519

A Clinician’s Approach to Peripheral Neuropathy

Peter Siao, MD1 Michelle Kaku, MD1

1 Department of Neurology, Boston University School of Medicine, Address for correspondence Peter Siao, MD, Department of
Neuromuscular Unit and Electromyography Laboratory, Boston Neurology, Boston University School of Medicine, Neuromuscular Unit
Medical Center, Boston, Massachusetts and Electromyography Laboratory, Boston Medical Center, 725
Albany Street, Suite 7B, Boston, MA 02118 (e-mail: psiao@bu.edu).
Semin Neurol 2019;39:519–530.

Abstract Peripheral neuropathies are a group of disorders that affect the peripheral nervous system,
for which hundreds of etiologies have been identified. This article presents a stepwise
approach to the evaluation and workup of peripheral neuropathy, which starts with a
detailed history of symptoms, family and occupational history, and a neurological as well as
general physical exam. Pattern recognition of various neuropathies can help to build a

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differential diagnosis based on the presentation. Such patterns include acute versus
chronic, primary demyelinating versus axonal, hereditary versus acquired, asymmetric
versus symmetric, presence of facial palsies, sensory or motor predominant, and presence
of prominent autonomic symptoms. Early categorization of the type of neuropathy can
help focus the workup for peripheral neuropathy. Nerve conduction studies and electro-
myography (NCS/EMG) is the primary diagnostic tool in the evaluation of patients with
large-fiber polyneuropathy. One of the most important roles of NCS/EMG is to help
categorize polyneuropathy as primary axonal versus primary demyelinating. The finding of
a primary demyelinating polyneuropathy narrows the differential diagnosis of polyneur-
opathy dramatically and increases the chances of finding a treatable etiology. Laboratory
Keywords workup includes serum studies and potentially cerebrospinal fluid, genetic studies,
► peripheral immunological markers, and fat pad biopsy for select patients. Skin biopsy may be used
neuropathy to assess intraepidermal nerve fiber density if small-fiber neuropathy is suspected, and
► polyneuropathy nerve biopsy may be useful in select cases. In recent years, magnetic resonance imaging
► diagnosis and neuromuscular ultrasound have also shown promise in the evaluation of peripheral
► clinical neuropathy. Identification of the etiology of neuropathy is crucial and often time-sensitive,
► neurophysiologic as an increasing number of causes are now reversible or treatable.

Clinical Approach to Peripheral Neuropathy processes, or actually reverse the patients’ neurologic deficits
and allow for return to their neurological baseline. Unfortu-
The prevalence of chronic symmetrical polyneuropathy is nately, when a treatable polyneuropathy is diagnosed late in the
estimated at 8% in persons over 55 years of age.1 This article course, after significant axonal loss has occurred, the neurologic
is dedicated to the clinical and neurophysiologic approach in deficits may be irreversible. Even hereditary neuropathies are
patients with polyneuropathy. The laboratory evaluation is important to diagnose early, as disease-modifying therapies are
discussed in a different article. The goal of the clinician is to now available, such as in the case of neuropathic hereditary
determine the etiology of the polyneuropathy to help guide transthyretin amyloidosis (otherwise known as familial amy-
treatment. There are literally hundreds of causes of peripheral loid polyneuropathy). Early diagnosis of hereditary neuropathy
neuropathy and it may take several clinic visits to find the with liability to pressure palsy (HNPP) is also important so that
etiology. Early diagnosis and treatment of certain types of patients and anesthesiologists can be warned about the risks of
polyneuropathy can prevent further worsening of neuropathic prolonged immobility and pressure on peripheral nerves.

Issue Theme Peripheral Neuropathies; Copyright © 2019 by Thieme Medical DOI https://doi.org/
Guest Editors, Michelle Kaku, MD, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1694747.
Peter Siao, MD New York, NY 10001, USA. ISSN 0271-8235.
Tel: +1(212) 584-4662.
520 Approach to Peripheral Neuropathy Siao, Kaku

The diagnosis of peripheral neuropathy is not always confirm the diagnosis.5 Fine-needle aspiration biopsy of the
straightforward. It is not infrequent to see patients referred abdominal fat pad with Congo Red staining is a minimally
for the evaluation of peripheral neuropathy who are ulti- invasive procedure used to demonstrate tissue deposits of
mately found to have bilateral lumbosacral radiculopathy or amyloid in patients with neuropathy related to amyloidosis.6
even cervical myelopathy. We have actually sent a few For patients with autonomic neuropathy, the quantitative
patients who were referred for evaluation of peripheral sudomotor axon reflex sweat test (QSART) is the most widely
neuropathy to the emergency room because they ended up used test of autonomic sudomotor function.7 Quantitative
having subacute cervical myelopathy. At times, patients with sensory testing is useful in documenting sensory dysfunc-
multiple sclerosis may present with gait imbalance and tion in patients with polyneuropathy.8 Magnetic resonance
numbness in the feet.2 When faced with a patient with imaging (MRI)9 and neuromuscular ultrasound10 have also
symmetrical numbness of the feet, with or without numb- been shown to be helpful in the evaluation of patients with
ness of the hands, one has to make sure the patient’s peripheral neuropathy. With the current advances in
symptoms are due to peripheral neuropathy before embark- neurophysiologic, immunologic, and genetic testing in
ing on an exhaustive search for the etiology of peripheral peripheral neuropathy, the use of nerve biopsy is now
neuropathy. Even patients with known peripheral neuropa- primarily limited to patients with possible vasculitic neu-
thy may develop new symptoms unrelated to their periph- ropathy, select patients with possible amyloid neuropathy,
eral neuropathy. Patients with peripheral neuropathy can and atypical forms of chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP).11

