Lewy Body Disord ers

Douglas Galasko, MD

KEYWORDS
 Lewy body  a-synuclein  Dementia  Diagnosis  Management

KEY POINTS
 Cognitive disorders associated with Lewy Bodies are arbitrarily divided into Parkinson’s
Disease-Dementia and Dementia with Lewy bodies depending on the order in which
symptoms arise.
 Clinical evaluation should include movement, cognition, behavior, sleep and autonomic
function.
 Biomarkers including brain imaging and polysomnography may be helpful diagnostic
tools.
 Medications can help to manage many of the diverse symptoms.

INTRODUCTION

Dementia syndromes associated with Lewy body pathology are subdivided into de-
mentia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD), arbitrarily
based on the timing of cognitive decline in relation to motor symptoms. DLB is an
underdiagnosed cause of dementia in the elderly. In addition to symptoms of Alz-
heimer disease (AD) and Parkinson disease (PD), DLB has distinctive neurobehavioral
and cognitive features.1,2 A major clinical diagnostic question is how to distinguish
DLB and AD. PDD starts with the movement disorder characteristic of PD, followed
by cognitive decline after years or even decades. PDD, therefore, is not a diagnostic
puzzle. The distribution of pathology in DLB and PDD helps to explain the diversity of
symptoms.3,4 The key pathologic feature in these disorders is aggregation of the pro-
tein a-synuclein, forming structures called Lewy bodies (LB) in neuronal cell bodies
and neurites in neuronal processes. Much evidence implicates the spread of a-synu-
clein between neurons in the progression of disease.

Disclosures: Dr D. Galasko has received research funding from the National Institute on Aging,
the California Institute for Regenerative Medicine, the Alzheimer’s Drug Discovery Foundation,
and from the Michael J. Fox Foundation. He has received honoraria for serving as an advisor to
vTv Therapeutics. He is a paid editor for the journal Alzheimer’s Research and Therapy. He has
served on data safety boards for Eli Lilly and Company and Prothena Inc.
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla,
CA 92093-0948, USA
E-mail address: dgalasko@ucsd.edu

Neurol Clin 35 (2017) 325–338

http://dx.doi.org/10.1016/j.ncl.2017.01.004 neurologic.theclinics.com
0733-8619/17/ª 2017 Elsevier Inc. All rights reserved.
326 Galasko

THE WHAT AND WHERE OF DEMENTIA WITH LEWY BODIES PATHOLOGY

In addition to the classic involvement of the substantia nigra in PD, a-synuclein pathol-
ogy has a predilection for the olfactory nerve, branches and nuclei of the vagus nerve,
and the locus ceruleus and other brainstem nuclei.5 Dysfunction of these structures
results in loss of sense of smell, constipation and autonomic dysfunction, altered alert-
ness, and rapid eye movement (REM) sleep behavior disorder (RBD), which are com-
mon to both PD and DLB and may precede motor or cognitive symptoms by years.6 In
DLB and PDD, a-synuclein pathology includes cortical regions of the brain.
In DLB, there are 3 variations of a-synuclein pathology: brainstem predominant,
limbic (also called transitional), and neocortical. Brainstem lesions affect the substan-
tia nigra, nuclei of the vagus and glossopharyngeal nerves, reticular nuclei, and locus
ceruleus. Limbic or transitional pathology occurs in the amygdala, transentorhinal cor-
tex, and cingulate. Neocortical pathology is found in areas such as the temporal, fron-
tal, and parietal cortex. Limbic and neocortical a-synuclein lesions are associated with
clinical features characteristic of DLB and also distinguish PDD from PD.4 AD pathol-
ogy often coexists in DLB and PDD. Concomitant AD pathology contributes to cogni-
tive impairment and may mask or attenuate the neurobehavioral features of DLB.
Unlike AD pathology, LB and Lewy neurites in the neocortex are not obviously asso-
ciated with neuron loss or atrophy.
Is the association of AD and a-synuclein lesions a coincidence? In sporadic DLB
and PDD, AD pathology may also be present simply because of age. However, about
20% to 30% of patients with autosomal dominant early onset familial AD have wide-
spread a-synuclein pathology,7 and a similar proportion of people with Down syn-
drome (DS), who develop accelerated AD pathology, also have a-synuclein lesions.
This finding suggests more than a chance relationship because the onset of dementia
in familial AD and DS is younger than the typical age of onset of PD. How amyloid pa-
thology may accelerate a-synuclein aggregation in a subset of people is unknown.

