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CHAPTER 13 Multiple System Atrophy (MSA) Gregor K. Wenning and Florian Krismer Summary Multiple system atrophy (MSA) is an adult-onset atypical parkin- sonian disorder (A PD) characterized by either rapidly progressive levodopa-unresponsive parkinsonism or a cer ebellar syndrome associated with early autonomic failure (1). According to cur- rent consen sus criteria two motor subtypes can be distinguished clinically, namely a parkinsonian vari ant labeled MSA-P and a cerebellar variant labeled MSA-C (2). Abundant (oligodendro-) glial cytoplasmic inclusions (GCIs) represent the histopathologi- cal signature lesion that is a ccompanied by a selective neuronal multisystem degeneration (3). Th e principal component o f GCIs is -synuclein, a fi nding which fi rmly places MSA among other -synucleinopath ies such as Parkinson \200\231s disease (PD) and dementia with Lewy bodies (DLB) (4). Curre ntly, the management of MSA patients is based on symptomatic treatment targeting parkinsoni an and autonomic features. Although research into disease-modifying strategies has accelera ted, eff ective neuroprotective treatments are still lacking (5). case \200\223control study in Europe, of which only the methodology has been published (14) , showed a signifi cantly higher risk of develop- ing MSA in subjects who had worked in agr iculture (14). Smoking seems to be less frequent in MSA cases than in healthy controls (15) . Th e fact that the inverse association with smoking found previously in PD is shared by M SA but not by progressive supra- nuclear palsy (PSP) lends epidemiological support to the n otion that diff erent smoking habits are associated with diff erent groups of neurodegenera tive disease (15). A French case \200\223control study dem- onstrated that MSA was not asso ciated with exposure to pesticides, solvents, and other occupational toxins. However, aspir in intake, alcohol consumption, and consumption of fi sh and seafood were more common in th e control group (16). MSA is generally considered to be a sporadic disease, but recent reports of familial cluste ring suggest the presence of monogenic MSA with autosomal inheritance (17 \200\22319). Howe ver, no MSA genes have been identifi ed in these pedigrees so far. Intriguingly, two indepe ndent research groups have demonstrated an association of single-nucleotide polymorphisms w ithin the -synuclein gene ( SNCA ) and increased MSA disease risk (20, 21). Essential background Epidemiology MSA aff ects both sexes equally and the median age at dis ease onset is around 55 years. Th e patient \200\231s median survival is 9 years, with surv ival rates at 5 and 10 years of 83.5% and 39.9%, respectively (6 \200\22310). However, ther e is considerable variation in the rate of dis- ease progression, with individual cases rep orted with survival for as long as 15 years. Th e annual incidence rate is 0.6 cases per 10 0 000 (11). MSA disease risk increases with age. In the age group above 50 years, the annua l incidence rate is estimated to be 3 cases per 100 000 (11). Th e prevalence rate of MSA i s estimated to be 4.4 per 100 000 (12). Pathophysiology Th e underlying pathophysiology is not completely understood. According to the consensus criteria, widespread aggregates of misfolded proteins within oligodendroglial cells (GCI) are required for a defi nite diagnosis of MSA (2). Th ese aggregates are compo sed of -synuclein and an increasing number of other proteins (3). Th e origin of oligode ndroglial -synuclein remains to be determined as -synuclein mRNA expression is absent in both healthy and MSA oligodendrocytes (22). Nonetheless, oli- godendroglial dysfunction is regarded as a principal mechanism in MSA pathogenesis (23), and this has been further s upported by the discovery of early phosphoprotein-25-alpha (p25 ) accu- mulation in olig odendrocytes (23 \200\22325). p25 is a phosphopro- tein functionally associated with mye lination (26), but in MSA it appears to relocate within oligodendrocytes, shift ing from th e myelin sheath towards the cell bodies (25). Moreover, p25 has been shown to co-localiz e with -synuclein-positive GCI in MSA brains, and in vitro data suggest that p25 favo rs the fi brillation of -synuclein (25, 27). In summary, both the assumption that Etiology and genetics Th ere is little information on environmental and occupational risk f actors in MSA. A