msa review article

Seediscussions,stats,andauthorprofilesforthispublicationat:http://www.researchgate.net/publication/5234495

Multiplesystematrophy

ARTICLEinTHENEUROLOGIST·AUGUST2008

ImpactFactor:1.16·DOI:10.1097/NRL.0b013e318167b93f·Source:PubMed

CITATIONS

7

READS

94

2AUTHORS,INCLUDING:

HelenLing

UniversityCollegeLondon

51PUBLICATIONS408CITATIONS

SEEPROFILE

Availablefrom:HelenLing

Retrievedon:08November2015

http://www.researchgate.net/publication/5234495_Multiple_system_atrophy?enrichId=rgreq-7e1d9106-7d65-4d9c-81dc-dac86319cb48&enrichSource=Y292ZXJQYWdlOzUyMzQ0OTU7QVM6MTUwMDA5MDAxNTQ5ODI0QDE0MTI3NzYzNDE2NDA%3D&el=1_x_2

http://www.researchgate.net/publication/5234495_Multiple_system_atrophy?enrichId=rgreq-7e1d9106-7d65-4d9c-81dc-dac86319cb48&enrichSource=Y292ZXJQYWdlOzUyMzQ0OTU7QVM6MTUwMDA5MDAxNTQ5ODI0QDE0MTI3NzYzNDE2NDA%3D&el=1_x_3

http://www.researchgate.net/?enrichId=rgreq-7e1d9106-7d65-4d9c-81dc-dac86319cb48&enrichSource=Y292ZXJQYWdlOzUyMzQ0OTU7QVM6MTUwMDA5MDAxNTQ5ODI0QDE0MTI3NzYzNDE2NDA%3D&el=1_x_1

http://www.researchgate.net/profile/Helen_Ling?enrichId=rgreq-7e1d9106-7d65-4d9c-81dc-dac86319cb48&enrichSource=Y292ZXJQYWdlOzUyMzQ0OTU7QVM6MTUwMDA5MDAxNTQ5ODI0QDE0MTI3NzYzNDE2NDA%3D&el=1_x_4


http://www.researchgate.net/institution/University_College_London?enrichId=rgreq-7e1d9106-7d65-4d9c-81dc-dac86319cb48&enrichSource=Y292ZXJQYWdlOzUyMzQ0OTU7QVM6MTUwMDA5MDAxNTQ5ODI0QDE0MTI3NzYzNDE2NDA%3D&el=1_x_6


REVIEW ARTICLE

Multiple System Atrophy

Roongroj Bhidayasiri, MD, MRCP (UK),*† and Helen Ling, BMBS, FRCP (T)*

Background: It has been almost 4 decades since the descriptions ofthe 3 parts of multiple system atrophy (MSA) have taken place,characterized clinically by dysautonomia, parkinsonism, and cere-bellar dysfunction. The discovery of a distinctive pathologic makerhas finally provided the conceptual synthesis of these 3 entities intothe universal designation of MSA as a distinct disease process witha complex combination of clinical presentations. Although advanceshave been made in terms of awareness and knowledge concerning theclinical features and pathophysiology of MSA, it remains challengingfor neurologists who treat these patients to differentiate MSA from itsmimics as well as providing them with effective treatment.Review Summary: The aim of this review is to provide an overviewof the advances in the knowledge of the disease, to highlight typicalfeatures useful for the recognition of its entity, and to enlist differenttreatment options.Conclusion: Despite the fact that there is still no treatment modalitythat can alter the disease progression, a number of useful symptom-atic treatment measures are available and should be offered topatients to ameliorate the nonmotor features of MSA and even themotor features that may at least transiently respond to treatment.

Key Words: multiple system atrophy, olivopontocerebellaratrophy, Shy-Drager syndrome, striatonigral degeneration,parkinsonism

(The Neurologist 2008;14: 224–237)

Multiple system atrophy” (MSA) is a syndrome withcardinal features of dysautonomia, parkinsonism, cer-

ebellar ataxia, and pyramidal signs. Historically, MSA wasdescribed in 3 different ways. First, Dejerine and Thomas1

introduced the term olivopontocerebellar atrophy (OPCA) todescribe the main pathologic changes in MSA patients with asporadic, late-onset, predominantly cerebellar syndrome, butalso with parkinsonism and dysautonomia. Subsequently, Shyand Drager2 emphasized neurogenic central autonomic fail-ure in patients who also had parkinsonism and cerebellarsigns. Lastly, Adams et al3 highlighted the features of rapidlyprogressive parkinsonism in patients with the pathology ofstriatonigral degeneration (SND). The consensus term ofMSA was ultimately introduced to collectively describe thesedifferent manifestations of the same condition with overlap-ping pathology.4 Nowadays, MSA is considered as a sporadic,adult-onset progressive neurodegenerative disorder encompass-ing cases of sporadic OPCA �MSA-cerebellar (MSA-C); butexcluding dominantly inherited OPCA� and SND �MSA-parkinsonism (MSA-P)�.5,6 Patients are classified as MSA-Cor MSA-P depending on the predominance of cerebellarataxia or parkinsonism, with dysautonomia being a constantfeature in both subtypes.

The precise incidence figures of MSA are not known,but it is likely that MSA is under-recognized and misdi-agnosed. Approximately 10% of patients with parkinson-ism have MSA; giving a calculated prevalence of 16.4 per100,000 population.7 This number is actually higher thanthe estimates from population based studies, which rangedfrom 1.9 to 4.9 cases per 100,000 population.8 –11 Thesefigures indicate a prevalence of MSA that is quite similarto that of other well-known neurologic disorders, such asHuntington chorea, myotonic dystrophy, and motor neurondisease. Limited information is available on the incidenceof MSA. By applying the medical records-linkage systemof the Rochester Epidemiology project to identify subjectswhose records contained documentation of parkinsonismbetween 1976 and 1990, only 9 incident cases of MSAwere found, giving the annual incidence rate of 3 patientsper 100,000 per year for the ages between 50 and 99years.12 No cases of MSA had onset before 50 years of age.So far, no single environmental factor has been conclu-sively shown to increase or to reduce the risk of MSA.However, a small number of case-control studies revealeda higher risk of disease onset associated with occupationalexposure to organic solvents, smoking, farming, plasticmonomers, pesticides, and metals.13–15

From the *Division of Neurology, Chulalongkorn Comprehensive Move-ment Disorders Center, Chulalongkorn Univerisity Hospital, Bangkok,Thailand; and †Department of Neurology, David Geffen School ofMedicine at UCLA, Los Angeles, California.

Reprints: Roongroj Bhidayasiri, MD, MRCP (UK), Division of Neurology,Chulalongkorn Comprehensive Movement Disorders Center, ChulalongkornUniversity Hospital, Bangkok 10330, Thailand. E-mail: [email protected].

Copyright © 2008 by Lippincott Williams & WilkinsISSN: 1074-7931/08/1404-0224DOI: 10.1097/NRL.0b013e318167b93f

“Multiple system atrophy” is a syndrome with

cardinal features of dysautonomia,

parkinsonism, cerebellar ataxia, and

pyramidal signs.

The Neurologist • Volume 14, Number 4, July 2008224

CLINICAL PRESENTATIONMSA usually manifests in middle age (the median age

of onset is 53 years), affects men slightly more than women(1.3:1) and progresses relentlessly with a mean survival of 6to 9 years.16–21 There is a substantial variation in diseaseprogression with survival of more than 15 years in someinstances, but the disease duration was found to be signifi-cantly shorter than the duration of PD.22 As the term indi-cated, the initial presentation of MSA may vary, but usuallyincludes autonomic failure, parkinsonism, cerebellar ataxia,and pyramidal signs. According to one descriptive study,46% of MSA patients presented with asymmetric akinetic-rigid parkinsonism (MSA-P), associated with postural andaction tremor.17,23 However, a classic pill-rolling rest tremorwas observed in only 9% of patients. The parkinsoniansubtype (MSA-P) maybe a predictor for poor survival.24

Postural instability maybe compromised early, but recurrentfalls at disease onset are unusual in contrast to progressivesupranuclear palsy (PSP).25 Supranuclear vertical gaze palsyand increased age at symptom onset are useful clinical fea-tures to help distinguish PSP from MSA.25,26 Sometimes,bilateral vocal cord paralysis, stridor and respiratory insuffi-ciency can be the primary presenting symptoms of MSA.27

Although most MSA patients respond poorly to levodopa,29% of patients were reported to have a good or excellentresponse at some stage. Differentiation between MSA-P andPD can be very difficult in the early stages because of theiroverlapping features such as asymmetric akinesia, resttremor, and initial good levodopa response.22,28,29 In mostcases, a fully developed clinical picture of MSA-P evolveswithin 5 years of disease onset, allowing a clinical diagnosisto be made during follow-up.30

Similarly to parkinsonism, dysautonomia was the initialfeature in 41% of patients with MSA and was found in 97%at 7-year follow-up.17 Early development of autonomic dys-function may predict a poor prognosis in patients withMSA.31 Impotence was almost universal among male patientsand in women was urinary urge incontinence.32 Indeed,disorders of micturition in MSA are caused by changes in thecomplex peripheral and central innervation of the bladder andcommonly appear earlier and are more severe than in PD.32

By contrast, constipation occurs equally in PD and MSA.Although symptomatic postural hypotension occurred in 68%of patients, it was usually mild to moderate and recurrentsyncopal attacks were present in only 15% of patients.Although autonomic dysfunction can be a feature in bothMSA and PD, the presence of severe autonomic dysfunc-tion, autonomic dysfunction that precedes parkinsonism,and history of inspiratory stridor are all individually sug-gestive of MSA.33

Only a minority of MSA patients (5%) have cerebellarsymptoms or signs as initial features, comprising of predominantgait ataxia, limb ataxia, and dysarthria.17 Spontaneous or gaze-evoked nystagmus, often subtle, was detected in 25% of pa-tients.17 Interestingly, MSA-C appears to be more common thanMSA-P and MSA-A in Japan, compared with western coun-tries.20,34 At an early stage, many MSA-C patients have adisease restricted clinically to cerebellar signs, and maybe indis-tinguishable from other patients with idiopathic late-onset spo-radic ataxia. The development of extracerebellar symptoms(such as autonomic failure or parkinsonism) within the first 4years after ataxia is usually supportive of MSA-C.35,36

As indicated, patients with MSA may initially presentwith parkinsonism indistinguishable to PD, autonomic dys-function similar to pure autonomic failure, or cerebellarataxia compatible with other sporadic adult-onset ataxia.These presentations make the correct diagnosis difficult,particularly when applied only at disease onset.37 However,the progressive nature of MSA is characterized by the gradualinvolvement of other initially unaffected systems.20,37–39

Thus, patients who initially present with extrapyramidal fea-tures usually progress to develop autonomic dysfunction,cerebellar disorders, or both. Similarly, symptoms and signsin other types of MSA (MSA-A, MSA-C) often evolve toother systems outside its initial presentation. In a series of100 cases of clinically probable MSA, at the last evaluation,97% of patients had autonomic failure, 91% had parkinson-ism, 52% had cerebellar features, and 61% had pyramidalsigns.16,17 In addition, certain other features, if present, mayraise suspicion of MSA, or at least suggest that one might notbe dealing with PD.40,41 These features, so called “red flags,”are often early warning signs of MSA.40,42 Although thesefeatures are helpful, the presence of one of the followingsshould not be considered as diagnostic (Table 1).

