Multiple system atrophy

doi:10.1016/S1474-4422(03)00662-8

The Lancet Neurology

Volume 3, Issue 2, February 2004, Pages 93-103

https://doi.org/10.1016/S1474-4422(03)00662-8 Get rights and content

Summary

Multiple system atrophy (MSA) is a sporadic neurodegenerative disorder characterised clinically by any combination of parkinsonian, autonomic, cerebellar, or pyramidal signs and pathologically by cell loss, gliosis, and glial cytoplasmic inclusions in several CNS structures. Owing to the recent advances in its molecular pathogenesis, MSA has been firmly established as an α-synucleinopathy along with other neurodegenerative diseases. In parallel, the clinical recognition of MSA has improved and the recent consensus diagnostic criteria have been widely established in the research community as well as movement disorders clinics. Although the diagnosis of this disorder is largely based on clinical expertise, several investigations have been proposed in the past decade to assist in early differential diagnosis. Symptomatic therapeutic strategies are still limited; however, several candidate neuroprotective agents have entered phase II and phase III clinical trials.

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Epidemiology

There are only a few descriptive epidemiological studies on MSA. Bower and colleagues¹⁵ reported the incidence of MSA over 14 years in Olmsted County, Minnesota, USA. Nine new cases of MSA were identified, none of which had an onset before the age of 50 years. The reported crude incidence was 0·6 patients per 100 000 population per year; when the age band >50 years was examined, the estimated incidence rose to 3 patients per 100 000 population, per year. Estimates of the prevalence of MSA in

Clinical presentation

Multiple system atrophy affects both men and women; it generally starts in the sixth decade of life and progresses with a mean survival of 6–9 years.23, 24, 25, 26 There is substantial variation of disease progression with survival of more than 15 years in some instances.

The main features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. Previous studies suggest that 29–33% of patients with isolated late-onset cerebellar ataxia and 8% of

Clinical diagnostic criteria

Clinical diagnostic criteria for MSA were first proposed by Quinn11, 34 who classified patients as either striatonigral-degeneration type or olivopontocerebellar-atrophy type MSA depending on the predominance of parkinsonism or cerebellar ataxia. These criteria define two levels of clinical diagnostic certainty—possible and probable—and reserve a definite diagnosis to neuropathological confirmation.

Clinicopathological studies have shown good specificity, but poor sensitivity³⁵ of the Quinn

Investigations

The diagnosis of MSA rests on clinical history and neurological examination. According to the consensus conference on the diagnosis of MSA,¹² additional investigations such as autonomic function tests, sphincter electromyography, or neuroimaging may be used to support the diagnosis or to exclude other diseases. The abnormalities reviewed below have been observed in patients with advanced rather than early disease. In the early stages the investigations may give equivocal results. Therefore, the

Autonomic function tests

Findings of severe autonomic failure early in the course of the disease make the diagnosis of MSA more likely, although the specificity in a single patient in comparison to other neurodegenerative disorders is unknown. Pathological results of autonomic function tests may account for many symptoms in patients with MSA and should prompt specific therapeutic steps to improve quality of life and prevent secondary complications like injuries caused by hypotension induced falls or ascending urinary

Cardiovascular function

A history of postural faintness or other evidence of orthostatic hypotension (eg, neck ache on rising in the morning or posturally related changes of visual perception) should be sought in all patients in whom MSA is suspected. After taking a comprehensive history, cardiovascular function should be tested. According to the consensus statement of the American Autonomic Society and the American Academy of Neurology on the definition of orthostatic hypotension, pure autonomic failure, and MSA, a

Bladder function

Assessment of bladder function is mandatory in MSA and provides evidence of involvement of the autonomic nervous system at an early stage of the disease (when bladder function is still normal in most patients with PD). After a thorough history of frequency of voiding, difficulties in initiating or suppressing voiding, and the presence of urinary incontinence, a standard urine analysis will exclude infection. The residual volume after voiding needs to be determined sonographically or with

Sphincter electromyogram

An abnormal sphincter electromyogram may be found in many patients with clinically definitive MSA, including those who, as yet, have no urological or anorectal problems. In at least 80% of patients with MSA, electromyography of the external anal sphincter reveals signs of neuronal degeneration in Onuf's nucleus with spontaneous activity and increased polyphasia.33, 50, 51 The prevalence of abnormalities in early stages of MSA is unknown. These findings do not reliably differentiate between MSA

MRI

Routine 1–5 Tesla MRI, including diffusion-weighted imaging, should be done in all patients with suspected MSA because brainstem or basal-ganglia abnormalities suggestive of MSA may appear during early disease stages. These changes include an olivopontocerebellar-atrophy-like pattern indistinguishable from autosomal dominant cerebellar ataxia.⁵⁶ MRI measures of basal-ganglia pathology in MSA are less well established and naked-eye assessments are often unreliable. In advanced cases, putaminal

Symptomatic therapy

There is no effective treatment for the cerebellar features of the disease.111, 112 Therefore, medical treatment is largely aimed at the alleviation of parkinsonism and dysautonomia (Panel 5).

Parkinsonism

The commonly held belief that patients with MSA are non-responsive or poorly responsive to levodopa is misleading. Clinical series have documented levodopa efficacy in up to 40% of patients with possible or probable MSA.26, 113, 114, 115 Data obtained from series with pathological confirmation are more

Other therapies

Because the results of drug treatment for MSA are generally poor, other therapies are all the more important. Physio-therapy helps maintain mobility and prevent contractures, and speech therapy can improve speech and swallowing and provide communication aids. Dysphagia may necessitate feeding through a nasogastric tube or even percutaneous endoscopic gastrostomy. These palliative management decisions should be based on careful clinical judgement, taking into account the expectations of both

Conclusion

During the last 15 years there have been major advances in our understanding of the cellular pathology and clinical features of MSA. However, this disorder has a serious prognosis, and therapies are little more than moderately or poorly effective. Future therapeutic trials are urgently needed and should be directed towards novel symptomatic or neuroprotective agents, as well as non-pharmacological treatments.

Search strategy and selection criteria

References for this review were identified by searches of MEDLINE between 1969 and 2003 and references from relevant articles; numerous articles were also identified through searches of the extensive files of the authors. The search terms “MSA”, “striatonigral degeneration”, “olivopontocerebellar atrophy”, “Shy-Drager syndrome”, “diagnosis”, “autonomic function”, “imaging”, “animal models”, “a-synuclein”, and “therapy were used. Abstracts and reports from meetings were also included. Only

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