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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Journal ofNeurology, Neurosurgery, and Psychiatry. Special Supplement 1989:78-89

Multiple system atrophy the nature of the beast

NIALL QUINN From the University Department ofClinical , Institute ofNeurology, The National Hospitalfor Nervous Diseases, London, UK

SUMMARY (MSA) is generally considered a rare disease, but may account for up to 10% of patients with . The profusion of names for this disease, which may present to general physicians, psychiatrists, cardiologists, autonomic specialists, general neurologists and those with a special interest in Parkinsonism (this author's own perspective) or cerebellar disorders, together with ignorance of its protean manifestations, may account for its under- recognition and misdiagnosis. In this article, the history and nosology of the condition are considered, and provisional diagnostic criteria are advanced. The usefulness (or otherwise) of ancillary investigations is addressed, and the shortcomings of current methods of treatment are stressed. As with idiopathic Parkinson's disease, the ultimate goal of eradicating the disease entails better diagnosis in order to establish the cause, and thence to develop a radical treatment capable of preventing or arresting the disease process. Protected by copyright.

Multiple system atrophy (MSA)' is a degenerative pathological features (see fig). This has resulted in disease ofthe central . Clinically it may considerable confusion among neurologists. The main present with any combination of extrapyramidal, aim of this review is hopefully to bring together the pyramidal, cerebellar and autonomic signs and symp- strands to weave a coherent picture of the condition. toms, and may change its clinical emphasis as it evolves. Pathologically, it is characterised by cell loss The history ofMSA and occurring in a selection ofthe following "at Once a disease has been delineated, it is always risk" structures: , caudate, putamen instructive to return to earlier descriptions which, with (especially posterior part), globus pallidus (especially hindsight, probably dealt with the same condition. pars externa), inferior olives, pontine nuclei, cerebellar Although other French and German workers may Purkinje cells, intermediolateral cell columns of the have described cases of this condition in the late and Onuf's nucleus. Locus coeruleus, nineteenth century, Dejerine and Thomas,2 in 1900, in dorsal motor nucleus of vagus, vestibular nuclei, and anterior horns may also be involved. This pattern of involvement may hold the Jdwi/o4 JtoshA9<, key to the mechanism of cell loss, explaining why http://jnnp.bmj.com/ certain cells are susceptible to whatever causes the disease whilst adjacent cells and structures are spared. 1S Together with this distribution ofcell loss, the absence S of Lewy bodies distinguishes it from idiopathic Park- inson's disease and the lack of neurofibrillary tangles separates it from Steele-Richardson-Olszewski disease and post-encephalitic Parkinsonism. 018flP6dA

MSA has always been considered a rare condition, on October 2, 2021 by guest. yet it has also attracted a number of different and complex names related to its varied clinical and She-)t (4). Address for reprint requests: Dr Niall Quinn, University Department of Neurology, Institute of Neurology, Queen Square, London WCI 3BG, UK. Accepted January 1989 Fig Simple is beautiful. 78 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Multiple system atrophy-the nature ofthe beast 79 describing, two sporadic cases, were the first to , but in case 1 this was a slight exophoria and in introduce the term olivopontocerebellar atrophy case 2 "inability to converge and weakness of the (OPCA). Their first case was a woman of 52 years, the medial rectus muscle bilaterally". Both had reduced second a man of 42. Both developed , dysarth- facial expression, case 2 noted slowness ofmovements, ria, akinesia, rigidity and brisk leg reflexes. The and rigidity was present in both. woman developed incontinence of urine, and died Post-mortem examination ofcase 2 showed cell loss after 3 years. The man developed , incontinence and/or gliosis in many areas, but most marked in the ofurine, and probable symptomatic postural hypoten- caudate, substantia nigra, olives, locus coeruleus, sion ("etourdissements"). Pathological examination and intermediolateral cell columns of the of the first case revealed atrophy of the olives, pons spinal cord; the putamen, globus pallidus and pons and cerebellum. The substantia nigra and striatum were also affected. In the introduction, the authors were not examined, or at least not commented upon. defined the full syndrome as comprising the following The next piece of the jigsaw was a paper by features: , urinary and rectal Bradbury and Eggleston in the American Heart Jour- incontinence, loss of sweating, iris atrophy, external nalin 1925 entitled "Postural hypotension. A report of ocular palsies, rigidity, tremor, loss of associated three cases".3 Here they described three male subjects movements, impotence, the findings of an atonic whose symptoms began in middle life (aged 36, 47, 60 bladder and loss ofthe rectal sphincter tone, fascicula- years) and who were seen after from 3 to 7 years of tions*, wasting of distal muscles, evidence of a illness. Common to all three were symptomatic pos- neuropathic lesion in the electromyogram that sug- tural hypotension and anhidrosis. Patient 1 had gests involvement of the anterior horn cells*, and the additional impotence and , cases 2 and 3 finding of a neuropathic lesion in the muscle biopsy. had unequal pupils and brisk leg reflexes, and case 3 Items with an asterisk* were found only in case 2. It is had bilateral extensor plantar responses. Two patients of interest to note that neither cerebellar nor died suddenly, and two years later4 they reported post- pyramidal signs appear in this definition of the full Protected by copyright. mortem findings in one of these cases, but unfortun- syndrome. ately the central nervous system was not examined. In the previous year Van der Eecken, Adams and Over subsequent years, a number of authors began to van Bogaert had made a brief presentation to the recognise in some patients a clinical association be- American Association of Neuropathologists entitled tween orthostatic hypotension and disease of the "Striopallidal-nigral degeneration. An hitherto unde- central nervous system, especially Parkinsonism.56 scribed lesion in agitans" which was pub- The case of Langston5 was a man of 56 with a 7 year lished in 196O.' They called attention to the finding of history of autonomic failure followed by Parkinson- pronounced shrinkage and brownish discoloration of ism with antecollis, husky and uncontrollable speech, parts ofthe putamen and globus pallidus as well as the "peculiar involuntary movements resembling laugh- usual depigmentation of the substantia nigra. Micro- ter" and emotionalism. Young's patient,6 a man of43, scopically, one of the most striking lesions was the also had a 5 year history comprising autonomic virtual disappearance ofthe small cells ofboth caudate failure, Parkinsonism, an unsteady, staggering gait and putamen. and a husky voice. A left vocal cord paresis was noted. The same authors (Adams et a) in 1961 published a The next developments took place in 1960. It is longer paper entitled: "Degenerescences nigro-striees important to remember that this was before the et cerebello-nigro-striees".9 In it, they gave clinical and levodopa era, and to keep in mind that today the pathological details of 3 patients (2 M, 1 F) with http://jnnp.bmj.com/ degree of clinical response to levodopa is the single sporadic disease. All had an akinetic-rigid syndrome most useful diagnostic pointer in the differential with tremor (slight action, slight rest, and 4-5 Hz diagnosis of Parkinsonism. Shy and Drager in 19607 respectively). Reflexes were brisk in all three, plantars described "A neurological syndrome associated with extensor in case 2, and there was ataxia and intention orthostatic hypotension". They had seen four cases, tremor in case 3. Cases 1 and 3 had severe speech and reported two in detail, with pathology in one. disturbance, case 1 had blackouts and impotence, and Both were male. Case 1 began at age 39, and was seen case 2 double incontinence. The pathology involved at age 46 after 7 years of disease. Case 2 began at age not only striatum and nigra, but also olives and on October 2, 2021 by guest. 49, and died at age 551 after 6j years of disease. Both cerebellum in all three cases, with additional pontine had marked autonomic failure, slurred speech, lesions in cases 1 and 3. Case 2 also had Lewy bodies in impaired co-ordination and distal muscle wasting. substantia nigra. Neither clinically nor pathologically, Both had tremor at rest affecting the hands, and case 1 therefore, was striatonigral degeneration a pure and also had tremor on movement. Case 1 had pyramidal restricted entity resulting from pathology of these signs, case 2 equivocal plantar responses and fascicula- structures alone. tions. Both are said to have had external ocular muscle It seems surprising that accounts of striatal patho- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