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also have multiple etiologies.
One can categorize the etiology of peripheral neuropathy
into two groups, hereditary and acquired. Hereditary
A Stepwise Approach
neuropathies include Charcot–Marie–Tooth (CMT) disease,
hereditary sensory and autonomic neuropathy, neuropathic The seasoned clinician uses pattern recognition to evaluate
hereditary transthyretin amyloidosis, hereditary neuralgic patients with peripheral neuropathy. During history taking and
amyotrophy, porphyria, Fabry disease, Refsum disease, meta- neurological examination, the clinician goes through several
chromatic leukodystrophy, adrenoleukodystrophy, and steps almost simultaneously and not always in the same order.
others. Acquired neuropathies can be due to dysmetabolic For the purposes of discussion, we will present these as a series
states, drugs, toxins, immune-mediated, infectious, cancer- of steps in the approach to peripheral neuropathy.
related, compressive etiologies, and cryptogenic. First, the acuity of the neuropathy is one of the first things
The process of finding the etiology of peripheral neuropathy the clinician has to determine because the differential diag-
starts with a careful history that includes a detailed family noses for acute polyneuropathy (►Table 1) and chronic
history and a complete list of medications. Aside from chemo- polyneuropathy (►Table 2) are quite different. Additionally,
therapeutic agents that may cause polyneuropathy, commonly patients with chronic polyneuropathy can also develop
used medications associated with polyneuropathy include the subacute worsening from another neuropathic process.
following: pyridoxine (vitamin B6), phenytoin, linezolid, met- Only a carefully taken history will allow one to appreciate
ronidazole, nitrofurantoin, isoniazid, chloramphenicol, dap- if there is a secondary process. For example, diabetic patients
sone, reverse transcriptase inhibitors, amiodarone, colchicine, with chronic axonal sensorimotor polyneuropathy may
and disulfiram.3 Certain drugs, such as barbiturates, hydantoins, develop subacute worsening due to a superimposed lumbo-
and sulfonamide antibiotics can trigger an acute and severe sacral radiculopathy, common fibular neuropathy across the
axonal motor polyneuropathy. Family history should include fibular head, lumbosacral plexopathy, or CIDP. Patients with
ethnic background, consanguinity, and details about parents CMT disease can also develop superimposed entrapment
and siblings such as the presence of high-arched feet, flatfeet, neuropathies or a second etiology for their generalized
hammertoes, “skinny legs,” gait dysfunction, and other signs of neuropathy, such as CIDP.12–14 Patients with cervical radi-
possible inherited neuropathies. We find it most helpful to culopathy can have superimposed entrapment neuropathies
examine family members for signs of polyneuropathy. Concur-
rent bilateral carpal tunnel syndrome and autonomic dysfunc-
tion should arouse suspicion for neuropathy associated with Table 1 Acute polyneuropathy
amyloidosis. In a series of patients referred to the Mayo Clinic
with undiagnosed peripheral neuropathy, a hereditary neurop- Guillain–Barre syndrome (GBS)
athy was found in 42%.4 Social history includes the patient’s Acute porphyric neuropathy
country of origin, occupation and potential occupational expo- Toxic neuropathy
sure, sexual history, sexual orientation, as well as alcohol and
Critical illness neuropathy/myopathy
drug use. The search for infectious causes of polyneuropathy
Vasculitis
should be guided by social history as well as travel history.
The cornerstone of diagnostic evaluation of patients with Infectious neuropathy
large-fiber peripheral neuropathy is nerve conduction Mimics of acute polyneuropathy
studies and electromyography (NCS/EMG). In patients sus- Botulism
pected to have small-fiber neuropathy, skin biopsy to evalu-
Tick paralysis
ate intraepidermal nerve fiber density (IENFD) is useful to

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 Approach to Peripheral Neuropathy Siao, Kaku 521

Table 2 Chronic polyneuropathy

Diabetic symmetric distal (axonal) polyneuropathy

Metabolic (diabetes, hypothyroid, celiac disease)
Alcohol and other toxic polyneuropathy (drugs, heavy metals)
Heavy metal toxicity (zinc, lead,16 thallium,17 arsenic18)
Immune-mediated neuropathies (chronic inflammatory demyelinating polyradiculoneuropathy [CIDP] and
CIDP variants—MMN, MADSAM, and DADS—including anti-MAG neuropathy)
Inherited neuropathies
Medication induced neuropathies (nitrofurantoin,19 lithium,20 phenytoin,21 etc.)
Vitamin B1, B6, B12, E, copper deficiency18
Vitamin B6 toxicity18
Paraproteinemia-related neuropathies (MGUS, multiple myeloma, Waldenstrom’s macroglobulinemia, POEMS)22,23
Connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, Sjögren’s syndrome, systemic sclerosis,
or scleroderma)24
Infectious (Lyme,25 HIV,26 leprosy,27 brucellosis28)