EPIDEMIOLOGY AND RISK FACTORS

Autopsy studies from research centers suggest that DLB pathology occurs in about
20% to 25% of cases of dementia in the elderly. However, more thorough studies us-
ing antibodies against a-synuclein reveal amygdala pathology in as many as 40% to
50% of cases. The clinical significance of amygdala-only a-synuclein pathology is un-
clear, as no unique or characteristic features identify these patients during life. In
brains originating from community-based studies, the frequency of DLB pathology
is lower, about 10%.8 The prevalence of DLB has rarely been assessed in
population-based clinical studies. It is estimated to account for about 4% of cases
of dementia in community-based studies and about 7% in clinic series.9 Clinical
and pathologic studies indicate that age is a risk factor for DLB: the typical age at
onset ranges from about 70 years to 85 years. DLB is more common in men than
women, as is RBD, one of the characteristic symptoms associated with brainstem
LB. DLB has been studied mainly among Caucasian and Japanese populations,
and its worldwide occurrence is unknown. Although there are no environmental fac-
tors that have been definitively shown to modify the risk of DLB or PDD, one study
has suggested that caffeine intake may be a protective factor.10
Cognitive impairment is common in PD, and dementia may eventually affect as many
as 80% of patients.11,12 Age and PD duration are the leading risk factors for PDD. The
underpinnings of PDD include degeneration of nuclei and pathways involving cholin-
ergic, dopaminergic and noradrenergic pathways,13 a-synuclein pathology in the
medial temporal lobe, and coexisting AD pathology in more than 50% of cases.14
 Lewy Body Disorders 327

Many genetic alterations contribute to PD. The most common of these are leucine
rich receptor kinase 2 (LRRK2) mutations (particularly G2019S, which is found world-
wide, with an increased frequency in people of Ashkenazi Jewish or North African
descent) and glucocerebrosidase A (GBA) mutations. Mutations in the gene for a-syn-
uclein (SNCA) are rare. People with PD due to GBA and SNCA mutations have a high
likelihood of developing cognitive decline and a clinical picture of DLB. Genome-wide
association studies for late-life DLB or PDD have identified 5 genes linked to PD that
are also associated with the risk for DLB and/or PDD, namely, GBA, LRRK2, microtu-
bule-associated protein tau (MAPT), scavenger receptor class B member 2 (SCARB2)
and SNCA.15 Also, apolipoprotein E (APOE) e4, the strongest genetic risk factor for
late-onset AD, is linked to DLB and PDD.16 Shared PD and AD genetic risk is consis-
tent with the admixture of a-synuclein and AD pathology in DLB. Although genetic fac-
tors may shed light on mechanisms of disease, there is no role for clinical genetic
testing in DLB or PDD at present.

DIAGNOSTIC CRITERIA AND A CLINICAL APPROACH TO PARKINSON DISEASE WITH

DEMENTIA AND DEMENTIA WITH LEWY BODIES

Diagnostic criteria for PDD17 focus on the assessment of cognitive decline and its
impact on functional abilities. At the stage of PD when dementia typically occurs,
neuropsychiatric, sleep, movement, and autonomic symptoms may be present. The
difficult part of the diagnosis is determining whether functional impairment results
from cognitive changes and is not solely due to advanced motor features of PD. By
contrast, the major clinical problem in DLB is distinguishing it from AD. Diagnostic clin-
ical criteria for DLB were developed in 19961 and updated in 2005.2 The 1-year rule
was proposed to split DLB and PDD: PDD is diagnosed if motor symptoms precede
cognitive decline by more than a year; DLB is used if cognitive decline precedes or ac-
companies the first motor symptoms. These distinctions are arbitrary, and it may
sometimes be difficult to judge which symptom started first. Separating DLB and
PDD has been questioned because the clinical features and brain pathology overlap.
However, for research purposes and to enhance diagnostic awareness, DLB remains
a useful concept. Table 1 lists the clinical features and Table 2 the biomarkers that
may be used to evaluate patients with PDD and DLB. The discussion that follows fo-
cuses on DLB, but the approach to PDD is similar.

