Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:709-717

Diffuse Lewy body disease: clinical features in 15 cases

E JANE BYRNE,* GRAHAM LENNOX,tT JAMES LOWE,$RICHARD B GODWIN-AUSTENtFrom the Departments ofHealth Care of the Elderly,* Neurology,t and Pathology,: Queen's Medical Centre,Nottingham, UK

SUMMARY Fifteen cases of diffuse Lewy body disease were diagnosed on pathological groundsduring a single year in one health district. The range and frequency of clinical features contraststrikingly with previous reports. The majority of cases presented with classical levodopa-responsiveParkinson's disease either alone (6 cases) or with mild cognitive impairment (3 cases); the remaining 6cases presented with cognitive impairment alone. In time almost all patients developed both dementiaand Parkinsonism. The dementia was cortical in type, but unusual in that most (12 cases) showed day-to-day fluctuation in severity at some point in their illness. These findings suggest that diffuse Lewybody disease is not rare, and that it presents in a range of ways from dementia with subsequentParkinsonism to Parkinson's disease with subsequent dementia. The latter mode of presentationsuggests that it should be considered as a significant pathological substrate of dementia inParkinson's disease.

Diffuse Lewy body disease is a neuropathologicalentity in which rounded eosinophilic inclusion bodies(Lewy bodies') are found within brainstem nuclei (in amanner identical to that which characterisesidiopathic Parkinson's disease2) and throughout thecerebral cortex. Previous reports have described caseswith progressive dementia, with or without psychiatricfeatures, extrapyramidal syndromes, orthostatichypotension and motor neuron disease."32 Thesereports have generally described single or small num-bers of cases and may therefore give an unrepresen-tative view of the clinical features.

In an effort to broaden this perspective we describethe 15 cases ofdiffuse Lewy body disease identified in asystematic survey of all brains referred to this institu-tion from one health district during a single year.

Materials amd methods

All 216 brains received during the year 1 April 1985 to 31March 1986 were examined for Lewy bodies. No attempt wasmade to influence routine referral patterns. Diffuse Lewybody disease was diagnosed where conventional haema-toxylin and eosin (H&E) stains revealed classical brainstemLewy bodies in association with cortical Lewy bodies in both

Address for reprint requests: Dr G Lennox, Department ofNeurology, Queen's Medical Centre, Nottingham NG7 2UH.

Received 12 August 1988 and in revised form 30 December 1988.Accepted 10 January 1989

limbic and neocortical regions (fig 1). All cases were alsostudied with solochrome-cyanin, thioflavine-S, the Crossmodified Palmgren stain,33 and ubiquitin34 and neuro-filament" immunohistochemistry.

All cases identified spent time under the care of theDepartment of Health Care of the Elderly and most hadtherefore undergone prospective clinical evaluation as part ofa continuing study of dementia in old age. The evaluationcomprised detailed history and physical examination (withbedside tests of higher mental function supplemented inselected cases with the mental status questionnaire, FolsteinMini Mental State Examination and detailed psychometrictesting including the Clifton Assessment Procedure for theElderly and the Weschler Adult Intelligence Scale), routinebiochemical, haematological and radiological investigations,and functional assessments by nurses, occupational thera-pists and physiotherapists. Assessment ofthe clinical featureswas based upon this evaluation, together with otherbehavioural information recorded in the hospital case notesand general practitioner records. Clinical and neuro-pathological assessments were made blind with respect toeach other.

Results

Fifteen cases of diffuse Lewy body disease wereidentified from a total of 216 brains referred fromwithin the Nottingham Health District (population616,000) during one year. All fifteen cases came fromwithin a subgroup of 57 cases known to suffer fromdementia, an extrapyramidal syndrome or both. Therewas no evidence of geographical or occupational

709

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Difuse Lewy body disease: clinicalfeatures in 15 cases

clustering of cases within the district to suggest a localenvironmental cause.

