Lewy Body Dementia

Lewy body dementia is a form of dementia in which spherical structures called Lewy bodies develop in the brain. There may be fluctuating episodes of confusion and visual hallucinations. Falls are also common. 

Introduction

Lewy bodies are spherical neuronal inclusions, first described by the German neuropathologist Friederich Lewy (1) while working in Alzheimer's laboratory in Munich in 1912. In 1961, Okazaki published case reports about two elderly men who presented with dementia and died shortly after with severe extrapyramidal rigidity. Autopsy showed Lewy bodies in their cerebral cortex. (2) Over the next 20 years, 34 similar cases were reported, all by Japanese workers.

Lewy body disease was thus considered to be a rare cause of dementia, until a series of studies in Europe and North America, in the late 1980s, identified Lewy bodies in the brains of between 15 and 20 per cent of elderly demented cases reaching autopsy. (3,4) Dementia with Lewy bodies (DLB) is unlikely to be a newly occurring disorder, since re-examination of autopsy material collected from elderly demented patients in Newcastle during the 1960s, reveals cortical Lewy bodies in 17 per cent of cases. The recent recognition of DLB as the second most common form of degenerative dementia in old age is largely due to the widespread use of improved neuropathological techniques, in particular antiubiquitin immunocytochemistry.

The spectrum of Lewy body disease

Lewy bodies probably do not occur in normal ageing. Their presence indicates neurological disease, the clinical presentation varying according to the site of Lewy body formation and associated neuronal loss. (5) Three main clinicopathological syndromes have been described.

  1. Parkinson's disease, an extrapyramidal movement disorder—associated with degeneration of subcortical neurones, particularly in substantia nigra.
  2. Dementia with Lewy bodies, a dementing disorder with prominent neuropsychiatric features—associated with degeneration of cortical neurones, particularly in frontal, anterior cingulate, insular, and temporal regions.
  3. Primary autonomic failure with syncope and orthostatic hypotension—associated with degeneration of sympathetic neurones in spinal cord.

In clinical practice, elderly patients often have heterogenous combinations of parkinsonism, dementia, and autonomic failure, reflecting pathological involvement at multiple locations.

Clinical features

Dementia is usually, but not always, the presenting feature; a minority of patients present with parkinsonism alone, some with psychiatric disorder in the absence of dementia, and others with orthostatic hypotension, falls, or transient disturbances of consciousness.

Fluctuation in cognitive performance and functional ability, which is based in variations in attention and level of consciousness, is the most characteristic feature of DLB It is usually evident on a day-to-day basis, and often apparent within much shorter periods. The marked amplitude between best and worst performance distinguishes it from the minor day-to-day variations that commonly occur in dementia of any aetiology.

Repeated visual hallucinations are present in about two-thirds of patients. They take the form of vivid, colourful, and sometimes fragmented figures of people and animals, which are usually described in great detail.

Emotional responses vary from intense fear to indifference or even amusement. Although patients may respond to their hallucinations, for example trying to feed an imaginary dog, they later often have good insight into their unreality. Others develop elaborate systematized delusions, usually persecutory or of a phantom boarder. Auditory hallucinations are much less frequent, and only a small minority of patients have olfactory or tactile experiences.

Depressive symptoms are common and about 40 per cent of patients will have a major depressive episode, similar to the rate in Parkinson's disease and significantly greater than in Alzheimer's disease (AD). The frequency and severity of spontaneous motor features of parkinsonism varies greatly from one clinical setting to another.

Bradykinesia, limb rigidity, and gait disorder are the most common manifestations, rest tremor occurring in only 20 per cent or less. Less than half of DLB cases have parkinsonism at presentation and a quarter continue to have no evidence at any point in their illness.

Clinicians, particularly in non-movement disorder specialties, must therefore be prepared to make the diagnosis of DLB in the absence of extrapyramidal motor features—if they do not, their case detection rates will be unacceptably low.

Recurrent falls and syncope occur in up to a third of DLB cases, reflecting autonomic nervous system involvement. Transient disturbances of consciousness, in which patients are found mute and unresponsive for periods of several minutes, may represent the extreme of fluctuation in attention and arousal and are often mistaken for transient ischaemic attacks despite a lack of focal neurological signs.