80 Quinn logy in some cases of Parkinsonism should only have MSA. A key clinicopathological review by Bannister begun to appear in the 1960s. However, some such and Oppenheimer in 1972 entitled: "Degenerative cases were in fact described earlier, but taken to be part diseases of the nervous system associated with auto- ofthe spectrum ofParkinson's disease. Thus Messing, nomic failure"'2 considered this division. They des- in 1930, described the case ofa woman aged 62 years'0 cribed 16 pathologically studied cases of autonomic who presented "the classical picture of Parkinson's failure: four personal cases (three MSA, one Lewy disease". Post-mortem examination of the body) and 12 cases from the literature (eight MSA, revealed "total atrophy of the ponto-cerebellar sys- four ). In the five Lewy body cases (4 M, tem, partial atrophy of the inferior olives and their 1 F) mean age of disease onset was 65 years (range connections, marked atrophy of the supero-lateral 56-73), mean survival 5 years (range 1-5-13) and mean portions of the cerebellum and of the vermis ... and age at death 70 years. In the 11 MSA cases (8 M,.3 F), fibrosis of the globus pallidus ... together with mean age at onset was 49 years (range 36-58), mean dysmyelination of the putamen and the anterior survival 6 years (range 2-11) and mean age at death 55 portion ofthe caudate nucleus ... This was certainly a years. The striking difference in age of disease onset case of Parkinson's disease, with an unusual disguises the much worse prognosis of MSA cases. additional lesion: atrophy ofthe cerebellar pathways". Among the five Lewy body cases, three had pure Malamud's 1957 atlas of neuropathology" devoted autonomic failure and two Parkinsonism with auto- one page of text to "Parkinson's disease (paralysis nomic failure; pyramidal and cerebellar signs were agitans) ... Besides the postencephalitic and other absent. Among the 11 MSA patients, all had auto- symptomatic forms of Parkinsonism, there is a nomic failure with pyramidal and/or cerebellar signs, primary degeneration form that generally begins in and eight had additional Parkinsonism. Although in late middle or advanced age ... The predominant this series no MSA patients had isolated Parkinsonism pathology is either in the striopallidum or in the with autonomic failure, this combination can undoub-

substantia nigra, although some cases show more tedly occur. No patients in either group had receivedProtected by copyright. diffuse cerebral involvement. Case 1: a 73 year old man levodopa. with a two year history ... gradually became bedfast Pathologically, all 11 cases ofMSA with progressive ... He exhibited a pill-rolling tremor. . ., rigidity and autonomic failure had involvement of pigmented weakness ..., a slurred, unintelligible speech, yet a nuclei. Intermediolateral cell columns were relatively normal mental status. His course was involved in 10, putamen in 10 and caudate in four, rapidly downhill. The brain showed symmetrical atro- whilst the olives were affected in 10, pons in six, phy of the putamen and globus pallidus, with grayish cerebellum in 10, pyramidal tracts in five and anterior discoloration of the former". Neither of these horns in four. accounts document nigral pathology, nor is there any Takei and Mirra, in 1973, described seven cases of mention of the presence or absence of Lewy bodies. striatonigral degeneration (with pathology).'3 Six of Thus, despite the major discoveries of both Lewy and the seven had been diagnosed in life as Parkinson's Tretiakoff in the early 1900s, there was still no disease, four had pyramidal signs, two ataxia and one neuropathological consensus on the diagnosis of orthostatic hypotension. Pathologically, in only one idiopathic Parkinson's disease until almost half a case was involvement limited to the striatum and century had elapsed. nigra. They concluded: "Although we treated all our Thus far, we have encountered four "conditions" seven cases as examples of SND, which implies a