Case reports

The clinical features in this series differ in several importantrespects from those previously reported, and we thereforepresent brief individual case reports. These are summarisedin table 1. The terms rigidity and tremor refer to theextrapyramidal forms unless otherwise stated. No case had a

relevant family or past medical history. In all cases investiga-tions for treatable causes ofdementia and Parkinsonism were

normal or negative unless otherwise stated.Case 1 A Polish emigree developed problems of immobilityin early 1984 at the age of 74 years; in particular sheexperienced difficulty in getting out of bed. In February 1985she was admitted to hospital following a fall. She hadmoderate generalised rigidity and bradykinesia, mildbilateral tremor, a flexed posture and a shuffling gait; she wasalso disorientated with poor recollection of recent events.Treatment with levodopa/carbidopa produced improvementin her motor signs but her mental state continued todeteriorate. By August 1985 she showed global cognitiveimpairment with, for example, disorientation in time andplace, gross impairment of immediate and distant recall, andnominal dysphasia. She became intermittently agitated anddisruptive, and required sedation with phenothiazines withconsequent deterioration in her motor state. By October 1985her periods of agitation were alternating with periods ofdrowsiness which were unrelated to sedatives or intercurrentmedical illness. In March 1986 she died suddenly of massivepulmonary embolism.Case 2 A retired coach driver developed classical idiopathicParkinson's disease in August 1984 at the age of 82 years,with bilateral tremor and excessive sweating. By January1985 the tremor was disabling and he had developedhypomimia, and mild bradykinesia. Treatment withlevodopa/carbidopa produced considerable benefit, but also

711

epigastric discomfort and in October 1985 he changed toorphenadrine. By November 1985 he had developed posturalinstability; he was depressed, irritable and mildly forgetfulbut otherwise cognitively intact. He was admitted to hospitalin January 1986 after a series of falls; he was drowsy anddisorientated and had mild generalised rigidity. He also hadevidence of an acute exacerbation of chronic bronchitis; thisworsened despite treatment with antibiotics and he died one

week after admission.Case 3 A university lecturer developed classical idiopathicParkinson's disease in November 1981 at the age of 61 years,

with gradual onset of tremor, bradykinesis and gait distur-bance. There was no disturbance of intellectual function (fig2). His symptoms responded well to treatment with benz-hexol and amantadine. During the summer of 1983 he rapidlydeveloped global cognitive impairment which fluctuatedmarkedly in severity from day to day. There was prominentjargon dysphasia with spontaneous speech dominated bymeandering scientific and statistical phrases. Drug with-drawal produced deterioration in both mental and motorfunction; bromocriptine, amantadine and levodopa/car-bidopa were subsequently introduced, producing motor butnot mental improvement. By November 1984 he needed helpwith everyday activities; he had great difficulty in dressing(due to dyspraxia rather than bradykinesia), took up to twohours to eat his meals and frequently wandered at night. Hebecame emotionally labile and began to micturate in inap-propriate situations. His cognitive function continued todeteriorate in a fluctuating fashion, culminating in severe

dementia. He died from a perforated sigmoid volvulus inFebruary 1986.Case 4 A woman developed classical idiopathic Parkin-son's disease in 1980 at the age of 74 years, with rigidity andpostural instability with retropulsion. She responded well totreatment with levodopa/benserazide. In 1981 she developedfrequency of micturition treated briefly with propantheline.In 1983 she was -increasingly troubled by falls and haddeveloped persistent moderate impairment of memory; attimes this was accompanied by symptoms of depression, but

Table 1 Clinicalfeatures

Age Motorfeatures Neuropsychiatric featuresat

Case onset Dur' Levodopa Fluctno (yr) Sex (yr) Presentation Rig Bk Tr Gait Post response Mem Lang Prax Calc PsYch cogn

1 74 F 2 Parkinsonism + + + + + Definite + + + + +2 82 M 3 Parkinsonism + + + + Definite + - - - D3 58 M 5 Parkinsonism + + + + + Definite + + + +4 74 F 5 Parkinsonism + + + + Definite + D5 68 F 19 Parkinsonism .+ + + + + Definite + D +6 72 F 8 Parkinsonism + + + + + Definite + + +7 73 M 3 Both + + + + + Notnal + +8 62 M 4 Both + + + + + Definite + - + + H +9 75 M 5 Both + + - + Probable + +10 83 F 3 Dementia - - - - + No trial + + + + +11 65 F 2 Dementia + - - + + Notrial + + + + H +12 73 M 8 Dementia + + - + + Definite + + + + +13 71 F 6 Dementia + + + - Definite + + + + H +14 70 F 7 Dementia + - + + + Definite + + + + H +15 83 M 3 Dementia - - - + - No trial + + +

