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The Relevance of the Lewy Body to the Pathogenesis of Idiopathic Parkinson's Disease

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The Relevance of the Lewy Body to the Pathogenesis of Idiopathic Parkinson's Disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.51.6.745 on 1 June 1988. Downloaded from Journal of Neurology, Neurosurgery, and Psychiatry 1988;51:745-752 Occasional review The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease W R G GIBB, A J LEES From the Department ofNeuropathology, National Hospitalsfor Nervous Diseases, Maida Vale, London, UK SUMMARY The Lewy body is a distinctive neuronal inclusion that is always found in the substantia nigra and other specific brain regions in Parkinson's disease. It is mainly composed of structurally altered neurofilament, and occurs wherever there is excessive loss of neurons. It occurs in some elderly individuals and rarely in other degenerative diseases of the central nervous system. In 273 brains of patients dying from disorders other than Parkinson's disease, the age-specific prevalence of Lewy bodies increased from 3-8% to 12-8% between the sixth and ninth decades. Associated pathological findings suggest that these cases of incidental Lewy body disease are presymptomatic cases of Parkinson's disease, and confirm the importance of age (time) in the evolution of the Protected by copyright. disease. In view of the common and widespread occurrence of this disorder we propose that endo- genous mechanisms operating in early life may be more important than environmental agents in the pathogenesis of Lewy bodies and Parkinson's disease. Neuronal inclusions called Lewy bodies are present in rare disorders or rare variants of common disorders many surviving cells of the substantia nigra in all are also sometimes associated with Lewy bodies in the cases of Parkinson's disease fulfilling the UK Parkin- nervous system, usually in some of the same areas son's Disease Society Brain Bank clinical diagnostic affected in idiopathic Lewy body disease (table 2). criteria (table 1), ifalternative Parkinsonian disorders These differ, however, because most are familial, are identified and excluded by pathological exam- occur at a young age and are associated with addi- ination. Lewy bodies therefore provide a diagnostic tional pathological lesions. In contrast to Parkinson's marker and are as essential for the pathological disease Lewy bodies are not invariably present; for diagnosis as the specific distribution of cell loss. The example they are reported in only 10-15% of cases of absence of Lewy bodies in even one bilateral 7 pm Hallervorden-Spatz disease. section of substantia nigra excludes Parkinson's dis- ease.' Reports of Lewy bodies in individuals without IDIOPATHIC LEWY BODY DISEASE http://jnnp.bmj.com/ Parkinsonian features suggest a presymptomatic Distribution of Lewy bodies phase of the disease (incidental Lewy body disease).2 In Parkinson's disease the distribution of Lewy bod- Less commonly dementia34 and autonomic failure,5 ies is fairly specific and only certain medium to large- due to cell loss and Lewy body formation in extra- sized monoaminergic and cholinergic neurons are nigral sites, complicate Parkinson's disease, or rarely involved. In addition, the entire autonomic nervous occur alone. These other manifestations of the Lewy system is affected,'2-14 from the Edinger-Westphal body-Parkinson's disease spectrum encourage the nucleus, to the salivatory nuclei, dorsal vagal nucleus, inclusive pathological term of idiopathic Lewy body the intermediolateral nucleus, and sympathetic and on October 1, 2021 by guest. disease (table 2). parasympathetic ganglia. In Parkinson's disease the In recent years it has emerged that a small group of distribution of Lewy bodies is generalised, they can easily be found in neurons of the substantia nigra, Address for reprint requests: Dr W R G Gibb, National Hospitals locus coeruleus, dorsal vagal nucleus, nucleus basalis for Nervous Diseases, Maida Vale, London W9 ITL, UK. of Meynert and hypothalamus, and sometimes in Received 25 September 1987 and in revised form 5 February 1988. other sites such as the cerebral cortex, thalamus and Accepted 16 February 1988 autonomic ganglia. The selection of specific cell pop- 745 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.51.6.745 on 1 June 1988. Downloaded from 746 Gibb, Lees Table 1 UKParkinson's Disease Society Brain Bank clinical arranged in a radially orientated or haphazard for- diagnostic criteria mation.16 The deep eosinophilia of the core and halo is due to greater packing density and apparent STEP 1. Diagnosis of PARKINSONIAN SYNDROME. structural degradation of filaments. Polyclonal anti- BRADYKINESIA (slowness of initiation of voluntary movement bodies reacting with neurofilament proteins produce with progressive reduction in speed