Classification

Pathological

Lewy bodies are composed of intermediate neurofilament proteins, which are abnormally truncated and phosphorylated. Their presence indicates that a neurone is attempting to eliminate damaged proteins from its cytoplasm, a process which is usually followed by cell death. (5) Ubiquitin, a-synuclein, a- and b-crystalin, and associated enzymes are the main chemical constituents. Subcortical Lewy bodies have a dense hyaline core surrounded by a halo of radiating filaments, and are easily seen with conventional histopathological techniques. Cortical Lewy bodies lacking this characteristic core and halo appearance remained difficult to detect until the recent development of specific antiubiquitin immunocytochemical staining methods, (7) allowed their true prevalence to be appreciated.

Recommendations have been made (8) about which brain regions to examine for the presence of Lewy bodies, and a simple semiquantitative scoring system devised. These scores are added to generate three pathological categories.

  1. Brainstem-predominant DLB: predilection sites are substantia nigra, locus coeruleus, and dorsal nucleus of vagus.
  2. Limbic (or transitional) DLB: predilection sites are anterior cingulate and transtentorhinal cortex.
  3. Neocortical DLB: predilection sites are frontal, temporal, and parietal cortex.

Of DLB cases presenting via psychiatric clinics, 69 per cent have extensive neocortical Lewy body pathology, (9) but this is not essential for the development of dementia or other psychiatric symptoms, both of which may occur in the presence of disease limited to limbic structures (24 per cent of cases) or the brainstem (7 per cent).

A distinctive pattern of neuritic degeneration has additionally been identified in Lewy body disease. ‘Lewy neurites' are seen in the substantia nigra, hippocampal region CA2/3, dorsal vagal nucleus, basal nucleus of Meynert, and transentorhinal cortex. Ubiquitin immunocytochemistry and a-synuclein-specific, monoclonal antibody stains are beginning to reveal the extensive nature of these neuritic changes, (10) which are probably more relevant for symptom formation than the relatively sparsely distributed Lewy bodies.

Unresolved issues in classification

Two heated debates have developed around the classification of DLB. The first concerns the interpretation of coexistent Alzheimer-type pathology. (11) High senile plaque counts are found in 80 to 90 per cent of DLB cases, diffuse and neuritic b-amyloid plaques occurring in similar proportions as in pure AD. Significant tau pathology is absent, however, in 80 to 90 per cent of DLB cases, whether measured biochemically or by counting neocortical neurofibrillary tangles. Most DLB cases are therefore classified as ‘the Lewy body variant of AD' (3) if AD is defined by increased plaque density. Conversely, if AD is defined by frequent neocortical neurofibrillary tangles, equivalent to Braak stages 5 and 6, then 85 to 90 per cent of DLB cases will not fulfil such criteria. (4,11) Minor vascular pathology is additionally present in 30 per cent of DLB cases. (9)

The second controversy centres upon the classification of patients who present with motor symptoms of Parkinson's disease and later develop the typical features of DLB, sometimes after many years of severe motor disability. Antiparkinsonian medications are usually held responsible for hallucinations and confusion in Parkinson's disease, but research findings do not support this clinical impression. Factors associated with the development of visual hallucinosis are the later age of onset of Parkinson's disease, total duration of illness, and the presence of cognitive impairment. Patients who do or do not hallucinate are distinguished neither by the severity of their motor disability nor by the dosage of antiparkinsonian medication. Those with early-onset hallucinations are particularly likely to subsequently develop DLB. (12) The DLB consensus statement recommends(8) that if a syndrome meeting diagnostic criteria for DLB develops in a patient who has had motor Parkinson's disease for at least 12 months prior to the onset of neuropsychiatric features, a diagnosis of Parkinson's disease plus DLB, should be made. This 12-month period is purely arbitrary, and a more pragmatic approach may simply be to apply a clinical diagnosis which best describes the patient's current clinical presentation. The neurobiological basis of dementia in Parkinson's disease is discussed in detail here: Dementia in Parkinson's disease

In summary, there appear to be at least three recognizable anchor points along a spectrum of neurodegenerative disorders. Parkinson's disease is characterized by subcortical Lewy bodies and nigrostriatal degeneration. More extensively distributed Lewy bodies and significant senile plaque formation typify DLB. Lewy bodies are absent in AD, which is best defined by the presence of neocortical neurofibrillary tangles. Cerebrovascular and systemic disease frequently contribute to these pathological and clinical profiles.