which at first sight appeared separate, but may in fact disorder involving two sites, other structures were http://jnnp.bmj.com/ all include subjects with the same disease: OPCA, involved in some cases as well. The term is only idiopathic orthostatic hypotension, the Shy-Drager justified with the understanding that these two sites are syndrome and striatonigral degeneration. Graham the most dominant ofmultiple sites ofinvolvement.... and Oppenheimer' deserve our thanks for writing in It would be more meaningful to group these condi- 1969: ". . . unnecessary confusion is caused by invent- tions under a simple name, such as multiple system ing new names, of the type "pallido-subthalamo- atrophy". Unfortunately, they got carried away with vestibular atrophy" for unusual syndromes. What we the attractiveness of this notion, proposing that

wish to avoid is the multiplication of names for Huntington's disease, Pick's disease and Friedreich's on October 2, 2021 by guest. "disease entities" which, in fact, are merely the ataxia, among others, be included under this label. expression ofneuronal atrophy in a variety ofoverlap- Whilst multisystem degeneration might be a useful ping combinations. We therefore propose to use the shorthand term for these different conditions, the term term "multiple system atrophy" ". multiple system atrophy refers only to the specific During the early 1970s it became apparent that disease (or possibly group ofdiseases) addressed here. patients with neurogenic autonomic failure sometimes Returning to the cerebellar presentation of MSA, had Lewy body pathology rather than the changes of Miyazaki'4 in 1978 described 45 patients labelled J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Multiple system atrophy-the nature ofthe beast 81 clinically as suffering from sporadic adult onset picture emerging from large post-mortem series of OPCA. Twenty had positive autonomic function tests Parkinsonian is that cases of MSA are more for subclinical orthostatic hypotension; 17 of these common than previously thought, and also frequently (85%) subsequently developed , mis-diagnosed in life. seven (35%) had , and eight Before examining larger and more recent series, it is (40%) had pyramidal signs. salutary to consider a paper from Tygstrup and In their review of striatonigral degeneration,'5 N0rholm'6 in 1963, prior to the introduction of Adams and Salam-Adams excellently summarised the levodopa. They reported the necropsy results in 12 clinical heterogeneity of MSA: "SND, OPCD and patients from a larger series who had died from 1 week SDS symptomatically can occur singly or combined in to 4 years after a stereotactic operation for Parkinson- all possible ways. Each of the clinical syndromes may ism. All showed degeneration of substantia nigra. mark the beginning of the disease, but if the patient However, only five had Lewy bodies: two of the survives for many years the appearance of the other remaining seven had multiple system atrophy. Takei two syndromes can be predicted". Unfortunately, the and Mirra'3 found MSA in 7 9% of 89 brains of review ends by proposing the term "striatonigral- patients with Parkinsonism. This led them to feel "that cerebellar-autonomic degeneration"! An additional striatonigral degeneration is not an extremely rare problem in clinical assessment ofthese patients is that disease, but that this group constitutes a significant it can be well nigh impossible to state whether a patient proportion of Parkinsonian cases." Duvoisin, largely with severe Parkinsonism incorporating marked on clinical grounds, estimated that in his own consult- and postural instability has cerebellar signs, ing practice OPCA accounts for 5 to 6% of all and vice-versa. Moreover, the increase in tendonjerks Parkinsonism.'7 In my own experience in the King's in a rigid limb and the occasional presence of a College Hospital Parkinson's disease clinic, almost "striatal toe" or "dystonic foot response" makes it every study on Parkinson's disease has included difficult to recognise pyramidal signs in extra- patients who later turned out to have clinical or Protected by copyright. pyramidal disease. pathologically proven MSA. The difficulty in diag- One of the particular features of multiple system nosis is greatest in untreated patients: four of20 (20%) atrophy is that it sits astride a number of disciplines patients in a neuropsychological study of de novo and sub-specialities. Part of the difficulty experienced patients with Parkinson's disease'8 turned out to have by many physicians in conceptually getting to grips pathologically proven (n = 1) or clinical (n = 3) with the condition stems from precisely this character- MSA. Jellinger (personal communication) found it in istic. For me, the analogy of the blindfolded men 11% of 110 brains in his 1957-70, 3-6% of 490 brains examining different parts of an elephant and coming in his 1971-87, and 5-1% of 600 brains in his total away with different impressions of the nature of the 1957-87 series ofbrains from patients with Parkinson- beast is an excellent one. Much of what has been ism dying in three hospitals in and around Vienna. In written about MSA has been written by doctors with a the United Kingdom, the Parkinson's Disease Society special interest in the , for established a Brain Bank in 1984. Patients volunteer obvious reasons since the disease offers such an for the register, and are assessed at yearly intervals by a excellent model for its understanding. However, consultant neurologist with a special interest in Park- prominent autonomic symptoms may be absent in inson's disease. Disregarding those cases especially very many patients early in the disease, and indeed sent to the Brain Bank by neurologists because of throughout its course in some subjects. My own atypical disease, 11% of the first 83 brains received http://jnnp.bmj.com/ perspective of MSA, viewing from a Parkinson's had MSA, and a further 7% did not have IPD. It is disease clinic, is of an irregular lumpy iceberg. Above possible that this figure for MSA is an over-estimate of the surface is one mini-iceberg of pure autonomic the prevalence of the condition, since clearly in the failure, and another of OPCA. Beneath the waves lie first years of operation of a brain bank more regis- the bulk of MSA cases, these "striatonigral" variants tered individuals with MSA than with IPD will die who, unrecognised, swell the ranks of Parkinson's because of differing prognosis. It should, however, disease clinics, participating in drug trials and trans- reflect the incidence of the disease. MSA is therefore plantation programmes. The gradual recognition of not a rare disease. If, say, 10% of the Parkinsonian on October 2, 2021 by guest. their existence owes itself to three factors. Firstly, population of the UK were affected, this would make exposure to many Parkinsonian patients makes it prevalence 16-4 per 100,000, that is, more than twice easier to recognise what is typical and hence what is that of Huntington's disease. atypical. Secondly, the pathological proof in those An idea of the age of onset and prognosis can be cases clinically recognised as MSA who have had a obtained from tables in the large reviews of patho- post-mortem examination helps to confirm and hence logically proven MSA ofOppenheimer'9 (n = 41, in a validate clinical diagnostic criteria. And thirdly the chapter on the neuropathology of progressive auto- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