Orofacial dystonia in MSA may occur spontaneously oras part of levodopa-induced dyskinesias, which predomi-

Although autonomic dysfunction can be a

feature in both multiple system atrophy and

PD, the presence of severe autonomic

dysfunction, autonomic dysfunction that

precedes parkinsonism, and history of

inspiratory stridor are all individually suggestive

of multiple system atrophy.

The development of extracerebellar symptoms

(such as autonomic failure or parkinsonism)

within the first 4 years after ataxia is usually

supportive of multiple system

atrophy-cerebellar.

The Neurologist • Volume 14, Number 4, July 2008 Multiple System Atrophy

© 2008 Lippincott Williams & Wilkins 225

nantly affects craniocervical region.43 Interestingly, most ofthe dyskinesias were dystonic and there is no clear explana-tion for the topographic predilection and dystonic nature oflevodopa-induced dyskinesias in MSA. The dystonia mayalso occur in the absence of motor response.44 In some cases,the appearance of facial dystonia in MSA may reminiscent ofrisus sardonicus in cephalic tetanus.45,46

Pisa syndrome is a form of axial dystonia and campto-cormia is forward flexion of the trunk. Both conditions havebeen described in patients with MSA.47–49 However, theseare nonspecific features and maybe observed in other parkin-sonian disorders, including PD.50

Although rare, disproportionate anterocollis is consideredas a characteristic feature in MSA43,51–53 (Fig. 1). It may emergeat any time throughout the disease course.43,52 Whether theanterocollis represents true dystonic posture or myopathy of theneck extensor muscles is unknown.54 However, botulinum toxininjections into sternocleidomastoid muscles are usually of littlebenefits and may worsen dysphagia in these patients.55

Postural and action myoclonus in MSA; referred tominipolymyoclonus, are abnormal small amplitude, non-

rhythmic movements involving just 1 or a few fingers, ormore rarely the whole hand.23,56 These features have beenreported in patients with MSA-P.23

Dysarthria in patients with MSA maybe almost diag-nostic.57 In addition to hypophonic monotony of parkinsonianspeech, speech in patients with MSA-P usually have anincrease in pitch and a quivery croaky strained element,reminiscent of myoclonic speech.40

Over time, MSA patients are susceptible to sleep-relatedbreathing disorders, resulting in nighttime oxygen desatura-tion.16,58,59 Whether caused by vocal cord paralysis or dystoniaof the vocal cords, nighttime inspiratory stridor is a helpfuldiagnostic pointer, but also indicates a poor prognosis.60–62 Itmay develop at any disease duration and may present acutely asan abductor laryngeal paresis requiring immediate resuscitation.MSA patients can present with rapid eye movement sleepbehavior disorder.63 Polysomnographic studies also suggestedthat rapid eye movement sleep behavior disorder in the setting ofMSA were greater than in PD, suggesting a more severe dys-function in the structures that modulate rapid eye movementsleep.64 Sleep apnea in MSA can be central or peripheral as aresult of lower brainstem pathology and vocal cord dysfunc-tion.65 Sleep apnea may cause sudden nocturnal death in patientswith MSA, thus it warrants early detection and treatment.59 It isimportant to ask patients and caregivers regarding symptoms ofdaytime sleepiness and nocturnal sleep behavior, such as heavysnoring and witnessed apnea episode, to prompt early investi-gation and treatment.

The “cold hand sign” referring to cold, dusky, viola-ceous hands and fingers with poor circulatory return afterblanching by pressure is another clinical red flag, suggestinga defect in neurovascular control of distal extremities.66,67

Some MSA patients may experience Raynaud phenomena,characterized by initial hands or feet pallor, followed bycyanosis and later redness.68

Some patients with MSA may develop emotional in-continence, characterized by laughter and crying.40,69,70

HOW TO DIAGNOSE MSA?The diagnosis of MSA rests on clinical history and

neurologic examination identifying core diagnostic features,including parkinsonism, autonomic dysfunction, cerebellarfeatures, or pyramidal signs. The presence of clinical red flagsmaybe helpful in leading to the diagnosis of MSA, but theabsence of these features does not exclude the diagnosis. It isalso worth considering certain exclusion criteria that areapplied (Table 2). For instance, there has never been apathologically proven case of MSA starting before the age of

TABLE 1. “Red Flags” in Clinical Diagnosis of MultipleSystem Atrophy

Early severe autonomic dysfunction

Spontaneous or L-dopa-induced sustained orofacial dystonia

Disproportionate anterocollis, Pisa Syndrome

Stimulus-sensitive myoclonus or minipolymyoclonus

Dysarthria, characterized by high pitched, quivery croaky strained voice

Sleep apnea, inspiratory stridor, vocal cord paralysis/dystonia

Dysphagia

REM sleep behavior disorder (RBD)

“Cold hand sign” with poor microcirculation to distal extremities

Emotional incontinence

FIGURE 1. Disproportionate anterocollis and drooling of apatient with MSA-P.

Sleep apnea may cause sudden nocturnal death

in patients with multiple system atrophy, thus it

warrants early detection and treatment.

Bhidayasiri and Ling The Neurologist • Volume 14, Number 4, July 2008

© 2008 Lippincott Williams & Wilkins226

30 years.40 Frank dementia should also exclude the diagnosisbecause severe cognitive dysfunction is so unlikely at theearly stage of MSA. Despite some suggestions, there has notbeen a single instance of familial MSA with pathologic proofof diagnosis.71–73 A relative of typical PD would be moreacceptable by chance. The presence of eye movement abnor-malities, including slow saccades, limitation of vertical gaze,and initiating saccades should favor PSP or corticobasaldegeneration, but exclude MSA.26,74,75

A reliable diagnosis of MSA can be made on clinicalgrounds when patients present sporadically in middle agewith a combination of dysautonomia and parkinsonism ordysautonomia and cerebellar signs. A significantly more

difficult task is when patients present at symptom onset,particularly with an isolated clinical symptom or sign. Inone epidemiologic study, MSA was rarely recognized inclinical practice and is frequently mistaken for PD.9 Sim-ilarly, in a separate clinicopathologic study, primary neu-rologists (who followed up the patients clinically) identi-fied only 25% of MSA patients at the first visit (42 monthsafter disease onset).76 At their last follow-up (74 monthsafter disease onset), 50% of patients were still misdiag-nosed, with the correct diagnosis in the other half beingestablished on average 4 years after disease onset. Thisevidence suggests that the accuracy of clinical diagnosis ofMSA was suboptimal at both the first (56%) and the last(69%) visits.76

As a result, a set of diagnostic criteria has been pro-posed to improve the diagnostic accuracy. First, the Quinn’scriteria which classified patients as either SND or OPCA typeMSA, suggested 3 levels of diagnostic probability; possible,probable, and definite in addition to a set of exclusioncriteria.41,77 A definite diagnosis requires neuropathologicalconfirmation. Because of the suboptimal diagnostic accuracyof the Quinn’s criteria,78 an International Consensus Confer-ence promoted by the American Academy of Neurologydeveloped an optimized criterion, which is now widely usedfor the clinical diagnosis of MSA.6,79 Similar to the Quinn’scriteria, the consensus criteria specified 3 diagnostic categories ofincreasing certainty; possible, probable, and definite (Table 3). Adefinite diagnosis requires a typical neuropathologic lesion patternand deposition of �-synuclein glial cytoplasmic inclusions (GCI).The discrepancy between the 2 sets of diagnostic criteria largelyreflects the weight given to autonomic disorders by the consensus

TABLE 2. Exclusion Criteria for the Diagnosis of MultipleSystem Atrophy

1. History

Symptomatic onset under 30 yr of age

Family history of a similar disorder

Systemic diseases or other identifiable causes for clinical features

Hallucination unrelated to medication

2. Physical examination

Disease Statistical Manual (DSM) criteria for dementia

Prominent slowing of vertical saccades or vertical supranuclear gazepalsy

Evidence of focal cortical dysfunction such as aphasia, alien limbsyndrome, and parietal dysfunction

3. Laboratory investigation

Metabolic, molecular genetic, and imaging evidence of an alternativecause of clinical features

TABLE 3. Consensus Statement on the Diagnosis of Multiple System Atrophy, According to the Guidelines of the AmericanAutonomic Society and the American Academy of Neurology (Modified with permission from N Engl J Med.208)

Diagnosis Definition

Possible One criterion plus 2 disease characteristics from other domains Autonomic criterion plus criterion for poorly

Probable, MSA-P responsiveparkinsonismAutonomiccriterionpluscriterionforcerebellardysfunctionPathologicalconfirmation

Probable, MSA-C

Definite

Feature Defining Criteria Disease Charcteristics

Autonomic failure (i) Orthostatic fall in blood pressure by �30 mm Hg (systolic)or 15 mm Hg (diastolic)

(a) Orthostatic hypotension

(ii) Persistent urinary incontinence with erectile dysfunction (in men) (b) Urinary incontinence

(iii) Both (i) and (ii) (c) Bladder-emptying difficulty

(d) Erectile dysfunction

Parkinsonism Bradykinesia plus (i), (ii), or (iii) (a) Progressive reduction in speed and amplitude

(i) Rigidity with repetition of limb movements

(ii) Postural instability (b) Rigidity

(iii) Tremor (c) Primary postural reflex loss

(d) Tremor (postural, rest, or both)

(e) Minimal or transient response to levodopa orother dopaminergic drugs

Cerebellar dysfunction Gait ataxia plus (i), (ii), or (iii) (a) Wide-based stance and irregular steps

(i) Limb ataxia (b) Limb ataxia

(ii) Sustained gaze-evoked nystagmus (c) Ataxic speech

(iii) Ataxic dysarthria (d) Gaze-evoked nystagmus



guideline and to the inclusion of the abnormal sphincter electro-myographic (EMG) in the Quinn’s criteria.80

These published diagnostic criteria are commonly imple-mented in clinical studies or therapeutic trials. Indeed, there is noone set of ideal criteria and their selection for use largelydepends on the objectives of the clinical studies. A clinical trialthat aims to recruit true MSA cases for a proposed interventionthat is costly and relatively toxic will need to sacrifice sensitivityfor a high positive predictive value. In this case, the use ofconsensus probable category seems to be the best choice.81 Onthe other hand, a pragmatic trial of a cheap, safe, and effectivetherapy that requires initiation early in the disease course wouldfavor high sensitivity at the expense of positive predictive value.In this scenario, the Quinn’s possible category would be theoptimum choice.81 In a validation study, the application of eitherset of diagnostic criteria was superior to actual clinical diagnosismade early in the disease, but there was little difference by thelast clinic visit.81 Therefore, in clinical practice, these criteriashould also be used whenever the diagnosis of MSA is consid-ered to increase diagnostic accuracy. The high specificity ofthese diagnostic criteria reduces the chance of physicians falselydiagnosing PD as MSA, which has a much worse prognosis andlimited therapeutic benefits.