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Sarcoid neuropathy29
Cryptogenic polyneuropathy
Mitochondrial (neuropathy, ataxia, retinitis pigmentosa or NARP, myopathy and external ophthalmoplegia, neuropathy,
gastrointestinal, encephalopathy or MNGIE)30,31

Abbreviations: DADS, distal acquired demyelinating symmetric neuropathy; MADSAM; multifocal acquired demyelinating sensory and motor
neuropathy; MGUS, Monoclonal gammopathy of undetermined significance; MMN, multifocal motor neuropathy; POEMS, Polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathies, and skin changes.

such as carpal tunnel syndrome or cubital tunnel syndrome, present with asymmetric limb weakness. Adult patients with
otherwise known as double crush syndrome.15 CMT disease may have asymmetric weakness due to super-
The second question is the anatomic distribution of the imposed radiculopathy or entrapment neuropathies.
neuropathic process. The patient’s symptoms and signs will The involvement of the facial nerve can be a clue to several
help determine the anatomic distribution of the neuropathic possible etiologies of the neuropathy. In addition to Bell’s palsy,
process. Is the “neuropathic” process symmetric or asymmetric? the differential diagnosis of patients who present with an
If the process is asymmetric, one should consider disorders such acquired unilateral facial neuropathy includes Lyme disease,
as entrapment neuropathies, radiculopathies, plexopathies, human immunodeficiency virus (HIV), sarcoidosis, granulo-
motor neuron disease, mononeuropathy multiplex, or some matosis with polyangiitis (formerly called Wegener’s granu-
of the immune-mediated CIDPs, also called “CIDP variants” lomatosis), tuberculous meningitis, Sjögren’s syndrome, and
(►Table 3). Adult patients with spinal muscular atrophy and vasculitic neuropathy.33–37 Patients with recurrent ipsilateral
facioscapulohumeral muscular dystrophy (FSHMD) can also facial neuropathy should raise suspicion for neoplastic

Table 3 Asymmetric polyneuropathy

Entrapment neuropathies (including hereditary neuropathy with liability to pressure palsies-HNPP)

Radiculopathies (cervical, lumbosacral, thoracic)
Plexopathy (diabetic and nondiabetic lumbosacral radiculoplexus neuropathy, neuralgic amyotrophy, hereditary brachial
plexopathy)
Vasculitic neuropathy32
Sarcoid neuropathy
CIDP variants
Multifocal motor neuropathy (MMN)
Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM or Lewis–Sumner syndrome)
Mimics of asymmetric polyneuropathy
Amyotrophic lateral sclerosis
FSHMD with asymmetric limb weakness

Abbreviations: CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; FSHMD, facioscapulohumeral muscular dystrophy; HNPP,
hereditary neuropathy with liability to pressure palsy.

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522 Approach to Peripheral Neuropathy Siao, Kaku

etiologies (facial nerve schwannoma, parotid tumor, acoustic Table 5 Sensory predominant painful neuropathies
neuroma).38 Bilateral facial neuropathy may be seen in Lyme
disease, neurosarcoidosis, HIV, leptomeningeal carcinomato- Diabetes mellitus
sis, lymphoma, leukemia, syphilis, and a rare form of Guillain– Toxic neuropathies (arsenic,18 thallium17)
Barre syndrome (GBS).39–44 Reactivation of varicella zoster Amyloid neuropathy
virus (VZV) can present with Ramsay Hunt syndrome, which is
Vasculitic neuropathy32
a combination of facial palsy and an erythematous vesicular
rash on the ear or mouth, and tends to have a poorer prognosis HIV neuropathy26
than idiopathic Bell’s palsy.45 Sarcoidosis can present with Fabry disease
Heerfordt–Waldenstrom syndrome, characterized by parotid Cryptogenic sensory neuropathy
gland enlargement, facial palsy, anterior uveitis, and fever.46
Sensory ganglionopathy (paraneoplastic anti-Hu antibody
Melkersson Rosenthal syndrome is characterized by orofacial neuropathy,59 Sjögren’s syndrome,50 vitamin B6 toxicity,18
edema, recurrent facial palsy, and a fissured tongue.47 Gelso- cisplatinum toxicity60)
lin-related amyloidosis, an autosomal dominant disease, can
Sensory CIDP61
also present with facial nerve palsy involving the upper and
later lower branches of the facial nerve. Corneal lattice dystro- Abbreviations: CIDP, chronic inflammatory demyelinating polyradicu-
phy, open angle glaucoma, cataracts, and blepharochalasis are loneuropathy; HIV, human immunodeficiency virus.

