fffffffffffffffffffffffffffffffffffffffffffffffffffffffffffffffff

1. LEWY BODY DEMENTIA
Presenter: Dr Anagha N
Moderator: Dr.Prafulla J Wali

2. Introduction
• DLB is now considered to be the second most
common cause of dementia after Alzheimer disease
in the elderly.
• Operationalized diagnostic criteria for DLB have
been defined and revised over the past decade.
• DLB shares some clinical and pathological features
with both Alzheimer disease and Parkinson disease.
• As a result, complete discrimination among these
syndromes, even at autopsy, may not be possible.

3. Definition
• DLB is a neurodegenerative dementia characterized by progressive
cognitive decline of sufficient magnitude to interfere with normal social
or occupational function.
• Memory impairment needs not be prominent or persistent early in the
course of the illness.
• Deficits of attention and of frontal executive skills and visuospatial
ability may be more prominent early in the course.
• The core features of DLB include:
 (1) fluctuating cognition with pronounced variations in attention and
alertness,
 (2) recurrent visual hallucinations, which are typically well formed and
detailed, and
 (3) spontaneous motor features of parkinsonism.

4. Definition
• The presence of features that are suggestive of the diagnosis of
DLB are rapid eye movement (REM) sleep behavior disorder,
severe neuroleptic sensitivity, and low dopamine transporter
uptake in basal ganglia demonstrated by SPECT or PET imaging.
• Features supportive of the diagnosis include repeated falls and
syncope, transient unexplained loss of consciousness, severe
autonomic dysfunction, hallucinations in other modalities,
systematized delusions, depression, relative preservation of
medial temporal lobe structures on CT/MRI scan, generalized
low uptake on SPECT/PET perfusion scan with reduced occipital
activity, abnormal (low uptake) metaiodobenzylguanidine
myocardial scintigraphy, and prominent slow wave activity on
EEG with temporal lobe transient sharp waves.

5. History
• Lewy bodies, the intracytoplasmic, spherical, eosinophilic neuronal
inclusion bodies, identified originally in subcortical nuclei as one of
the hallmarks of idiopathic Parkinson disease, have also been
identified in the brain stems and cortex of elderly demented patients.
• Lewy body disease was first described in 1984 by Kosaka, who
distinguished “diffuse” Lewy body disease, where Lewy bodies are
present throughout cortical regions, from “brainstem-predominant”
Lewy body disease, where Lewy bodies are present primarily in brain
stem nuclei, and a “transitional type,” which is intermediate between
the two.
• Clinical and neuropathological diagnostic criteria were published by
the Consortium on Dementia with Lewy bodies in 1996 and revised in
2005.

6. Comparative Nosology
• Several historical terms have been used to describe what is now referred to in
general as DLB.
• These terms reflect the overlap clinically and pathologically with Alzheimer
disease and Parkinson disease and include Lewy body variant of Alzheimer
disease, Alzheimer disease with Parkinson disease changes, dementia
associated with cortical Lewy bodies, diffuse
• Lewy body disease, and senile dementia of the Lewy body type.
• The first consensus clinical criteria for DLB were published in 1996.
• These criteria defined the core clinical features and those clinical features that
were supportive of the diagnosis.
• The presence of one core feature was required for a diagnosis of possible DLB
and at least two core features for probable DLB.
• The distinction between DLB and Parkinson disease with dementia was
operationalized by requiring evidence of dementia within 1 year of the motor
symptoms for a diagnosis of DLB.

7. • The criteria did not exclude patients who simultaneously met
clinical and/or pathological criteria for a diagnosis of Alzheimer
disease. The criteria for DLB were revised in 2005, with efforts
made to clarify the overlap of DLB with Parkinson disease and
Alzheimer disease. Though the 1-year rule for differentiating DLB
and Parkinson disease with dementia was recommended in
research use, clinically the criteria were clarified to indicate that
DLB should be diagnosed when dementia precedes or is
concurrent with parkinsonian symptoms, and should not be
diagnosed when dementia arises in the “context of well-
established Parkinson disease.” It was also noted that any such
distinction, however, may be seen as arbitrarily dividing a
continuum of presentations due to underlying Lewy body disease.

