“When DLB, PD, and PSP masquerade as MSA” (Mayo autopsy study)

We’ve been waiting for this sort of article to be published for a long time.  And we need similar articles for all the disorders in our group, not just MSA.  The article calls into question diagnostic criteria (for PD and PSP) and calls into question assumptions made by clinicians (for MSA and PD).

A fascinating article was published in the journal Neurology this week.  It’s from Mayo researchers and focuses on 134 patients who had clinical diagnoses of MSA and donated their brains between 1998 and 2014.  As you may know, Brain Support Network helps people nationally donate a loved one’s brain. We were responsible for about 25% of those 134 (clinical) MSA brain donations!

Of the 134, 125 had adequate medical records to review.  (It’s so important to provide complete medical records when you are donating a loved one’s brain!  Sadly, not everyone does.)  Of the 134 patients, only 62% actually had MSA upon brain autopsy!  The most common misdiagnosis was DLB (37% – wow!), followed by PSP (29%) and Parkinson’s Disease (15%).  (18% had other diagnoses including CBD and vascular parkinsonism.)

Those who actually had DLB and PD, not MSA, had autonomic failure — which is what led the clinicians astray in their diagnosis.  (According to the PD diagnostic criteria, severe dysautonomia in early stages is an exclusionary criteria.)

Those who actually had PSP, not MSA, had cerebellar ataxia — which is what led the clinicians astray in their diagnosis.  (According to the PSP diagnostic criteria, cerebellar ataxia is an exclusionary criteria.)  Apparently, there is an atypical form of PSP called PSP-cerebellar.  The authors note that a recent study “has shown that older onset, early falls, and vertical gaze palsy without dysautonomia may differentiate PSP-C from MSA-C.”

We have certainly seen this in our local support group — people diagnosed with MSA but it turns out they have DLB, PD, or PSP.  Happens all the time.  In our local sample, the diagnostic accuracy is closer to 50%.  Clinicians do not seem to understand that:

(a) autonomic failure can occur in DLB,

(b) hallucinations and dementia do not occur in MSA, and

(c) poor tolerance of levodopa is not the same thing as poor response to levodopa.

The diagnostic accuracy was not different between general neurologists and movement disorder specialists.

Retrospectively, the 125 patients with clinical records were diagnosed with probable MSA, possible MSA, or unknown.  49 patients met the criteria for probable MSA, 35 for possible MSA, and the remaining 41 were not assigned due to lack of clinical information (such as whether the patient was responsive to levodopa).  Of those with probable MSA or possible MSA, the diagnostic accuracy was 71% and only 60% respectively.

The authors note that “Correctly diagnosed patients with MSA had a younger age at onset and age at death than patients with PD or PSP.”  Duration of symptoms wasn’t different.

The authors looked at frequency of clinical features among the various confirmed diagnoses.

“Comparing MSA and DLB, urinary incontinence, limb ataxia, nystagmus, and pyramidal signs were more frequent in MSA. Cognitive impairment and visual hallucinations were more frequent in DLB. Comparing MSA and PD, urinary incontinence was less frequent and visual hallucinations were more frequent in PD. Comparing MSA and PSP, urinary incontinence, constipation, orthostatic hypotension, and RBD were more frequent in MSA. Vertical gaze palsy was more frequent in PSP. Frequency of levodopa responsiveness and average Mini-Mental State Examination score were not different among the groups.”

This aspect of “levodopa responsiveness” is interesting to me because we are always told that one symptom of MSA, PSP, DLB, and CBD is that there’s either no or a poor response to levodopa, as compared to PD.  I asked Dr. Neng Huang, BSN’s medical advisor, about this recently as we have a local group member whose husband was diagnosed with MSA during life but PD on brain autopsy.  Dr. Huang pointed out that “poor tolerance” of levodopa is not the same thing as “poor response.”  Many people have side effects when taking levodopa and want to discontinue it.  This seems to be viewed in the movement disorder specialist’s mind as being non-responsive rather than poor-tolerance.

The abstract makes an interesting statement about DLB.  Apparently not everyone with DLB confirmed through autopsy had dementia during life!  If someone doesn’t have dementia, they don’t qualify for a DLB diagnosis during life.  The authors wonder if the cognitive impairment was overlooked because few of the DLB-masquerading-as-MSA patients had neuropsychological evaluations.

The researchers point out that a 62% diagnostic accuracy isn’t adequate for either patient care or MSA research.  Obviously, we won’t have success with MSA research if only 62% of the participants actually have MSA!

Those are the highlights.  The abstract is copied below.  You can now find the full paper for free online:




Here’s the abstract:

Neurology. 2015 Jul 2.  [Epub ahead of print]

When DLB, PD, and PSP masquerade as MSA: An autopsy study of 134 patients.

Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW.

To determine ways to improve diagnostic accuracy of multiple system atrophy (MSA), we assessed the diagnostic process in patients who came to autopsy with antemortem diagnosis of MSA by comparing clinical and pathologic features between those who proved to have MSA and those who did not. We focus on likely explanations for misdiagnosis.

This is a retrospective review of 134 consecutive patients with an antemortem clinical diagnosis of MSA who came to autopsy with neuropathologic evaluation of the brain. Of the 134 patients, 125 had adequate medical records for review. Clinical and pathologic features were compared between patients with autopsy-confirmed MSA and those with other pathologic diagnoses, including dementia with Lewy bodies (DLB), Parkinson disease (PD), and progressive supranuclear palsy (PSP).

Of the 134 patients with clinically diagnosed MSA, 83 (62%) had the correct diagnosis at autopsy. Pathologically confirmed DLB was the most common misdiagnosis, followed by PSP and PD. Despite meeting pathologic criteria for intermediate to high likelihood of DLB, several patients with DLB did not have dementia and none had significant Alzheimer-type pathology. Autonomic failure was the leading cause of misdiagnosis in DLB and PD, and cerebellar ataxia was the leading cause of misdiagnosis in PSP.

The diagnostic accuracy for MSA was suboptimal in this autopsy study. Pathologically confirmed DLB, PD, and PSP were the most common diseases to masquerade as MSA. This has significant implications not only for patient care, but also for research studies in MSA cases that do not have pathologic confirmation.

© 2015 American Academy of Neurology.
PMID: 26138942