Diagnosis and Treatment of Multiple System Atrophy: an Update

This review provides an update on the diagnosis and therapy of multiple system atrophy (MSA), a sporadic neurodegenerative disorder characterised clinically by any combination of parkinsonian, autonomic, cerebellar or pyramidal symptoms and signs and pathologically by cell loss, gliosis and glial cytoplasmic inclusions in several brain and spinal cord structures. The term MSA was introduced in 1969 although prior to this cases of MSA were reported under the rubrics of striatonigral degeneration, olivopontocerebellar atrophy, Shy-Drager syndrome and idiopathic orthostatic hypotension. In the late nineties, -synuclein immunostaining was recognised as the most sensitive marker of inclusion pathology in MSA: due to these advances in molecular pathogenesis, MSA has been firmly established as an -synucleinopathy along with Parkinson’s disease (PD) and dementia with Lewy bodies. Recent epidemiological surveys have shown that MSA is not a rare disorder (~5 cases per 100,000 population), and that misdiagnosis, especially with PD, is still common due to its variable clinical presentation. The diagnosis of MSA is largely based on clinical expertise, and this is well illustrated by the consensus diagnostic criteria which comprise clinical features only (divided into four domains including autonomic dysfunction, parkinsonism, cerebellar dysfunction and corticospinal tract dysfunction). Nevertheless, several autonomic function, imaging, neurophysiological and biochemical studies have been proposed in the last decade to help in the differential diagnosis of MSA. No drug treatment consistently benefits patients with this disease. Indeed, parkinsonism often shows a poor or unsustained response to chronic levodopa therapy although one third of the patients may show an initial moderate-to-good dopaminergic response. There is no effective drug treatment for the cerebellar ataxia. On the other hand, features of autonomic failure such as orthostatic hypotension, urinary retention or incontinence, constipation and impotence, may often be relieved if recognised by the treating physician. Novel symptomatic and neuroprotective therapies are urgently required. Introduction The clinical picture of multiple system atrophy (MSA) in its full blown form is distinctive (Fig. 1). The patient is hypomimic with orofacial and anterior neck dystonia resulting in a grinning smile akin to ‘risus sardonicus’ and sometimes disproportionate antecollis. The voice is often markedly impaired with a characteristic quivering highpitched dysarthria. The motor disorder of MSA is often mixed with parkinsonism, cerebellar ataxia, limb dystonia, myoclonus and pyramidal features occurring at the same time. However, akinesia and rigidity are the predominant features in 80% of patients, and cerebellar ataxia within the remaining 20% and according to the predominant motor presentation MSA patients may be labelled as either parkinsonian or cerebellar variant of MSA (MSA-P, MSA-C). Dysautonomia is characteristic of both MSA subtypes, primarily comprising urogenital and orthostatic dysfunction. Clinical diagnosis and clinical diagnostic criteria The clinical diagnosis of MSA is fraught with difficulty and there are no pathognomonic features to discriminate the common parkinsonian variant (MSA-P) from PD. In a clinicopathologic study, primary neurologists (who followed up the patients clinically) identified only 25% of MSA patients at the first visit (42 months after disease onset) and even at their last neurological follow-up (74 months after disease onset), half of the patients were still misdiagnosed with the correct diagnosis in the other half being established on average 4 years after disease onset. Mean rater sensitivity for movement disorder specialists was higher but still suboptimal at the first (56%) and last (69%) visit. In 1998 an International Consensus Conference promoted by the American Academy of Neurology was convened to develop new and optimised criteria for a clinical diagnosis of MSA, which are now widely used by neurologists. These criteria specify three diagnostic categories of increasing certainty: possible, probable and definite (Table 1). The diagnosis of possible and probable MSA are based on the presence of clinical features listed in Table 1, with clear exclusion criteria. A definite diagnosis requires a typical neuropathological lesion pattern as well as deposition of -synuclein-positive glial cytoplasmic inclusions (Fig. 2). However, whether the Consensus criteria will improve recognition of MSA patients especially in early disease stages needs to be investigated by prospective surveys with neuropathological confirmation in as many cases as possible. MSA usually manifests in middle age (the median age of onset is 53), affects both sexes equally, and progresses relentlessly with a mean survival of 6-9 years. MSA patients may present with akinetic-rigid parkinsonism that usually responds poorly to levodopa, and whilst this has been identified as the most important early clinical discriminator of MSA and PD, a subgroup of MSA patients may show a good or, rarely, excellent, but usually short-lived, response to levodopa. In patients presenting initially with pure isolated parkinsonism, the presence of atypical features that are usually absent in PD (so-called red flags) may alert the clinician towards MSA (Table 2). Progressive ataxia, mainly involving gait, may also be the presenting feature of MSA, and appears to be more common than the parkinsonian variant in Japan compared to Western countries. Autonomic failure with Gregor Wenning obtained an MD at the University of Münster (Germany) in 1991 and a PhD at the University of London in 1996. He received his neurology training at Münster, Tübingen, London and Innsbruck. Presently he holds a professorship at the Department of Neurology, University Hospital, Innsbruck. He is affiliated to the movement disorders unit and in charge of the neurodegeneration research laboratory. Section Review Article Figure 1: A patient with MSA with hypomimia, asymmetric orofacial dystonia more marked on the left and cervical dystonia affecting the platysma. The patient had a very distinctive quivering, strangled highpitched dysarthria as is seen in 80% of MSA patients. Reproduced with kind permission from John Wiley & Sons, Inc: Wenning et al., The risus sardonicus of MSA. Mov Disord 2003;18:1211. Felix Geser received his training in medicine and theology at the University of Innsbruck (Austria) and Freiburg (Germany). Presently he is a PhD student at the Department of Neurology, University of Innsbruck, investigating the natural history of MSA within the framework of the European MSA Study Group.