INVESTIGATIONSThe clinical diagnosis of MSA relies heavily on

history and neurologic examination, therefore additionalinvestigations are usually performed to exclude alternativediagnosis or to support the presence of multisystem in-volvement, particularly when the standard examinationgives equivocal results, as in autonomic dysfunction. Asshown in the consensus criteria, the abnormalities of theinvestigations are not listed as required features to supportthe diagnosis. Therefore, in a patient with compatiblehistory and examination, it is not always necessary torequest further investigations. In addition, the investiga-tions may also give equivocal results at the early stage ofthe disease. However, a number of investigations havebeen described and detailed below, which maybe consid-ered when indicated. They are grouped into 2 main cate-gories: neuroimaging and autonomic function tests.

NeuroimagingMagnetic Resonance Imaging (MRI)

At present, there is no MRI criterion capable of diag-nosing MSA. However, there are certain MRI abnormalitieswhich may assist in differentiating MSA from its mimics.82

However, it is important to note that none of these signs arediagnostic and the sensitivity and specificity of these changesare uncertain. In a minority of MSA patients, no abnormali-ties on MRI were seen.83 These features are detailed below.

MRI of the patients with MSA frequently disclosedatrophy of cerebellar vermis, and less so of cerebellar hemi-spheres, middle cerebellar peduncles, pons, and lower brain-stem.84,85 Although these changes maybe indistinguishablefrom patients with autosomal dominant cerebellar ataxia, thepattern of atrophy has been shown to correlate with thepathologic process in OPCA.35,86 Furthermore, signal hyper-

intensities within the pons and middle cerebellar pedunclehave been observed reflecting degeneration of the pontocer-ebellar fibers.84,87 Whether magnetic resonance volumetrywill contribute to the differential diagnosis of MSA fromother parkinsonian disorders remain to be confirmed.

In addition to putaminal atrophy,88 the presence ofaccentuated low signal intensity on T2-weighted image asso-ciated with hyperintense rim, presumed to be related to irondeposition, was observed in the external putamen, termed“slit-like void signal”84,89–93 (Fig. 2). Although these changesmay also occur in patients with PD or in patients withoutparkinsonism, slit-like void signal is considered as a rathersensitive and specific abnormality in patients with MSA.83,94–96

Increased putaminal hypointensities maybe associated with aslit-like hyperintense band lateral to the putamen, reflecting areactive gliosis and astrogliosis97 (Fig. 3). According to anumber of studies, the pattern consisting of hypointense andhyperintense T2 changes within the putamen is highly specificMRI sign of MSA, whereas hypointensity alone remains asensitive, but nonspecific sign of MSA.98,99 With the abovemen-tioned abnormalities, an algorithm has also been proposed forthe MRI diagnosis of MSA-P and PD.100

Less frequent than putaminal lesions, cruciform signalhyperintensity on T2-weighted images has been occasionallyobserved in mid pons, resembling a hot-cross bun (Fig. 4),traditionally baked for the last Thursday before Easter.83,85,101

“Hot-cross bun” appearance in MSA probably reflects theloss of pontine neurons and myelinated transverse cerebellarfibers with preservation of the corticospinal tracts.

Further to the above changes observed on MRI, diffu-sion-weighted images might provide additional support fordiagnosing MSA-P. Distinguished from patients with PD andhealthy volunteers, the increased putaminal regional apparentdiffusion coefficient was demonstrated in patients with MSA-P,suggesting ongoing SND.102 In a most recent study, diffu-sion-weighted images were shown to be superior to tilt testingand MIBG scintigraphy in the differential diagnosis of PDversus MSA-P.103

Proton magnetic resonance spectroscopy (1H-MRS) al-lows the study of brain metabolism, by detecting chemicalchanges in certain molecules within brain areas. In relation toMSA, principal metabolite signs detected by 1H-MRS N-acetylaspartate (NAA) as an indirect expression of the integ-rity of neurons, and creatine (Cr) as a marker for energymetabolism.104 By applying multiple regional single voxel1H-MRS to the putamen, basis pontis, and cerebral whitematter in patients with MSA, significant NAA/Cr reductions

The pattern consisting of hypointense and

hyperintense T2 changes within the putamen is

highly specific magnetic resonance imaging sign

of multiple system atrophy.



have been demonstrated in the basis pontis of patients withMSA-C and MSA-P whereas putaminal NAA/Cr was onlyreduced in patients with MSA-P.105 None of these abnormal-ities were observed in patients with PD and normal con-trols.105,106 These results suggest that combined assessment ofNAA/Cr in the basis pontis and the putamen maybe effective indifferentiating MSA-P from PD with high specificity.105

Functional ImagingDifferent functional imaging methods have been used

in the investigations of parkinsonism, including the assess-ment of receptor bindings and glucose metabolism. Gener-ally, we can measure the activity of presynaptic nigrostriataldopaminergic terminals by using ligands for dopa decarbox-ylase and the dopamine transporter. Alternatively, the func-tion of postsynaptic dopamine can be assessed by usingdopamine D2 receptor ligands. Similar to PD, the putaminaluptake of �18F�fluorodopa and S-�11C�nomifensine on positronemission tomography (PET) was reduced in patients withMSA.107,108 Although the caudate uptake was markedly re-duced in MSA patients, as opposed to moderate reduction inPD, the �18F�fluorodopa PET alone cannot be used to differ-entiate MSA from PD.109 Furthermore, measurements of

striatal dopamine D2 receptor densities using raclopride PETalso failed to differentiate between PD and MSA, demon-strating a similar loss of densities.110 In contrast to PD, inwhich FDG PET showed a characteristic pattern of increasedmetabolism in the lentiform nucleus, thalamus, pons, and cere-bellum, and relatively decreased metabolism in the lateral fron-tal, paracentral, and parietal areas, FDG PET in MSA patientsdisclosed a relative hypometabolism of the lentiform nucleusand the cerebellum even in early disease stages.111–113

In addition to PET, single photon emission computedtomography (SPECT), particularly with 2�-carboxy-me-thoxy-3�-4-�4-iodophenyl�tropane or �123I� �-CIT is alsoused to assess the activity of dopamine transporter at thepresynaptic level. Because of the common pathologic in-volvement of the striatum in MSA, PSP, corticobasal degen-eration, and PD, this method alone cannot be used to differ-entiate among various types of parkinsonism.114 However,(123I) �-CIT SPECT is probably useful in the differentiationof patients with parkinsonism from controls.115,116 At thepostsynaptic level, SPECT with �123I�-iodobenzamide as D2receptor ligand has demonstrated low binding of both stria-tum in patients with clinically probable MSA compared withpatients with PD or other controls.84,117 Although this neuro-imaging technique maybe used to differentiate MSA from PD or

FIGURE 2. Axial T1-weighted MRI of a patient with MSA-Pshowing attenuation of signal in the left putamen (whitearrow).

FIGURE 3. Axial T2-weighted MRI of a patient with MSA-Pshowing a border of hyperintense signal in the left lateralputamen (black arrow).



healthy controls, its low binding affinity to both striatum limitsits predictive value for early diagnosis of MSA.

Metaiodobenzylguanidine (MIBG) is a norepineph-rine analogue that is taken up and stored in sympatheticnerve endings, and when labeled with �123I�, MIBG can beused with SPECT to examine peripheral postganglionicsympathetic terminals.118 Although most imaging studieswith �123I� MIBG in PD patients yielded decreased cardiacuptake, indicating myocardial postganglionic sympatheticdysfunction, several MIBG investigations of MSA dis-closed a preserved cardiac binding.119 –124 One study dem-onstrated that �123I� MIBG has a capacity to differentiate246 patients with PD from 45 patients with MSA with asensitivity of 90% and a specificity of 95%.119

Autonomic Function Tests

According to the consensus criteria, the presence ofboth orthostatic hypotension and urinary dysfunction arerequired for the defining criteria of autonomic failure in theclinical diagnosis of MSA (Table 3). Although the presence

of these features makes the diagnosis of MSA more likely, itsspecificity in any individual patient is unknown. Indeed, thepresence of autonomic disturbance alone did not distinguishMSA from PD.33 Furthermore, the clinical combination ofparkinsonism and dysautonomia is as likely to be caused byPD as by MSA.125 Therefore, the presence of dysautonomiashould only be regarded as one of the contributory featureswhile taking other clinical features of individual patients intoaccount before the diagnosis of MSA can be concluded.

Cardiovascular FunctionIn contrast to PD, cardiovascular dysfunction in MSA

seems to be caused by central rather than peripheral auto-nomic failure.119,123 During supine rest, the norepinephrinelevels, representing postganglionic sympathetic efferent ac-tivity, were normal in patients with MSA and there was nodenervation hypersensitivity, which indicated a lack of in-creased expression of adrenergic receptors on peripheralneurons.126 The response to tilt testing was also impaired, butwith little increase in the level of norepinephrine. In addition,although perfusion pressure was significantly reduced duringhead-up tilt test, compensatory cerebral vasodilation wasshown to respond to orthostatic hypotension and, in turn,preventing reduction in cerebral oxygenation.127,128

Bladder FunctionBecause the nature of bladder dysfunction in MSA

maybe caused by degeneration of the pontine micturitioncenter as well as later involvement of Onuf’s nucleus,129–131

urodynamic studies show different characteristic patterns ofabnormality depending on the stage of the disease.32,132,133 Inthe early stage of MSA, there is often detrusor hyperreflexia,often with bladder neck incompetence because of abnormalurethral sphincter function, explaining the symptoms of earlyurgency and frequency, followed by urge incontinence. Dur-ing the advanced stage, the ability to initiate a voluntarymicturition reflex and the strength of the detrusor contractionsdiminish, which account for increased postmicturition resid-ual urine volumes and overflow incontinence.

Sphincter ElectromyogramThe selective degeneration of Onuf’s nucleus in

MSA129,130,134 has led to the use of EMG assessment of theanal and urethral sphincters in patients with MSA. Severalstudies demonstrated signs of denervation and renervation inthe sphincter electromyogram of patients with MSA, suggest-ing that it might be a reliable test to differentiate MSA fromPD.135–137 However, neurogenic changes of external analsphincter muscles have also been demonstrated in a numberof other neurodegenerative disorders, such as PD,138,139

PSP,140 thus, such findings are not specific to MSA. Up to82% of patients with MSA have been reported to have anabnormal sphincter EMG,136 however, the prevalence ofthese abnormalities in different stages of MSA remains to bedetermined. As a result, the sensitivity of the sphincter EMGtest in MSA still cannot be established and the presence of theabnormal test alone cannot reliably be used to distinguishMSA from its mimics.141,142

FIGURE 4. Axial T2-weighted MRI of a patient with MSA-Cshowing marked cerebellar atrophy and signal change inpons resembling hot-cross bun (black arrow).

