J Neurol (2003) 250 [Suppl 1]: I/39–I/42DOI 10.1007/s00415-003-1108-9

Reiner Benecke Diffuse Lewy body disease – a clinical syndrome or a disease entity?

Introduction

Most clinicians and researchers accept diffuse Lewybody disease (DLBD) as a clinicopathological entity, inwhich, clinically, parkinsonian symptoms and dementiaare presented. I prefer the term DLBD instead of “de-mentia with Lewy bodies” because the latter term un-derestimates the parallel occurrence of parkinsoniansyndromes and also discussing the diagnosis dementiawith Lewy bodies with patients and their relatives ofteninduces unwanted emotional stress because of the worddementia especially in early stages of the disease. Mostof the cases of DLBD had been characterised in centresengaged in research on dementia in the elderly. Due topatient selection it was believed that dementia is alwaysthe initial and dominant feature of the disorder, which islater followed by the development of parkinsonian fea-tures. However, in later studies published by neurolo-

gists it turned out that a similar population of patientswho present with extrapyramidal features followed bythe development of dementia can be generated fromneurological departments.

The history of DLBD began when Okasaki and co-workers (1961) noted widespread Lewy bodies in thecerebral cortex in two elderly individuals with progres-sive dementia. Dementia with Lewy bodies receivedmuch more attention after a series of reports by Kosaka(1978) who first described in detail the characteristicsand distribution of cortical Lewy bodies. Kosaka and co-workers (1984) also proposed the term DLBD as a des-ignation for a particular type of Lewy body disease.Withthe advent of immunohistochemistry, many exampleshave been identified of patients with progressive de-mentia who showed evidence of extensive Lewy bodyformation in the cerebral cortex (Lowe et al. 1988). Au-topsy studies of elderly patients with dementia indicatedthat about 25 % of cases with dementia have diffuse cor-

■ Abstract Most clinicians and re-searchers still accept diffuse Lewybody disease (DLBD) as a clinico-pathological entity. Dementia withfluctuating cognitive deficits, aparkinsonian syndrome, and visualhallucinations are the core symp-toms of this proposed disease en-

R. Benecke, MD (�)Department of NeurologyUniversity of RostockGehlsheimer Str. 2018147 Rostock, GermanyTel.: +49-3 81/4 94-95 11Fax: +49-3 81/4 94-95 12E-Mail:reiner.benecke@med.uni-rostock.de

tity. From a neuropathologicalpoint of view, many examples ofpatients with progressive dementiashowing evidence of extensiveLewy body formation in the cere-bral cortex together with the oc-currence of Lewy bodies in sub-stantia nigra and locus coeruleushave been identified. Confusingly, alarge majority of cases showingtypical features of DLBD also pre-sent with an Alzheimer pathologyin the hippocampus and cerebralcortex. It is far from clear thatDLBD represents a specific diseaseentity rather an intermediate vari-ant between Alzheimer disease andidiopathic parkinsonian syn-

dromes. Nevertheless, from a clini-cal point of view it may be of im-portance to characterize patientswith a symptomatology of DLBDbecause important management is-sues such as avoidance of severeneuroleptic sensitivity reactions,dopaminergic antiparkinsoniantreatment and a beneficial re-sponse to cholinesterase inhibitorscan be applied.

■ Key words diffuse Lewy bodydisease · Alzheimer’s disease ·idiopathic parkinsoniansyndromes · neuroleptic therapy ·cholinesterase inhibitors

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tical Lewy bodies.All these cases also demonstrate Lewybodies in the substantia nigra, in the locus coeruleus,ac-companied by gliosis and neuronal loss in these regions.Confusingly, a large majority of cases showing the typi-cal features of DLBD additionally present with anAlzheimer pathology in the hippocampus and cerebralcortex. Thus, DLBD is now categorised into two forms:common and pure (Kosaka 1990). The common form ofDLBD is distinguished by the presence of senile plaquesand neurofibrillary tangles of varying degrees in thecerebral cortex. It is believed that the common form usu-ally affects elderly individuals, whereas the pure formcan sometimes occur at less than 40 years of age. Someresearchers proposed to give this neuropathologicallymixed cases a separate term: senile dementia of Lewybody type (Perry et al. 1990) and Lewy body variant ofAlzheimer’s disease (Hansen et al. 1990).

The typical case

Two years ago a 62-year-old right-handed surgeon pre-sented with insidious and progressive cognitive dys-function. He frequently forgot the date, lost his car inparking lots, and demonstrated weakened reasoning.The patient’s medical history was unremarkable,with no history of hypertension, stroke or transientischaemic attack, head trauma, psychiatric illness oralcohol abuse. Mental status examination revealeddeficits in short-term memory and problem-solvingability. Motor examination revealed hypomimia, mini-mal rest tremor of the right hand, also evident on writ-ing, and mild signs of akinesia and rigidity on the rightside. Gait was normal. Cabidopa/levodopa 25/100 mgthree times a day improved motor disturbances consid-erably.The diagnosis of an idiopathic parkinsonian syn-drome was made.