CORE CLINICAL FEATURES

The essential feature of DLB is the D (dementia), referring to cognitive decline sufficient
to interfere with independence in complex daily activities. This cognitive decline typi-
cally has a gradual onset. Progression is similar to that of AD, although sometimes
DLB may progress more rapidly. The pattern of cognitive impairment in DLB may differ
from AD, with selective deficits on tests of attention, visuospatial, and executive func-
tion.18 Symptoms related to visuospatial difficulty include sitting down on the edges of
chairs, tripping on stairs, or misjudging distances while driving. General cognitive
symptoms in DLB include forgetfulness; impaired judgment, organization, and plan-
ning; and getting lost. Memory impairment may not be prominent early in DLB, although
patients with significant concomitant AD pathology show deficits on tests of memory
and learning. Brief screening tests, such as the Mini-Mental State Examination
(MMSE), may be insensitive to the early cognitive changes of DLB or PDD. Formal neu-
ropsychologic testing can more clearly identify deficits characteristic of DLB.
The clinical features of fluctuation, hallucinations, and parkinsonism are called core
features of DLB.1 The original diagnostic criteria for DLB specified that dementia plus 2
328 Galasko

Table 1
Clinical and diagnostic features of dementia with Lewy bodies and Parkinson disease with
dementia

DLB PDD
Major clinical features
Chronology of Dementia precedes or Motor symptoms precede
symptoms occurs together with dementia by 12 mo or
onset of motor features longer, often by many
of parkinsonism. years.
Dementia It may have prominent It is similar to DLB.
deficits on tests of
attention, executive
function, and
visuospatial ability.
Memory impairment is
often less prominent at
onset but occurs with
progression and if there
is concomitant AD.
Fluctuating cognition There is marked variation in It may be present.
alertness and attention.
Hallucinations It is recurrent, most often It is often present.
visual, well formed (eg,
people, animals), and
detailed.
Motor parkinsonism It is variable, may be mild; It is more likely to be
tremor is often absent. moderate to severe when
dementia develops.
RBD RBD is more common in men. It may precede DLB or PDD.
Associated clinical Features include daytime sleepiness, transient episodes of
features unresponsiveness, neuroleptic sensitivity, orthostatic
hypotension, urine incontinence, constipation, falls, and
anosmia.

Clinical features grouped as associated have been called supportive or suggestive in consensus
criteria for DLB and also occur commonly in PDD but are not essential for diagnosis.
Adapted from Refs.2,15,57

or more core features (fluctuation, hallucinations, parkinsonism) defined probable

DLB. One core feature indicated possible DLB, whereby there is a lower likelihood
that a-synuclein pathology contributes to dementia. These criteria are currently under
revision and will elevate RBD to a core feature and include the use of biomarkers to
support a diagnosis of probable DLB.
Fluctuation refers to changes in alertness, attention, and cognition and includes pe-
riods of decreased attention, staring spells, or confusion, lasting from seconds to
hours. Although it is sometimes striking, fluctuation may be difficult to identify in
DLB. Research tools to assess fluctuation include a detailed informant-based diary
or the use of psychometric tests that measure variability in choice reaction time. A brief
questionnaire about fluctuation19 and a set of 4 questions about daytime drowsiness,
sleeping 2 hours or more per day, staring into space, or episodes of disorganized
speech20 are more practical. In patients with varying alertness, delirium may need
to be considered; the workup should include factors such as infection, dehydration,
 Lewy Body Disorders 329