Diagnosis and differential diagnosis

Patients with DLB may present to psychiatric services (cognitive impairment, psychosis, or behavioural disturbance), internal medicine (acute confusional states or syncope), or neurology (movement disorder or disturbed consciousness). The details of clinical assessment and differential diagnoses will, to a large extent, be shaped by these symptom and specialty biases. (13) In all cases, a detailed history from the patient and reliable informants should document the time of onset of relevant key symptoms, the nature of their progression, and their effects on social, occupational, and personal function.

The recent consensus criteria for the clinical diagnosis of DLB are shown in Table 1.

Table 1: Consensus criteria for the clinical diagnosis of probable and possible dementia with Lewy bodies (DLB) (McKeith et al, 1996)

  1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social and occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Deficits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent.
  2. Two of the following core features are essential for a diagnosis of probable DLB, and one is essential for possible DLB: (a) Fluctuating cognition with pronounced variation in attention and alertness (b) Recurrent visual hallucinations that are typically well formed and detailed (c) Spontaneous motor features of parkinsonism.
  3. Features supportive of the diagnosis are: (a) Repeated falls (b) Syncope (c) Transient loss of consciousness (d) Neuroleptic sensitivity (e) Systematic delusions (f) Hallucinations in other modalities.
  4. A diagnosis of DLB is less likely in the presence of: (a) Stroke disease, evident as focal neurological signs or on brain imaging (b) Evidence of physical examination and investigation of any physical illness or other brain disorder sufficient to account for the clinical picture.

Particular emphasis needs to be given to recognizing the characteristic dementia syndrome. Attentional deficits and prominent frontosubcortical and visuospatial dysfunction are the main features—symptoms of persistent or prominent memory impairment are not always present early in the course of illness, although they are likely to develop in most patients with disease progression. Patients with DLB perform better than AD on tests of verbal recall, but relatively worse on tests of copying and drawing. (14) With the progression of dementia, the selective pattern of cognitive deficits may be lost, making differential diagnosis based on clinical examination difficult during the later stages.

Probable DLB can be diagnosed if any two of the three key symptoms (fluctuation, visual hallucinations, spontaneous motor features of parkinsonism) are present. Fluctuation is undoubtedly the most difficult symptom to establish. Some patients identify the variable cognitive state themselves, but generally the most productive approach is to interview a reliable informant. Questions such as ‘Are there episodes when his/her thinking seems quite clear and then becomes muddled?' may be useful probes. Substantial changes in mental state and behaviour may be seen within the duration of a single interview or between consecutive examinations. Parkinsonism and visual hallucinations pose fewer problems of identification.

Categories of disorder

There are four main categories of disorder that should be considered in the differential diagnosis of DLB.

Other causes of dementia

Of autopsy-confirmed DLB cases, 65 per cent meet the NINCDS–ADRDA clinical criteria for probable or possible AD, (15) and this is the most frequent clinical misdiagnosis of DLB patients presenting with a primary dementia syndrome. This suggests DLB should routinely be excluded when making the diagnosis of AD. Up to one-third of DLB cases are additionally misclassified as vascular dementia by the Hachinski Ischaemic Index, by virtue of items such as the fluctuating nature and course of illness. (15) Pyramidal and focal neurological signs are, however, usually absent. The development of myoclonus in patients with a rapidly progressive form of DLB may lead the clinician to suspect Creutzfeldt–Jakob disease (8). - see: Prion diseases

Other causes of delirium

In patients with intermittent delirium, appropriate examination and laboratory tests should be performed during the acute phase to maximize the chances of detecting infective, metabolic, inflammatory, or other aetiological factors. Pharmacological causes are particularly common in elderly patients. Although the presence of any of these features makes a diagnosis of DLB less likely, comorbidity is not unusual in elderly patients and the diagnosis should not be excluded simply on this basis.

