Organisms produce the exotoxin tetanospasmin within 4 to 8 hours, which travels via peripheral nerves (alpha
motor neurons) to the CNS [153]. A trans-synaptic migration of tetanus toxin occurs in spinal cord motor neurons.
Small amounts of toxin may be spread hematogenously to the CNS. Tetanus neurotoxin appears to prevent
synaptic vesicles from fusing with the cell membrane and prevents the release of neurotransmitters [154,155]. It is
active at the neuromuscular junction, autonomic terminals, and in inhibitory neurons in the CNS, with the central
effects usually predominating the clinical picture. Toxin causes disinhibition on gray matter gangliosides [106] and
binds the release of inhibitory neurotransmitters from interneurons (glycine) and from descending upper motor
neuron pathways (gamma aminobutyric acid) resulting in release of spinal cord and brainstem motor neurons
from inhibition and subsequent hyperexcitability [156,157]. In people, at high concentrations, tetanus toxin acts
like botulism toxin in that it inhibits the release of acetylcholine at cholinergic synapses [106].
Considerable species differences exist in susceptibility to tetanus. The dog is much less susceptible than the
horse, and tetanus is seen less commonly in cats than in dogs. Clinical signs usually are observed within 4 to 12
days of infection [158-162], although extensor rigidity and ptyalism were observed in one dog 3 weeks after a
routine ovariohysterectomy [151]. Frequently seen signs include stiffness of gait with extensor rigidity in all limbs,
dyspnea, and spasms of the masticatory and pharyngeal muscles resulting in trismus and dysphagia. The tail
may be elevated, facial muscles may be contracted to give a sneering expression ("risus sardonicus") with
wrinkling of the forehead and puckering of the skin around the eyes, and the third eyelid may be protruded.
Earflaps are usually held in an erect fashion, although low carriage has been noted early in the condition in some
animals [163]. Animals may assume a "sawhorse" stance. In severe disease, the animal may be recumbent and
opisthotonic. Affected animals are hypersensitive to external stimuli and reflex muscle spasms may occur.
Autonomic involvement, such as bradyarrhythmias [164], or tachycardia/tacchyarrhythmias [165], may result from
increased vagal tone or adrenergic stimulation, respectively. Death results from respiratory failure.
Localized tetanus may also be seen in dogs and cats with a localized limb injury and is usually characterized by
stiffness in one limb before gradually spreading to involve the opposite limb and eventually, the entire body [162].
Tetanus in cats and dogs may remain localized to one of the thoracic limbs, which is held in rigid extension and
caudally deflected (elbow extension and carpal flexion or extension) due to continuous involuntary muscle
spasms [166,167]. Intermittent spasms may be superimposed upon the tonic rigidity. In one of the affected cats,
the neck became twisted to the side [166]. The affected limb does not appear to be painful. Localization to both
thoracic limbs, along with mild trismus and forehead wrinking, has been seen in one affected cat [213].
Potential complications include bony fractures from spasms or seizures, dyspnea from laryngeal spasms,
inhalation pneumonia from dysphagia, and decubital ulcers. Urinary and fecal retention may be associated with
anal and urethral sphincter/bladder spasms. In such instances, urinary stasis may lead to hemorrhagic, purulent
cystitis [168,169]. Gastric and intestinal bloating may also occur [169]. Transient megaesophagus and/or hiatal
hernia have been reported in association with gastro-esophageal reflux and regurgitation [170,171]. It has been
reported that the hiatal hernia developed approximately 2 weeks after the beginning of clinical signs of tetanus
[171,172]. Tetanus has been reported as a complication in dogs during parturition [173] and pregnancy [174].
To my knowledge, structural changes in the CNS or PNS have not been reported in dogs or cats. In people,
degenerative changes may be found in the cerebral cortex and brainstem, along with hemorrhage, demyelination,
and gliosis in chronic cases [106]. Diagnosis of the severe form of tetanus is largely based on characteristic
clinical data. Mild forms of the disease may be difficult to diagnose since there are no specific ancillary aids
available. There is a lack of the usually observed electrical silence following needle insertion in electromyographic
studies. Nerve conduction studies are normal. Megaesophagus and/or hiatal hernia in animals with tetanus can
be diagnosed radiographically [170].
Since tetanus is often mild or localized in dogs and cats, prognosis is usually favorable with treatment, which
consists of penicillin G (e.g., 20,000 to 100,000 units/kg, qid, IV, as the aqueous potassium or sodium salt or IM,
as the procaine salt), and immediate administration of tetanus antitoxin (TAT) (e.g., 100 to 1,000 IU/kg IV) [160].
Antibiotic therapy is aimed at any remaining vegetative C. tetani organisms in the wound, while the antitoxin is
given to neutralize any toxin that remains unbound to the CNS. A test dose (e.g., 0.1 - 0.2 ml) of TAT can be
given SC 20 minutes prior to the intravenous dosage and the animal observed for any anaphylactic reaction. If a
wound is present, radical debridement and excision of all infected or necrotic-appearing tissue should be
performed, along with peroxide irrigation to reverse the anaerobic state, and local intramuscular instillation of
1,000 units of TAT and 1,000,000 units of procaine penicillin G, in and around the wound site. Metronidazole is
also effective (at 10 mg/kg, PO, tid, in dogs, and at 250 mg, PO, sid or bid, in cats). Antibiotic therapy should be
continued for at least 10 days. Chlorpromazine (e.g., 0.5 - 2.0 mg/kg IM, IV, or PO, bid or tid, in dogs and cats)
and pentobarbital (e.g., 3 - 15 mg/kg, IV or IM, every 2 - 3 hours, in dogs and cats) can be used to control reflex
spasms and convulsions. Tracheostomy may be needed if laryngeal spasms are severe [22]. Esophagostomy or
gastrostomy tubes or gastric tube feeding may be necessary if trismus prevents feeding or if megaesophagus
and/or hiatal hernia are present along with gastro-esophageal reflux and regurgitation [22,171].
Prompt treatment usually results in a favorable prognosis [150,161,171], although complete remission of clinical
signs in dogs and cats with generalized or localized tetanus may take 3 to 5 months [166]. A guarded to poor
prognosis has also been reported in severely affected animals [22,169]. Megaesophagus and/or hiatal hernia tend
to resolve with resolution of the tetanus [170], although, in one report, all dogs with this complication that were fed
normally, died [171]. Nursing care is important to monitor nutritional and fluid balance.
Thallium
Thallium poisoning, from ingestion of thallium-containing rodenticides, may produce vomiting, bloody diarrhea,
salivation, anorexia, depression, paralysis, trembling, dyspnea, and death in 3 - 5 days [175]. Degenerative
changes have been observed in peripheral nerves [176]. Today, thallium toxicosis is relatively rare as
rodenticides containing it are banned in the USA. Thallium toxicosis can be confirmed by detection of thallium in
the urine, using colorimetric analysis. Treatment involves use of diphenylthiocarbazone (dithizone) to increase the
rate of thallium excretion from the body, administration of antibiotics, fluid therapy, warm-water enemas, and oral
administration of activated charcoal slurries [177,178].