Six months later the patient had increased cognitiveproblems and performed activities of daily living withsome assistance of his wife. He began to have visual hal-lucinations and delusions at various times of the daylasting for hours. He sometimes meant to see deceasedrelatives or burglars especially during night time. Healso intermittently was convinced that his wife was plan-ning to poison him. His cognitive capacities fluctuatedbetween relatively lucid intervals and episodes of moresevere dysfunction, and were unexplained by medicalillness or mood alteration. Because of visual hallucina-tions and delusions he was admitted to a psychiatricclinic where levodopa therapy was stopped andhaloperidol was introduced. After 2 days on haloperidoltherapy the patient developed somnolence and later acomatose state and was taken over by the intensive careunit of a neurological department. Because of paralleldevelopment of a parkinsonian syndrome and fluctuat-ing cognitive functions in conjunction with visual hal-

lucinations, delusions and neuroleptic hypersensitivitythe patient was diagnosed as having DLBD. Haloperidoltherapy was stopped, levodopa therapy was reintro-duced and therapy with a cholinesterase inhibitor wasstarted. Furthermore, clozapin 12.5 mg three times a daywas given. Within one week the cognitive functions ofthe patient were stabilised on a higher level, motorsymptoms were improved and psychotic symptoms dis-appeared.

Diagnostic accuracy of DLBD

Preliminary attempts to determine whether particularclinical symptoms are associated with DLBD were basedon retrospective autopsy-proven case note reviews(Perry et al. 1990). These early operationalised criteriaproposed that the key symptoms suggestive of DLBDrather than AD are fluctuating cognitive impairmentwith episodic delirium, prominent psychiatric symp-toms, especially visual hallucinations, a parkinsoniansyndrome occurring spontaneously often as part of anabnormal sensitivity to neuroleptic medication (Mc-Keith et al. 1992). To improve diagnostic reliability andvalidity, consensus criteria for clinical diagnosis ofDLBD (McKeith et al. 1996) were outlined. At least, oneof the core features of DLBD fluctuation in cognitivefunction, visual hallucination and parkinsonian syn-drome must be present for making an at least possibleclinical diagnosis of DLBD. The use of two or more corefeatures for a diagnosis of probable DLBD was suggestedto confer higher diagnostic specificity and to be suitablefor most research applications. A progressive disablingmental impairment was said to be a mandatory require-ment for the diagnosis of DLBD. A variety of additionalclinical features have been included in reports of au-topsy-confirmed DLBD but had not yet been demon-strated to have sufficient diagnostic specificity to meritcore symptom status. Those considered of sufficient im-portance to warrant mention as supportive of a diagno-sis of DLBD were also included into the consensus crite-ria for the clinical diagnosis of probable and possibleDLBD (see Table 1).

Fluctuations in cognitive functions seem to be a com-mon phenomenon in DLBD (McKeith et al. 1992; Byrneet al. 1989). In the earliest stages, patients may showdeficits of cognitive function and global performancethat alternate with periods of normal performance.Fluctuations in cognitive functions may be paralleled byvariations in attention and alertness. Fluctuations aredescribed as occurring rapidly lasting only minutes orhours, as well as slower (weekly or monthly). No typicaldiurnal pattern of fluctuation has been identified inDLBD. DLBD patients may also show intermittent som-nolence which is often embedded in periods with pro-nounced deficits in cognitive function.

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Visual hallucinations, typically recurrent, formed,and detailed, have been described by most groups inves-tigating DLBD (Perry et al. 1990; Byrne et al. 1991; Mc-Keith et al. 1992; Klatka et al. 1996). Hallucinations inother modalities may also occur in DLBD but are clearlyless frequent. According to the themes, emotional re-sponses vary through fear, amusement, or indifference,and the degree of insight into the unreality is of majorimportance.

Akinesia, rigidity and tremor typically mild in earlystages of DLBD are the third core feature of DLBD.Otherfeatures of a parkinsonian syndrome such as hypo-phonic speech, hypomimia, stooped posture and a slowand shuffling gait can also occur. Resting tremor seemsto be less common. The order of onset of mental andmotor symptoms is variable, particularly in older pa-tients who often present a complex mixture of ex-trapyramidal and mental symptoms of almost simulta-neous onset. It is suggested that if dementia occurswithin 12 months of the onset of the extrapyramidalmotor symptoms, the patients should be assigned a pri-mary diagnosis of possible DLBD, and this will bestrengthened by the presence of additional core or sup-portive features. If the clinical history of parkinsonismis longer than 12 months, it has been suggested that PDwith dementia will usually be a more appropriate diag-nostic label (McKeith et al. 1996).