North American case \200\223control study reported increased frequencies o f exposure to metal dusts and fumes, plastic monomers and additives, organic solvents, and pesticides in MSA patients compared with healthy controls (13). Another multicentre Oxford Textbook of Movement Disorders 130 p25 misprocessing is the earliest detectable change in MSA and the observation that neur onal cells are relatively preserved when oligodendroglial involvement is present support th e hypothesis that MSA is a primary oligodendrogliopathy followed by second- ary neurodegene ration (23). wide-based gait ataxia, developed in 34 \200\22364% of patients (9, 10, 28, 32). Sustained gaze-evoked nystagmus is detected in 23 \200\22335% of patients (9, 10, 28), and cerebellar scanning dysarthria may occur in up to 69% (28). Th e fi nding of a mixed dysarthria with combina- tions of hypokinetic, ataxic, and spastic components is consistent with both the o verall clinical and the neuropathological changes in MSA (36). Cerebellar symptoms occur un iversally in MSA-C patients, and patients with MSA-P frequently also develop cerebel- lar a taxia. In an analysis of a European patient registry, cerebellar signs were observed in 47% of patients with MSA-P (28). On the other hand, patients with MSA-C commonly develop addit ional non-cerebellar symptoms and signs (28). Nevertheless, at early stages MSA-C patients may be indistinguishable from patients with related disorders, including idiopathic late-on set cerebellar ataxia (37). Clinical features MSA is an adult-onset rapidly progressive disorder characterized clinical ly by two major motor features, namely parkinsonism and cerebellar ataxia. Th ese motor fea tures serve as the basis for label- ling patients with predominant parkinsonism as MSA-P an d those with cerebellar ataxia as MSA-C (2). In a prospective European patient registry ana lysis, almost 70% of cases were classifi ed as MSA-P and autonomic failure was almost unive rsally present in both variants (28). Intriguingly, MSA-C outnumbered MSA-P in a Japanese c ohort (8). Autonomic failure in MSA includes urinary symptoms, such as urge incontinence an d incomplete bladder emp- tying, and orthostatic hypotension (28). Autonomic dysfunction comprising primarily urogenital and orthostatic dysfunction is almost universally present in the dis- ease course of both MSA subtypes (28). However, a retrospe ctive analysis of pathologically confi rmed MSA cases suggests that early autonomic symptom s (within 2 years of disease onset) occur in more than half of the patients with MSA (6). I n a clinical series urge incontinence was the most frequent symptom, followed by the appear ance of incomplete bladder emptying in 73% and 48%, respectively, and both symptoms were pr esent in a third of patients with MSA (28). Th ese fi ndings confi rm previous studies whic h identifi ed comparable frequencies (9, 10, 38 \200\22340). Overall, impair- ment of mictu rition in MSA occurs earlier, more frequently, and to a more severe degree than in PD (38). In a series of patients with probable MSA, 43 per cent of males had undergone futile prost atic or bladder neck surgery before the correct diagnosis was made, although more than half of them had neurological symp- toms or signs at the time of the procedure (38). Stress inc ontinence occurred in 57% of the women, and half of these underwent pelvic surgery with dis appointing results (38, 41). Early impotence is uni- versally present in men with MSA. In a series of 62 MSA patients, impotence occurred in 96% of the men and was the fi rst symptom in 37% (38). Th ese results were underpinned by a recent prospec- tive study observing ere ctile dysfunction in 84 per cent of male patients with MSA (28). Reduced genital sensitivit y with or with- out impaired libido has been reported in the majority of female MSA patient s (42). Presenting symptoms Th e most common is levodopa-refractory akinetic \200\223rigid parkinso nism, which is present in 58% of cases (10). Nevertheless, in this series of pathologically confi rmed MSA, 28% of patients had transient benefi t from levo- dopa treatment (10). Th ese eff ects lasted for a median duration of 3 years (28). In contrast with the post-mortem confi rmed series, only a minority of MSA patients experienced levodopa-associated adverse eff ects such as dyskinesias (27% and 7% in the post-mortem confi rmed and the prospective clinical