Table 2
Neuroimaging and other biomarkers in the diagnosis of Lewy body dementia

Biomarker DLB PDD

Dopamine transporter Low dopamine transporter Not needed for diagnosis
imaging using SPECT uptake in basal ganglia unless PD has not been
or PET previously diagnosed
MIBG cardiac scintigraphy Decreased uptake
Polysomnography Confirms RBD
Can identify other sleep problems, for example, obstructive
sleep apnea, periodic movements of sleep
MRI structural imaging Relative preservation of medial temporal lobe structures,
unless AD is also present
EEG Prominent posterior slow- —
wave activity on EEG with
periodic fluctuations in
the prealpha/theta range
CSF Ab42, tau, P-tau 181 Concomitant AD pathology indicated by decreased CSF Ab42
and increased tau or P-tau 181
CSF a-synuclein Decreased levels of a-synuclein in CSF in DLB or PDD not
diagnostically helpful because of extensive overlap with
controls and with AD

Abbreviations: CSF, cerebrospinal fluid; EEG, electroencephalogram; MIBG, metaiodobenzylguani-

dine; SPECT, single-photon emission computed tomography.

uncontrolled medical disorders, and the effects of central nervous system–active

medications.
Hallucinations, most commonly visual, are characteristic of DLB. Patients typically
report recurrent, complex visual hallucinations, for example, seeing people, animals,
or insects, and may describe them in great detail.1 Patients may misinterpret shadows
or patterns as people or objects, referred to as illusions. Patients with DLB with visual
hallucinations have more severe visuospatial dysfunction than those without.21 Pa-
tients may find the hallucinations frightening and can develop delusions related to
them. In PD, hallucinations occur in about 30% of patients, persist even after doses
of dopaminergic medications are decreased, and may be a predictor of dementia.
The anatomic basis of hallucinations is not clear, although weakening of interactions
between neural networks for attention and conscious perception may be important.22
The burden of LB in the inferior temporal lobe plus cholinergic deficits in the temporal
lobe and other cortical areas may play a role. Visual hallucinations occurring only in a
setting of delirium are not evidence for a diagnosis of DLB. In the presence of severe
vision loss, recurrent and vivid visual hallucinations suggest Charles Bonnet syndrome
rather than DLB.
In DLB, parkinsonian motor signs may be milder than those typically found in idio-
pathic PD.23,24 Rest tremor may be less common in DLB than in PD/PDD; axial signs,
such as stooped posture, slowing of gait, and postural instability, may be more
prominent. Tremor in DLB may worsen with walking or show overflow (involvement
of a wider distribution of muscles) when standing.25 Assessment of parkinsonism
in patients with advanced dementia may be difficult because cognitive impairment
and apraxia limit their ability to follow instructions to perform motor tasks. Assess-
ment of gait and postural instability are an important part of the examination regard-
less of diagnostic specificity. Patients with DLB do not always show a good or
330 Galasko

prolonged response to L-dopa, but a trial of treatment is warranted.26 This point may
be explained by widespread pathology in DLB that directly affects the striatum and
also by deficits in nondopamine neurotransmitter pathways. Other causes of slowing
of gait and impaired balance in elderly people include vascular pathology affecting
subcortical structures (eg, extensive white matter hyperintensities on MRI or lacunar
infarcts) as well as arthritis, pain, deconditioning, and fear of falling. Parkinsonian
findings may also be secondary to dopamine receptor blocking actions of potent
neuroleptic drugs.
RBD occurs frequently in patients with a-synuclein pathology, including DLB, PD,
and multisystem atrophy.27 It may precede these diagnoses by years, consistent
with the idea that a-synuclein pathology spreads or advances from the reticular acti-
vating system and nuclei such as the locus ceruleus to the substantia nigra and later to
limbic and cortical regions. RBD is much more common in men than women. Its symp-
toms are due to the lack of motor inhibition during REM sleep. During periods of REM
sleep, patients make vocalizations and movements, such as shouting, grunting,
thrashing, punching, or kicking, and seem to act out their dreams. They may describe
frightening dreams if awakened, such as being chased. Symptoms of RBD can be dis-
turbing to the patients’ bed partner and can result in injuries if patients fall out of bed.
The history alone may strongly indicate RBD. A formal sleep study may be needed
to confirm RBD if there is serious sleep disruption. Other disturbances during
sleep and arousal are common in DLB and PDD, including daytime drowsiness,
obstructive sleep apnea, and periodic limb movements in sleep, and may warrant
polysomnography.

