Ala, T. A., K. H. Yang, et al. (1997). Hallucinations and signs of parkinsonism help distinguish patients with dementia and cortical Lewy bodies from patients with Alzheimer's disease at presentation: A clinicopathological study. Journal of Neurology Neurosurgery and Psychiatry. 62: 16-21. Objectives - To compare, in a retrospective clinicopathological study, the presentation features of patients with dementia and cortical Lewy bodies (Lewy body dementia) with those of patients with Alzheimer's disease. Methods - From a population of 426 cases from the dementia brain bank, 39 cases of Lewy body dementia and 61 cases of Alzheimer's disease with presentation details were identified. Results - The Lewy body dementia group had significantly more frequent hallucinations (23% v 3%, P = 0.006) and signs of parkinsonism (41% v 5%, P < 0.0001) than the Alzheimer's disease group. The Lewy body dimentia group also had a greater proportion of men (62% v 34%, P = 0.013). Conclusion - Hallucinations and signs of parkinsonism help distinguish Lewy body dementia from Alzheimer's disease at presentation. These indicators may not be very sensitive, because they were reported for less than half of the patients with Lewy body dementia.

Albin, R. L., S. Minoshima, et al. (1996). Fluoro-deoxyglucose positron emission tomography in diffuse Lewy body disease. Neurology. 47: 462-466. We report six demented individuals with pathologically verified diffuse Lewy body disease (DLBD) studied with fluoro-deoxyglucose positron emission tomography (FDG-PET). Three subjects had pure DLBD and three subjects had combined DLBD and Alzheimer's disease (DLBD- AD) pathology. FDG-PET revealed evidence of diffuse cerebral hypometabolism in both pure DLBD and DLBD-AD with marked declines in association cortices with relative sparing of subcortical structures and primary somatomotor cortex, a pattern reported previously in AD. Unlike AD, however, these subjects also had hypometabolism in the occipital association cortex and primary visual cortex. These findings indicate the presence of diffuse cortical abnormalities in DLBD and suggest that FDG-PET may be useful in discriminating DLBD from AD antemortem.

Alptekin, K. and G. G. Yener (1995). LEWY CISMI TIP YASLILIK BUNAMASI: OLGU SUNUMU Senile dementia of Lewy body type: A case report. Noropsikiyatri Arsivi. 32: 205-208. Senile Dementia of Lewy Body Type (SDLT) is characterized clinically by presenting confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. There may be mild extrapyramidal symptoms. It has been presented a case with SDLT, beginning with visual hallucinations.

Armstrong, T. P., L. A. Hansen, et al. (1991). Rapidly progressive dementia in a patient with the Lewy body variant of Alzheimer's disease. Neurology. 41: 1178-80. A 65-year-old woman presented with a mild memory impairment, spatial disorientation, and poor task initiation. Progression was rapid over 3 months. She developed severe apathy, delusions, extrapyramidal features, and psychometrically quantified cognitive deterioration. Her brain showed many neocortical neuritic plaques and neurofibrillary tangles along with neocortical and brainstem Lewy bodies and temporal lobe spongiform vacuolization. This case is the most rapid deterioration documented of a patient with Alzheimer's disease and Lewy bodies.

Ballard, C., A. Patel, et al. (1996). Cognitive decline in patients with Alzheimer's disease, vascular dementia and senile dementia of Lewy body type. Age and Ageing. 25: 209-213. One hundred and twenty-four patients with DSM-III-R dementia were assessed with a standardized battery which included the Geriatric Mental State Schedule, the History and Aetiology Schedule, the Secondary Dementia Schedule and the CAMCOG. Eighty-nine patients were followed up for 1 year, 76 of whom completed a repeat CAMCOG. Patients with Alzheimer's disease, vascular dementia and senile dementia of Lewy body type (SDLT) all had a similar degree of cognitive impairment at the time of the baseline interview. Patients with Alzheimer's disease and vascular dementia each experienced a mean decline of 13 points on the CAMCOG in 1 year compared with a mean decline of 27 points in patients with SDLT. Patients with SDLT had a significantly greater decline of verbal fluency than both the other groups. Women were significantly more impaired than men at the time of the baseline assessment but experienced a similar decline during the year of follow-up.

BenShlomo, Y., A. S. Whitehead, et al. (1996). Parkinson's, Alzheimer's, and motor neurone disease - Clinical and pathological overlap may suggest common genetic and environmental factors. British Medical Journal. 312: 724.

Bergeron, C. and M. Pollanen (1989). Lewy bodies in Alzheimer disease--one or two diseases? Alzheimer Dis Assoc Disord. 3: 197-204. To clarify the significance of the Lewy body (LB) in Alzheimer disease (AD), we determined the incidence and distribution of LB in 150 cases of AD and 75 controls. We also examined the pathological changes in the substantia nigra and quantified neocortical alterations, including the density of neuritic plaques, neurofibrillary tangles, and LB. LBs were present in 25% of AD cases, but in only 5% of controls. The presence of LB was associated with significantly lower numbers of neurofibrillary tangles as compared with cases of AD without LB, whereas the mean density of neuritic plaques remained unchanged. Two possibilities are discussed to explain these findings. First, the high frequency of LB in AD may reflect a predisposition of AD patients to develop idiopathic Parkinson disease. Second, the LB may represent a nonspecific cytoskeletal change in selected vulnerable neuronal populations in some subjects with AD, rather than the presence of a second pathological process.

Bhatia, K. P., S. E. Daniel, et al. (1993). Familial parkinsonism with depression: a clinicopathological study. Ann Neurol. 34: 842-7. A family with autosomal dominant inheritance of an early-onset and rapidly progressive parkinsonian syndrome and associated severe depression is reported. Three members had parkinsonism with depression, 3 had parkinsonism alone, and 2 suffered depression only. Pathological brain examination in 2 members with parkinsonism and depression revealed distinctive changes, with devastation of the substantia nigra, scarce Lewy bodies, and gliosis of the caudate nucleus and globus pallidus. The clinical and pathological findings were similar to those in four previously described families with autosomal dominant parkinsonism, depression, and alveolar hypoventilation.

Bodhireddy, S., D. W. Dickson, et al. (1994). A case of Down's syndrome with diffuse Lewy body disease and Alzheimer's disease. Neurology. 44: 159-61. Almost all Down's syndrome (DS) patients over the age of 35 to 40 years have histologic features of Alzheimer's disease (AD). However, the presence of extrapyramidal features in up to 36% of these patients has no satisfactory pathologic explanation. We report an older patient with DS, dementia, and parkinsonian signs who showed pathologic changes of Parkinson's disease and cortical Lewy bodies in addition to AD. These parkinsonian changes may be related to chromosome 21 abnormalities.

Boothby, H. (1996). Anticholinergics in Lewy Body Dementia: Are they even worse than antidopaminergics? [2]. International Journal of Geriatric Psychiatry. 11: 660-661.

Byrne, E. J., G. Lennox, et al. (1989). Diffuse Lewy body disease: clinical features in 15 cases. J Neurol Neurosurg Psychiatry. 52: 709-17. Fifteen cases of diffuse Lewy body disease were diagnosed on pathological grounds during a single year in one health district. The range and frequency of clinical features contrast strikingly with previous reports. The majority of cases presented with classical levodopa-responsive Parkinson's disease either alone (6 cases) or with mild cognitive impairment (3 cases); the remaining 6 cases presented with cognitive impairment alone. In time almost all patients developed both dementia and 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 Lewy body disease is not rare, and that it presents in a range of ways from dementia with subsequent Parkinsonism to Parkinson's disease with subsequent dementia. The latter mode of presentation suggests that it should be considered as a significant pathological substrate of dementia in Parkinson's disease.

Byrne, E. J., G. Lennox, et al. (1990). Diffuse Lewy body disease: the clinical features. Adv Neurol. 53: 283-6.

Byrne, E. J., J. Lowe, et al. (1987). Dementia and Parkinson's disease associated with diffuse cortical Lewy bodies [letter]. Lancet. 1: 501.

Cercy, S. P. and F. W. Bylsma (1997). Lewy bodies and progressive dementia: A critical review and meta- analysis. Journal of the International Neuropsychological Society. 3: 179-194. Researchers disagree as to whether Lewy body disease (LBD) constitutes a variant of Alzheimer's (AD) or Parkinson's disease (PD), or alternatively, whether it is an independent disease process. The neuropathological, genetic, and clinical characteristics of LBD are reviewed and compared to those of AD and PD. Data for 150 cases of LBD reported in the literature were compiled and grouped according to neuropathological status. Patients with pure LBD (with limited or no concurrent AD pathology) tend to present at a younger age with extrapyramidal signs followed by dementia, whereas patients with mixed LBD-AD (concurrent LB and AD pathology) are somewhat older and tend to present with dementia. The cognitive profile of LBD patients, and the relationships among LBD, AD, and PD remain unclear due to methodological limitations and the paucity of studies comparing the groups directly.

Chang, C. M., Y. L. Yu, et al. (1992). Vascular pseudoparkinsonism. Acta Neurol Scand. 86: 588-92. Vascular pseudoparkinsonism may be confused with idiopathic Parkinson's disease. Patients may be unnecessarily treated with anti-parkinsonian drugs while their underlying vascular disease is ignored. We investigated 250 parkinsonian patients seen in our Movement Disorders Clinic for a possible vascular etiology. After excluding those with a known secondary cause such as drug-induced parkinsonism, progressive supranuclear palsy, multiple system atrophy and hyperparathyroidism, brain computed tomography and/or magnetic resonance imaging were performed on those who showed poor or no response to levodopa. In those with an ischemic lesion demonstrated on neuroimaging, anti-parkinsonian drugs were stopped and the patients were reassessed. Eleven patients (4.4%) had ischemic brain lesions accounting for their parkinsonism. All were initially diagnosed as Parkinson's disease because of the prominence of bradykinesia and rigidity. Gait disturbance was also common, but resting tremor was distinctly absent. Three anatomical patterns with different prognosis were identified. Three patients with basal ganglia lacunar infarct recovered spontaneously, three with frontal lobe infarcts remained static and five with periventricular and deep subcortical white matter lesions had progressive deterioration. Autopsy in one patient confirmed bilateral frontal lobe watershed infarcts and the absence of brain stem Lewy bodies. Parkinsonian patients with poor or no response to levodopa therapy should be investigated for a vascular etiology.

Crowe, S. F., R. F. Peppard, et al. (1992). Diffuse Lewy body disease and progressive dementia in a young woman. Aust N Z J Psychiatry. 26: 507-11. This report details the emergence of a progressive parkinsonian syndrome, dementia and behavioural disturbance in a 33 year-old woman which can be dated to the delivery of her first child. The findings of this case indicate that cortical Lewy body disease should be considered in any patient with temporoparietal dementia and idiopathic Parkinson's disease irrespective of the age of onset.

Crystal, H. A., D. W. Dickson, et al. (1990). Antemortem diagnosis of diffuse Lewy body disease. Neurology. 40: 1523-8. Using the presence of widespread cortical Lewy bodies (LB) as the pathologic criteria of diffuse Lewy body disease (DLBD), we describe serial neurologic and mental status examinations in 6 patients with DLBD, 3 patients with Alzheimer's disease (AD), and 1 patient with Parkinson's disease (PD). The 6 patients with DLBD included 3 with neocortical neurofibrillary tangles (NFT) consistent with coincident AD. Most patients with DLBD had gait impairment concurrent with mild to moderate dementia. Abnormalities of tone or resting tremor were also prominent early symptoms in the subjects with DLBD, but not AD. Patients with DLBD frequently had abnormal EEGs with background posterior slowing and a frontally dominant burst pattern at the time of mild to moderate dementia. Agitation, hallucinations, and delusions were frequent early symptoms in DLBD patients. Patients with DLBD without concomitant AD had numerous Alz-50 negative cortical plaques. Patients with DLBD have a distinct clinical syndrome that can be differentiated from AD. Pathologic features, including the absence of Alz-50 immunoreactivity, also differentiate DLBD from AD.

