10ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:160-166

Clinicopathological study of 35 cases of multiplesystem atrophy

G K Wenning, Y Ben-Shlomo, M Magalhaes, S E Daniel, N P Quinn

AbstractThe clinical and pathological features of35 cases with multiple system atrophycollected in the United KingdomParkinson's Disease Society Brain Bank(UKPDSBB) between 1985 and 1992 havebeen analysed. The median age of onsetwas 55 (range 33.3-75-8) years andmedian survival was 7-3 (range 2-1-11.5)years. Parkinsonism, usually asymmet-ric, occurred in all, and autonomic fail-ure in all but one case. Cerebellar signswere noted in 34% and pyramidal fea-tures in 54% of the cases.

Glial cytoplasmic inclusions werefound in all cases with adequate fixation.Lewy bodies were detected in three cases.The substantia nigra was (usuallyseverely) depleted of cells in all cases.With two exceptions the putamen wasatrophic; the caudate and pallidum wereless commonly and less severely affected.

Overall nigrostriatal cell loss corre-lated with severity of disease at the timeof death. The latest, but not the best,recorded levodopa response tended to beinversely related to the degree of puta-minal degeneration. The olivopontocere-bellar system was involved in 88% of thecases, the cerebellar vermis usually beingmore severely affected than the hemi-spheres. The presence of associated cere-bellar pathology was, however, unrelatedto the presence of cerebellar signs in life.

(J Neurol Neurosurg Psychiatry 1995;58:160-166)

Keywords: multiple system atrophy; striatonigraldegeneration; olivopontocerebellar atrophy.

UniversityDepartment ofClinical Neurology,Institute ofNeurology,Queen Square,London WC1N 3BG,UKG K WenningY Ben-ShlomoM MagalhaesS E DanielN P QuinnCorrespondence to:Dr N P Quinn.Received 23 May 1994and in revised form2 August 1994Accepted 10 August 1994

Multiple system atrophy is a sporadic degen-erative disease of the nervous system thatcauses any combination of parkinsonism,autonomic and cerebellar dysfunction, andpyramidal signs.'-3 Pathologically, it is charac-terised by varying degrees of cell loss and glio-sis principally affecting the substantia nigraand putamen (striatonigral degeneration),pontine nuclei, cerebellar Purkinje cells, andinferior olives (olivopontocerebellar atrophy),intermediolateral cell columns of the thoracicspinal cord, and Onuf's nucleus in the sacralcord.45 The medical literature contains more

than 300 pathologically established cases.

Most reports involve only a few cases, how-ever, or give limited clinical information to

correlate with the pathological findings.

Materials and methodsThe United Kingdom Parkinson's DiseaseSociety Brain Bank (UKPDSBB) hadreceived 370 brains of patients with parkin-sonism by October 1992. Of these, 35 (9 5%)showed the pathological changes of multiplesystem atrophy and form the basis of thispaper. Thirteen of these patients, all with aclinical diagnosis of multiple system atrophy,had been seen in life by one of us (NPQ). Theremaining 22 had been followed up by otherphysicians, 17 of whom were neurologists.Clinicopathological details of nine and anassessment of levodopa response in 21 ofthese cases have previously been reported.67

CLINICAL DATAThe clinical features of the 35 cases wereabstracted from clinical records by GKW andentered on a database for subsequent analysis.If no mention of a clinical feature could befound in the notes, then the feature was codedas absent. In some cases, a patient may havehad such a feature but this was either not eval-uated or recorded. Hence the proportions ofpatients with the presence of a feature shouldbe treated as a "conservative" estimate.

Autonomic failure was defined as the pres-ence of any of the following: symptomaticpostural hypotension, urinary urge inconti-nence, faecal incontinence, urinary retentionrequiring catheterisation, or persistent erectilefailure. Severe autonomic failure, for men,was defined as two or more of the followingfive symptoms: syncope, urinary inconti-nence, faecal incontinence, urinary retention,and erectile failure. For women, the definitionof severe autonomic failure was based on twoor more of the symptoms, excluding erectilefailure.

