10.1192/bjp.165.3.324Access the most recent version at DOI: 1994, 165:324-332.BJP 

I G McKeith, A F Fairbairn, R H Perry and P Thompsonbody type (SDLT).The clinical diagnosis and misdiagnosis of senile dementia of Lewy

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British Journal of Psychiatry (1994), 165, 324—332

Although the clinical and neuropathologicalcharacteristics of senile dementia were first describedat the beginning of this century, a comprehensive,reliable and valid clinical classification has yet to beestablished. The progressmade in recent years hasbeen largely based upon surveys of the neuropathological findings at autopsy in elderly patientswith well documented histories of seniledementia,and compared with aged normals (e.g. Tomlinsonet a!, 1970). Estimates were made of the relativeprevalences of differing neuropathological substratesof the dementia syndrome.That the majorityof caseswere due to dementia of Alzheimer type(DAT; 50%), multi-infarct dementia (MID; 17%)or ‘¿�mixed'pathology (18%) carried the implication that clinical diagnostic methods shouldbe developed with particular sensitivity andspecificity for these disorders, and that otherdiagnosesmight be regarded as relatively uncommon.Theseearly cinicopathological studieshave exertedconsiderable influence upon clinical practice andscientific research into degenerativedementia overthe last 20 years.

The current clinical diagnostic systems haveadopted a nosology based upon the anticipatedneuropathological categories;the most widely usedsystem is the Diagnostic and Statistical Manualof Mental Disorders (DSM—III—R;American

Psychiatric Association, 1987). It refers to the widerange of possible aetiologies of dementia, butcontains operational criteria for only primarydegenerativedementia of Alzheimer type and multiinfarct dementia, with brief criteria for alcoholrelated dementia.

Review of the recentciicopathological literaturesuggeststhat degenerative dementias other than DATmay not be as uncommon as previously thought.Severalstudies(Lennox eta!, 1989;Perry eta!, 1990;Dickson eta!, 1991)suggestthat dementiaassociatedwith subcortical and cortical Lewy body (LB)formation may be responsiblefor between 7—30%of casesof dementia in the elderly, making it themost common cause after DAT. The difficulty ofdetecting cortical LB prior to the development ofanti-ubiquitin immunocytochemicalstaining(Lennoxet a!, 1989) and the frequent coexistenceof largenumbersof senileplaques(SP),althoughnotusuallyneurofibrillary tangles(NVF) may have led to manysuchcasesbeing pathologically classifiedasDAT inearlier studies.

Debate continues as to whether this grouprepresents a ‘¿�Lewybody variant' of Alzheimer'sdisease(Hansen et a!, 1990), part of a spectrum ofLewy body disorders(Perry et a!, 1990), or a broadand diversemiddle band in a spectrumof LB-DATdisorders (Dickson et a!, 1991). Regardlessof how

324

The Clinical Diagnosis and Misdiagnosis of Senile Dementiaof Lewy Body Type (SDLT)

I.G. McKEITH,A. F.FAIRBAIRN,A.H.PERRY andP.THOMPSON

Background.Currentclinicalclassificationsdo not containspecificdiagnosticcategoriesforpatientswith seniledementiaof the Lewybodytype (SDLT),recentlyproposedasthe secondcommonestneuropathologicalcauseof dementiain the elderly.This study determineshowexistingclinicaldiagnosissystemslabelSDLTpatientsandsuggestshow suchpatientsmaybe identified.Method. A range of clinicaldiagnosticcriteria for dementia were appliedto case notes ofautopsy-confirmedSDLT(n= 20), dementiaof Alzheimertype (DAT;n = 21) andmulti-infarctdementia(MID; n =9) patientswho hadreceivedpsychogeriatricassessment.The predictivevalidity of each set of clinical criteria was calculated against the external criterion ofneuropathologicaldiagnosis.Results.Many SDLT patientserroneouslymet criteriafor MID (35% with Hachinskiscores

@ 7) orfor DAT (15% by NINCDS‘¿�probableAD', 35% by DSM-lll-R DAT and50% by NINCDS‘¿�possibleAD'). Upto 85% of SDLTcasescouldbecorrectlyidentifiedusingrecentlypublishedspecificcriteria.Conclusions. SDLT usually has a discernible clinical syndrome and existing clinicalclassificationsmay need revisionto diagnosecorrectlysuch patients.

SENILE DEMENTIA OF LEWY BODYTYPE 325

thisiseventuallyresolved,ifdementiaassociatedwithLB formation(variouslycalledLewy bodydementia(LBD), diffuse Lewy body disease(DLBD)or seniledementiaof Lewy body type(SDLT))is indeed as common as recent hospital-basedautopsyseriessuggest,the clinicianis facedwitha diagnosticproblem, since no guidelinesexistfortheirclinicalclassificationwithinthepresentframework.The objectof thepresentstudywasto determinehow theexistingclinicaldiagnosticsystemwould classifythe casehistoriesof aseriesof patientswithautopsy-confirmedSDLT.The opportunitywas alsotakento estimatethepredictivevalidityof theoperationalcriteriafortheclinicaldiagnosisof SDLT whichwe havesuggestedpreviously(McKeitheta!,l992a,1994)(seeTable 1).

