J Neurol Neurosurg Psychiatry 1998;65:933–938 933 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

CLINICOPATHOLOGICAL CASE CONFERENCE

Behavioural disturbance and visual in a 78 year old man

David W Schultz, Graham G Lennox, James W Ironside, Charles P Warlow

Case presentation

This 78 year old widower was referred for hos- sant drugs. These usually occurred at night and pital admission in late September with short- involved women, one of whom he identified as ness of breath. He was an ex-smoker and had a his late wife. He had insight into this problem, past history of chronic obstructive airways dis- and also admitted to feeling disoriented on ease and ischaemic heart disease, having had a occasions. He had been experiencing floaters in myocardial infarction 12 years earlier. He was both eyes for about a year, in association with a experiencing weekly attacks of angina at rest gradual deterioration of his vision. He thought and with exertion. His regular medications that his memory had been deteriorating, and he included bronchodilators, diuretics, and dig- often mislaid objects around the house. On oxin, and he had also recently been started on mental state examination he had a mild global a course of prednisolone with omeprazole impairment aVecting attention, short term cover, for a presumed exacerbation of chronic memory, calculation, construction, and knowl- obstructive airways disease. edge of current aVairs. It was considered that On examination, he was apyrexial and not his general ill health, polypharmacy, and prob- short of breath at rest. Although having able eye pathology were contributing to his copyright. evidence of chronic obstructive airways dis- visual hallucinations, and that he had a mild ease, there was no evidence of any acute respi- depression for which he was begun on ratory compromise. He was in atrial fibrillation sulpiride. Little change was noted at outpatient at a rate of 80/minute and had an aortic systo- review 1 month later. lic murmur but no evidence of cardiac failure. In view of the concerns raised by the warden No neurological abnormality was noted. he was again reviewed by the psychiatrists Shortness of breath did not seem to be a sig- while an inpatient for his breathing problems. nificant problem in hospital. Blood gases They noted a significant decline physically, and disclosed mild hypoxaemia and hypercapnia on considered that he had an agitated depression, air similar to previous recordings, and echo- being upset at the prospect of losing his

cardiography confirmed moderate aortic ste- accomodation. His antidepressant was http://jnnp.bmj.com/ nosis with normal left ventricular function. changed to trazodone. However, the sheltered accomodation from During a home visit in early October, it was Department of Clinical which he was referred refused to accept him clear that he was disorientated and unsafe in his Neurosciences back. It then became apparent that the main own kitchen, with no insight into his problems. D W Schultz reason for his referral to hospital was because He was unable to read the cooker dials and C P Warlow of concern about his recent behaviour at home. would assess which one was on by touching the Neuropathology He had been living in a warden controlled resi- rings until he found the hot one! He became Laboratory, Western dence for the previous 6 months, and had increasingly disruptive on the ward, wandering on September 27, 2021 by guest. Protected General Hospital, recently become disruptive, especially at night. and falling occasionally, and continuing to call Edinburgh, UK He often became anxious and called out the out, requiring intermittent thioridazine to J W Ironside warden or his general practitioner (GP) many settle. He developed urinary and faecal incon- Division of Clinical times each week. A similar pattern of behaviour tinence, but with no evidence of a urinary tract , Queen’s was noted during his hospital stay, often need- infection. He became markedly confused and Medical Centre, ing reassurance at night. He had seen psychia- was noted to have a shuZing gait, after which Nottingham, UK trists intermittently during the past 5 years. the thioridazine was stopped. His upgaze was G G Lennox When he was first seen, he was assessed as hav- poor, but there were no other focal neurologi- Correspondence to: ing a prolonged grief reaction after his wife’s cal signs. His blood screens remained normal Dr David W Schultz, sudden death 12 months earlier. He was except for mild hypercapnia (paCO2 7.4 kpa) as Department of Neurology, reviewed again 4 years later, at which stage he noted on admission. A brain CT was at- Flinders Medical Centre, was considered to have a reactive depression tempted, but was unsuccessful as he would not Bedford Park, South Australia 5042. and was begun on the antidepressant sertra- lie still. Courses of augmentin and ceftriaxone line. He had again been referred by his GP in were given although no focus of infection was Received 7 January 1998 and the month before the present admission after identified. in revised form 9 July 1998 developing visual hallucinations, coinciding By late October he had become increasingly Accepted 25 July 1998 with the recent withdrawal of his antidepres- withdrawn and developed a resting hand 934 Schultz, Lennox, Ironside, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

