The extrapyramidal illness, on the whole, is eventually more severe than in Parkinson disease, as more than 40 percent of patients are confined to a wheelchair or otherwise severely disabled within 5 years. These observations generally match the findings in the group described by Quinn and colleagues, but they emphasized that pyramidal signs were present in 60 percent. Features that are considered not supportive of the diagnosis of MSA include the typical “pill rolling” tremor of Parkinson disease, hallucinations not induced by medications (more compatible with Lewy body or Parkinson disease), dementia, or family history of ataxia or parkinsonism.
Colosimo and colleagues reviewed the clinical findings in 16 pathologically verified cases of MSA and found that several signs, namely, relative symmetry of the signs and rapid course, the lack of response to l-dopa, absence or minimal amount of tremor, and the early presence of autonomic disorders, reliably distinguished this syndrome from Parkinson disease. These observations are in keeping with our own and we would add that abnormalities of eye movement are not prominent in MSA. Additional features occurring occasionally in MSA are remarked upon in other series; anterocollis or dystonia of the lower facial muscles, for example, is striking in a few cases. It is noteworthy that levodopa has had little or no effect or has made these patients worse early in the disease but we have seen exceptions. The lack of l-dopa effect is probably attributable to the loss of striatal dopamine receptors.
The diagnosis of MSA, especially the form with ataxia, has been aided by imaging techniques. Both MRI and CT scanning frequently show atrophy of the cerebellum and pons in those with cerebellar features. The putamina are hypointense on T2-weighted MRI and may show an increased deposition of iron in the parkinsonian form. In the cerebellar form, a “hot cross bun” sign has been emphasized on MRI; it reflects atrophy of the pontocerebellar fibers that manifest high T2 signal intensity in an atrophic pons. Studies with PET have disclosed impairment of glucose metabolism in the striatum and to a lesser extent in the frontal cortex, a reflection, no doubt, of the loss of functioning neuronal elements in these parts.
Although the cause of this process is not known, and the majority of cases is sporadic, The Multiple-System Atrophy Research Collaboration identified a mutation in COQ2 in a Japanese cohort, coding for a protein involved in the synthesis of coenzyme Q10, in both familial cases and a very small proportion of sporadic ones. The mutation has not been found in European or North American families.
Pathology In recent years, attention has been drawn to the presence of abnormal staining material in the cytoplasm of astroglia and oligodendrocytes and in some neurons as well. These cytoplasmic aggregates have been referred to as glial cytoplasmic inclusions (Papp et al). Although they bear little resemblance morphologically to other discrete inclusions that have come to be accepted as characteristic of certain degenerative CNS diseases (e.g., Lewy bodies), they are composed of α-synuclein (the main component of Lewy bodies). These have become the histopathologic hallmark of MSA as suggested by Chin and Goldman and by Lantos, but their presence is not specific; they have been identified in practically every degenerative disease that has been subjected to sensitive silver impregnation stains. Many types of inclusions are, of course, nonspecific, as, for example, α-synuclein–positive inclusions have been detected in several neurodegenerative syndromes. Appropriate control studies to determine whether the glial inclusions are found in nondegenerative lesions in brain (e.g., at the edge of an infarct) are needed. Also lacking is information about the frequency of these cytoplasmic inclusions in relation to the aging brain.