Dementia with Lewy bodies

doi:10.1016/S1474-4422(03)00619-7

The Lancet Neurology

Volume 3, Issue 1, January 2004, Pages 19-28

https://doi.org/10.1016/S1474-4422(03)00619-7 Get rights and content

Summary

Dementia with Lewy bodies (DLB) is the second commonest cause of neurodegenerative dementia in older people. It is part of the range of clinical presentations that share a neuritic pathology based on abnormal aggregation of the synaptic protein α-synuclein. DLB has many of the clinical and pathological characteristics of the dementia that occurs during the course of Parkinson's disease. Here we review the current state of scientific knowledge on DLB. Accurate identification of patients is important because they have specific symptoms, impairments, and functional disabilities that differ from those of other common types of dementia. Severe neuroleptic sensitivity reactions are associated with significantly increased morbidity and mortality. Treatment with cholinesterase inhibitors is well tolerated by most patients and substantially improves cognitive and neuropsychiatric symptoms. Clear guidance on the management of DLB is urgently needed. Virtually unrecognised 20 years ago, DLB could within this decade be one of the most treatable neurodegenerative disorders of late life.

Section snippets

Diagnostic concepts

DLB and PDD are clinically defined syndromes; although consensus clinical criteria have been validated for DLB,² no formal clinical diagnostic criteria have been proposed or validated for PDD (the subject of a recent comprehensive review in this journal).¹¹ An arbitrary “1-year rule” has until now been used to separate DLB from PDD; onset of dementia within 12 months of parkinsonism qualifies as DLB and more than 12 months of parkinsonism before dementia as PDD. The limitations of this approach

Clinical and pathological criteria for DLB

There is some convergence of agreement on the core clinical features of DLB, which are fluctuating cognitive impairment, recurrent visual hallucinations, and parkinsonism.¹⁷ The clinical distinctions between DLB and Alzheimer's disease are increasingly recognised (panel).² The presence of Alzheimer's pathology in DLB modifies the clinical presentation, with the lower rate of visual hallucinations and parkinsonism making such cases harder to differentiate clinically.¹⁸ The specificity and

Epidemiology

In population-based clinical studies of people aged 65 years or older, the prevalences of DLB and PDD were reported to be 0·7% and 0·3%, respectively, which suggests that each could account for up to 10% of all dementia cases, a proportion consistent with DLB rates of 10–15% from hospital-based autopsy series. A community study of people aged over 85 years found that 5·0% met consensus criteria for DLB (3·3% probable, 1·7% possible) representing 22% of all demented cases,³⁰ similar to other

Clinical phenomenology of DLB Cognitive

Cognitive impairment is the presenting feature of DLB in most, but not all, cases. The disorder typically presents with recurrent episodes of confusion on a background of progressive deterioration. Patients with DLB show a combination of cortical and subcortical neuropsychological impairments34, 35 with substantial attentional deficits and prominent frontosubcortical and visuospatial dysfunction³⁶ that help to differentiate this disorder from Alzheimer's disease.37, 38 Patients with DLB do

Psychiatric

Psychiatric manifestations are common in DLB–predominantly visual hallucinations, delusions, apathy, and anxiety. They are generally present early in the course of illness and may be the initial reason for referral. They also tend to persist; for example, hallucinations were stable in a placebo-treated DLB group over 20 weeks¹³ and in a cohort in which the disorder took its natural course over 52 weeks.⁴¹ The hallucinations are similar to those reported in PDD in that they are vivid, colourful,

Neurological

Extrapyramidal signs are reported in 25–50% of patients with DLB at diagnosis, and most develop some such signs during the natural course. In up to 25% of autopsy-confirmed cases, however, there may be no record of extrapyramidal signs, which shows that parkinsonism is not necessary for clinical diagnosis of DLB. Indeed, the main reason for “missing” DLB clinically in a prospective clinicopathological study was the absence of extrapyramidal signs.¹⁶ The next most common reason for missing the

Sleep

Rapid-eye-movement (REM) sleep behaviour disorder is a parasomnia manifested by vivid and frightening dreams associated with simple or complex motor behaviour during REM sleep. The disorder is frequently associated with the synucleinopathies, DLB, Parkinson's disease, and multiple system atrophy, but it rarely occurs in amyloidopathies and tauopathies.⁵² The neuropsychological pattern of impairment in REM sleep behaviour disorder/dementia is similar to that reported in DLB and qualitatively

Autonomic failure

Autonomic abnormalities including orthostatic hypotension and carotid-sinus hypersensitivity are more common in patients with DLB than in those with Alzheimer's disease or in age-matched controls.⁵⁷ Clinical presentation of DLB is commonly with “dizziness,” presyncope, syncope, and falls,58, 59 and autonomic dysfunction is a risk factor for falls in 65% of these cases, through either orthostatic hypotension or carotid-sinus hypersensitivity. Urinary incontinence has been reported early in the