Akinesia (usually with rigidity) was neces-sary for a diagnosis of parkinsonism. Tremorwas neither obligatory, however, nor sufficienton its own. The Hoehn and Yahr stage forcases was derived from the notes. Early loss ofbalance was defined as Hoehn and Yahr stageIII or worse within three years of onset ofsymptoms. Response to levodopa, based onthe recorded estimate in the records of eitherthe patient, or physician, or both, was gradedon a four point scale (1 = 0-29%, 2 =

30-49% (both poor), 3 = 50-69% (good), 4= 70-100% (excellent)). Initial, best, and latestrecorded response to levodopa were noted.Response data on four cases were missing.

Cerebellar features that were recordedincluded limb ataxia, intention tremor, gaitataxia, and nystagmus, in isolation or in

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Clinicopathological study of35 cases of multiple system atrophy

Figure 1 Frequency ofvarious combinations ofclinicalfeatures in 35 casesofpathologically confirmedmultiple system atrophy.Park = parkinsonism;Auto = autonomic failure;Cereb = cerebellar signs;Pyr = pyramidal signs.

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combination. Pyramidal features comprisedequivocal or extensor plantar responses andhyperreflexia. Equivocal plantar responsesand hyperreflexia had to occur together to beaccepted as pyramidal signs.

Patients were diagnosed as clinically proba-ble multiple system atrophy of striatonigraldegeneration type if parkinsonism was theonly (pure striatonigral degeneration type) or

predominant (predominant striatonigraldegeneration type) motor syndrome. Multiplesystem atrophy of olivopontocerebellar typewas diagnosed if a cerebellar syndrome wasthe only (pure olivopontocerebellar atrophytype) or predominant (predominant olivopon-tocerebellar atrophy type) motor syndrome.

In addition, clinical notes were screened fora variety of other symptoms or signs includingdiplopia, hypometric saccades, reduced hori-zontal or vertical gaze, dysarthrophonia, dys-phagia, excessive snoring, respiratory stridor,myoclonus, disproportionate antecollis, andsensory dysfunction (subjective or objective).Age at onset of autonomic failure, parkinson-ism, cerebellar, and pyramidal signs wererecorded for analysis of the evolution of multi-ple system involvement in multiple systematrophy.

POSTMORTEM MATERIALAll cases were subject to full neuropathologi-cal examination by routine techniques. Tissueblocks were taken from the cerebrum, brain-stem, and cerebellum, and a variety of histo-logical stains were used, includinghaematoxylin-eosin, luxol fast blue, modifiedBielschowsky silver impregnation, andimmunocytochemistry for glial fibrillary acidicprotein and ubiquitin.A pathological diagnosis of multiple system

atrophy was based on cell loss and gliosis inany two of the following structures: striatum,substantia nigra, locus ceruleus, other pontinenuclei, cerebellar Purkinje cells, and inferiorolives, together with the presence of oligoden-

droglial cytoplasmic inclusions on modifiedBielschowsky silver impregnation or antiubiq-uitin staining.89 As it was available for onlynine of the 35 cases, we have not includedspinal cord pathology in this paper.The average degree of cell loss and gliosis

in the affected parts (severity) was semiquanti-tatively rated by one of the authors (SED),without knowledge of clinical features, on a 4point scale ranging from normal (0) to severe(3) in the following sites: putamen, caudatenucleus, globus pallidus, substantia nigra,locus ceruleus, pontine nuclei, inferior olives,and cerebellar Purkinje cells. In addition tothe degree of cell loss (severity), the area ofputaminal damage was assessed by dividingthe lateromedial extent of the putamen at thelevel of the anterior commissure into eightsegments and expressing the area of damageas the number of segments (0 to 8) involved.A total measure for putaminal damage wasobtained by multiplying the severity ofdamage (0 to 3) by area (0 to 8) to give a totalputaminal score (range 0 to 24). Nigral andputaminal severity counts were combined as astriatonigral degeneration score (range 0 to6), and severity counts in inferior olives,pontine nuclei, and cerebellar Purkinje cells asan olivopontocerebellar atrophy score (range0 to 9).

STATISTICAL ANALYSISIn presenting data for continuous variables,we have used median values as these were notalways normally distributed. Non-parametrictests of significance have been carried out withthe Wilcoxon-Mann-Whitney test for contin-uous or nominal variables, but for ease ofinterpretation mean values have been shownwhen comparing nominal data on pathologi-cal severity. Correlations were calculated withthe Spearman correlation coefficient, andexact confidence intervals (95%) were calcu-lated for proportions with the binomial for-mula.'0 Contingency tables were analysedwith either a x2 test or Fisher's exact test whenthe smallest expected value was less than five.All significance tests are two sided and use ana value of 0-05.

