Pulmonary embolism: an under-recognized yet frequent cause of death in parkinsonism.

There are very few detailed reports on the cause of death in patients with Parkinson syndrome, and most reports lack postmortem verification. Pulmonary embolism has been reported as an infrequent terminal event. We reviewed the results of 60 complete autopsies performed on patients with Parkinson syndrome personally cared for at our institution. Pulmonary embolism was second only to pneumonia as the most common cause of death overall.

Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects.

In order to determine whether, besides the severe striatal dopamine (DA) loss, other brain neurotransmitter changes may be a constant biochemical feature of idiopathic Parkinson's disease (iPD), we measured the concentration of the three major brain monoamines noradrenaline (NA), DA, and serotonin (5-HT) and their metabolites in five rostro-caudal subdivisions of the hypothalamus of eight control patients and nine patients with morphologically confirmed iPD. In the whole hypothalamus of the iPD patients we found a mild to moderate mean reduction of NA (-52%, P < 0.05), DA (-25%), and 5-HT (-26%). At the subregional level, the most consistently affected area was the intermediate subdivision of the hypothalamus proper where all three monoamines were statistically significantly reduced. Evaluation of individual patient values indicated that, in contrast to the constant and severe DA reduction present in putamen of each of the iPD patients (DA loss ranging from 96% to 99%), several of these patients had whole (and subregional) hypothalamic monoamine values well within the range of controls. We conclude that, although possibly involved in autonomic and/or endocrine disturbances in some patients with iPD, none of the observed monoamine changes in the hypothalamus is an obligatory feature of iPD. Our study demonstrates the need for evaluation of individual patient values rather than mean differences in order to permit valid conclusions to be drawn as to whether an observed neurochemical change can be regarded as specific to a given brain disorder.

Alzheimer's disease and idiopathic Parkinson's disease coexistence.

Idiopathic Parkinson's disease (IPD) and Alzheimer's disease (AD) are common neurologic diseases of old age. Parkinson syndrome is easy to recognize even at an early stage, but identifying early AD is often difficult. Accurate clinical diagnosis is important for assigning the prognosis and for studies aimed at assessing the efforts to slow down progression of these diseases. During 22 years, we identified six patients who had clinical features of parkinsonism and dementia and who at autopsy had both IDP and AD and 20 parkinsonian patients without dementia who at autopsy had only IPD. The clinical profile in these two groups was compared. The onset of Parkinson syndrome in the patients with dual pathology had a bimodal distribution--before or after age 65 years. In the three cases with onset before age 65 years, there was sequential evolution of IPD and AD. In contrast, those older than 65 years at onset manifested the clinical features of both IPD and AD simultaneously. The mode of onset and the dominant parkinsonian features in the three patients with sequential clinical evolution were similar to those seen in the nondemented IPD cases; however, lack of self-confidence and inability to make decisions resulted in considerably greater functional disability than could be accounted for by parkinsonism alone. These characteristics may be helpful in early recognition of dual IPD and AD pathology. Psychiatric side effects of levodopa therapy were more common in those with dual pathology than in those with IPD alone.

Fahr's disease associated with astrocytic proliferation and astrocytoma.

This report documents the neuropathological findings of astrocytic proliferation and astrocytoma in a patient with Fahr's disease. At autopsy, there was extensive bilateral symmetrical calcification involving basal ganglia, sulcal depth of the cerebral cortex, and dentate nuclei of the cerebellum. A large low-grade astrocytoma was identified in the left parietal lobe. Astrocytic proliferation was also noted in the areas of early calcification and at the margins of large calcareous deposits, away from the tumor.

Significance of parkinsonian manifestations in essential tremor.

Parkinsonian features, notably resting tremor may be seen in some essential tremor patients but the significance of those is unknown. The reported risk of parkinsonism in essential tremor patients varies from being unchanged to 35 times higher than expected. We studied 9 patients with essential tremor who had autopsies. In 6 of the 9 (66%) resting tremor was noted and in 3 (33%) cases fully developed parkinsonism was noted. The parkinsonism was consequent to neuroleptic usage in 2 and to basal ganglia status lacunaris and cribrosus in one case but no consistent abnormalities were noted in 3 essential tremor only and 3 essential tremor plus resting tremor cases. We conclude that resting tremor is an age-related natural evolution in some essential tremor patients. We recommend that the additional diagnosis of parkinsonism in the essential tremor be made only when resting tremor, bradykinesia and rigidity are all evident. The risk of ideopathic Parkinson's disease in essential tremor cases is similar to the general population.

Clinicopathologic observations in essential tremor: report of six cases.

Essential tremor (ET) is the most common pathologic tremor, but only eight cases have been studied pathologically. We report detailed clinical and neuropathologic studies of six additional patients. We did not find any neuropathologic lesions that might be specific for ET. Moreover, there were no abnormalities of the substantia nigra consistent with Parkinson's disease. The neuropathologic substrate of ET remains unknown.

Accuracy of clinical diagnosis in parkinsonism--a prospective study.

