Thirty Years of Multiple System Atrophy (1989–2019): Are We Better at Diagnosing It Than Previously?

It has been 30 years since Quinn, referring to Graham and Oppenheimer’s proposal, suggested multiple system atrophy (MSA) as a unifying term for the conditions previously described as striatonigral degeneration, olivopontocerebellar atrophy, and ShyDrager syndrome, and outlined the first set of diagnostic criteria. Despite our advances in understanding this disease, today there is still no reliable biomarker for a definite diagnosis in life, which is still neuropathological. Miki and colleagues analyzed the clinical records and pathology of 203 patients diagnosed in life with MSA. The aims of this article were: (1) to identify clinical features predictive of MSA pathology and thus useful in differentiating MSA from its lookalikes, and (2) to evaluate the utility of red flags (which were previously validated only as differentiators of MSA with predominant parkinsonism (MSA-P) from Parkinson’s disease) in the differential diagnosis between MSA-P as well as MSA with predominant cerebellar ataxia (MSA-C) and its mimics. The main findings were: (1) diagnosis of MSA was confirmed at postmortem examination in 79% of the cases; misdiagnosed patients mainly had Lewy body disease (LBD) or progressive supranuclear palsy (PSP) pathology; (2) pill-rolling tremor was highly unusual in pathologically confirmed MSA and PSP; (3) positive pull test was not useful in distinguishing between MSA and MSA lookalikes; (4) early ataxia, stridor, early dysphagia and early falls were reasonable differentiators between MSA and LBD, whereas ataxia and stridor between MSA and PSP; (5) early autonomic dysfunction favored MSA over PSP; (6) severe orthostatic hypotension and/or urinary incontinence requiring urinary catheter in patients with atypical parkinsonism should prompt consideration of MSA; (7) several red flags (orofacial dystonia, inspiratory sighs, contractures of hands or feet, polyminimyoclonus) proved useful in predicting MSA pathology, even when applied to MSA-C patients; (8) cognitive impairment and hallucinations were less common in MSA than in other forms of atypical parkinsonism, and this may account for the lower rate of institutionalization; however, when cognitive impairment was present, MSA patients reached that disability milestone earlier than LBD; (9) 40% of MSA patients presented a beneficial response to levodopa, and it was not significantly different when compared to other conditions. This study is important first because it validated clinical criteria including red flags in a large population of autopsy-proven MSA patients against a cohort of atypical LBD and PSP that resembled MSA in life, thus reinforcing the diagnostic power of these features and reminding clinicians to make an effort to look for and pick all these signs. The differentiating value of the red flags is likely to be even greater when compared to typical LBD and PSP patients. Second, it challenged the reliability of some features that have been considered so far highly suggestive of MSA, such as poor levodopa response and preserved cognition, which were instead found to be the best predictors of MSA in the retrospective analysis of 38 autopsy-proven cases by Wenning and colleagues. These topics were also discussed in an article by the Movement Disorder Society MSA Study Group, suggesting a need for revisions in the current diagnostic criteria. In conclusion, although the mainstays of “the beast” have not changed during 30 years of research, we have certainly broadened our knowledge about it. Despite the changes in the two consensus criteria that followed since 1989, we are currently no better at predicting MSA pathology, and the variant presentations of both MSA and other atypical parkinsonisms further increase the clinical overlap and potential for misdiagnosis. Therefore, MSA diagnostic criteria need to be implemented to better define this highly complex and multifarious disease.