Brain Vol. 127 No. 12 © Guarantors of Brain 2004; all rights reserved
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From the Archives
Cambridge
Degenerative diseases of the nervous system associated with autonomic failure. By Roger Bannister and D. R. Oppenheimer (From the National Hospital for Nervous Diseases, Queen Square, London, St Mary's Hospital, London and Department of Neuropathology, Radcliffe Infirmary, Oxford.). Brain 1972: 95; 457–474.
Bannister and Oppenheimer make the point that Shy and Drager's 1960 paper on autonomic failure with other neurological disturbances merely drew together the existing literature. Although a first neuro-anatomical account of this disorder was included, Shy and Drager had not linked the clinical features of autonomic dysfunction to neuronal loss in the intermediolateral columns of the spinal cord. Despite 12 subsequent pathological reports, this clinico-pathological correlation was still ambiguous. In some material, cytoplasmic inclusions were apparent at restricted sites; in others, widespread neuronal loss was more widely distributed representing ‘a multiple system atrophy of olivo-ponto-cerebellar or striato-nigral type’. Adding four sporadic cases to their own earlier series of three patients with primary autonomic failure (Bannister R, Ardill L, Fentem P. Defective autonomic control of blood vessels in idiopathic postural hypotension. Brain 1967; 90: 725–746), Bannister and Oppenheimer showed that the autonomic failure is due to loss or de-afferentiation of pre-ganglionic cells, and a feature either of idiopathic paralysis agitans or of multiple system atrophy.
In the best traditions of such papers, rigorous clinical description and physiological and pharmacological measurement of autonomic function laid the foundation for pathological analysis allowing the conclusion that the autonomic failure is symmetrical and progressive, central but without involvement of higher autonomic centres, more efferent than afferent, pre-ganglionic rather than post-ganglionic, and with the suspicion of an added defect on the effector side of the peripheral autonomic nervous system. The four patients, aged between 35 and 65 years at presentation, showed autonomic failure plus parkinsonism—with or without pyramidal tract and brainstem involvement—progressing to death within 4–10 years. Three of their four cases had atrophy affecting the striatum, substantia nigra, pontine nuclei, cerebellar cortex, inferior olives, medial vestibular and dorsal vagal nuclei, lower cranial nerve nuclei, intermediolateral columns and posterior root ganglia; in the remaining patient, there was restricted nigral degeneration with Lewy body neuronal inclusions. Drawing together the evidence from all published cases offering clinico-pathological correlations, the high prevalence of cell loss in the intermediolateral columns of the spinal cord and in the dorsal vagal nuclei was apparent. The hypothalamus was uninvolved. Given the widespread neuronal loss, Bannister and Oppenheimer debated, but soon rejected, the hypothesis that the degeneration is due to ischaemia following repeated faints and falls.
Their analysis pointed clearly to two diseases with related clinical phenotypes. Collating the entire literature identified two patterns. There were five cases of autonomic failure, occurring in isolation or with parkinsonism but no ataxia or more distributed symptomatology. These clinical features were the expression of neuronal loss in the nigrostriatal pathway and autonomic ganglia, with the pathological signature of Lewy bodies. Conversely, eleven patients had autonomic failure, parkinsonism and more widespread neurological features. In this group, the pathology revealed neuronal loss without inclusions in the striatum, substantia nigra, pontine nuclei, inferior olives, cerebellar cortex and autonomic ganglia. The three remaining cases showed overlap between these discrete patterns. Positive predictive features for making the distinction were later age of onset and a better prognosis in the Lewy body-positive cases. Thus, Bannister and Oppenheimer were ‘splitters’: three existing types of Parkinson's disease (idiopathic, post-encephalitic and ‘vascular’) existed to which could now be added the two distinct variants of multiple system atrophy—parkinsonism with olivopontocerebellar degeneration, or with striatonigral degeneration. Biochemical characterization of tissue and classifications based on mechanisms were then in their infancy. Bannister and Oppenheimer could only speculate on what might be found, and suggest how these pathological changes affected the physiological and pharmacological properties of local functional circuits. They favoured a primary defect of neurons projecting onto pre-ganglionic nuclei with secondary trans-neuronal degeneration across autonomic synapses.
Thirty-two years on, Sir Roger recalls their mutual surprise at the extent of cell loss in intermediolateral column based on Oppenheimer's rigorous morphological criteria for the definition of these neurones, and how the examination in detail of a very few cases illuminated the neurology of parkinsonian syndromes – the clinical discussion periodically interrupted by David Oppenheimer's passages on the cello kept in his office. With this paper, the heterogeneity of parkinsonism was on a sound descriptive and pathological basis but not until the late 1990 s did advances in neurobiology reveal the molecular structure of the Lewy body as aggregates of alpha synuclein (Spillantini MG, Schmidt ML, Lee VM et al. Alpha-synuclein in Lewy bodies. Nature 1997: 388: 339–40), later extended to the demonstration of alpha synuclein inclusions in oligodendrocytes from cases of multiple system atrophy.
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