434 J Neurol Neurosurg Psychiatry 2000;68:434–440 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.4.434 on 1 April 2000. Downloaded from What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson’s disease? G K Wenning, Y Ben-Shlomo, A Hughes, S E Daniel, A Lees, N P Quinn Abstract Multiple system atrophy (MSA) is a clinically Objectives—Few studies have attempted and pathologically distinctive neurodegenera- to identify what premortem features best tive disease.1 Historically, it has been de- diVerentiate multiple system atrophy scribed in three diVerent ways: olivopontocer- (MSA) from Parkinson‘s disease (PD). ebellar atrophy (OPCA),2 striatonigral These studies are limited by small sample degeneration (SND),3 and the Shy-Drager size, clinical heterogeneity, or lack of syndrome, (SDS).4 The considerable clinico- postmortem validation. We evaluated the pathological overlap among these three sub- sensitivity and specificity of diVerent groups led Graham and Oppenheimer to clinical features in distinguishing patho- introduce MSA as an umbrella term.5 There is logically established MSA from PD. now general agreement that MSA is one Methods—One hundred consecutive cases distinct entity among many multisystem de- of pathologically confirmed PD and 38 generations. In recent years glial cytoplasmic cases of pathologically confirmed MSA in inclusions have been described in oli- one Parkinson’s disease brain bank were godendrocytes that are present in the brains of included. All cases had their clinical notes all patients with MSA of whatever reviewed by one observer (AH). Clinical denomination.6–8 This abundant presence of features were divided into two groups: glial cytoplasmic inclusions in all clinical sub- those occurring up to 5 years after onset of types of MSA has introduced further grounds disease and those occurring up to death. for considering SDS, SND, and many cases of Statistical analysis comprised multivari- sporadic OPCA together as MSA. ate logistic regression analysis to choose It is often diYcult to distinguish clinically and weight key variables for the optimum between MSA and Parkinson’s disease, par- predictive model. ticularly early in the disease. In the United Department of Results—The selected early features and Kingdom Parkinson’s Disease Society Re- Neurology, University their weightings were: autonomic features search Centre (UKPDSRC) study of 35 cases Hospital, Innsbruck, of MSA, one third of the patients died with a Austria (2), poor initial levodopa response (2), G K Wenning early motor fluctuations (2), and initial misdiagnosis. Even when a correct premortem rigidity (2). A cut oV of 4 or more on the diagnosis of MSA had been made, this still took http://jnnp.bmj.com/ 9 Department of Social ROC curve resulted in a sensitivity of an average of 4 years after presentation. Poor Medicine, University 87.1% and specificity of 70.5%. A better diagnostic sensitivity for MSA among move- of Bristol, Bristol, UK ment disorder specialists has been reported by Y Ben-Shlomo predictive model occurred if the following 10 features up to death were included: poor Litvan et al. Mean rater sensitivity in their Austin and response to levodopa (2), autonomic fea- study was 56% at the first clinic visit and this Repatriation Medical tures (2), speech or bulbar dysfunction had increased to 69% by the last visit. Centre, Heidelberg (3), absence of dementia (2), absence of However, primary neurologists, who followed West, Victoria, on September 28, 2021 by guest. Protected copyright. levodopa induced confusion (4), and falls up the patients clinically, achieved even lower Australia sensitivities of only 25% and 50% at the first A Hughes (4). The resulting ROC curve based on individual scores showed a best cut oV and last visit respectively. The reasons for such Parkinson’s Disease score of at least 11 of 17 (sensitivity 90.3%, poor diagnostic accuracy have not been studied Society Research specificity 92.6%). systematically. However, overlapping clinical Centre, London, UK 11–12 Conclusions—Predictive models may help features probably contribute. For example, S E Daniel asymmetry of the cardinal features of parkin- A Lees diVerentiate MSA and PD premortem. sonism normally associated with PD is also Hitherto poorly recognised features, sug- 13 Institute of Neurology, gestive of MSA, included preserved cogni- seen in most patients with MSA. In addition, Queen Square, tive function and absence of psychiatric atypical features that suggest non-idiopathic London, UK eVects from antiparkinsonian medication. disease such as poor response to levodopa, N P Quinn autonomic failure, cerebellar incoordination, Diagnostic accuracy was higher in those and pyramidal signs as well as severe immobil- Correspondence