8. • The distinction between neuropathologically defined DLB and
Alzheimer disease was also addressed in the revised criteria.
This issue is complicated by the awareness that most
individuals with cortical Lewy bodies have evidence of cortical
amyloid deposition as well, and that Lewy bodies may be
present even in individuals with familial early-onset Alzheimer
disease due to mutations in APP, presenilin 1, and presenilin 2.
The 2005 revisions to the criteria for DLB made a shift to
conceptualize the neuropathological diagnosis of DLB and
Alzheimer disease using probabilistic assessments as to
whether the clinical syndrome had a low, intermediate, or
high likelihood of being due to DLB.

9. • Other revisions in 2005 included the addition of the presence of
REM sleep behavior disorder and functional imaging evidence for
reduced striatal dopamine transporter activity, and increasing the
diagnostic weighting of severe neuroleptic sensitivity as suggestive
features. In addition, new features considered supportive of the
diagnosis of DLB were added. The DSM-5 has incorporated the
above described criteria in the diagnosis major neurocognitive
disorder with Lewy bodies. For a diagnosis of major neurocognitive
disorder with Lewy bodies, an individual must have two core
features or one suggestive feature with one or more core features;
if an individual only has one core feature or one or more suggestive
features then a diagnosis of possible neurocognitive disorder with
Lewy bodies is made.

10. Epidemiology
• The prevalence of DLB is dependent on whether clinical
or pathological criteria are used and what patient
population is studied.
• As a consequence of these confounds and the unclear
clinical and neuropathological boundaries between DLB,
Alzheimer disease, and Parkinson disease dementia in
early diagnostic criteria, there remains uncertainty
regarding the incidence or prevalence of DLB.
• The prevalence of DLB in populations over 65 has been
found to range from 0.1 to 5 percent.

11. • Clinical studies suggest that DLB likely accounts for 15 to
35 percent of all dementia patients.
• One population-based study calculated the incidence of
DLB to be 3.5 per 100,000 person years, with peak
incidence in the 70- to 79-year age group.
• Neuropathological studies conducted to date are best
understood as describing the frequency of Lewy body
pathology in community samples, where it is typically the
third most common chronic neuropathological change
after lesions of Alzheimer disease and vascular lesions, and
often in combination with both of those

12. Etiology
• Lewy bodies are comprised of abnormal fibrillar deposits of α-synuclein.
• Normally, α-synuclein is a protein located in presynaptic axon terminals,
and presumed to have a role in synaptic function.
• Mutations and copy number variations in the gene encoding α-synuclein,
SNCA, result in disorders with Lewy body pathology, including DLB and
Parkinson disease.
• Mutations in β-synuclein, SNCB, and in GBA resulting in DLB have also
been described.
• Mutations in other genes (LRRK2, EIF4G1, VPS35, PARK2, PINK1, and
PARK7) are associated with autosomal dominant or recessive Parkinson
disease.
• Their relationship to DLB, however, is not clear.
• The APOE ε4 allele has also been associated with increased risk of DLB.
• The causes of most cases of sporadic DLB remain unknown.

13. Diagnosis and Clinical Features
• The central features of DLB include a progressive
cognitive decline of sufficient magnitude to interfere
with normal social or occupational function.
• Memory impairment may not necessarily be
prominent or persistent in early stages but becomes
more evident with progression of the illness. The
cognitive profile includes both cortical and subcortical
features, with deficits of attention, executive function,
and visuospatial ability especially prominent.