Key:M = male; F = female; + = present;- = absent; = not recorded; Rig = rigidity; Bk = bradykinesia; Tr = tremor; Gait = gaitdisturbance; Post = postural deformity; D = depression; H = hallucination; Mem = memory impairment; Lang = dysphasia;Prax = dyspraxia; Calc = dyscalculia; Psych = psychiatric symptoms; Fluct cogn = fluctuations in cognition.

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f al~~Fig 2 An example ofconstructional dyspraxia (Case 3).The attempt to draw a house has resulted in an "exploded"diagram; the windows and roof tiles can be seen alongside andabove the house respectively, while the numerals adjacent tothe roofgable represent perseveration ofa previous(unsuccessful) attempt to draw a clock.

there was no cognitive improvement on treatment withantidepressants. By 1986 she had developed a bilateraltremor. She fell fracturing her left hip in February 1986;operative repair and rehabilitation were initially successfulbut she was readmitted in March 1986 with broncho-pneumonia and died.Case 5 A woman developed classical idiopathic Parkin-son's disease in 1966 at the age of 68 years, manifestedpredominantly as left-sided tremor and bradykinesia. In 1969she underwent right cryogenic thalamotomy; the procedurewas complicated by a transient mild left hemiparesis andacute confusional state but produced substantialimprovement in her motor symptoms and signs. By 1971 shehad developed resting tremor of the right upper limb, andhad become intermittently forgetful; treatment withlevodopa was commenced with initial motor improvement,but by 1976 her motor state had deteriorated such that shewas unable to walk without assistance. In 1978 she wasadmitted for continuing care. She had mild global cognitiveimpairment with episodic exacerbation which was notexplained by routine investigations, together with markedbradykinesia, generalised rigidity and blepharospasm. Hertreatment was changed to levodopa/carbidopa and mian-serin with some motor but no cognitive improvement. In1979 she developed disinhibited and inappropriatebehaviour. Over the next six years her mental state continuedto fluctuate whilst her mobility gradually deteriorated. Herantiparkinsonian treatment was withdrawn on severaloccasions because of her recurrent confusional states; on

each occasion this produced no change in mental state butmarked motor deterioration. By 1984 she had moderateglobal dementia, had adopted a flexed posture and requiredthe assistance of two nurses to transfer from bed to chair. InAugust 1985 she developed bronchopneumonia and died.Case 6 A woman developed classical idiopathic Parkin-son's disease in early 1978 at the age of 72 years, withhypomimia, moderate generalised rigidity, predominantlyright sided tremor, and slowness of gait. She responded totreatment with benzhexol and levodopa/benserazide. ByNovember 1978 she had developed impairment of short termmemory and severe dyscalculia. Benzhexol was withdrawn