SUGGESTIVE FEATURES FOR DEMENTIA WITH LEWY BODIES

Several clinical features in patients with DLB are either less specific or not common
enough to be considered as core features. These features have been termed sugges-
tive in consensus criteria for DLB and include neuroleptic sensitivity, autonomic
symptoms, repeated falls, delusions, and depression. Neuroleptic sensitivity was first
reported in elderly patients with DLB treated with typical antipsychotic medications
but later in some patients treated with atypical agents.1,2‘Sensitivity included marked
cognitive and motor deterioration that could require hospitalization and was some-
times fatal. Therefore, use of neuroleptics in DLB is discouraged and a neuroleptic
challenge should not be considered as a diagnostic test. Dysfunction of the auto-
nomic nervous system is common in DLB, PD, and PDD and due to a-synuclein pa-
thology in central autonomic pathways, such as branches of the vagal nerve or in
neurons in paraspinal autonomic ganglia. The most prominent symptoms are ortho-
static hypotension and syncope, whereas others may include erectile dysfunction,
excess salivation, constipation, altered sweating, and seborrhea. Transient loss of
consciousness or awareness may be due to presyncope or to fluctuation. Urine in-
continence is common in dementia and aging from a variety of causes and is not
a specific indicator of autonomic problems in DLB. Patients with DLB and PDD
may have repeated falls because of parkinsonism, impaired postural reflexes, auto-
nomic impairment and impaired visuospatial judgment, and also general factors,
such as aging, deconditioning due to lack of activity, and dementia. Delusions are
fairly common in DLB, as in other dementias. In some patients they may relate to
the visual hallucinations and may be systematized. Depression is common in DLB.
Apathy without a depressed mood may be prominent, although not specific. With
the progression of dementia, anxiety and agitation often develop and may require
treatment.
 Lewy Body Disorders 331

EARLY STAGES OF PARKINSON DISEASE WITH DEMENTIA AND DEMENTIA WITH LEWY
BODIES

Disease-modifying treatment of PDD and DLB is more likely to succeed when started
as early as possible; therefore, early diagnosis is a priority. For PD, a stage of mild
cognitive impairment (MCI) was recently defined28 and prodromal DLB is being stud-
ied.29 Loss of sense of smell and constipation are overrepresented in patients with
DLB and PD, and may occur years before cognitive or motor symptoms. However,
these symptoms are nonspecific. RBD is a strong predictor of PD or DLB.30 The cogni-
tive profile of MCI that progresses to PDD or DLB varies: in some patients, mild deficits
on visuospatial and executive tests occur, but others show an amnestic picture. Fluc-
tuations and hallucinations rarely precede the general picture of DLB.