not thought to be typically parkinso- get some vital information in the window of nian. He would open his eyes but tended to opportunity before he started to go downhill so stare ahead, and he no longer spoke. His oral quickly when he underwent a cognitive exam- intake was poor and he became dehydrated, ination. We are told that there was mild global developing a raised plasma sodium of 163 impairment aVecting attention, short term mmol/l (normal 135–145 mmol/l) and renal memory, calculation, construction, and knowl- failure, with a urea concentration of 54.8 edge of current aVairs. This is immensely help- mmol/l (normal 3.3–6.6 mmol/l) and a creati- ful as it tells us something of the anatomy of the nine concentration of 319 µmol/l (normal disorder. There was involvement of the poste- 70–110 µmol/l). rior hemispheres with the problems with calcu- An EEG disclosed a widespread patchy dis- lation and construction. Anterior executive turbance, with intermixed non-specific tran- functions and attention were also aVected. sient wave forms and more overt epileptiform Indeed as the illness progresses there are other sharp waves. “Twitches” of the upper limbs behavioural suggestions of both anterior and were noted during the recording. Correlation posterior dysfunction. He cannot recognise the between the “twitches” and any electrocerebral controls on his cooker (which could be disturbance was generally poor; however, on interpreted as ), but he has no occasion there was coincidence of the EEG and insight into the fact that he is unsafe (which clinical change (cortical ). suggests frontal impairment). At this stage he was first reviewed by a neu- He then became confused and agitated, and rologist, who thought that he was cortically was put on thioridazine. He became inconti- blind, but could find no other focal neurologi- nent of urine and faeces. He developed a shuf- cal features. There were no myoclonic jerks or fling gait and later a resting tremor; this raises frontal lobe reflexes demonstrable. the possibility of , perhaps un- He continued to deteriorate and at the masked by the neuroleptic drug. The only request of the family was begun on a other neurological finding at that stage was diamorphine infusion to alleviate any distress. impaired upwards gaze, which is unremarkable He died 24 hours later. Consent was obtained at the age of 78 years but also occurs in a wide for a limited postmortem examination. range of degenerative diseases of the including Alzheimer’s disease, Parkin- Discussion son’s disease, with Lewy bodies, Dr G Lennox Steele-Richardson syndrome, corticobasal de- Charles Warlow asked me to discuss this case generation, and Creutzfeldt-Jakob disease. A copyright. as if it was a normal Friday afternoon referral vertical gaze palsy also occurs with hydro- from the medical wards. He made this easy! As cephalus or tumours of the pineal region (as in most such consultations, we have very little part of Parinaud’s syndrome). history, the patient was not properly examined Later he became mute and twitchy. He had at the relevant time, and the results of crucial an EEG which showed generalised slowing, investigations were unavailable. We are, how- and some discharges which seemed to correlate ever, told that the patient was a 78 year old with the twitches suggesting that they were due man. At least this means that we do not have to to cortical myoclonus. This is again a non- worry about rare leukodystrophies and storage specific feature. One sees myoclonus in all of diseases. the cortical degenerations, and in any event he There are two possible scenorios in relation was metabolically deranged, with carbon diox-

to his neurological disease. Either this was a ide retention and uraemia which can both http://jnnp.bmj.com/ very nasty illness which started at the end of cause myoclonic jerks. He was finally examined September and caused him to die at the begin- by a neurologist who thought he was cortically ning of November, or it was a more slowly pro- blind. gressive illness with a long psychiatric pro- In summary, we have a 9 month history of a drome. dementing illness with or withouta5yearhis- Five years before his admission he had what tory of a prodromal psychiatric illness. The was thought to be a prolonged grief reaction or dementia was characterised initially by anxiety a reactive depression, but did not respond to and visual hallucinations, then a period of agi- on September 27, 2021 by guest. Protected treatment. Even at the beginning of the year of tation and confusion, and then gait disturbance his admission, 9 months before he died, the and tremor which may or may not have been symptoms were largely behavioural; he was induced by drugs. He rapidly developed anxious and disruptive, and kept calling out his myoclonic jerks, became definitely mute, prob- warden and his GP. Then, in the month before ably blind, and died. admission, he developed complex formed In dementia, just as in any other neurological visual hallucinations. We are told that his problem, the history is of paramount eyesight was poor. Complex visual hallucinosis importance. You hope to obtain information in the presence of poor is known that will give you some idea of the overall pattern as the Charles Bonnet syndrome. Recently it of the illness, and a clue to the likely type and has become clear that visual hallucinations are distribution of the pathology. The range of particularly severe in dementing illnesses when neurological symptoms, the presence or absence the visual acuity is poor.1 of additional non-neurological symptoms, and Whatever interpretation is made of these whether the patient has insight into the problem earlier behavioural symptoms, it is quite clear or not, are all extremely important. A family his- that in the last couple of months of this man’s tory may be helpful: we increasingly recognise illness there really was a very rapid decline. We that many neurodegenerative diseases have a Behavioural disturbance and visual hallucinations in a 78 year old man 935 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