Byrne, Lennox, Lowe, Godwin-Austenwithout any cognitive improvement. By August 1984 she haddeveloped bradykinesia and a tendency to retropulsion; hercognitive impairment had become global and tended tofluctuate with periods of lethargy and withdrawal which werenot relieved by mianserin. In March 1985 she was admittedhaving fallen and fractured her right hip. She was uncom-municative, profoundly demented and had developed flexioncontractures of the lower limbs. She died suddenly inNovember 1985 from severe coronary atherosclerosis.Case 7 A man developed symptoms and signs typical ofidiopathic Parkinson's disease early in 1983 at the age of 73years, with mild bilateral tremor and gait disturbance,together with mild cognitive impairment. Investigationsrevealed a macrocytic anaemia with folate and vitamin B 12deficiency due to late-onset coeliac disease but his mental andmotor impairment did not improve following correction ofthese abnormalities. By May 1985 he had developedhypomimia, generalised rigidity, micrographia and posturalinstability; his cognitive function fluctuated with periods ofnear-normality alternating with episodes of marked con-fusion for which no cause was found. By November 1985 hehad persistent moderate global cognitive impairment; he wasadmitted to hospital and died in January 1986 of pulmonaryembolism.Case 8 This case has been described in detail elsewhere.4 Insummary, a 62 year old retired gravestone cleaner developedsymptoms and signs typical of idiopathic Parkinson's diseasewith bradykinesia, rigidity, festinant gait disturbance andabnormality of posture; shortly afterwards he developedglobal cognitive impairment which fluctuated in severityfrom day to day. The motor features responded to treatmentwith levodopa/carbidopa, but the cognitive features did not;he became profoundly demented, increasingly dependent onnursing care and died of bronchopneumonia four years afterthe onset of symptoms.Case 9 A retired railwayman developed forgetfulness andfluctuating confusion in 1980 at the age of 75 years, togetherwith motor difficulties, with an unsteady, shuffling gait andfrequent falls. By June 1982 he was confused regarding recentevents and had hypomimia, moderate generalised rigidityand bradykinesia, a festinant gait, and loss of posturalreflexes. He was treated with levodopa/benserazide withsome motor but no cognitive improvement. In August 1983he fell fracturing his left hip; despite operative repair hegradually became increasingly immobile to the point wheretwo nurses were needed to turn him in bed. His mental statealso continued to deteriorate in a fluctuating fashion, withrecurrent exacerbations of his intellectual impairment. Onsome occasions these exacerbations were associated withevidence of urinary, respiratory or gastrointestinal infection,but in general their aetiology remained obscure. In February1984 he developed pemphigoid which was successfully sup-pressed with prednisolone. By March 1985 he was severelydemented; he developed bronchopneumonia and died.Case 10 A woman developed gradually progressive cog-nitive impairment in late 1983 at the age of 83 years. By 1985she required constant supervision and had become intermit-tently hostile and suspicious. She had an abnormal posturewith cervical flexion and lumbar extension, but no otherextrapyramidal signs. Her condition initially fluctuatedmarkedly, such that at times she was able to hold aconversation, albeit with some expressive dysphasia, whilst

Difuse Lewy body disease: clinicalfeatures in 15 cases

on other occasions she was mute and unable to stand withoutassistance. Investigations revealed no cause for these fluctua-tions. She became profoundly demented and in October 1985fell fracturing her right wrist; she subsequently developedbronchopneumonia and died.Case 11 A woman developed neuropsychiatric symptomsin 1983 at the age of 65 years, with intellectual deterioration,paranoid delusions and auditory hallucinations; for example,she had difficulty in recognising her children, ate dog food,accused her family of plotting against her, and heard strangemen talking in her flat. She became restless and distractable,with marked fluctuation in her mental state: CAPE andMMS scores varied by more than 50% from one day to thenext. During 1984 there was rapid deterioration, with firstnominal and then jargon dysphasia and constructionaldyspraxia developing over a period of six weeks. Shedeveloped a spastic tetraparesis with axial rigidity and severe

cervical flexion. A diagnosis ofCreutzfeldt-Jakob disease wasconsidered, and serial electroencephalography showed tri-phasic waves posteriorly consistent with this diagnosis, butthere was no ataxia or myoclonus and her condition stabil-ised from September 1984 until September 1985 when shedeveloped bronchopneumonia and died.Case 12 This case has also been described in detail else-where.4 In summary, a pharmaceutical packer became forget-ful at the age of 75 years and subsequently developed globalcognitive impairment and a Parkinsonian syndrome withbradykinesia, rigidity, tremor, gait disturbance and abnor-mality of posture. There was motor but not cognitiveimprovement on treatment with levodopa/carbidopa; hebecame increasingly immobile and demented and died ofbronchopneumonia eight years after the onset of symptoms.Case 13 A woman looked after a disabled lodger until April1979 when, at the age of 71 years, she developed neuro-