Curran, T. and A. E. Lang (1994). Parkinsonian syndromes associated with hydrocephalus: case reports, a review of the literature, and pathophysiological hypotheses. Mov Disord. 9: 508-20. We present nine cases of obstructive hydrocephalus (OH) associated with marked parkinsonism. Four patients had noncommunicating OH (NCOH) [three nontumoral aqueductal stenosis (AS), one tumoral AS]. The presentation was that of acute or subacute parkinsonism, usually at the time of acute recurrent ventricular obstruction. Three had a marked response to levodopa and required short-term treatment after shunting. However, one has remained levodopa dependent after 2 1/2 years. Three of the five patients with communicating OH (COH) presented with shunt-responsive normal pressure hydrocephalus (NPH), only later to develop progressive parkinsonism. One of these was found to have progressive supranuclear palsy (PSP) at autopsy and PSP was clinically suspected in one other patient. A third had an atypical course suggestive of PSP; however, autopsy demonstrated the combination of Lewy body parkinsonism and the sequelae of hydrocephalus. The remaining two COH patients presented with levodopa-responsive parkinsonism. Subsequent clinical features and imaging studies suggested the presence of NPH. The pathophysiology of hydrocephalic parkinsonism probably involves variable sites of dysfunction in the nigrostriatal pathway and/or the cortico-striato-pallido-thalamo-cortical circuit. At certain locations these pathways lie in close proximity to the ventricular system and may be subjected to mass effects and ischemic changes secondary to ventriculomegaly. The additional importance of possible associations between subcortical cerebral ischemia, NPH, and "degenerative" disorders such as PSP and Parkinson's disease is discussed.

de Bruin, V. M., A. J. Lees, et al. (1992). Diffuse Lewy body disease presenting with supranuclear gaze palsy, parkinsonism, and dementia: a case report. Mov Disord. 7: 355-8. A 67-year-old man with a family history of parkinsonism had visual complaints due to difficulty in convergence, which was followed 2 years later by development of bradykinesia and rigidity. The diagnosis of Steele-Richardson-Olszewski syndrome was made on the basis of a supranuclear gaze palsy, bradykinesia, rigidity, and poor response to levodopa. However, subsequent neuropathological examination revealed diffuse Lewy body disease with no evidence of neurofibrillary tangles involving either subcortical or brain stem structures.

de Vos, R. A., E. N. Jansen, et al. (1995). 'Lewy body disease': clinico-pathological correlations in 18 consecutive cases of Parkinson's disease with and without dementia. Clin Neurol Neurosurg. 97: 13-22. One of the characteristic histological features of Parkinson's disease (PD), with or without dementia, is the presence of Lewy bodies (LBs) in the brainstem and neocortical and limbic structures. They are often accompanied by Alzheimer type pathology (ATP). In the present retrospective study the clinical features and post-mortem findings of 18 consecutive and unselected PD patients were compared, with special reference to the frequent but not exclusive association of LBs with ATP in Lewy body disease (LBD). LBD is the term applied to a particular pattern of neuronal degeneration associated with LBs. In this study of idiopathic PD patients ATP seems to be the major determinant of the cognitive decline in most patients. Cortical Lewy Bodies (CLBs) were present in all patients reviewed, whether or not dementia was present. It was not possible to distinguish a specific pattern in the cognitive or psychopathological symptoms of dementia that would differentiate LBD from Alzheimer's disease (AD). Although in most cases hippocampal CA2-3 ubiquitin immunoreactive neurites were observed, here again there was no correlation with the presence of dementia.

De Vos, R. A. I. and E. N. H. Jansen (1996). Diffuse Lewy body disease dementia? Clinical Neurology and Neurosurgery. 98: 64.

Delisle, M. B., P. Gorce, et al. (1987). Motor neuron disease, parkinsonism and dementia. Report of a case with diffuse Lewy body-like intracytoplasmic inclusions. Acta Neuropathol (Berl). 75: 104-8. The clinicopathological findings in a 49-year-old man who presented multisystemic neurological degenerative disease are reported. The patient presented, at the age of 36, distal upper limb amyotrophy and 8 years later pyramidal signs with fasciculations. In his last year of life, he suffered extrapyramidal hypertonus and mental deterioration. Neuropathological examination showed anterior spinal root and cerebral atrophy. Myelin pallor was mild and predominated on posterior cords. Anterior horn neuronal loss was noted in the spinal cord as well as Alzheimer-type changes in the brain. Inclusion bodies consistent with Lewy bodies were diffusely apparent. The peculiar clinical progression in this case and the extension of neuropathological lesions with inclusion bodies mainly in the substantia nigra and cerebral cortex are an interesting subject of discussion.

DelSer, T., D. G. Munoz, et al. (1996). Temporal pattern of cognitive decline and incontinence is different in Alzheimer's disease and diffuse Lewy body disease. Neurology. 46: 682-686. Incontinence is a hallmark of dementia, but little is known about its inception in different types of dementing diseases. We recorded the dates of onset of dementia and of urinary incontinence in 73 demented patients followed for 5.6 +/- 2.5 years. The pathologic diagnosis was Alzheimer's disease (AD) in 29 cases, diffuse Lewy body disease (DLBD) in 11 cases, AD with Lewy bodies (AD+LB) in 13 cases, and AD with vascular lesions (AD+VL) in 20 cases. The onset of urinary incontinence was significantly earlier in DLBD cases (3.2 +/- 1.4 years after dementia onset) than in AD (5.9 +/- 2.5), AD+LB (5.8 +/- 2.4), and AD+VL (6.5 +/- 2.3) (p < 0.01). At the onset of bladder incontinence, the mean score in the Extended Dementia Scale was significantly higher (i.e., cognition was better) in DLBD cases (109.3 +/- 70.8) than in AD (21.3 +/- 40.4), AD+LB (45.6 +/- 45.1), and AD+VL (39.2 +/- 54.9) cases (p < 0.01). Urinary incontinence is associated with severe cognitive decline in pure AD but usually precedes severe mental failure in DLBD cases. This temporal pattern of cognitive decline and incontinence could be useful in differentiating these two dementing illnesses.

Dickson, D. W. (1990). Lewy body variant [letter; comment]. Neurology. 40: 1147-50.

Ditter, S. M. and S. S. Mirra (1987). Neuropathologic and clinical features of Parkinson's disease in Alzheimer's disease patients. Neurology. 37: 754-60. While dementia in Parkinson's disease (PD) is well described, PD features in Alzheimer's disease (AD) are being increasingly recognized. In 20 neuropathologically confirmed AD brains, 11 cases (55%) showed PD changes (Lewy body formation, neuronal loss, and gliosis of pigmented nuclei), with no significant difference in age or symptom duration between those cases with and without PD pathology. A history of rigidity in the absence of neuroleptic medication was noted in 80% of those with PD pathology but only 14% of those without PD pathology. Tremor was not observed in either group. This suggests that extrapyramidal signs, especially rigidity, noted in many AD patients are related to coexistent PD pathology.

Donnemiller, E., J. Heilmann, et al. (1997). Brain perfusion scintigraphy with 99mTc-HMPAO or 99mTc-ECD and 123I- beta-CIT single-photon emission tomography in dementia of the Alzheimer-type and diffuse Lewy body disease. European Journal of Nuclear Medicine. 24: 320-325. Dementia of the Alzheimer-type (DAT) is characterized by progressive cognitive decline, variably combined with frontal lobe release signs, parkinsonian symptoms and myoclonus. The features of diffuse Lewy body disease (DLBD), the second most common cause of degenerative dementia, include progressive cognitive deterioration, often associated with levodopa-responsive parkinsonism, fluctuations of cognitive and motor functions, psychotic symptoms (visual and auditory hallucinations, depression), hypersensitivity to neuroleptics and orthostatic hypotension. A recent report suggests that positron emission tomography studies in patients with degenerative dementia may be useful in the differential diagnosis of DAT and DLBD. However, the diagnostic role of single-photon emission tomography (SPET) studies remains to be established. The aim of this study was therefore to evaluate regional cerebral perfusion [with either technetium-99m hexamethylpropylene amine oxime (99mTc-HMPAO) or 99mTc-ethyl cysteinate dimer (99mTc-ECD) SPET] and striatal dopamine transporter density [using iodine-123 2beta-carboxymethoxy- 3beta-[4-iodophenyl]tropane (123I-beta-CIT) SPET] in patients with DAT and DLBD. Six patients with probable DAT and seven patients with probable DLBD were studied. Blinded qualitative assessment by four independent raters of 99mTc-HMPAO or 99mTc-ECD SPET studies revealed bilateral temporal and/or parietal hypoperfusion in all DAT patients. There was additional frontal hypoperfusion in two patients and occipital hypoperfusion in one patient, In the DLBD group, regional cerebral perfusion had a different pattern. In addition to temporoparietal hypoperfusion there was occipital hypoperfusion resembling a horseshoe defect in six of seven patients. In the DAT group, the mean 3-h striatal/cerebellar ratio of 123I-beta-CIT binding was 2.5 +/- 0.4, with an increase to 5.5 +/- 1.1 18 h after tracer injection. In comparison, in the DLBD patients the mean 3-h striatal/cerebellar ratio of 123I-beta-CIT binding was significantly reduced to 1.7 +/- 0.3, with a modest increase to 2.1 +/- 0.3 18 h after tracer injection (P < 0.05, Scheffe test, ANOVA). These results suggest that 99mTc-HMPAO or 99mTc-ECD and 123I-beta-CIT SPET may contribute to the differential diagnosis between DAT and DLBD, showing different perfusion patterns and more severe impairment of dopamine transporter function in DLBD than in DAT.

Drach, L. M. (1996). Dementia with Lewy bodies - Tower of babel tumbled down? Clinical Neuropathology. 15: 248.

Ellis, R. J., M. Caligiuri, et al. (1996). Extrapyramidal motor signs in clinically diagnosed Alzheimer disease. Alzheimer Disease and Associated Disorders. 10: 103-114. We reviewed clinical case series published over a 10-year period addressing the cross-sectional frequency, incidence, and diagnostic and prognostic significance of extrapyramidal signs (EPS) in Alzheimer disease (AD). The review was prompted by recent reports of Lewy body (LB) pathology in the brains of many AD patients and the association of LB pathology with clinical parkinsonism in AD. In the clinical case series reviewed, we evaluated several possible determinants of prevalent EPS, including neuroleptic use, EPS assessment technique, and dementia severity. Neuroleptics were a well recognized cause of parkinsonism in these reports, though some failed to document the frequency of neuroleptic use. Assessment methods were also important: Studies using structured clinical research scales to rate EPS reported higher frequencies than studies employing routine neurological examination. The relationship between parkinsonism and dementia severity was complex. Some studies found bradykinesia, facial masking, and parkinsonian postural changes even in mildly demented, neuroleptic-naive AD patients. Rigidity, on the other hand, became increasingly common as dementia progressed. AD patients with EPS showed faster cognitive and functional decline and earlier death than those without EPS, even after consideration of differences in initial dementia severity. In the differential diagnosis of dementia with parkinsonism, LB disease in its various forms, including AD with LB, is the principal diagnostic consideration. Future studies of parkinsonism in AD should employ standardized clinical rating scales and should exclude patients on neuroleptics or analyze their results separately. Investigators should report frequencies for individual parkinsonian signs in addition to the overall prevalence of EPS to facilitate meaningful comparisons across studies.