genetic basis. The examination must test a range haemorrhagic lesions from amyloid angiopa- of cognitive domains, including memory, atten- thy, although this can occasionally present as a tion, language, praxis, visuospatial abilities, and dementia. More diYcult to exclude is subcorti- frontal lobe function, to discover which brain cal small vessel arteriosclerosis, traditionally regions are aVected. We need to establish if the termed Binswanger’s disease, because this can cognitive deficit is focal or widespread, whether present as a smoothly progressive disorder. it aVects mainly temporoparietal functions or These patients typically present with the mainly frontal functions, and so on. This assess- so-called clinical triad of normal pressure ment is supplemented by the conventional (frontal cognitive impairment, neurological examination. Additional specific chaotic gait disturbance, and incontinence of neurological features that have diagnostic value urine). Binswanger’s disease is possible but include abnormal movements, upper or lower does not fully explain the global nature of this motor neuron signs, and peripheral neuropathy. patient’s deficits, nor the very rapid progres- Finally the examination must include an assess- sion. The same arguments apply to cerebral ment of mental state, with depression represent- vasculitis and, furthermore, there are no ing an important and potentially treatable positive features of this group of disorders, element in many .2 such as or any systemic features. In this case, the history is a little vague, there Finally, subdural haematoma is extremely are no specific physical signs, and the diVeren- unlikely with the preceding evidence of wide- tial diagnosis is broad. We must start by spread bilateral cognitive impairment, before considering the causes of a rapidly progressive the patient started to deteriorate rapidly, but dementia, before moving on to consider the should be excluded by appropriate imaging. possible relevance of the prodromal psychiatric Next we must consider infections. He was features. I am assuming that the screening tests elderly and taking steroids, which would make excluded a metabolic or toxic , him more vulnerable to unusual infections. including (given his visual complaints), digoxin Progressive multifocal leucoencepalopathy intoxication, which can produce yellow vision. could account for a dementia with cortical The next thing to consider is a malignant blindness, although usually there are other process, particularly a poorly localisable malig- focal signs at some point along the line, and nancy such as a glioma arising in the corpus usually the patient goes through a phase of callosum and spreading out into the cerebral being hemianopic before losing vision alto- hemispheres as a butterfly lesion, and multifo- gether. Opportunistic infections, HIV, and the cal tumours such as metastases and primary more chronic meningitic illnesses are statisti- copyright. cerebral lymphoma. These must be excluded cally unlikely. Whipple’s disease is statistically by imaging where possible. In any rapidly pro- very unlikely; indeed, this is a disease which gressive neurological disorder, the possibility of only occurs in clinicopathological conferences. a paraneoplastic syndrome must be consid- If you ever need to diagnose Whipple’s disease, ered. Limbic generally causes just ask yourself “Am I in a clinicopathalogical amnesia, usually swiftly followed by brainstem conference?” and if you are not you can relax. signs (which were not noted here). Even here there are things which are against it We know that this patient had multiple being Whipple’s disease; there are no systemic vascular risk factors. If this had been a one oV features such as arthralgia or malabsorption. illness or a stuttering illness, in which the The patient does not have the characteristic patient went into this state over the course of a (but not pathognomic) neurological manifesta- week rather than a couple of months, the possi- tion in which the eyes and jaw move simultane- http://jnnp.bmj.com/ bility of basilar thrombosis would have to be ously, so-called oculomasticatory myorhyth- considered, giving a top of the basilar syn- mia. Finally, the patient has been treated drome. These patients, because they can blindly with antibiotics, including cepha- infarct deep diencephalic structures, may losporins, which would probably have killed off become drowsy and irritable or even frankly the Whipple’s organism if this was Whipple’s delirious and, unlike most acute confusional disease. Similarly, there are no positive signs of states, this can go on for weeks. Visual field neurosyphilis. defects are common, but usually give rise to a We must next turn to a disease which we on September 27, 2021 by guest. Protected hemianopia rather than cortical blindness. should perhaps categorise as of uncertain Against this diagnosis are the duration of the aetiology—Creutzfeldt-Jakob disease (CJD). I history and the lack of additional brainstem am sure this is a diagnosis which has occurred and pupillary signs such as skew deviation and to many people in the audience here in distorted, teardrop shaped pupils. Edinburgh. The prominent early anxiety is not A more likely possibility is multi-infarct just a feature of the new variant form of CJD dementia, due to either multiple emboli from and occurs in some patients with conventional the heart or multiple in the carotid ter- sporadic CJD. The rapid progression, if it truly ritory. The early mild global pattern of was a very short illness, would also be consist- cognitive impairment makes a succession of ent with CJD, as indeed would be the develop- large infarcts relatively unlikely. Indeed, it ment of a . Extrapyramidal would seem that this patient’s decline was rela- features are relatively common in prion demen- tively smooth and relentless rather than step- tia, although I think a true resting tremor wise. We are also told that there were no focal would be a very unusual manifestation. The signs at any stage so I think that we can be rela- myoclonus would be consistent with CJD, but tively confident in ruling out multiple large it was rather evanescent here. The EEG would vessel infarcts. The same argument applies to certainly be consistent with early CJD, but does 936 Schultz, Lennox, Ironside, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