and amplitude of repetitive actions). homogeneous or peripheral ring-like staining And at least one of the following: of Lewy bodies in the substantia nigra and locus a. muscular rigidity b. 4-6 Hz rest tremor coeruleus.17 Similar results are obtained with mono- c. postural instability not caused by primary visual, vestibular, clonal antibodies to neurofilament polypeptidest8-21 cerebellar or proprioceptive dysfunction. demonstrating that at least some amino acid STEP 2. Exclusion criteria for Parkinson's disease. sequences are common to neurofilaments and Lewy history of repeated strokes with stepwise progression of Parkin- bodies. The pattern of immunostaining appears to be sonian features determined the structural arrangement of the history of repeated head injury by history of definite encephalitis Lewy body, the better preserved filaments showing oculogyric crises preferential staining. This explains why cortical and neuroleptic treatment at onset of symptoms more than one affected relative some brainstem Lewy bodies stain centrally,22 while sustained remission most brainstem Lewy bodies showing a central den- strictly unilateral features after three years supranuclear gaze palsy sity (core) stain peripherally (fig 1, b & c). The outer cerebellar signs part of the halo contains few filaments, mixed with early severe autonomic involvement other organelles, and does not stain. The potential early severe dementia with disturbances of memory, language and praxis contribution of other cytoskeletal elements to the Babinski sign Lewy body is under investigation. presence ofa cerebral tumour or communicating hydrocephalus on CT scan. There are other morphological changes in Parkin- negative response to large doses of levodopa (if malabsorption son's disease that mirror the distribution of Lewy excluded) bodies. One of these is the granular pale body which, Protected by copyright. MPTP exposure in contrast to the Lewy body, is round or irregularly STEP 3. Supportive prospective positive criteria for PARKINSON'S shaped, finely granular in texture and up to 30 in DISEASE. Three or more required for diagnosis of definite Parkin- pm son's disease. diameter. It fails to react with conventional histo- unilateral onset logical stains including silver (fig Id). It should be rest tremor present distinguished from the Lewy body, because its progressive disorder persistent asymmetry affecting the side of onset most appearance is less specific and is mimicked by neu- excellent response (70-100%) to levodopa ronal changes in a variety of disorders including severe levodopa-induced chorea levodopa response for 5 years or more clinical course of 10 years or more Table 2 Classification of Lewy body diseases Sporadic ulations (pathoklisis)"5 and the apparent absence of specific, generalised distribution of Lewy bodies transynaptic or retrograde degeneration is one of the idiopathic* (primary) Lewy body disease asymptomatic (presymptomatic) main characteristics of the disease process. Cell loss is Lewy body-Parkinson's disease documented for most locations in which Lewy bodies cortical Lewy body dementia occur and consequently the Lewy body is considered Lewy body-autonomic failure a marker of neuronal degeneration. subacute sclerosing panencephalitis http://jnnp.bmj.com/ Sporadic or familial mode of inheritance Structure and composition of the Lewy body specific, generalised distribution of Lewy bodies juvenile Parkinsonian syndrome6 In pigmented cells of the substantia nigra and locus autosomal dominant coeruleus the Lewy body is usually eosinophilic, olivopontocerebellar atrophy7 intracytoplasmic, round and 5-25 pm in diameter. autosomal dominant Joseph disease8 Most consist of a central body surrounded by a pale- autosomal dominant staining halo. Classical, but less common forms also Hallervorden-Spatz disease9 recessive or utosomal "sporadic" on October 1, 2021 by guest. have a darker centre (core) and/or darker rings (lami- ataxia-telangiectasia'o nae) (fig la). Lewy bodies also exist within nerve cell autosomal recessive processes and free in the neuropil when released from Lewy bodies only in motor neurons a dying cell. Inclusions in nerve cell processes are motor neuron disease" common in the dorsal vagal nucleus and sympathetic autosomal dominant or "sporadic" ganglia, where they are frequently elongated or com- *the term "idiopathic" is used here to denote that the disease is plex in shape. Ultrastructurally the body is formed not associated with familial inheritance or other pathological from aggregated filament, 7-15 nm in diameter, lesions. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.51.6.745 on 1 June 1988. Downloaded from The relevance of the Lewy body to the pathogenesis ofidiopathic Parkinson's disease 747 ~~....~ ~-A.. 4. Protected by copyright. Fig 1 (a) Lewy body with core (C), body
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