Study population

(McKeitheta!, l992a)andarethereforesuitableforuse in determiningthe predictivevalidity of thecriteria.Casesarereferredto asDAT 1-21, SDLT1—20and MID 1—9,thesenumberscorrespondingto clinical details tabulated previously(McKeithet al, 1992b).

All patients had received comprehensiveassessmentin psychogeriatric units in Newcastleand Gateshead, and detailed case notes wereavailable from time of first presentation untildeath. Case notes from nursing homes andinformation from general practitioners were alsosought to ensure that full details of physicaland mental state and results of investigationsand a record of medication history were available.

Neuropathologicalmethods

Methodsfortissuepreparationand pathologicaldiagnosishavebeendescribedpreviously(Tomlinsonet a!, 1970;Perry et a!, 1990).Thecasenotesofthe50patientswererandomised

andreviewedblindto neuropathologicaldiagnosis.Simultaneous application of the following sets ofdiagnostic criteria were made:

(a) DSM—III—Rdementia syndrome;(b) DSM—III—Rprimary degenerative dementia

of Alzheimer type;(c) DSM—III—Rprimary degenerative dementia

of multi-infarct type;(d)ProbableAlzheimer'sdisease(NINCDS

ADRDA) (McKhann et a!, 1984);(e) Possible Alzheimer's disease (NINCDS

ADRDA);(f) Hachinski Ischaemic Index (HI!) score

(Hachinski et a!, 1975);(g) Nottingham Group criteria for Dementia

associatedwith cortical Lewy bodies (Byrneet a!, 1991);

(h) Newcastle Criteria for SDLT (McKeith et a!,l992a) (see Table 1).

These were applied not only for the totalduration of illnessbut alsoat the time of presentationto the clinical services. Since the Nottinghamcriteria do not specifically refer to the possibilityof Parkinsonism in dementia associated withcortical Lewy bodies being due to neuroleptics,they were applied firstly ignoring the possiblerole of neuroleptics, and then again discountingany Parkinsonism judged to be secondary toneuroleptics.

The predictive validity of clinical diagnosisagainst the criterion of neuropathological diagnosis

Methods

Fifty elderly patients who died in hospital withdementiafor whomneuropathologicaldiagnosiswasobtainedat autopsywereincludedfor study.Thesecomprised20 caseswith SDLT, 21 caseswith DATandninecaseswithMID. TheSDLT andDAT caseswere independentof those originally used toconstruct the operational criteria for SDLT

Table 1Operationalcriteriaforseniledementiaof Lewybodytype

(SDLT)

(a) Fluctuatingcognitive impairmentaffecting both memory andhighercortical functions (suchas language,visuospatialability,praxis or reasoning skills). Fluctuation is marked with the

occurrenceof both episodicconfusionandlucid intervals,as indelirium, and is evident either on cognitive testing or by variableperformanceindailylivingskills

(b) At leastone of the following

(i) Visual and/or auditory hallucinationswhich are usuallyaccompaniedbysecondaryparanoiddelusions

(ii) Mild spontaneousextrapyramidalfeaturesor neurolepticsensitivitysyndrome,i.e. exaggeratedadverseresponsesto standarddosesof neurolepticmedication

(iii) Repeatedunexplainedfalls and/or transient clouding orlossofconsciousness

(c) Despitethe fluctuating patternthe clinicalfeaturespersistovera longperiodoftime(weeksormonths)unlikedeliriumwhichrarelypersistsaslong.Theillnessprogresses,oftenrapidly,toanendstageofseveredementia

(d) Exclusionofanyunderlyingphysicalillnessadequatetoaccountforthefluctuatingcognitivestate,byappropriateexaminationandinvestigation

(e) Exclusionofpasthistoryofconfirmedstrokeand/orevidenceofcerebralischaemicdamageonphysicalexaminationorbrainimaging

DAT

(n=21)SDLT (n=20)MID(n=9)Age

(years)'81.3(78.6-83.9)77.1 (74.1-80.0)78.8(72.1-85.5)Sex

(male:female)―6:15(0.40)13:7 (1.86)5:4(1.25)Total

durationtof68.537.746.7illness(months)(52.0-84.9)(24.9-50.5)(4.4—89.0)

DAT

(n=21)SDLT(n=20)MID(n=9)Fluctuating

cognitive1(4.8%)18 (90%)3(33.3%)impairment'Visual

hallucinations'4(19.1%)16 (80%)3(33.3%)Auditoryhallucinations'0(0%)9 (45%) 1(11.1%)Delusions'4(19.1%)16