Farina, E., A. P. Cannata, et al. (1996). Non-Alzheimer forms of cortical degeneration: Frequency in clinical practice and clinical report of six cases. Aging - Clinical and Experimental Research. 8: 235-242. Recent clinical and neuropathological studies suggest the possibility of distinguishing some forms of cortical degeneration from Alzheimer's disease. We report data on the frequency of non-Alzheimer forms of cerebral atrophy that were diagnosed on the basis of clinical criteria. Six examples of these neurological disorders are described: two patients with Lewy body disease; two patients with frontal lobe type dementia, one of whom had associated features of motor neuron disease; a patient with primary progressive aphasia; and a patient with a familial dementia that was probably an atypical form of Pick's disease.

Fearnley, J. M., T. Revesz, et al. (1991). Diffuse Lewy body disease presenting with a supranuclear gaze palsy. J Neurol Neurosurg Psychiatry. 54: 159-61. A patient with diffuse Lewy body disease presented with supranuclear vertical and horizontal ophthalmoplegia, dementia, axial rigidity and falls, bradykinesia and pyramidal signs. This broadens the clinical presentation of this pathological diagnosis and re-emphasises the heterogeneity of patients diagnosed clinically as progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome).

Forstl, H., A. Burns, et al. (1993). The Lewy-body variant of Alzheimer's disease. Clinical and pathological findings. Br J Psychiatry. 162: 385-92. At post-mortem, Lewy bodies (LBs) were found in the brainstem and neocortex of eight out of 65 patients who had been collected during a prospective long-term study on clinically diagnosed Alzheimer's disease. All eight patients had accompanying Alzheimer pathology which was less severe than in a sample of eight age- and sex-matched patients from the same study with neuropathologically verified Alzheimer's disease. Parkinsonian features were more common in patients with LBs. There were no particular differences in duration of illness, severity of cognitive impairment, presence of hallucinations, or fluctuations in the course of illness. Frontal cerebral atrophy was more marked in patients with LBs, as was the loss of neurons in the basal nucleus of Meynert and the substantia nigra. Cognitive performance correlated with the number of pigmented neurons in the substantia nigra. We conclude that the differential diagnosis of LB dementia should be considered in patients satisfying NINCDS-ADRDA criteria for Alzheimer-type dementia who show marked Parkinsonian features and a frontal accentuation of cerebral atrophy.

Galasko, D., L. A. Hansen, et al. (1994). Clinical-neuropathological correlations in Alzheimer's disease and related dementias. Arch Neurol. 51: 888-95. OBJECTIVE: To compare neurologists' initial clinical diagnoses made according to National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) and Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition guidelines with neuropathological diagnoses of Alzheimer's disease (AD) and related dementias. DESIGN: Consecutive autopsies in a prospective cohort study. SETTING: Community-dwelling patients with dementia referred to neurologists at an Alzheimer's Disease Research Center and satellite clinics (n = 151) and patients initially evaluated when institutionalized (n = 19). PATIENTS: Of 204 elderly patients who had an autopsy performed, 170 had received a complete dementia evaluation according to NINCDS-ADRDA guidelines. MAIN OUTCOME MEASURES: Percentage agreement between neurologists' initial clinical diagnoses and pathological findings. RESULTS: Of 137 patients clinically diagnosed as having probable or possible AD, 123 (90%) had AD neuropathological findings; this included 29 with AD accompanied by Lewy bodies, and 14 with AD and one or more infarcts. Cases of vascular and mixed dementia (AD and infarct[s]) had lower rates of agreement with pathological findings. Possible AD cases were more likely than probable AD cases to show pathological features other than AD. Clinicians predicted the presence or absence of AD pathological findings significantly better than chance. In patients with AD pathological lesions, older age of onset and male gender were significantly associated with shorter duration from disease onset to death. CONCLUSIONS: Clinicians accurately predicted AD pathological findings or their absence in most cases. Attributing other degenerative dementias to AD, misdiagnosing patients with combined AD and Lewy bodies and misjudging the vascular contribution to dementia were the major areas of inaccuracy. Formal criteria for dementia associated with non-AD lesions, Lewy bodies, and infarcts need to be developed and tested.

Gash, A. and S. Chhabra (1996). Adverse reactions to depot neuroleptics in patients with dementia [1]. International Journal of Geriatric Psychiatry. 11: 1018-1020.

Geldmacher, D. S. and Whitehouse Pj, Jr. (1997). Differential diagnosis of Alzheimer's disease. Neurology. 48: S2-S9. Accurate diagnosis of dementia is essential to provide appropriate treatment as well as patient and family counseling. It may be difficult to differentiate dementia from delirium. In addition, several features distinguish dementia from depression, but the two can coexist and the distinction may be uncertain. Dementias can be grouped into two categories: dementia that presents without prominent motor signs and dementia that presents with prominent motor signs. Dementias without prominent motor signs include Alzheimer's disease, frontotemporal dementia, and Creutzfeld-Jakob and other prion diseases. Dementias characterized at onset by prominent motor signs include dementias with Lewy bodies, idiopathic Parkinson's disease, progressive supranuclear palsy, cortico-basal ganglionic degeneration, hydrocephalus. Huntington's disease, and vascular dementia. Routine diagnostic steps include a careful history, mental status screening, laboratory and imaging studies, and neuropsychologic testing. Genetic testing is available, but its use is controversial and raises complex ethical questions.

Geroldi, C., G. B. Frisoni, et al. (1997). Drug treatment in Lewy body dementia. Dementia and Geriatric Cognitive Disorders. 8: 188-197. The treatment of Lewy body dementia (LBD) is particularly difficult for the co-occurrence of psychiatric and parkinsonian symptoms: antipsychotic drugs can worsen parkinsonism, and antiparkinsonian drugs can precipitate delusions and hallucinations. The aim of this study was to describe treatment strategies and outcomes of 10 clinically diagnosed LBD patients. Two patients had mainly motor symptoms, L-dopa therapy was moderately successful, and psychotic symptoms did not worsen. Eight had relevant psychiatric symptoms needing neuroleptic therapy. Six of these had sufficient response to low-dose neuroleptics and 2 did not respond; parkinsonism worsened in all 8 and L-dopa therapy or treatment with an antiparkinsonian drug was started in 6. L-Dopa or antiparkinsonian drugs were given also to those 2 patients who did not receive neuroleptics. Of the 8 patients taking L-dopa or antiparkinsonian drugs, 6 had a moderate or good response with no or only mild adverse effects. Psychiatric symptoms were sensitive to trazodone or clozapine in 2 patients, without side effects. A flow chart of drug therapy in LBD is proposed.

Gibb, W. R. (1989). Dementia and Parkinson's disease. Br J Psychiatry. 154: 596-614. Recent research into the dementia of Parkinson's disease has exposed a complex area in which it has not always been possible to match clinical and pathological observations. Certain neuropsychological deficits result from a disruption of basal ganglia and frontal lobe interactions. These are unrelated to a global dementia, the prevalence of which exceeds twice that in the normal population. The associated pathological lesions comprise cortical pathology, either Alzheimer's disease or Lewy bodies, in combination with moderate degeneration of the subcortical, cholinergic, basal nucleus of Meynert.

Gibb, W. R., M. M. Esiri, et al. (1987). Clinical and pathological features of diffuse cortical Lewy body disease (Lewy body dementia). Brain. 110: 1131-53. Four patients with severe dementia and a parkinsonian syndrome are described. Dysphasia, dyscalculia, dyspraxia, visual and verbal memory disturbance and psychosis, usually of depressive type, occurred early in the course of the illness. Pathologically they were characterized by the presence of numerous Lewy bodies throughout both the cerebral cortex and brainstem. Three cases also had severe neurofibrillary tangle change or senile plaques in the neocortex, compatible with Alzheimer's disease, but the cortical tangle distribution did not always match that of the Lewy bodies. This disorder may form part of the spectrum of pathology in Parkinson's disease, where it may be one possible cause of dementia.

Gibb, W. R. and A. J. Lees (1988). A comparison of clinical and pathological features of young- and old-onset Parkinson's disease. Neurology. 38: 1402-6. We compared 46 patients having onset of Parkinson's disease before age 45 years with 52 having onset after age 70. Young-onset cases more often presented with muscular stiffness (43%) and old-onset with difficulty walking (33%). One-third of young-onset cases had off-period dystonia, mostly affecting the legs, but no dystonia was recorded in old-onset cases. Presentation with rest tremor occurred in 41% of young-onset and 63% of old-onset. There were no differences in the number of affected relatives, endocrine disease, personality characteristics, dementia, or dyskinesia. A pathological study of 12 young-onset and 22 old-onset cases showed 24% greater nigral cell loss in the young, but no differences in the basic Lewy body pathology. Median disease duration in young cases was 5 years longer in the clinical study and 12 years longer in the pathological study. These studies show that the Parkinson's disease process is similar in young- and old-onset cases.

Gibb, W. R., P. J. Luthert, et al. (1989). Cortical Lewy body dementia: clinical features and classification. J Neurol Neurosurg Psychiatry. 52: 185-92. Seven patients, aged 65-72 years, are described with dementia and cortical Lewy bodies. In one patient a Parkinsonian syndrome was followed by dementia and motor neuron disease. In the remaining six patients dementia was accompanied by dysphasia, dyspraxia and agnosia. One developed a Parkinsonian syndrome before the dementia, in three cases a Parkinsonian syndrome occurred later, and in two cases not at all. All patients showed Lewy bodies and cell loss in the substantia nigra, locus coeruleus and dorsal vagal nucleus, as in Parkinson's disease. The severity of cell loss in the nucleus basalis varied from mild to severe. Lewy bodies were also present in the parahippocampus and cerebral cortex, but Alzheimer-type pathology was mild or absent, and insufficient for a diagnosis of Alzheimer's disease. Patients with moderate or severe dementia, some with temporal or parietal features, may have cortical Lewy body disease, Alzheimer's disease, or a combination of the two. Cortical Lewy body disease may be associated with dementia in Parkinson's disease more often than realised, but is not necessarily associated with extensive Alzheimer pathology.

Gnanalingham, K. K., E. J. Byrne, et al. (1996). Clock-face drawing to differentiate Lewy body and Alzheimer type dementia syndromes [20]. Lancet. 347: 696-697.

Gnanalingham, K. K., E. J. Byrne, et al. (1997). Motor and cognitive function in Lewy body dementia: Comparison with Alzheimer's and Parkinson's diseases. Journal of Neurology Neurosurgery and Psychiatry. 62: 243-252. Methods - A range of neuropsychological function and extrapyrimidal signs (EPS) was assessed in 16 patients with Lewy body dementia, 15 with Parkinson's disease, 25 with Alzheimer's disease, and 22 control subjects. Results - The severity of total motor disability scores increased in the following order: controls ~= Alzheimer's disease << Parkinson's disease < Lewy body dementia. Compared with patients with Parkinson's disease, patients with Lewy body dementia had greater scores for rigidity and deficits in the finger tapping test, but rest tremor and left/right asymmetry in EPS were more evident in Parkinson's disease. Patients with Lewy body dementia were also less likely to present with left/right asymmetry in EPS at the onset of their parkinsonism. 'Sensitivity' to neuroleptic drugs was noted in 33% of patients with Lewy body dementia. Alzheimer's disease and Lewy body dementia groups had greater severity of dementia compared with the Parkinson's disease group and controls. Neuropsychological evaluation disclosed severe but similar degrees of impaired performances in tests of attention (digit span), frontal lobe function (verbal fluency, category, and Nelson card sort test) and motor sequencing in both Lewy body dementia and Alzheimer's disease groups, than Parkinson's disease and controls. In the clock face test, improved performance was noted in the 'copy' compared to 'draw' part of the test in controls, patients with Alzheimer's disease, and those with Parkinson's disease, but not in the patients with Lewy body dementia, who achieved equally poor scores in both parts of the test. Conclusions - EPS in Lewy body dementia resemble those seen in idiopathic Parkinson's disease, although less rest tremor and left/right asymmetry but more severe rigidity favours a diagnosis of Lewy body dementia. The unique profile of patients with Lewy body dementia seen in the clock face test suggests that this simple and easy to adminster test may be useful in the clinical setting to differentiate Lewy body dementia and Alzheimer's disease.

