Lewy bodies are spherical neuronal inclusions, first described by the German neuropathologist Friederich Lewy 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.⁽¹⁾ 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.^(2,3) 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, initially antiubiquitin immunocytochemistry, and more recently specific staining for alpha-synuclein which is a core constituent of Lewy bodies and related lesions.

Dementia is usually, but not always, the presenting feature of DLB. 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. Episodes of confusion, progressive cognitive decline, and dementia follow in due course. Fluctuation in cognitive performance and functional abilities, which is based in variations in attention and level of consciousness, is the most characteristic feature of DLB and the one which causes greatest diagnostic difficulties. 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. 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. 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 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 from one clinical setting to another due to referral biases. Postural instability and gait difficulty are the most common manifestations, tremor dominant symptoms occurring in only 20 per cent or less.⁽⁴⁾ 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 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. Severe neuroleptic sensitivity reactions 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.⁽⁵⁾ Acute D₂ 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.⁽⁶⁾ Sleep disorders have more recently been recognized as common in DLB with daytime somnolence and rapid eye movement sleep behaviour disorder as prodromal features.⁽⁷⁾ Recurrent falls and syncope occur in up to a third of DLB cases, reflecting autonomic nervous system involvement which may also be evident as early urinary incontinence, constipation, and sexual dysfunction.

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. Ubiquitin, α-synuclein, α- and β-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 are more easily visualized using antiubiquitin staining but this lacks specificity and immunohistochemical staining for alpha-synuclein, is now the most sensitive and specific method currently available for detecting Lewy bodies and Lewy-related pathology. Current thinking is that Lewy bodies form within neurones as a cytoprotective response in an attempt to sequester toxic alpha-synuclein oligomers. Widely distributed aggregates of alpha-synuclein (Lewy neurites) probably represent an earlier stage in the neurodegenerative process than Lewy body formation itself. 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 α-synuclein-specific monoclonal antibody stains are beginning to reveal the extensive nature of these neuritic changes, which are probably more relevant for symptom formation than the relatively sparsely distributed Lewy bodies. The presence of Lewy neurites in presynaptic terminals is thought to have a particularly severe impact on synaptic function.⁽⁸⁾

Recommendations have been made⁽⁹⁾ about which brain regions to examine for the presence of Lewy bodies and Lewy neurites and a simple semi-quantitative scoring system devised. These scores are added to generate three pathological categories:

Of DLB cases presenting via psychiatric clinics, 69 per cent have extensive neocortical Lewy body pathology,⁽¹⁰⁾ 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).

Interpretation of the significance of coexistent Alzheimer-type pathology is a major issue in the pathological assessment of DLB cases. High senile plaque counts are found in 80 to 90 per cent of DLB cases, diffuse and neuritic β-amyloid plaques occurring in similar proportions as in pure AD. Significant tau pathology is absent, however, in 80 to 90 per cent whether measured biochemically or by counting neocortical neurofibrillary tangles. Most DLB cases are therefore classified as ‘the Lewy body variant of AD’⁽²⁾ 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.⁽¹¹⁾ (The pathological classification of AD is also discussed in Chapter 4.1.2.) The most recent revision of pathological diagnostic criteria for DLB suggests that both Lewy and Alzheimer pathologies should be fully reported. A probability matrix (see Table 4.1.5.1) is then used to predict the likelihood of the patient having presented with a DLB clinical syndrome, this being directly related to the severity of Lewy-related pathology, and inversely related to the severity of concurrent AD-type pathology.⁽⁹⁾ Minor vascular pathology is additionally present in 30 per cent of DLB cases⁽¹⁰⁾ and this is also likely to impact upon the clinical manifestations.

There has been extended debate about 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. This is a common outcome reported in up to 78 per cent of PD patients followed over an 8-year period. No major differences between DLB and Parkinson’s disease dementia have been found in any variable examined including cognitive profile, neuropsychiatric features, sleep disorders, autonomic dysfunction, type and severity of parkinsonism, neuroleptic sensitivity, and responsiveness to cholinesterase inhibitors. It has been suggested that DLB should be diagnosed when dementia occurs before or concurrently with parkinsonism and Parkinson’s disease dementia should be used to describe dementia that occurs in the context of well-established Parkinson’s disease.^(9,12) This distinction between DLB and Parkinson’s disease dementia has two distinct clinical phenotypes, based solely on the temporal sequence of appearance of symptoms that has been criticized by those who regard the different clinical presentations as simply representing
different points on a common spectrum of LB disease, itself underpinned by abnormalities in alpha-synuclein metabolism.

The neurobiological basis of dementia in Parkinson’s disease is discussed in detail in Chapter 4.1.6.