(80%) 1(11.1%)Repeatedunexplained5(23.8%)10 (50%)3(33.3%)fallsObserved

disturbances5(23.8%)5 (25%)2(22.2%)ofconsciousnessParkinsonian

features'4(19.1%)17 (85%)2(22.2%)-spontaneousordrug-induced

326 McKEITH ET AL

Table2Age, sex anddurationof illnessof patients

Table3Frequencyof key clinicalsymptomsoccurringat any

stage1

(mean +95% confidence interval)‘¿�ANOVAF247 =2.15 (NS); “¿�P=0.02 (Fisher's exact test);tANOVA F247=3.66, P= <0.05.

is expressedin terms of sensitivity and specificity.These ratios were calculated using the formulae:

Sensitivity= a/(a + c) x 100%Specificity = d/(b + d) x 100%

in which a = true positive, those defined as positivebyboththetestandcriterion;b= falsepositive,thoseincorrectlydefinedaspositiveby thetest;c= falsenegative,thoseincorrectlydefmedasnegativebythetest;andd= truenegative,thosedefinedasnegativeby both the test and criterion.

Results

Age, sex and duration of illness

Details of the three diagnostic groups are shown inTable 2. There were no significant age differences,but the DAT casessurvivedsignificantlylongerthanthe other two groups and were significantly moreoftenfemale.

Key clinical symptoms

Table 3 shows the frequencywith which thekey clinical symptoms assessedin the operationalcriteria for SDLT occurred at any stage of illnessin the three groups. Using Fisher's exact test ina 3x 2 table,fluctuatingcognitiveimpairment,visual and auditory hallucinations, delusionsand Parkinsonian features differed at a highlysignificant level (P< 0.001) between groups. Posthoc inspection using 2 x 2 tables showed thisto be due to increased frequencies in the SDLTpatients.Fluctuatingcognitiveimpairmentoccurredon

33.3°/aof MID patients and 4.8°loof DAT patients(P= 0.06). No other comparisonsbetweenDAT andand MID groups approached significance.

1. Figures are numbers (percentages) of patients.‘¿�P<0.01(Fisher'sexacttest).

InspectionofSDLT and MID groupsshowedasignificantlyincreasedfrequencyinSDLT patientsoffluctuation(90°/av.33.3°/a,P= 0.0001),visualhallucinations(80°/av. 33.3°/a,P= 0.0003),delusions(80°/av. 11.1°/a,P= 0.0003), and Parkinsonianfeatures(85°/ov. 22.2°/a,P= 0.0002), suggestingthat theseitems in the clinicalcriteria for SDLTmay be of use in the discriminationfrom multiinfarct cases.

Specificity

Table 4 showsspecificityrates(aspercentages)foreachsetof criteria applied.Criteria werenot requiredto bemutuallyexclusiveandeachpatientcouldfulfilmore than one set. The table may be easilyinterpretedby subtractingfrom 100thespecificityratein a column correspondingto a particularneuropathologicaldiagnosis.The remainingfigurerepresentsthe percentageof patients with thatneuropathologicaldiagnosiswho met the clinicalcriteriaspecifiedon thatrow (i.e.clinicalfalsepositive cases). Brief details of each of theseindividual misdiagnosesis given below.

Neuropatho!ogica! diagnosisDAT

Veryfewfalsepositiveclinicaldiagnosesweremade.DAT case9 (an89-year-oldwomanwith fluctuatingdeliriumand hallucinations)met NewcastleSDLTcriteria,and DAT case6 had a HachinskiscoreofseventherebybeingmisclassifiedasMID. DAT cases1 and 2 werediagnosedas Nottingham‘¿�probable'and‘¿�possible'casesrespectively.ThesetwopatientsbothexhibitedParkinsonianfeaturesafterreceiving

SENILE DEMENTIA OF LEWY BODYTYPE 327

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328 McKEITH ET AL

neuroleptics(case1severe,case2mild)—¿�whenthiswasaccountedfor whenapplyingthe criteria, neithercasewas misclassified.

Neuropatho!ogica! diagnosisMID

Although no false positive diagnoses were made byany criteria for the neuropathological MID caseswhen the whole history was available, the situationat presentation was that 33°/aof patients hadHI! scoresbetween0—4,22°/amet NINCDS criteriafor ‘¿�possible'AD and 11°/amet DSM-.III—Rcriteria for DAT. No falsediagnosesweremade witheither Newcastleor Nottingham Lewy body criteria.