Graham, C., C. Ballard, et al. (1997). Variables which distinguish patients fulfilling clinical criteria for dementia with Lewy bodies from those with Alzheimer's disease. International Journal of Geriatric Psychiatry. 12: 314-318. Objectives. To compare patients fulfilling clinical criteria for Lewy body dementia with those meeting clinical criteria for Alzheimer's disease. Design. Prospective cohort study. Setting. Psychiatric services and a memory clinic. Sample. 124 patients with DSM-III-R dementia. Measures. The assessment included the GMS/HAS/SDS package, the CAMCOG, the Cornell Depression scale and the Burns Symptom Checklist. Dementia was diagnosed according to DSM-III-R, NINCDS ADRDA, McKeith, Byrne, Hachinski and HAS AGECAT criteria. Results. Patients meeting McKeith et al. criteria for senile dementia of Lewy body type were significantly more likely to have clouding of consciousness, significant Parkinsonian symptoms and less severely impaired recent memory than patients with NINCDS ADRDA Alzheimer's disease. Each of these variables also distinguished patients meeting Byrne et al.'s criteria for dementia with Lewy bodies from those with a diagnosis of Alzheimer's disease. Conclusions. It is suggested that one set of criteria could encompass those overlapping groups of patients, Work is needed to further develop the diagnostic criteria for Lewy body dementia.

Hansen, L., D. Salmon, et al. (1990). The Lewy body variant of Alzheimer's disease: a clinical and pathologic entity. Neurology. 40: 1-8. Thirty-six clinically diagnosed and pathologically confirmed Alzheimer's disease (AD) patients included 13 with cortical and subcortical Lewy bodies (LBs). The patients with LBs appeared to constitute a distinct neuropathologic and clinical subset of AD, the Lewy body variant (LBV). The LBV group showed gross pallor of the substantia nigra, greater neuron loss in the locus ceruleus, substantia nigra, and substantia innominata, lower neocortical ChAT levels, and fewer midfrontal tangles than did the pure AD group, along with a high incidence of medial temporal lobe spongiform vacuolization. Analysis of neuropsychological tests from 9 LBV subjects and 9 AD patients matched for age and degree of dementia revealed greater deficits in attention, fluency, and visuospatial processing in the LBV group. Similar comparisons of neurologic examinations showed a significant increase in masked facies; in addition there was an increase in essential tremor, bradykinesia, mild neck rigidity, and slowing of rapid alternating movements in the LBV group. Extremity rigidity, flexed posture, resting tremor, or other classic parkinsonian features were not characteristic of the LBV patient. In some cases, it may be possible to diagnose LBV premortem on the basis of the clinical and neuropsychological features.

Hansen, L. A. and W. Samuel (1997). Criteria for Alzheimer's disease and the nosology of dementia with Lewy bodies. Neurology. 48: 126-132. Dementia with brainstem and neocortical Lewy bodies (LB) is a source of ongoing nosologic controversy and confusion. Differing opinions about concomitant Alzheimer's disease (AD) have produced competing nomenclatures. We applied neocortical plaque-based criteria for the diagnosis of AD from the National Institute on Aging and from the Consortium to Establish a Registry for AD for definite, probable, and possible AD to 58 dementia brains with LB, 10 elderly nondemented controls, and 58 brains with neuropathologically pure AD. We also employed diagnostic criteria requiring both neocortical plaques and tangles, and assessed the extent of neurofibrillary pathology in all 126 specimens using a modified version of the Braak and Braak staging protocol for changes related to AD. The percentages of mixed LB disease and AD versus pure LB disease varied from 91% mixed and 9% pure to 34% mixed and 66% pure, depending upon which diagnostic criteria for AD were employed. Most dementia brains with LB occupied higher modified Braak stages than controls, but lower ones than pure AD specimens. A minority of the dementia brains with LB had no more AD- type pathology than controls.

Hely, M. A., W. G. J. Reid, et al. (1996). Diffuse Lewy body disease: Clinical features in nine cases without coexistent Alzheimer's disease. Journal of Neurology Neurosurgery and Psychiatry. 60: 531-538. Objective - To further elucidate the relation between diffuse Lewy body disease and Parkinson's disease. Methods and results - The clinical features of nine cases of pure diffuse Lewy body disease without pathological evidence of coexisting Alzheimer's neuritic pathology are reported. All patients were aged less than 70 years at onset (mean 62 years). Five patients presented with clinical features, which included assymetric resting tremor and levodopa responsiveness, which were initially indistinguishable from idiopathic Parkinson's disease. All five patients later became demented (mean of three years after presentation). Two further patients presented with parkinsonism and dementia and two patients presented with dementia and developed parkinsonism at a later stage. Hallucinations appeared 2.5-9 years after the onset of symptoms in six patients and were a presenting feature in one patient. All patients met the pathological criteria of idiopathic Parkinson's disease, with respect to the midbrain changes, in addition to having diffuse cortical Lewy bodies. Conclusions - Diffuse Lewy body disease may present as parkinsonism, dementia, or both depending on whether the Lewy body pathology begins in the midbrain, the cortex, or both together. When it begins in the midbrain, diffuse Lewy body disease is indistinguishable initially from idiopathic Parkinson's disease. Diffuse Lewy body disease may be a common cause of dementia complicating Parkinson's disease.

Howard, R., A. David, et al. (1997). Seeing visual hallucinations with functional magnetic resonance imaging. Dementia and Geriatric Cognitive Disorders. 8: 73-77. We have used blood oxygenation level dependent imaging with functional magnetic resonance imaging (fMRI) to investigate the visual cortex response to photic stimulation during and in the absence of continuous visual hallucinations. A patient with cortical Lewy body dementia who experienced persistent and vivid complex hallucinations underwent fMRI on and off treatment with risperidone. When he was not hallucinating, photic stimulation produced a normal bilateral activation in striate cortex. During hallucinations, very limited activation in striate cortex could be induced. We interpret this result as indicating that at least part of the activity in the brain responsible for the experience of visual hallucinations is located in the primary visual cortex.

Hughes, A. J., S. E. Daniel, et al. (1993). A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol. 50: 140-8. The clinical details of 100 cases of histologically confirmed Parkinson's disease were examined and correlated with pathologic findings. Age at disease onset (mean, 62.4 years), disease duration (mean, 13.1 years), and age at death (mean, 75.5 years) were similar to those in previous smaller series. Asymmetric, tremulous onset was most common, although 23% of patients had no rest tremor. Motor fluctuations and dyskinesias occurred in 60% of levodopa-treated patients. All patients had clinical parkinsonism; however, 12 had atypical clinical features of Parkinson's disease, including severe early dementia, fluctuating confusional states, no response to levodopa, and early marked autonomic disturbance. Neuropathologic examination found coexistent Alzheimer-type change in 17 cases and striatal abnormality--mainly vascular--in 34 cases. Cortical Lewy bodies were present in all cases, but only four satisfied proposed criteria for diffuse Lewy body disease. Dementia occurred in 44% of cases; 29% had Alzheimer's disease, 10% had numerous cortical Lewy bodies, and 6% had a possible vascular cause; in 55% no definite pathologic cause was found. Nigral cell loss correlated with disease duration and severity. Although the general pattern of disease conformed to traditional descriptions, the findings broaden the present clinical and pathologic spectrum of Parkinson's disease.

Hughes, A. J., S. E. Daniel, et al. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson's disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 55: 181-4. Few detailed clinico-pathological correlations of Parkinson's disease have been published. The pathological findings in 100 patients diagnosed prospectively by a group of consultant neurologists as having idiopathic Parkinson's disease are reported. Seventy six had nigral Lewy bodies, and in all of these Lewy bodies were also found in the cerebral cortex. In 24 cases without Lewy bodies, diagnoses included progressive supranuclear palsy, multiple system atrophy, Alzheimer's disease, Alzheimer-type pathology, and basal ganglia vascular disease. The retrospective application of recommended diagnostic criteria improved the diagnostic accuracy to 82%. These observations call into question current concepts of Parkinson's disease as a single distinct morbid entity.

Hughes, A. J., S. E. Daniel, et al. (1993). The clinical features of Parkinson's disease in 100 histologically proven cases. Adv Neurol. 60: 595-9.

Imai, H. and H. Narabayashi (1990). A case of pure akinesia due to Lewy body parkinson's disease with pathology [letter; comment]. Mov Disord. 5: 90-1.

Kalra, S., C. Bergeron, et al. (1996). Lewy body disease and dementia: A review. Archives of Internal Medicine. 156: 487-493. Lewy bodies (LBs) are intracytoplasmic neuronal inclusions sometimes found in the brain stem, diencephalon, basal ganglia, and cerebral cortex. Cases designated as diffuse Lewy body disease (DLBD) demonstrate widespread cortical and subcortical Lewy body formation. The fact that DLBD is possibly the second most common cause of dementia after Alzheimer's disease is not generally recognized. We hope to emphasize the importance of this common neurodegenerative disorder by reviewing the literature and our own experience with DLBD. The English-language literature dealing with the clinical and pathological features of DLBD was reviewed. Pathological material from the Canadian Brain Tissue Bank, Toronto, Ontario, was reviewed over a 2-year period from 1991 through 1993. Prominent LB pathology may occur in isolation or mixed with pathological changes seen in Alzheimer's disease. Lewy body diseases include Parkinson's disease that presents with a classic movement disorder and sometimes dementia, and DLBD where LBs occur in a widespread distribution in the cortex in addition to the usual sub-cortical sites. Diffuse LB disease usually presents with a neurobehavioral syndrome that may include hallucinations, delusions, and psychosis; all patients eventually become demented. A day-to-day fluctuating mental state may be an important distinguishing clinical feature. Parkinsonism may follow the psychiatric disturbance although occasionally it is a presenting feature. Serious life- threatening side effects may occur with the use of standard neuroleptics. The variable clinical features and additional presence of Alzheimer-type pathological changes in many cases of DLBD has led to a confusing and inconsistent classification of LB disease and, together with little awareness of its existence, its misdiagnosis. Although DLBD may be the second most common cause of dementia, the terminology and classification of LB disorders and their relationship to Alzheimer's disease remain sources of intense debate. Further research is needed to resolve these issues and to provide insight into the pathogenesis of LB formation and accompanying neuronal degeneration.

Klatka, L. A., R. B. Schiffer, et al. (1996). Incorrect diagnosis of Alzheimer's disease: A clinicopathologic study. Archives of Neurology. 53: 35-42. Objectives: To examine the accuracy of clinical diagnoses of Alzheimer's disease (AD) in subjects enrolled in the Rochester Alzheimer's Disease Project (RADP) who were examined at autopsy, and to present a list of clinical 'red flags.' Design: Autopsy examination of both prospective and retrospective subjects consecutively enrolled in this clinicopathologic study of the RADP. Setting: University hospital and research center, using a multidisciplinary geriatric neurology clinic, satellite clinics, nursing home visits, and home visits. Patients: One hundred seventy subjects clinically diagnosed as having AD who were enrolled in the RADP between 1983 and 1993 underwent neuropathologic examination. Of these, 93 had been enrolled prospectively and 77 retrospectively. Main Outcome Measures: Agreement between clinical and pathologic diagnoses. Results: One hundred forty-nine subjects of 170 clinically diagnosed as having AD fulfilled the pathologic criteria for AD, yielding an accuracy rate of 88%. Of 93 subjects enrolled prospectively and diagnosed as having AD, 83 (90%) met the histologic criteria for AD. Of the 77 subjects enrolled retrospectively, neuropathologic examination indicated definite AD in 66 (86%). Conclusions: There was a high correlation between clinicians' diagnoses and final pathologic diagnoses. The most common clinical errors involved the misdiagnosis of dementias due to Parkinson's disease and cerebrovascular disease. There was no significant difference in the accuracy rates of subjects enrolled prospectively and retrospectively.