series, respectively) and ON \200\223OFF fl uctuations (24% versus 3.5%) in a pro spective clinical series (10, 28). Th e second most common initial motor disturbance was ce rebellar ataxia, with 29% of MSA patients being aff ected (10). Unusual presenting symptoms in pathologically proven cases include stroke-like episodes evolving into parkinsonism and tran- sient ischaemic attacks in the anterior or posterior circulation (29), as well as RE M sleep behavior disorder (30). initial motor disturbance in MSA Established disease Parkinsonism associated with MSA is characterized by brady- kinesia, ri gidity, postural tremor, and gait unsteadiness (28). Moreover, patients frequently exhibit orofacial dystonia associ- ated with a characteristic quivering high-pitched dysarthria (31 ). Although postural instability is common in early stages of the dis- ease course, recurre nt falls at disease onset are unusual (32). It has been suggested that a symmetric atremulo us picture might distin- guish MSA-P from PD (33, 34). However, motor disturbance was asymm etric in 74% of patients in a clinical series, and unilateral symptoms at onset were presen t in 47% of literature cases (10). Furthermore, some sort of tremor was present in the majo rity of cases in a clinical series (10). Th erefore the diff erential diagnosis of MSA-P an d PD may be diffi cult in the early stages because of a number of overlapping features such as rest tremor or asymmet- ric akinesia and rigidity. Nevertheless, the characteristic cli nical picture of MSA-P usually evolves within 5 years of disease onset, allowing a clinical diagnosis to be made with greater certainty dur- ing follow-up (6, 35). Orthostatic dysregulation is the second most common feature of autonomic dysfunction in MSA . Consensus criteria require a systolic blood pressure drop of at least 30 mmHg or a fall i n diastolic blood pressure of 15 mmHg for the diagnosis of MSA-associated orthostatic hypot ension (2). Characteristic symptoms of orthos- tatic hypotension include light-headedness, visual blurring, dizzi- ness, pre-syncope, and recurrent syncopal episodes. Intriguingly, r ecurrent syncope (more than three falls) was reported in only 15% of subjects, whereas post ural faintness was present in up to 53% (9, 10, 40). Th ese fi ndings were confi rmed in a recent clini- cal series estimating the frequency of orthostatic complaints and recurrent f alls to be 60% and 20%, respectively (28). Orthostatic symptoms may be further aggravated b y dopaminergic drugs, fl uid depletion, extensive food ingestion, and general physi- cal de conditioning. Indeed, patients with autonomic failure are susceptible to substantial drops in blood pressure aft er high carbohydrate intake and suffi cient fl uid intake may benefi cially alter orthostatic dysregulation (43 \200\22345). In severe cardiovascular Th e cerebellar disorder comprises gait ataxia, limb kinetic ataxia, and scanning dysarthri a, as well as cerebellar oculomotor disturbances. Cerebellar signs, most commonly manifesti ng as a CHAPTER 13 Multiple System Atrophy (MSA) 131 autonomic failure, the loss of barorefl exes may cause recumbent arterial hypertension (46) . Finally, the emergence of early auto- nomic failure in MSA patients within 2.5 years aft er disease onset is an independent predictor of rapid disease progression and reduced survi val (6, 47). most of the MSA patients identifi ed in the epidemiological sur- vey by Schrag et al. (12) were diagnosed during the study period, emphasizing the fact that MSA is poorly recognized in clinical practice (35). Clinical diagnostic criteria Th e diagnosis of MSA is based on history and physical examina tion. Th e fi rst set of diagnostic criteria for MSA was proposed by Quinn in 1989 (57), an d slightly modifi ed in 1994 (62). Optimized diag- nostic criteria were developed during an International Consensus Conference held in 1998 (63). However, clinical advances in MSA re quired a revision of the consensus criteria (2). Th ese criteria specify three levels of in creasing certainty: possible, probable, and defi nite MSA. While defi nite MSA requires pos t-mortem confi r- mation of neuronal multisystem degeneration and the proof of abundant GCI s (3), the diagnosis of probable and possible MSA relies on clinical and neuroimaging featu res (2). Probable MSA requires clear evidence of autonomic failure, including orthostatic h ypotension (i.e. decrease of blood pressure by at least 30 mmHg systolic or 15 mmHg diastol ic within 3 min of standing) and uri- nary dysfunction (i.e. inability to control bladder e mptying) in association with either levodopa-refractory parkinsonism or a cer- ebellar synd rome (Table 13.1) (2). Possible MSA is characterized as sporadic progressive adult-onset di sease with either parkinson- ism or a cerebellar syndrome associated with at least one feat ure suggesting autonomic failure and one additional feature suggestive of MSA according to consensus criteria (Table 13.2) (2). Disease onset is defi ned as the fi rst occurrence of any motor symptom or the involvement of autonomic pathways determined by suggestive autonom ic symptoms, with the exception of male erectile dysfunc- tion (2). Table 13.3 lists the \200\230red fl ags \200\231 for MSA, which are features that support a diagnosis of MSA, an d Table 13.4 lists the fi ndings that do not support a diagnosis of MSA according to consen sus criteria (2). Anhidrosis or hypohidrosis occur frequently in patients with MSA (48). However, the underly ing site of the lesion is not well established. Although postganglionic structures might be involved in MSA-associated sudomotor dysfunction, anhidrosis in patients with MSA is mainl y caused by preganglionic impairment. A recent prospective study suggested that there was m ore severe and diff use anhidrosis in MSA patients than in PD patients (49). Additionally, impaired sympathetic skin response, altered heat tolerance, and skin temperature dysregulat ion have been described in MSA (48, 50, 51). Finally, patients with MSA oft en present with cold dusky violaceous hands and poor circulatory return aft er blanching by pressure, sugg estive of impairment in neurovascular control of the distal extremities ( \200\230cold blue hand sign \200\231) (52). Th is fi nding is a clinical \200\230red fl ag \200\231 that sh ould raise the suspicion of MSA (53). In addition, some patients may also develop a Raynaud -like phenomenon (54). Sialorrhoea is a frequent and disabling condition in patients with parkinsonian conditions, and is an expression of swallow- ing diffi culties rather than excessive saliva production (55, 56). Furthermore, severe dysphagia, which can be found in a third of patients with MS A-P, is an additional clinical \200\230red fl ag \200\231, suggesting bulbar dysfunction ( 53). Although the literature on MSA-associated constipation is limited, it is widely accepted th at patients with MSA experience reduced bowel frequency (57, 58) and diffi culties in evacu ation (58). Indeed, in an analysis of the European MSA registry, a third of MSA patients co mplained of chronic constipation (28). Th e under- lying mechanism involves the degeneratio n of sacral autonomic nuclei, particularly Onuf \200\231s nucleus (59). Management Currently, disease-modifying medical treatments are lacking. Hence the managemen t of MSA rests largely on the alleviation of parkinsonian and autonomic symptoms. Although autonomic fail- ure is almost universally present in MSA, only a third of aff ected patient s receive appropriate pharmacological treatment (28). Diagnosis According to clinical consensus criteria, patients with MSA are classifi ed into two subtypes according to the predominant motor presentation. Patients with parkinsonism ar e designated MSA-P, and if cerebellar ataxia predominates the label MSA-C is recom- mended (2). However, many patients presenting with parkinson- ism show ataxia during the disease c ourse, and vise versa. Hence, the designation MSA-P or MSA-C refers to the predominant fea- ture at the time the patient is evaluated, and the predominant fea- ture can change with t ime. Nevertheless, in the western hemisphere MSA-P is more common (68% of cases) (28), wher eas in a Japanese study MSA-C was observed more frequently (70% of cases) (8). In addition, autonomic failure is observed universally in both motor presentations. Neuroprotective strategies Substantial progress towards underlying pathogenic mechanisms as well as the development of diagnostic consensus criteria and MSA-specifi c rating scales h ave allowed clinical investigators to conduct multisite randomized controlled trials to tes t the effi cacy of Table 13.1 Diagnostic criteria for probable MSA A sporadic, progressive, adult (>30 y) \200 \223onset disease characterized by: \227\206 Autonomic failure involving urinary