Neuropatho!ogica! diagnosis SDLT

DSM—III—Rcriteria for MID made only one falsepositive diagnosis (SDLT case5)- an 82-year-old manwho at a late stage developed leftsided weakness,suggestiveof stroke diseasebut not substantiatedat autopsy. Four (20°/a)of SDLT cases fulfilledDSM—III—Rcriteria for DAT at presentationand seven (35°/a)did so for the total illness. Thisparadoxicalincreasein misdiagnosisrateasthe illnessprogresses was due to the exclusion of SDLT cases byDSM-III-R criteria at an early stagebecausetheyfailed to meet criteria for the dementia syndrome.Four of the seven patients (57°/a)who eventuallyfulfilled DSM-III-R criteria for DAT attracted asubcode‘¿�withdelirium' and six of the seven(86°/a)also met Newcastle SDLT criteria. Only one SDLTcase(number18),an87-year-oldwomanwithgraduallyprogressivedementia of five years duration showedno fluctuationand appearedclinicallyto be a ‘¿�typical'DAT patientwho wasundetectableby any criteria forSDLT.

A similar picture was seenfor NINCDS ‘¿�probable'AD criteria (15°/afalse positive rate), the moredemandingrequirementstendinghoweverto increaseoverallspecificityat somecostto sensitivity.However,if the lessstringent NINCDS ‘¿�possible'criteria areapplied, a further 50% of SDLT casesare misclassified,65°/ain total therefore meeting either ‘¿�probableorpossible' criteria for AD. The explanation for thisappears to be the frequent use of the criterion‘¿�variationsin onset and clinical course' whichaccommodates the often relatively abrupt onset andfluctuating pattern seenin SDLT patients. SDLT cases1,7—13,15, 16, 18—20weremisclassifiedas‘¿�possible'AD in this way, all of theseexceptcase18againbeingcorrectly identified by NewcastleSDLT criteria.

Hachinski scoresof sevenor more were recordedin 25°/aof the SDLT casesat presentationandin 35°/aoverthe total illness.Of thesevenSDLT casesscoringseven or more on the HI!, all (100°/a)

wereratedasshowinga fluctuatingcourseof illness,six(86°/a)ashaving relativepreservationof personality,four (57°/a)ashaving an abrupt onsetof illnessandthree (43°/a)as showing stepwise deterioration.Clinical evidenceof atherosclerosiswasdocumentedin four (57°/a),and focal neurological signs in two(29°/a- case15with extensorplantarsand caseSwitha resolvingleft hemiparesis).Case5 wasthe only caseinwhicha positiveHachinskiratingwasmade fora history of strokes. Six of thesesevenpatients (allexcept caseS) were correctly identified as SDLT bythe Newcastlecriteria.

SDLT case14failed to meetany of the diagnosticcriteriaapplied.This62-year-oldmanmetDSM-III-Rcriteria for major depressivedisorder at presentation,with prominent mood congruentdelusions.He laterdeveloped memory impairment and word-findingdifficulties, the diagnosis then being changed toorganic mood syndrome, the postulated underlyingcause being fibrotic lung disease of which heeventually died.

Sensitivity

Sensitivities(percentage)of the different schemaarealso shown in Table 4.

Twenty-eight per cent (14 cases)failed to meetDSM—III—Rcriteria for dementia syndrome atpresentation, 13of thesebeing SDLT patients andone with DAT. Twelve per cent failed to meetthesecriteria at any point in their illness because ofpersisting evidence of normal cognitive function(including short-term memory) betweenfluctuations(SDLT cases2, 3, 4, 6 and 14) and DAT case 19(seebelow).

Neuropatho!ogical diagnosis DAT

NINCDS ‘¿�probableand possible' and DSM—III—Rcriteriawerebothequallysensitive(bothexcludingonly DAT case 19, a 77-year-old woman whopresentedwith mild short-term memory impairmentonly, thought to be secondary to depression).

Neuropatho!ogica! diagnosis MID

Both DSM—III—Rcriteria and the Hachinski scoreshoweda low initial sensitivity for MID (56°/aand44%), althoughwith both systemsthis improvedwithillness duration as confirmation of stroke diseasedeveloped(89°/aand 78°/a).

Neuropatho!ogica! diagnosis SDLT

Nottingham criteria for Lewy body dementia showeda sensitivity of only 35—50°/aat presentation, the

SENILE DEMENTIA OF LEWY BODY TYPE 329

higher figure being obtained by disregardingthe possible role of neuroleptics in producingParkinsonism(i.e.byratingall observedParkinsonismas significant for diagnosis). For the total illnessthe sensitivity was up to 80°/a,again ignoringneurolepticsand allowing ‘¿�possible'cases(in whomParkinsomsm was a mild or late feature). Atthe other extreme only 35°/aof caseswere everdetectedby ‘¿�probable'criteria when the possibilitythat Parkinsonismwassecondaryto neurolepticswastaken into account.NewcastleSDLT criteriaweremore sensitive,

detecting75°/aat presentationand 85°/afor the totalillness. Five cases (25°/a)were not detected atpresentation(caseS,excludedbecauseof presumedstroke disease,case14with delusional depression,case18who hadanapparentlyuneventfulprogressivedementia and cases17 and 19 who presentedwithmotor Parkinson's disease). Case 17, initiallydiagnosedas Parkinson's diseaseand case19 alsopresentingwith Parkinson's diseasewith prominentvisual hallucinations and falls were both correctlyidentified later dueto thedevelopmentof fluctuatingconfusion, increasingthe overall sensitivity to 85°/a.