Kosaka, K. (1990). Diffuse Lewy body disease in Japan. J Neurol. 237: 197-204. Thirty-seven Japanese autopsy cases with diffuse Lewy body disease (DLBD) were reviewed from a clinicopathological viewpoint. Based on the neuropathological finding of whether or not many concomitant senile plaques (SPs) and/or neurofibrillary tangles (NFTs) are present. DLBD is divided into two forms: a common form and a pure form. In the common form not only numerous Lewy bodies but also many SPs and/or NFTs are found in the cerebral cortex, whereas in the pure form there are no or few senile changes. Of the 37 cases, 28 cases had the common form, and 9 had the pure form of DLBD. In the common form all cases had shown progressive cortical dementia in the presenile or senile period. About 60% of the cases began with memory disturbance, while 25% showed Parkinson's or Shy-Drager syndrome initially. Parkinson's syndrome, consisting mainly of muscular rigidity and akinesia, was usually marked in the later stage, although there were also 8 cases (28.6%) in which no parkinsonian symptoms were detected even in the terminal stage. On the other hand, almost all cases with the pure form of DLBD showed juvenile Parkinson's syndrome, followed by progressive cortical dementia, although there was one presenile case with mild dementia and Parkinson's syndrome. These Japanese cases are compared with cases reported in Western countries.

Kosaka, K. (1993). Dementia and neuropathology in Lewy body disease. Adv Neurol. 60: 456-63. In order to elucidate the pathological differences between demented and nondemented patients with Lewy body disease, brains from 35 patients were clinicopathologically examined. In diffuse Lewy body disease, cortical lesions, including numerous Lewy bodies and senile changes, were found to be responsible for the dementia. In some of the cases with the brain-stem type of Lewy body disease, the dementia was attributed to an Alzheimer pathology, while in many cases the various combinations of degeneration in the subcortical nuclei, mainly the nucleus basalis of Meynert and locus ceruleus, played a major role in the dementia. Forty-four Japanese cases with diffuse Lewy body disease were reviewed. Then diffuse Lewy body disease was divided into two forms: a common form (33 cases) and a pure form (11 cases). In the common form, all cases showed progressive cortical dementia in the presenile or senile period. Parkinson syndrome was usually marked in the terminal stage. However, about a fifth of the cases had no parkinsonism. Neuropathologically, the common form had many concomitant senile changes in the cerebral cortex. Most cases with the pure form showed juvenile Parkinson syndrome followed by progressive cortical dementia, while a few cases were of presenile or senile occurrence. Neuropathologically, the pure form had no or few senile changes. This suggests that numerous cortical Lewy bodies alone can cause cortical dementia.

Kosaka, K. (1995). Diffuse Lewy body disease. Clinical Neurology. 35: 1455-1456. Diffuse Lewy body disease (DLBD), which we have proposed since 1976, has received great attention among both researchers and clinicians. Recently, it was reported by some English and American research groups that DLBD is the second most frequent dementing illness in the elderly, following Alzheimer- type dementia (ATD). Our recent research of 79 autopsied dementia cases in a hospital disclosed that DLBD (15.4%) was the second most common degenerative dementia, following ATD (43.6%). In 1980 we proposed Lewy body disease, and classified it into three types: brain stem type, transitional type, and diffuse type. Diffuse type of LBD is now called DLBD. In 1990 we divided DLBD into two forms: common form and pure form. The common form DLBD has more or less Alzheimer pathology, and pure form has none. Very recently, we proposed the cerebral type of LBD, in which numerous Lewy bodies are found in the cerebral cortex and amygdala, but no PD pathology is present in the brain stem.

Kosaka, K. and E. Iseki (1996). Dementia with Lewy bodies. Current Opinion in Neurology. 9: 271-275. Dementia with Lewy bodies is a generic term which was proposed at the first International Workshop on Lewy Body Dementia. It is an all encompassing term that includes various types of disorder such as diffuse Lewy body disease, senile dementia of Lewy body type, and Lewy body variant of Alzheimer's disease. Epidemiological, clinical, neuropathological, biochemical, molecular biological, and therapeutic contributions to the understanding of dementia with Lewy bodies are reviewed.

Kosaka, K., K. Tsuchiya, et al. (1988). Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol. 7: 299-305. The pathological basis for dementia in Lewy body disease (LBD) remains controversial. While some investigators propose that cortical lesions are responsible, others favor a subcortical basis for this dementia. Brains from 35 patients with LBD (11 demented with diffuse LBD; 12 demented and 12 non-demented with a brainstem type of LBD) were clinicopathologically examined to elucidate the pathological differences between demented and non-demented patients with LBD. In cases of diffuse LBD, the cortical lesions were found to be responsible for the dementia. In some of the cases (25%) with the brainstem type of LBD, the dementia was attributed to an Alzheimer pathology, while in many cases (75%), degeneration in the subcortical nuclei, mainly the nucleus basalis of Meynert, played a major role in the dementia.

Kosunen, O., H. Soininen, et al. (1996). Diagnostic accuracy of Alzheimer's disease: A neuropathological study. Acta Neuropathologica. 91: 185-193. This prospective study focused on the accuracy of diagnosis of Alzheimer's disease (AD). We recruited 100 dementia patients and 20 controls who underwent a systematic evaluation. The clinical diagnosis of probable AD or possible AD according to the NINCDS-ADRDA criteria was assigned in 69% of the patients, 21% had vascular dementia (VaD) (DSM-III-R) and 8% had mixed AD-VaD; only 2 patients (2%) had the Lewy body variant of AD (AD-LB). During a 3-year period 57 patients died, 53 of them (93%) being autopsied. Neuropathological examination according to the CERAD criteria showed definite AD in 27 out of 28 (96%) patients diagnosed as probable AD. In the possible AD group, the diagnostic accuracy was also high, 86% showed at least some degree of AD pathological alterations. The neocortical senile plaque scores correlated significantly with tangle scores in patients with AD pathology, and there was a significant negative correlation between age of on-set and neocortical tangle scores. The concordance between the clinical diagnosis and pathological findings was clearly lower in VaD than in AD. In the clinical VaD group, 8 of 10 patients had at least some degree of AD changes together with vascular changes and only 2 of 10 patients had pure VaD. This study confirms the high accuracy of the NINCDS-ADRDA criteria for diagnosing AD. In contrast, uncertainty in the clinical diagnosis of VaD should be taken into account, for example, in drug trials with VaD patients.

Kulisevsky, J., M. J. Marti, et al. (1988). Meige syndrome: neuropathology of a case. Mov Disord. 3: 170-5. Primary Meige syndrome is a form of cranial dystonia of unknown cause. Only three postmortem studies have been reported, and the results of these studies have not been consistent. We have examined the brain of a 72-year-old man with typical primary Meige syndrome and found mild to moderate cell loss in the zona compacta of the substantia nigra, locus ceruleus, midbrain tectum, and dentate nucleus of the cerebellum. Also frequent Lewy bodies were present in pigmented nuclei of the brainstem. No abnormalities were detected elsewhere. These pathological findings support the notion that brainstem pathology is important in the pathophysiology of cranial dystonia.

Kuzuhara, S. and M. Yoshimura (1993). Clinical and neuropathological aspects of diffuse Lewy body disease in the elderly. Adv Neurol. 60: 464-9. This chapter reports the clinical and neuropathological findings of eight cases of "diffuse Lewy body disease" verified by autopsy. The age at onset was between 60 and 82 years; the age at death was between 75 and 92 years. The initial symptoms were amnesia in three cases, orthostatic dizziness in three, visual hallucination in two, but parkinsonism in none. The cardinal clinical symptoms included dementia in all cases, hallucinatory-delusional state in six, akinesia and rigidity in five, and orthostatic hypotension in five. Antemortem diagnoses were senile dementia in five, and hallucinatory-delusional state, Parkinson's disease and Shy-Drager syndrome in one each. Despite the clinical symptoms differences from each other, neuropathological findings were alike. Abundant Lewy bodies were present in the neurons of the cerebral cortex as well as in the brainstem nuclei and diencephalon. Concomitant senile changes including senile plaques and Alzheimer's neurofibrillary tangles (NFTs) were also present in varying degree. Immunocytochemical study with anti-ubiquitin for Lewy body, anti-tau protein for NFT, and beta-protein of amyloid for senile plaque suggested that dementia of DLBD might have resulted not from a single pathology but from the complex of Lewy bodies, NFTs and senile plaques.

Lebert, F., F. Pasquier, et al. (1996). Sundowning syndrome in demented patients without neuroleptic therapy. Archives of Gerontology and Geriatrics. 22: 49-54. Characterisation of sundowning syndrome, defined as 'an exacerbation of symptoms indicating increased arousal or impairment in late afternoon, evening or at night, among elderly demented individuals', is complicated by neuroleptic therapy and frequent failure to specify the nature of the associated dementia. Screening by a memory disorders unit of an institutionalized population of 30 neuroleptic- free demented patients revealed 8 sundowners, with diagnoses of probable Alzheimer's disease (n = 5), frontal lobe dementia (n = 1), Lewy body disease (n = 1), and sequelae of herpes encephalitis (n = 1). Sundowners did not differ from non-sundowners in age, Mini Mental State score, degree of temporal and spatial disorientation or perceptual delusion. Sundowning was related to restlessness (P < 0.0001), sleep disorder (P < 0.003) and a history of hypotension lipothymia (P < 0.08). These results provide further evidence for a chronobiological explanation of sundowning syndrome.

Lennox, G., J. S. Lowe, et al. (1989). Diffuse Lewy body disease: an important differential diagnosis in dementia with extrapyramidal features. Prog Clin Biol Res. 317: 121-30. Fifteen cases of diffuse Lewy body disease were identified in a systematic survey of all 216 brains referred to this hospital from a single health district in a single year. These cases presented with Parkinson's disease (40%), cognitive impairment (40%) and both (20%). Quantitative neuropathological studies using anti-ubiquitin immunocytochemistry revealed that dementia severity was related to cortical Lewy body density. The prevalence of diffuse Lewy body disease may have been underestimated in the past because of the neuropathological difficulties in making the diagnosis. Firstly, cortical Lewy bodies have a subtle appearance and are easy to overlook. Secondly, senile plaques are a common feature of diffuse Lewy body disease and may lead the unwary to make an erroneous diagnosis of Alzheimer's disease or "plaque-only Alzheimer's disease'. Diffuse Lewy body disease is a common and important cause of parkinsonian dementia, including the dementia of Parkinson's disease itself.

Leverenz, J. and S. M. Sumi (1986). Parkinson's disease in patients with Alzheimer's disease. Arch Neurol. 43: 662-4. Because patients with Alzheimer's disease often develop clinical manifestations of Parkinson's disease, we examined the substantia nigra in 40 cases of pathologically confirmed Alzheimer's disease for the changes of Parkinson's disease (neuronal loss, Lewy bodies, or neurofibrillary tangles). Eighteen patients had one or more of these changes in the substantia nigra. Subsequently, we reviewed their clinical records and found that rigidity, with or without tremor, had been noted in 13 patients, and nine patients had a second diagnosis of possible or definite Parkinson's disease. Eleven (85%) of these patients had the pathologic changes of Parkinson's disease. These findings suggest that the majority of patients with Alzheimer's disease with extrapyramidal signs have the pathologic changes of Parkinson's disease in the substantia nigra.

Lewis, A. J. and M. J. Gawel (1990). Diffuse Lewy body disease with dementia and oculomotor dysfunction. Mov Disord. 5: 143-7. The case is presented of an elderly patient who had dementia, axial rigidity, and bradykinesia with limitation of horizontal and vertical gaze. Pathological examination disclosed Lewy and Lewy-like bodies in the substantia nigra, locus ceruleus, and neocortex, leading to a final diagnosis of diffuse Lewy body disease. Similar inclusions were found in areas of the pons and midbrain believed to be associated with gaze control. Moderate numbers of neuritic plaques, but no neurofibrillary tangles, were present in limbic cortex and neocortex. Review of the literature has not shown previous association of diffuse Lewy body disease with both horizontal and vertical gaze anomalies.