often concurrent findings (►Table 4).48

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Table 6 Motor predominant neuropathies
There are a few unusual patterns of deficits that can be
important clues to the etiology of the neuropathy. The
Porphyria62
sensory deficits in leprosy are known to affect the coolest
areas of the body such as the tip of the nose, the ear helices, Lead poisoning18
and the distal extremities.27 Tangier disease can present Multifocal motor neuropathy (MMN)
with bifacial weakness and proximal sensory loss, including GBS (in AIDP and AMSAN)
a syringomyelia-like pattern.51,52 Porphyric neuropathy is
CIDP (sensorimotor deficits but the presentation is usually
known to manifest as early and severe proximal weakness weakness)
with a proximal pattern of sensory loss or “bathing trunk”
Mimics of motor predominant neuropathy
pattern.53 Another disorder that can present with a syringo-
myelia-like pattern is facial onset sensory and motor neu- Amyotrophic lateral sclerosis
ronopathy (FOSMN syndrome). These patients present with Spinal muscular atrophy including Kennedy disease
numbness in a trigeminal distribution before progressing to Distal myopathies
involve the scalp, neck, upper trunk, and upper limbs in a
Abbreviations: AIDP, acute inflammatory demyelinating polyneurop-
sequential order. Later, motor symptoms develop including
athy; AMSAN, acute motor and sensory axonal neuropathy; CIDP,
dysphagia, dysarthria, and muscle weakness.54 chronic inflammatory demyelinating polyradiculoneuropathy; GBS,
The third step is to determine which nerve fibers are Guillain–Barré syndrome.
affected. Is the patient suffering from a sensory predominant
(►Table 5), motor predominant (►Table 6), or sensorimotor
polyneuropathy? Does the patient have prominent autonom- Table 7 Prominent autonomic symptoms
ic symptoms (►Table 7)? Although patients with pure
Diabetic autonomic neuropathy
Table 4 Neuropathy with facial palsy Guillain–Barre syndrome
Toxic neuropathies (ciguatera,63 heavy metals,
Lyme disease39 organic solvents, acrylamide,64 cisplatin,60 vincristine,65
HIV49 paclitaxel,66 amiodarone67)
Sarcoidosis40 Paraneoplastic and immune-mediated neuropathies
33 (paraneoplastic neuropathies, lupus,68
Granulomatosis with polyangiitis
rheumatoid arthritis,69 mixed connective tissue disease
Sjögren’s syndrome50 [MCTD],70 Sjögren’s syndrome)
Leptomeningeal carcinomatosis Neuropathy related to amyloidosis71
Syphilis44 Hereditary neuropathies (porphyria,53 HSAN,
Fabry disease,72 Tangier disease, Allgrove syndrome,73
Lymphoma49
Navajo neuropathy,74 multiple endocrine
Leukemia neoplasia type 2b75)
Gelsolin-related amyloidosis48 Infectious diseases (HIV, botulism, Chagas disease,76
diphtheria,77 leprosy27)
GBS variants (pharyngo-cervico-brachial, Miller Fisher
syndrome) Vincristine neuropathy65

Abbreviations: GBS, Guillain–Barré syndrome; HIV, human immunode- Abbreviations: HIV, human immunodeficiency virus; HSAN, hereditary
ficiency virus. sensory and autonomic neuropathy.

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 Approach to Peripheral Neuropathy Siao, Kaku 523

sensory neuropathy will have normal motor NCS, the loss of Another categorization is primary axonal versus primary
sensory feedback will often lead to a sense of weakness or demyelinating polyneuropathy. When a patient with acute
abnormal motor function. Likewise, patients with pure mo- or chronic polyneuropathy has been found to have a primary
tor neuropathy such as multifocal motor neuropathy (MMN) demyelinating polyneuropathy, the differential diagnosis
may have some sensory symptoms but without objective narrows down considerably, and the possibility of improve-
sensory loss.55 Recent studies demonstrate that patients ment with immunomodulating therapy increases. When
with MMN with conduction block may eventually develop demyelinating disease is suspected, a lumbar puncture can
a reduction in sensory nerve action potential (SNAP) ampli- be helpful to identify elevated cells, or in the case of a GBS,
tude, which may represent more severe disease and more elevated protein with normal cells, or albuminocytologic
prominent axonal loss.56 dissociation. MRI of the lumbar spine may show spinal
If one is dealing with a pure sensory neuropathy, is it a root and plexus hypertrophy in CIDP.85 The role of NCS/
small-fiber neuropathy, small- and large-fiber neuropathy, or EMG in the diagnosis of primary demyelinating polyneur-
large-fiber neuropathy? Patients with small-fiber neuropathy opathy will be discussed later.
can be identified by their chief complaint of painful symptoms.
The small sensory fibers mediate pinprick and temperature
Clinical Examination in the Evaluation of
sensation, while the large sensory fibers mediate joint posi-
Peripheral Neuropathy
tion, light touch, and vibration sensation. Sensory symptoms