incontine nce (inability to control the release of urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of blood pressure within 3 min of standing by at least 30 mmHg systolic or 15 mmHg diastolic AND Th e challenge of diagnosing MSA-P is aggravated by the fact that MSA and PD share not only parkinsonian features, but also numerous non-motor symptoms, as shown in several clinicopa tho- logical and prospective clinical studies. Indeed, in a clinicopatho- logical study con ducted by Litvan et al. (60), primary neurologists (who performed clinical follow-ups) iden tifi ed only 25% of MSA patients correctly at the fi rst visit (on average at 42 months aft er disease onset). Because of this overlap, MSA and PD are frequently indistinguishable in the early course of the disease, even when for- mal criteria are applied (61). Consistent with this observation, \227\206 Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or postural instability) OR \227\206 A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) Modi \201 ed according to Gilman et al. (2) and reproduced from Wenning and Stefanova (106 ) (with kind permission of Springer Science+Business Media). Oxford Textbook of Movement Disorders 132 candidate targets (5). Unfortunately, every multicentre randomized controlled trial so far has failed to confi rm disease modifi cation of candidate drugs. However, a placebo-control led double-blind trial assessing the therapeutic value of recombinant human growth hormone (r-HGH) in patients with MSA revealed a trend towards reduction in progression of motor sym ptoms that failed to reach sig- nifi cance (64). Aft er confi rming the neuroprotective eff ects of mino- cycline in a pre-clinical MSA study (65) and in models of related neurodegen erative disorders (66, 67), this broad-spectrum tetracy- cline antibiotic was assessed in a phase II trial. Th is multisite trial conducted by the European MSA study group (EMSA-SG) (http: // www.emsa-sg.org) failed to show a clinical eff ect on symptom sever- ity assessed by clinical motor function. Interestingly, data acquired by 11 C-(R)-PK11195 positron emis sion tomography (PET) suggested that minocycline may interfere with microglial activation ( 68). Another candidate drug which was assessed in a multisite setting was the antiglutamate rgic agent riluzole (32). Th is study confi rmed previous results obtained in a randomized controlled pilot trial prov- ing riluzole to be ineff ective. In contrast, a rather controv ersial trial was conducted by a South Korean research group which assessed effi cacy and fe asibility of autologous mesenchymal stem cell therapy. Th ese stem cells appeared to delay the progression of neurological defi cits in patients with MSA (69). Meanwhile, preclinical evidence supported a putative neuroprotective effi cacy of these stem cells, suggesting tr ans-diff erentiation and the induction of non-specifi c immunological responses as underlyi ng mechanisms (70). Table 13.2 Diagnostic criteria for possible MSA A sporadic progressive adult-onset (>30 yea rs) disease characterized by: \227\206 Parkinsonism (bradykinesia with rigidity, tremor, o r postural instability) OR \227\206 A cerebellar syndrome (gait ataxia with cerebellar dys arthria, limb ataxia, or cerebellar oculomotor dysfunction) AND \227\206 At least one feature suggesting autonomic dysfunction (otherwise unexplained urin ary urgency, frequency, or incomplete bladder emptying, erectile dysfunction in males, or s igni \201 cant orthostatic blood pressure decline that does not meet the level required in probable MSA) AND \227\206 At least one of the additional features: \227\206 Possible MSA-P or MSA-C Babinski sign with hyperre \202 exia \200 Stridor \227\206 Possible MSA-P Rapidly progressive parkinsonism \200 Poor response to levodopa \200 Postural instabili ty within 3 years of motor onset \200 Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 years of motor onset \200 Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum \227\206 Possible MSA-C Parkinsonism (bradykinesia and rigidity) \200 Atrophy on MRI of putamen, middle cerebella r peduncle, or pons \200 Hypometabolism on FDG-PET in putamen \200 Presynaptic nigrostr iatal dopaminergic denervation on SPECT Symptomatic treatment Autonomic failure Autonomic symptoms have a major impact on the quali ty of life, and therefore it is essential to treat autonomic failure thoroughly. Furthermor