According to the consensus criteria, the

presence of both orthostatic hypotension and

urinary dysfunction are required for the defining

criteria of autonomic failure in the clinical

diagnosis of multiple system atrophy.



In addition to the above investigations, many other testshave been studied in patients with MSA, such as growthhormone response to arginine143 or clonidine infusion,144

polysomnography,63,145 and sudomotor test.146 The details ofeach test are beyond the scope of this review.

PATHOLOGYAs the name entails, the term MSA signifies the patho-

logic involvement of multiple systems, including the substan-tia nigra pars compacta, the locus coeruleus, the putamen, theinferior olives, the pontine nuclei, the Purkinje cells, and theintermediolateral columns, suggesting the anatomic relation-ship between these structure, or “linked” degeneration.16,147

However, the preferential involvement of different anatomicstructures largely depends on the MSA subtype. For example,the main pathologic involvement in MSA-P is the nigrostri-atal system, with lesser widespread degeneration, which alsoincludes olivopontocerebellar system.147,148 The caudal anddorsolateral regions of the putamen are selectively involved,particularly in the early stage along with the degeneration ofthe substantia nigra pars compacta. On the contrary, the bruntpathologic change in MSA-C is in the olivopontocerebellarsystem with lesser involvement of the striatum and thesubstantia nigra. There is a disproportionate depletion of themiddle cerebellar peduncles, compared with the loss of pon-tine neurons, consistent with a “dying back” process. Lastly,pathologic involvements of the dorsal motor nucleus of thevagus nerve,149 the locus coeruleus,16 and in the cat-echolaminergic neurons of ventrolateral medulla150 havebeen shown in MSA with predominant autonomic dysfunc-tion. Bladder, rectal, and sexual dysfunction are probablyrelated to cell loss in parasympathetic preganglionic nuclei ofthe spinal cord, particularly the Onuf’s nucleus, locatedbetween S2 and S4 segments.129–131,138 Pathologic involve-ment of the autonomic neurons maybe a poor prognosticfactor of MSA.151 Among different structures reported to beinvolved in MSA, the cerebral cortex, the thalamus, thesubthalamic nucleus (STN), the caudate nucleus, the globuspallidus, the dentate nucleus, the nucleus ambiguous, thevestibular nuclei, the anterior horn cells, and the pyramidaltracts were relatively preserved.16

Cell depletion, gliosis, and myelin loss were found toinvolve various neuronal populations in MSA. There is asubstantial difference in the extent and distribution of neuro-nal damage varying from case to case. Further supportingevidence of predominant glial pathology in MSA came fromthe discovery of the GCIs, which are now considered as abiologic hallmark of MSA.152,153 GCIs, composed of classic

cytoskeleton antigens such as ubiquitin and tau, are argyro-philic, and are of variable size and shape, often occupying thecytoplasm to displace the nucleus eccentrically.154,155 Impor-tantly, �-synuclein, a presynaptic protein that is affected bypoint mutations in familial PD and is present in Lewybodies,156 has also been found in both neuronal and GCIs inthe brains of patients with MSA.157,158 According to bothcriteria, the definite diagnosis of MSA relies on the patho-logic confirmation of �-synuclein-positive GCIs.41,79 Thedistribution of GCIs is system-related to include the primaryand higher motor areas of the cerebral cortex, the extrapyra-midal, pyramidal, and corticocerebellar systems, the su-praspinal autonomic systems, and their targets.159 There is asignificant correlation between the abundance of GCIs, andthe severity of the neuronal cell loss, and between thesepathologic changes and disease duration.160 Whether the�-synuclein aggregation is a primary trigger or is induced bysome factors in MSA pathology is currently unknown.161

However, the discovery of GCIs has led to biochemical evidenceshowing that the major component of GCIs is abnormallymisfolded, relatively insoluble �-synuclein, which is heavilycoated with an amorphous material.162–164 The inability ofoligodendrocytes to degrade �-synuclein probably results inabnormal subcellular aggregation in MSA.157

TREATMENTCurrently, there is still no proven treatment to halt the

neurodegenerative process in MSA. The therapeutic strategyrelies on the control of clinical symptoms and improvementof quality of life. Because of the progressive nature of thisdisorder, the treatment regimen should be titrated accordingto individual needs.165 Future therapeutic trials are urgentlyneeded and should be directed towards novel symptomatic orneuroprotective agents. To this regard, a specific rating in-strument (Unified MSA Rating Scale) has been developed tostandardize severity assessments in specialized clinics andresearch programs worldwide.166 Currently, the pharmaco-logic therapies are mainly available for the treatment ofparkinsonism and autonomic dysfunction.

Treatment of Parkinsonism

It is often misunderstood that patients with MSA arenonresponsive or poorly responsive to levodopa, even at theearly stage of the disease. This belief is largely based on theunderstanding that the neurodegeneration in MSA occurs inboth the pre- and postsynaptic levels, whereas in PD, the

Clinical series have documented the efficacy of

levodopa, at least transiently, in up to 69% of

patients with possible or probable multiple

system atrophy.

The definite diagnosis of multiple system

atrophy relies on the pathologic confirmation of

�-synuclein-positive glial cytoplasmic inclusions.



dopaminergic neuronal loss is predominant presynaptic. Pro-gressive loss of striatal postsynaptic D2 receptors is thoughtto account for levodopa unresponsiveness. Although this factholds some truth, different clinical series have documentedthe efficacy of levodopa, at least transiently, in up to 69% ofpatients with possible or probable MSA.28,44,167,168 A mod-erate to marked response to levodopa therapy ranges from33.3%169 to 69%.22 Therefore, the levodopa response rate inMSA maybe even higher than stated in the published diag-nostic criteria.170 Therefore, an escalating dose of levodopaof at least 1 g/d should be tried if tolerated.171 Whateverresponse the patients experience, it usually declines after afew years of therapy and the progression of the illness is alsomore rapid than that seen in PD. Approximately 50% of thepatients develop dyskinesias, predominantly orofacial dystonia,with levodopa therapy.43,44 Coexisting severe autonomic dys-function may reduce the chance of a worthwhile therapeuticresponse to levodopa in these patients because intolerable ortho-static hypotension may occur on initial challenge with the drug.

There have been only a few clinical trials that studiedthe efficacy of dopamine agonists in MSA. Most of themwere small open-label trials involving the use of bromocrip-tine,172 lisuride,173 and apomorphine.174 Overall results sug-gest that these agents are no more effective than levodopa.Only 13.3% improvement in motor scores was observed withacute apomorphine challenge test in patients with MSA.174

Although a negative response to acute challenges with orallevodopa and subcutaneous apomorphine may favor MSAover PD, these challenges are not useful as a diagnostic testfor either PD or MSA.

In addition to dopaminomimetics, a number of drugsacting through different mechanisms have been explored astherapeutic agents for the treatment of parkinsonism in pa-tients with MSA. Amantadine, a N-methyl-D-aspartate antag-onist, was tested in a short-term open trial in 5 patients withMSA who were unresponsive to levodopa,175 and subse-quently in a placebo-controlled study.176 Despite some pre-vious positive anecdotal evidence,17 there was no significantclinical improvement in both studies.175,176 Riluzole wasrecently tried as an antiparkinsonian medication in patientswith MSA.177 Although well tolerated, this placebo-con-trolled trial did not demonstrate any clinically meaningfuleffect of riluzole. In a study involving the use of paroxetineat a dose up to 90 mg daily for 2 weeks, a significantimprovement of motor abilities of the upper limbs and speechwere observed in patients with MSA over placebo.178 Al-though this result is encouraging, it is preliminary, but maysuggest the therapeutic role of serotonergic agents in MSA.

Focal dystonia may occur in patients with MSA, in-cluding blepharospasm, facial dystonia, limb dystonia, andanterocollis. Although these dystonias, particularly limb dys-tonia, may respond to local injections of botulinum toxin typeA,179 cautions are raised concerning the risk of dysphagia inpatients with disproportionate anterocollis receiving botuli-num toxin treatment.55 In patients with excessive drooling,botulinum toxin injection under ultrasonographic guidanceinto parotid and submandibular glands is considered as a safeand effective treatment option.180 Botulinum toxin injection

into adductor muscles may also improve stridor in patientswith MSA.61

Surgery has rarely been performed in patients withMSA. Medial pallidotomy failed to improve motor dysfunc-tion in MSA.181,182 The evidence for the efficacy and poten-tial adverse effects of deep brain stimulation (DBS) in MSAis lacking, and therefore, is not recommended for patientswith MSA.183,184 In a single case report with bilateral globuspallidus interna DBS, there was a marked increase in akinesiapostoperatively although dystonic features were markedlyattenuated.185 Similarly, 1 patient with pathologically provenMSA did not respond to bilateral STN DBS even though thepatient was responsive to levodopa.186 In contrast, a benefi-cial effect of STN DBS lasting up to 2 years was reported in4 patients with MSA with improvement in rigidity andakinesia, but not the postural instability and gait disturbanc-es.187 In a separate study using motor cortical stimulation in5 patients with MSA, no benefits were obtained and worsen-ing of motor scores was likely due to disease progression.188

In addition to different pharmacologic options, physical,occupational, and speech therapies are helpful to reduce pa-tient’s disability and to maintain patient’s independence as wellas psychologic support. Gait training and assistive devicesshould be considered when patients are at risk for falling.

Treatment of Autonomic DysfunctionTreatment of autonomic dysfunction in MSA is largely

supportive, guided by the patient’s symptoms and disability.For example, if the patient’s orthostatic hypotension isasymptomatic, no specific therapy is required. Once symp-toms become disabling, some conservative measures arerecommended, such as the avoidance of aggravating factors(large meal, alcohol, straining, certain medications), the useof elastic stocking, head-up tilt of the bed at night, andincreased salt intake. When the above measures fail, a num-ber of drugs with different mechanisms of action maybe tried.Either fludrocortisone or midodrine is generally considered asthe drug of choice for orthostatic hypotension. However, onlymidodrine was tested in randomized double-blind placebo-con-trolled trials to confirm its efficacy.189,190 Norepinephrine pre-cursor, L-threo-dihydroxy-phenylserine, is another option, but itsavailability is limited.191 Other agents such as desmopressin,erythropoietin,192 and octreotide could also be considered.