Liberini, P., A. Valerio, et al. (1996). Lewy-body dementia and reponsiveness to cholinesterase inhibitors: A paradigm for heterogeneity of Alzheimer's disease? Trends in Pharmacological Sciences. 17: 155-160. The concept of heterogeneity of Alzheimer's disease is based on molecular, neuropathological, clinical and neuropsychological features, and also supported by the observation that Alzheimer's patients differ in their response to pharmacological interventions. Recent investigations evaluating the therapeutic potential of cholinesterase inhibitors have disclosed the existence of at least two subsets of patients with dementia, defined as 'responders' and 'nonresponders' to this therapy. In this article, Paolo Liberini and colleagues suggest that the cluster of responders to the cholinesterase inhibitors might include a significant number of subjects with a rather selective dysfunction of the cholinergic system, as in the case of Lewy-body dementia. A neuropathological demonstration of this correlation should open up new therapeutic perspectives.

Lippa, C. F., T. W. Smith, et al. (1994). Alzheimer's disease and Lewy body disease: a comparative clinicopathological study [published erratum appears in Ann Neurol 1994 Mar; 35(3):380]. Ann Neurol. 35: 81-8. The exact nature of the relationship between Lewy body disease and Alzheimer's disease (AD) is unknown. To investigate this, we compared cases of pure Lewy body disease, mixed Lewy body disease with AD, and pure AD to see what pathological features were shared and how they differed. We counted neurons, Lewy bodies, diffuse and neuritic senile plaques, neurofibrillary tangles, and neuropil threads in the frontal and medial temporal cortex and hippocampus from 5 autopsied cases of Lewy body disease (without AD histopathology), 7 with combined Lewy body disease and AD, 6 with AD, and 5 age-matched normal control subjects. Average neuronal counts in the cases with Lewy body disease were indistinguishable from those of control subjects, but higher than those for AD and combined Lewy body disease and AD. Diffuse plaque densities were similar in all disease forms. Neuritic senile plaques, neurofibrillary tangles, and neuropil threads were numerous in AD and combined Lewy body disease and AD, but sparse or absent in Lewy body disease and controls. Pure Lewy body disease and AD appear to be distinct clinicopathological entities except for the common feature of diffuse plaques in both disorders.

Litvan, I., Y. Agid, et al. (1996). Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology. 46: 922-930. We assessed the validity and interrater reliability of neurologists who, using four different sets of previously published criteria for the clinical diagnosis of progressive supranuclear palsy (PSP), also called Steele- Richardson-Olszewski syndrome, rated 105 autopsy- proven cases of PSP (n = 24), Lewy body disease (n = 29), corticobasal ganglionic degeneration (n = 10), postencephalitic parkinsonism (n = 7), multiple system atrophy (n = 16), Pick's disease (n = 7), and other parkinsonian or dementia disorders (n = 12). Cases were presented in random order to six neurologists. Information from each patient's first and last visits to the medical center supplying the case was presented sequentially to the rater, and the rater's diagnosis was compared with the neuropathologic diagnosis of each case. Interrater agreement for the diagnosis of PSP varied from substantial to near perfect, but none of the criteria had both high sensitivity and high predictive value. Because of these limitations, we used a logistic regression analysis to identify the variables from the data set that would best predict the diagnosis. This analysis identified vertical supranuclear palsy with downward gaze abnormalities and postural instability with unexplained falls as the best features for predicting the diagnosis. From the results of the regression analysis and the addition of exclusionary features, we propose optimal criteria for the clinical diagnosis of PSP.

Litvan, I., G. Campbell, et al. (1997). Which clinical features differentiate progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome) from related disorders? A clinicopathological study. Brain. 120: 65-74. The difficulty in differentiating progressive supranuclear palsy (PSP, also called Steele-Richardson-Olszewski syndrome from other related disorders was the incentive for a study to determine the clinical features that best distinguish PSP. Logistic regression and classification and regression tree analysis (CART) were used to analyse data obtained at the first visit from a sample of 83 patients with a clinical history of parkinsonism or dementia confirmed neuropathologically including PSP (n = 24), corticobasal degeneration (n = 11), Parkinson's disease (PD, n = 11), diffuse Lewy body disease (n = 14), Pick's disease (n = 8) and multiple system atrophy (MSA, n = 15). Supranuclear vertical gaze palsy, moderate or severe postural instability and falls during the first year after onset of symptoms classified the sample with 9% error using logistic regression analysis. The CART identified similar features and was also helpful in identifying particular attributes that separate PSP from each of the other disorders. Unstable gait, absence of tremor-dominant disease and absence of a response to levodopa differentiated PSP from PD. Supranuclear vertical gaze palsy gait instability and the absence of delusions distinguished PSP from diffuse Lewy body disease. Supranuclear vertical gaze palsy and increased age at symptom-onset distinguished PSP from MSA. Gait abnormality, severe upward gaze palsy bilateral bradykinesia and absence of alien limb syndrome separated PSP from corticobasal degeneration. Postural instability successfully classified PSP from Pick's disease. The present study may help to minimize the difficulties neurologists experience when attempting to classify these disorders at early stages.

Louis, E. D., J. E. Goldman, et al. (1995). Parkinsonian features of eight pathologically diagnosed cases of diffuse Lewy body disease. Mov Disord. 10: 188-94. Premortem diagnosis of diffuse Lewy body disease (DLBD) is difficult, and knowledge of the parkinsonian features of DLBD might facilitate the diagnosis. In this study, we compared the parkinsonian syndrome of DLBD and Parkinson's disease (PD). We retrospectively reviewed the charts of Columbia-Presbyterian Medical Center (CPMC) Brain Bank cases (1989-1993) with pathologically diagnosed DLBD or PD, and the literature on the parkinsonian features in DLBD patients presenting with parkinsonism. Parkinsonism accompanied or preceded cognitive/psychiatric changes in most CPMC cases (DLBD 100%, PD 88%). DLBD had an earlier mean age of onset than PD did (57 versus 64 years), a similar male:female ratio (1.7:1 versus 1.9:1), and similar mean disease duration (12-13 years). Cognitive/psychiatric changes were less frequent in PD than in DLBD (65 versus 100%) (p = 0.025). Rest tremor was specifically mentioned in 29% of DLBD versus 56% of PD (p = 0.10). Bradykinesia was less common in PD (56% versus 86%) (p = 0.05). All those with PD responded to L-Dopa, as did all those with DLBD who received L-Dopa. In conclusion, there are subtle differences between PD and DLBD in age of onset, frequency of cognitive/psychiatric changes, bradykinesia, and rest tremor. However, even when taken together, these cannot be used to distinguish these entities.

Mark, M. H., J. I. Sage, et al. (1994). Meige syndrome in the spectrum of Lewy body disease. Neurology. 44: 1432-6. We report a patient with Meige syndrome (segmental cranial dystonia) who had neuropathologic changes of Parkinson's disease on postmortem examination. Neuropathologic examination showed typical and atypical Lewy bodies in the pigmented nuclei of the brainstem (substantia nigra, locus ceruleus), the nucleus basalis of Meynert, and the nucleus ambiguus. Neurochemical analysis of postmortem brain tissue showed evidence for decreased dopamine turnover in the substantia nigra, striatum, and nucleus accumbens. We propose that some cases of Meige syndrome may be included in the spectrum of Lewy body disease.

Mark, M. H., J. I. Sage, et al. (1992). Levodopa-nonresponsive Lewy body parkinsonism: clinicopathologic study of two cases. Neurology. 42: 1323-7. We report two patients with a primarily akinetic form of parkinsonism who were nonresponsive to treatment with levodopa. At autopsy, both patients had many Lewy bodies in brainstem and diencephalic nuclei, with sparse Lewy bodies in association cortices and more numerous Lewy bodies in the limbic cortices, consistent with the transitional form of Lewy body disease. These cases emphasize that (1) Lewy body Parkinson's disease cannot be excluded on the basis of atypical presentation or levodopa nonresponsiveness, and (2) the clinicopathologic spectrum of Lewy body disease is varied.

McKeith, I., A. Fairbairn, et al. (1992). Neuroleptic sensitivity in patients with senile dementia of Lewy body type. Bmj. 305: 673-8. OBJECTIVE--To determine the outcome of administration of neuroleptics to patients with senile dementia of Lewy body type confirmed at necropsy. DESIGN--Retrospective analysis of clinical notes blind to neuropathological diagnosis. SETTING--Specialist psychogeriatric assessment units referring cases for necropsy to a teaching hospital neuropathology service. PATIENTS--41 elderly patients with diagnosis of either Alzheimer type dementia (n = 21) or Lewy body type dementia (n = 20) confirmed at necropsy. MAIN OUTCOME MEASURES--Clinical state including extrapyramidal features before and after neuroleptic treatment and survival analysis of patients showing severe neuroleptic sensitivity compared with the remainder in the group. RESULTS--16 (80%) patients with Lewy body type dementia received neuroleptics, 13 (81%) of whom reacted adversely; in seven (54%) the reactions were severe. Survival analysis showed an increased mortality in the year after presentation to psychiatric services compared with patients with mild or no neuroleptic sensitivity (hazard ratio 2.70 (95% confidence interval 2.50-8.99); (chi 2 = 2.68, p = 0.05). By contrast, only one (7%) of 14 patients with Alzheimer type dementia given neuroleptics showed severe neuroleptic sensitivity. CONCLUSIONS--Severe, and often fatal, neuroleptic sensitivity may occur in elderly patients with confusion, dementia, or behavioural disturbance. Its occurrence may indicate senile dementia of Lewy body type and this feature has been included in clinical diagnostic criteria for this type of dementia.

McKeith, I. G., A. F. Fairbairn, et al. (1994). An evaluation of the predictive validity and inter-rater reliability of clinical diagnostic criteria for senile dementia of Lewy body type. Neurology. 44: 872-7. Several recent autopsy studies suggest that senile dementia of Lewy body type (SDLT) may be the second most common neuropathologic cause of dementia in the elderly, accounting for 7 to 30% of all cases. Operational criteria for the antemortem clinical diagnosis of SDLT have already been proposed by our group. The performance of these is now examined by randomizing the case notes from a new series of SDLT, Alzheimer, and multi-infarct dementia patients for psychiatric assessment by four raters of varying clinical experience and blind to pathologic diagnosis. Using the SDLT criteria, the two most experienced raters agreed in 94% of cases (kappa = 0.87), with the least experienced rater agreeing in 78% (kappa = 0.50). Diagnostic specificity for SDLT was uniformly high (90.0 to 97.0%), with a mean sensitivity of detection of 74%, and was greater by the experienced (90.0%) than the least experienced (55%) clinician. The antemortem identification of SDLT patients can therefore be achieved with a high degree of diagnostic specificity using such operationalized criteria, although there remains a minority of patients who present with either "typical" Alzheimer-type symptoms or with paranoid or delusional symptoms in the absence of substantial cognitive impairment. Sensitivity to neuroleptics may be a useful diagnostic pointer in these patients.