Disease progression and survival

There is conflicting evidence from comparative studies with Alzheimer's disease about both symptom progression and survival in DLB. Most data have been obtained retrospectively. The most parsimonious explanation from the available findings is that there is no difference in progression between DLB and Alzheimer's disease,⁶¹ but mean values from large studies could conceal disease heterogeneity, and some patients with DLB have a very rapid disease course.62, 63 The conclusion is that either there

Clinical diagnosis of DLB

DLB can initially present to general practitioners, geriatric psychiatrists, movement-disorder specialists, or emergency services. As with all dementias, accurate clinical diagnosis can only be made after a thorough clinical assessment including a detailed history (from the patient and an informant) and full mental-state, cognitive, and physical (including neurological) examinations.² There should be particular emphasis on eliciting the core diagnostic features of fluctuating cognitive

Laboratory and neuroimaging investigations

Systemic and pharmacological causes of delirium need to be excluded. The standard EEG may show early slowing, epoch-by-epoch fluctuation, and transient temporal slow-wave activity.68, 69, 70 There are as yet no clinically applicable genotypic or CSF markers to support a diagnosis of DLB.71, 72, 73, 74, 75, 76, 77 There have been, however, sufficient studies to allow the conclusion that neuroimaging investigations can be helpful in supporting the clinical diagnosis. Changes associated with DLB

Pathophysiology of DLB

Consensus criteria for DLB include ubiquitin immunohistochemistry for Lewy-body identification2, 16 and staging into three categories (brainstem-predominant, limbic, or neocortical) depending on the numbers and distribution of Lewy bodies. The recently developed α-synuclein immunohistochemistry is a better marker86, 87 that visualises more Lewy bodies and also shows previously under-recognised neuritic pathology, termed Lewy neurites (figure 3). Use of antibodies to α-synuclein moves the

Management of DLB

A four-stage approach to the management of DLB has been described: accurate diagnosis; identification of target symptoms with patient and carer; non-pharmacological interventions; and pharmacological interventions.⁹⁸ Target symptoms can include extrapyramidal motor features, cognitive impairment, neuropsychiatric features (including hallucinations, depression, sleep disorder, and associated behavioural disturbances), or autonomic dysfunction. Patients, carers, and clinicians can differ in their

Trial designs and regulatory issues

There are no treatments licensed for DLB. Regulatory authorities seem prepared to accept DLB as an indication for regulatory approval of a pharmacological treatment on condition that its existence is widely accepted by experts, that it can be operationally defined by reliable and valid criteria, and that outcomes for studies use validated and standardised outcome measures. The US Food and Drug Administration has considered DLB as an indication and initially has suggested that there be dual

Trial designs

Few DLB treatment trials have been reported, partly because the disorder was only recently described, but also because of restricted expertise in clinical diagnosis. The current approach is to address DLB and PDD separately, but the close relation of these disorders and the logistics of recruitment provide the opportunity for both populations of patients to enter into a single clinical trial with a harmonised set of entry criteria. Post-hoc subanalysis could be used to assess for differential

Outcome measures

Specific measures of attention and cognitive fluctuation, which are both part of the clinical profile of DLB and PDD, are sensitive to response to treatment intervention.¹⁰⁹ Other key domains of executive functioning, visual perception, and memory systems must also be measured. The most important neuropsychiatric target symptoms include visual hallucinations, delusions, delusional misidentification, apathy, anxiety, and depression. The desired behavioural outcomes might be a reduction in both

Global awareness of DLB and educational and treatment needs

Most dementia research has been done in North America, Australia, and Europe, but even in these regions, awareness of DLB is only now becoming widespread within specialist care. In countries with less developed dementia services and with greater reliance on primary care, there are substantial difficulties in translating current methods of case detection and diagnosis–eg, administration of cognitive tests to patients who are illiterate or have little education. In most cultures, dementia has

Conclusions

DLB is one of a group of neurodegenerative disorders that has been characterised as the α-synucleinopathies. The group includes Parkinson's disease with and without dementia and primary autonomic failure. Clinical criteria and assessment scales for the accurate diagnosis of DLB have been developed in the past decade, and these are useful in the differentiation of DLB from other dementia subtypes, particularly Alzheimer's disease and vascular cognitive impairment. But diagnostic accuracy of DLB

Search strategy and selection criteria

This review was based on articles identified by a MEDLINE search with the terms “Lewy body”, “dementia”, and “Parkinson's disease” as the main keywords or identified from the reference lists of relevant articles, review papers, and book chapters. Articles for citation were chosen for their historical value, importance, ease of access, and timeliness based on the expert knowledge of the delegates.

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