Geriatric MedicineTier 1Disease (DEADMAN)

Dementia syndromes - dementia with Lewy bodies

Description

Second commonest neurodegenerative dementia after Alzheimer disease; an alpha-synucleinopathy
Dementia + at least two of: fluctuating cognition, visual hallucinations, REM sleep behaviour disorder, parkinsonism

Cognitive profile - NOT amnestic early

Attention, executive function and visuospatial ability hit first
- Fails clock drawing, cube copy, intersecting pentagons; memory relatively preserved early - a common reason the diagnosis is missed
Fluctuation - minutes to days; staring spells, transient unresponsiveness, "good days and bad days"
- Often mistaken for recurrent delirium or TIAs

Core clinical features

Visual hallucinations - well-formed, detailed, recurrent, often people or animals; insight variable, usually non-threatening early
REM sleep behaviour disorder - acting out dreams, often years to decades before cognitive symptoms; ask the bed partner
Parkinsonism - usually symmetrical, rigid-akinetic, axial, with less tremor; poorly levodopa-responsive
Severe antipsychotic sensitivity

The 1-year rule

Dementia BEFORE or within 1 year of parkinsonism -> DLB
Parkinsonism for >1 year before dementia -> Parkinson disease dementia
Same pathology, same treatment - the distinction is arbitrary but is examined

Epidemiology

~4-8% of dementia clinically; ~15-20% at autopsy - substantially under-diagnosed in life
M>F (~1.5:1) - unusual among dementias
Onset typically 50-80 yr
Coexisting Alzheimer pathology is very common - mixed pathology accelerates decline

Aetiopathogenesis

Lewy bodies = intraneuronal aggregates of misfolded alpha-synuclein, with ubiquitin
- Distribution: brainstem -> limbic -> neocortical (Braak synuclein staging)
- Cortical Lewy bodies -> dementia; brainstem -> parkinsonism and autonomic failure
*Cholinergic deficit is more severe than in Alzheimer disease* - marked loss in nucleus basalis of Meynert
- This is why cholinesterase inhibitors work better in DLB, and why anticholinergics are catastrophic
Dopaminergic nigrostriatal loss -> parkinsonism + D2 receptor upregulation/supersensitivity -> neuroleptic sensitivity
Occipital hypoperfusion/hypometabolism -> visual hallucinations
Mostly sporadic; GBA and SNCA variants increase risk (GBA also a Parkinson disease risk gene)
Pathological continuum: DLB - Parkinson disease dementia - multiple system atrophy are all synucleinopathies

Diagnosis

Consensus criteria (DLB Consortium, 4th report)

Essential: dementia
Core features: fluctuating cognition/attention; recurrent well-formed visual hallucinations; REM sleep behaviour disorder; spontaneous parkinsonism
Indicative biomarkers: abnormal DaT SPECT/PET; abnormal MIBG cardiac scintigraphy; polysomnographic confirmation of REM sleep without atonia

	Requirement
Probable DLB	>=2 core features, OR 1 core + >=1 indicative biomarker
Possible DLB	1 core feature, OR >=1 indicative biomarker alone

Supportive: severe antipsychotic sensitivity, postural instability and falls, autonomic dysfunction (orthostatic hypotension, constipation, urinary), hypersomnia, hyposmia, delusions (Capgras is characteristic), apathy, depression

Imaging - the discriminators from Alzheimer disease

DaT SPECT: reduced striatal dopamine transporter uptake - the most useful single imaging test; normal in Alzheimer disease
FDG-PET: occipital hypometabolism with relative preservation of the posterior cingulate = "cingulate island sign"
- Alzheimer disease shows the opposite - posterior cingulate and temporoparietal hypometabolism
MRI: medial temporal lobes relatively PRESERVED (vs hippocampal atrophy in AD)
MIBG cardiac scintigraphy: reduced uptake (post-ganglionic sympathetic denervation)
Polysomnography: REM sleep without atonia
EEG: prominent posterior slow-wave activity with pre-alpha/theta variability

Exclude

Delirium (the commonest misdiagnosis given fluctuation - but DLB fluctuation is chronic and recurrent)
Alzheimer disease, vascular dementia, PSP/CBD, drug-induced parkinsonism (antipsychotics, metoclopramide, prochlorperazine), Charles Bonnet syndrome (hallucinations with visual loss, intact cognition)

Management

The management question is nearly always "which symptom is most disabling now?" - treating one often worsens another.