BIOMARKERS

Neuroimaging markers can help in the diagnostic workup of DLB. For PDD, they have
research utility, because dementia is a clinical diagnosis in the setting of an estab-
lished diagnosis of PD. Although there is no way to image or biochemically detect ag-
gregates of a-synuclein in the brain, imaging may provide indirect evidence of
a-synuclein pathology. Dopamine nerve terminal density in the basal ganglia, reflect-
ing projections from the substantia nigra, can be imaged using single-photon emis-
sion computed tomography (eg, DaTscan) or PET. Decreased binding has
sensitivity of about 80% for DLB and high specificity to distinguish DLB from
AD.31,32 Peripheral sympathetic cardiac denervation, imaged using metaiodobenzyl-
guanidine scintigraphy, is highly sensitive and specific for DLB.33,34 Occipital lobe
hypometabolism occurs on fluorodeoxyglucose (FDG) PET imaging in about 70%
to 80% of patients with DLB but not in AD.35 The pathologic basis of this finding is
not clear. The cingulate island sign, an area of preserved normal uptake in the mid-
cingulate or posterior cingulate, is another FDG PET feature that is characteristic of
DLB.36
MRI shows relative preservation of the hippocampus and medial temporal lobe in
DLB compared with AD and cannot clearly distinguish DLB from other causes of de-
mentia.37 Longitudinal MRI studies show similar rates of atrophy in patients with AD
and those with DLB with concomitant AD.38 In PD-MCI and PDD, changes on MRI
include cortical atrophy, often with preservation of medial temporal lobe structures,
and changes in white matter tracts.39 PET imaging methods that detect fibrillar am-
yloid beta protein allow AD plaque pathology to be diagnosed during life. In one of
the larger studies to date that examined people with a spectrum of a-synuclein dis-
orders, those with DLB had a higher amyloid burden than those with PDD, PD-MCI,
PD, or age-comparable controls. In DLB but not the other groups, the extent of am-
yloid burden correlated with scores on tests of semantic memory but not other
cognitive domains.40 This finding suggests that fibrillar amyloid pathology may be
more relevant to DLB than to PDD. PET imaging probes of abnormal fibrillar forms
of tau were recently developed. In a preliminary study in PD/DLB/PDD, some pa-
tients showed increased tau uptake in areas, such as the inferior temporal gyrus, pre-
cuneus, and neocortex, which correlated with impaired cognition. This finding
reaffirms that tau pathology may contribute to cognitive deficits across the PD/
PDD/DLB spectrum.41
Analysis of electroencephalogram shows differences between DLB and AD,
particularly in posterior regions (reviewed in Ref.42), but measures and methods
have not been validated for routine use. Cerebrospinal fluid (CSF) biomarkers
can provide evidence of AD-related pathophysiology (low CSF Ab42 and high
332 Galasko

tau). Patients with DLB are more likely to have low CSF Ab42, sometimes with
increased total tau or phospho-tau (P-tau) 181.43 In a recent multicenter study,
about two-thirds of patients with DLB had decreased CSF Ab42 and almost one-
third had increased tau or P-tau levels. Abnormally low Ab42 or increased tau or
P-tau was associated with more rapid cognitive decline over 24 months.44 In pa-
tients with PD, decreased CSF Ab42 is related to a higher risk of progressive
cognitive decline,45 consistent with amyloid PET studies indicating that coinci-
dental AD amyloid pathology is associated with faster clinical progression. CSF
levels of a-synuclein may be slightly decreased in DLB or PD relative to AD and
controls, but these are not diagnostically useful.45 Recently, it was found that olig-
omeric a-synuclein is increased in CSF in DLB and PDD46; this promising initial
finding requires validation.

MANAGEMENT AND TREATMENT OF PARKINSON DISEASE WITH DEMENTIA AND

DEMENTIA WITH LEWY BODIES

Overall management begins with a detailed evaluation of cognitive, behavioral, sleep,

movement, and autonomic symptoms. Education of the family and caregivers about
PDD or DLB, and about general concerns for patients with dementia, such as manag-
ing finances and medications, home safety, caregiving needs, and the importance of
cognitive and social stimulation and maintaining physical strength and walking skills,
are important. Organizations such as the Lewy Body Disorders Association (www.
lbda.org) and the Alzheimer’s Association (www.alz.org) are excellent resources for in-
formation about DLB, PDD, and caregiving.
Medications should be selected according to target symptoms. The decision to use
a medication depends on the severity of the symptoms; for example, mild, nonthreat-
ening, visual hallucinations may not require treatment. Table 3 shows target symp-
toms and lists some suggested medications. Of note, high-level evidence to
support treatment of the diverse symptoms associated with DLB or PDD does not
exist because there have been few clinical trials in this area.47 Some options can be
extrapolated from clinical trials on patients with AD or PD. In general, symptomatic
medications should be started at low doses and titrated in light of target symptoms
and side effects. It is best to introduce one new medication at a time to be able to
clearly interpret benefits and side effects. The diverse symptoms associated with
DLB and PDD often require use of multiple medications, some of which may interact.
For example, an acetylcholinesterase inhibitor (AChEI) for cognition, a selective sero-
tonin reuptake inhibitor (SSRI) for depression or apathy, an appropriate dose of L-dopa
for parkinsonism, and an atypical antipsychotic to control hallucinations may all be
needed. To limit the potential for drug-drug interactions, medications that do not
clearly help after a reasonable trial should be stopped.
For parkinsonism in DLB, a trial of L-dopa is recommended. Because L-dopa may
worsen neurobehavioral symptoms, a low dose should be started and increased
slowly. The clinical response to L-dopa may be less dramatic in DLB than in idiopathic
PD,26 although some patients show improvement in gait, movement speed, and even
alertness. Dopamine agonists are problematic in DLB because of their high risk of pro-
voking behavioral symptoms or other side effects. In PDD, similar careful titration of L-
dopa and other medications is needed to obtain the best balance between benefits
and side effects.
For cognitive impairment, a trial of an AChEI, such as donepezil, rivastigmine, or gal-
antamine, is worthwhile. Neuropathologic studies report a severe cholinergic deficit in
limbic and cortical regions in DLB, suggesting that these patients may be particularly
 Lewy Body Disorders 333