Clinical diagnosis of Parkinson's syndrome (PS) is reasonably easy in most cases but the distinction between different variants of PS may be difficult in early cases. The correct diagnosis is not only important for counselling and management of patients but also in conducting pharmacological and epidemiological studies. There is very little critical literature on the pathological verification of the clinical diagnosis in PS. We report our 22 years experience to address that issue. Between 1968 and 1990, 65 PS patients came to autopsy. Complete data are available in 59 (M-50, F-19) cases. The initial diagnosis made by a qualified neurologist was idiopathic Parkinson's disease (IPD) in 43 cases. Of those 28 (65%) had Lewy body pathology. After a mean duration of 12 years the final diagnosis was IPD in 41 cases which was confirmed in 31 (76%). The IPD could not be clinically distinguished from cases with severe substantia nigra neuronal loss without inclusions or from those with neurofibrillary tangle inclusions and neuronal loss at the anatomical sites typically involved in IPD. All progressive supra-nuclear palsy, olivopontocerebellar atrophy, Jakob-Creutzfeldt's disease and the majority of the multiple system atrophy cases were diagnosed correctly during life. The correct clinical diagnosis in most non-IPD variants of PS was possible within 5 years of onset (range: 2 months to 18 years). We recommend that studies aimed at including only the IPD cases restrict the enrollment to those cases that have had PS motor manifestations for five years or longer duration.

Occurrence of resting tremor in Parkinson's disease.

Several previous studies have noted that resting tremor (RT) is absent in 10% to 30% of idiopathic Parkinson's disease (IPD) patients. We report our 22-year observations in 47 pathologically verified parkinsonian patients. In all the IPD cases with median follow-up of 3.7 years, RT was noted on at least one evaluation. Among other parkinsonian syndrome variants characterized by widespread subcortical pathology with median follow-up of 2.86 years, RT was seen in 31% of the cases. Our data indicate that the sites typically involved in IPD are sufficient to produce RT.

Levodopa efficacy and pathological basis of Parkinson syndrome.

Levodopa is the most effective drug for symptomatic control of Parkinson syndrome (PS). We report a 22-year clinicopathological study of 59 PS cases. Of the entire group, 37 (63%) had an adequate trial on levodopa. Some improvement was noted on that drug in 24 (65%) cases. Improvement was seen in 94% of idiopathic Parkinson's disease cases as well as in all cases in which the pathology was characterized by neuronal loss in the substantia nigra without Lewy body inclusions. Improvement was also noted in 60% of patients with the dual pathology of idiopathic Parkinson's disease and Alzheimer's disease, and in one-third of early multiple system atrophy cases. We conclude that improvement on levodopa is a strong indication that the pathological basis of the parkinsonism is the damage to substantia nigra neurons. A favorable response to levodopa, however, is not an indication of idiopathic (Lewy body) Parkinson's disease.

Regional metal concentrations in Parkinson's disease, other chronic neurological diseases, and control brains.

Metal deficiency or toxicity states have been recognized as a cause of several neurological disorders and are suspected in others. We analyzed four brain regions (frontal cortex, caudate nucleus, substantia nigra, and cerebellum) in 36 human brains for concentrations of 24 metals (Ag, Al, As, B, Be, Ca, Cd, Co, Cr, Cu, Fe, K, Pb, Mg, Mn, Mo, Na, Ni, P, Se, Ti, V, W, Zn). Regional metal concentrations, measured using atomic absorption and atomic emission spectroscopy, were compared between 9 Parkinson's disease (PD) brains, 15 brains from patients with other chronic neurological diseases, and 12 control brains. No significant metal concentration differences were noted between brains from PD and other chronic neurologic disease. However, parkinsonian brains (PD and parkinsonism secondary to neurofibrillary tangle disease) showed lower concentrations of magnesium in the caudate nucleus and copper in the substantia nigra than control brains. These findings may represent an etiologically important clue to parkinsonism.

Parkinsonism and neurofibrillary tangle pathology in pigmented nuclei.

Four parkinsonian patients had neurofibrillary tangles, neuronal loss, and gliosis restricted to the substantia nigra and locus ceruleus. No Lewy body inclusions or other neuropathological changes accounting for parkinsonism were found in any of these patients. Their clinical features were characterized by an early age of onset, absence of dementia, absence of other neurological abnormalities, good response to drug therapy, and a long, slowly progressive course of illness. None of the patients had any history of encephalitis. These patients either represent a forme fruste of postencephalitic parkinsonism or a new entity thus far not described.

A new type of neuronal cytoplasmic inclusion: histological, ultrastructural, and immunocytochemical studies.