psychiatric symptoms. She became forgetful, neglectedhousehold duties, and complained of visual hallucinationssuch as seeing animals in the house. By the end of 1979 shehad severe but fluctuating global cognitive impairment (withamnesia, constructional dyspraxia and expressive dys-phasia), ideas of reference and paranoid delusions (forexample, attributing her symptoms to the malign influence ofthe television set, believing that she was being followed andthat people were stealing her money). She was treated initiallywith chlormethiazole and in June 1980 with haloperidol. InOctober 1980 she developed a Parkinsonian syndrome, withhypomimia, tremor, rigidity and sialorrhoea, which persisteddespite withdrawal of haloperidol. By 1982 her Parkinsoniansyndrome had worsened to the point where she requiredassistance with all everyday activities. Levodopa/carbidopawas introduced, producing initial motor improvement butincreased agitation. Her condition steadily deteriorated andby 1985 she had become mute, rigid, immobile and incon-tinent; she developed bronchopneumonia and died.Case 14 A woman developed slowly progressive memoryimpairment in 1979 at the age of 70 years. In early 1981 shedeveloped bilateral tremor which responded to treatmentwith benzhexol. In August 1981 her cognitive impairmentworsened acutely, with auditory and visual hallucinations.No underlying cause was found, and episodic exacerbationsof her cognitive impairment persisted over the next threeyears despite withdrawal of anticholinergic treatment. HerParkinsonian syndrome worsened gradually and by 1984 she

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had severe tremor, rigidity, gait disturbance and markedflexed postural deformity. She was treated with levodopa/carbidopa with considerable motor improvement. Hermental and motor condition continued to deteriorate,however, and by 1985 she was mute and immobile. Shedeveloped pressure sores and bronchopneumonia, and diedin December 1985.Case 15 This man began to experience forgetfulness in 1983at the age of 83 years. He developed a series of overvaluedideas, attributing his memory disturbance to non-steroidalanti-inflammatory treatment and ruminating about animagined abnormality of his testicles. His speech becamerambling and incomprehensible. He was admitted to hospitalin 1986 following a fall. He was agitated with profoundglobal cognitive impairment, including a marked expressiveand receptive dysphasia, and a shuffling gait, requiring theassistance of two people to walk. He received sedation withthioridazine. He died suddenly four weeks after admissionfrom myocardial infarction.

NeuropathologicalfeaturesThe neuropathological features will be described in detailelsewhere. In brief, all cases showed cell loss in the substantianigra, with classical Lewy bodies in remaining neurons.These changes were indistinguishable from those whichcharacterise uncomplicated idiopathic Parkinson's disease.All cases also showed large numbers of Lewy bodies in thecerebral cortex, most frequently in small neurons within thedeeper layers of the temporal, anterior cingulate, insular,entorhinal and frontal cortices. These are the features ofdiffuse Lewy body disease.Four cases (Cases 4, 13, 14 and 15) also showed sufficient

numbers of neurofibrillary tangles in the hippocampus andtemporal cortex to suggest a second diagnosis of Alzheimer'sdisease. No other neuropathological diagnoses were made; inparticular there was no evidence of Pick's disease, Hallervor-den-Spatz disease, von Economo's encephalitis, or significantcerebrovascular disease.

ClinicalfeaturesThe mean age at onset of symptoms was 72 years (range 58-83 years) and the mean duration of illness was 5-5 years(range 2-19 years).Parkinsonian features Six (40%) cases presented withsymptoms and signs which were typical of and indistin-guishable from those of idiopathic Parkinson's disease. Allsix had extrapyramidal rigidity, bradykinesia, rest tremorand classical gait disturbance; four also had a markedlyflexed posture. All of these cases responded well to treatmentwith levodopa and deteriorated abruptly whenever it waswithdrawn. Cognitive impairment developed an average offour years (range 1-14 years) after the onset of motorsymptoms.A further three (20%) cases had similar Parkinsonian

features together with mild cognitive impairment either at orshortly after presentation. Of these, one case was definitelylevodopa-responsive; one was probably levodopa-responsivein that motor improvement occurred on commencing treat-ment but this coincided with a period of intensive rehabilita-tion; one did not receive levodopa.The other six (40%) cases showed motor features later in

their illnesses (average interval four years; range 1-6 years).