to: models taking into account all clinical fea- ity may all take several years to become evident. Professor N Quinn, tures occurring up to death. Further stud- University Department of However, as prognosis and treatment response ies need to be based on new incident Clinical Neurology, Institute is diVerent for patients with MSA compared of Neurology, Queen Square, cohorts of parkinsonian patients with sub- with PD14 15 a correct diagnosis is important. London WC1N 3BG, UK sequent neuropathological evaluation. We are aware of only three previous studies (J Neurol Neurosurg Psychiatry 2000;68:434–440) Received 20 April 1999 and which have attempted to identify what premor- in revised form 27 October 1999 Keywords: multiple system atrophy; Parkinson’s dis- tem features best diVerentiate MSA from Accepted 3 December 1999 ease; clinicopathological study; diVerential diagnosis PD.10 16 17 All three have had 20 or fewer cases What distinguishes definite multiple system atrophy from Parkinson’s disease? 435 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.4.434 on 1 April 2000. Downloaded from of MSA and have compared these either to clinical, (c) drug side eVects, and (d) miscella- other parkinsonian patients10 or to various other neous features. In some cases, the same neurological conditions.10 17 The study by Alba- variable was classified twice, either at onset or nese et al provides the most realistic setting early in the course of the disease, or alterna- as it evaluated consecutive parkinsonian tively at any time in the clinical history. This outpatients.16 However, features were compared distinction is useful in determining which with a clinical diagnosis, partially based on those features may be early predictors. features, without pathological confirmation, Autonomic failure was defined as the therefore resulting in an inherent circularity. In presence of any of the following: symptomatic the present study we aimed to determine the postural hypotension, urinary urge inconti- sensitivity and specificity of diVerent features in nence, faecal incontinence, urinary retention distinguishing pathologically established MSA requiring catheterisation, or persistent erectile from PD. We also determined the best combina- failure. tion of predictor variables using multivariate Akinesia (usually with rigidity) was necessary methods in an attempt to produce a fairly simple for a diagnosis of parkinsonism. However, clinical diagnostic index. tremor was neither obligatory nor suYcient on its own. Response to levodopa, based on the Methods estimate in the records of either the patient or SELECTION OF SUBJECTS physician, or both, was graded on a four point We studied 100 consecutive patients with scale (1=0%-29%, 2=30%-49% (both “poor”), pathologically confirmed PD and 38 patients 3=50%-69% (“good”), and 4=70–100% (“ex- with pathologically confirmed MSA, whose cellent”)). Subsequently, for the purpose of brains were collected by the Parkinson’s analysis, levodopa response was defined as poor Disease Society Brain Bank (PDSBB) in Lon- (0%-49%) or definite (50%-100%). Early fluc- don, UK, between June 1987 and July 1993. tuations, dyskinesias, neuropsychiatric toxicity, Most of the patients with PD and some of the and dementia were defined as occurring within 5 patients with MSA were registered donors and years of onset. Cerebellar features recorded many had been prospectively assessed annually included limb ataxia, intention tremor, gait by neurologists associated with the PDSBB. ataxia, and nystagmus, in isolation or in combi- About a third of the patients with MSA, all with nation. Pyramidal features comprised equivocal a clinical diagnosis of MSA, had been seen in or extensor plantar responses and hyperreflexia. life by one of us (NPQ). Selected clinicopatho- Speech or bulbar features comprised dysarthria, logical features of some of the patients with PD dysphagia, and excessive sialorrhoea. “Other or MSA have been previously reported.9 11 17–22 signs” is a catch all heterogeneous category that included any other features seen that were atypi- POSTMORTEM DIAGNOSIS cal for PD. The defining histological characteristics for PD were depletion of pigmented neurons in the STATISTICAL METHODS substantia nigra and locus ceruleus, with Lewy For each variable, the sensitivity, specificity, bodies in some remaining nerve cells and else- and positive and negative predictive values where in the nervous system. The striatum was were calculated as well as the ÷2 value. The normal and there were no glial cytoplasmic diagnostic utility of each variable to correctly http://jnnp.bmj.com/ inclusions or additional pathology to account detect MSA is for a combination of pathologi- for the presence of parkinsonism.18