14. • The three core features of DLB are :
(1) fluctuating cognition with pronounced variation in attention
and alertness
(2) recurrent visual hallucinations that are typically well formed
and detailed,
(3) spontaneous motor features of parkinsonism.
• Fluctuation in cognitive function and pronounced variation in
attention and alertness is common in DLB.
• Fluctuation may occur rapidly in minutes to hours or slower
with weekly or monthly variation in level of attention or
alertness.
• Patients may exhibit daytime drowsiness and lethargy with
lengthy naps, followed by periods of confusion upon awakening.

15. • They may have reduced awareness of the
environment, manifest as staring into space. They
may even appear to “switch off” or go blank at times.
There may be episodes of disorganized speech. Then
there may be periods of marked lucidity during which
patients appear to spontaneously remit. Global
performance may fluctuate with cognition, attention,
and alertness with periods of pronounced
impairment in functioning alternating with periods of
normal or near-normal functioning.

16. • Visual hallucinations occur early in the course
of DLB, whereas in Alzheimer disease,
hallucinations are generally a later
complication. The visual hallucinations are
usually recurrent, formed, and detailed, and
tend to persist. A common theme is animals or
people intruding into the home. Seeing
inanimate objects or writing on the walls and
ceiling is not infrequent.

17. • Patients may have delusional explanations of the
hallucinations or they may have insight into their unreality.
Emotional responses to the hallucinatory experiences can
range from indifference to amusement to fear. Visual
hallucinations may be more common during periods of
reduced consciousness and exacerbated by visual impairment.
Patients with visual hallucinations demonstrate more
profound visuoperceptual dysfunction compared to those
without hallucinations. Visual hallucinations correlate with a
higher density of Lewy bodies in anterior and inferior
temporal lobe and amygdala as well as reduced occipital
perfusion in primary and secondary visual cortex.

18. • Spontaneous motor features of parkinsonism are another core
feature. If dementia onset precedes or is concurrent with the
onset of parkinsonian symptoms, a diagnosis of DLB is
warranted. The most common extrapyramidal symptoms
noted in DLB are rigidity and bradykinesia, followed by
hypophonic speech, masked facies, stooped posture, and a
slow and shuffling gait. Postural instability is also common.
The parkinsonism seen in DLB tends to include greater
postural instability, gait impairment, and facial immobility
compared to those patients with Parkinson disease without
dementia. Resting tremor may occur, but is less common in
DLB than in Parkinson disease.

19. • Other clinical features suggestive of a diagnosis of DLB include REM
sleep behavior disorder, severe neuroleptic sensitivity, and low
dopamine transporter uptake in basal ganglia demonstrated by SPECT
or PET imaging. REM sleep behavior disorder is characterized by vivid
and often frightening dreams during REM sleep accompanied by lack of
muscle atonia allowing for “acting out of dreams.” Patients respond to
vivid visual images with vocalizations, thrashing about, arising from bed,
and often moving about violently. Bed partners are therefore at risk of
injury. Patients usually have little or no recall of their dreams or these
episodes. The diagnosis can be confirmed by polysomnography. REM
sleep behavior disorder may predate the emergence of parkinsonism or
dementia by many years; that is, REM sleep behavior disorder may be a
manifestation of an evolving synucleinopathy.

20. • Severe neuroleptic sensitivity is present in about half of patients with
DLB. They will demonstrate acute onset or exacerbation of
parkinsonism and impaired consciousness with even a low dose of a
first- or second generation antipsychotic agent. Even though some
patients may tolerate antipsychotics, this does not preclude a
diagnosis of DLB. Sensitivity to antipsychotics has profound treatment
implications in DLB. Visual hallucinations, hallucinations in other
modalities, and delusions are common, but the standard treatment
for these psychotic symptoms, namely antipsychotic medications, can
cause severe adverse effects. Therefore, in DLB, antipsychotics should
generally be avoided in the treatment of psychotic symptoms.
Functional imaging of the dopamine transporter system with SPECT
or PET may be used to assess the nigrostriatal dopaminergic system.