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Four developed syndromes which were Parkinsonian in thatthey showed gait disturbance which was described as "festi-nant", "shuffling" or "Parkinsonian", together with two orthree of the four other cardinal signs of Parkinson's disease(that is, extrapyramidal rigidity, bradykinesia, rest tremorand flexed postural deformity). Three of these patientsreceived and responded to treatment with levodopa. Theremaining two cases showed flexed postural deformity andgait disturbance alone.Neuropsychiatric features Six (40%) cases presented withneuropsychiatric disturbance; of these six cases, one eachpresented with memory impairment alone, memory impair-ment with overvalued ideas, dementia alone, dementia withparanoid ideas, dementia with auditory and visual hallucina-tion, and dementia with both paranoid delusions andhallucination. All 15 cases eventually showed some neuro-psychiatric disturbance; all 15 had impairment of memorywhich was mild in Case 2 (and associated with depression)and moderate to very severe in the other 14 cases. In these 14cases, where detailed neuropsychological assessment waspossible there was clear evidence of cortical deficits includingdysphasia (eight cases), dyscalculia (10 cases) and visuo-spatial, constructional and ideomotor dyspraxia (nine cases);the remaining cases were too obtunded at the time of clinicalevaluation to allow detailed assessment but in all casesdisturbance ofcortical functions such as language and praxiscould be inferred from behavioural observations.

In twelve (80%) cases there was striking fluctuation incognitive impairment. For example, some patients would bemuddled one day and alert the next. The fluctuations wereusually diagnosed as acute confusional states, but in generalinvestigations revealed no underlying cause. Cognitive fluc-tuations were recorded in drug-naive patients and could notbe attributed to changes in levodopa or other treatment; inpatients receiving levodopa cognitive fluctuations were notaccompanied by fluctuations in motor state, making itunlikely that they were related to variations in levodopalevels (which, in any case, tend to occur over hours ratherthan days).36

Three patients, all from the group presenting with Parkin-son's disease, showed evidence of depression. Five patients,all from the groups presenting with dementia, had auditoryor visual hallucinations or delusions with paranoid content.

Discussion

The literature on diffuse Lewy body disease has grownsteadily since the first two cases were described byOkazaki et alin 1961.25 By the end of 1987 44 cases hadbeen reported with individual clinical details,27232whilst a further seven cases had been summarised inabstracts.3'28 There are at least a further 16 case reportsin the literature where diffuse Lewy body disease issuspected but not definitely diagnosed;3237 this groupof cases is not included in the analysis below. Thepresent report describes the clinical features of afurther 15 cases showing the neuropathologicalfeatures of diffuse Lewy body disease.

Incidence ofdiffuse Lewy body diseaseThe increasing frequency of reports of diffuse Lewy

Byrne, Lennox, Lowe, Godwin-Austenbody disease almost certainly reflects improvingneuropathological recognition rather than a trueincrease in incidence. It is a condition that is easilyoverlooked, unless specifically sought. By the sys-tematic use of routine H&E stains we have identified15 cases from a limited population in a single year. Aretrospective post-mortem series such as this is inevit-ably subject to bias; in particular, post-mortemexaminations are more likely to be requested onhospital inpatients (who tend to be elderly and heavilydependent) and the clinically puzzling. The series isespecially likely to underestimate of the incidence ofdiffuse Lewy body disease in young patients who areoften cared for at home by their fit spouses. Despitethese limitations, the fact that 15 cases of diffuse Lewybody disease were identified within a limited popula-tion in a single year suggests that the disease is not asrare as the literature would suggest.

Range ofclinicalfeaturesThis study documents for the first time the clinicalfeatures of a large and systematic series of cases ofdiffuse Lewy body disease. None of the clinicalfeatures described here is previously unreported, butmany of them were much more common than onewould expect from the literature (table 2). To someextent these differences may reflect the brevity ofmanyprevious reports (for example, 11 ofthe 51 reports giveno information regarding mode of presentation).