not show the classic picture of triphasic thick casenotes full of negative urine and complexes. Finally, if he was truly cortically sputum cultures, and negative searches for cer- blind by the end of his illness, this would also ebrovascular disease. be consistent with CJD. But it must be remem- Finally, the visual agnosia must be consid- bered that CJD remains a rare disease, particu- ered. As an early symptom, this raises the larly in very old people like this. There are also possibility of the focal posterior dementia syn- several hints that the history may be longer dromes. These are much rarer than frontal than the dramatic final few months that are syndromes, but have broadly speaking the same described in detail. The longer the history, the pathological diVerential diagnosis. As already less likely this is to be CJD. noted, this symptom excludes frontotemporal Finally, while we are dealing with rapidly dementias, but none of the other degenerative progressing disorders I want to mention conditions. It is perfectly compatible with dementia with Lewy bodies. This is the current Alzheimer’s disease, multi-infarct dementia of consensus term for a disease which has been any kind, dementia with Lewy bodies, and described under a range of diVerent rubrics CJD. such as Lewy body dementia, diVuse Lewy So my diVerential diagnosis is starting to body disease, or cortical Lewy body disease. become clear. I am seriously considering CJD Although this is normally a slowly progressive and I would want to clarify the duration of his- dementing illness with a tempo similar to that tory if I possibly can. Nothing so far excludes of Alzheimer’s disease, it can occasionally Alzheimer’s disease which is far and away the present in a very fulminant and aggressive commonest degenerative dementia, but the way.34 Such patients often subsequently pla- constellation of features that I have described teau out and stabilise for a few months before would make that an unusual pathological diag- they die. nosis. So, finally, I return to dementia with Returning to the possibility that the history is Lewy bodies. The current consensus criteria longer than a few months, the relevance of the for the diagnosis of probable and possible neuropsychiatric prodrome must be consid- dementia with Lewy bodies have recently been ered. This raises the possibility of a frontotem- published.7 These require a dementia syn- poral dementia. This is a syndrome with a wide drome of the kind seen here, together with at range of diVerent pathologies, including proc- least two out of (1) fluctuating cognition, (2) esses which resemble recurrent visual hallucinations, and (3) sponta- and corticobasal degeneration (despite the neous parkinsonism. This patient seems to absence of the usual clinical manifestations of have had the first and second of these; his par- copyright. these disorders) and classic Pick’s disease kinsonism is also consistent with the diagnosis, pathology (although this is rare).56Frontotem- but does not add diagnostic weight because it poral dementia is a syndrome which starts with followed neuroleptic therapy and was not behavioural change, agitation, anxiety, and disproportionate (there was no “neuroleptic endless trips to the GP with multiple somatic sensitivity”). I personally have never seen a complaints before it becomes obvious that patient with dementia with Lewy bodies who I there is cognitive impairment and before the was certain was completely cortically blind, but patient’s behavioural repertoire shrinks down that might just be because I do not routinely to a range of stereotyped behaviours, stere- examine people shortly before they die. otyped utterances, and finally a mute state. The In conclusion, I think that the primary hallmark of , however, pathological diagnosis will be dementia with is that the posterior functions are spared and in Lewy bodies. As this man is 78 years old he will http://jnnp.bmj.com/ particular visuospatial functions are normal. also have some plaques and very probably This eVectively excludes it from consideration some tangles but I personally would not regard here. Again, dementia with Lewy bodies will sometimes present with very hypochondriacal features. This is a reflection of frontal predomi- nance of pathology and so when Alzheimer’s disease happens to involve the frontal lobe par- ticularly severely it too can present in the same on September 27, 2021 by guest. Protected way. Turning to the visual hallucinations, these do seem to be statistically most common in dementia with Lewy bodies. You are perhaps beginning to see which way I am thinking. His “persistent confusional state“ may also provide a clue. We do not truly know if this was confu- sion as we are not told enough about the phe- nomenology, but it would seem likely that there have been at least some episodes of nocturnal confusion. Obviously intercurrent medical problems which may well have been operative here have to be born in mind, but patients with dementia with Lewy bodies commonly have recurrent episodes of confusion for which Figure 1 The substantia nigra in the midbrain shows a intercurrent medical problems are never marked loss of pigment with a yellow/grey discolouration on found. These are patients who end up with very macroscopic examination. Behavioural disturbance and visual hallucinations in a 78 year old man 937 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