Other neurological syndromes

In patients with a prior diagnosis of Parkinson's disease, the onset of visual hallucinations and fluctuating cognitive impairment may be attributed to side-effects of antiparkinsonian medications, and this must be tested by dose reduction or withdrawal. Other atypical parkinsonian syndromes associated with poor levodopa response, cognitive impairment, and postural instability include progressive supranuclear palsy and multisystem atrophy. Syncopal episodes in DLB are often incorrectly attributed to transient ischaemic attacks, despite an absence of focal neurological signs. Recurrent disturbances in consciousness accompanied by complex visual hallucinations may suggest complex partial seizures (temporal lobe epilepsy), and vivid dreaming with violent movements during sleep may meet criteria for REM-sleep behaviour disorder. Both these conditions have been reported as uncommon presenting symptoms of autopsy-confirmed DLB. (16,17)

Late-onset functional psychiatric disorder

DLB should be considered if a patient spontaneously develops parkinsonian features or cognitive decline (or shows excessive sensitivity to neuroleptic medication) in the course of late-onset delusional disorder, depressive psychosis, or mania. (16)

Investigations

Prominent atrophy of the medial temporal lobes on CT or magnetic resonance imaging is indicative of AD rather than DLB. (18) Single-photon emission CT (SPECT) HMPAO imaging shows generalized reductions in cortical uptake, similar to AD. [ 123I]IBZM and [123I]FP-CIT are novel SPECT ligands that label postsynaptic D 2 receptors and the presynaptic dopamine transporter site, respectively. Both show marked changes in the caudate-to-putamen ratio in DLB, reflecting nigrostriatal dysfunction, and may prove to be sensitive and specific in the discrimination from AD and other non-Lewy body disorders. (19) Early slowing of dominant electroencephalography rhythms is characteristic of DLB, being associated in 50 per cent of cases with focal delta-wave transient activity in temporal regions. (20)

Diagnostic accuracy

The predictive validity of the consensus criteria for DLB have not yet been fully established. When retrospectively applied to clinical records of autopsy-confirmed cases(21) they had a sensitivity of 0.75 and specificity of 0.79. Inter-rater reliability was acceptable for all key symptoms with the exception of fluctuation (k = 0.25–0.36). In the first prospective validation study (9) the consensus criteria show a tendency to clinically underdiagnose DLB (sensitivity 0.83); false-positive diagnoses are uncommon (specificity 0.95). Although it is possible within a specialist centre to diagnose DLB with an accuracy similar to that for AD or Parkinson's disease, further clarification of the criteria would assist in their routine clinical use, particularly for the items relating to fluctuating cognition.

Epidemiology

Several studies in a range of settings have suggested that DLB accounts for just under 20 per cent of all cases of dementia referred for neuropathological autopsy. (3,4,8) The male-to-female ratio in these autopsy series is 1.5:1, but it is unclear to what extent this represents increased male susceptibility or reduced survival. Age at onset ranges from 50 to 83 years and an age at death of between 68 and 92 years. (22) In all, 26 per cent of clinical referrals for dementia to an old age psychiatry service (23) and 24 per cent of demented day-hospital attenders met the clinical criteria for DLB. (24) No estimates of prevalence and incidence in primary-care and community-based samples have been reported. Epidemiological surveys using memory-based screening instruments are likely to miss early DLB cases in whom memory function is relatively intact.

Aetiology

The aetiopathogenesis of Lewy bodies is poorly understood. They presumably form from an interplay between environmental stimuli and the intrinsic responsiveness of neurones.(5) Dementia with Lewy bodies, like Parkinson's disease, does not appear to have a strong heritable component, although the possession of an apolipoprotein e4 allele appears to confer a risk of developing DLB rather than Parkinson's disease. An inactive allelic variant of cytochrome oxidase (CYP2D6B) is more frequent in Parkinson's disease than controls, but there is disagreement whether the same is true for DLB.

Course and prognosis

Progression is usually more rapid than in AD, typically 1 to 5 years from onset to an endstage of profound dementia and parkinsonism. Men appear to have a worse prognosis than women. Even in the early stages, personal and social function and performance in daily living skills may be markedly impaired by a combination of cognitive, psychiatric, and neurological disability. (25) Psychotic symptoms,particularly visual hallucinations, tend to be very persistent throughout the whole course of illness. There have been three overlapping stages of the illness described. (16)

The first stage is often recognized only in retrospect, and may extend back 1 to 3 years' prepresentation with occasional minor episodes of forgetfulness, sometimes described as lapses of concentration or ‘switching off'. A brief period of delirium is sometimes noted for the first time, often associated with genuine physical illness and/or surgical procedures. Disturbed sleep, nightmares, and daytime drowsiness often persist after recovery.