Tick Paralysis
This is a flaccid, afebrile ascending motor paralysis in animals and people, produced by a neurotoxin generated
by some but not all strains of certain species of ticks. Not all infested animals become paralyzed. Cats in the U.S.
appear to be relatively resistant to tick paralysis, although signs of paralysis have been reported [179]. In North
America, the common wood tick, Dermacentor variabilis, and Dermacentor andersoni (the Rocky Mountain wood
tick) are incriminated most often. In Australia, especially along the east coast, Ixodes holocyclus is the most
important species. Other species that occasionally cause paralysis are Ixodes cornuatus and Ixodes hirsti. Ixodes
scapularis, the principal vector of the agent of Lyme disease (Borrelia burgdorferi) in the Northeast, Midwest, and
Southeast of the United States, can also cause tick paralysis in dogs [180]. This tick is also a primary vector of the
agent of human and rodent babesiosis. Ixodes pacificus has also been incriminated in dogs in the Grass Valley
area (Nevada Co.) of northern California [181,182]. In Australia, Ixodes holocyclus is the vector for Lyme disease
and spotted fever, caused by Rickettsia australis [183]. There is circumstantial evidence that some dogs bitten by
Ixodes holocyclus develop signs of chronic illness similar to Lyme disease [183]. With tick paralysis, adult ticks,
especially females, produce a salivary neurotoxin that circulates in the host animal and interferes with
acetylcholine liberation at the neuromuscular junction and/or impulse propagation along motor axon terminals. In
Australia, heavy infestations with nymphs or larvae may result in paralysis [184].
Onset of clinical signs is gradual, paralysis first becoming evident as an incoordination in the pelvic limbs,
resulting in an unsteady gait. Altered voice, cough, and dysphagia can be early signs. Dogs become recumbent in
24 to 72 hours. Reflexes are lost but sensation is preserved. Jaw muscle weakness and facial paresis may be
present. Death may occur within several days from respiratory paralysis. Electromyographic studies reveal
absence of spontaneous potentials and lack of motor unit action potentials. No muscle response follows direct
nerve stimulation. Motor and sensory nerve conduction velocity may be slower that normal. Prognosis is usually
good with recovery occurring in 1 to 3 days following tick removal or dipping the animal in an insecticide solution.
Administration of a systemic insecticide (e.g., cythioate, 3 - 6 mg/kg, PO) can be used to kill any hidden ticks on
dogs. Assisted ventilation is necessary in cases with respiratory failure.
In Australia, tick paralysis is a far more serious and life-threatening condition [185-188]. Central effects include
sympathetic stimulation that can produce peripheral vasoconstriction, arterial hypertension, increased pulmonary
capillary hydrostatic pressure, pulmonary congestion and edema, tachyarrhythmias, and pupillary dilation.
Respiratory embarrassment, in addition to diaphragmatic and intercostal paralysis, may stem from intoxication of
medullary respiratory centers. Furthermore, hypoxia, hypercarbia, and respiratory acidosis may accompany
respiratory failure. Clinical signs usually begin with pelvic limb weakness that progresses to paralysis within a few
hours. Ascending paralysis soon involves the forelimbs. Mydriatic pupils are poorly or unresponsive to light. Other
signs may include voice change, depressed gag reflex, megaesophagus, salivation, regurgitation and/or vomition,
labored breathing, dyspnea, and cyanosis. Death occurs within 1 to 2 days if dogs are untreated. Similar signs are
seen in cats with tick paralysis due to Ixodes sp. Focal forms of tick paralysis, such as asymmetrical facial
paralysis and anisocoria, have been seen in some dogs, while others may only present with vomiting and loss of
voice [184,189]. Short-term, acquired humoral immunity develops in animals following exposure to the toxin.
Treatment involves removal of ticks, neutralization of circulating toxins, and supportive therapy. Painting ticks with
pyrethroids and leaving the tick to die in situ may reduce mortality and analphylactoid reactions in sensitized
patients [190]. Intravenous polyclonal hyperimmune serum (e.g., 0.5 - 1.0 ml/kg, IV) is suggested for dogs. For
affected cats, administration of hydrocortisone (30 mg/kg, IV) followed by slow intravenous injection of serum (5 -
10 ml) is recommended [184]. This antiserum treatment is expensive and effective only in the early stages of
paralysis [191]. In a recent survey from Australia, adverse reactions following tick antitoxin serum were reported in
3% of dogs and 6% of cats, with only a small percentage of these reactions associated with anaphylaxis [192].
The majority of adverse reaction were attributed to the Bezold-Jarisch reflex, a vagally mediated reflex initiated by
chemical stimulation of cardiac receptors in the posterior wall of the left ventricle. Bradycardia, hypotension,
reduction in total peripheral resistance and a slight reduction in myocardial contractility occurs with activation of
these receptors [192]. A 1:1,000 solution of epinephrine should be available if animals show signs of anaphylaxis.
Recommended dosage is 0.01 ml/kg IV or IM up to a maximum of 0.2 - 0.5 ml; repeat every 15 to 20 minutes if
needed [192]. Due to the cholinergic nature of the Bezold-Jarisch reflex, atropine (at 0.1 - 0.2 mg/kg IV) will
attenuate or abolish its clinical manifestations. A combination of phenoxybenzamine hydrochloride (e.g., 1 mg/kg
as a 0.1% solution, given IV, over 15 minutes, every 12 to 24 hours) and acepromazine (0.05 - 0.10 mg/kg, IV,
every 6 to 12 hours) produces sedation, helps relieve the respiratory distress, and resolves any cardiac
arrhythmias [184,193]. Phenoxybenzamine hydrochloride, an alpha-adrenergic blocking drug, is thought to
attenuate the arterial hypertension [188,193]. Some severely affected animals may require supplemental oxygen
or intermittent positive pressure ventilation. Affected animals should be kept in a quiet, air-conditioned
environment [184]. Food and water should be withheld until animals are walking and have not vomited for 24
hours. Weekly dips, use of collars impregnated with insecticide (e.g. permethrin) [190], or regular use of the
organophosphate agent cythioate (3 mg/kg, PO, every 3 days) will help prevent tick paralysis in Australia. In a
recent report from Australia, a correlation was noted between use of Lufenuron (a member of the
benzoylphenylurea group of compounds used in dogs and cats for flea control) and lack of
envenomation/paralysis caused by Ixodes holocyclus [194]. Despite treatment, prognosis can be guarded with
this form of tick paralysis. In a recent survey of 577 dogs affected by tick paralysis, younger dogs were more likely
to survive, and respiratory and gait scores reflected disease severity and were good prognostic indicators, in that
dogs with mild disease recovered more quickly, whereas those with severe disease that received an additional
dose of tick antitoxin serum were significantly less likely to survive [195].
Sensitive biological assays of toxin/antitoxin potency have been developed to assist in research on
characterization of salivary toxins of the Australian paralysis tick Ixodes holocyclus and on immunity to tick
paralysis [196]. The aim of current research is to develop a recombinant veterinary vaccine based on the tick
neurotoxin peptide sequence. A successful vaccine would provide cost-effective, long-term protective immunity