82 Quinn nomic failure) and of Gosset et al0 (n = 35, in an described (which I have never seen), or to the path- article on SND and OPCA, reproduced in Adams and ology which revealed atrophy ofmultiple systems? My Salam-Adams' chapter in the Handbook of Clinical own view is that, whilst acknowledging their major Neurology on SND'5). Between them, these tables contribution in recognising the somatic neurological document 59 different cases of pathologically proven features associated with some cases of autonomic MSA with age of onset in 58 and disease duration in failure and in describing the underlying pathology, we 57. Median age ofdisease onset was 53 years (range 36 should cease to use the term Shy-Drager syndrome to 74), with 62% starting between 45 and 59 years, and since its meaning has become so imprecise. Ifthe term 90% between 40 and 64 years. Older patients with is to be retained at all, then I think it should refer to the Parkinsonism and autonomic failure are thus more clinical picture of Parkinsonism with autonomic likely to have Lewy body disease. Median disease failureplus features incompatible with IPD, viz lack of duration to death was 5 years (range 1 to 11), and 88% response to levodopa, or the presence ofpyramidal or were dead within 7 years of disease onset. Some cerebellar signs. authors have stressed a male preponderance of cases. Progressive autonomic failure (PAF) is a term that Thus, in considering 41 cases of "autonomic failure gradually supplanted idiopathic orthostatic hypoten- with MSA", Oppenheimer found 26 males and 15 sion. More recently, terminology has again changed, females. However, Gosset et al, considering 35 cases of so that PAF now stands for pure autonomic failure.23 "SND and OPCD" found 14 males, 20 females and But how is autonomic failure defined? All one sex unknown. Taken together, these series physicians recognise "barn-door" autonomic failure document MSA in 58 cases ofknown sex. Males were when confronted with it, but where does mild auto- affected in 31 cases, females in 27. It is possible that nomic dysfunction (as seen in many patients with because impotence and urinary symptoms tend to be Parkinson's disease and also some normal subject) end noted more in males than anorgasmia and urinary and autonomic failure begin? The autonomic research disturbance in (especially parous) females, an community have not yet agreed universal criteria for aProtected by copyright. artifically high rate of autonomic disturbance may be diagnosis of autonomic failure.2' There are certainly a recorded among the former. However, MSA seems to number of tests of autonomic function which have affect the sexes equally. been validated in control populations, and for which it is possible to state that an individual lies outside the Nosology and diagnostic criteria normal range, or one or two standard deviations from It can reasonably be asserted that Shy and Drager the mean. But how many of these single tests need to were responsible for first placing the combination of be how abnormal before autonomic failure is diag- autonomic failure, neurological signs and the nosed, and how can the diagnosis be made in less associated CNS pathology firmly on the neurological severe cases without recourse to an autonomic func- map. However, confusion reigns over how the term tion laboratory? McLeod and Tuck' require abnor- Shy-Drager syndrome should be used. The two mal results in two or more of the following tests: the patients they described had clinical features incom- response of blood pressure to change in posture and patible with idiopathic Parkinson's disease (IPD). The isometric contraction, heart rate response to standing, term cannot therefore be used as a form of shorthand variation in heart rate with respiration, Valsalva ratio, to refer simply to Parkinsonism with autonomic sweat tests and plasma noradrenaline measurements. failure (which can be due either to Lewy body disease Moreover, none of the usual tests of autonomic or MSA), though many physicians use it that way. function can distinguish between autonomic failure as http://jnnp.bmj.com/ Also, should the autonomic failure always precede the part of MSA and as part of Lewy body disease, neurological features? This uncertainty is exemplified although dynamic tests of circulating noradrenaline by Chokroverty,2' who wrote: "Although there are concentrations may help (see below). occasional reports of patients with Shy-Drager syn- Even the definition of orthostatic hypotension drome presenting initially with somatic neurological varies greatly from one group to another (table 1).132 manifestations before dysautonomic symptoms, it is Beyond the question of what numerical drop in difficult to decide whether these patients do in fact systolic/diastolic/mean blood pressure on assuming have the Shy-Drager syndrome". Moreover, one ofhis the erect posture is significant, other confounding on October 2, 2021 by guest. previously published cases (case 1 in an article in factors abound. How long should the subject be supine Brain' entitled "The syndrome ofprimary orthostatic before standing? Should the patient's blood pressure hypotension") developed somatic neurological be recorded after active standing (some MSA patients features 31 years after the onset ofpure may be unable to do this because of their motor and, at necropsy, had classic pathological findings of disability) or using a tilt-table (the latter will give a "the Shy-Drager syndrome"." Does Shy-Drager syn- different pulse and blood pressure profile),33 and for drome refer only to the full clinical syndrome they how long? Should Korotkow phase IV or V be used? J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Multiple system atrophy-the nature ofthe beast 83 Table I Some definitions oforthostatic hypotension

Schatz et al, 19635: The simultaneous occurrence of and with a decline in standing blood pressure of 30/20 mm Hg. Thomas & Schirger, 1963a: The simultaneous occurrence of giddiness, syncope or both, in association with a persistent drop of at least 50 mm Hg in systolic and a corresponding drop in diastolic pressure upon standing. Johnson et al, 1965f: A fall in systolic pressure ofmore than 20 mm Hg. Nick et al, 19672: An orthostatic drop of > 40 mm Hg systolic and > 30 mm Hg diastolic. Thomas & Schirger, 197029: A minimal orthostatic drop of 25 mm Hg in diastolic blood pressure from supine to standing position on at least one ofmany blood pressure readings. Thomas et al, 19813°: A consistent and persistent fall of 30 mm Hg or more in systolic and 15 mm Hg or more in diastolic pressure, accompanied by clinical symptoms. Cohen et al, 1987': The presence of orthostatic syncope or presyncope and sphygmomanometric confirmation (orthostatic reduction in systolic BP by > 30 mm Hg, or mean arterial pressure by > 20 mm Hg). Bannister & Mathias, 198832: When a fall ofmore than 20 mm Hg systoiic pressure on standing is found in a patient with symptoms, further investigation is justified.