Progression to the second stage frequently prompts psychiatric or medical referral. A more sustained cognitive impairment is established, albeit with marked fluctuations in severity. Recurrent confusional episodes are accompanied by vivid hallucinatory experiences, visual misidentification syndromes, and topographical disorientation. Extensive medical screening is usually negative. Attentional deficits are apparent as apathy, and daytime somnolence and sleep behaviour disorder (17) may be severe. Gait disorder and bradykinesia are often overlooked, particularly in elderly subjects. Frequent falls occur due either to postural instability or syncope.

The third and final stage often begins with a sudden increase in behavioural disturbance, leading to requests for sedation or hospital admission by perplexed and exhausted carers. The natural course from this point is variable and obscured by the high incidence of adverse reactions to neuroleptic medication. For patients not receiving, or not tolerating, neuroleptics a progressive decline into severe dementia with dysphasia and dyspraxia occurs over months or years, with death usually due to cardiac or pulmonary disease. During this terminal phase patients show continuing behavioural disturbance including vocal and motor responses to hallucinatory phenomena. Lucid intervals with some retention of recent memory function and insight may still be apparent. Neurological disability is often profound, with fixed flexion deformities of the neck and trunk and severe gait impairment. Parkinsonian signs and paraplegia in flexion may also occur in advanced AD and other dementias. Parkinsonism occurring for the first time late in the course of a dementia is therefore consistent with a diagnosis of DLB, but not specific for it.

Treatment

Review of evidence

Pharmacological treatment strategies are based upon our knowledge of the neurochemical deficits underlying specific symptoms in DLB. (13) The most clearly established is a correlation between substantia nigra neurone loss and severity of parkinsonism. Levodopa responsiveness is less predictable in DLB than in Parkinson's disease. (22) Activity of the cholinergic enzyme choline acetyltransferase is lower in DLB than AD, particularly in temporal and parietal cortex. (26) Clouding of consciousness, confusion, and visual hallucinations are recognized effects of anticholinergic drug toxicity, and the summative effects of subcortical and cortical cholinergic dysfunction probably play a major role in the spontaneous generation of similar fluctuating symptoms in DLB. Reductions in choline acetyltransferase activity are correlated with the severity of cognitive impairment, (27) and hallucinations may be related to hypocholinergic and (relatively) hypermonoaminergic neocortical neurotransmitter function. (28)

There have been several reports that patients who respond well to cholinesterase inhibitor treatments are more likely to have DLB than AD at autopsy. (25,29,30) This is consistent with the neurochemical profile of DLB and the fact that postsynaptic cortical muscarinic receptors are functionally intact. (28) Case reports suggest that cholinesterase inhibitors can reduce psychotic symptoms in DLB, (31) and placebo-controlled studies are in progress.

Advice about management

The most important practice point in the management of a patient with DLB is caution in (or preferably avoidance of) the use of neuroleptic medications, which are the mainstay of antipsychotic treatment in other patient groups. Severe neuroleptic sensitivity reactions (16,32) can precipitate irreversible parkinsonism, further impair consciousness level, and induce autonomic disturbances reminiscent of neuroleptic malignant syndrome. They occur in 40 to 50 per cent of neuroleptic-treated DLB cases and are associated with a two- to threefold increased mortality. Acute D 2 receptor blockade is thought to mediate these effects; and, despite initial reports, atypical antipsychotics seem to be as likely to cause neuroleptic sensitivity reactions as older drugs. 

Until safe and effective medications become available, there is no doubt that the mainstay of clinical management is to educate patients and carers about the nature of their symptoms and to suggest coping strategies. The clinician must ascertain which symptoms are most troublesome for the sufferer and explain the risks and benefits associated with changes in medication. (33) In these circumstances where the clinician is walking a therapeutic tightrope between parkinsonism and psychosis, the best outcome is invariably a compromise between a relatively mobile but psychotic patient and a non-psychotic but immobile individual. The patient and his carers may only be able to decide which is the lesser of these evils after experiencing both states.

Possibilities for prevention

Since the aetiopathogenesis of Lewy body and neurone loss are unknown, specific disease slowing or prevention strategies for DLB are lacking, a situation analogous to Parkinson's disease. The overlap with Alzheimer-type and vascular pathologies suggests that the range of putative neuroprotectives for these disorders, including anti-inflammatories and antioxidants, may confer some advantages in DLB. L-Deprenyl, used for disease slowing in Parkinson's disease, is prone to precipitate hallucinations and is best avoided. 

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