Wenning, Gregor Karl; (1996) A clinicopathological and animal experimental study of multiple system atrophy. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Multiple system atrophy (MSA) is a sporadic degenerative disease of the nervous system causing autonomic failure, parkinsonism, cerebellar or pyramidal signs in any combinations. Its clinical features, prognosis and natural history were studied in: 1) 100 patients with clinically probable MSA seen at the National Hospital for Neurology and Neurosurgery , 2) 35 patients with pathologically proven MSA at the UK Parkinson's Disease Society Brain Bank (UKPDSBB) and 3) 322 patients with pathologically proven MSA reported in the literature. Parkinsonism was the most frequent motor disorder of MSA (84-100%). Motor disturbance was asymmetrical in 74% of patients in the clinical series. Tremor present at rest was observed in 29 to 40% of cases. However, a classical parkinsonian pill-rolling resting tremor was reported in only 7 to 9% of subjects. The levodopa response was not always disappointing. Dyskinesias developed in half of the patients and were predominantly orofacial in nature. Some degree of autonomic failure was present in most MSA patients. It was dominated by impotence in males and urinary incontinence. Pyramidal and/or cerebellar signs developed in 50% of patients. In the three MSA series, the median survival increased from 6.0 years in the literature series through 7.3 years in the UKPDSBB series to 9.3 years in the clinical series. Olfactory function was severely impaired in IPD, but only mildly impaired (MSA) or unimpaired (corticobasal degeneration, Steele-Richardson-Olszewsky syndrome) in atypical parkinsonian syndromes. Most MSA patients had an abnormal sphincter EMG, indicating denervation and reinnervation consistent with anterior hom cell loss in Onufs nucleus, but only 40% had either abnormal nerve conduction studies (17.5%) or abnormal skeletal muscle EMG (22.5%). Visual and magnetic evoked potentials as well as cranial computerized tomography were unhelpful in the diagnosis of MSA. The majority of patients in the UKPDSBB and literature series had moderate or severe degenerative change in the nigrostriatal and olivopontocerebellar system. There was a characteristic pattern of cell loss in the olivopontocerebellar system with predominant cell depletion in inferior olives and pontine nuclei compared to cerebellar Purkinje cells. Cases with pure parkinsonism had more severe cell loss in the nigrostriatal system than patients with pure cerebellar ataxia who had more severe cell loss in the olivopontocerebellar system. A rodent model of SND was developed. A 6-OHDA lesion of the left medial forebrain bundle resulted in ipsiversive rotation to (+)-amphetamine and contraversive rotation to apomorphine. Following an additional ipsilateral striatal lesion with quinolinic acid, (+)-amphetamine-induced ipsilateral rotation persisted, but apomorphine-induced contralateral rotation was reduced or abolished. Rats with combined nigral and striatal grafts showed a reduction or reversal of (+)- amphetamine-induced rotation. This was not observed in animals receiving striatal grafts alone. Apomorphine-induced contraversive rotation was restored after striatal grafts, but only partially in animals receiving sham- or co-grafts. Immunocytochemistry for tyrosine-hydroxylase and DARPP-32 showed mesencephalic and striatal graft survival in most animals. This study demonstrated that combined unilateral lesioning of rodent medial forebrain bundle and striatum results in a characteristic drug-induced rotational response that can be partly restored by mesencephalic striatal co-grafts, and these results may provide a first step towards restorative therapy in MSA.

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