Table 3
Medications to treat symptoms of Lewy body dementia (Parkinson disease with dementia and
dementia with Lewy bodies)

Symptoms Medications Comments

Cognitive impairment
Forgetfulness, poor AChEIs: Tolerability of AChEIs possibly
attention, Donepezil limited by gastrointestinal side
fluctuation Rivastigmine effects
Galantamine Minimize concomitant
medications with
anticholinergic effects
Memantine Well tolerated, but small effect
Apathy, decreased Antidepressants, for Sometimes improves on L-dopa
initiative, example, SSRI or and/or AChEIs
psychomotor SNRI drugs Possible side effects, such as
slowing Stimulants, for orthostasis, with older
example, modafinil antidepressants, for example,
tricyclic antidepressants
Motor impairment
Bradykinesia, slowing L-dopa/carbidopa Hallucinations, anxiety, agitation,
of gait, increased sleepiness
tone, tremor Dopamine agonists, Higher risk of hallucinations in
for example, DLB and PDD
ropinirole
Neuropsychiatric symptoms
Hallucinations, AChEIs Small effects on these symptoms
delusions Clozapine Needs regular monitoring of
blood count
Risperidone, olanzapine, Black box warning, risk of
aripiprazole neuroleptic sensitivity
Quetiapine Black box warning
Short acting, wide dose range
Pimavanserine Effective in 6-wk RCT; lacks
postmarketing safety data
Agitation, insomnia Atypical antipsychotics Black box risks
Trazodone, gabapentin, No evidence from RCTs, but widely
topiramate, valproic acid used, for example, in AD
Depression Fluoxetine, paroxetine, Tolerance of SSRIs potentially
sertraline, citalopram better than TCAs in PD
Anxiety Paroxetine, sertraline, Minimal study in RCTs in PD
buspirone Benzodiazepines not
recommended because of
potential for confusion and falls
RBD Melatonin —
Clonazepam
Daytime Stimulants, for —
hypersomnolence example, modafinil
Autonomic impairment
Orthostasis Fludrocortisone Fluid retention, edema
Midodrine

Abbreviations: AChEIs, acetylcholinesterase inhibitors; RCT, randomized clinical trial; SNRI,

serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tri-
cyclic antidepressant.
334 Galasko

