Lewy body dementia

Etiology

• idiopathic (not transmissible)
• may be same disorder as Parkinson's disease with dementia differing in presentation, rather than in etiology or pathology
• risk factors
  • subacute constipation
  • anosmia/hyposmia
  • parasomnia

Epidemiology

• 2nd most common cause of dementia (after Alzheimer's disease)
• 15-25% of cognitively impaired elderly

Pathology

• Lewy bodies*
  • mesencephalon (midbrain)
    • substantia nigra
    • locus ceruleus
  • diencephalon
  • basal ganglia
    • nucleus basalis of Meynert
  • cerebral cortex
• neurofibrillary tangles
  • often confined to medial temporal lobe (entorhinal cortex)
• neuritic plaques absent in pure form, but often present
• neuronal loss & gliosis
  • same regional distribution as Lewy bodies
• Lewy neurites
• most, but not all have pathology of Alzheimer's disease
• diminished choline acetyltransferase activity in the neocortex
  • due to neuronal loss in the nucleus basalis of Meynert
  • far more severely depleted and occurs earlier in clinical course than in Alzheimer's disease
  • correlates with dementia
• spongiform vacuolization of the neuropil may be present
  • if present, staining is negative for prion protein
  • generally confined to entorhinal cortex, temporal neocortex, amygdala, cingulate gyrus
• granular cytoplasmic deposits of phosphorylated ERK

* requisite for diagnosis

Genetics

• associated with defects in alpha-synuclein (SNCA)
• increased frequency of CYP2D6B allele (0.306) compared with general population (0.163)

Clinical manifestations

also see dementia for general features

• early dementia, with progressive cognitive decline
  • dementia occurs at onset of disease, within 1 year of onset of parkinsonism
• parkinsonism*
  • only a minority of patients meet clinical criteria for Parkinson's disease
  • parkinsonism is generally mild
  • rigidity generally more prominent than bradykinesia or tremor
    • absence of rigidity excludes diagnosis
  • parkinsonian gait (festination, retropulsion, & en bloc turning)
  • more axial than limb symptoms
  • extrapyramidal symptoms
• spontaneous visual hallucinations*
  • single best predictor of LBD, sensitivity only 22%
  • hallucinations in other modalities
  • tend to occur early (40%)
  • usually complex & vivid
  • children & small animals common
• fluctuating cognitive status*
  • variations in attention & alertness
  • disproportionately severe executive dysfunction (problem-solving) & visuospatial dysfunction#
    • getting lost driving
  • confusion
  • memory impairment; memory may be generally preserved
  • seizure-like activity
  • staring spells
  • prominent daytime drowsiness, extended naps
• dysautonomia
  • orthostatic hypotension, constipation, erectile dysfunction
  • urinary retention or urinary incontinence
• postural instability, early & repeated falls
  • contribution from cognitive dysfunction
• syncope/transient loss of consciousness
• systematized delusions
• sleep disorders
  • nightmares with dream enactment behavior
    • rapid eye movement sleep behavioral disorder
      • helpful for establishing diagnosis
      • may occur in prodromal phase
      • dementia with rapid eye movement sleep behavioral disorder is likely Lewy body dementia even in the absence of hallucinations or parkinsonism
  • hypersomnia
• pronounced sensitivity to extrapyramidal side effects of neuroleptics
• depression, blunted affect
• anosmia is common

* Dementia plus >=2 of the following for clinical diagnosis

• parkinsonism
• visual hallucinations
• fluctuating cognitive status
• rapid eye movement sleep behavioral disorder

# inattention, executive dysfunction, & visuospatial dysfunction is more prominent in Lewy body dementia than in other dementias

# visuospatial deficits may be most sensitive distinguishing feature from Alzheimer's disease

Laboratory

• alpha synuclein aggregates in CSF
  • high sensitivity & specificity in detecting underlying Lewy body pathology in elderly with mild cognitive impairment
• alpha-synuclein seed amplification assay may be useful
• CSF alpha-synuclein seeding activity correlates with clinical features of Lewy body dementia
• L-dopa decarboxylase in CSF
• also see dementia

Diagnostic procedures

• electroencephalography (EEG) may be useful in early disease

Radiology

• magnetic resonance imaging may show frontal & temporal lobe atrophy
• positron emission tomography (PET) {18F-fluorodeoxyglucose}
  • cortical hypometabolism, including occipital cortex
  • hypometabolism of the cerebellum
  • low dopamine uptake in the basal ganglia

Differential diagnosis

• condition is called Parkinson's disease dementia if dementia occurs > 1 year after onset of parkinsonism, or Lewy body dementia if both symptoms occur within a year of each other
• Alzheimer's disease (AD) with parkinsonism/ Alzheimer's psychosis
  • parkinsonism develops > 1 year after onset of dementia
    • paratonia also occurs in both AD & LBD
  • visual hallucinations & delusions tend to be mid-to late stage in AD
  • shuffling gait of AD does not involve festination, retropulsion or en bloc turning
• rapid eye movement sleep behavioral disorder suggests LBD

Management

• parkinsonism
  • Sinemet
    • motor features may respond well
    • psychiatric side effects (esp visual hallucinations)
  • adjunctive treatment with zonisamide may be of benefit
• pronounced sensitivity to extrapyramidal side effects of neuroleptics (50%); symptoms may resemble neuroleptic malignant syndrome
  • less so with atypical antipsychotics
  • quetiapine preferred agent for treatment of delirium or psychosis & agitation in Lewy body disease
  • low-dose quetiapine (Seroquel) or clozapine (Clozaril) may be useful for agitation
  • avoid using high-affinity dopamine receptor antagonists (haloperidol, risperidone ..) in patients with Lewy body dementia
    • may worsen cognition
    • may result in neuroleptic malignant syndrome
    • quetiapine preferred agent for patients with Lewy body disease
  • pimavanserin may be useful for psychosis (hallucinations & delusions)
• cholinesterase inhibitors
  • patients with behavioural disturbance or psychiatric problems, including psychosis & agitation, may benefit
  • response to cholinesterase inhibitors may be better than in Alzheimer's disease due to pathology involving nucleus basalis
  • donepezil improves both cognition & behavior
    • 5 mg QD may be optimal dose
    • MMSE change >=3 points relative to placebo
  • rivastigmine beneficial for cognition, behavior, falls & hallucinations
  • cholinesterase inhibitors improve activities of daily living
  • benefit of cholinesterase inhibitors unclear
  • cholinesterase inhibitors with or without memantine reduce length of stay in hospitalized patients & reduce mortality
• memantine of marginal benefit
  • no improvement in cognitive function
  • beneficial for falls & hallucinations
• REM sleep disorder may respond to clonazepam 0.25-1.5 mg QHS or melatonin 3-12 mg QHS
• benzodiazepines, especially in combination with antidepressants are associated with faster functional decline

* Prognosis:

• mean survival time 7.7 +/- 3.0 years vs 9.3 +/- 3.5 years for Alzheimer's disease

* Prevention of Lewy body dementia:

• alpha-1 blockers terazosin, doxazosin, alfuzosin
  • reduce risk by 40% vs tamsulosin & 37% vs 5-alpha reductase inhibitors finasteride or dutasteride
• effect may associated with activation of phosphoglycerate kinase-1 (PKG1)

More general terms

• synucleinopathy (includes alpha-synucleinopathy)
• dementia; Alzheimer's disease & related dementias (ADRD)

Additional terms

• Lewy body
• Lewy body variant of Alzheimer's disease (AD)

Patient information

Lewy body dementia patient information

Database

• OMIM: https://mirror.omim.org/entry/127750