The treatment of neurogenic bladder in MSA is usuallycomplex involving intermittent catheterization and the use ofanticholinergics if symptoms of detrusor hyperreflexia exist,especially in the early disease course.193,194 The use of asuprapubic vibration device maybe a useful alternative toclean intermittent self-catheterization.195 �-Adrenergic re-ceptor antagonists may improve voiding with reduction ofresidual volumes.196 Urological surgery should be avoided atall cost because of the possibility of postoperative worseningof bladder control.32,137

Erectile dysfunction is present in 96% of men withMSA.32,197 The efficacy of sildenafil for the treatment oferectile dysfunction in patients with MSA has been confirmedin a double-blind, placebo-controlled study.198 However, itsuse may exacerbate orthostatic hypotension. Therefore, lyingand standing blood pressure should be measured before and



after the administration of sildenafil and adequate patienteducation regarding the possible side effects is necessary.198

As the disease continue to progress, it is important forphysicians to identify commonly overlooked problems, suchas constipation and depression.199 Simple symptomatic ther-apies may relieve the patients’ distress and improve theirquality of life. Constipation maybe relieved by increasing thewater content of the stool and its volume, thereby looseningits consistency. Macrogol 3350 has been shown to be aneffective and safe option for the treatment of chronic consti-pation in MSA.200 Facilitating acetylcholine release fromcholinergic enteric neurons, mosapride citrate, a 5-HT4 re-ceptor agonist, works by augmenting lower gastrointestinalmotility, and thereby ameliorating chronic constipation inpatients with MSA.201 Continuous positive airway pressuremaybe useful in patients with nocturnal stridor.202 On thecontrary, tracheostomy may fatally exacerbate central sleepapnea as a result of the alteration of PaCO2 levels on therespiratory center59,62,203 Sudden nocturnal death from hyp-oxia can occur because of the dysfunction of respiratoryregulation to hypoxic drive in patients with MSA.204 Previousstudy showed that the chemosensitivity to hypercapnia isintact in patients with MSA,204 thus, the removal of airwayobstruction disables such respiratory regulation previouslydriven by hypercapnia. Nevertheless, tracheostomy remains thetreatment of choice for selected patients with daytime stridor,immobile vocal cords, or stridor intractable to continuous posi-tive airway pressure. Finally, growth hormone therapy has re-cently been tried in an attempt to modify the disease progres-sion.205 Although the results were not statistically significant,there was a trend to lessen worsening in Unified MSA RatingScale with growth hormone therapy than placebo.

CONCLUSIONAlthough major advances have been made in terms of

the molecular biology and diverse clinical presentations inMSA, therapeutic options are still limited to symptomatictherapies that are temporarily effective. At present, 2 Euro-pean (EMSA-SG, NNIPPS)206 and 1 North-American(NAMSA-SG)207 research initiatives have been establishedand are actively conducting multicenter intervention trials inMSA. At the same time, prospective data is being collectedand surrogate markers are being developed. These trials aswell as others will change and widen our therapeutic ap-proach to MSA. Working along these lines will lead us to abetter understanding of this devastating illness. There is thehope that effective therapies and neuroprotective agents forMSA may soon become available.

REFERENCES1. Dejerine J, Thomas A. L’atrophie olivo-ponto-cerebelleuse. Nouv

Iconogr Salpetriere. 1900;13:300–370.2. Shy GM, Drager GA. A neurological syndrome associated with ortho-

static hypotension. Arch Neurol. 1960;2:511–527.3. Adams RD, van Bogaert P, Eecken VD. Degenerescences nigro-striees

et cerebello-nigro-striees. Psychiatr Neurol. 1961;142:219–259.4. Graham JG, Oppenheimer DR. Orthostatic hypotension and nicotine

sensitivity in a case of multiple system atrophy. J Neurol NeurosurgPsychiatry. 1969;32:28–34.

5. Gilman S, Low PA, Quinn N, et al. Consensus statement on the

diagnosis of multiple system atrophy. J Auton Nerv Syst. 1998;742:189–192.

6. Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosisof multiple system atrophy. American Autonomic Society and Amer-ican Academy of Neurology. Clin Auton Res. 1998;8:359–362.

7. Vanacore N. Epidemiological evidence on multiple system atrophy.J Neural Transm. 2005;112:1605–1612.

8. Tison F, Yekhlef F, Chrysostome V, et al. Prevalence of multiplesystem atrophy. Lancet. 2000;355:495–496.

9. Schrag A, Ben-Shlomo Y, Quinn NP. Prevalence of progressive su-pranuclear palsy and multiple system atrophy: a cross-sectional study.Lancet. 1999;354:1771–1775.

10. Wermuth L, Joensen P, Bunger N, et al. High prevalence of Parkin-son’s disease in the Faroe Islands. Neurology. 1997;49:426–432.

11. Chio A, Magnani C, Schiffer D. Prevalence of Parkinson’s disease inNorthwestern Italy: comparison of tracer methodology and clinicalascertainment of cases. Mov Disord. 1998;13:400–405.

12. Bower JH, Maraganore DM, McDonnell SK, et al. Incidence ofprogressive supranuclear palsy and multiple system atrophy in OlmstedCounty, Minnesota, 1976 to 1990. Neurology. 1997;49:1284–1288.

13. Vanacore N, Bonifati V, Fabbrini G, et al. Case-control study ofmultiple system atrophy. Mov Disord. 2005;20:158–163.

14. Vanacore N, Bonifati V, Fabbrini G, et al. Smoking habits in multiplesystem atrophy and progressive supranuclear palsy. European StudyGroup on Atypical Parkinsonisms. Neurology. 2000;54:114–119.

15. Nee LE, Gomez MR, Dambrosia J, et al. Environmental-occupationalrisk factors and familial associations in multiple system atrophy: apreliminary investigation. Clin Auton Res. 1991;1:9–13.

16. Wenning GK, Tison F, Shlomo B, et al. Multiple system atrophy: a reviewof 203 pathologically proven cases. Mov Disord. 1997;12:133–147.

17. Wenning GK, Ben Shlomo Y, Magalhaes M, et al. Clinical features andnatural history of multiple system atrophy. An analysis of 100 cases.Brain. 1994;117:835–845.

18. Ben-Shlomo Y, Wenning GK, Tison F, et al. Survival of patients withpathologically proven multiple system atrophy: a meta-analysis. Neu-rology. 1997;48:384–393.

19. Testa D, Monza D, Ferrarini M, et al. Comparison of natural historiesof progressive supranuclear palsy and multiple system atrophy. NeurolSci. 2001;22:247–251.

20. Watanabe H, Saito Y, Terao S, et al. Progression and prognosis inmultiple system atrophy: an analysis of 230 Japanese patients. Brain.2002;125:1070–1083.

21. Papapetropoulos S, Tuchman A, Laufer D, et al. Causes of death inmultiple system atrophy. J Neurol Neurosurg Psychiatry. 2007;78:327–329.

22. Colosimo C, Albanese A, Hughes AJ, et al. Some specific clinicalfeatures differentiate multiple system atrophy (striatonigral variety)from Parkinson’s disease. Arch Neurol. 1995;52:294–298.

23. Salazar G, Valls-Sole J, Marti MJ, et al. Postural and action myoclonusin patients with parkinsonian type multiple system atrophy. MovDisord. 2000;15:77–83.

24. Saito Y, Matsuoka Y, Takahashi A, et al. Survival of patients withmultiple system atrophy. Intern Med. 1994;33:321–325.

25. Litvan I, Campbell G, Mangone CA, et al. Which clinical featuresdifferentiate progressive supranuclear palsy (Steele-Richardson-Olsze-wski syndrome) from related disorders? A clinicopathological study.Brain. 1997;120:65–74.

26. Bhidayasiri R, Riley DE, Somers JT. Pathophysiology of slow verticalsaccades in progressive supranuclear palsy. Neurology. 2001;57:2070–2077.

27. Glass GA, Josephs KA, Ahlskog JE. Respiratory insufficiency as theprimary presenting symptom of multiple-system atrophy. Arch Neurol.2006;63:978–981.

28. Albanese A, Colosimo C, Bentivoglio AR, et al. Multiple systematrophy presenting as parkinsonism: clinical features and diagnosticcriteria. J Neurol Neurosurg Psychiatry. 1995;59:144–151.

29. Wullner U, Schmitz-Hubsch T, Abele M, et al. Features of probablemultiple system atrophy patients identified among 4770 patients withparkinsonism enrolled in the multicentre registry of the German Com-petence Network on Parkinson’s disease. J Neural Transm. 2007;114:1161–1165.



30. Wenning GK, Ben-Shlomo Y, Hughes A, et al. What clinicalfeatures are most useful to distinguish definite multiple systematrophy from Parkinson’s disease? J Neurol Neurosurg Psychiatry.2000;68:434 – 440.

31. Tada M, Onodera O, Tada M, et al. Early development of autonomicdysfunction may predict poor prognosis in patients with multiplesystem atrophy. Arch Neurol. 2007;64:256–260.

32. Beck RO, Betts CD, Fowler CJ. Genitourinary dysfunction in multiplesystem atrophy: clinical features and treatment in 62 cases. J Urol.1994;151:1336–1341.

33. Magalhaes M, Wenning GK, Daniel SE, et al. Autonomic dysfunctionin pathologically confirmed multiple system atrophy and idiopathicParkinson’s disease–a retrospective comparison. Acta Neurol Scand.1995;91:98–102.

34. Yabe I, Soma H, Takei A, et al. MSA-C is the predominant clinicalphenotype of MSA in Japan: analysis of 142 patients with probableMSA. J Neurol Sci. 2006;249:115–121.

35. Klockgether T, Schroth G, Diener HC, et al. Idiopathic cerebellarataxia of late onset: natural history and MRI morphology. J NeurolNeurosurg Psychiatry. 1990;53:297–305.

36. Abele M, Burk K, Schols L, et al. The aetiology of sporadic adult-onsetataxia. Brain. 2002;125:961–968.

37. Lachenmayer L. Differential diagnosis of parkinsonian syndromes:dynamics of time courses are essential. J Neurol. 2003;250(suppl1):I11–I14.

38. Geser F, Wenning GK, Seppi K, et al. Progression of multiple systematrophy (MSA): a prospective natural history study by the EuropeanMSA Study Group (EMSA SG). Mov Disord. 2006;21:179–186.

39. Seppi K, Yekhlef F, Diem A, et al. Progression of parkinsonism inmultiple system atrophy. J Neurol. 2005;252:91–96.

40. Quinn NP. How to diagnose multiple system atrophy. Mov Disord.2005;20(suppl 12):S5–S10.

41. Quinn N. Multiple system atrophy–the nature of the beast. J NeurolNeurosurg Psychiatry. 1989;suppl:78–89.

42. Gouider-Khouja N, Vidailhet M, Bonnet AM, et al. “Pure” striatonigraldegeneration and Parkinson’s disease: a comparative clinical study.Mov Disord. 1995;10:288–294.