Should symptoms be produced? Does failure to record decarboxylase inhibitor) because of faintness or sick- an abnormal drop on one occasion mean the patient ness. Nevertheless, whilst some such patients seem to does not have orthostatic hypotension? Does a single have IPD, a higher proportion of pathologically recording ofabnormal postural drop mean the subject proven MSA subjects have manifested such has orthostatic hypotension? What importance should intolerance to levodopa preparations. Curiously, one attach to post-prandial orthostatic hypotension, some of these are able to tolerate (with or when the patient is being treated with levodopa or a ), but usually without dramatic resultant agonist? clinical benefit. Quite apart from these uncertainties about the Although a few patients may display inappropriate diagnosis of autonomic failure, the diagnosis of MSA laughter or crying, numerous clinical accounts of also rests on shifting sands. The most recent criteria pathologically confirmed MSA have called attention Protected by copyright. used at the Mayo Clinic3' require: "The presence of to the striking preservation of intellect in the face of autonomic failure (see table 1). When striatonigral or severe motor disability. seems therefore not olivopontocerebellar involvement was confirmed on to be an integral feature of MSA. Coincidental , the diagnosis of MSA was Alzheimer's disease can certainly occur in MSA made". Unless levodopa unresponsiveness is specified patients,3s6- but at a rate no higher than among the these criteria could potentially include as MSA general age-matched population. In addition, a num- patients with Lewy body Parkinson's disease with ber of cases showing Parkinsonism, dementia and autonomic failure! autonomic dysfunction, with poor or absent response The term "Parkinson plus syndrome" has recently to levodopa, in life have been shown at post-mortem to enjoyed favour among neurologists attempting to be suffering from "cortical" or "diffuse" Lewy body separate out cases with atypical Parkinsonism whose disease.39 For practical purposes, dementia rules out features are incompatible with the idiopathic disease. uncomplicated MSA. Whilst this expression is useful, particularly in avoid- Lewy bodies have been found restricted largely to ing definitive alternative diagnosis where none can be pigmented brainstem nuclei in some patients also made with certainty, it neglects the single most showing the striatal pathology of MSA.404 We now suspicious feature, viz the lack of response to appreciate that incidental Lewy bodies, with some levodopa. Perhaps "Parkinson minus syndrome" degree of cell loss, may be seen in the brains of many http://jnnp.bmj.com/ would be just as clinically useful. Thus, a dramatic individuals who did not manifest clinical Parkinson- clinical motor response to treatment with levodopa at ism during life.49 It does not now seem necessary to an adequate dose for an adequate period oftime is for propose that cases showing MSA and Lewy bodies practical purposes always seen in patients with patho- have a "transitional variant" of the disease," merely logically proven uncomplicated Lewy body Parkin- that this is a chance superimposition of a common son's disease.4 A poor or absent response is the rule in pathological finding. However, the finding ofinciden- MSA patients, although transient significant benefit tal Lewy bodies does raise the possibility of an has occasionally been reported.35 In the absence of erroneous pathological diagnosis of IPD if the on October 2, 2021 by guest. clear pyramidal or cerebellar signs, this difference striatum is not also examined. IPD must have Lewy constitutes a major clinical tool for differentiating bodies in substantia nigra, but the presence of Lewy between IPD and MSA. It therefore seems bodies and cell loss in substantia nigra is not synony- appropriate that it should be included among diagnos- mous with clinical IPD, and hence does not exclude tic criteria for MSA with Parkinsonian features. One MSA. drawback, however, concerns patients who cannot The question of inheritance of MSA is best ap- tolerate an adequate trial oflevodopa (with peripheral proached through those cases presenting with Parkin- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

84 Quinn sonism and autonomic failure. There has been only a study ofHarding4). Moreover, mean disease duration handful of cases with pathologically proven MSA to death in familial cases was 14-9 years, and in where one other family member is affected by Parkin- sporadic cases was 6-3 years.53 In the clinical study of sonism,12 1340 a rate corresponding to the chance Harding' on 36 living sporadic cases of late onset occurrence of IPD. The family reported by Lewis in , mean duration of symptoms was 1964' is always cited as evidence that MSA can be 12-5 years. Only three (8%) patients had impassive inherited, but there was no pathology and the clinical facies, but no other extrapyramidal features. Nine features were atypical. Thus, the four cases examined patients (25%) had urinary symptoms. This series had had the disease for 7, 34 and 19 years, and 6 clearly differs from what we recognise as MSA, partly months respectively. The clinical features included because only cerebellar ataxia was needed for orthostatic hypotension, cerebellar, pyramidal and inclusion, and perhaps partly because, in an effort to extrapyramidal signs, but there was also amyotrophy, exclude cases with paraneoplastic cerebellar degenera- , footdrop and pes cavus. Given this tion, patients with a subacute course or a disease unusual clinical picture and given that no patho- duration ofless than two years were excluded. Ophth- logically proven cases of truly familial typical MSA almoplegia was more frequent, and pigmentary retinal have been recorded, it seems likely that this family did degeneration and optic atrophy only found, in familial not have MSA. Could they perhaps have had the cases.5' Since the predominantly striatonigral variant adult-onset familial with autonomic ofMSA is sporadic, it seems appropriate to include in failure described by Eldridge et al?5' The other the rubric of MSA only sporadic cases of OPCA celebrated instance ofinherited so-called striato-nigral (although this restriction would be at variance with the degeneration is the Joseph family.52 In this large wider usage of the term by Oppenheimer himself to dominant pedigree, disease onset usually occurs in the include familial OPCA). Moreover, to be considered twenties or thirties, and the clinical features vary as clinically probable cases of MSA, they should also