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can be categorized as a negative or positive sensation. Most General examination should include assessment of the
clinicians know that when patients complain of “numbness,” patient’s joints. Enlargement and deformities of the joints
the term can mean different things. Patients may say numb- may be due to loss of pain sensation, leading to chronic
ness to mean a lack of sensation (which is a negative sensory trauma (such as the presence of Charcot joints). Palpation of
symptom) or an abnormal “buzzing,” “falling asleep,” “thaw- peripheral nerves may reveal nerve enlargement. The ulnar
ing,” or “pins and needles” sensation (which would be consid- nerve at the elbow, the radial sensory nerve at the radial
ered a positive sensory symptom). The loss of sensation to light wrist, and the greater auricular nerve behind the ear are
touch and pinprick would indicate loss of small-fiber function, common sites of nerve enlargement that can be palpated.
while the loss of sensation to joint position and vibration The presence of hypermobile joints and/or hyperelastic skin
would indicate loss of large-fiber function. Prominent loss of may suggest Ehlers–Danlos syndrome. Scapular winging can
joint position sensation (proprioception) should lead one to provide clues to the etiology of the patient’s weakness.
think of a ganglionopathy (►Table 8). The loss of propriocep- Muscle atrophy and contractures of the joints (fingers,
tion can lead to gait ataxia and pseudoathetoid movements of wrists, elbows, and ankles) are clues to the chronicity of
the hands, known as piano-playing fingers.57 Significant pro- the weakness as well as the anatomic localization of the
prioceptive loss with neuropathy should also lead one to nerve dysfunction. Contractures of elbow joints can be a clue
suspect chronic ataxic neuropathy ophthalmoplegia IgM para- to a myopathic process, while contractures of the ankles can
protein cold agglutinins disialosyl antibodies (CANOMAD) be a clue to a myelopathic process or central nervous system
which can also have marked sensory ataxia, areflexia, oph- disorder such as cerebral palsy. The relative absence of
thalmoparesis, bulbar involvement.58 At times, the patient muscle atrophy in a weak muscle may be suggestive of a
may present with transient positive sensory symptoms asso- primary demyelinating polyneuropathy or a superimposed
ciated with neck movements (Lhermitte’s sign), which should central nervous system disorder. The range of motion of the
lead one to look for a spinal cord lesion or multiple sclerosis. shoulder and the presence or absence of scapular winging
should be documented in any patient with shoulder pain.
Sensory examination should include pinprick sensation to
Table 8 Sensory ganglionopathies document any loss of small-fiber function, vibratory sensa-
tion, and proprioceptive sensation to evaluate large-fiber
Paraneoplastic syndrome78,79 function. Patients with significant joint position sensory loss
Immune-mediated (Sjögren’s syndrome,80 SLE, can develop involuntary piano-playing movements of their
celiac disease, autoimmune hepatitis)81 extended fingers. Testing pinprick sensation should start
Chemotherapy-induced18 with the area with suspected sensory deficits and move to
Vit B6 toxicity18 the area with normal sensation. One should avoid touching
the pin on the patient’s skin repeatedly to avoid the phe-
Friedreich’s ataxia82
nomenon of temporal summation. In a patient with length-
Infectious (HIV, EBV, VZV, HTLV-1)81 dependent sensory loss, one should start testing pinprick
Miller Fisher syndrome, Bickerstaff’s brainstem sensation distally in the toes or fingers and move proximally
encephalitis83 to document the level of sensory deficit. The pressure of the
Cerebellar ataxia, neuronopathy, vestibular areflexia pin against the skin should be held constant as much as
syndrome (CANVAS)84 possible. When done properly, one can document sensory
Abbreviations: EBV, Epstein–Barr virus; HIV, human immunodeficiency
loss to pinprick sensation with some degree of reproducibil-
virus; HTLV-1, human T-cell leukemia virus type 1; SLE, systemic lupus ity over time to monitor the patient’s sensory loss. In the
erythematosus; VZV, varicella zoster virus. lower extremity, vibratory sensation can be documented to

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524 Approach to Peripheral Neuropathy Siao, Kaku

be absent or present in the toes, dorsal foot, ankle, mid-shin, The Role of Nerve Conduction Studies/
knee, and hip. In the upper extremity, vibratory sensation Electromyography in the Evaluation of
should be tested in the distal phalanx of the finger, knuckle, Peripheral Neuropathy
wrist, elbow, and shoulder. If present, one can time the
duration when the patient can feel the vibration. When The following discussion is primarily focused on the role of
testing joint position sense, the patient should relax their NCS/EMG in the evaluation of patients with generalized
limbs and the examiner should hold the sides of the finger, neuropathy or polyneuropathy (►Table 9). NCS/EMG pro-
wrist, toe, or ankle to avoid pressing down on the top or the vides the clinician neurophysiologic confirmation that the
bottom of the limbs. The speed and degree of passive joint patient has large-fiber peripheral neuropathy. In contrast,
movements should be also consistent. Faster speed and patients with pure small-fiber neuropathy will not have
greater displacement of the joint would be less sensitive in nerve conduction abnormalities.
detecting sensory deficits. NCS/EMG should be considered an extension of the
Muscle strength testing of the upper and lower extremi- neurological examination. The process starts with a brief
ties should be performed and documented in a consistent neuromuscular consultation. Prior to NCS/EMG, the clinical
fashion to allow the clinician to make a conclusion, with a neurophysiologist begins with the history (including the ques-
reasonable level of certainty, regarding the stability of the tion being asked by the ordering physician), a focused neuro-
peripheral neuropathy. Examination should include an logical examination, formulation of a clinical diagnosis with a