McKeith, I. G., A. F. Fairbairn, et al. (1994). The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT). Br J Psychiatry. 165: 324-32. BACKGROUND. Current clinical classifications do not contain specific diagnostic categories for patients with senile dementia of the Lewy body type (SDLT), recently proposed as the second commonest neuropathological cause of dementia in the elderly. This study determines how existing clinical diagnosis systems label SDLT patients and suggests how such patients may be identified. METHOD. A range of clinical diagnostic criteria for dementia were applied to case notes of autopsy-confirmed SDLT (n = 20), dementia of Alzheimer type (DAT; n = 21) and multi-infarct dementia (MID; n = 9) patients who had received psychogeriatric assessment. The predictive validity of each set of clinical criteria was calculated against the external criterion of neuropathological diagnosis. RESULTS. Many SDLT patients erroneously met criteria for MID (35% with Hachinski scores or = 7) or for DAT (15% by NINCDS 'probable AD', 35% by DSM-III-R DAT and 50% by NINCDS 'possible AD'). Up to 85% of SDLT cases could be correctly identified using recently published specific criteria. CONCLUSIONS. SDLT usually has a discernible clinical syndrome and existing clinical classifications may need revision to diagnose correctly such patients.

McKeith, I. G., D. Galasko, et al. (1996). Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology. 47: 1113-1124. Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.

McKeith, I. G., R. H. Perry, et al. (1992). Operational criteria for senile dementia of Lewy body type (SDLT). Psychol Med. 22: 911-22. Recent reports have suggested that brain stem and cortical Lewy body formation may identify a neurodegenerative disorder in elderly demented individuals which accounts for up to 20% of cases of senile dementia coming to autopsy. Retrospective analysis of case notes of 21 autopsy patients with neuropathologically proven senile dementia of Lewy body type (SDLT) and 37 cases with neuropathologically proven Alzheimer's disease (AD) identified a characteristic clinical syndrome in SDLT. Fluctuating cognitive impairment; psychotic features including visual and auditory hallucinations, and paranoid delusions; depressive symptoms; falling and unexplained losses of consciousness were all seen significantly more often than in AD. Over half of the SDLT patients in this series who were given neuroleptics in standard dose showed acute and often irreversible adverse reactions indicative of a neuroleptic sensitivity syndrome. The survival time of drug treated patients was reduced by 50%. Operational criteria to aid in the clinical distinction between SDLT and AD patients are proposed and hypotheses regarding possible aetiology and treatment discussed.

McShane, R., J. Keene, et al. (1997). Do neuroleptic drugs hasten cognitive decline in dementia? Prospective study with necropsy follow up. British Medical Journal. 314: 266-270. Objective: To investigate the contribution of neuroleptic drugs to cognitive decline in dementia. Design: Two year prospective, longitudinal study consisting of interviews every four months, with necropsy follow up. Setting: Community settings in Oxfordshire. Subjects: 71 subjects with dementia, initially living at home with informant. Main outcome measures: Cognitive function (score from expanded minimental state examination); behavioural problems (physical aggression, hallucinations, persecutory ideas, and disturbance of diurnal rhythm); and postmortem neuropathological assessment (cortical Lewy body pathology). Results: The mean (SE) decline in cognitive score in the 16 patients who took neuroleptics was twice that in the patients who did not (20.7 (2.9) v 9.3 (1.3), P = 0.002). An increased rate of decline was also associated with aggression, disturbed diurnal rhythm, and persecutory ideas. However, only use of neuroleptics and severity of persecutory ideas were independently associated with more rapid cognitive decline when all other variables were adjusted for. The start of neuroleptic treatment coincided with more rapid cognitive decline: median rate of decline was 5 (interquartile range 8.5) points per year before treatment and 11 (12) points per year after treatment (P = 0.02). Cortical Lewy body pathology did not account for association between neuroleptic use and more rapid decline. Conclusions: Neuroleptic drugs that are sometimes used to seat behavioural complications of dementia may worsen already poor cognitive function. Randomised controlled trials are needed to confirm a causal relation.

Mega, M. S., D. L. Masterman, et al. (1996). Dementia with lewy bodies: Reliability and validity of clinical and pathologic criteria. Neurology. 47: 1403-1409. Clinical criteria for dementia with Lewy bodies (DLB) have been proposed, but their formulation, reliability, and validity require further study. Pathologic criteria for DLB are also undergoing evolution. Two studies were conducted with the goal of identifying the components of these evolving criteria that may benefit from further refinement; one study evaluated the components of the clinical criteria and another study operationalized the pathologic criteria for DLB. Twenty-four patients with a premorbid diagnosis of probable or possible Alzheimer's disease (AD) (n = 18), Parkinson's disease (PD) (n = 5), or progressive supranuclear palsy (PSP) (n = 1) were studied. Inter-rater reliability and validity of the clinical criteria were determined by a retrospective chart review, done by five neurologists, and a blinded pathologic evaluation. The Consortium on dementia with Lewy bodies (CDLB) pathologic criteria were operationalized to compare past criteria and test the validity of the evolving clinical criteria on the dementia patients. Three or more cortical fields (at 250x magnification) with many (four or more) Lewy bodies (LBs) on ubiquitin immunoreactive sections were required to meet the CDLB neocortical score of >6. Fifteen of the AD patients had at least one LB in a cortical section, four had many LBs, while three had no LBs; all patients with movement disorder had at least one LB in a cortical section. The sensitivity/specificity ratio of the CDLB probable DLB clinical criteria based upon many LBs being present was 75%/79%. Reformulated clinical criteria that require the presence of extrapyramidal signs significantly predicted those patients with many LBs versus those with few or no LBs (chi2 = 5.48, p = 0.02) and increased clinical specificity to 100%. This preliminary study identifies components of the evolving clinical and pathologic criteria for DLB that require further refinement.

Mendez, M. F., A. R. Mastri, et al. (1991). Neuropathologically confirmed Alzheimer's disease: clinical diagnoses in 394 cases. J Geriatr Psychiatry Neurol. 4: 26-9. In the absence of pathognomonic clinical features, the clinical diagnosis of Alzheimer's disease (AD) remains one of exclusion of other dementias. We investigated the clinical diagnoses among 394 neuropathologically confirmed AD cases in a dementia brain bank. Most patients were correctly diagnosed as AD (348 or 88%). Among the misdiagnosed patients, AD was mistaken for a primary depressive disorder in 14, multi-infarct dementia in 13, Parkinson's disease in nine, and alcoholic dementia in four. The number of misdiagnosed AD patients did not differ between physician specialties but was greater among AD patients with agitation, depression, paranoia, or delusions. This retrospective study suggests that the diagnostic sensitivity for AD is high among a cross-section of practicing physicians and that an important factor in mistaking AD for another illness is unfamiliarity with the potential psychiatric symptoms of AD.

Mori, H., M. Yoshimura, et al. (1986). Progressive supranuclear palsy with Lewy bodies. Acta Neuropathol (Berl). 71: 344-6. An autopsy case is reported which revealed not only clinical and neuropathological features of progressive supranuclear palsy, but also the presence of large numbers of Lewy bodies in the brain stem nuclei and cerebral cortex. This case seems to be progressive supranuclear palsy with Lewy bodies distributed as in Parkinson's disease. Such case has not been previously reported.

Moutoussis, M. and W. Orrell (1996). Baclofen therapy for rigidity associated with Lewy body dementia. British Journal of Psychiatry. 169: 795.

Mullan, E., C. Cooney, et al. (1996). Mania and cortical Lewy body dementia. International Journal of Geriatric Psychiatry. 11: 837-839. A case of mania occurring after the onset of cortical Lewy body dementia is described in a lady with no family history or previous history of affective disorder. It is proposed that cortical Lewy body dementia should be considered as a cause of secondary mania. The difficulties of treating mania in this context are discussed.

Oken, R. J. (1996). Lewy body diseases: Possible new directions in prophylaxis and therapy. Medical Hypotheses. 46: 222-224. No therapy exists for the Lewy body diseases, which are an important cause of dementia. We regard Lewy body diseases and Parkinson disease as components of a spectrum of disorders having a degree of Alzheimer disease neuropathology. Immunologic features of Alzheimer disease and Parkinson disease suggest the involvement of similar phenomena in Lewy body diseases pathogenesis. Based on the efficacy of anti- inflammatory medication in arresting the progression of Alzheimer disease and the presence of common immunologic features in Alzheimer disease and Parkinson disease, a case is made for therapeutic intervention at the immune system level. Anti-inflammatory medications appear to be an appropriate therapeutic approach to Lewy body diseases.

Olichney, J. M., D. Galasko, et al. (1995). The spectrum of diseases with diffuse Lewy bodies. Adv Neurol. 65: 159-70.

Pasquier, F., I. Lavenu, et al. (1997). The use of SPECT in a multidisciplinary memory clinic. Dementia and Geriatric Cognitive Disorders. 8: 85-91. We tested the interobserver reliability of visual rating of HMPAO- SPECT imaging in 271 outpatients referred to a memory clinic, and followed over 1 year. The clinical diagnoses were Alzheimer's disease (n = 156), frontotemporal dementia (n = 47), vascular dementia (n = 21), senile dementia of Lewy body type (n = 12), anxiety/depressive disorders (n = 14) and miscellaneous memory disorders (n = 21). The interobserver agreement was good (k = 0.68). However, the heterogeneity of the patterns - independent from demographic data, age at onset and duration of the disease - and their lack of sensibility and specificity limited the contribution of SPECT for diagnostic purposes in routine practice.

Perry, E. K., I. McKeith, et al. (1991). Topography, extent, and clinical relevance of neurochemical deficits in dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease. Ann N Y Acad Sci. 640: 197-202. Cholinergic and monoaminergic (dopaminergic and serotonergic) activities have been examined in postmortem brain tissue in senile dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease. Quantitative data suggest that although extrapyramidal symptoms relate to striatal levels of dopamine, cognitive impairment is most closely associated with cholinergic (but not monoaminergic) deficits in temporal and archicortical areas. Hallucinations, which are most frequent in Lewy body dementia, appear to be related to an extensive cholinergic deficit in temporal neocortex and the resulting imbalance between decreased cholinergic and relatively preserved serotonergic activities. Topographic analyses such as these including consideration of quantitative "threshold" effects, may be relevant to the future anatomic focus of neurochemical investigations in dementia and to the development of appropriate experimental models.

Perry, R. H., D. Irving, et al. (1990). Senile dementia of Lewy body type. A clinically and neuropathologically distinct form of Lewy body dementia in the elderly. J Neurol Sci. 95: 119-39. A dementing syndrome has been identified in a group of psychiatric cases aged 71-90 years, presenting initially with a subacute/acute confusional state, often fluctuating and associated with visual hallucinations and behavioural disturbances. Clinically, these cases did not meet criteria for a diagnosis of Alzheimer's disease, and many were assigned to the multiinfarct dementia group, although no significant ischaemic lesions were evident at autopsy. Mild extrapyramidal features were apparent in a number of cases but the characteristic clinical triad of Parkinson's disease, i.e., tremor, rigidity, and akinesia, was absent. Detailed neuropathological examination revealed Lewy body formation and selective neuronal loss in brain stem and other subcortical nuclei, accompanied by Lewy body formation in neo- and limbic cortex, at densities well below those previously reported in diffuse Lewy body disease. A variable degree of senile degenerative change was present; numerous senile plaques and minimal neurofibrillary tangles in most cases. Neither the clinical nor the neuropathological features of this group are typical of Parkinson's or Alzheimer's disease, but suggest a distinct neurodegenerative disorder, part of the Lewy body disease spectrum, in which mental symptoms predominate over motor disabilities and lead to eventual psychogeriatric hospital admission. In a sequential series of autopsies conducted on clinically assessed demented patients, neuropathological analysis has indicated that such cases may comprise up to 20% of a hospitalized population of demented old people over the age of 70 years, an observation clearly relevant to the diagnosis and management of dementia in the elderly.

Perry, R. H., D. Irving, et al. (1989). Senile dementia of Lewy body type and spectrum of Lewy body disease [letter; comment]. Lancet. 1: 1088.