considerably. Spasticity, ophthalmoplegia, peripheral display either Parkinsonian features or autonomic Protected by copyright. neuropathy and cerebellar signs frequently occur, with failure, or both. only mild extrapyramidal signs and without promi- Neuropathological examination of the brain and nent autonomic failure. The pathology shows spinal cord cannot at present distinguish between invariant symmetrical degeneration of the cerebellum many cases of familial OPCA and sporadic cases of and thoracic cord, variable degeneration of the basis MSA, although the value ofintermediolateral column pontis, oculomotor nuclei, peripheral nerves, nigra, cell counts in this respect has not been fully assessed. striatum, but the inferior olives are always spared. Should this deter one from separating such cases? I MSA of SND predominance seems therefore to be a think not. A myocardial infarct due to coronary sporadic disease. atherosclerosis may look the same in someone with When one turns to OPCA, the genetic picture is familial hypercholesterolaemia as in a heavy eater and more complex. Among adult-onset cases of OPCA, smoker, yet the ultimate cause is different: on the one rather less than half seem to be inherited, as a hand genetic, on the other acquired. It should not dominant trait; the remainder have apparently arisen surprise us that a similar or even an identical patho- sporadically. Neither clinical features alone nor path- logical picture should develop via a common mechan- ology may suffice to differentiate between the inherited ism triggered by different root causes, one genetic and and the sporadic form in an individual case, although one perhaps acquired. in 1982 A group differences exist. Thus, Berciano's number of MSA subjects may display abnormal http://jnnp.bmj.com/ review53 of 117 cases of pathologically confirmed eye movements. Most commonly, this consists of OPCA, 39% of54 familial cases showed Parkinsonism impaired or absent convergence, hypometric volun- (55% of 63 sporadic cases), 50% pyramidal signs tary saccades and/or saccadic pursuit, and sometimes (46%), 96% cerebellar signs (87%) and 39% sphincter a supranuclear gaze palsy for up (and rarely down) disturbance (48%). Pathologically, in addition to gaze.55 Indeed, MSA is one of a number of causes of involvement of olives, pons and cerebellum, striatum the clinical picture of progressive supranuclear palsy, was affected in 22% of familial cases (38% of which is often erroneously taken to be synonymous and in 46% with sporadic) substantia nigra (48%). Thus, Steele-Richardson-Olszewski disease. Thus, a on October 2, 2021 by guest. neither Parkinsonian features nor sphincter distur- number of cases of MSA would fulfil the clinical bance, and neither striatal nor nigral pathology, diagnostic criteria for Steele-Richardson disease clearly differentiates between familial and sporadic proposed by both Golbe et al56 and Lees.5" Because of cases of OPCA. However, mean age of onset in the potential for confusion between the two diseases, I hereditary cases is earlier than in sporadic cases (28 would propose that a predominant downgaze paresis years versus 49 years in the clinicopathological study should constitute an exclusion criterion for the clinical of Berciano53; 39 years versus 49 years in the clinical diagnosis of MSA. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Multiple system atrophy-the nature ofthe beast 85 Table 2 Multiple system atrophy: proposed diagnostic Table 3 "Redflags": clinicalfeatures raising doubts about criteria a diagnosis ofideopathic Parkinson's disease

SND type OPCA type Early instability and falls ?Absent/atypical levodopa (predominant (predominantly AIMs parkinsonism) cerebellar) Rapid progression ?Disproportionate antecollis Irregularjerky tremor ?PH of hypertension ? Sporadic adult-onset Possible Poor or absent response to an ?Raynaud's or ergotism non/poorly adequate trial of levodopa levodopa responsive Autonomic failure parkinsonism* Abnormal eye movements beyond Above, plus severe Probable Sporadic adult-onset IPD range symptomatic cerebellar ± pyramidal Severe dysarthria/dysphonia autonomic failuret syndrome* Pain unrelieved by levodopa + /or cerebellar signs with severe Severe levodopa intolerance + /or pyramidal signs symptomatic *Pyramidal signs autonomic failuret *Cerebellar signs + /or parkinsonism tDSM III dementia p/m confinned Definite p/m confirmed Never part of IPD. tUncommon in both IPD and MSA. *Without DSM III dementia, predominant downgaze PSNP or other identifiable cause. tPostural syncope or presyncope and/or marked urinary incontinence or retention not due to other causes. of Parkinsonism may be over-represented. Sporadic: one other case of typical clinical IPD among 1st or 2nd Rapid clinical deterioration despite dopaminergic degree relatives allowable. treatment is also highly suspicious. Indeed, many Adult onset: onset age 30 years or above. physicians recognise this, and only consider MSA in Parkinsonian patients with cerebellar features or