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observation of the patient’s gait and the ability to stand up differential, and then designs the NCS/EMG. The design of the
from a chair, with or without the use of the hands to push up. NCS/EMG is an active process. Depending on the clinical
To detect mild weakness of the gastrocnemius muscle, one scenario, the patient’s tolerance to the discomfort of the
should ask the patient to walk on their toes and observe for studies, and the stability of the temperature of the patient’s
any drop in the heels. The strength of neck flexors is best limbs, the neurophysiologist has to decide on the number and
tested with the patient supine. Hip flexion strength is best sequence of NCS and needle EMG examination. Toward the end
assessed with the patient supine and the knee bent. Any of the neurophysiologic evaluation, the neurophysiologist
associated low back pain while testing hip flexion should be should try to answer the referring physician’s questions. If
documented. Likewise, patients with shoulder pain may the neurophysiologist has an alternate diagnosis, relevant to
complain of shoulder pain when testing the strength of the the patient’s clinical problem but not being entertained by the
deltoid. referring physician, the neurophysiologist should perform the
Muscle strength testing of the upper extremities should appropriate studies to confirm or exclude the diagnosis.
include the major muscles (deltoid, biceps, triceps, flexor A common clinical scenario is a patient with predominantly
carpi radialis, first dorsal interosseous, abductor digiti min- lower extremity symptoms who presents to the EMG labora-
imi, and abductor pollicis brevis). Depending of the clinical tory with a referral for NCS/EMG of the lower extremities. The
problem, the strength of other muscles such as flexor dig- sensory potentials in the lower extremities are all absent and
itorum profundi, flexor pollicis longus, flexor carpi ulnaris, the motor responses are either very small or absent. These
extensor digitorum communis, extensor carpi radialis, ex- findings would not allow the neurophysiologist to conclude if
tensor carpi ulnaris, infraspinatus, and supraspinatus should the polyneuropathy is primarily axonal or primarily demye-
be documented. In the lower extremities, muscle strength linating. The neurophysiologist should take the initiative to
testing should include the following major muscles (extensor perform additional NCS of the upper extremities, with or
halluces, flexor halluces, tibialis anterior, tibialis posterior, without proximal stimulations (Erb’s point or cervical root
peroneus longus, gastrocnemius, quadriceps femoris, ham- stimulation), or blink reflexes, to evaluate for possible primary
strings, iliopsoas, and gluteus maximus). demyelinating polyneuropathy.

Table 9 Role of NCS/EMG in polyneuropathy

1. To confirm the presence or absence of large-fiber polyneuropathy

2. To identify the predominant nerve fiber involved (sensory, motor, or sensorimotor)
3. To demonstrate the existence of superimposed compression neuropathies or radiculopathies
4. To demonstrate the distribution of nerve involvement (distal symmetric, multiple mononeuropathy, polyradiculoneuropathy,
predominantly involvement of upper or lower extremities)
5. To determine the underlying pathophysiologic process (primary axonal or primary demyelinating)
6. To show the symmetry or the asymmetry of the polyneuropathy
7. To determine the severity of the polyneuropathy
8. To determine if the polyneuropathy is acquired or inherited
9. To follow patients over time to show the stability, worsening, or improvement of the polyneuropathy
10. To monitor the effects of therapeutic interventions on the polyneuropathy

Abbreviations: NCS, nerve conduction studies; EMG, electromyography.

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 Approach to Peripheral Neuropathy Siao, Kaku 525

Table 10 Primary demyelinating polyneuropathy

GBS
CIDP
CIDP variants (MMN, DADS, MADSAM, POEMS, MGUS,
Waldenstrom’s macroglobulinemia, CISP, anti-MAG
neuropathy, gait disorder, antibody, late-age onset,
polyneuropathy [GALOP] syndrome)
Diphtheria
Toxic exposure (hexane, arsenic, buckthorn, tellurium)
Drugs (amiodarone,67 gold, taxols)
Fig. 1 Markedly prolonged distal motor latency.
Abbreviations: CIDP, chronic inflammatory demyelinating polyradicu-
loneuropathy; DADS, distal acquired demyelinating symmetric neu-
ropathy; CISP, chronic immune sensory polyradiculopathy; GBS,
Guillain–Barré syndrome; MADSAM; multifocal acquired demyelinating
sensory and motor neuropathy; MGUS, Monoclonal gammopathy of
undetermined significance; MMN, multifocal motor neuropathy;

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POEMS, Polyneuropathy, organomegaly, endocrinopathy, monoclonal
gammopathies, and skin changes.

Primary Axonal versus Primary Demyelinating

Polyneuropathy
The primary role of a clinician is to determine the etiology
and treat the polyneuropathy appropriately. Finding the
etiology will lead to appropriate treatment. One important
role of NCS/EMG or the neurophysiologist is to help catego-
rize the polyneuropathy as primary axonal or primary de-
myelinating. One cannot overemphasize the fact that the
Fig. 2 Markedly prolonged F latency.
finding of a primary demyelinating polyneuropathy narrows
down the differential diagnosis of polyneuropathy dramati-
cally and increases the chances of finding an acquired and
treatable etiology of the polyneuropathy (►Table 10).
Categorizing polyneuropathy as primary axonal versus
primary demyelinating is usually based on changes in motor
NCS. In general, sensory NCS are not used to show evidence of
a primary demyelinating polyneuropathy because SNAPs are
very small (measured in microvolts). The SNAP is actually a
compound SNAP. It is the summation of many different
individual single sensory fiber action potentials. Any in-
crease in temporal dispersion (due to demyelination) of a
SNAP often results in an unrecordable potential. In contrast,
compound muscle action potentials (CMAPs) are significant- Fig. 3 Markedly slow motor nerve conduction velocity.
ly larger (measured in millivolts). Temporal dispersion of a
CMAP would result in a markedly dispersed morphology. block of the tibial nerve between the ankle and popliteal
Therefore, primary demyelinating polyneuropathy can be fossa is also not strong evidence of primary demyelination
documented with markedly prolonged distal motor latency unless it is shown to be asymmetric. The absence of F
(►Fig. 1), very prolonged F latencies (►Fig. 2), very slow response in the presence of a distal CMAP amplitude >80%
conduction velocity (►Fig. 3), and markedly dispersed of lower limit of normal can be a demyelinating feature. The
CMAPs or prolonged CMAP duration (►Fig. 4). Focal demye- finding of markedly reduced neurogenic recruitment (needle
lination causing conduction block can be documented as EMG examination) in a muscle with a relatively normal
motor conduction block (►Fig. 5) if one can stimulate the amplitude motor response can be considered as evidence
nerve distal and proximal to the site of conduction of proximal demyelination.86 The study of the blink reflex
block. ►Table 11 shows the motor nerve conduction features can support the diagnosis of primary demyelinating poly-
of primary demyelination. Motor conduction block of the neuropathy.87 Axonal polyneuropathy is usually length-de-
ulnar nerve across the elbow or the median nerve across the pendent. Since the blink reflex is mediated by very short
wrist are not considered strong evidence of primary demye- cranial nerves (trigeminal sensory fibers and facial motor
linating polyneuropathy because these are common sites of fibers), it is usually preserved in patients with severe axonal
entrapment neuropathies. The finding of motor conduction polyneuropathy.

