Excerpt from Multiple System Atrophy

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Background

The concept of multiple system atrophy (MSA) as a unitary diagnosis encompassing several clinical syndromes has a long history. The first cases of MSA were presented 106 years ago. The term MSA was introduced in 1969. The discovery of glial cytoplasmic inclusions (GCIs) and alpha-synuclein immunostaining as a sensitive marker of MSA was the major milestone in the definition of MSA as a clinicopathological entity (Table 1).

Table 1. Historical Milestones in the Definition of Terms for MSA
 

MSA is defined as a sporadic, progressive, neurodegenerative disease of undetermined etiology, characterized clinically by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination (definition by the Consensus Committees representing the American Autonomic Society and the American Academy of Neurology in 1996 and 1998). MSA is characterized pathologically by cell loss, gliosis, and GCIs in several brain and spinal cord structures.

MSA can be ascertained as possible, probable, or definite based on the features and criteria in the 3 clinical domains: (1) autonomic and/or urinary dysfunction, (2) parkinsonism, and (3) cerebellar dysfunction (Table 2, Table 3, Table 4, Table 5, Table 6). The nomenclature is based on features, which define the disease characteristic, and criterion, which is the defining feature. Possible MSA can be diagnosed when 1 criterion and 2 features separate from other clinical domains are found. The diagnosis of probable MSA requires the criterion of autonomic and/or urinary dysfunction and the presence of poorly levodopa-responsive parkinsonism or cerebellar ataxia. Only pathologic findings, a high density of alpha-synuclein-positive GCIs degenerative changes in the nigrostriatal or olivopontocerebellar pathways, can confirm the diagnosis of MSA.

When autonomic failure predominates, MSA is sometimes termed Shy-Drager syndrome. When extrapyramidal features predominate, the term striatonigral degeneration, parkinsonian variant, or MSA-P is sometimes used. When cerebellar features predominate, MSA is sometimes termed sporadic olivopontocerebellar atrophy or MSA-C.

The clinical and diagnostic distinctions between MSA and pure autonomic dysfunction are reviewed in Table 7.

Table 2. Clinical Domains and Features in the Diagnosis of MSA

*Incidence of clinical features recorded during the lifetimes of 203 patients.

Adapted from Gilman et al.

Table 3. Exclusion Criteria for Diagnosis of MSA

Table 4. Diagnostic Categories of MSA*

*Features and criteria for each clinical domain are defined in Table 2.

Pathophysiology

MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the CNS. The etiology of the cell loss is still unknown. Autoimmune mechanisms and toxic agents have been suggested as potential causes of MSA, but evidence for these etiologies is weak. No evidence of a genetic etiology has been found. The clinical symptoms of MSA correlate with cell loss in different CNS sites (Table 5).

Researchers initially assumed that gray-matter damage caused MSA. The discovery of oligodendroglial cytoplasmic inclusions (Table 8) indicated that damage primarily affects the white matter. The chronic alterations in glial cells may impair trophic function between oligodendrocytes and axons and cause secondary neuronal damage. Whether the inclusions represent primary lesions or nonspecific secondary markers of cellular injury remains unknown. In addition to the GCIs, extensive myelin degeneration occurs in the brain. Changes in myelin may play an important role in the pathogenesis of MSA.

Table 5. Clinicopathologic Correlations

Adapted from Wenning et al and other sources.

Frequency

United States

The prevalence of MSA is reported to be between 1.9-4.9 cases per 100,000 population. An estimated 25,000-100,000 Americans have MSA. Most patients do not receive the correct diagnosis during their lifetime because of the difficulty in differentiating MSA from other disorders (eg, Parkinson disease, pure autonomic failure [PAF], other rare movement disorders). About 29-33% of patients with isolated late-onset cerebellar ataxia and 8-10% of patients with parkinsonism will develop MSA. Therefore, a higher prevalence than that estimated can be assumed.

International

In the United Kingdom, the prevalence is 0.9-8.4 cases per 100,000 population; in France, 1.8-2.7 per 100,000 population.

Mortality/Morbidity

Patients with MSA have a poor prognosis. The disease progresses rapidly. Patients survive an average of 6-9 years after the onset of the illness.

• MSA-P and MSA-C have the same survival times, but MSA-P shows more rapidly dysfunctional progression.
• Bronchopneumonia (48%) and sudden death (21%) are common terminal conditions.

Race

MSA has been encountered in Caucasian, African, and Asian populations.

• In Western countries, MSA-P predominates with 66-82% of patients.
• In Eastern countries, MSA-C is common with 67% of patients.

Sex

The disease more often affects men than women.

• Female-to-male ratios of 1:3-9 are reported.
• Early and easy diagnosis of impotence may lead to the male predominance of MSA.

Age

The mean age at onset in MSA is 52.5-55 years. The disease progresses over intervals of 1-18 years.

• Median survivals of 6.2-9.5 years from the onset of first symptoms have been reported in the last 2 decades.
• An older age at onset has been associated with shorter duration of survival.
• The overall nigrostriatal cell loss is correlated with the severity of disease at the time of death.

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