pyramidal signs together with profound autonomic Protected by copyright. On the basis of the above considerations, and failure who deteriorate towards death within 5 or 6 following the proposals of groups formulating diag- years. Yet a number of cases of MSA survive 10 years nostic criteria for ' and for Alz- or longer after the onset ofclinical symptoms or signs, heimer's disease,57 I propose the diagnostic classifica- and may never develop cerebellar or pyramidal signs. tion set out in table 2. Undoubtedly this will need Failure to recognise this leads to a self-fulfilling further modification in the future, particularly in prophecy whereby MSA cases with longer disease regard to the definition ofautonomic failure, and also progression are not diagnosed as such in life. in the light of pathological verification of cases Similarly, failure to recognise the unusual nature of fulfilling these diagnostic criteria. Moreover, this the case makes a post-mortem examination less likely clinical diagnostic schema mirrors the drawbacks to be sought. considered above, in that it fails to exclude cases of Dating the onset ofthe disease is also problematical. Steele-Richardson disease not yet displaying a Should one take the first sign ofrelatively non-specific predominant downgaze paresis. impotence or sphincter disturbance, or date disease onset only from the onset of symptomatic postural "Redflags" (table 3) hypotension or ofthe first motor symptoms and signs? Besides the poor response to levodopa, and the Indeed, do any of these features in fact correspond to

additional presence ofpyramidal or cerebellar signs or the actual onset of the disease process? There is now http://jnnp.bmj.com/ autonomic failure as major diagnostic criteria, certain evidence to suggest that the onset of IPD may other clinical features may either raise a suspicion of considerably antedate the first clinical signs, perhaps MSA, or at least suggest that one might not be dealing by 20 years or even more. Given the redundancy with IPD. margin of central neuronal populations, it seems Symmetrical onset and absence ofa classical resting probable that in MSA, too, disease onset may long tremor have often been proposed as features distin- antedate clinical features. In this respect, it is of guishing MSA from IPD. However, marked and interest to examine the past history and previous persistent asymmetry and the presence of a classical records of cases of clinical MSA. A number have had on October 2, 2021 by guest. resting tremor may both be seen in cases of path- arterial hypertension diagnosed, and sometimes ologically proven MSA. Early instability and falls treated, several years before the first symptoms, only suggest a cause other than IPD. A consequence ofthis to later become normo- or hypotensive. Could this is that among patients whose Parkinsonism is revealed relate to early denervation hypersensitivity causing by, and persists after, treatment with neuroleptic supine hypertension? It is tempting also to speculate agents (eg prochlorperazine) given to combat vague on the significance of Raynaud's phenomenon occur- feelings of unsteadiness, those with alternative causes ring before, or during, treatment with dopaminergic J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

86 Quinn drugs. I vividly recall a patient with apparent nightly was experienced by 85%, daytime frequency of untreated IPD who, on monotherapy, six times or more by 74%, and 71% had been "caught developed severe vasospasm of all fingers of both short" with a dribble at least occasionally. Twenty five hands. His Parkinsonism did not improve and he went per cent said their hands and feet were bone dry in hot on to die of pathologically proven MSA. Was the or humid conditions, 15% experienced increasing Raynaud's a manifestation of an ergot drug acting on faintness between the onset ofParkinson's disease and an already abnormal autonomic nervous system? dopaminergic treatment, and 37-5% subsequent to Another man had attended 27 years earlier with a treatment (corresponding figures for postural black- complaint of dizziness of unknown cause, which outs were 6% and 9% respectively). Normal erections subsequently settled. Could this have been, in retro- were achieved only occasionally or never by 23% of spect, the first sign of his illness? males, with occasional erectile problems in as many as Myoclonic jerks, usually affecting the fingers, of 73%. Our judgement of the diagnostic significance of small amplitude, and often stretch-sensitive, occur in a autonomic symptoms in Parkinsonism as a pointer to number of patients with MSA, but are otherwise rare autonomic failure must be weighed against these rates, in non-demented Parkinsonians. An irregular, jerky and also those for an age-matched control population tremor of the hands is also a feature more commonly (work in progress). seen in MSA than IPD. Bizarre contractures of the hands may be more Investigations common in non-idiopathic Parkinsonism. Well recog- Autonomic function tests can demonstrate various nised in post-encephalitic cases, and in Parkinsonism- aspects of autonomic failure, but not its cause. dementia, they can also occur in MSA.363858 A more However, resting supine plasma noradrenaline (NA) frequent and characteristic feature suggesting MSA is levels, and their response to standing, may help to the development of a relatively fixed, disproportionate differentiate between groups of subjects with MSA antecollis538 59 hampering feeding, communication and and those with pure autonomic failure (which mostProtected by copyright. vision. commonly shows Lewy body pathology'"). Thus, Speech is almost always more severely affected in MSA patients usually have normal or slightly elevated MSA than in IPD. As well as the low volume plasma NA levels, whereas those with PAF usually monotony of Parkinsonism, a quivering, irregular, have low plasma NA levels.62 In contrast to normal severely hypophonic or slurring dysarthria is "often so subjects, neither group increases the plasma NA level characteristic that the diagnosis can be suggested by on standing.62 However, the clinical usefulness of listening to the patient on the telephone".59 Res- plasma NA levels as a diagnostic tool in individual piratory , especially at night, is also a helpful cases has not been demonstrated.62 diagnostic pointer, since vocal cord paralysis com- Computed tomographic (CT) scanning appears to monly occurs.' be ofonly limited usefulness in the diagnosis of MSA. Marked focal muscular atrophy and , In subjects with a predominantly cerebellar presenta- whilst reported in some cases with MSA,7 are in my tion, cerebellar and/or brainstem atrophy may be seen, experience most unusual. but since this is also seen in many familial cases of Pain, characteristically in, or maximal in, the most adult onset cerebellar atrophy this finding may not severely affected limbs, is not uncommon in IPD. In help in differential diagnosis. Among cases presenting such cases, it is usually dramatically improved or a predominantly, or a pure, Parkinsonian syndrome

abolished when levodopa turns the patient "on".6' the CT scan is usually normal. In only a minority of http://jnnp.bmj.com/ Some cases of MSA may experience similar deep cases will the scan demonstrate clear atrophy of aching limb pains59 which, in contrast, persist through- posterior fossa structures. Striatal CT images are out the day and are not relieved by levodopa. normal in all forms of MSA. In a patient with Parkinsonism, the significance of Magnetic resonance imaging, however, may well the presence and degree of autonomic symp- prove useful in demonstrating striatal pathology in tomatology may be very difficult to assess. I recently MSA, and its absence in IPD. Early studies using 1 5 asked 34 patients (23 male, 11 female, mean age 49-6, tesla T2 weighted images suggested that cases of