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526 Approach to Peripheral Neuropathy Siao, Kaku

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Fig. 4 Markedly dispersed motor response or prolonged CMAP duration. CMAP, compound muscle action potential.

Fig. 5 Motor conduction block. Fig. 6 Very small motor response with no temporal dispersion in
axonal polyneuropathy.
Table 11 Motor nerve conduction features of primary
demyelination

Markedly prolonged distal motor latency

Markedly prolonged F latencies
Markedly slow motor nerve conduction velocity
Abnormal temporal dispersion of motor responses
Motor conduction block

The quest to find neurophysiologic evidence of primary

demyelinating polyneuropathy can be time consuming.
When the polyneuropathy is severe, motor NCS of the lower Fig. 7 Very small motor response with abnormal temporal dispersion
extremities are oftentimes not helpful because the motor may be seen in either severe axonal polyneuropathy or primary
responses are either absent or very small. The finding of very demyelinating polyneuropathy.
small and synchronous motor responses with mildly reduced
velocities is indicative of a primary axonal process (►Fig. 6). dysmyelinating polyneuropathy from an acquired primary
In contrast, the finding of normal or mildly reduced ampli- demyelinating polyneuropathy. The underlying pathologic
tude motor responses with abnormal temporal dispersion is process in the demyelinating (or more appropriately called
indicative of a primary demyelinating process (►Fig. 4). “dysmyelinating”) type of inherited neuropathies, such as
However, the finding of very small and dispersed motor CMT disease type IA, is an abnormal development of the
responses with very slow velocity and prolonged distal myelin sheath. Since all the nerve fibers are uniformly
latencies may be seen in either severe axonal polyneurop- affected, the recorded motor response is synchronous
athy or in severe primary demyelinating polyneuropathy (►Fig. 8A). In acquired demyelinating polyneuropathy such
(►Fig. 7). Motor NCS can also help differentiate an inherited as CIDP or the demyelinating type of GBS, the underlying

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 Approach to Peripheral Neuropathy Siao, Kaku 527

pathology is patchy demyelination. Since the nerve fibers are

not uniformly affected, the recorded motor response often
shows abnormal temporal dispersion (►Fig. 8B). However,
there are exceptions. Some demyelinating types of inherited
neuropathies can have motor responses with abnormal
temporal dispersion.
When faced with a patient with polyneuropathy, an
important role of a clinical neurophysiologist is to help
categorize the polyneuropathy as primary demyelinating
or primary axonal. Therefore, if the motor responses in the
lower extremities are absent or very small, the next step is to
perform motor NCS of the upper extremities. Motor NCS in all
four limbs may be required to find evidence of a primary
demyelinating polyneuropathy. In addition to the median
and ulnar nerves, a commonly neglected nerve is the radial
nerve. We have seen a few patients with primary demyelin-
ating polyneuropathy in which the radial motor NCS provid-

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ed crucial evidence of demyelination. The question of which
nerves to study, how many nerves to study, and how many
sites to stimulate for each nerve (the need for proximal
stimulation) should be individualized. Since NCS can be
used to monitor patients with CIDP for many years, having
a four-limb baseline study can be helpful. We have devised an
Fig. 8 Hereditary dysmyelinating polyneuropathy (A) versus ac- algorithm that can help guide the novice neurophysiologist
quired demyelinating polyneuropathy (B).
in the evaluation of patients with polyneuropathy with the

Table 12 Algorithm of nerve conduction studies in patients with different clinical presentations to increase the diagnostic yield of
primary demyelinating polyneuropathy