responsive to AChEI treatment. Randomized clinical trials of AChEIs have been con-
ducted in DLB48,49 and PDD.50 The first trial in DLB assessed rivastigmine and found
no major effect on the MMSE but significant improvement on computerized tests of
attention and a trend for benefit on behavioral symptoms. A later trial of donepezil
found benefits relative to placebo on the MMSE that were maintained with open-
label follow-up for 52 weeks.49 A trial of rivastigmine in PDD showed favorable
treatment-placebo differences in measures of cognition (including computerized
timed tests of attention), global ratings, and activities of daily living. Rivastigmine
did not affect parkinsonism, although 10% of patients showed worsening of tremor.47
Gastrointestinal side effects were the most common reason to discontinue AChEIs in
all of these trials. Although evidence is limited,47 it is reasonable to try an AChEI for
cognition or fluctuation in DLB or PDD. Memantine is approved for the treatment of
AD. In DLB and PDD, randomized clinical trials found that memantine was safe and
well tolerated and had small effects on global ratings and tests of attention but not
on other cognitive or behavioral symptoms.51,52
Apathy and decreased initiative may contribute to cognitive and functional impair-
ment and are not necessarily part of depression. Although L-dopa may incidentally
help these symptoms, other medications may be worth considering if apathy and
inertia are disabling. SSRI or serotonin-norepinephrine reuptake inhibitor antide-
pressants may be tried, with experience drawn from their extensive use in depres-
sion in PD.53 Sometimes apathy is accompanied by daytime hypersomnia.
Additional treatment possibilities in this situation may include stimulants, such as
methylphenidate or modafinil. Anxiety and depression may co-occur in PDD and
DLB. Although evidence from formal clinical trials is limited, analyses suggest that
SSRIs are better tolerated and may be more efficacious than tricyclic antidepres-
sants in PD.54
For behavioral symptoms, such as hallucinations, psychosis, and agitation, non-
medication approaches, for example, distraction, should be tried. For delusions and
agitation, the impact of general health factors (eg, pain, infections) and environ-
mental and interpersonal triggers should be explored. If high doses of L-dopa are
being used, reduction may lead to improvement. Visual hallucinations may require
drug treatment only if they are disturbing to patients. Sometimes AChEI treatment
may help with hallucinations.48 Typical neuroleptics should be avoided because of
risks of worsening parkinsonism or causing severe reactions with cognitive and mo-
tor decline (neuroleptic sensitivity). Atypical antipsychotic agents, such as olanza-
pine or risperidone, should be used cautiously because they have weak D-2
receptor blocking activity. Atypical antipsychotic agents, such as quetiapine or clo-
zapine, have support from clinical trials in PD with psychotic symptoms (reviewed in
Refs.47,53), although the blood monitoring required for clozapine makes it imprac-
tical. Many classes of medications have been tried for delusions and agitation in pa-
tients with dementia but lack evidence from randomized clinical trials. Medications,
such as trazodone, and anticonvulsants, such as valproate, gabapentin, or topira-
mate, may be considered. Sedatives, such as alprazolam, should be avoided
because of risks of confusion and falls. Meta-analyses of elderly patients treated
with neuroleptic medications have shown increases in morbidity and mortality,55
and these medications carry a black box warning from the Food and Drug Admin-
istration (FDA). Nevertheless, the judicious use of atypical antipsychotic agents,
such as quetiapine (which has an advantage of being short acting), can be consid-
ered, at least as a short-term intervention, with careful clinical monitoring for poten-
tial side effects, such as drowsiness. Pimavanserin, a serotonin inverse agonist,
recently received FDA approval for treatment of hallucinations and delusions
 Lewy Body Disorders 335

associated with PD psychosis56 based on 6 weeks of treatment in a randomized

clinical trial. Postmarketing data will be important to determine its longer-term ben-
efits and safety.
Sleep disorders in patients with DLB/PDD should be carefully characterized to
determine the best treatment. If the clinical description is inadequate or uncertain, pol-
ysomnography is helpful. For obstructive sleep apnea, standard approaches, such as
nasal continuous positive airway pressure or bi–positive airway pressure, may
improve symptoms. To control RBD symptoms, melatonin or clonazepam are worth-
while.27 For insomnia, similar medications to those used for agitation may be consid-
ered as well as low doses of benzodiazepines, such as zolpidem. Newer sleep-
promoting agents, such as eszopiclone, zaleplon, and extended-release zolpidem,
have a theoretic advantage of lower risk of tolerance but have not been formally stud-
ied in patients with DLB.

FUTURE DIRECTIONS

Revised diagnostic criteria and use of biomarkers may help to develop earlier and
more accurate diagnosis of DLB and stronger predictors of PDD. Further studies
will clarify whether there are biological and meaningful clinical differences between
DLB and PDD. Genetic studies may improve our understanding of mechanisms of
disease and suggest new treatment targets. Biomarkers that allow monitoring
of a-synuclein pathology would greatly help with disease staging and development
of disease-modifying treatment. Because the pathology of many patients with DLB in-
cludes deposition of amyloid beta protein, it is likely that antiamyloid treatments will be
useful in DLB and in some patients with PDD.

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