ResultsCLINICAL FEATURESThere were 19 men and 16 women (ratio1 2:1). Median age at disease onset was 55(range 33 3-75 8) years. Death was at 62-8(range 39-3-81 3) years, and median survivalwas 7-3 (range 2-1-15) years. There were nosignificant differences in any of these variablesby sex. Thirty (86%) of the patients were con-sidered to have multiple system atrophy of thestriatonigral degeneration type, and five(14%) multiple system atrophy of the olivo-pontocerebellar atrophy type (table 1).The proportion of cases with some evi-

dence of abnormalities in four major systemswere as follows: autonomic 97 (95% confi-dence interval (95% CI) 85-100)%, parkin-sonian 100 (95% CI 90-100)%, cerebellar 34(95% CI 19-52)%, and pyramidal 54 (95% CI

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Table 1 Distribution of subgroups among 35 cases ofmultiple system atrophy

Pure SND 23SND 30

Predominant SND 7Mixed 12

Predominant OPCA 5OPCA 5

Pure OPCA 0

SND= Striatonigral degeneration; OPCA = olivoponto-cerebellar degeneration.

Table 2 Basic clinicalfeatures in 35 pathologicallyestablished cases of multiple system atrophy

ParkinsonismAkinesia/rigidityTremor

Present at restClassicalPosturalAction

Cerebellar featuresLimb ataxiaIntention tremorGait ataxiaPostural instabilityNystagmus

Autonomic featuresRecurrent syncope ( 3 episodes)Symptomatic postural hypotensionUrinary incontinenceUrinary retentionFaecal incontinenceImpotence (men)-see also text

Pyramidal featuresExtensor plantarsEquivocal plantarsHyperreflexia

Cases withfeature recorded

% (95% CI)

100 (90-100)100 (90-100)80 (63-92)34 (19-52)11 (3-26)29 (15-46)9 (2-23)

34 (19-52)31 (17-49)11 (3-27)29 (15-46)89 (73-97)14 (5-30)

97 (85-100)20 (8-37)51 (34-69)51 (34-69)34 (19-52)3 (0-19)

62 (32-86)

54 (37-71)37 (22-55)17 (7-34)57 (39-74)

36&7-71-2)%. Figure 1 shows the pattern ofinvolvement of these four systems. The mostfrequent combination of clinical features wasautonomic involvement with parkinsonism.Of the 35 cases, 22 (63%) had involvement ofthree or more systems; the remainder onlyshowed clinical features of parkinsonism with(n = 12) or without (n = 1) autonomicinvolvement.

Table 2 provides more detail on the pres-ence of specific clinical features. Akinesia andrigidity were present in all patients and wereusually asymmetric throughout the diseasecourse. Tremor at rest was seen in a third ofpatients; however, a classical pill rolling resttremor had been documented in only 11 %.

Table 3 Other clinicalfeatures

Cases with feature recorded% (95% CI)

Diplopia 14 (5-30)Hypometric saccades 29 (15-46)Reduced upgaze 20 (8-37)Reduced downgaze 9 (2-23)Reduced horizontal gaze 9 (2-23)Dysarthophonia 89 (73-97)Dysphagia 51 (34-69)Excessive snoring 17 (7-34)Stridor 34 (19-52)Myoclonus 29 (15-46)Disproportionate antecollis 9 (2-23)Sensory dysfunction 20 (8-37)Symptoms only 11 (3-27)Signs ± symptoms 9 (2-23)

All but one patient had autonomic failureaccording to our definition. Although sympto-matic postural hypotension was noted in 71 %of the patients this was rarely severe, withrecurrent (> 3) syncopal attacks occurring inonly 20%. Urinary urge incontinenceoccurred in half of the patients, but faecalincontinence in one patient only. Urinaryretention was less common, affecting a thirdof the patients. Persistent erectile dysfunctionwas reported by almost two thirds of men;there was no mention of potency in theremaining third.

Cerebellar gait ataxia and limb ataxia wereseen in about 30% of the patients, and pyra-midal signs were detected in 54%.

