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. Motor symptoms General approach Although some patients may benefi t from drug treatment of MSA motor symptoms in the short term, the long-term results are gener- ally considered to b e poor. Th erefore non-pharmacological thera- pies are even more important. Physiotherapy h elps to maintain mobility and prevent contractures. Furthermore, speech therapy can not onl y improve speech and swallowing, but also provide com- munication aids. Severe dysphagia wi th pulmonary penetration of ingested food and fl uids may require feeding by nasogastric tu be or even percutaneous endoscopic gastrostomy (PEG). Occupational therapy with regular hom e visits may limit the burden resulting from the patient \200\231s disabilities. Provision of a four-wheel walker, and subsequently a wheelchair, is usually dictated by the liability of falls because of postural instability and gait ataxia, but not by akinesia and rigidity per se . Psychological support improves the quality of life for patients and their familie s. Th e peptide erythropoietin may be benefi cial in some patients, particularly in those with erythropoietin-associated normocytic nor- mochromic anemia. Th e substitution of erythropo ietin increases red blood cell mass and subsequently improves cerebral oxygena- tion (79, 8 0). Interestingly, the neuroprotective eff ects of erythropoi- etin were demonstrated in a preclinical study of MSA (81). With regard to neurogenic bladder dysfunction presenting with post-void residual volumes, c lean intermittent catheterization three to four times per day is a widely accepted approach to prevent sec- ondary consequences. If mechanical obstruction in the urethra or motor sym ptoms of MSA prevent uncomplicated catheterization, permanent transcutaneous suprapubic cat heterization may become necessary (82). Parkinsonism Parkinsonism is the predominating motor symptom of MSA-P and therefore is a ma jor target for symptomatic treatment. Despite the lack of randomized controlled trials, lev odopa is the most frequently used antiparkinsonian agent in MSA. An analysis of a multisite patient registry revealed that up to 40% of MSA patients benefi t from levodopa treatment (28). Unfortunately, this response is oft en transient, lasting for 3 years on average (92) . Pre-existing orthostatic hypotension is oft en unmasked or exac- erbated by levodopa trea tment in patients with MSA. In contrast, psychiatric or toxic confusional states appear to be less common than in PD (9). Pharmacological options including anticholinergic, procholin- ergic, and adrenergic substan ces are not usually successful in adequately reducing post-void residual volume in MSA. How ever, anticholinergic agents, such as oxybutynin, can improve symptoms of detrusor hyperref l exia or sphincter \200\223detrusor dyssynergia early in the course of the disease (38). A nticholinergic treatment might be dose limited by central nervous adverse eff ects. More re cently, a peripherally acting anticholinergic agent, trospium chloride, has been shown to b e equally eff ective in patients with detrusor hyperrefl exia without causing central nervo us adverse eff ects (83). Nevertheless, this drug has not yet been specifi cally investigat ed in MSA patients. Finally, -adrenergic receptor antagonists (prazosin and moxisylyte) have been shown to improve voiding with reduc- tion of residual volumes in MSA patients (84 ). Treatment with dopamine agonists has been disappointing. Severe psychiatric side eff ects o ccurred in a double-blind crossover trial of six patients treated with lisuride, with night mares, visual hallucinations, and toxic confusional states (93). Wenning et al. (9) reporte d a response to oral dopamine agonists in only four of forty-one patients; none of thirty p atients receiving bromocriptine improved, but four of ten who received pergolide had some b enefi t. Twenty-two percent of the levodopa responders had good or excel- lent response to at least one dopamine agonist (9). Pathological hypersexuality, predominantly linked to adj uvant dopamine agonist treatment, has been reported in two MSA patients (94). Amantadine pr oduced antiparkinsonian eff ects in four out of twenty-six MSA patients (9); however, there was no signifi cant improvement in another open study of nine patients with atypical parki nsonian conditions, including fi ve MSA patients (95). A more recent ran- domized placebo-c ontrolled trial confi rmed these observations by demonstrating amantadine to be ineff ectiv e in MSA patients (96). Interestingly, the selective serotonin-reuptake inhibitor paroxet- ine improved motor abilities of the upper limb and speech (97). In contrast with observatio ns in PD, anticholinergics did not improve motor function in MSA; however, they may be help ful in alleviating severe and disturbing sialorrhoea. Th e necessity for specifi c treatment of sexual dysfunction needs to be evaluated individu ally in each patient. Th e phosphodieste- rase type 5 inhibitor sildenafi l improved male e rectile function in a placebo-controlled double-blind study (85). However, sildenafi l may only be prescribed aft er exclusion of severe postural hypoten- sion, as this compound may unmask or worsen orthostatic hypo- tension. Furthermore, male impotence can be partially am ended by the use of intracavernosal papaverine (86), apomorphine (87), prostaglandin E1, or penile implants (88). Finally, erectile failure in MSA may also be improved by oral yohimb ine (38). With regard to gastrointestinal symptoms, such as constipation, non-pharmacological treatme nt should be considered fi rst. Th is includes daily exercise, high fl uid and fi bre intak e, and the consump- tion of fruit juices. If laxative therapy becomes necessary, polycar- b ophil and mosapride citrate may relieve constipation symptoms, as suggested by two small op en-label studies (89). An increase in Oxford Textbook of Movement Disorders 134 Ten per cent of MSA patients show dystonia (28). Local botuli- num toxin injections are eff ective in orofacial dystonia, including blepharospasm and limb dystonia (98). However, bot ulinum toxin injections should be avoided in the therapy of disproportionate antecollis as severe dysphagia resulting in the need for a nasogastric feeding tube has been reported (99 ). assessing clinical symptoms and disability have greatly facilitated large multicentre trial s (2, 100, 101). Finally, candidate SNP studies have identifi ed variants of the -synucl ein gene with signifi cantly increased disease risk (20, 21), reinforcing current basic res earch activities that address the role of -synuclein toxicity in MSA pathogenesis (105). Unfortunately, we are not yet able to alter the course of MSA; however, recent progress wi ll accelerate research into novel interventional therapies. Similarly to PD, sialorrhoea probably results from swallowing diffi culty and may be substa ntially decreased by diminution of sali- vary production using botulinum toxin injections i nto the parotid and submandibular glands, as suggested by a double-blind placebo controlled trial (56). Top clinical tips Cerebellar ataxia Cerebellar ataxia is the clinical hallmark of MSA-C and present in nearly two-thirds of MSA patients (28). Currently, there is no eff ective pharmacological treatme nt for MSA-associated cerebel- lar ataxia, although several case reports suggest benefi cia l eff ects mediated by a variety of compounds including cholinergics, NMDA receptor antagon ists, derivatives of -aminobutyric acid, non-selective beta-blockers, 5-hydroxytryptopha n, and isoniazid. However, none of these medications has been proved to be eff ective in la rger patient series (31). MSA is an orphan disease with approximately 30 000 cases in EU countries. \227\206 MSA is an atypical parkinsonian disorder with prominent auto- nomic failure and variably at axia. \227\206 MSA is an -synucleinopathy associated with glial cytoplasmic inclusions and neuronal mul tisystem degeneration. \227\206 Genetic vulnerability in MSA is refl ected by studies and familial MSA. associa tion \227\206 Symptomatic therapy targets orthostatic hypertension, urogeni- tal failure, and parkinsonis m (levodopa response in 30%). \227\206 Key advances Important advances in the understanding of MSA have been achieved in the last decade. Not only the revision of clinical con- sensus diagnostic criteria subdividing MSA a ccording to the predominance of parkinsonism versus ataxia into MSA-P and MSA-C (2), but al so the development and validation of clinical rating scales, including the unifi ed MSA rat ing scale (UMSARS) (100) and MSA-QoL (101), will allow investigators to conduct multicentre clinical trials. Furthermore, research into functional and structural neuroimaging tools f or early diagnosis and pro- gression monitoring have provided surrogate markers which can b e used in clinical trials (102). Finally, the development of ani- mal models (103, 104) has permitted the testing of hypotheses regarding pathogenesis and accelerated preclinical res earch into disease-modifying drugs (5). Transgenic models of MSA are now available for target detection and drug development. \227\206 Th ere are now MSA research networks in Europe (http://www. emsa-sg.org), the USA, and Japa n. \227\206 References 1. 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