43. Boesch SM, Wenning GK, Ransmayr G, et al. Dystonia in multiplesystem atrophy. J Neurol Neurosurg Psychiatry. 2002;72:300–303.

44. Hughes AJ, Colosimo C, Kleedorfer B, et al. The dopaminergicresponse in multiple system atrophy. J Neurol Neurosurg Psychiatry.1992;55:1009–1013.

45. Wenning GK, Quinn NP, Daniel SE, et al. Facial dystonia in patho-logically proven multiple system atrophy: a video report. Mov Disord.1996;11:107–109.

46. Wenning GK, Geser F, Poewe W. The ‘risus sardonicus’ of multiplesystem atrophy. Mov Disord. 2003;18:1211.

47. Skidmore F, Mikolenko I, Weiss H, et al. Camptocormia in a patientwith multiple system atrophy. Mov Disord. 2005;20:1063–1064.

48. Slawek J, Derejko M, Lass P, et al. Camptocormia or Pisa syndrome inmultiple system atrophy. Clin Neurol Neurosurg. 2006;108:699–704.

49. Diederich NJ, Goebel HH, Dooms G, et al. Camptocormia associatedwith focal myositis in multiple-system atrophy. Mov Disord. 2006;21:390–394.

50. Colosimo C. Pisa syndrome in a patient with multiple system atrophy.Mov Disord. 1998;13:607–609.

51. Geser F, Wenning GK. Disproportionate antecollis: a warning sign formultiple system atrophy. Mov Disord. 2007;22:1986.

52. Rivest J, Quinn NP, Marsden CD. Dystonia in Parkinson’s disease,multiple system atrophy, and progressive supranuclear palsy. Neurol-ogy. 1990;40:1570–1578.

53. Quinn N. Disproportionate antecollis in multiple system atrophy. Lan-cet. 1989;1:844.

54. Askmark H, Eeg-Olofsson K, Johansson A, et al. Parkinsonism andneck extensor myopathy: a new syndrome or coincidental findings?Arch Neurol. 2001;58:232–237.

55. Thobois S, Broussolle E, Toureille L, et al. Severe dysphagia afterbotulinum toxin injection for cervical dystonia in multiple systematrophy. Mov Disord. 2001;16:764–765.

56. Truong DD, Bhidayasiri R. Myoclonus and parkinsonism. In: KollerWC, Melamed E, eds. Handbook of Clinical Neurology Parkinson’s

Disease and Related Disorders. Philadelphia, PA: Elsevier B; 2007:549–560.

57. Kluin KJ, Gilman S, Lohman M, et al. Characteristics of the dysarthriaof multiple system atrophy. Arch Neurol. 1996;53:545–548.

58. Munschauer FE, Loh L, Bannister R, et al. Abnormal respiration andsudden death during sleep in multiple system atrophy with autonomicfailure. Neurology. 1990;40:677–679.

59. Shimohata T, Shinoda H, Nakayama H, et al. Daytime hypoxemia,sleep-disordered breathing, and laryngopharyngeal findings in multiplesystem atrophy. Arch Neurol. 2007;64:856–861.

60. Hughes RG, Gibbin KP, Lowe J. Vocal fold abductor paralysis as asolitary and fatal manifestation of multiple system atrophy. J LaryngolOtol. 1998;112:177–178.

61. Merlo IM, Occhini A, Pacchetti C, et al. Not paralysis, but dystoniacauses stridor in multiple system atrophy. Neurology. 2002;58:649–652.

62. Silber MH, Levine S. Stridor and death in multiple system atrophy.Mov Disord. 2000;15:699–704.

63. Plazzi G, Corsini R, Provini F, et al. REM sleep behavior disorders inmultiple system atrophy. Neurology. 1997;48:1094–1097.

64. Iranzo A, Santamaria J, Rye DB, et al. Characteristics of idiopathicREM sleep behavior disorder and that associated with MSA and PD.Neurology. 2005;65:247–252.

65. Vetrugno R, Liguori R, Cortelli P, et al. Sleep-related stridor due todystonic vocal cord motion and neurogenic tachypnea/tachycardia inmultiple system atrophy. Mov Disord. 2007;22:673–678.

66. Reich SG. The cold hands sign in MSA. Multiple system atrophy.Neurology. 2003;60:719.

67. Klein C, Brown R, Wenning G, et al. The “cold hands sign” in multiplesystem atrophy. Mov Disord. 1997;12:514–518.

68. Santens P, Crevits L, Van der Linden C. Raynaud’s phenomenon in acase of multiple system atrophy. Mov Disord. 1996;11:586–588.

69. Lauterbach EC. The neuropsychiatry of Parkinson’s disease and relateddisorders. Psychiatr Clin North Am. 2004;27:801–825.

70. Parvizi J, Joseph J, Press DZ, et al. Pathological laughter and crying inpatients with multiple system atrophy-cerebellar type. Mov Disord.2007;22:798–803.

71. Soma H, Yabe I, Takei A, et al. Heredity in multiple system atrophy.J Neurol Sci. 2006;240:107–110.

72. Hara K, Momose Y, Tokiguchi S, et al. Multiplex families withmultiple system atrophy. Arch Neurol. 2007;64:545–551.

73. Ozawa T, Healy DG, Abou-Sleiman PM, et al. The alpha-synucleingene in multiple system atrophy. J Neurol Neurosurg Psychiatry.2006;77:464–467.

74. Vidailhet M, Rivaud S, Gouider-Khouja N, et al. Eye movements inparkinsonian syndromes. Ann Neurol. 1994;35:420–426.

75. Leigh RJ, Riley DE. Eye movements in parkinsonism: it’s saccadicspeed that counts. Neurology. 2000;54:1018–1019.

76. Litvan I, Goetz CG, Jankovic J, et al. What is the accuracy of theclinical diagnosis of multiple system atrophy? A clinicopathologicstudy. Arch Neurol. 1997;54:937–944.

77. Quinn N. Multiple system atrophy. In: Marsden CD, Fahn S, eds. Move-ment Disorders. London: Butterworth-Heinemann; 1994:262–281.

78. Litvan I, Booth V, Wenning GK, et al. Retrospective application of aset of clinical diagnostic criteria for the diagnosis of multiple systematrophy. J Neural Transm. 1998;105:217–227.

79. Gilman S, Low PA, Quinn N, et al. Consensus statement on thediagnosis of multiple system atrophy. J Neurol Sci. 1999;163:94–98.

80. Colosimo C, Vanacore N, Bonifati V, et al. Clinical diagnosis ofmultiple system atrophy: level of agreement between Quinn’s criteriaand the consensus conference guidelines. Acta Neurol Scand. 2001;103:261–264.

81. Osaki Y, Wenning GK, Daniel SE, et al. Do published criteria improveclinical diagnostic accuracy in multiple system atrophy? Neurology.2002;59:1486–1491.

82. Seppi K, Schocke MF, Wenning GK, et al. How to diagnose MSAearly: the role of magnetic resonance imaging. J Neural Transm.2005;112:1625–1634.

83. Schrag A, Kingsley D, Phatouros C, et al. Clinical usefulness ofmagnetic resonance imaging in multiple system atrophy. J NeurolNeurosurg Psychiatry. 1998;65:65–71.



84. Schulz JB, Klockgether T, Petersen D, et al. Multiple system atrophy:natural history, MRI morphology, and dopamine receptor imaging with123IBZM-SPECT. J Neurol Neurosurg Psychiatry. 1994;57:1047–1056.

85. Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypicalparkinsonian syndromes with routine MRI. Neurology. 2000;54:697–702.

86. Wullner U, Klockgether T, Petersen D, et al. Magnetic resonanceimaging in hereditary and idiopathic ataxia. Neurology. 1993;43:318–325.

87. Savoiardo M, Strada L, Girotti F, et al. Olivopontocerebellar atrophy:MR diagnosis and relationship to multisystem atrophy. Radiology.1990;174:693–696.

88. Seppi K, Schocke MF, Prennschuetz-Schuetzenau K, et al. Topographyof putaminal degeneration in multiple system atrophy: a diffusionmagnetic resonance study. Mov Disord. 2006;21:847–852.

89. Wakai M, Kume A, Takahashi A, et al. A study of parkinsonism inmultiple system atrophy: clinical and MRI correlation. Acta NeurolScand. 1994;90:225–231.

90. O’Brien C, Sung JH, McGeachie RE, et al. Striatonigral degeneration:clinical, MRI, and pathologic correlation. Neurology. 1990;40:710–711.

91. Drayer BP, Olanow W, Burger P, et al. Parkinson plus syndrome:diagnosis using high field MR imaging of brain iron. Radiology.1986;159:493–498.

92. Pastakia B, Polinsky R, Di Chiro G, et al. Multiple system atrophy(Shy-Drager syndrome): MR imaging. Radiology. 1986;159:499–502.

93. Lang AE, Curran T, Provias J, et al. Striatonigral degeneration: irondeposition in putamen correlates with the slit-like void signal ofmagnetic resonance imaging. Can J Neurol Sci. 1994;21:311–318.

94. Schwarz J, Kraft E, Vogl T, et al. Relative quantification of signal onT2-weighted images in the basal ganglia: limited value in differentialdiagnosis of patients with parkinsonism. Neuroradiology. 1999;41:124–128.

95. Kraft E, Trenkwalder C, Auer DP. T2*-weighted MRI differentiatesmultiple system atrophy from Parkinson’s disease. Neurology. 2002;59:1265–1267.

96. Stern MB, Braffman BH, Skolnick BE, et al. Magnetic resonanceimaging in Parkinson’s disease and parkinsonian syndromes. Neurol-ogy. 1989;39:1524–1526.

97. Schwarz J, Weis S, Kraft E, et al. Signal changes on MRI and increasesin reactive microgliosis, astrogliosis, and iron in the putamen of twopatients with multiple system atrophy. J Neurol Neurosurg Psychiatry.1996;60:98–101.

98. Konagaya M, Konagaya Y, Iida M. Clinical and magnetic resonanceimaging study of extrapyramidal symptoms in multiple system atrophy.J Neurol Neurosurg Psychiatry. 1994;57:1528–1531.

99. Kraft E, Schwarz J, Trenkwalder C, et al. The combination of hypoin-tense and hyperintense signal changes on T2-weighted magnetic reso-nance imaging sequences: a specific marker of multiple system atro-phy? Arch Neurol. 1999;56:225–228.

100. Bhattacharya K, Saadia D, Eisenkraft B, et al. Brain magnetic reso-nance imaging in multiple-system atrophy and Parkinson disease: adiagnostic algorithm. Arch Neurol. 2002;59:835–842.

101. Bhidayasiri R, Perlman S. Medical image. “Hot cross bun” sign. The NZ Med J. 2007;120:U2563.

102. Schocke MF, Seppi K, Esterhammer R, et al. Diffusion-weighted MRIdifferentiates the Parkinson variant of multiple system atrophy fromPD. Neurology. 2002;58:575–580.

