Movement Disorders Val. 5 , No. 2, 1990, pp. 143-147, 0 1990 Movement Disorder Society

Diffuse Lewy Body Disease With Dementia and Oculomotor Dysfunction A. J. Lewis and M. J. Gawel Departments of Pathology (Neuropathology) and Medicine (Neurology), Sunnybrook Medical Centre, University of Toronfo, Toronto, Ontario, Canada

Summary: The case is presented of an elderly patient who had dementia, axial rigidity, and bradykinesia with limitation of horizontal and vertical gaze. Pathologicalexamination 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. Key Words: Lewy body disease-Dementia-Gaze.

ma1 resting tremor. Reflexes were preserved and plantar responses were downgoing. He had almost total elimination of upward gaze, and lateral gaze was limited to a maximum deviation of 30” from the midline: Downward gaze was affected little. Reflex eye movements were preserved. He was not sufficiently cooperative to assess such features as eyelid apraxia, and neither formal neuroophthalmological nor formal neuropsychological studies could be performed. Computed tomography scan was reported as showing mild diffuse cortical atrophy. He was admitted for assessment and therapeutic studies. His current medication of carbidopa/ levodopa (Sinemet) 50/200 mg b i d . was stopped for 5 days with no apparent change in clinical state. Carbidopdlevodopa was restarted at a dose of 25/ 100 mg daily, increasing to 25/100 mg t.i.d. Again, no response was noted. A diagnosis of possible progressive supranuclear palsy was made, based on the combination of ocular findings, dementia, axial rigidity, and lack of response to dopaminergic medication. He progressively deteriorated with increasing dementia and rigidity and died 8 months later. Autopsy was performed elsewhere, and the general pathological findings included moderate atherosclerotic heart disease and patchy bronchopneumonia.

With the increasing recognition of cognitive disturbance in Parkinson’s disease (1,2), a small proportion of such cases have been found at autopsy to have Lewy-like bodies in the cortex. These cases of “diffuse Lewy body disease” have usually presented with dementia and axial rigidity but no significant degree of tremor, and several have also had orthostatic hypotension. We present here a case of diffuse Lewy body disease in whom a prominent feature was impairment of both vertical and horizontal gaze. CASE REPORT A 76-year-old Estonian man presented with a 12year history of parkinsonism. There was no family history of neurological disease. He had been treated with levodopa and carbidopa for 8 years with little effect, and had developed memory problems and dementia. On admission he was unable to give a coherent account of his illness. He had profound rigidity, mainly axial, with bradykinesia and mini-

Address correspondence and reprint requests to Dr. A. J. Lewis, Department of Pathology, Sunnybrook Medical Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

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The fixed brain weighed 1,285 g, and was symmetrical with no apparent atrophy. Meninges and vessels were normal. Coronal sections showed slight symmetrical dilatation of the lateral ventricles but were otherwise normal. The brainstem was reduced in size although normally proportioned, and pigmentation of the substantia nigra and Locus ceruleus was reduced. The cerebellum was normal. Multiple blocks were taken, and sectians were stained by Luxol-hematoxylin-eosin and Bielschowsky techniques. Neuronal counts were made of the substantia nigra, locus ceruleus, nucleus of Meynert, and nucleus of diagonal band of Broca, and were compared with similar counts from three neurologically normal controls ages 73, 77, and 80 years. Two 6 km Bielschowsky-stained sections 48 pm apart were counted for each region, using a MOP-40 Video system with digitizer tablet and counting only nucleolated neurons. Because no significant left-right asymmetry was found, each brain region yielded the average of six control and two patient counts. The brainstem showed severe neuronal loss from the substantia nigra and ventral tegmental nucleus (controls 726, patient 67, loss 91%) and from the locus ceruleus (controls 130, patient 22, loss 83%). These areas both showed mild astrocytic hyperplasia and some accumulation of extracellular melanin. They also showed both early and well-formed Lewy bodies (LBs), some of which were intracellular (and often multiple) and others were extracellular. Lewy bodies in small numbers were also seen in the dorsal vagal nuclei, perihypoglossal nuclei, midline pontine neurons including the central superior and dorsal raphe nuclei, Edinger-Westphal nuclei, nuclei of Cajal and Darkshevich, and the interstitial nucleus of the medial longtitudinal fasciculus. No abnormalities were seen in the oculomotor, trochlear, or abducent nuclei. The brainstem contained no neurofibrillary tangles except for a few in the dorsal raphe nucleus. The cerebellum was normal. Sections from the magnocellular basal nuclei showed somewhat moderate neuronal loss (controls 55, patient 29, loss 42%) from the medial part (nucleus of the diagonal band of Broca) but more severe loss (controls 248, patient 67, loss 734%)in the lateral part, corresponding to the nucleus of Meynert. Intracellular (often multiple) and extracellular LBs were seen in both parts, as well as scanty neurofibrillary tangles and neuritic plaques. The amygdalae showed numerous neuritic plaques, of-