A. *Antipsychotic sensitivity - the safety message*

Up to ~50% have a severe reaction: marked rigidity, immobility, sedation, autonomic instability, an NMS-like syndrome - sometimes irreversible, with increased mortality
*Avoid all antipsychotics, especially typical agents (haloperidol) and risperidone*
If unavoidable for life-threatening agitation: quetiapine at the lowest possible dose, brief, with explicit consent and close monitoring
Also avoid: metoclopramide, prochlorperazine, droperidol (use ondansetron or domperidone for nausea)
Flag prominently in the notes, medication chart and with the family

B. Cognition - the best-responding dementia

Cholinesterase inhibitors (rivastigmine, donepezil) are first line and produce a larger benefit than in Alzheimer disease
- Improve cognition, apathy, fluctuation and hallucinations
- May worsen tremor/parkinsonism, and cause bradycardia - check ECG
Memantine - modest additional benefit in moderate-severe disease
*Stop every anticholinergic* - oxybutynin, amitriptyline, promethazine, older antihistamines

C. Hallucinations and psychosis

Treat only if distressing - many patients tolerate them
Review and remove precipitants: infection, dehydration, constipation, pain, dopaminergic drugs, anticholinergics, poor lighting, visual impairment
Cholinesterase inhibitor first, then consider pimavanserin (not available in Australia) or low-dose quetiapine
Optimise vision and lighting

D. Parkinsonism

Levodopa only if motor symptoms are disabling - start low, go slow
- Response is poorer than in Parkinson disease and it often worsens hallucinations and confusion
*Avoid dopamine agonists, amantadine, anticholinergics and MAO-B inhibitors* - higher psychiatric risk
Physiotherapy, falls prevention

E. REM sleep behaviour disorder

Environmental safety first - remove bedside hazards, consider separate beds
Melatonin (high dose) is preferred to clonazepam in the elderly (clonazepam causes falls, sedation and confusion)

F. Autonomic features

Orthostatic hypotension: review antihypertensives, compression stockings, salt and fluid, fludrocortisone or midodrine
Constipation, urinary symptoms (avoid oxybutynin - use a beta-3 agonist such as mirabegron)

G. General

Anaesthetic caution - marked sensitivity, high post-operative delirium risk; flag preoperatively
Depression: SSRI; avoid tricyclics
Carer education about fluctuation and hallucinations; ACAT, advance care planning, driving assessment (early cessation - visuospatial deficits)

Associations

REM sleep behaviour disorder - often the earliest sign; up to 80% of isolated RBD converts to a synucleinopathy over 10-15 yr
Autonomic failure - orthostatic hypotension, constipation, urinary dysfunction, erectile dysfunction
Hyposmia
Recurrent falls and syncope
Depression, anxiety, apathy, Capgras delusion
Excessive daytime sleepiness
Coexisting Alzheimer pathology (very common)
GBA and SNCA variants; overlap with Parkinson disease dementia and MSA

Natural history & complications

Median survival ~5-8 yr from diagnosis - shorter than Alzheimer disease
More rapid functional decline, more falls, more hospitalisations, earlier institutionalisation
Higher carer burden than Alzheimer disease at the same cognitive stage (hallucinations, RBD, fluctuation, falls)
An antipsychotic sensitivity reaction may cause abrupt, sometimes permanent, deterioration - an avoidable iatrogenic event
Death usually from aspiration pneumonia, immobility complications or falls

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