against tick-induced paralysis [191].
Toad Toxicity
This condition occurs in animals that bite or mouth various species of toads that contain bufotoxins within their
parotid glands. Toxic species include the Colorado River toad (Bufo alvarius) and the marine toad (Bufo marinus).
Toxicity is common in dogs in Florida and in Australia, especially in Queensland, where there is a seasonal
incidence, primarily from September/October through April [197]. In one report from Florida, most dogs were
treated during the spring and summer [198]. Toads tend to breed during the warmer and wetter months and
hibernate during the colder and dryer months. Terrier breeds are commonly affected associated with their
inquisitive nature and their tendencies to pursue hopping toads [197]. Cats are infrequently reported. Clinical
signs develop within minutes of mouthing the toad and include profuse salivation, head shaking, ataxia, vomiting,
polypnea, hemorrhagic diarrhea, and seizures in severe cases. Some dogs are presented in status epilepticus.
Other neurological signs may include stupor, nystagmus, extensor rigidity, and opisthotonus [198]. Common EKG
findings with Bufo Marinus include sinus arrhythmia, tachycardia, and occasionally ventricular fibrillation [198,199].
Abnormal cardiac depolarization and arrhythmias have been experimentally shown using resibufogenin and
bufalin from toad venom [200]. Bufalin, from the Bufo marinus toad, is structurally and functionally similar to
digitalis glycosides [201]. Death may occur within 30 minutes. Treatment involves washing the buccal mucosa
with a swab or hose to dilute the toxin, intravenous diazepam (e.g., 0.25 to 1 mg/kg, IV), intravenous atropine
(e.g., 0.04 mg/kg) and, if required, intravenous pentobarbital (e.g., 2.5 to 7.5 mg/kg, IV). Propranolol (e.g., 1.5 to
5.0 mg/kg, IV, rapidly, followed by a repeat dose in 20 minutes, for dogs and cats) is recommended, especially if
ventricular fibrillation develops [199]. Prognosis will depend on the potency of the toxin, quantity absorbed, and
size of the patient. It is usually favorable when animals are treated promptly [198], but may be guarded once
seizures are seen [197].
Toluene/Dichlorophen
Toluene/dichlorophen anthelmintics (effective against ascarids, hookworms, and some tapeworms of dogs and
cats) may cause adverse effects in healthy cats and dogs following oral administration of less than 1.5 times the
recommended product dose [202]. Clinical signs usually are observed within 6 hours of dosing and include ataxia,
aberrant behavior, mydriasis, vomiting, depression, muscle tremor, and hypersalivation. In this report, the four
most common products associated with toxicosis in cats were Daltrek Tri-Wormer, De-Vos Control III Worm Caps,
Zema Pulvex Multi-Purpose Worm Caps, and Vermiplex. In dogs, commonly involved products were Happy
Jack's Trivermicide Worm Capsule, Farnam Triple Wormer, Zema Pulvex Multi-Purpose Worm Caps, Anchor
Canine Wormer, and Performer Brand Dog Wormer. In most cases, clinical signs disappear within a few hours to
a day with general supportive care.
Tricyclic Antidepressants
Tricyclic antidepressants (TCAs), a class of psychotherapeutic medications, are widely prescribed for human
patients, thereby increasing the potential for accidental oral ingestion by companion animals [203]. Animals
ingesting TCA in an amount exceeding 15 mg/kg are in grave danger. TCAs block re-uptake of biogenic amines
(e.g., epinephrine), have anticholinergic (atropine-like) effects, and quinidine-like action on the cardiovascular
system. Clinical signs in animals include hyperexcitement and vomiting followed by ataxia, lethargy, and muscular
tremors. Bradycardia and cardiac arrhythmias should be anticipated in the later stages of the TCA toxic syndrome
[203]. In a review of over 450 cases reported to the Illinois Animal Poison Information Center between 1985 and
1989, more than 7% of affected animals eventually died [203]. Initial therapy includes intubation, oxygen
administration, enterogastric lavage, and activated charcoal via a stomach tube. Animals in a hyperactive state
should receive diazepam (0.5 mg/kg IV or IM, repeated as needed, every 10 minutes for three doses), followed by
activated charcoal (2 gm/kg, every 3 - 4 hours, PO) and a suitable cathartic, such as sorbitol (0.5 gm/kg, PO) or
sodium sulfate (Glauber’s salts) at 0.25 gm/kg, PO. Magnesium sulfate (Epsom salts) is not recommended
because of the TCS-induced decrease in GI motility. Intravenous sodium bicarbonate at 2 - 3 mEq/kg, over 15 -
30 minutes, should be given if acidosis, hypotension, tachycardia, or other cardiac abnormalities are noted. Blood
pH should be maintained above 7.5.
Vincristine
Vincristine is a vinca alkaloid widely utilized in cancer chemotherapy. Its major clinical limitation is due to a drug
induced sensory-motor neuropathy, the pathogenesis of which is poorly understood. In cats with experimental
vincristine neuropathy, major pathological lesions were focal axonal swellings (giant axon formations) due to
malaligned accumulations of neurofilaments and secondary paranodal demyelination [204]. These were primarily
confined to the proximal portions of the peripheral nerves. Wallerian degeneration involved a small number of
nerve fibers in the distal regions. Muscle spindles were affected and motor nerve conduction velocities were
reduced by 30% [205]. We reported a vincristine-induced peripheral neuropathy in a 12 year old, female, Golden
Retriever that received 16 weekly doses of vincristine (0.5 mg/m2) as part of a regimen for treatment of mycosis
fungoides [206]. The dog was presented for sudden onset of a shuffling pelvic limb gait, intermittent collapse, and
difficulty negotiating turns and stairs. Neurological examination revealed mild ataxia in the pelvic limbs, depressed
pelvic limb postural reactions, and depressed patellar and pelvic limb withdrawal reflexes. Electromyographic
testing revealed fibrillation potentials and positive sharp waves consistent with denervation. Sciatic motor nerve
conduction velocity was decreased. Evoked muscle potentials were polyphasic and had reduced amplitude and
prolonged duration. Severe nerve fiber degeneration, nerve fiber loss, and endoneurial fibrosis were seen in a
nerve biopsy sample. The neuropathy improved after vincristine was discontinued. Results of a repeat nerve
biopsy taken 10 weeks after cessation of vincristine administration showed fewer degenerating nerve fibers and
presence of demyelination-remyelination. The dog appeared neurologically normal at this time. In people,
vincristine-induced neurotoxicity is aggravated by itraconazole [207,208].
Zolpidem
Zolpidem is a nonbenzodiazepine hypnotic and sedative of the imidazopyridine class used for treating short-term
insomnia in humans. The drug increases the frequency of chloride channel opening and inhibits neuronal
excitation. A retrospective review of zolpidem ingestion in 33 dogs that were reported to the ASPCA Animal
Poison Control Center between January 1998 and July 2000 revealed that ingested dosages ranged from 0.24 to
21 mg/kg [211]. Clinical signs reported included ataxia, hyperactivity, vomiting, lethargy, panting, disorientation,
nonspecific behavior disorder, hypersalivation, tachycardia, tremors, apprehension, vocalization, weakness, and
hyperesthesia. In most instances, clinical signs developed within 1 hour and typically resolved within 12 hours.
Treatment includes induction of emesis within the first 1 to 2 hours (or gastric lavage), use of activated charcoal in