A novel type of non-viral cytoplasmic inclusion is described, which was seen in virtually every neuron in the brain and spinal cord of a child with a presumed metabolic disorder whose clinical picture and CNS pathology were compatible with Leigh Syndrome. The ovoid to round inclusions were sharply demarcated, measuring up to 11 microns in diameter. They showed no distinctive staining with a battery of routine histological techniques. The ultrastructural features are unique, comprising non-membrane-bounded aggregates of randomly oriented plate-like structures with parallel linear densities depicting a periodicity of 11-16 nm. Immunocytochemical studies revealed strong staining with antisera to tropomyosin and weaker staining with antisera to actin. There was no reactivity with antibodies against neurofilaments, microtubules and their associated proteins, paired helical filaments, ubiquitin, vinculin or alpha-actinin. It is postulated that the metabolic disorder resulted in a neurodegenerative condition which manifested pathologically with lesions compatible with those of Leigh Syndrome. Associated with the condition was the discrete accumulation of cytoplasmic proteinaceous components, including tropomyosin, in the form of neuronal cytoplasmic inclusions possibly resulting from an alteration of the neuronal cytoskeleton.

Familial oculoleptomeningeal amyloidosis. Report of a new family with unusual features.

A family had a dominantly inherited amyloid angiopathy that involved the meninges of the brain and spinal cord, retina, vitreous humor, peripheral nerves, and systemic organs. Clinical features included hemiplegic migraine, periodic obtundation, psychosis, seizures, intracerebral hemorrhage, myelopathy, visual impairment, deafness, and peripheral neuropathy. Pathological findings consisted of amyloid deposition in the leptomeningeal and retinal vessels, in the vitreous humor, and in perivascular tissue throughout the body. Evaluation of the amyloid showed it to be a transthyretin (prealbumin). A brief course of plasmapheresis produced a short-lived decrease concentration in circulating transthyretin.

Cerebral malignant tumors with ependymal and choroidal differentiation in two siblings.

Two siblings in a family without a history of phacomatosis or cerebral tumors developed malignant tumors in the posterior fossa at age 28 months and in the left cerebral hemisphere at age 15 months, respectively. Dual ependymal and choroid plexus epithelium differentiation was established by histological, ultrastructural, and immunocytochemical studies. The development of this rare tumor in siblings suggests an inherited predisposition, a common environmental insult, or both.

Shy-Drager syndrome: the transitional variant.

The clinicopathological features of a patient with the transitional variant of the Shy-Drager syndrome is described. The only previously reported case of the transitional variant was reexamined and pathological similarities to the present case are reviewed. Both patients exhibited features of Parkinson's disease with Lewy bodies in the substantia nigra and locus ceruleus. Striato-nigral degeneration and olivo-ponto-cerebellar atrophy were evident in both cases. They can thus be considered as transitional forms of the Shy-Drager syndrome with feature of both Parkinson's disease and multiple system atrophy.

Regional distribution of metals in human brain.

Progress in understanding the role of metals in diseases of the nervous system has been hampered to a large extent by a lack of normal metal concentration values in the human brain. Since several metals interact metabolically, concurrent metal levels are essential for clinical correlation. We are reporting a simultaneous analysis of 24 metals in 4 different areas of 9 human brains. Our data on previously studied metals are comparable to the past observations. Therefore, we suggest the values of all metals reported here should be regarded as "normal" for ages 58-78 years.

Elevated gamma-aminobutyric acid level in striatal but not extrastriatal brain regions in Parkinson's disease: correlation with striatal dopamine loss.

We measured the concentration of gamma-aminobutyric acid (GABA), glutamic acid, and o-phosphoethanolamine in autopsied brain of 9 patients who died with idiopathic Parkinson's disease and 10 control subjects. In the control striatum GABA showed an uneven rostrocaudal distribution pattern with rostral subdivisions containing about 40 to 50% higher levels. When compared with controls, GABA concentrations in Parkinson's disease striatum were generally elevated. The GABA elevation was most pronounced in the caudal subdivision of the putamen; this striatal subdivision also showed the most severe dopamine loss. We observed in the caudal putamen a significant negative correlation between the (elevated) GABA and (reduced) dopamine levels (the latter expressed as the sum of dopamine plus 3-methoxytyramine). Milder nonsignificant elevations of GABA levels were observed in intermediate and rostral putamen followed by the caudate head subdivisions. GABA levels were normal in all extrastriatal brain areas examined. Striatal glutamic acid levels were markedly elevated in 3 of the 9 patients with Parkinson's disease. We suggest that the altered GABA metabolism in the striatum, especially the putamen, is consequent to the nigrostriatal deficiency in this disorder. This secondary change in striatal GABA function is likely to contribute to the basal ganglia dysfunction produced by the striatal dopamine loss and thus may be related to certain aspects of parkinsonian symptomatology.

Malignant intracranial fibrous histiocytomas. Histologic, ultrastructural and immunohistochemical studies of two cases.

Two cases of malignant intracranial fibrous histiocytoma are presented. In Case 1 the tumour arose from the meninges and showed a disseminated spread throughout the neuroaxis. In the second case the tumour appeared to arise from within the brain substance. In this case surgical intervention and radiotherapy appeared to have achieved a cure, since no residual tumour was found at autopsy. The tumours were examined using ultrastructural and immunohistochemical techniques, which appeared advantageous in delineating this rare tumour from other intracranial neoplasms.