Discussion

The results of this study suggest that patientswith a neuropathological diagnosis of SDLT arefrequently misclassified by the existing diagnosticsystem.Fifteen per cent meetNINCDS criteria forprobable AD, 35°/ameet DSM—III—Rcriteria forDAT and 50°/aNINCDS criteria for possibleAD.If these are added to the 35°/awho score sevenor more points on the HI!, it is apparent thatthe majority of SDLT patients can be wronglyaccommodated by current diagnostic concepts.A false positive diagnosisof MID was unlikely tobe made using operationalised criteria requiring ahistory of, or neurologicalsignssuggestiveof, strokes(e.g. DSM—III—RMID).

The composition of the study sample is not, ofcourse, representative of the relative prevalencesof SDLT, DAT and MID in the general clinicalpopulation. If one corrects for a predicted ratioof 2.5 DAT cases:1 SDLT case:0.5 MID cases,approximating to Perry et al's (1990) figures, itis possible to calculate the likely impact of thesefindings on typical clinical or researchsamples.Forpatients meetingNINCDS probable AD criteria thepredicted erroneous inclusion rate of SDLT casesis 7°/orising to 21°/afor NINCDS probable andpossiblecasestogether.The correspondingcalculationfor DSM-IH-R criteriayieldsa 12°/amisclassificationrate.

The positive predictive value of a Hachinskiscore @7is only 53°/awhen calculated in a similarway, the remaining 47°/aof high scorespotentiallybeing SDLT patients.

Thepredicted‘¿�contamination'ratesof putativeDATpopulationscalculatedfromthisdatacorrespondwell with the actual rates observed in the onlytwo studies which have looked for LB at autopsyin cohorts of patients diagnosed using NINCDScriteria (12°/a—¿�Förstlet al, 1993; 36°/a—¿�Hansenet a!, 1990).

The implications for clinical and researchpracticeof a possible 7—21°/afalse positive rate for thediagnosis of DAT by currently acceptedmethodsprompt a re-evaluation of some existing conceptsabout the clinical symptomsand courseof DAT, itsepidemiology and therapeutics.

If a significant number of SDLT patients areclinically misidentified as having DAT, one wouldexpecttheir clinical featuresto havebeencommentedupon previously. Clinical heterogeneityin patientsmeetingdiagnosticcriteriaforDAT hasindeedbeenrecognisedfor severalyears,two influential reports(Chui eta!, 1985;Mayeux et al, 1985)suggesting thatsuch heterogeneity might be an important factorin determining diseaseprogressionand outcome inpatients meeting DSM—III criteria (AmericanPsychiatricAssociation,1980).The majorclinicalsign associatedwith reduced survival was the earlypresenceof Parkinsonian features, which occurredin 30°/aof patients, with psychotic symptomsbeingpredictive of a more rapid cognitive decline, a fmdingconfirmed by severalsubsequentstudies(Drevets&Rubin, 1989;Burns eta!, 1990b;Lopez eta!, 1991;Rosen& Zubenko, 1991).

Parkinsonianfeatures,psychoticsymptoms,rapidcognitive declineand reducedsurvival haveall nowbeenidentified ascharacteristicsdistinguishingSDLTfrom DAT patients (McKeith et a!, 1992a), andit seemsjustifiable to speculatethat some of theclinical heterogeneityof DAT previously describedand supported by the outcome studiescited abovehas been due to the erroneous inclusion of SDLTcasesby clinical criteria for DAT.

In support of this interpretation are the findingsin a previous autopsy study of 37 DAT casesinNewcastle, in which caseswith LB pathology werepositivelyexcluded.Neither the presenceof psychoticsymptomsnor of spontaneousParkinsonianfeatureswereassociatedwith a significantly different clinicalcourse in thesepatients (Jabeen et a!, 1992).Theoverall rates of delusionsand hallucinations (11°/oand 14°/arespectively)were slightly lessthan thoseof Burns et a! (1990a) (15.7°/aand 16.9°/a)andconsiderably lower than thosereported by Rosen&

330 McKEITH ET AL

Zubenko (1991)(35°/aand 34°/a),Drevets& Rubin(1989) (43°/aand 27°/a)and Merriam eta! (1988) (56°/aand 28°/a).Parkinsonian featuresnot attributable toneurolepticswereseenin only 9.5°/aof Jabeenet a!'s(1992) DAT cases, compared with 30°/areportedby Mayeux et a! (1985), 36°/aby Förstl et a! (1992)and 55°/aby Ditter & Mirra (1987).The consistentlyhigher report rates for psychotic symptoms andParkinsonism in these clinically diagnosed DATgroups are again likely to be due in part to theunrecognisedinclusion of a significant number ofcases with LB pathology. This has indeed beenconfirmed in those studieswhich included autopsyexamination: Ditter & Mirra (1987)—¿�40°/awith LBin SN and a further 15°/awith cortical LB; Burnset a! (1990a) and Förstlet a! (1992) —¿�12°/awithcortical LB.