Table 3 shows the prevalence of additionalfeatures. Reduced downgaze was noted inthree (9%) patients; however, this deficit wasonly mild, and none of the cases had a promi-nent supranuclear downgaze palsy.Dysarthrophonia affected all but four patientsand was commonly atypical with elements ofstraining, quivering, slurring, or scanning aswell as the usual hypophonia and monotonyof parkinsonism. Recorded sensory symptomswere uncommon (seven cases) and sensoryloss even rarer (three cases).When comparing sex distribution, age of

onset, age at death, duration of disease, andresponse to levodopa for clinical subgroups,cases with cerebellar features (34%) weremore likely to be men (p = 0.001), have ayounger age of onset (p = 0.0005), andyounger age of death (p = 0 003), but survivalwas little different from the other subgroups.Cases with severe autonomic involvement(37%) were also more likely to have a youngerage of onset (p = 0 02) and of death (p =0-05) and tended to have a poor response tolevodopa although this failed to reach statisticalsignificance (p = 0 06).

Levodopa was given to all but two patients.The initial clinical response for the wholesample was excellent (4) in 13%, good (3) in25%, and poor (1-2) in 62%. The bestrecorded levodopa response was excellent (4)in 13%, good (3) in 32%, and poor (1-2) in55%. The last recorded response in the notes,however, showed only 7% with a goodresponse and 93% with a poor response.Motor response fluctuations were recorded in60% of treated patients. Dyskinesiae devel-oped in 52% of patients, involving facial mus-culature in 59% (12% unilateral) and limbs in53% of them. Psychiatric side effects occurredin 15% (confusion in 9%, hallucinations andnightmares in 6% each).

Figure 2 shows the disease progression-namely, the median number of years to reachdifferent Hoehn and Yahr stages in thesecases with multiple system atrophy in compar-ison with published data from 123 treatedcases of Parkinson's disease." It is clear thatthe progression of disability in multiple sys-tem atrophy is faster than that seen inParkinson's disease, the difference being mostpronounced for latency to reach stage III(bilateral disease plus postural instability).

Initially 26 cases (74%) were thought to

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Clinicopathological study of35 cases of multiple system atrophy

Figure 2 Median numberofyears to reach differentHoehn and Yahr stages for35 cases ofpathologicallyconfirmed multiple systematrophy (empty bars)compared with 123patients with clinicallydiagnosed Parkinson'sdisease (black bars). Datafor Parkinson's diseasetaken from Hoehn. " Barsindicate range.

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Figure 3 Age of onset distribution for 35 cases of multiplesystem atrophy according to final clinical diagnosis

have idiopathic Parkinson's disease. Among (multiple system atrophy or Parkinson's disease). Emptythem, 14 (40%) subsequently had their diag- bars indicate patients diagnosed as multiple system atrophy

nosis changed to multiple system atrophy p life, black bars indicate patients misdiagnosed asParkinson's disease.

after a median disease duration of 4-4(0-3-7-8) years. None of our own 13 cases,but 12 (55%) of the other 22 cases, died still dence of severe autonomic involvement beencarrying an erroneous diagnosis of noted in life, but two had pyramidal features.Parkinson's disease. We examined whether, Their age of onset was significantly older thaneven in retrospect, any of these 12 cases had the 23 correctly diagnosed cases (63A4 v 50-6any atypical features recorded that might sug- years p = 0-002, fig 3), and there was a non-

gest the diagnosis of multiple system atrophy. significant trend for better levodopa responseIn none of them had cerebellar features or evi- in this group.