conjunction with a catharctic, such as sorbitol, and fluid administration. Note that supportive treatment (e.g.,
phenothiazines or barbiturates) may be used to treat signs of stimulation and hyperactivity; however, the use of
diazepam or other benzodiazepines should be avoided.
Nutritional Disorders
K. G. Braund
Several nutritional disorders involving selective deficiency or excess of one or more essential dietary ingredients
may have neurological implications in dogs and cats. In most instances, these essential dietary ingredients
involve vitamins. Complications may arise in precise diagnosis in some cases due to possible multiple
deficiencies co-existing in patients in association with conditions such as malnutrition and malabsorption disorders.
The following nutritional disorders involving the CNS will be discussed:
Cobalamin Deficiency
Hypervitaminosis A
Nutritional Secondary Hyperparathyroidism
Thiamine Deficiency
Vitamin E Deficiency
Cobalamin Deficiency
Cobalamin (vitamin B12) is an essential cofactor for two enzyme systems (a) folate-dependent methionine
synthetase activity, which is required for nucleic acid synthesis and for normal development, growth, and
hematopoiesis. This cytosolic enzyme catalyzes the conversion of homocysteine and methyltetrahydrofolate to
produce methionine and tetrahydrofolate; methionine is further metabolized to S-adenosylmethionine, a substrate
necessary for methylation of myelin sheath proteins and phospholipids. (b) Methylmalonyl CoA mutase, which
uses adenosylcobalamin for the degradation of proprionate through methylmalonyl CoA to succinate in
mitochondria [1,2]. Selective cobalamin malabsorption associated with chronic inappetance, lethargy, cachexia,
and failure to thrive has been reported in Giant Schnauzer puppies and is inherited as an autosomal recessive
trait [3,4]. This disorder is characterized by methylmalonic aciduria, homocysteinemia, and low serum levels of
cobalamin, and due to a selective defect of cobalamin absorption at the level of the ileal enterocyte [4]. The
spontaneous disorder is believed to be analogous to Imerslund-Grasbeck syndrome in humans [4]. Hereditary
cobalamin deficiency has also been reported in Border Collie puppies [5]. Acquired cobalamin deficiency may
occur in older dogs and cats in association with malnutrition, malabsorption, exocrine pancreatic insufficiency, or
bacterial overgrowth of the small intestine [6-13]. A condition similar to the inherited disorder has been recently
described in a 6 month old beagle presented with a three-month history of failure to gain weight, lethargy,
intermittent vomiting, and seizures [14]. Laboratory test results of low serum cobalamin concentrations, anemia,
leucopenia, and methylmalonic aciduria while the dog was receiving a balanced commercial canine diet were
suggestive of a congenital selective malabsorption of cobalamin. Treatment with repeated injections of parenteral
cyanocobalamin at 50 g/kg every two weeks corrected the cobalamin-deficient state and reversed all the clinical
abnormalities. The pathogenesis of the neurological dysfunction in this dog remains unclear, although cobalamin
is converted to adenosyl or methyl coenzymes that are necessary for normal neural metabolism [15].
A progressive encephalomyelopathy has been reported in a 12 week old Labrador Retriever with a variety of
signs including stiffness and ataxia that progressed to tetraparesis, persistent turning of the neck/body to the right,
changing nystagmus, decreased menace response, anisocoria, decreased oculocephalic reflex, ventrolateral
strabismus, diminished gag reflex, and apparent dysphonia [69]. Gross changes revealed enlargement of the
lateral, third, and fourth ventricles of the brain and white and grey matter atrophy. Syringomyelia and hydromyelia
of the central canal into the dorsal funiculus of the spinal cord extended from the cervical intumescence to the
lumbar intumescence. Significant biochemical abnormalities included methylmalonic and malonic aciduria, mild
lactic and pyruvic aciduria. Disordered cobalamin metabolism was suspected, although serum cobalamin levels
were normal. Neither ketoacidosis nor hyperammonemia were present. The condition was considered to
represent an inborn error of metabolism resulting in abnormal organic acid accumulation (accumulation of citric
acid cycle intermediates including succinic, aconitic, and fumaric acids, and evidence of abnormal fatty acid
oxidation, were also noted), with similarities to methylmalonic acidemia in neonatal humans, an autosomal
recessive disorder caused by defective activity of methylmalonyl CoA mutase or by defective intramitochondrial
processing of vitamin B12 [70]. Many of the human patients respond to large doses of vitamin B12. Interestingly,
an 8 week course of L-carnitine (1000 mg/day), vitamin B12 (0.5 mg/day), and a protein restricted diet resulted in
marked improvement in the organic acid values of this dog, but no clinical improvement.
Malonic aciduria without elevated methylmalonic acid has been reported in a family of Maltese dogs with signs of
episodic seizures and stupor (the dog described was 3 years of age), along with hypoglycemia, acidosis and
ketonuria [71]. Treatment with frequent feedings of a low-fat diet high in medium-chain triglycerides successfully
reversed signs and resolved the malonic aciduria.
In people, vitamin B12 deficiency results in spongy demyelination of the posterior (dorsal) columns and
corticospinal tracts (once termed "subacute combined degeneration of the spinal cord"), and white matter of the
cerebral hemispheres [16]. Peripheral neuropathy has also been reported that is usually axonal in nature [17], or
less often, demyelinating [18]. Results of experimental studies suggest the pathogenesis of the myelopathy
associated with vitamin B12 deficiency is related to interference with the methylation reactions in the central
nervous system (CNS) that are processed by S-adenosylmethionine, which is controlled by its product, S-
adenosylhomocysteine [19,20]. As a consequence, there may be inhibition of methyltransferases involved in the
synthesis of myelin. Neuropathological studies on vitamin B12 deficiency are sparse in small animals. However, a
degenerative spinal myelinopathy with similarities to subacute combined degeneration of the spinal cord in people
has been reported in dogs fed a diet composed mainly of ruminant stomachs (see hound ataxia) [21]. The
disorder was associated with methionine deficiency and altered methionine synthetase activity. Peripheral nerves
appeared normal. The condition disappeared when the diet was changed to one containing a high proportion of
meat. A possible relationship between degenerative myelopathy (especially in German Shepherds) and vitamin
B12 deficiency has been studied but no consistent abnormalities in serum cobalamin levels could be shown [22].
Furthermore, parenteral cobalamin was ineffective in preventing progression of the neurological signs (see [23]).
Hypervitaminosis A
Hypervitaminosis A or deforming cervical spondylosis is a crippling degenerative and proliferative bony disorder
typically affecting the vertebral column and various long bones in cats fed whole liver (usually beef or sheep, but
also pig and chicken) diets [24-29]. The disorder is caused by excessive intake of vitamin A in the liver. Excessive
intake of vitamin A supplements can also produce the disease. In serum, vitamin A is transported in a retinol
binding protein and as retinylesters (retinylpalmitate, -stearate) in very-low and low-density lipoproteins [30].