From the dementia standpoint, the consensus guide-lines (McKeith et al. 1996) emphasised characteristicfeatures of DLBD that were less common in other de-menting conditions such as AD.Applying the diagnosticcriteria, diagnostic sensitivity ranged from 53 % to 83 %,

with specificity from 83 % to 95 % (Gomez-Isla et al.1999; McKeith et al. 2000). The 30 % diagnostic sensitiv-ity reported by Lopez et al. (2002) supports their call forimprovements in the clinical criteria for diagnosingDLBD. The fact that many neuropathologically diag-nosed DLBD cases meet clinical criteria for AD maylimit diagnostic position, however, because concomitantpathological findings typical of AD are common andmay mask whatever clinical signs Lewy bodies alonemight produce.

Therapeutic aspects

Although it is not clear of whether DLBD represents aspecific disease entity, from a clinical point of view itseems to be of importance to characterise patients withthe symptomatology of DLBD because of importanttherapeutic issues. The main guidelines for therapy ofDLBD are given in Table 2.

Conclusions

It is far from clear that DLBD represents a specific dis-ease entity rather than an intermediate variant thatwould be anticipated if idiopathic parkinsonian syn-dromes and Alzheimer’s disease (AD) were polar ex-tremes of a singular neurodegenerative disorder (Perl etal. 1998). Perl and co-workers (1998) argue that suchoverlap reflects a common pathogenic mechanism forthe neurodegeneration encountered within specific vul-nerable neuronal populations. This hypothesis suggeststhat the current nosologic approach, which attempts toseparate AD from PD, fails to properly deal with the is-sue of overlap and that a new classification of the neu-rodegenerative disorders should be considered. In

Table 1 Consensus criteria for the clinical diagnosis of probable and possible DLBD

1. The central feature required for a diagnosis of DLBD is progressive cognitivedecline of sufficient magnitude to interfere with normal social or occupa-tional function.Prominent or persistent memory impairment may not necessarily occur in theearly stages but is usually evident with progression. Deficits on tests of at-tention and of frontal-subcortical skills and visuospatial ability may be espe-cially prominent.

2. Two of the following core features are essential for a diagnosis of probableDLB, and one is essential for possible DLBD:� Fluctuating cognition with pronounced variations in attention and alert-

ness� Recurrent visual hallucinations that are typically well formed and detailed� Spontaneous motor features of parkinsonism

3. Features supportive of the diagnosis are� Repeated falls� Syncope� Transient loss of consciousness� Neuroleptic sensitivity� Systematised delusions� Hallucinations in other modalities

4. A diagnosis of DLBD is less likely in the presence of� Stroke disease, evident as focal neurologic signs or on brain imaging� Evidence on physical examination and investigation of any physical illness

or other brain disorder sufficient to account for the clinical picture

Table 2 Therapeutic guidelines in patients with DLBD

1. In most cases the symptoms of the parkinsonian syndrome (akinesia, rigidity,tremor) can be improved by levodopa. In most cases 300 mg/d is the maxi-mal dosis because of psychiatric side effects.

2. Psychotic symptoms occur spontaneously but can be triggered or exacer-bated by levodopa therapy.

3. Therapy with dopamine agonists cannot be recommended because of higherprevalence of psychiatric side effects.

4. In case of wearing-off phenomena therapy with a COMT inhibitor can be per-formed at a decreased dose of levodopa.

5. Visual hallucinations and delusions can be improved by therapy with atypicalneuroleptics (clozapin, risperidon, quetiapin). Clozapin seems to be the drugof first choice. Doses of 3 x 12.5 up to 3 x 50 mg/d can be used. Rarely atypi-cal neuroleptics worsen parkinsonian symptoms and state of consciousness.

6. Fluctuating cognitive deficits can be improved by treatment withcholinesterase inhibitors (donezepil, rivastigmin, galantamin).

7. Orthostatic hypotonia can be treated with sympathicomimetica, bladder dys-functions with α-receptor blockers or with anticholinergics.

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essence, this suggestion would mean that the neurode-generative diseases termed PD, DLBD, AD and the clini-copathological mixtures belong to one common diseasewhich would show an enormous intra- and interindi-vidual variation. There is no name for this super diseaseso far, Lewy-Alzheimer disease could be a proposal.

Although from a puristic point of view the suggestionof Perl and co-workers (1998) could turn out to be valid,from a clinical point of view it may be of importance tocharacterise patients with the symptomatology of DLBD

because important management issues such as avoid-ance of severe neuroleptic sensitivity reactions, achiev-ing optimal level of antiparkinsonian treatment withoutexacerbating psychiatric symptoms and a beneficial re-sponse to cholinesterase inhibitors can be applied. In thelight of considerable nosologic uncertainties it can beproposed to characterise these patients clinically as hav-ing a parkinsonian syndrome with early dementia in-stead of using the apparently not well-established dis-ease entity DLBD.

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