7.5.3 Dementia with Lewy bodies and Parkinson's disease dementia

The Lewy body spectrum and the one-year rule

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) share alpha-synuclein pathology in Lewy bodies and neurites. Their clinical features overlap, so they are separated by timing, not by their features.

• DLB is dementia that comes before, with or within one year of parkinsonism.

• PDD is dementia that develops in well-established Parkinson's disease.

• The one-year rule is a convention, not a biological boundary.

Pathology

• Misfolded alpha-synuclein collects in the substantia nigra, nucleus basalis of Meynert, dorsal vagal nucleus, and limbic and cortical networks.

• Nigrostriatal dopamine loss causes parkinsonism, and autonomic involvement causes dysautonomia.

• A marked cholinergic deficit drives the cognitive and psychiatric symptoms, which is why cholinesterase inhibitors are used.

• Coexisting amyloid and tau pathology is common and can make the presentation more amnestic.

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Clinical picture

DLB presents as a progressive dementia over months with fluctuating cognition, recurrent well-formed visual hallucinations and parkinsonism, sometimes with Capgras-type misidentification. This picture separates it from Alzheimer's disease, delirium, depressive pseudodementia and frontotemporal dementia.

• Attention, executive function and visuospatial ability are impaired early and disproportionately in DLB, while memory is relatively spared at first.

• Alzheimer's disease, by contrast, is memory-led.

Diagnostic criteria

2017 DLB Consortium criteria

Dementia is required. The criteria divide features into four core features, a longer list of supportive features, and indicative and supportive biomarkers.

• Probable DLB needs two or more core features, or one core feature plus an indicative biomarker.

• Possible DLB is one core feature without a biomarker, or an indicative biomarker without core features.

• Biomarkers alone cannot establish probable DLB.

ICD-11

ICD-11 lets an established dementia be attributed to Lewy body disease from the history when two or more core features are present. One core plus one supportive feature does not count.

REM sleep behaviour disorder

• REM sleep behaviour disorder is dream enactment with REM sleep without atonia.

• Isolated REM sleep behaviour disorder is a prodrome of alpha-synuclein disease: Parkinson's disease, DLB or multiple system atrophy.

• Sleep apnoea and other nocturnal behaviours can mimic it, so a bed partner's account helps and uncertain cases should be confirmed.

Biomarkers

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• The National Institute for Health and Care Excellence (NICE) recommends DaTscan when DLB is suspected but the diagnosis is uncertain.

• DaTscan uptake is reduced in Lewy body disease and normal in Alzheimer's disease, but it does not separate DLB from other degenerative parkinsonism.

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Differential diagnosis

In DLB, cognitive decline comes early alongside parkinsonism and falls; this timing separates it from PDD and from the atypical parkinsonian syndromes.

Treating cognition

Cholinesterase inhibitors are first-line.

• Donepezil and rivastigmine have placebo-controlled evidence for cognition and for hallucinations and other neuropsychiatric symptoms in DLB.

• Antipsychotics give no cognitive benefit.

• Cholinesterase inhibitors are recommended in PDD, with placebo-controlled evidence of a modest cognitive benefit.

• They are not used in frontotemporal dementia, where they can worsen behaviour.

• Rivastigmine is cleared by cholinesterase hydrolysis rather than hepatic cytochrome P450 (CYP), so it is chosen when a strong CYP2D6 inhibitor must continue.

• Donepezil and galantamine depend on CYP2D6 and CYP3A4.

• Check pulse, syncope and weight, especially with autonomic dysfunction.

Antipsychotic sensitivity and psychosis

• Severe antipsychotic sensitivity causes profound rigidity, reduced consciousness and potentially fatal autonomic instability, in up to about half of exposed patients in historical series.

• Avoid dopamine-blocking antipsychotics wherever possible, above all potent ones such as haloperidol.

• Before treating hallucinations, look for distress, risk, delirium, drug triggers and environmental causes; benign hallucinations may need only explanation.

• New psychosis in PDD is first managed by reducing the dopaminergic drug most likely to have triggered it, with specialist advice, before adding an antipsychotic or cholinesterase inhibitor.

• Quetiapine is the preferred antipsychotic in DLB because its weak, transient D2 binding carries the lowest risk of worsening parkinsonism or provoking neuroleptic sensitivity.

• Low-dose clozapine has the strongest trial evidence in Lewy body psychosis without worsening parkinsonism, once cholinesterase inhibitors and non-drug measures have failed; it needs mandatory blood monitoring.

• Quetiapine is the weaker-evidenced alternative to clozapine.

Other symptoms

• Disabling motor symptoms need cautious levodopa titration, because dopamine agonists raise hallucination and impulse-control risks.

• Anticholinergic antiparkinsonian drugs and amantadine can worsen confusion.

• Injurious REM sleep behaviour disorder is managed with a safe bedroom and melatonin or low-dose clonazepam.

• Postural hypotension is managed by reviewing drugs and hydration, then midodrine or fludrocortisone.

Course

• Mean survival is about six years (five to eight from onset), shorter than in Alzheimer's disease.

• Falls, syncope, swallowing problems and delirium are common, and new confusion needs assessment rather than being put down to fluctuation.

• Record DLB and any antipsychotic sensitivity clearly, including for unrelated admissions.