Presentation with ParkinsonianfeaturesFew of the previously reported cases of diffuse Lewybody disease presented with symptoms or signs ofParkinson's disease. Ikeda et al " described a 30 yearold man who presented with slight gait disturbance,bradykinesia and hypomimia, which worsened oversix years to include generalised rigidity and slighttremor; there was a remarkable response to levodopabut the patient died suddenly aged 38. Kono et al'5described a 55 year old woman who presented withdizziness, hand tremor and bradykinesia, and whosubsequently developed rigidity, orthostatic hypo-tension and dementia; no trial oflevodopa is recorded.Sima et alP described a 72 year old woman whopresented with Parkinsonism; she subsequentlydeveloped a spastic tetraparesis, emotional labilitywith intermittent aggression, bradykinesia andrigidity; levodopa produced little benefit. Finally Gibbet al'0 described a 33 year old woman who presentedwith depression and irritability but within a monthdeveloped left-sided tremor, rigidity and bradykinesiawhich was levodopa-responsive; she subsequentlydeveloped flexed posture, shuffling gait and pro-gressive dementia with paranoid delusions andauditory hallucinations. These four cases constitute8% of those in the previous literature. This contrasts

Diffuse Lewy body disease: clinicalfeatures in 15 casesstrikingly with the findings in the present series, wherethe majority of patients presented with Parkinson'sdisease, either alone (40%) or with mild cognitiveimpairment (20%).

Subsequent development of Parkinsonian syndromeIn the literature, most cases of diffuse Lewy bodydisease eventually develop both dementia and aParkinsonian syndrome, although in many instances(48% ofcases) the latter was limited to only one or twoof the cardinal features of Parkinson's disease whilst11 cases (22%) had dementia without motor features(table 2). Again this contrasts strikingly with thepresent series where all 15 cases developed bothcognitive and motor features, and where the motorfeatures were minor in only two (13%).

In general the clinical features of these cases wereconsistent with those found in the subgroup ofpatientswith Parkinson's disease who are elderly anddemented, which we have elsewhere termed Type IIParkinson's disease.38

Levodopa responseIt is increasingly recognised that patients with anakinetic-rigid Parkinsonian syndrome who do notrespond to levodopa may have illnesses other thanidiopathic Parkinson's disease.39 Only three (6%)

Table 2 Clinicalfeatures ofpresent series compared withprevious reports3-32

Present series Previous reportsClinical Number of Number offeature cases (%) cases (%)

A. At presentation:Parkinsonism alone 6 (40) 3 (6)Parkinsonism & n/psych 3 (20) 1 (2)Neuropsychiatric alone 6 (40) 34 (67)Other 0 2(4)Unspecified 0 11(22)

15 51B. Subsequently:

Parkinsonism without 0 1 (2)dementia

Dementia without 0 10 (22)Parkinsonism

Dementia with gait 2 (13) 4 (8)disturbance or flexedposture alone

Dementia with tremor, 0 7 (14)rigidity, orbradykinesia alone

Dementia with two of the 0 13 (26)above

Dementia with three of 3 (20) 8 (16)the above

Dementia with four or 10 (67) 3 (6)more

Dementia with unspecified 0 5 (10)Parkinsonism

15 51C. Levodopa-response 11 (75) 3 (6)

715previous reports of diffuse Lewy body disease des-cribed a response to levodopa; these reports are thoseof Ikeda" and Gibb'° cited above, and that ofYoshimura3' who described a 60 year old man whopresented with symptoms of orthostatic hypotension;he subsequently developed akinesia and rigidity whichresponded transiently to levodopa, and dementiawhich did not. In general previous reports do notmention attempts at treatment, but those of Mit-suyama24 and Sima et al29 describe two patients whoreceived little or no benefit from levodopa. However,the present series gives a markedly different impres-sion. Eleven patients received levodopa; ten showeddefinite and one probable benefit, suggesting a highlevel of levodopa-responsiveness in this group.