Alzheimer’s disease as the likely cause of his of incidental mild vascular disease, but I’m not problem. Because of his age and his multiple hedging my bets; the diagnosis here is demen- vascular risk factors he may well have a little bit tia with Lewy bodies.

Dr J W Ironside The clinical diagnosis at the top of the list in our hospital was CJD, which is why I was asked to examine the brain. The brain was fixed and weighed 1190 g. On cross section there was a mild degree of cortical atrophy with accompa- nying ventricular dilatation, but nothing too abnormal for the patient’s age. There were some prominent perivascular spaces in the basal ganglia but nothing to suggest infarction or haemorrhage. There was no diVuse white matter disease, no sign of progressive multifo- cal leucoencephalopathy, or any other focal lesions, nor evidence of a glioma, lymphoma, or any sort of tumour. There was nothing abnor- mal in the meninges, no haemorrhages, and no evidence of vasculitis. The cerebellum was largely normal and certainly not atrophied, but in one area there was a little blurring of the Figure 2 Histological examination of the substantia nigra shows numerous Lewy bodies in grey-white matter outline to make me wonder surviving pigmented neurons, with multiple inclusions present within some cells (centre). if perhaps there was an area of ischaemic dam- The adjacent tissue is markedly gliotic. Haematoxylin and eosin stain. age, not quite in a typical vascular boundary zone. In the midbrain, the substantia nigra was pale (fig 1) and dissection down to the pons showed the locus coeruleus to be poorly defined, suggesting the possibility of Lewy body disease. In the discoloured area of the cerebellar cor- tex, when examined microscopically, there was copyright. evidence of ischaemic damage with quite a marked loss of Purkinje cells, reactive gliosis, and some granular cell loss. This ischaemic damage in the cerebellum was not recent, and there was no extensive infarction in the cerebellum or brainstem. In the substantia nigra, Lewy bodies were indeed present on microscopy (fig 2), with multiple inclusions in some cells and pigment accumulation in macrophages. The locus coeruleus histologi- cally also contained Lewy bodies, which suggests the diagnosis of Parkinson’s disease. http://jnnp.bmj.com/ Figure 3 An occasional neuron in the anterior cingulate gyrus contains an ill defined globose homogenous eosinophilic inclusion characteristic of a cortical Lewy body (centre). Ubiquitin immunocytochemistry on the sub- Haematoxylin and eosin stain. stantia nigra shows how well these inclusions stain with this particular antibody. If it is appropriate to look for cortical Lewy bodies, this is the method of choice after the experience from Nottingham.8 In the cerebrum, there was cell loss in the hippocampus, but only to a mild degree. In routinely stained sections of the cor- on September 27, 2021 by guest. Protected tex the cores of a few plaques were identified. These were not prion plaques but the Aâ plaques occurring in Alzheimer’s disease. On immunocytochemistry neurites were evident throughout these plaques, and a few of the sur- viving pyramidal neurons in the hippocampus contained neurofibrillary tangles. These tan- gles were not particularly excessive in relation to the patient’s age and certainly using the established CERAD (Consortium to Establish a Registry for Alzheimer’s Disease) criteria,9 a diagnosis of Alzheimer’s disease would not be made. Immunocytochemistry for the Aâ pro- tein of Alzheimer’s disease again showed quite Figure 4 Ubiquitin immunocytochemistry shows strong brown positive staining of a a lot of plaques, often rather diVuse in cortical Lewy body within the cingulate gyrus (centre). Occasional positively stained dot-like structures are present within the adjacent neuropil, possibly representing small structure, within the temporal and frontal cor- neuritic processes. tex. A few larger plaques were present in layers 938 Schultz, Lennox, Ironside, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.65.6.933 on 1 December 1998. Downloaded from