Table 4 Pathologicalfindings in 35 cases of multiple system atrophy

SND OPCAscore score Pu score

Case (0-6) (0-9) CC CN Pu (0-24) Pa Sn LB Lc PN IO CP

1 2 0 - + - 0 + +++ - +++ - - +2 3 1 - - - 0 - + - +++ - - +3 4 NA - - + + - + + + + + +++NE4 4 NA - - + 1 - + ++- + + NA + V>H5 4 4 - + + + 4 + + + + (5) + + + + + + + V>H6 4 9 NA - + + 6 + + + + + - + + + +++ + + + + + + V>H7 4 9 - + ++ 4 - ++ - + + ++ + ++ + +++ V=H8 5 4 - + + + + 8 + + + + - - + + - + + V>H9 5 5 - + + + 6 + + + + (6) + + - + + +++V>H10 5 6 NA + + + 8 + + + + - + + + + + + + + +11 5 7 - + +++ NA + ++ - ++ ++ ++ ++ +12 5 8 NA - + + + NA - + + + - + + + +++ + +13 5 9 - - + + + NA + + + + - + + + + + + +++ + + +14 5 9 - - ++ 6 + +++ - +++ +++ +++ +++15 6 NA - - + + + NA + + + + + - + + + NE NA +16 6 NA - + + + + + 21 + + + + + - + + + +++ + + NA17 6 0 - ++ +++ 18 ++ +++ + - - - (7)18 6 0 - ++ +++ 18 - +++ - +++ - + (7)19 6 0 - - + + + NA NE + + + - + + - - -20 6 0 - + +++ 24 ++ +++ - +++ - - -21 6 2 (1) + + + + + 9 + + + + + + + + + + - + + V=H22 6 2 NA ++ +++ 24 ++ +++ - ++ - + + V=H23 6 2 (2) + + + + 18 + + + + + + + + - + + V=H24 6 3 - +++ +++ 24 +++ +++ - +++ + + +25 6 4 - + + + + + 21 + + + + - + + + + + + + V>H26 6 5 - + + + + 23 + + + + - + + + - + + +++V>H27 6 5 - + + ++ 21 + + + + - + + + + + + + + V>H28 6 5 - + + + +++ 24 +++.++ - + + + + + + + + V>H29 6 6 - + + + + 18 + + + + - + + + + + + + + + V>H30 6 6 (3) + + + + 21 + + + + + + + + + + ++ + +++V>H31 6 9 (4) + + + + + 24 + + + + + - + + + +++ + + + + + + V=H32 2 NA NA + + 1 - + - + + - - NE33 NA NA - ART + + NA ART ART - ART ART ART ART34 NA NA NA INF INF INF NE + - NA - ART ART35 NA 4 - INF INF INF + + + +++ - + + + + + + + V>H

SND = Striatonigral degeneration; OPCA = olivopontocerebellar atrophy (for scores refer to methods); CC = cerebral cortex;CN = caudate nucleus; Pu = putamen; Pa = pallidum; Sn = substantia nigra; LB = Lewy bodies; PN = pontine nuclei; TF= transverse fibres; IO = inferior olives; CP = cerebellar Purkinje cells; V = vermis; H = hemisphere; -, +, + +, + ++ =

absent, mild, moderate, severe cell loss ± gliosis; NA = not available; NE = not examined; ART = artefact; INF = infarction;(1), (2), (3) = LBs present in CC; (4) = Alzheimer type change in CC; (5) = pale inclusion bodies in Sn; (6) = eosinophilicdegeneration present; (7) = agonal change.

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PATHOLOGYCell loss in the substantia nigra was identifiedin all but one case, which showed postmortemartefact (table 4), and was severe in 79%(27/34) of them. The locus ceruleus was, withfew exceptions, equally severely depleted.

Putaminal cell loss and gliosis were pro-nounced in 20 (61 %) and moderate or mild in11 cases (33%). In two cases there was noputaminal cell loss and in two others infarc-tion made interpretation of the extent ofdegenerative change difficult. Nevertheless, inall four cases both substantia nigra and locusceruleus showed cell loss and gliosis withoutLewy bodies. The pathological diagnosis ofmultiple system atrophy in the cases withoutputaminal cell loss would not have been possi-ble but for the demonstration of glial cytoplas-mic intrusions.z2The caudate nucleus was much less

severely affected: only two (6%) cases hadsevere cell loss and gliosis (usually diffuse)and 21 (66%) cases had mild or moderategliosis, often in a focal dorsolateral distribu-tion. There were no changes in nine (28%)cases. The external pallidum was invariablyinvolved with gliosis except for the two caseswithout putaminal cell loss.

Degenerative changes in the olivoponto-cerebellar system were seen in 29 of 34 (88%)cases studied. Assessment was not possiblein one case due to postmortem artefact.Pronounced Purkinje cell depletion was seenin the cerebellar cortex of 12 (40%) of thecases, and only two (6%) cases appeared tohave no cell loss at all. When present, cell losswas more severe in the cerebellar vermis rela-tive to hemispheres in 12 of 17 (71%) cases inwhich comparisons were possible. The den-tate nuclei were only mildly affected by glio-sis, without cell loss, in seven of 20 (35%)cases in which we were able to examine them.Dentate hilum and superior cerebellar pedun-cle were unaffected. The dorsal vagal nucleuswas mildly to severely affected in 14 of 27(52%) cases examined.