21. • Low dopamine transporter uptake in the basal ganglia supports the diagnosis of DLB. Clinical features
that are supportive of a diagnosis of DLB, but that do not have diagnostic specificity, are repeated
falls and syncope, transient unexplained loss of consciousness, severe autonomic dysfunction,
hallucinations in other modalities, systematized delusions, and depression. Imaging and other
diagnostic findings that are supportive of a diagnosis of DLB are relative preservation of medial
temporal lobe structures on CT or MRI scan, generalized low uptake on SPECT/PET perfusion scans
with reduced occipital activity, abnormal (low uptake) metaiodobenzylguanidine myocardial
scintigraphy, and prominent slow wave activity on EEG with temporal lobe transient sharp waves.
• Repeated falls are common in DLB, although they are not limited to this subtype of dementia. In DLB,
falls are generally not associated with focal neurological signs and symptoms as would be present in
balance disorders or transient ischemic attacks. Syncope may be associated with brain stem and
autonomic nervous system Lewy body pathology. Transient loss of consciousness may represent an
extreme form of fluctuation in attention and alertness. Systematized delusions may arise to provide
an explanation for the hallucinations or other perceptual disturbances. They are often complex and
bizarre as compared to the less well-developed delusions in Alzheimer disease. The most common
delusions in DLB are persecution and theft, phantom boarders, television characters in the room,
spousal infidelity, and Capgras syndrome (delusional misidentification syndrome). Patients may also
have hallucinations in other modalities such as auditory, olfactory, or tactile. Apathy and anxiety are
also seen in DLB.

22. Pathology and Laboratory Examination
• Lewy bodies are the only essential finding in
the pathological diagnosis of DLB. Lewy bodies
are spherical intracytoplasmic eosinophilic
neuronal inclusion bodies (see Fig. 10.3–6).
“Classic” Lewy bodies are inclusions with a
hyaline core and pale halo and are typically
seen in the brain stem nuclei, substantia nigra,
and locus coeruleus.

23. • Cortical Lewy bodies are less-well-defined spherical inclusions. Lewy bodies are composed predominantly of
fibrillar deposits of α-synuclein, and can also include neurofilament proteins and ubiquitin. Though Lewy
bodies can be detected with hematoxylin and eosin stain and anti-ubiquitin antibodies, they are most
sensitively and specifically labeled with antibody against α-synuclein. In addition to forming intracytoplasmic
inclusions, aggregates of α-synuclein occur in neuronal processes, called Lewy neurites. The number of
cortical Lewy bodies correlates significantly with cognitive impairment in DLB. There are also other
pathological changes that may be seen in DLB but that are not required for diagnosis. Alzheimer disease
pathology, particularly amyloid-containing plaques, is also a common feature in most cases of DLB. In
contrast, the presence of cortical neurofibrillary tangles indicates that DLB is less likely. Microvacuolation or
spongiform changes may also occur in some cases of DLB.
• Structural imaging studies, CT and MRI, are not able to effectively differentiate Alzheimer disease from DLB.
Medial temporal lobe atrophy is seen in a slightly higher percentage of patients with Alzheimer disease than
DLB, although this is not enough to differentiate the two conditions. Functional imaging of cerebral perfusion
and cerebral metabolism using SPECT and PET imaging, respectively, is a better tool for distinguishing
between Alzheimer disease and DLB. In some studies, patients with DLB have greater hypoperfusion with
FDG-PET in occipital regions than Alzheimer disease. Imaging the presynaptic dopaminergic terminals using
123I-FP-CIT SPECT or 18F-dopa PET reveals a marked loss of presynaptic dopaminergic terminals in the
corpus striata in DLB, whereas there is no change in these terminals in normal individuals and in patients
with Alzheimer disease (see Fig. 10.3–7). EEG shows early generalized background slowing with abnormal
transient sharp waves in the temporal lobes or frontally dominant burst patterns