SD 8-9 years, mean disease duration 11, SD 4 9 years) "Parkinson's disease" with rapid progression and on October 2, 2021 by guest. to complete an autonomic questionnaire. All had been poor response to treatment showed altered signal diagnosed as suffering from Parkinson's disease, and particularly in putamen, and it was proposed this were attending a weekend meeting for younger might be due to abnormal deposition of iron in this sufferers organised by the Parkinson's Disease structure. The debate over iron content of the puta- Society. The group could certainly have included one minal pigments63 and its relationship to the MRI or more cases of MSA, but overall I had no reason to images continues unresolved at present. However, doubt the diagnosis of IPD. Nocturia at least once whatever the ultimate cause of the altered signal, it is J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

Multiple system atrophy-the nature ofthe beast 87 beginning to look as if MRI scanning can detect the results of a number of investigations must be taken putaminal pathology so characteristic of striatonigral into account in making the diagnosis. For the time cases ofMSA, thus differentiating them from IPD."" being, only clinical criteria have been advanced in Positron emission tomography (PET) scans ofMSA table 2. However, when more clinicopathological patients have so far been few in number. It comes as no correlation has permitted validation of diagnostic surprise that '8F-fluorodopa scans show low concen- tests, used singly or, more likely, in concert, we may tration of activity in striatum, as in IPD.6" The most arrive at a schema similar to that for multiple sclerosis, modem scanners with sufficient resolution also where categories of laboratory supported diagnosis' demonstrate a lower caudate uptake in MSA subjects have appeared. in contrast to relatively preserved caudate uptake in IPD.' However, it is likely that measures of post- synaptic function will prove more useful in differen- Treatment tiating between MSA and IPD, so that the results of Sadly, the treatment of MSA is most disappointing. "C-raclopride studies are awaited with interest. If Levodopa preparations may transiently give useful these scans can demonstrate clear and unequivocal improvement, but often either cause no improvement, differences, and if a ligand can be or give rise to intolerable nausea and vomiting and/or developed for SPET studies, then SPET scanning may symptomatic postural hypotension." However, it emerge as a useful diagnostic tool. should be realised that some patients who seem not to Electrophysiological investigations have been be responding to levodopa can still deteriorate sig- applied to a number of patients with clinical MSA. nificantly when the drug is withdrawn. Head-up tilt of Nerve conduction studies may sometimes reveal a the bed at night, elastic support stockings, fluorocor- subclinical polyneuropathy,3' and EMG studies may tisone and/or indomethacin, , DDAVP or suggest neurogenic atrophy in some individuals.7 atrial pacing may help cardiovascular problems.24"

Thermal threshold, visual and somatosensory evoked can reduce urinary frequency (but Protected by copyright. responses, and electrical and magnetic central motor may precipitate retention). Retention with overflow, conduction times have not yet been adequately or incomplete bladder emptying with infections, can explored. The EEG is not useful. One group has be managed with intermittent self-catheterisation (if demonstrated an abnormal latency and an abnor- hand mobility permits) or indwelling suprapubic or mality of the amplitude ratio of waves V/I of the urethral catheterisation. High fibre diet, bulk lax- brainstem auditory evoked responses (BSAEPs) in 11 atives, suppositories or enemas may be needed for and 13 patients out of 14 respectively with a clinical constipation. Tracheostomy for intermittent res- diagnosis of MSA.' However, our own unpublished piratory stridor (especially at night) must be con- investigations showing normal BSAEPs in a number sidered with the utmost care. It may only cruelly of, mostly less severely affected, subjects (including prolong a precarious existence before inevitable death. one with pathologically proven MSA) lead us to doubt Similarly, cricopharyngeal myotomy or gastrostomy the specificity of this abnormality in patients earlier in in patients with severe dysphagia is seldom, if ever, the course of the disease. indicated. The paramedical specialities of physio- One particular electrophysiological investigation therapy, , speech therapy (often appears to be extremely useful in supporting a clinical directed at swallowing problems and communication diagnosis of MSA. In an initial study in 14 patients aids rather than improving speech per se) and social

with clinical MSA (Parkinsonism, autonomic failure work often are of much more practical use than http://jnnp.bmj.com/ and pyramidal signs in all 14, additional cerebellar anything the physician can offer. With their grave signs in two), individual motor units recorded from the prognosis and their lack ofresponse to levodopa, these striated component of the urethral sphincter were patients are, to my mind, more in need of a break- consistently abnormal, showing polyphasia and long through in neuronal implant treatment than those duration.' Subsequent studies in a further 26 subjects with idiopathic Parkinson's disease. If embryonic with probable, 15 with possible MSA, and 13 with nigral implants can be shown to work in IPD, then probable IPD, have shown that this investigation has logically the next patient groups to be offered (this high specificity (0 92) but less sensitivity (0.62) in time striatal) implant treatment should be those with on October 2, 2021 by guest. differentiating between probable MSA and probable MSA. IPD.' Moreover, one probable MSA subject with We desperately need better diagnosis of MSA if we abnormal results has since died, with pathological are to seek the cause, and hence a preventive or confirmation of the diagnosis. retardant treatment, for this terrible affliction. In the It is therefore apparent that no single clinical feature meantime, we need to draw on all our skills and or investigational abnormality is diagnostic of MSA. compassion to help and comfort those who are struck Rather, the complete clinical picture together with the by this disease. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.52.Suppl.78 on 1 June 1989. Downloaded from

88 Quinn

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