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.