e, because of the progressive course of MSA a regular treatment review is mandatory to adju st measures according to clinical needs. or PET Modi \201 ed according to Gilman et al. (2) and reproduced from Wenning and Stefanova (106 ) (with kind permission of Springer Science+Business Media). Table 13.3 Red \202 ags for MSA \227\206 Orofacial dystonia \227\206 Disproportionate a ntecollis \227\206 Camptocormia (severe anterior \202 exion of the spine) and/or Pisa sy ndrome A broad range of drugs have been used in the treatment of pos- tural hypotension. Unfortuna tely, the benefi ts and side eff ects of many of these drugs have not been evaluated in MSA patients in randomized controlled trials. However, the concept of treatment of orthostatic hypotension is based on increasing intravascular volume and the prevention of blood poolin g in lower body parts. (severe lateral \202 exion of the spine) \227\206 Contractures of hands or feet \227\206 Inspiratory sighs \227\206 Severe dyspho nia \227\206 Severe dysarthria \227\206 New or increased snoring \227\206 Cold hands and feet \227\206 Pathological laughter or crying \227\206 Jerky myoclonic postural/action t remor Non-pharmacological options include suffi cient fl uid intake, a high-salt diet, more frequ ent, but smaller, meals (spreading of total daily carbohydrate intake) to reduce postprandi al hypotension, and custom-made elastic body garments. Head-up tilt during the night increa ses intravascular volume by up to 1 liter within a week, which is particularly helpful for improving early morning hypotension. Th e benefi cial eff ects of this approach can be enha nced by the prescription of fl udrocortisone, which further supports sodium retention (44). Modi \201 ed according to Gilman et al. (2) and reproduced from Wenning and Stefanova (106 ) (with kind permission of Springer Science+Business Media). Among the large number of vasoactive agents that have been eval- uated in MSA, only one, th e directly acting -agonist midodrine, complies with the criteria of evidence based medic ine (71, 72). Side eff ects are usually mild and rarely require withdrawal of treat- ment. Th e most frequent adverse eff ects are supine hypertension, urinary retention, goose bumps and paresthesias including trou- blesome scalp-tingling. Additionally, the parasympathomim etic and reversible cholinesterase inhibitor pyridostigmine provides a moderate but signifi cant improvement in orthostatic hypotension via enhanced sympathetic activity (73). Table 13.4 Non-supporting features of MSA \227\206 Classic pill-rolling rest tremor \227 \206 Clinically signi \201 cant neuropathy \227\206 Onset after age of 75 years \227\206 Family history of ataxia or parkinsonism \227\206 Dementia (on DSM-IV) \227\206 White ma tter lesions suggesting multiple sclerosis \227\206 Hallucinations not induced by drugs Modi \201 ed according to Gilman et al. (2) and reproduced from Wenning and Stefanova (106 ) (with kind permission of Springer Science+Business Media). CHAPTER 13 Multiple System Atrophy (MSA) 133 intraluminal fl uid, which can be achieved with a macrogol \200\223water solution, may alle viate such symptoms as well (90). Another promising drug appears to be the noradrenaline precur- sor l -threo-dihydroxy-pheny lserine ( l -threo DOPS, droxidopa), which is widely used in Japan and whose effi cacy has been demon- strated in two double-blind placebo-controlled trials (74, 75). in about 30% of patients. Th erapeutic approaches include the use of continuous positive ai rway pressure (CPAP), which may attenuate sleep apnoea and nocturnal stridor (91). However, in severe cases tracheostomy may be required. Inspiratory stridor develops Furthermore, octreotide, which is a somatostatin analog, might alleviate postprandial hypot ension without causing or increasing nocturnal hypertension (76). Th is eff ect is probably mediated by the inhibition of the release of vasodilatory gastrointestinal pep- tides (77) . Additionally, the vasopressin analog, desmopressin, which acts on renal tubular vasopress in-2 receptors, reduces noc- turnal polyuria and improves early-morning postural hypotensio n (78). Sympathomimetics, such as ephedrine, have both direct and indirect eff ects which m ight be useful in central autonomic dys- function. However, side eff ects arise with higher doses, including tremulousness, loss of appetite, and urinary retention, particularly in m en.