Chronic hypervitaminosis A in cats is characterized by new bone formation or exostoses, principally involving
cervical vertebrae, and in the region of tendon, ligament, and joint capsule attachments [26]. Early changes
involve periarticular cartilaginous and osseous hyperplasia of cervical vertebrae, especially the first three
diarthrodial joints, without changes in the articular hyaline cartilage or other signs of inflammation [26]. These
lesions tend to coalesce, overgrow joints, and cause complete bony ankylosis [25,31]. Cartilaginous epiphyseal
growth plates are seriously disrupted in kittens [32]. In chronic cases, all cervical and cranial thoracic vertebrae
may become involved, as well as sternebrae, periarticular regions of long bones and ribs. Nerve roots are often
damaged secondary to exostoses encroaching on intervertebral foramina. Histopathological changes include
subperiosteal proliferation of new woven bone around joints of affected vertebrae and proliferation of cartilage
from the margins of the articular hyaline cartilage. There is erosion of adjacent cortical and cancellous bone and
fibrous replacement of the myeloid marrow [25,31]. Periosteal proliferation may involve the tendinous insertions of
muscle on the vertebrae and extend into surrounding muscle causing replacement and atrophy of the muscle
fibers. In a study using back-scattered scanning electron microscopy [33], the more recently formed areas of bony
proliferation were composed mainly of chondroid tissue surrounded by different degrees of woven bone. As the
bony reaction continued, trabecular remodeling occurred leading to progressive substitution of chondroid tissue
by woven bone surrounded by apposition of lamellar bone. In this study, there was no evidence of calcified
cartilage present. In animals with extensive involvement of the spinal nerve roots, the spinal cord may show
atrophy with disappearance of neurons and fibers, especially in the dorsal horns of the gray matter [25].
The underlying pathophysiologic mechanisms are not fully understood, but vitamin A toxicosis does appear to
induce bone lesions via a direct effect on skeletal tissue. In young animals, toxicosis results in suppression of
both chondrocytic and osteoblastic activity, leading to growth retardation and thinning of cortices. A high intake of
vitamin A is necessary for several months or years before cervical exostoses develop, although experimental
studies in kittens indicate that radiographic changes in the cervical spine can be detected as early as 15 weeks
after beginning a diet rich in vitamin A [26]. After 24 weeks on the diet, the cervical spine from the occiput to C6
became completely rigid. Trauma may be a contributing factor in the pathogenesis due to constant movement of
the neck in coat cleaning [26]. It seems that an individual predisposition to disturbances of vitamin A metabolism
may be an important factor in the pathogenesis of the disease [34]. There are reports of some cats having no
symptoms while others in the household develop typical lesions [35].
Clinical signs usually occur in adult cats (e.g., 2 to 10 years of age) of either sex and in any breed [31,35-37].
Affected animals may be depressed, walk with pelvic limbs flexed, and may show lameness of one or both
thoracic limbs associated with periarticular exostoses around the elbow joints, which, in chronic cases, are
typically fixed in a flexed position. There may be ankylosis of the shoulder and carpal joints. Palpable exostoses
of the forelimb distal to the elbow or of other regions of the skeleton are relatively uncommon [25]. Cats frequently
assume a characteristic rabbit or kangaroo-like sitting posture. The head may be held in a ventroflexed position
and there may be scoliosis of the cervical spine, which is frequently palpably rigid. The atlantoaxial joint is often
fused, thus preventing any head-neck movement. Manipulation of the neck may be painful. Neurogenic muscle
atrophy and signs of cervical hyperesthesia can result from spinal nerves compressed by the bony proliferation.
Cutaneous hyperesthesia may be present over the shoulder and neck regions. Affected cats often have an
unkempt coat because of inability to groom themselves. Affected cats typically have a fixed stare, presumably
associated with reduced movement of the eyeballs caused by the head-neck rigidity [25]. Some animals have a
voice change, probably related to proliferative exostoses that compress laryngeal structures (e.g., larynx,
laryngeal muscles, and nerves). Some cats may show aggressiveness when handled [31,35]. Cats with advanced
disease tend to become emaciated. In 6 to 8 week-old kittens fed raw sheep liver, severe retardation of skeletal
growth was accompanied by delayed eruption, retention, and displacement of the incisor teeth with diffuse
hypercementosis of the roots [38].
Radiographic studies reveal extensive new bone formation and variable autolysis of cervical and rostral thoracic,
and sometimes, lumbar vertebrae [25,39]. In some cats, the skull and the cervical and first few thoracic vertebrae
can be rigidly fused [25,40]. Periosteal exostoses can be seen involving multiple long bone articulations,
especially in elbow and shoulder joints, and also ribs (in the region of vertebral articulation), sternebrae (showing
irregular bony overgrowth, replacement and deformation of sternebrae with ankylosis of sternebral articulations),
pelvic girdle, and hip joints. Curiously, there have been a few instances in which exostoses involving the pelvic
girdle and hip joint were the major skeletal changes, without involvement of the cervical spine or forelimbs [25,33].
Rarely, affected cats showing typical clinical signs have no radiographic abnormalities in the cervical spine [40].
Vitamin A serum levels are elevated, but other hematologic and blood chemistries are usually normal, including
alkaline phosphatase activity, serum calcium, and blood inorganic phosphate levels [25,29,37]. Vitamin A
concentration is very high in liver and kidney [31,32] and there is extensive lipoid infiltration of the spleen [26], and
fatty changes in the liver have been observed occasionally [29].
Prognosis of chronically affected cats is guarded to poor. Change in diet may halt further new bone formation and
exostoses; however resolution of radiographic changes and clinical signs is unlikely, although some remodeling of
bone may occur over a long period. Epiphyseal damage is irreversible. Nevertheless, encouraging improvement
in signs has been noted in some cats following removal of liver from the diet [35,41] ( along with use of analgesic
drugs, e.g., phenylbutazone, 13 mg PO, bid [37]. Cats have been treated with higher doses of phenylbutazone
(12 - 16 mg/kg PO bid) for over a year without any toxic side-effects noted [25]. Rarely, temporary or permanent
recovery may occur spontaneously [34]. Note that liver is highly palatable to cats and a change to another diet
may be met with resistance [41].
The particular susceptibility of cats to hypervitaminosis A is difficult to explain. Spontaneous hypervitaminosis is
rare in dogs but it has been experimentally induced in mixed Labrador Retriever pups [42]. Clinical signs were
loss of body weight, dullness, emaciation, roughened coat, pain in limb joints, and retarded growth. Radiographic
findings included reduced length and thickness of long bones, with osteophyte formation, periosteal reactions,
and premature closure of epiphyses. No vertebral involvement was reported.
Nutritional Secondary Hyperparathyroidism