103. Kollensperger M, Seppi K, Liener C, et al. Diffusion weighted imagingbest discriminates PD from MSA-P: a comparison with tilt table testingand heart MIBG scintigraphy. Mov Disord. 2007;22:1771–1776.

104. Davie C. The role of spectroscopy in parkinsonism. Mov Disord.1998;13:2–4.

105. Watanabe H, Fukatsu H, Katsuno M, et al. Multiple regional 1H-MRspectroscopy in multiple system atrophy: NAA/Cr reduction in pontinebase as a valuable diagnostic marker. J Neurol Neurosurg Psychiatry.2004;75:103–109.

106. Davie CA, Wenning GK, Barker GJ, et al. Differentiation of multiplesystem atrophy from idiopathic Parkinson’s disease using proton mag-netic resonance spectroscopy. Ann Neurol. 1995;37:204–210.

107. Brooks DJ, Salmon EP, Mathias CJ, et al. The relationship betweenlocomotor disability, autonomic dysfunction, and the integrity of thestriatal dopaminergic system in patients with multiple system atrophy,pure autonomic failure, and Parkinson’s disease, studied with PET.Brain. 1990;113:1539–1552.

108. Brooks DJ, Ibanez V, Sawle GV, et al. Differing patterns of striatal18F-dopa uptake in Parkinson’s disease, multiple system atrophy, andprogressive supranuclear palsy. Ann Neurol. 1990;28:547–555.

109. Burn DJ, Sawle GV, Brooks DJ. Differential diagnosis of Parkinson’sdisease, multiple system atrophy, and Steele-Richardson-Olszewskisyndrome: discriminant analysis of striatal 18F-dopa PET data. J Neu-rol Neurosurg Psychiatry. 1994;57:278–284.

110. Brooks DJ, Ibanez V, Sawle GV, et al. Striatal D2 receptor status inpatients with Parkinson’s disease, striatonigral degeneration, and pro-gressive supranuclear palsy, measured with 11C-raclopride andpositron emission tomography. Ann Neurol. 1992;31:184–192.

111. Gilman S, Markel DS, Koeppe RA, et al. Cerebellar and brainstemhypometabolism in olivopontocerebellar atrophy detected with positronemission tomography. Ann Neurol. 1988;23:223–230.

112. Eidelberg D, Takikawa S, Moeller JR, et al. Striatal hypometabolismdistinguishes striatonigral degeneration from Parkinson’s disease. AnnNeurol. 1993;33:518–527.

113. Antonini A, Kazumata K, Feigin A, et al. Differential diagnosis ofparkinsonism with �18F�fluorodeoxyglucose and PET. Mov Disord.1998;13:268–274.

114. Varrone A, Marek KL, Jennings D, et al. �(123)I�beta-CIT SPECTimaging demonstrates reduced density of striatal dopamine transportersin Parkinson’s disease and multiple system atrophy. Mov Disord.2001;16:1023–1032.

115. Bhidayasiri R. How useful is ((123)I) b-CIT SPECT in the diagnosis ofParkinson’s Disease? Rev Neurol Dis. 2006;3:19–22.

116. A multicenter assessment of dopamine transporter imaging withDOPASCAN/SPECT in parkinsonism. Parkinson Study Group. Neu-rology. 2000;55:1540–1547.

117. van Royen E, Verhoeff NF, Speelman JD, et al. Multiple systematrophy and progressive supranuclear palsy. Diminished striatal D2dopamine receptor activity demonstrated by 123I-IBZM single photonemission computed tomography. Arch Neurol. 1993;50:513–516.

118. Reinhardt MJ, Jungling FD, Krause TM, et al. Scintigraphic differen-tiation between two forms of primary dysautonomia early after onset ofautonomic dysfunction: value of cardiac and pulmonary iodine-123MIBG uptake. Eur J Nucl Med. 2000;27:595–600.

119. Braune S. The role of cardiac metaiodobenzylguanidine uptake in thedifferential diagnosis of parkinsonian syndromes. Clin Auton Res.2001;11:351–355.

120. Taki J, Nakajima K, Hwang EH, et al. Peripheral sympathetic dysfunc-tion in patients with Parkinson’s disease without autonomic failure isheart selective and disease specific. Eur J Nucl Med. 2000;27:566–573.

121. Takatsu H, Nagashima K, Murase M, et al. Differentiating Parkinsondisease from multiple-system atrophy by measuring cardiac iodine-123metaiodobenzylguanidine accumulation. JAMA. 2000;284:44–45.

122. Druschky A, Hilz MJ, Platsch G, et al. Differentiation of Parkinson’sdisease and multiple system atrophy in early disease stages by means ofI-123-MIBG-SPECT. J Neurol Sci. 2000;175:3–12.

123. Braune S, Reinhardt M, Schnitzer R, et al. Lucking CH. Cardiac uptakeof �123I�MIBG separates Parkinson’s disease from multiple systematrophy. Neurology. 1999;53:1020–1025.

124. Orimo S, Ozawa E, Nakade S, et al. (123)I-metaiodobenzylguanidinemyocardial scintigraphy in Parkinson’s disease. J Neurol NeurosurgPsychiatry. 1999;67:189–194.

125. Riley DE, Chelimsky TC. Autonomic nervous system testing may notdistinguish multiple system atrophy from Parkinson’s disease. J NeurolNeurosurg Psychiatry. 2003;74:56–60.

126. Polinsky RJ, Kopin IJ, Ebert MH, et al. Pharmacologic distinction ofdifferent orthostatic hypotension syndromes. Neurology. 1981;31:1–7.

127. Asahina M, Sato J, Tachibana M, et al. Cerebral blood flow andoxygenation during head-up tilt in patients with multiple system atro-phy and healthy control subjects. Parkinsonism Relat Disord. 2006;12:472–477.



128. Pavy-Le Traon A, Hughson RL, Thalamas C, et al. Cerebral autoreg-ulation is preserved in multiple system atrophy: a transcranial Dopplerstudy. Mov Disord. 2006;21:2122–2126.

129. Mannen T, Iwata M, Toyokura Y, et al. The Onuf’s nucleus and theexternal anal sphincter muscles in amyotrophic lateral sclerosis andShy-Drager syndrome. Acta Neuropathol. 1982;58:255–260.

130. Chalmers D, Swash M. Selective vulnerability of urinary Onufmotoneurons in Shy-Drager syndrome. J Neurol. 1987;234:259 –260.

131. Yamamoto T, Sakakibara R, Uchiyama T, et al. When is Onuf’snucleus involved in multiple system atrophy? A sphincter electromyo-graphy study. J Neurol Neurosurg Psychiatry. 2005;76:1645–1648.

132. Bonnet AM, Pichon J, Vidailhet M, et al. Urinary disturbances instriatonigral degeneration and Parkinson’s disease: clinical and urody-namic aspects. Mov Disord. 1997;12:509–513.

133. Stocchi F, Carbone A, Inghilleri M, et al. Urodynamic and neurophys-iological evaluation in Parkinson’s disease and multiple system atro-phy. J Neurol Neurosurg Psychiatry. 1997;62:507–511.

134. Pramstaller PP, Wenning GK, Smith SJ, et al. Nerve conductionstudies, skeletal muscle EMG, and sphincter EMG in multiple systematrophy. J Neurol Neurosurg Psychiatry. 1995;58:618–621.

135. Eardley I, Quinn NP, Fowler CJ, et al. The value of urethral sphincterelectromyography in the differential diagnosis of parkinsonism.Br J Urol. 1989;64:360–362.

136. Palace J, Chandiramani VA, Fowler CJ. Value of sphincter electro-myography in the diagnosis of multiple system atrophy. Muscle Nerve.1997;20:1396–1403.

137. Chandiramani VA, Palace J, Fowler CJ. How to recognize patients withparkinsonism who should not have urological surgery. Br J Urol.1997;80:100–104.

138. Libelius R, Johansson F. Quantitative electromyography of the externalanal sphincter in Parkinson’s disease and multiple system atrophy.Muscle Nerve. 2000;23:1250–1256.

139. Giladi N, Simon ES, Korczyn AD, et al. Anal sphincter EMG does notdistinguish between multiple system atrophy and Parkinson’s disease.Muscle Nerve. 2000;23:731–734.

140. Valldeoriola F, Valls-Sole J, Tolosa ES, et al. Striated anal sphincterdenervation in patients with progressive supranuclear palsy. Mov Dis-ord. 1995;10:550–555.

141. Vodusek DB. Sphincter EMG and differential diagnosis of multiplesystem atrophy. Mov Disord. 2001;16:600–607.

142. Vodusek DB. Sphincter EMG in possible multiple system atrophy: todo or not to do? J Neurol Neurosurg Psychiatry. 2001;71:575–576.

143. Pellecchia MT, Longo K, Pivonello R, et al. Multiple system atrophy isdistinguished from idiopathic Parkinson’s disease by the argininegrowth hormone stimulation test. Ann Neurol. 2006;60:611–615.

144. Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parkin-son’s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet. 1997;349:1877–1881.

145. Boeve BF, Silber MH, Ferman TJ, et al. Association of REM sleepbehavior disorder and neurodegenerative disease may reflect an under-lying synucleinopathy. Mov Disord. 2001;16:622–630.

146. Cohen J, Low P, Fealey R, et al. Somatic and autonomic function inprogressive autonomic failure and multiple system atrophy. Ann Neu-rol. 1987;22:692–699.

147. Kume A, Takahashi A, Hashizume Y. Neuronal cell loss of thestriatonigral system in multiple system atrophy. J Neurol Sci. 1993;117:33–40.

148. Wenning GK, Tison F, Elliott L. Olivopontocerebellar pathology inmultiple system atrophy. Mov Disord. 1996;11:157–162.

149. Sung JH, Mastri AR, Segal E. Pathology of Shy-Drager syndrome.J Neuropathol Exp Neurol. 1979;38:353–368.

150. Benarroch EE, Smithson IL, Low PA, et al. Depletion of catecholamin-ergic neurons of the rostral ventrolateral medulla in multiple systemsatrophy with autonomic failure. Ann Neurol. 1998;43:156–163.

151. Ozawa T. Morphological substrate of autonomic failure and neurohor-monal dysfunction in multiple system atrophy: impact on determiningphenotype spectrum. Acta Neuropathol. 2007;114:201–211.

152. Lantos PL. The definition of multiple system atrophy: a review ofrecent developments. J Neuropathol Exp Neurol. 1998;57:1099 –1111.

153. Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNSof patients with multiple system atrophy (striatonigral degeneration,olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci.1989;94:79–100.

154. Cairns NJ, Atkinson PF, Hanger DP, et al. Tau protein in the glialcytoplasmic inclusions of multiple system atrophy can be distinguishedfrom abnormal tau in Alzheimer’s disease. Neurosci Lett. 1997;230:49–52.