1. Symmetric distal sensory loss with or without distal weakness with symptoms and signs limited to the lower extremities
(LEs; mild sensorimotor polyneuropathy presentation)
Start with nerve conduction studies of bilateral LEs. One may have to evaluate for possible superimposed lumbosacral
radiculopathy.
If the motor nerve conduction studies in the LEs are normal and the sensory potentials are abnormal, this is likely an axonal
neuropathy.
If the motor nerve conduction studies in the LEs are abnormal or the clinical suspicion of a primary demyelinating
polyneuropathy is high, proceed to the upper extremities (UEs) for possible subclinical motor nerve conduction abnor-
malities.
2. Symmetric distal sensory loss with or without weakness with symptoms and signs in the LEs more than the UEs (moderate to
severe sensorimotor polyneuropathy presentation)
Start with bilateral LEs and proceed to the UEs. One may have to evaluate for possible superimposed radiculopathy and
compression neuropathies. Include F responses and H-reflexes. If the criteria for primary demyelinating polyneuropathy are
not met, consider radial motor nerve conduction study, blink reflex, and proximal stimulation at the Erb’s point and/or cervical
root.
3. Symmetric proximal and distal weakness of the upper and LEs with sensory loss (possible CIDP, GBS).
Start with one LE and one UE. If the criteria for primary demyelinating polyneuropathy are not met, proceed to the
contralateral side. Include F responses and H-reflexes. If necessary, perform radial motor nerve conduction study, blink reflex,
and proximal stimulation at the Erb’s point or cervical root.
4. Symmetric sensory loss (with or without weakness) with signs of upper motor neuron dysfunction (possible Vit B12 deficiency,
copper deficiency, Friedreich ataxia, metachromatic leukodystrophy, adrenomyeloneuropathy).
Start with one LE and one UE. Consider the contralateral extremities to rule out superimposed radiculopathy, compression
neuropathies.
5. Symmetric weakness without sensory loss (with distal weakness: possible hereditary motor neuropathy, with proximal and
distal weakness: possible spinal muscular atrophy).
Start with one LE and one UE. Consider the contralateral extremities to rule out superimposed radiculopathy, compression
neuropathies.
6. Asymmetric distal weakness without sensory loss and without signs of upper motor neuron dysfunction (possible multifocal
motor neuropathy, progressive muscular atrophy, juvenile monomelic amyotrophy, multifocal acquired motor axonopathy)
Start with bilateral UEs or bilateral LEs depending on the limbs that are most symptomatic. May need to study all four limbs to
show asymmetry and to increase diagnostic yield for demyelinating features. Include F responses and H-reflexes. If necessary,
perform radial motor nerve conduction study, blink reflex, and proximal stimulation at the Erb’s point or cervical root.
(Continued)

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528 Approach to Peripheral Neuropathy Siao, Kaku

Table 12 (Continued)

7. Asymmetric distal weakness with sensory loss but without signs of upper motor neuron dysfunction (possible MADSAM,
vasculitic neuropathy, HNPP)
Start with bilateral UEs or bilateral LEs depending on the limbs that are most symptomatic. May need to study all four limbs to
show asymmetry and to increase diagnostic yield for demyelinating features. Include F responses and H-reflexes. If necessary,
perform radial motor nerve conduction studies, blink reflex, and proximal stimulation at the Erb’s point or cervical root.
8. Asymmetric distal weakness without sensory loss but with signs of upper motor neuron dysfunction (possible ALS)
Start with one LE and one UE. Include needle EMG of cranial-innervated muscles and midthoracic paraspinals.
9. Asymmetric distal and proximal weakness with sensory loss (polyradiculopathy, plexopathy)
Start with bilateral UEs or bilateral LEs depending on the limbs that are most symptomatic. May need to study all four limbs to
show asymmetry and to increase diagnostic yield for demyelinating features. Include F responses and H-reflexes. If necessary,
perform radial motor nerve conduction studies, blink reflex, and proximal stimulation at the Erb’s point or cervical root.

Abbreviations: ALS, amyotrophic lateral sclerosis; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EMG, electromyography; GBS,
Guillain–Barré syndrome; HNPP, hereditary neuropathy with liability to pressure palsy; MADSAM; multifocal acquired demyelinating sensory and
motor neuropathy.

Table 13 EFNS/PNS electrodiagnostic criteria for diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

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1. Definite: at least one of the following:
a. Partial motor conduction block:
50% reduction in CMAP amplitude if distal CMAP is
20% of LLN (lower limit of normal) in
two nerves. If seen in only one nerve, then requires another demyelinating finding in another nerve
b. Abnormal temporal dispersion:
30% increase in proximal CMAP duration in two nerves
c. Conduction velocity:
30% reduction below LLN in two nerves
d. Distal motor latency:
50% above the ULN (upper limit of normal) in two nerves excluding median neuropathy at the wrist
from carpal tunnel syndrome
e. F latency:
30% above the ULN in two nerves
f. Absent F responses in two nerves if these nerves have distal CMAP
20% of LLN þ one other demyelinating parameter in one
other nerve
g. Increased distal CMAP duration in two nerves þ one other demyelinating parameter in one other nerve. (Median
6.6 ms,
ulnar
6.7 ms, peroneal
7.6 ms, tibial
8.8 ms.)
2. Probable:
Partial conduction block or
30% amplitude reduction between distal and proximal stimulation sites (excluding the posterior
tibial nerve) if distal negative peak CMAP amplitude
20% of LLN in two nerves. If seen in only one nerve, then requires another
demyelinating finding in another nerve.
3. Possible:
Only one nerve meeting one of the definitive EDx parameters in (1)

Abbreviations: CMAP, compound muscle action potential; EFNS/PNS, European Federation of Neurological Societies/Peripheral Nerve Society.

primary goal of maximizing the diagnostic yield of motor Conflict of Interest

NCS in primary demyelinating polyneuropathy (►Table 12). None declared.
There are several neurophysiologic criteria available in
the literature that help diagnose patients with primary
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