Once this condition was relatively common in small animals but is now infrequent with the advent of commercially
available balanced pet foods. The cause of nutritional secondary hyperparathyroidism (NSH) is chronic dietary
calcium deficiency which leads to increased serum levels of parathormone, and accelerated bone resorption.
Neurological signs most often relate to spinal fractures associated with severe osteopenia (decreased calcification
or density of bone) associated with increased mobilization of calcium from bone. In a recent report of NSH in cats,
seizures were a common reason for presentation [43]. Additional information on NSH is found in the section on
hypocalcemia.
Thiamine Deficiency
Thiamine or vitamin B1 deficiency (also called Chastek paralysis) occurs sporadically in dogs and cats if their
commercial rations are naturally low in thiamine [44-47], or if their food (e.g., liver-beef diets in cats and mutton or
mutton-beef in dogs) is overcooked prior to feeding or in processing of canned foods [44,48]. Sufficient quantities
of thiamine to meet the requirements of dogs and cats are usually found in fresh meat [49]. Thiamine and
thiamine pyrophosphate are thermolabile and destruction by heat (e.g. temperatures over 100ºC) increases from
a slight amount at pH 3.0 to a considerable degree at pH 7.0 [48,50]. In cats especially, thiamine deficiency may
occur with an all-fish diet, since viscera of many freshwater and saltwater fish contain thiaminase [50]. Storage
may have an effect on thiamin levels [47]. Thiamine in food, especially processed meats, is also destroyed by
sulfites or sulfur dioxide used as a preservative [49,51]. Experimentally-induced thiamine deficiency has also been
studied in dogs and cats [44,50,52,53].
The metabolically active form of thiamine is thiamine pyrophosphate that plays an essential role in the
intermediary metabolism of carbohydrate, and is especially involved in three enzyme systems [2]:
a. Pyruvate dehydrogenase (converts pyruvate to acetyl coenzyme A);