Finally, apart from the presence of glialcytoplasmic inclusions and age related neu-ritic plaques, the cerebral cortex was normalin 25 out of 30 (83%) cases studied. Three(10%) cases showed widespread Lewy bodiesin all areas of cerebral neocortex studied aswell as in the substantia nigra. SevereAlzheimer's disease type changes were seen inthe neocortex in two (7%) cases.

CLINICOPATHOLOGICAL CORRELATIONThere was no correlation between semiquan-titative measures of pathological damage inthe putamen, nigra, and olivopontine area andage at onset, age at death, and duration of dis-ease. There was a trend, however, for thedegree of nigral and putaminal damage to begreater in those cases with longer diseaseduration.

Only 18% (3/17) patients with a putaminaldamage score of 18 or less died with arecorded Hoehn and Yahr stage of V by con-trast with 70% (7/10) of those with putaminaldamage of more than 18 (p < 0-02). The

combined score of striatonigral degenerationand olivopontocerebellar atrophy did not,however, correlate with severity of motor dis-ability.

Thirty five per cent of patients with a puta-minal score < 18 showed either a good (12%,2/17) or moderate (24%, 4/17) latest recordedlevodopa response whereas only one of 10(10%) patients with a putaminal damagescore of >i 18 retained a moderate response,but this was not significant (p = 0 20). Therewas no relation between the latest levodoparesponse and degree of nigral degeneration.The estimated degree of olivopontocerebel-

lar atrophy was unrelated to levodopa respon-siveness. The presence of fluctuations anddyskinesiae was more often associated withsevere striatonigral (striatonigral degenerationscore 6) or putaminal (putamen score > 18)degeneration.

Cerebellar signs had been noted in life inonly nine of the 26 (35%) cases that showedcerebellar Purkinje cell loss at postmortem. In12 cases this Purkinje cell loss predominatedin the vermis. Although all of them werenoted to have postural instability in life, onlythree of them had definite evidence of gaitataxia.We also examined the association between

pathological damage and clinical features andsubgroups. All the cases had parkinsonismand all showed pronounced damage to thenigra, and cases with cerebellar features orclassified as olivopontocerebellar atrophy typehad greater damage in the olivopontine area.Perhaps surprisingly, early loss of balance cor-related significantly with putaminal damagebut not with the olivopontocerebellar atrophypathological score.

DiscussionThe nosology of multiple system atrophy iscomplex, and related to the relative predomi-nance of parkinsonism (striatonigral degener-ation)," cerebellar signs (olivopontocerebellaratrophy), 14 or autonomic failure. Shy andDrager'4 reported two patients; pathology,which showed the classic changes of multiplesystem atrophy (both striatonigral degenera-tion and olivopontocerebellar atrophy), wasobtained in one of them. Over subsequentyears, the term Shy-Drager syndrome' hasbeen used for cases of multiple system atro-phy, and also misused to describe cases ofLewy body parkinsonism associated withsevere autonomic failure. As virtually allpatients with multiple system atrophy havesome degree of clinical autonomic dysfunc-tion (usually mild cardiovascular and moresevere bladder involvement), we believe that itis most useful to divide them, according totheir motor disorder, into parkinsonism pre-dominant (striatonigral degeneration) or cere-bellar predominant (olivopontocerebellaratrophy).

This study confirms and extends ourknowledge about multiple system atrophy in anumber of areas. It is a rapidly progressivedisease, with a median survival of only five to

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six years from first symptom in over 200 casesof pathologically established multiple systematrophy recorded in the literature.8 In thisseries we found a longer median survival, of7-3 (range 2 1 to 15) years, a discrepancy thatmight be due to the relative lack of clinicaldata in many of the published case reports.Moreover, in a follow up study of 100 patientswith clinically probable multiple system atro-phy we found a still longer median survival of9 5 years.'6 The total disease duration fromfirst symptom to death for our five patientswith predominant olivopontocerebellar atro-phy was similar to that for the 30 patients withpredominant striatonigral degeneration, andthe response of their (by definition mild ormoderate) parkinsonism to levodopa was uni-formly disappointing.The finding of parkinsonism in 100% of