The correct clinical classification of dementedpatients with LB may needto be deferred until thenatureof the relationshipbetweenLB andAlzheimertype pathologies hasbeenresolved. If the majorityof such patients are deemedpathologically to havea LB variant of DAT, current ideasabout clinicalheterogeneitywithin DAT will require only minoramendment. By contrast, if cortical LB pathologyis determined to be a sufficient cause of clinicalsymptoms independent of the Alzheimer typepathology, then a substantial revision of the clinicalclassification will be needed.

Although a false positive diagnosisof MID wasunlikely to be made using operationalised criteriarequiring a history of or neurologicalsignssuggestiveof strokes, the HI! misdiagnosed 35°/aof SDLTpatients due to the fluctuating nature and courseofillness, relative preservation of personality, abruptonset and stepwisedeterioration. Selection of theitemsin the HI! wasoriginally basedupon prevailingviews of clinical features discriminating betweenDAT and MID. Sinceneither the neuropathologicalnor clinical concepts of Lewy body dementia hadbeen developed at that time, it is not surprisingthat the HII performs relatively poorly in theirdifferentiation.

Methodological considerations

Retrospective case note studies are potentially limitedby the quality, standardisation and completenessofdata, a deficiency minimised in the present studiesby the longstandingusein Newcastlepsychogeriatricunits of a uniform assessmentprocedure whichincludes physical examination and investigations,routine mental state assessmentsand quantifiedcognitivetesting.ThepredominantsamplingbiasesaffectingtheNewcastleseriesweretowardspsychiatric

presentationsprogressingto dementia (but with norequirementtomeetanyspecifiedclinicalpattern)andwithaslightnegativebiastowardspatientswithestablishedParkinson's disease(thesepatientsbeingreferredtoa separateneurologicalservice).ThisdiffersfromthebiasesintheotherrelativelylargeLB cohorts reported - the Nottingham series(Byrneeta!, 1989;n = 15) in which Pa.rkinsonismfrequentlyoccurred as a presenting feature due to the partialinclusion of a neurology referred population; or theLewy body variant of Alzheimer's disease patientsof Hansen et a! (1990; n = 13) and Förstlet a!(1993; n = 8), all of whom had to fulfil the clinicalconstraintsof NINCDS-ADRDA criteria for AD, inorder to be recruited for study. Selectionbiaseswillinevitably have a major effect upon the outcomeof a study of this type and it is worth noting thatthe generalclinical profile of the NewcastleSDLTpatientsis similar to that of the total numberof casesreported in the literature to date (n = 150) withParkinsonian features being mild and relativelyuncommon, particularly in the early stages, andneuropsychiatric features progressing to dementiabeing almost always present.

The Nottingham criteria for dementia associatedwith cortical LB show high diagnostic specificitywhen applied to the present sample but appearrelatively insensitive, certainly at presentation andparticularly if only ‘¿�spontaneous'Parkinsonism(thatnot attributable to neuroleptics)is eligible. Basedoncurrent evidence it seemslikely that they will besensitive in detecting patients with Parkinson'sdisease who later develop the neuropsychiatricmanifestations of SDLT (for whom the diagnosticcategory, ‘¿�Parkinson'sdisease + SDLT' may bepreferred), but less so in identifying those withother presentations. Our retrospective case notedesignmay, however,havefailed to recordmild andearly Parkinsonian features and the Nottinghamcriteria needto be assessedin a clinical prospectivestudy before this conclusion can be justified.

The Newcastlecriteria had sensitivity (0.85) andspecificity (0.97) values which compare favourablywith those reported for the diagnosis of DAT(sensitivity0.76, specificity0.80 for DSM-III criteriaand0.92,0.65 for NINCDS—ADRDA‘¿�probableandpossible' DAT) (Kukull eta!, 1990a,b). The failureof the Newcastle criteria to detect three patients(15°/a)requires further consideration. One (case18)had a gradually progressivedementing syndromewhich was indistinguishable from ‘¿�typical'DAT, one(case 5) was erroneously thought to have strokediseasebecauseof focal neurological signs whichdevelopedlate,andone(case14)presentedwithadelusionaldepressionwithno clearevidenceof

SENILE DEMENTIA OF LEWY BODYTYPE 331

cognitiveimpairment.InapreviousseriesofSDLTcases(McKeitheta!,1992a)twoof21SDLT casespresentedwith ‘¿�typicalDAT' and onewith auditoryhallucinationsand delusionsdiagnosedasdueto lateparaphrenia. It is plausible that LB diseasemayproduce mental symptoms other than cognitiveimpairment in a minority. Birkett eta! (1992)foundan admissiondiagnosisof paranoid disorderand thesubsequentuse of ECT (for the combination ofdelusionsand depression)to be associatedwith thefinding of LB at autopsy. The accurate clinicalidentification of such patients remains elusive,althoughthespontaneousdevelopmentof Parkinsonianfeatures,excessivesensitivityto neurolepticmedicationor the late appearanceof cognitive impairment in apatient with a previous diagnosisof a paranoid ordepressivedisordershouldraisethe possiblediagnosisof underlying LB disease.Until the detailed neuropathological correlates of such presentationshavebeen compared with those of patients with moretypical SDLT symptoms it is premature to commentfurther upon their correct classification.