b. Alpha ketoglutarate dehydrogenase (catalyzes the conversion of alpha ketoglutarate to succinate in the
Krebs cycle); and
c. Transketolase (catalyzes the pentose monophosphate shunt).
Thiamine is thus essential for complete oxidation of glucose through the Krebs cycle (citric acid cycle or
tricarboxylic acid cycle). As a consequence of thiamine deficiency, serum levels of pyruvate and lactate are
increased, along with reduced red blood cell transketolase activity. Tissues dependent on glucose or lactate-
pyruvate for energy, such as the brain and heart, are particularly compromised in thiamine deficiency. It still
remains uncertain how thiamine deficiency leads to the phenomenon of selective vulnerability of neuronal cell
death [2,52]. Impaired vascular perfusion might play a role in this disorder; results of experimental studies suggest
that hemorrhages could be related to hemodynamic changes resulting from thiamine deficiency-induced vascular
dysfunction [54]. In addition, events such as blood-brain barrier breakdown, N-methyl-D-aspartic acid receptor-
mediated excitotoxicity, and increased reactive oxygen species have been implicated [55,56].
Clinical signs in dogs include anorexia, emesis, depression, wide-based hind limb stance, kyphosis, sensory
ataxia, progressive spastic paraparesis, crouching hind limb gait, torticollis, head ventroflexion, circling,
exophthalmos, generalized tonic-clonic seizures, profound muscular weakness, recumbency, opisthotonus, coma
and death [48,53]. Patella reflexes are usually exaggerated, and there may be proprioceptive and menace deficits,
tremors, and occasionally, nystagmus. Some dogs show signs of hysteria [53]. In cats, vestibular signs, head
tremor, ataxia-dysmetria, transient seizures often precipitated by handling, depression, ventroflexion of the head
with the chin almost touching the sternum (especially when the cat is suspended by the hind limbs), lying in a tight
semicircular posture, dilated, poorly-responsive pupils, and absent menace response may be observed [50,57].
Cats with severe lesions may manifest semicoma, persistent crying, opisthotonus and limb spasticity, followed by
death. Electrocardiographic abnormalities have been cited in dogs and cats, including bradycardia, tachycardia,
sinus arrhythmias, QRS prolongation, P waves with notched peaks, elevation of the ST segment, and T-waves
flattening or inversion [53]. Whole blood thiamine content is reduced in affected dogs [48].
Pathological findings in dogs and cats with experimental or spontaneous thiamine deficiency are similar and are
characterized by polioencephalomalacia with bilaterally symmetrical spongiosis, necrosis, and hemorrhage of
upper brainstem nuclei, primarily in periventricular gray matter [50,52,58]. The caudal colliculi are consistently
involved and hemorrhagic or yellow-tan or brown malacic lesions may be seen macroscopically [48,50]. Gross
lesions have also been noted occasionally in ventromedial and dorsomedial occipital cortex, dorsomedial parietal
cortex, hippocampal gyrus, medial vestibular nuclei and cerebellar nodulus in dogs with experimentally-induced
thiamine deficiency [52]. Microscopically, lesions involving the caudal colliculi consist of severe/total parenchymal
necrosis with intense reactive changes associated with hypertrophy and hyperplasia of endothelial and adventitial
cells, edema, gitter cell formation and intense microgliosis [48]. Spongy changes may be present in ventromedial
and dorsomedial occipital cortex and dorsomedial parietal cortex, basal nuclei, red nucleus, oculomotor nucleus,
vestibular nuclei, rostral olives, cerebellar peduncles, cerebellar nodulus and/or lingula, and cerebellar roof nuclei.
Other findings include microvascular proliferation and occasional mild, lymphocytic perivascular cuffing.
Spongiosis is due to hydropic vacuolation of the neuropil and myelin sheaths. This constellation of pathology
varies with the stage of the disease: early, intermediate, and advanced lesions have been described in
experimentally-induced thiamine deficiency in dogs [52]. Ultrastructurally, there is hydropic swelling of astrocytic
processes and intramyelinic edema. In advanced stages, there is lysis of the neuropil, marked demyelination,
accumulation of lipid macrophages, and variable axonal degeneration. White matter lesions are reportedly
minimal and limited to the corona radiata adjacent to areas of cerebrocortical necrosis, and to medullary cores of
folia within totally affected cerebellar cortex [52]. No spinal cord or peripheral nerve lesions have been observed
in dogs or cats [48,50,52]. Myocardial degeneration has also been reported in hearts of affected dogs and cats
[52,59]. In humans, thiamine deficiency may also lead to peripheral nerve axonal degeneration [60].
Prompt administration of thiamine hydrochloride, even in severely affected animals, can result in complete
remission of clinical signs, e.g., 25 to 50 mg/day IM in dogs, and 10 to 20 mg/day IM, in cats, over several days;
although learning deficits have been reported in cats that recovered from experimentally-induced thiamine
deficiency [61].
Vitamin E Deficiency
Vitamin E is a fat-soluble vitamin of plant origin. Alpha-tocopherol is the most active form of vitamin E and it
appears to be taken up preferentially by the CNS [62]. Alpha-tocopherol is incorporated into chylomicrons in the
small intestine prior to absorption, and in the liver it is bound and recycled by alpha-tocopherol transfer protein
and incorporated into low-density and very-low density lipoproteins. It is delivered to cells where alpha-tocopherol
functions as an antioxidant and helps prevent free radical peroxidation and injury to cell membranes [2].
Deficiency can occur at any level of tocopherol metabolism. In humans, vitamin E deficiency is associated with
axonal membrane injury leading to axonal degeneration of peripheral nerves, dorsal root ganglia and posterior
(dorsal) columns. In dogs and cats, vitamin E deficiency appears to be rarely involved with pathology of the
nervous system. At one time, degenerative myelopathy (especially in German Shepherds) was considered to be
possibly related to vitamin E deficiency [23]; however Averill failed to find evidence for vitamin E deficiency in his
group of dogs [63] and recent studies suggest that this association is unlikely (in fact serum alpha-tocopherol
concentration was significantly higher in German Shepherd dogs with the condition) [64]. Additionally, vitamin E
supplementation had no effect on clinical signs. Statistical studies in this report indicated that the concentration
varied more widely in individual affected dogs than in unaffected dogs, irrespective of breed. Vitamin E deficiency
has been reported in visually impaired Walker Hounds and Beagles that were fed a diet of table scraps [65].
Sensory retinal degeneration was found in all dogs, and severity of changes varied with age of the dog. Plasma,
serum, and tissue concentrations of vitamin E were low in affected dogs. Lipofuscin accumulation was found in
retinal pigment epithelium and neurons of the CNS. Findings were consistent with nutritional vitamin E deficiency
and oxidative injury to photoreceptors of the retina. Changes in these dogs were similar to those described for
central progressive retinal atrophy and equine lower motor neuron disease. Vitamin E deficiency has occasionally
been associated with reports of myopathies in dogs and cats (see vitamin E-selenium-responsive myopathy).
Serum vitamin E concentrations are reportedly lower in adult and immature Brittany Spaniels with hereditary
canine spinal muscular atrophy [66] . Vitamin E deficiency has been implicated in distemper vaccination failures
[67] and generalized lipofuscinosis in dogs [68].