our cases comes as little surprise given thatthe source of our material was a parkinsonianbrain bank, but parkinsonism was alsoreported in 89% of pathologically establishedmultiple system atrophy cases in the litera-ture. Almost all patients with multiple systematrophy in our series had developed clinicalsigns of multisystem involvement by the timeof death. Apart from one (2.9%) case withisolated parkinsonism, there was no case withautonomic failure, cerebellar, or pyramidalsigns persisting in isolation throughout thecourse of disease. Among pathologicallyestablished cases of multiple system atrophyin the literature 90% had accrued in life fea-tures in two or more of these four clinicaldomains and only 10% apparently hadparkinsonism in isolation at the time of death.A good or excellent initial motor response

to levodopa was seen in a third of this series ofpatients with multiple system atrophy. Thiswas sustained until death, however, in only7% of them. Thus although encountered inonly a few patients, a positive and sustainedlevodopa response, even until death in somecases, can occur in multiple system atrophy.In this series there was a trend for the last, butnot best, recorded levodopa response to beinversely associated with the degree of puta-minal damage, consistent with previous moredetailed morphometric data in a subgroup ofcases.6 This finding might suggest that theseverity of the nigral lesion precedes that ofthe striatal one. Further evidence for initialand more severe nigral cell loss is derivedfrom two cases in our series with "minimalchange" multiple system atrophy in whichsevere neuronal cell loss in substantia nigrawas associated with preserved putaminalneurons12; however, typical glial cytoplasmicinclusions were found throughout the stria-tum and many other sites, indicating extra-nigral subcellular pathology. One of these twopatients had a good, and one a negligible,response to levodopa. The substrate of levo-dopa unresponsiveness in multiple systematrophy is uncertain. Although loss of striataldopamine receptors plays a part, much of thelevodopa resistance in multiple system atro-phy, and its heterogeneity between patients, isprobably due to the variable degeneration of

additional cell populations within the basalganglia, involving other neurotransmitter sys-tems.8 Dyskinesiae developed in half of thetreated patients. By contrast with patientswith Parkinson's disease there was strikinglypredominant involvement of orofacial andoften neck muscles, with sustained dystonicelements in almost 60% of dyskinetic patients,which may reflect striatal somatotopy.Dyskinesiae also occurred in the absence ofobvious improvement in motor function insome cases.7Among patients still carrying a diagnosis of

Parkinson's disease at death, we know that24% do not have Parkinson's disease, andthat multiple system atrophy is the most fre-quent cause of this error.'7 18 Examining thisquestion from a different angle, 12 of our 35cases of multiple system atrophy remainedmisdiagnosed as Parkinson's disease untildeath. These constituted 34% of the entireseries, and 55% of the cases not seen in life byus. Even retrospectively it was impossible in10 of these cases to make a diagnosis of multi-ple system atrophy on the basis of the infor-mation recorded in their notes. The other twopatients had developed pyramidal signs beforedeath but remained diagnosed as Parkinson'sdisease. Although the presence of abnormalsigns may suggest a diagnosis of multiple sys-tem atrophy, in many cases it may be the sus-picion of multiple system atrophy that leads tothe discovery of abnormal signs. Therefore ahigher index of suspicion and regular followup neurological examinations in all patientswith parkinsonism may lead to more accuratediagnosis. Most cases of multiple system atro-phy seem to start younger than is usual forParkinson's disease, and it is of interest thatthe mean age of onset in the persistently mis-diagnosed subgroup was significantly olderthan in the correctly diagnosed group. Evenamong those patients in whom an initial diag-nosis of Parkinson's disease was subsequentlychanged to one of multiple system atrophy,this took an average of 4-4 years, indicatingthe difficulty of accurately diagnosing multi-ple system atrophy within the first five years. '7Our pathological study showed that both

substantia nigra and putamen were severelydepleted in most cases. In a few cases severenigral atrophy was associated with mild ormoderate putaminal degeneration and in twocases definite cell loss was restricted to sub-stantia nigra and locus ceruleus only.'2 Theseverity of pathological striatonigral degenera-tion did not correlate with age of onset andduration of disease, but did correlate withseverity of disease at death.