3 and 4, but there really was no convincing evi- prodrome. The teaching message of this case is dence of amyloid angiopathy. The white matter it can present in an aggressive and fulminant was unremarkable with no evidence of demyeli- way. The interrelation with Alzheimer type nation and no inflammation. pathology is extremely interesting and probably Looking in greater detail at the cortex, it is reflects the inadequacy of disease labels to necessary to establish whether or not there are describe a complex situation where a mesh of Lewy bodies in the cortical neurons. On diVerent genetic risk factors probably acts to routine stains it was often rather diYcult to generate the diVerent types of neuropathology. find a convincing example of these inclusions, but a few were identified in the anterior cingu- The case was presented in this form as a clinicopathological late gyrus (fig 3). Immunocytochemistry for conference at the Edinburgh Advanced Neurology Course, 28 March 1996. ubiquitin stained these inclusions quite strongly (fig 4), and in some areas you can see 1 McShane R, Gedling K, Reading M, et al. Prospective study that there were actually multiple inclusions of relations between cortical Lewy bodies, poor eyesight, and hallucinations in Alzheimer’s disease. J Neurol within the anterior cingulate and temporal cor- Neurosurg Psychiatry 1995;59:185–8. tex. In relation to the clinical possibility of cor- 2 Goodwin GM. Functional imaging, aVective disorder and dementia. Br Med Bull 1996;52:495–12. tical blindness, the was not 3 Byrne EJ, Lennox G, Lowe J, et al.DiVuse Lewy body severely involved, and so I cannot provide a disease: clinical features in fifteen cases. J Neurol Neurosurg Psychiatry 1989;52:709–17. good pathological correlation in the absence of 4 Lennox G. Lewy body dementia. In:Rossor MN, ed. any other abnormalities in the and Unusual dementias. Balliere’s Clinical Neurology 1992;1:653– 76. related areas. 5 Jackson M, Lowe J. The new neuropathology of degenera- So, to summarise, I have to agree that the tive frontotemporal dementias. Acta Neuropathol (Berl) 1996;91:127–34. diagnosis is dementia with Lewy bodies. The 6 Cooper PN, Jackson M, Lennox G, et al. Tau, ubiquitin and relation between Lewy bodies and Aâ plaques alphaB-crystallin define the principal causes of degenera- 10 tive frontotemporal dementia. Arch Neurol 1995;52:1011– is of considerable current interest. Addition- 15. ally there is evidence of mild cerebrovascular 7 McKeith IG, Galasko D, Kosaka K, et al. Consensus guide- lines for the clinical and pathological diagnosis of dementia disease, which is unlikely to have contributed with Lewy bodies (DLB): report of the consortium on significantly to the final illness. DLB international workshop. Neurology 1996;47:1113–24. 8 Lennox G, Lowe J, Landon M, et al.DiVuse Lewy body disease: correlative neuropathology using anti-ubiquitin Comment immunocytochemistry. J Neurol Neurosurg Psychiatry 1989; 52:1236–47. Dr G Lennox 9 Mirra SS, Heyman A, McKeel D, et al. The Consortium to The key to the diagnosis of dementia with Establish a Registry for Alzheimer’s Disease (CERAD). Lewy bodies is to consider it in patients with Part II. Standardisation of the neuropathologic assessment of Alzheimer’s disease. Neurology 1991;41:479–86. copyright. dementia and any degree of parkinsonism, par- 10 Gibb WRG, Mountjoy CQ, Mann DMA, et al. A pathologi- ticularly if there are features of fluctuating cog- cal study of the association between Lewy body disease and Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1989;52: nition, visual hallucinations, and a psychiatric 701–8. http://jnnp.bmj.com/ on September 27, 2021 by guest. Protected