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Braund's Clinical Neurology in Small Animals: Localization, Diagnosis and

II Etiological Categories of Neurological Diseases

III Neurodiagnostic Techniques

IV Special Therapeutic Techniques

Why do the neurological examination?

There are 5 components to the neurological examination:

3. Postural Reactions - Muscle Size

4. Spinal Reflexes - Muscle Tone

Where is the lesion?

Where is the lesion?

Where is the lesion?

Where is the lesion?

Facial and Trigeminal Neurons

- Menace Response II - central visual pathway to occiptal lobe

- Menace Response II - VII

- Palpebral Reflex V - VII

- Palpebral Reflex V - VII - cutaneous, autonomus zones

- Nociception Nasal mucosa - Ophthalmic branch V

- Masticatory muscles V - Mandibular branch V

- Tongue Size Movement XII

- Reflex Gagging, IX, X

The following syndromes will be discussed:

Table 1. Principal Signs of the Lumbosacral Syndrome

• Weakness/paralysis of pelvic limbs and tail

Table 2. Diseases Associated with the Lumbosacral Syndrome

Degenerative Disorders None

Neurotoxic Disorders None

Storage Disorders None

Traumatic Disorders Spinal trauma

• Weakness or paralysis of pelvic limbs

Table 4. Diseases Associated with the Thoracolumbar Syndrome

Neurotoxic Disorders None

Storage Disorders Globoid leukodystrophy; mucopolysaccharidosis type VI

Traumatic Disorders Spinal trauma

Table 5. Principal Signs of the Cervicothoracic Syndrome

Table 6. Diseases Associated with the Cervicothoracic Syndrome

Neurotoxic Disorders None

Storage Disorders Globoid leukodystrophy

Traumatic Disorders Spinal trauma; brachial plexus avulsion

Table 7. Principal Signs of the Cervical Syndrome

• Weakness or paralysis in:

Table 8. Diseases Associated with the Cervical Syndrome

Neurotoxic Disorders None

Storage Disorders Globoid leukodystrophy;mucopolysaccharidosis type 1

Traumatic Disorders Spinal trauma

Table 9. Principal Signs of the Pontomedullary Syndrome

• Weakness or paralysis in:

Table 10. Diseases Associated with the Pontomedullary Syndrome

Degenerative Disorders Alaskan Husky encephalopathy

Endogenous Metabolic Disorders None

Neurotoxic Disorders Tetanus

Neurovascular Disorders Infarction; hemorrhage

Nutritional Disorders None

Storage Disorders Fucosidosis; globoid leukodystrophy

Traumatic Disorders Cranial trauma

Table 11. Principal Signs of the Cerebellar Syndrome

• Spastic, goose-stepping gait in all limbs, especially thoracic, with

Table 12. Diseases Associated with the Cerebellar Syndrome

Neurotoxic Disorders Hexachlorophene; metronidazole

Neurovascular Disorders Infarction; hemorrhage