24. • . Differential Diagnosis. DLB overlaps with Alzheimer disease both in terms of clinical presentation and neuropathological changes. The distinction between
DLB and Alzheimer disease is complex. The clinical symptoms are overlapping, and no specific cutoff based on number or pattern of core, suggestive, and
supportive features present is definitive, though the presence of at least two of the core features in the early disease course (fluctuating attention,
prominent visual hallucinations, and parkinsonism) indicates DLB with high specificity. However, even patients who present with a typical insidious amnestic
syndrome characteristic of Alzheimer disease may have Lewy body pathology at autopsy. There may be overlap with the two conditions not being mutually
exclusive and patients meeting criteria for both. There is also considerable clinical and pathological overlap and comorbidity between DLB and Parkinson
disease. The primary diagnosis should be made based on the temporal relationship of the onset of cognitive and motor symptoms. DLB should be diagnosed
when dementia occurs with or before parkinsonism. Parkinson disease with dementia should be diagnosed when dementia develops in a patient with well
established Parkinson disease. Dementia develops in at least 30 percent of patients with Parkinson disease, and perhaps even up to 78 percent when
patients are followed over 8 years. In cases where there is not a clear temporal relationship between the motor and cognitive symptoms, the term Lewy
body disease may be useful. For research purposes, the “1-year rule” should be used between the onset of parkinsonism and dementia to distinguish
between these two entities. While the distinction is useful clinically, both diagnoses likely represent a common spectrum of Lewy body pathology with a
common pathophysiology of abnormalities in α synuclein metabolism.
• Multiple system atrophy (MSA), which also has α-synuclein involvement, may also be considered in the differential. Clinical symptoms of MSA include
parkinsonism, cerebellar ataxia, pyramidal symptoms, and autonomic dysfunction. Autonomic dysfunction is necessary for a diagnosis of MSA, and includes
orthostatic hypotension, erectile dysfunction in males, constipation, and urinary symptoms (frequency, urgency, incontinence, and incomplete bladder
emptying), and decreased sweating. Dementia is much less common in MSA compared to the other neurodegenerative illnesses with parkinsonism, and
according to the second consensus statement is a nonsupporting feature of the diagnosis. However, there is recent evidence that certain cognitive domains
are affected, with frontal executive dysfunction being the most common, and memory and visuospatial dysfunction also showing impairments.
Distinguishing between delirium and DLB can be challenging. Delirium and DLB share several common symptoms. The fluctuating level of alertness and
consciousness in DLB is also a hallmark of delirium. Visual hallucinations are also common in both conditions, although they may be less well formed and less
detailed in delirium. DLB, like other dementias, may also increase the risk for a superimposed delirium due to medications, medical illness, and after
hospitalization for any reason. Delirium, however, should typically have an acute or subacute onset, and a duration limited to the period of exposure to the
underlying causal agent. The contribution of medications or other comorbid medical conditions to worsening cognitive, hallucinatory, motor, or behavioral
symptoms should be investigated (see Chapter 10.2 for a further discussion of delirium).
• Vascular dementia should also be considered in the differential diagnosis. A history of stroke as evident by focal neurological signs or brain imaging makes
the diagnosis of DLB less likely. However, white matter lesions in the periventricular and deep white matter regions, microvascular changes, and lacunes may
be present in up to 30 percent of autopsy confirmed DLB cases, suggesting that a diagnosis of both DLB and cerebrovascular disease may be appropriate in
many cases. CJD may be considered in patients who develop myoclonus, which is also characteristic of a rapidly progressive form of DLB.

25. Course and Prognosis
• DLB has an insidious and gradual onset, with the
mean age at onset being 75 years old with a range
from 50 to 80 years. There is a slight male
predominance. DLB usually presents with one of the
core features. It may have a more rapidly progressing
course than Alzheimer disease or vascular dementia.
Survival time is usually about 10 years, although it
may be as little as 1 to 2 years. The course is often
marked by psychosis and behavioral disturbances,
which makes management more complicated.