Although 88% of our cases with availablepostmortem material had some evidence ofolivopontocerebellar atrophy in addition tonigrostriatal cell loss, only 34% of them haddefinite cerebellar signs in life. Definite gaitataxia was only recorded in three of 12 caseswith severe cerebellar (vermis) involvement,but impairment of postural reflexes with orwithout falls was present in all. The apprecia-tion of a possible cerebellar component con-tributing to the disturbance of gait and

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Wenning, Ben-Shlomo, Magalhdes, Daniel, Quinn

postural control in multiple system atrophy ishampered by the presence of severe parkin-sonism or symptomatic postural hypotensionin many patients. The low number of caseswith definite gait ataxia is therefore almostcertainly an underestimate.The association of olivopontocerebellar

atrophy with striatonigral degeneration insuch a large proportion of cases confirms theneed for the term multiple system atrophy.I Inour series, all cases with adequately fixedbrains contained oligodendroglial inclusionsthat have been reported by a number ofgroups in the brains of patients with multiplesystem atrophy of various clinical subtypes,and are rarely if ever found in other sporadicor hereditary neurodegenerative diseasesincluding hereditary olivopontocerebellaratrophy. As in previous reports, in our seriesthese inclusions were found not only in theolivopontocerebellar and striatonigral sys-tems, but also in a number of areas not previ-ously considered to be affected in this diseaseincluding the cerebral cortex, external cap-sule, and brainstem reticular formation.9 19 22

The presence of these inclusions may accountfor more widespread alterations in cerebralfunction, such as the frontal lobe deficitsdocumented in patients with multiple systematrophy.23 2 Furthermore, they constitutecytological grounds for considering sporadicstriatonigral degeneration, Shy-Drager syn-drome, and olivopontocerebellar atrophytogether as multiple system atrophy, for dif-ferentiating them from hereditary olivoponto-cerebellar atrophy, and for defining multiplesystem atrophy as a specific entity that is onlyone among many different multisystemdegenerations.26

GKW and SED are supported by the UK Parkinson's DiseaseSociety, YBS by the Wellcome Trust, and MM by thePortuguese Health Service.

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9 Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclu-sions in the CNS of patients with multiple system atro-phy (striatonigral degeneration, olivopontocerebellaratrophy and Shy Drager syndrome). 7 Neurol Sci1989;94:79-100.

10 Lenter C. Geigy scientific tables Vol 2. Basle: Ciba-Geigy,1982.

11 Hoehn MM. Parkinsonism treated with levodopa: pro-gression and mortality. . Neural Traiisns 1985;19(suppl) :253-64.

12 Wenning GK, Quinn N, Magalhaes M, Mathias C, LeesA, Daniel SE. "Minimal change" multiple system atro-phy. Mov Disord 1994;9:161-6.

13 Adams RD, van Bogaert L, van der Eecken H.Degenerescences nigro-striees et cerebello-nigro-striees.Psychiatria et Neurologia 1961;142:219-59.

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19 Nakazato Y, Yamazaki H, Hirato J, et al. Oligodendroglialmicrotubular tangles in olivopontocerebellar atrophy. .7Neuropathol Exp Neurol 1990;49:521-30.

20 Costa C, Duyckaerts C, Cervera P, et al. Les inclusionsoligodendriales, un marqueur des atrophies multisyste-matisees. Rev Neurol 1992;148:274-80.

21 Mochizuki A, Mizusawa H, Ohkoshi N, et al.Argentophilic intracytoplasmic inclusions in multiplesystem atrophy. _7 Neurol 1992;239:311-6.

22 Papp MI, Lantos PL. Accumulation of tubular structuresin oligodendroglial and neuronal cells as the basic alter-ation in multiple system atrophy. _7 Neurol Sci 1992;107:172-82.

23 De Volder AG, Francart J, Laterre C, et al. Decreasedglucose utilization in the striatum and frontal lobe inprobable striatonigral degeneration. Anni Neurol 1989;26:239-47.

24 Eidelberg D, Takikawa S, Moeller JR, et al. Striatalhypometabolism distinguishes striatonigral degenerationfrom Parkinson's disease. Ann Neurol 1993;33:518-27.

25 Robbins TW, James M, Lange KW, Owen AM, QuinnNP, Marsden CD. Cognitive performance in multiplesystem atrophy. Brain 1992;115:271-91.

26 Lantos PL, Papp MI. Cellular pathology of multiple sys-tem atrophy. _7 Neurol Neurosurg Psychiatry 1994;57:129-33.

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