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Lewy body dementia

Etiology: 1) idiopathic (not transmissible) 2) may be same disorder as Parkinson's disease with dementia differing in presentation, rather than in etiology or pathology [19] 3) risk factors - subacute constipation - anosmia/hyposmia - parasomnia [8] Epidemiology: 1) 2nd most common cause of dementia (after Alzheimer's disease) 2) 15-25% of cognitively impaired elderly Genetics: - associated with defects in alpha-synuclein (SNCA) - increased frequency of CYP2D6B allele (0.306) compared with general population (0.163) [11] Pathology: 1) Lewy bodies* a) mesencephalon (midbrain) 1] substantia nigra 2] locus ceruleus b) diencephalon c) basal ganglia -> nucleus basalis of Meynert d) cerebral cortex 2) neurofibrillary tangles - often confined to medial temporal lobe (entorhinal cortex) 3) neuritic plaques absent in pure form, but often present 4) neuronal loss & gliosis - same regional distribution as Lewy bodies 5) Lewy neurites 6) most, but not all have pathology of Alzheimer's disease [3] 7) diminished choline acetyltransferase activity in the neocortex a) due to neuronal loss in the nucleus basalis of Meynert b) far more severely depleted and occurs earlier in clinical course than in Alzheimer's disease [3,7] c) correlates with dementia 8) spongiform vacuolization of the neuropil may be present a) if present, staining is negative for prion protein b) generally confined to entorhinal cortex, temporal neocortex, amygdala, cingulate gyrus 9) granular cytoplasmic deposits of phosphorylated ERK [10] * requisite for diagnosis [3] Clinical manifestations: also see dementia for general features 1) early dementia, with progressive cognitive decline - dementia occurs at onset of disease, within 1 year of onset of parkinsonism [2] 2) parkinsonism* a) only a minority of patients meet clinical criteria for Parkinson's disease b) parkinsonism is generally mild c) rigidity generally more prominent than bradykinesia or tremor - absence of rigidity excludes diagnosis [8] d) parkinsonian gait (festination, retropulsion, & en bloc turning) e) more axial than limb symptoms f) extrapyramidal symptoms [8] 3) spontaneous visual hallucinations* a) single best predictor of LBD, sensitivity only 22% [15] b) hallucinations in other modalities c) tend to occur early (40%) d) usually complex & vivid [8] e) children & small animals common [8] 4) fluctuating cognitive status* a) variations in attention & alertness b) disproportionately severe executive dysfunction (problem-solving) & visuospatial dysfunction# - getting lost driving c) confusion d) memory impairment; memory may be generally preserved e) seizure-like activity [2] f) staring spells g) prominent daytime drowsiness, extended naps [8] 5) dysautonomia - orthostatic hypotension, constipation, erectile dysfunction - urinary retention or urinary incontinence 6) postural instability, early & repeated falls - contribution from cognitive dysfunction [8] 7) syncope/transient loss of consciousness 8) systematized delusions 9) sleep disorders - nightmares with dream enactment behavior - rapid eye movement sleep behavioral disorder [2,14] - helpful for establishing diagnosis [2] - may occur in prodromal phase [38] - dementia with rapid eye movement sleep behavioral disorder is likely Lewy body dementia even in the absence of hallucinations or parkinsonism [12] - hypersomnia [2] 10) pronounced sensitivity to extrapyramidal side effects of neuroleptics [2] 11) depression, blunted affect 11) anosmia is common * Dementia plus >=2 of the following for clinical diagnosis [8] 1) parkinsonism 2) visual hallucinations 3) fluctuating cognitive status 4) rapid eye movement sleep behavioral disorder # inattention, executive dysfunction, & visuospatial dysfunction is more prominent in Lewy body dementia than in other dementias [8] # visuospatial deficits may be most sensitive distinguishing feature from Alzheimer's disease [15] 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 [47] - CSF alpha-synuclein seeding activity correlates with clinical features of Lewy body dementia [54] - L-dopa decarboxylase in CSF [49] - also see dementia Special laboratory: - electroencephalography (EEG) may be useful in early disease [39] Radiology: 1) magnetic resonance imaging may show frontal & temporal lobe atrophy [9] 2) positron emission tomography (PET) {18F-fluorodeoxyglucose} a) cortical hypometabolism, including occipital cortex b) hypometabolism of the cerebellum c) low dopamine uptake in the basal ganglia [8] 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 [20] - 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 [8] - rapid eye movement sleep behavioral disorder suggests LBD [2] Management: 1) parkinsonism a) Sinemet - motor features may respond well - psychiatric side effects (esp visual hallucinations) b) adjunctive treatment with zonisamide may be of benefit [34] 2) pronounced sensitivity to extrapyramidal side effects of neuroleptics (50%); symptoms may resemble neuroleptic malignant syndrome [2] a) less so with atypical antipsychotics [8] b) quetiapine preferred agent for treatment of delirium or psychosis & agitation in Lewy body disease [8] c) low-dose quetiapine (Seroquel) or clozapine (Clozaril) may be useful for agitation d) avoid using high-affinity dopamine receptor antagonists (haloperidol, risperidone ..) in patients with Lewy body dementia [52] 1] may worsen cognition 2] may result in neuroleptic malignant syndrome 3] quetiapine preferred agent for patients with Lewy body disease [52] e) pimavanserin may be useful for psychosis (hallucinations & delusions) [35] 3) cholinesterase inhibitors a) patients with behavioural disturbance or psychiatric problems, including psychosis & agitation, may benefit [2,14,26] b) response to cholinesterase inhibitors may be better than in Alzheimer's disease due to pathology involving nucleus basalis [15] c) donepezil improves both cognition & behavior [22,26] 1] 5 mg QD may be optimal dose 2] MMSE change >=3 points relative to placebo [22] d) rivastigmine beneficial for cognition, behavior, falls & hallucinations [26] e) cholinesterase inhibitors improve activities of daily living [26] f) benefit of cholinesterase inhibitors unclear [23] g) cholinesterase inhibitors with or without memantine reduce length of stay in hospitalized patients & reduce mortality [48] 4) memantine of marginal benefit [21] - no improvement in cognitive function [26] - beneficial for falls & hallucinations [26] 5) REM sleep disorder may respond to clonazepam 0.25-1.5 mg QHS or melatonin 3-12 mg QHS 6) benzodiazepines, especially in combination with antidepressants are associated with faster functional decline [41] * Prognosis: - mean survival time 7.7 +/- 3.0 years vs 9.3 +/- 3.5 years for Alzheimer's disease [18] * 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) [53]

Interactions

disease interactions

Related

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

Useful

General

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

Properties

PATHOLOGY: Lewy body

Database Correlations

OMIM 127750

References

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