Fluctuation in cognitive stateAlthough unexplained, fluctuation in the severity ofcognitive impairment is the only early clinical featurein this series which distinguishes the dementiaassociated with diffuse Lewy body disease from otherforms ofcortical dementia. It has been reported beforeby Forno et al,9 Ikeda et al,'2 Clark et al5 and Gibb etal ' (two cases), that is, in 10% of reported cases. Thiscontrasts with the 12 (80%) cases in this series whoshowed marked cognitive fluctuation at some point intheir illnesses. This disparity may simply reflect thepaucity of clinical detail offered in the majority of casereports. A similar phenomenon is noted by Woodard'amongst the 27 cases of neuropsychiatric illness withbrainstem Lewy bodies which he identified in aretrospective study of 400 brains from mentalhospitals, although he does not comment on thepresence or absence of cortical Lewy bodies in thesecases.

Regardless of the mode of presentation, the latefeatures ofdiffuse Lewy body disease are dementia andParkinsonism. This, together with the fluctuatingcognitive impairment, frequently led to an erroneousclinical diagnosis of multi-infarct dementia in thisseries. Multi-infarct dementia is, however, probablyan unusual complication of idiopathic Parkinson'sdisease; vascular disease in general is less common inParkinsonians than the general population as judgedby a case-control study (RB Godwin-Austen and GStern, unpublished observations). Parkinsonianfeatures are also commonly found in other forms ofcortical dementia including that judged clinically to besenile dementia of the Alzheimer type.4' Recentevidence suggests that in these cases the Parkinsonianfeatures may in fact be attributable to coexistentbrainstem Lewy body pathology;42 clearly a largeprospective clinicopathological study is required toelucidate the nosology of these "extrapyramidaldementias". The importance of such a study has beenemphasised by the recent observation that the sub-

716group ofdementia patients with Parkinsonian featureshave a poorer prognosis than patients with dementiaalone.43

Neuropsychiatric aspectsThe psychiatric features of diffuse Lewy body diseasehave received increasing attention in recent casereports.7 10 In this series the majority of patients (53%)experienced psychiatric disorder. Depression, which isthought to be common in Parkinson's disease,occurred in three cases and responded to conventionaltricyclic antidepressant treatment. Auditory andvisual hallucinations, and paranoid ideation (oftenaccompanied by aggressive behaviour) occurred in afurther five cases; it was more difficult to manage,because conventional dopamine antagonist treatmentproduced marked deterioration in extrapyramidalfunction.

Conclusions

Although a retrospective survey of this type cannotgive accurate information regarding prevalence, itsuggests that diffuse Lewy body disease is not rare. Itconfirms that diffuse Lewy body disease presents in avariety of ways, with a spectrum ranging from aParkinsonian syndrome with subsequent dementia todementia with a subsequent Parkinsonian syndrome.It suggests that the former mode of presentation,indistinguishable from idiopathic Parkinson's diseasein clinical features and levodopa-response, may be farcommoner than has previously been realised, and thusthat diffuse Lewy body disease may be a significantcause ofdementia in Parkinson's disease. It shows thatthe latter mode of presentation, with "extrapyramidaldementia", is also common in diffuse Lewy bodydisease; the disease must be considered in thedifferential diagnosis of such cases, especially inassessing differences in prognosis in prospectiveclinical studies of dementia. Finally, it shows that thedementia ofdiffuse Lewy body disease generally showscortical features, and may fluctuate in severity fromday-to-day.We hope that these observations will stimulate

further research into this poorly-understood patho-logical entity. A prospective clinicopathologicalstudy, conducted by neuropathologists familiar withthe appearances of diffuse Lewy body disease, is nowrequired to establish its place amongst the other, moreestablished, causes of dementia with extrapyramidalfeatures and in particular to determine the frequencywith which it forms the pathological basis of thecommon and important problem of dementia inParkinson's disease.

This research was supported in part by the Parkinson's

Bvrne, Lennox, Lowe, Godwin-AustenDisease Society, The Stanhope Trust and The SpecialTrustees of the Nottingham University Hospitals. Theauthors thank the many doctors who allowed access totheir records, the pathologists who referred brains,Prof John Mayer and Dr Michael Landon for provid-ing ubiquitin antibody, Mr David McQuire and MrKen Morrell for technical assistance, and Mr BillBrackenbury for photomicrography.

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