Conclusions

ResearchintodementiawithcorticalLB isalreadyleadingtore-examinationofseveralpreviouslyheldviewsaboutneurodegenerativeconditions.Evenatthisearlystage,cliniciansand researchworkersassessingelderlypatientswithcognitiveimpairmentmust be made aware of the possible diagnosisof SDLT and the symptomatic, prognostic andtherapeuticimplicationsassociatedwith it. Preliminaryevidencesuggests,for example, that SDLT patientscan benefit from cholinergic replacement therapy.The unsuspectedinclusionof such patientsintreatment studies of presumedAlzheimer patientsmay well be responsible for at least some of thepositive reports about cholinesterase inhibitorsin DAT.

Diagnostic criteria for the ante-mortemdetectionof such patients which have been developed inthese and other (Byrne et a!, 1991) studies neednow to be independently validated and refined asnecessaryfor wider use. It is unfortunate that suchdevelopmentshave cometoo late to influence eitherof the major classificationsystemswhich will operateover the next decade (DSM—IV (AmericanPsychiatric Association, 1994) and ICD—10(WorldHealth Organization, 1992)). Prospective studies ofsuitable design, preferably a multicentrecollaboration, based in the community, woulddescribe the prevalence, clinical symptoms andcourseof PD, SDLT, DAT and their interforms andfollow theseto autopsy. They would also allow for

the evaluation of investigative methods with thepotential to assist in differential diagnosis. EEGmeasuresmay have a particular role in this lattercontext, with preliminary observations in theNewcastleseriesand by Crystal eta! (1990)of focalfronto-temporal slowing in SDLT. Appropriate neuropsychological test procedures are also likely todemonstrate clinically useful differences betweengroups (Sahgalet a!, 1992).

Acknowledgement

Thanks are due to Maureen Middlemist for typing the manuscript.

References

AMERICAN PSYCHIATRICMSOOA1iON (1980) Diagnostic and StatisticalManual of Mental Disorders (3rd edn)(DSM-III). Washington,DC: APA.

(1987) Diagnostic and StatisticalManual of Mental

Disorders(3rd edn revised)(DSM-III-R). Washington,DC:APA.

(1994) Diagnostic and Statistical Manual of MentalDisorders (4th edn) (DSM-IV). Washington, DC: APA.

Bi@m, D. P., DESOUKY,A., HAN, L., ci a! (1992) Lewy bodiesin psychiatric patients. International Journal of GeriatricPsychiatry, 7, 235—240.

BURNS, A., LUThERT, P., LEVY, R., et al (1990a) Accuracy ofclinical diagnosis of Alzheimer's disease. British Medical Journal,301, 1026.

JACOBY, R. & LEVY, R. (1990b) Psychiatric phenomena inAlzheimer's disease I-IV. British Journal of Psychiatry, 157,72—94.

BYRNE, E. J., LENNOX, 0., Lowa, J., ci al (1989) Diffuse Lewybody disease: clinical features in 15cases. Journal of Neurology,Neurosurgeryand Psychiatry, 52, 709—717.

ci al (1991)(NottinghamGroup for theStudy of Neurodegenerative Disorders) Diagnostic criteria fordementia associated with cortical Lewy bodies. Dementia, 2,283—284.

CHUI, H., TENG, E. L., HENDERSON, V. W., ci a! (1985) Clinicalsubtypes of dementia of the Alzheimer type. Neurology, 35,1544—1550.

CRYSTAL, H. A., DICKSON, D. W., LEZARDI, J. E., et a! (1990)Antemortem diagnosis of diffuse Lewy body disease. Neurology,40, 1523—1528.

DIacsoN, D. W., RyAN,D., CRYSTAL,H., ci at (1991)Hippocampaldegeneration differentiates diffuse Lewy body disease (DLBD)from Alzheimer's disease: Light and electron microscopicimmunocytochemistry of CA2-3 neurites specific to DLBD.Neurology,41, 1402-1409.

DrrrnR, S. M. & Miani@, 5.5. (1987) Neuropathologic and clinicalfeatures of Parkinson's disease in Alzheimer disease patients.Neurology, 37, 754-760.

DREVET5,W. C. & RUBIN, E. H. (1989) Psychotic symptoms andthe longitudinal course of senile dementia of Alzheimer type.BiologicalPsychiatry,25, 39—48.