26. Treatment
NONPHARMACOLOGICAL TREATMENT.:
• Nonpharmacological inter​
ventions have not been systematically studied in DLB. Strategies
to increase levels of arousal and attention by social interaction and environmental novelty
may reduce the visual hallucinations and fluctuations in cognition and function.
• PHARMACOLOGICAL TREATMENT
Cholinesterase Inhibitors:- The cholinesterase inhibitors are the mainstay of treatment for
the cognitive impairment of DLB. A randomized placebo controlled trial showed that
donepezil was associated with improvements in cognition, behavior, and global functioning,
as well as reductions in caregiver burden. A randomized placebo-​
controlled trial of
rivastigmine demonstrated significant improvement in apathy, anxiety, delusions,
hallucinations, and cognitive functioning.
Memantine:-Data in regard to the usage of memantine is mixed. While there are some
studies that have shown that memantine is associated with improved quality of life and
improvements in global clinical status, a recent systematic review found that there was no
benefit on motor function, cognitive function, or activities of daily living. There have also
been case reports of worsening hallucinations and delusions with memantine as well.

27. • FIGURE 10.3–7. 123I-FP-CIT single-photon emission computed tomography
(SPECT) images of normal brains and brains affected by dementia with Lewy
Bodies. Left images: The normal appearance of a 123I-FP-CIT image. There
is a symmetrical appearance of the presynaptic dopaminergic terminals in
the corpus striata (caudate, globus pallidus, and putamen). This normal
appearance is also seen in patients with Alzheimer disease as there is no
significant loss of these dopaminergic terminals. Right image: The abnormal
appearance of a 123I-FP-CIT image in a 78-year-old patient with fluctuating
cognitive impairment and recurrent, vivid, and detailed visual
hallucinations. There is a marked loss of the presynaptic dopaminergic
terminals in the corpus striata as seen in patients with dementia with Lewy
bodies. Only a few terminals remain in the caudate nuclei. This appearance
is also seen in Parkinson disease. Note that this patient with dementia with
Lewy bodies had a highly abnormal scan even though there were no clinical
features of parkinsonism.
•

28. • Antipsychotics. First-generation antipsychotics are generally not well tolerated
in DLB and should be avoided. There is little data to guide the use of second-
generation antipsychotics, for which DLB patients may also have low
tolerance. A placebo-controlled study of olanzapine in psychosis in Alzheimer
disease looked at a subgroup of patients retrospectively diagnosed with DLB.
These patients demonstrated a decrease in positive symptoms of psychosis
without worsening of parkinsonism or cognition with olanzapine. A small
open-label study of quetiapine for psychosis and agitation in DLB found a
clinically significant reduction in symptoms in about half the patients, but
several had to discontinue treatment due to somnolence and orthostatic
hypotension. There is a lack of data for the other second-generation
antipsychotics. Although there are no controlled trials involving the use of
clozapine in the treatment of neuropsychiatric symptoms of DLB, given this
medication’s utility in treating psychosis in Parkinson disease, there may be
some clinical value in its treatment of psychotic symptoms in DLB as well.

29. • Antidepressants. Antidepressants have not been systematically studied
in DLB. SSRIs and selective and norepinephrine reuptake inhibitors
(SNRIs) are probably preferred as antidepressants with anticholinergic
properties should be avoided. Benzodiazepines. Clonazepam may have
benefit for the treatment of REM sleep behavior disorder, but like all
long half-life benzodiazepines must be used cautiously in the elderly.
• Antiparkinsonian Medications. Antiparkinsonian medications in​
cluding
L-dopa and direct dopamine agonists may be tried in DLB. Responses
are variable, but generally less robust than in Parkinson disease. Given
their increased potential for neuropsychiatric complications, initial
doses should be small, with gradual increases while monitoring
behavioral symptoms. Anticholinergic medications are generally not
recommended, because of the associated cognitive side effects