Popovitch, E. R., H. M. Wisniewski, et al. (1987). Young adult-form of dementia with neurofibrillary changes and Lewy bodies. Acta Neuropathol (Berl). 74: 97-104. Alzheimer's neurofibrillary tangles, Lewy bodies and chromatolytic neurons were found in the brain at autopsy of a 28-year-old male with pyramidal and extrapyramidal signs, and severe dementia of 7-year duration prior to his death. Review of histological material showed generalized changes involving both cortical and subcortical structures. These changes were characterized by the presence of neurofibrillary myelin in long tracts and in subcortical regions. The neurofibrillary tangles were mostly composed of Alzheimer's paired helical filaments (PHF), PHF were immunostained with both polyclonal and monoclonal antibodies to PHF and the microtubule-associated protein tau. Some Lewy bodies were immunolabelled with monoclonal antibodies to PHF. To the best of our knowledge it is the first reported case of a young adult-form of dementia with extensive formation of neurofibrillary changes and Lewy bodies.

Quinn, N. P., P. Luthert, et al. (1989). Pure akinesia due to lewy body Parkinson's disease: a case with pathology. Mov Disord. 4: 85-9. The case of a patient with levodopa-responsive pure akinesia and freezing of gait for 17 years, whose brain showed the classical changes of Lewy body Parkinson's disease at postmortem is presented. A short trial of DL-threo-DOPS was ineffective. Intellectual function was preserved despite the presence of Lewy bodies and mild cell loss in subcortical cholinergic nuclei. Pure akinesia is likely to be a heterogeneous condition, with most cases having little or no response to levodopa therapy. However, this case demonstrates that this clinical picture may be caused by Lewy body Parkinson's disease.

Sawada, H., F. Udaka, et al. (1992). SPECT findings in Parkinson's disease associated with dementia. J Neurol Neurosurg Psychiatry. 55: 960-3. Dementia in Parkinson's disease is thought to be attributable not only to subcortical lesions but also to cortical alterations, especially frontal lobe dysfunction. To evaluate cortical function, the regional cerebral blood flow (rCBF) was estimated of 13 demented and 13 non-demented age matched patients with Parkinson's disease compared with that of 10 age matched controls using I-123 iodoamphetamine single photon emission tomography (IMP-SPECT). The rCBF of the nondemented Parkinson's patients showed no significant differences from that of the control subjects. In the demented patients, the bilateral frontal and parietal and left temporal regional blood flow was significantly less than in the controls. Four demented patients showed isolated frontal hypoperfusion, 8 showed fronto-parietal hypoperfusion, and 1 showed isolated parietal hypoperfusion. Frontal hypoperfusion was therefore present in 12 of the 13 demented patients, and this finding agrees with the frontal lobe dysfunction hypothesis. Parietal rCBF had a significant positive correlation with cortical functions such as calculation and language ability in the MMSE scores. The parietal and temporal reduction in rCBF probably reflects the presence of Alzheimer pathology, cortical Lewy body disease, or both.

Sudarsky, L., J. Morris, et al. (1989). Dementia in Parkinson's disease: the problem of clinicopathological correlation. J Neuropsychiatry Clin Neurosci. 1: 159-66. Four cases of Parkinson's disease with advanced dementia are described. Postmortem examination revealed cell loss in the substantia nigra, with Lewy bodies present, and loss of cells in the basal nucleus of Meynert. A few tangles were observed in the hippocampus, but no senile plaques or neurofibrillary tangles were found in the neocortex. The authors note that a dramatic dementia syndrome may occur with Parkinson's disease alone, without the associated cytoskeletal markers of Alzheimer's disease. Cases were characterized by disorientation, episodic confusion and hallucinations persisting off medication, disturbed behavior, and the absence of aphasia.

Swanwick, G. R. J., R. F. Coen, et al. (1996). Clock-face drawing to differentiate dementia syndrome [4]. Lancet. 347: 1115.

Tuite, P. J., J. P. Provias, et al. (1996). Atypical dopa responsive parkinsonism in a patient with megalencephaly, midbrain Lewy body disease, and some pathological features of Hallervorden-Spatz disease. Journal of Neurology Neurosurgery and Psychiatry. 61: 523-527. A 38 year old patient with megalencephaly, mental retardation, and lifelong tremor developed levodopa responsive parkinsonism in his mid-30s followed by the appearance of dyskinesiae, motor fluctuations, hallucinations, and dementia. Brain MRI showed, as well as other changes, iron deposition in the globus pallidus, substantia nigra, and the pulvinar of the thalamus. Postmortem examination disclosed depigmentation of the substantia nigra pars compacta with neuronal loss, gliosis, and Lewy body formation. Axonal dystrophic spheroids, neuronal loss, calcification, and iron deposition were found in the substantia nigra pars reticulata. Less severe changes without neuronal loss were seen in the globus pallidus. This combination of megalencephaly with neuroaxonal changes predominently in the pars reticulata and Lewy body degeneration isolated to the substantia nigra pars compacta has not been previously reported.

Turjanski, N., K. Bhatia, et al. (1993). Comparison of striatal 18F-dopa uptake in adult-onset dystonia-parkinsonism, Parkinson's disease, and dopa-responsive dystonia. Neurology. 43: 1563-8. We studied six patients with adult-onset dystonia-parkinsonism (DYS-P) with 18F-6-fluoro-dopa (18F-dopa) positron emission tomography and compared their influx constants (Ki values) with those of six patients with classical childhood-onset dopa-responsive dystonia (DRD), 12 age-matched Parkinson's disease (PD) patients without dystonia, and 21 normal controls. The DYS-P group had significantly reduced mean caudate (67% of normal) and putamen (45% of normal) 18F-dopa uptake. These Ki values were similar to mean caudate and putamen Ki values obtained for the PD group. In contrast, the DRD group showed minor reductions in mean caudate (9%) and putamen (18%) 18F-dopa uptake when compared with normals. The mean caudate:putamen Ki ratio was 1.7 in the DYS-P group and 2.1 in the PD group. In the DRD and normal groups, the caudate:putamen ratios were close to unity. The findings of this study are that adult-onset DYS-P targets the nigrostriatal dopaminergic projections in a pattern similar to PD, with the putamen being more affected. This provides support for the hypothesis that DYS-P may be a phenotypic variant of Lewy body disease. DYS-P seems distinct from childhood-onset DRD, in which striatal 18F-dopa uptake is either normal or only mildly reduced.

Uchiyama, M., K. Isse, et al. (1995). Incidental Lewy body disease in a patient with REM sleep behavior disorder. Neurology. 45: 709-12. We studied an 84-year-old man with a 20-year history of nocturnal violent behavior during sleep, but no other clinically evident neuropsychiatric disorders. Polysomnographic investigations confirmed that he suffered from REM sleep behavior disorder (RBD). Histopathologic examination revealed he had Lewy body disease with a marked decrease of pigmented neurons in the locus ceruleus and substantia nigra. These histologic findings represent the first documented evidence of a loss of brainstem monoaminergic neurons in clinically idiopathic RBD and suggest that Lewy body disease might provide an explanation for idiopathic RBD in the aged.

Van Duijn, C. M. (1996). Epidemiology of the dementias: Recent developments and new approaches. Journal of Neurology Neurosurgery and Psychiatry. 60: 478-488.

van Ingelghem, E., M. van Zandijcke, et al. (1994). Pure autonomic failure: a new case with clinical, biochemical, and necropsy data. J Neurol Neurosurg Psychiatry. 57: 745-7. Postmortem examination of a patient with pure autonomic failure showed loss of intermediolateral column cells and of sympathetic ganglionic neurons; there were Lewy bodies in sympathetic neurons. No neuronal loss or Lewy bodies were seen in pigmented brainstem nuclei. This case indicates that pure autonomic failure can occur in the absence of presymptomatic Parkinson's disease. Furthermore, it supports the view that in pure autonomic failure the lesion is more distal than in autonomic failure associated with multiple system atrophy.

Weiner, W. F., R. C. Risser, et al. (1996). Alzheimer's disease and its Lewy body variant: A clinical analysis of postmortem verified cases. American Journal of Psychiatry. 153: 1269-1273. Objective: The authors compared clinical findings of Alzheimer's disease and the so-called Lewy body variant of Alzheimer's disease. Method: Available data were analyzed on the clinical features of 58 patients with Alzheimer's disease and 24 patients with the Lewy body variant of Alzheimer's disease who underwent postmortem examinations. Results: The proportion of men was significantly larger in the Lewy body variant group than in the Alzheimer's disease group (66.7% versus 34.5%), and, concordantly, the Lewy body variant group was slightly taller. The prevalence of hallucinations and delusions was significantly higher in Lewy body variant subjects than the Alzheimer's disease subjects, but there were no significant differences between the two groups in educational attainment, family history of dementia, age at onset, duration of illness, cognitive impairment, overall severity of illness, or neuropsychological findings. Patients with the Lewy body variant of Alzheimer's disease tended to experience more frequent extrapyramidal side effects of neuroleptics than did the patients with Alzheimer's disease, but for patients in two groups who were not exposed to neuroleptics, there was little difference in frequency of extrapyramidal side effects. CSF concentration of bomovanillic acid (HVA) was significantly lower in the Lewy body variant patients, even when correction was made for height. Conclusions: The Lewy body variant of Alzheimer's disease may be suspected in elderly male dementia patients who otherwise meet criteria for Alzheimer's disease but who manifest significant psychiatric symptoms and neuroleptic-induced extrapyramidal side effects and have low levels of CSF HVA.

Williams, T. L., P. J. Shaw, et al. (1995). Parkinsonism in motor neuron disease: case report and literature review. Acta Neuropathol (Berl). 89: 275-83. This report describes a patient who had clinical features of both motor neuron disease and Parkinson's disease. Neuropathological examination and immunocytochemical studies showed that he had motor neuron disease of the progressive muscular atrophy type, and Lewy body Parkinson's disease, with intracytoplasmic inclusion bodies characteristic of both conditions. This is the first detailed description of these two diseases occurring concurrently in the same patient. A review of all previously reported cases of combined motor neuron disease and parkinsonism has led to the following conclusions: (1) that these two neuropathologically defined diseases occur together very infrequently, but (2) that parkinsonism and substantia nigra degeneration are not uncommon as part of the multi-system disease process underlying motor neuron disease.

Yamamoto, T. and T. Imai (1988). A case of diffuse Lewy body and Alzheimer's diseases with periodic synchronous discharges. J Neuropathol Exp Neurol. 47: 536-48. Periodic synchronous discharges were consistently observed in a 68-year-old man with a four-year history of progressive dementia. Pathological examination revealed diffuse atrophy of the brain with remarkable dilatation of the temporal horns. Histologically there were severe changes of Alzheimer's disease and diffuse Lewy bodies (LB), either typical or less distinctive ones without clear halos. Cerebellar LB were also observed in the cerebellum. Four types of abnormal intraneuronal filamentous structures were observed: neurofibrillary tangles, accumulated neurofilaments, thick linear structures studded with ribosome-like dense granules, and fuzzy, thin filaments similar to, but generally wider than, a neurofilament.

Yoshimura, M. (1988). Pathological basis for dementia in elderly patients with idiopathic Parkinson's disease. Eur Neurol. 1: 29-35. We have examined the pathological basis for dementia in elderly patients with Lewy-type Parkinson's disease (PD). 37 (66.1%) of 56 examined cases (mean age of 77.9 years) had evidence of dementia. According to the distribution pattern of Lewy bodies and senile changes, as well as abiotrophic changes of the nucleus basalis of Meynert, nucleus paranigralis and locus ceruleus, demented PD could be subdivided into three groups: (1) demented PD without cerebral alzheimerization (21.6%, 8 cases); (2) demented PD with cerebral alzheimerization (64.9%, 24 cases), and (3) demented PD with combined senile-vascular changes (13.5%). Based on neuropathological findings, damage not to a single, but to multiple neuronal networks including the innominatocortical cholinergic, ceruleocortical noradrenergic as well as mesocortical dopaminergic systems could play a role in the development of dementia in PD. We also discussed the nosological situation of 'diffuse Lewy body disease', regarding it as one distinct disease entity.