FOasm, H., BURNS,A., LEVY,R., ci a! (1992) Neurologic signs inAlzheimer's disease. Results of a prospective clinical andneuropathologic study. Archives of Neurology, 49, 1038-1042.

LUTHERT, P., et al (1993) The Lewy-Body variantof Alzheimer's disease. Clinical and pathological findings. BritishJournalof Psychiatry,162, 385-392.

HACHINSKI, V. C., Kwr, L. D., ZIuciIA, E., et al (1975) Cerebral

blood flow in dementia.Archives of Neurology, 32, 632-637.

332

HANSEN, L. A., SALMON, D., GALASKO, D., cial (1990) The Lewy

body variant of Alzheimer's disease: a clinical and pathologicentity. Neurology, 40, 1-8.

JABEEN, S., McKEITE, I. 0., FAIRBAIRN, A. F., ci al (1992)

Psychotic symptoms in Alzheimer's disease. InternationalJournal of Geriatric Psychiatry, 7, 341—345.

KUKULL, W. A., LARSON, E. B., REWLER, B. V., ci al(1990a) The

validity of 3 diagnostic criteria for Alzheimer's disease.Neurology, 40, 1364—1369.

ci al (l990b) Inter-rater reliability ofAlzheimer's disease diagnosis. Neurology, 40, 257-260.

LENNOX, 0., LowE, J., MORRELL, K., ci al (1989) Anti-ubiquitin

immunocytochemistry is more sensitive than conventionaltechniques in the detection of diffuse Lewy body disease. Journalof Neurology, Neurosurgery and Psychiatry, 52, 67-71.

Lopaz, 0. L., BECKER,J. T., BRENNER,R. P., ci al (1991)Alzheinier's disease with delusions and hallucinations: neuro

psychological and electroencephalographic correlates.Neurology,41, 906-912.

MAYEUX, R., STERN, Y. & SPANTON, S. (1985) Heterogeneity in

dementias of the Alzheimer type: Evidence for subgroups.Neurology, 35, 453—461.

McKEIm, I. G., PERRY,R. H., FAIRBAIRN,A. F., ci al (1992a)Operational criteria for senile dementia of Lewy body type(SDLT). Psychological Medicine, 22, 911—922.

FAIRBAIRN, A. F., PERRY, R., ci al (199Th) Neuroleptic

sensitivity in patients with senile dementia of Lewy body type.British Medical Journal, 305, 673—678.

—¿�, , BOTHwELL, R. A., ci al (1994) Inter-rater

reliability and predictive validity of clinical diagnostic criteriafor senile dementia of Lewy body type (SDLT). Neurology,44, 872—877.

McKiw'm, G., DBAQmAN,D., Foizremi, M., ci al(1984) Clinicaldiagnosis of Alzheimer's disease: report of the NINCDS-ADRDAWork Group under the auspices of Department of Health andHuman Services Task Force on Alzheimer's disease. Neurology,34, 939—944.

Mmutw@i, A., ARONSON,N., GASTON,P., ci al (1988) Thepsychiatric symptoms of Alzheimer's disease. Journal of theAmerican Geriatric Society, 36, 7-12.

PERRY,R. H., IRvmio, D., BLESSED,0., ci al(1990) Senile dementiaof Lewy body type. A clinicallyand neuropathologicallydistincttype of Lewy body dementia in the elderly. Journal of theNeurological Sciences, 95, 119—139.

ROSEN, J. & ZuasniKo, J. 5. (1991) Emergence of psychosis and

depression in the longitudinal evaluation of Alzheimer's disease.Biological Psychiatry, 29, 224-232.

SAN0AL,A., GALLOWAY,P. 0., MCKEITH,I. G., ci al (1992)Matching-to-sample deficits in patients with senile dementia ofAlzheimer and Lewy body types. Archives of Neurology, 49,1043—1046.

TOMLINSON,B. E., BLrssEn, 0. & Rom, M. (1970) Observations onthe brains of demented old people. Journal of the NeurologicalSciences, 11, 205—242.

WORLD HBALm ORGANIzATION (1992) The lCD-JO Classification

of Mental and Behavioural Disorders. Geneva: WHO.

(First received August 1993, final version received October 1993, accepted November 1993)

McKEITH ET AL

Ian G. McKelth, MD, MRC Neurochemical Pathology Unit, Brighton Clinic, Newcastle Mental Health(NHS) Trust; Andrew F. Fairbairn, MRCPsych,University Department of Old Age Psychiatry, BrightonClinic, Newcastle Mental Health (NHS) Trust; Robert H. Perry, FRCPath,Department of Neuropathology,Newcastle General Hospital, Newcastle upon Tyne; Peter Thompson, MRCPsych,Bensham Genera!Hospital,Gateshead,Tyne and Wear

Correspondence: Dr McKeith, MRC Neurochemical Pathology Unit, Newcastle General Hospital, Westgate Road,Newcastleupon Tyne NE4 6BE