Movement Disorders, Vol. 5 , No. 2 , 1990

ten with amyloid cores, but neither neurofibrillary tangles nor LBs were noted. Both hippocampi showed moderate numbers of neuritic plaques and Hirano bodies, but neither neurofibrillary tangles nor granulovacuolar degeneration were seen. No LBs or other pathological changes were found in the basal ganglia, thalamus, hypothalamus, red nucleus, or subthalamic nucleus. All neocortical and limbic cortical sections showed moderate numbers of neuritic plaques but no neurofibrillary tangles. Both intracellular and extracellular (neuritic ?) atypical LBs were present; they were slightly irregular in shape, eosinophilic or amphophilic, and most lacked the characteristic halo. A few pyramidal neurons showed eosinophilic degeneration and swelling without discrete intracytoplasmic bodies. Although widely distributed, cortical LBs were infrequent: some were seen in the superior frontal and temporal polar cortex, and fewer in the frontal polar, cingulate, entorhinal, superior temporal, and superior parietal regions. None were found in the precentral or calcarine cortex.

DISCUSSION We report a patient who had dementia, axial rigidity, bradykinesia and gaze palsies, but little tremor. The clinical diagnosis was possible progressive supranuclear palsy. The pathological findings consisted of typical (LB) in the brainstem (including rostra1 midbrain) and scanty atypical bodies in the cortex. The pathological diagnosis was diffuse LB disease (DLBD), in which LBs are found in the neocortex, always in association with the more typical distribution, which includes the substantial nigra, locus ceruleus, dorsal vagal nucleus, and nucleus of Meynert. They are frequently atypical both on light and electron microscopy, several observers (3-5) having noted that they are irregular and less eosinophilic than usual, and show no clear differentiation of core and halo. These characteristics are apparent in our case. On electron microscopy their fibrillary structure is less organized, especially lacking the radial orientation at the periphery. Of 41 cases of DLBD individually reported (327), 30 male and 11 female, all were rigid, 40 were demented, and 31 did not exhibit unequivocal tremor. All had the usual pathological brainstem findings of idiopathic parkinsonism as well as cortical changes. Other reports (28-30) bring the total number of cases to well over 50. The cause of de-

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mentia in DLBD is uncertain. Most of the cases showed neurofibrillary tangles, neuritic plaques, or both, and a diagnosis of concurrent Alzheimer’s disease was often considered. However, pathological criteria for Alzheimer’s disease are not defined, because the changes differ from those of nondementing aging only in their intensity and distribution and have not been acceptably quantified (3134). Moreover, in DLBD case reports documentation of Alzheimer-like changes are not comparable from case to case, and it is not always clear which areas of limbic or neocortex were examined. Some more recent articles (5,23,24) explicitly stated that the Alzheimer-like changes were not adequate to make a diagnosis of Alzheimer’s disease. In our patient the only neurofibrillary tangles were scattered examples in the dorsal raphe nuclei and nuclei of Meynert, and the numbers and distribution of neuritic plaques were similar to those seen in many of

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our neurologically normal older patients. We consider the Alzheimer-like changes in our case to be age-compatible and highly unlikely to be responsible for the patient’s dementia. It has become clear that parkinsonian patients may exhibit dementia even in the absence of detectable cortical pathology (1,2,35-37), and that many of the clinical features of parkinsonian dementia are dissimilar from those seen in Alzheimer’s disease. The pathogenesis of dementia in these cases is uncertain, but a role for the neuronal depletion usually seen in the nucleus of Meynert and the ventral tegmental nucleus has been considered (38,39). In our case, there is severe neuronal depletion in both the ventral tegmental nucleus and in Meynert’s nucleus. To the best of our knowledge supranuclear palsy has not been previously reported in parkinsonian patients, either with or without cortical Lewy bod-

FIG. 1. Lewy and Lewy-like bodies in the nucleus of Darkshevich (a), paramedian pontine reticular formation @), and neocortex (c and d). (Luxol-hematoxylin-eosin ~400.)

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ies. A variety of oculomotor dysfunctions have been described (40), including moderate limitation of lateral gaze, but without pathological verification. Some difficulty in vertical gaze may occur in the elderly (41). Vertical gaze centers have been described (42) in the rostra1 midbrain (interstitial nucleus of medial longtitudinal fasciculus, nuclei of Cajal and Darkshevich) and lower medulla (perihypoglossal nuclei), and horizontal centers in the paramedial pontine reticular formation. Two reported cases of Parkinson’s disease (43) showed LB in the Edinger-Westphal and Darkshevich nuclei with generalized midbrain gliosis. Our patient showed scattered Lewy bodies with mild neuronal loss and gliosis in all sites mentioned above (Fig. l), and we have seen a similar distribution of globose neurofibrillary tangles in several cases of progressive supranuclear palsy.

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Movement Disorders, Vol. 5. N o . 2, 1990

Diffuse Lewy body disease with dementia and oculomotor dysfunction.

The case is presented of an elderly patient who had dementia, axial rigidity, and bradykinesia with limitation of horizontal and vertical gaze. Pathol...
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