155. Chin SS, Goldman JE. Glial inclusions in CNS degenerative diseases.J Neuropathol Exp Neurol. 1996;55:499–508.

156. Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewybodies. Nature. 1997;388:839–840.

157. Tu PH, Galvin JE, Baba M, et al. Glial cytoplasmic inclusions in whitematter oligodendrocytes of multiple system atrophy brains containinsoluble alpha-synuclein. Ann Neurol. 1998;44:415–422.

158. Wakabayashi K, Hayashi S, Kakita A, et al. Accumulation of alpha-synuclein/NACP is a cytopathological feature common to Lewy bodydisease and multiple system atrophy. Acta Neuropathol. 1998;96:445–452.

159. Papp MI, Lantos PL. The distribution of oligodendroglial inclusions inmultiple system atrophy and its relevance to clinical symptomatology.Brain. 1994;117:235–243.

160. Ozawa T, Paviour D, Quinn NP, et al. The spectrum of pathologicalinvolvement of the striatonigral and olivopontocerebellar systems inmultiple system atrophy: clinicopathological correlations. Brain. 2004;127:2657–2671.

161. Armstrong RA, Cairns NJ, Lantos PL. Multiple system atrophy (MSA):topographic distribution of the alpha-synuclein-associated pathologicalchanges. Parkinsonism Relat Disord. 2006;12:356–362.

162. Campbell BC, McLean CA, Culvenor JG, et al. The solubility of alpha-synuclein in multiple system atrophy differs from that of dementia withLewy bodies and Parkinson’s disease. J Neurochem. 2001;76:87–96.

163. Miake H, Mizusawa H, Iwatsubo T, et al. Biochemical characterizationof the core structure of alpha-synuclein filaments. J Biol Chem. 2002;277:19213–19219.

164. Gai WP, Pountney DL, Power JH, et al. Alpha-Synuclein fibrilsconstitute the central core of oligodendroglial inclusion filaments inmultiple system atrophy. Exp Neurol. 2003;181:68–78.

165. Colosimo C, Tiple D, Wenning GK. Management of multiple systematrophy: state of the art. J Neural Transm. 2005;112:1695–1704.

166. Wenning GK, Tison F, Seppi K, et al. Development and validation ofthe Unified Multiple System Atrophy Rating Scale (UMSARS). MovDisord. 2004;19:1391–1402.

167. Wenning GK, Ben-Shlomo Y, Magalhaes M, et al. Clinicopathologicalstudy of 35 cases of multiple system atrophy. J Neurol NeurosurgPsychiatry. 1995;58:160–166.

168. Parati EA, Fetoni V, Geminiani GC, et al. Response to L-DOPA inmultiple system atrophy. Clin Neuropharmacol. 1993;16:139–144.

169. Rajput AH, Rozdilsky B, Rajput A, et al. Levodopa efficacy andpathological basis of Parkinson syndrome. Clin Neuropharmacol.1990;13:553–558.

170. Constantinescu R, Richard I, Kurlan R. Levodopa responsiveness indisorders with parkinsonism: a review of the literature. Mov Disord.2007;22:2141–2148.

171. Stefanova N, Kollensperger M, Hainzer M, et al. High dose levodopatherapy is not toxic in multiple system atrophy: experimental evidence.Mov Disord. 2007;22:969–973.

172. Goetz CG, Tanner CM, Klawans HL. The pharmacology of olivopon-tocerebellar atrophy. Adv Neurol. 1984;41:143–148.

173. Lees AJ, Bannister R. The use of lisuride in the treatment of multiplesystem atrophy with autonomic failure (Shy-Drager syndrome). J Neu-rol Neurosurg Psychiatry. 1981;44:347–351.

174. Rossi P, Colosimo C, Moro E, et al. Acute challenge with apomorphineand levodopa in Parkinsonism. Eur Neurol. 2000;43:95–101.

175. Colosimo C, Merello M, Pontieri FE. Amantadine in parkinsonianpatients unresponsive to levodopa: a pilot study. J Neurol. 1996;243:422–425.

176. Wenning GK. Placebo-controlled trial of amantadine in multiple-system atrophy. Clin Neuropharmacol. 2005;28:225–227.

177. Seppi K, Peralta C, Diem-Zangerl A, et al. Placebo-controlled trial ofriluzole in multiple system atrophy. Eur J Neurol. 2006;13:1146–1148.



178. Friess E, Kuempfel T, Modell S, et al. Paroxetine treatment improvesmotor symptoms in patients with multiple system atrophy. Parkinson-ism Relat Disord. 2006;12:432–437.

179. Muller J, Wenning GK, Wissel J, et al. Botulinum toxin treatment inatypical parkinsonian disorders associated with disabling focal dysto-nia. J Neurol. 2002;249:300–304.

180. Mancini F, Zangaglia R, Cristina S, et al. Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxintype A in the treatment of drooling in parkinsonism. Mov Disord.2003;18:685–688.

181. Lang AE, Lozano A, Duff J, et al. Medial pallidotomy in late-stageParkinson’s disease and striatonigral degeneration. Adv Neurol. 1997;74:199–211.

182. Pereira LC, Palter VN, Lang AE, et al. Neuronal activity in the globuspallidus of multiple system atrophy patients. Mov Disord. 2004;19:1485–1492.

183. Tarsy D, Apetauerova D, Ryan P, et al. Adverse effects of subthalamicnucleus DBS in a patient with multiple system atrophy. Neurology.2003;61:247–249.

184. Shih LC, Tarsy D. Deep brain stimulation for the treatment of atypicalparkinsonism. Mov Disord. 2007;22:2149–2155.

185. Santens P, Vonck K, De Letter M, et al. Deep brain stimulation of theinternal pallidum in multiple system atrophy. Parkinsonism RelatDisord. 2006;12:181–183.

186. Chou KL, Forman MS, Trojanowski JQ, et al. Subthalamic nucleusdeep brain stimulation in a patient with levodopa-responsive multiplesystem atrophy. Case report. J Neurosurg. 2004;100:553–556.

187. Visser-Vandewalle V, Temel Y, Colle H, et al. Bilateral high-fre-quency stimulation of the subthalamic nucleus in patients with multiplesystem atrophy—parkinsonism. Report of four cases. J Neurosurg.2003;98:882–887.

188. Kleiner-Fisman G, Fisman DN, Kahn FI, et al. Motor cortical stimu-lation for parkinsonism in multiple system atrophy. Arch Neurol.2003;60:1554–1558.

189. Low PA, Gilden JL, Freeman R, et al. Efficacy of midodrine vs placebo inneurogenic orthostatic hypotension. A randomized, double-blind multi-center study. Midodrine Study Group. JAMA. 1997;277:1046–1051.

190. Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypo-tension: a double-blind, placebo-controlled study with midodrine.Am J Med. 1993;95:38–48.

191. Mathias CJ, Senard JM, Braune S, et al. L-threo-dihydroxyphenylserine(L-threo-DOPS; droxidopa) in the management of neurogenic orthostatichypotension: a multi-national, multi-center, dose-ranging study in multiplesystem atrophy and pure autonomic failure. Clin Auton Res. 2001;11:235–242.

192. Winkler AS, Marsden J, Parton M, et al. Erythropoietin deficiency andanaemia in multiple system atrophy. Mov Disord. 2001;16:233–239.

193. Winge K, Fowler CJ. Bladder dysfunction in Parkinsonism: mecha-nisms, prevalence, symptoms, and management. Mov Disord. 2006;21:737–745.

194. Ito T, Sakakibara R, Yasuda K, et al. Incomplete emptying and urinaryretention in multiple-system atrophy: when does it occur and how dowe manage it? Mov Disord. 2006;21:816–823.

195. Dasgupta P, Haslam C, Goodwin R, et al. The ‘Queen Square bladderstimulator’: a device for assisting emptying of the neurogenic bladder.Br J Urol. 1997;80:234–237.

196. Sakakibara R, Hattori T, Uchiyama T, et al. Are alpha-blockers in-volved in lower urinary tract dysfunction in multiple system atrophy?A comparison of prazosin and moxisylyte. J Auton Nerv Syst. 2000;79:191–195.

197. Papatsoris AG, Papapetropoulos S, Singer C, et al. Urinary and erectiledysfunction in multiple system atrophy (MSA). Neurourol Urodyn.2008;27:22–27.

198. Hussain IF, Brady CM, Swinn MJ, et al. Treatment of erectiledysfunction with sildenafil citrate (Viagra) in parkinsonism due toParkinson’s disease or multiple system atrophy with observations onorthostatic hypotension. J Neurol Neurosurg Psychiatry. 2001;71:371–374.

199. Benrud-Larson LM, Sandroni P, Schrag A, et al. Depressive symptomsand life satisfaction in patients with multiple system atrophy. MovDisord. 2005;20:951–957.

200. Eichhorn TE, Oertel WH. Macrogol 3350/electrolyte improves consti-pation in Parkinson’s disease and multiple system atrophy. Mov Dis-ord. 2001;16:1176–1177.

201. Liu Z, Sakakibara R, Odaka T, et al. Mosapride citrate, a novel 5-HT4agonist and partial 5-HT3 antagonist, ameliorates constipation in par-kinsonian patients. Mov Disord. 2005;20:680–686.

202. Iranzo A, Santamaria J, Tolosa E. Continuous positive air pressureeliminates nocturnal stridor in multiple system atrophy. BarcelonaMultiple System Atrophy Study Group. Lancet. 2000;356:1329–1330.

203. Jin K, Okabe S, Chida K, et al. Tracheostomy can fatally exacerbatesleep-disordered breathing in multiple system atrophy. Neurology.2007;68:1618–1621.

204. Tsuda T, Onodera H, Okabe S, et al. Impaired chemosensitivity tohypoxia is a marker of multiple system atrophy. Ann Neurol. 2002;52:367–371.

205. Holmberg B, Johansson JO, Poewe W, et al. Safety and tolerability ofgrowth hormone therapy in multiple system atrophy: a double-blind,placebo-controlled study. Mov Disord. 2007;22:1138–1144.

206. Geser F, Seppi K, Stampfer-Kountchev M, et al. The European Mul-tiple System Atrophy-Study Group (EMSA-SG). J Neural Transm.2005;112:1677–1686.

207. Gilman S, May SJ, Shults CW, et al. The North American MultipleSystem Atrophy Study Group. J Neural Transm. 2005;112:1687–1694.

208. Schlossmacher MG, Hamann C, Cole AG, et al. Case records of theMassachusetts General Hospital. Weekly clinicopathological exer-cises. Case 27-2004. A 79-year-old woman with disturbances ingait, cognition, and autonomic function. N Engl J Med. 2004;351:912–922.



msa review article

Documents

msa patients

snd msaparkinsonism

pathophysiology of msa

msacor msap

nonmotor features of

theclinical features

themotor features

cerebellar syndrome