Abstract
We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson’s disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson’s disease (i.e. Parkinson’s disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson’s disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson’s disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson’s disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson’s disease mimic versus typical Parkinson’s disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson’s disease or progressive supranuclear palsy (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson’s disease or progressive supranuclear palsy.
Highlights
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized by the presence of autonomic failure, levodopa unresponsive parkinsonism, and/or cerebellar ataxia.[1,2,3,4] Neuropathologically, abnormal a-synuclein accumulates in oligodendrocytes and, to a lesser extent, neurons in association with neurodegeneration in the striatonigral or olivopontocerebellar structures.[5,6,7] The current diagnostic criteria define two clinical types of MSA: one with predominant parkinsonism (MSA-P), reflecting striatonigral degeneration (SND), and one with predominant cerebellar ataxia (MSA-C) related to olivopontocerebellar atrophy (OPCA)
We examined whether the proportion of MSA-SND or -OPCA differed between MSA-P cases and progressive supranuclear palsy (PSP) mimics, but found no difference
Parkinson’s disease patients (OR: 4.6, 95% confidence interval (CI): 2.4–8.6, P 5 0.01), we found no difference in frequencies of the seven red flag features between Parkinson’s disease mimic and typical Parkinson’s disease
Summary
Multiple system atrophy (MSA) is a sporadic neurodegenerative disease characterized by the presence of autonomic failure, levodopa unresponsive parkinsonism, and/or cerebellar ataxia.[1,2,3,4] Neuropathologically, abnormal a-synuclein accumulates in oligodendrocytes and, to a lesser extent, neurons in association with neurodegeneration in the striatonigral or olivopontocerebellar structures.[5,6,7] The current diagnostic criteria define two clinical types of MSA: one with predominant parkinsonism (MSA-P), reflecting striatonigral degeneration (SND), and one with predominant cerebellar ataxia (MSA-C) related to olivopontocerebellar atrophy (OPCA). Red flag features, defined as clinical features to support a diagnosis of MSA, occur less frequently in clinically atypical MSA.[8,13] previous clinicopathological studies have found that 12–29% and 6% of autopsy-proven MSA cases had an antemortem diagnosis of Parkinson’s disease (Parkinson’s disease mimics) and PSP (PSP mimics), respectively.[14,15,16] atypical MSA cases, who would not have met the current diagnostic criteria for MSA, are likely to be erroneously diagnosed as having Parkinson’s disease or PSP in life. Previous clinicopathological studies have not systematically studied these cases as separate subgroups so that much of the existing clinical literature consists of the clinical features of a mixture of both typical and atypical MSA cases
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