Multiple System Atrophy 

Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, progressive neurodegenerative disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. MSA is characterized neuropathologically by cell loss in the striatonigral and olivopontocerebellar structures of the brain and spinal cord accompanied by profuse, distinctive glia cytoplasmic inclusions (GCIs) formed by fibrillized alpha-synuclein proteins (defined as alpha-synucleinopathy of unknown etiology). (See Etiology and Pathophysiology, History and Physical Examination, and Workup.)^[1]

A consensus statement by the American Autonomic Society and American Academy of Neurology in 2007^[2] categorized MSA in MSA-P with predominant parkinsonism and MSA-P with dominant cerebellar features (MSA-C). (See Categories of MSA below.)

The concept of MSA as a unitary diagnosis encompassing several clinical syndromes has a long history. The first cases of MSA were presented 106 years ago, and the term MSA was introduced in 1969. The discovery of GCIs and alpha-synuclein immunostaining as a sensitive marker of MSA were major milestones in the definition of MSA as a clinicopathologic entity. (See Table 1, below).^[3]

Table 1. Historical Milestones in the Definition of Terms for MSA (Open Table in a new window)

A consensus conference in 2007^[6] simplified the older definition of MSA—as determined by the Consensus Committee representing the American Autonomic Society and the American Academy of Neurology in 1996 and 1998^[2] —and incorporated current knowledge for a better assessment of the disease.^[7]

Categories of MSA

The 2 categories of MSA are as follows:

• MSA with predominant parkinsonism (MSA-P) - Extrapyramidal features predominate; the term striatonigral degeneration, parkinsonian variant is sometimes used
• MSA with cerebellar features (MSA-C) - Cerebellar ataxia predominates; it is sometimes termed sporadic olivopontocerebellar atrophy

The designation of MSA-P or MSA-C depends on the dominant feature at the time of evaluation, which can change with time.

Shy-Drager syndrome

When autonomic failure predominates, MSA was sometimes termed Shy-Drager syndrome (not defined in the present consensus anymore).

Characteristics of MSA

Features indicating the presence of MSA (tables 2a and 2b) or of another disorder (Table 3) are described below. (Corticospinal tract dysfunction with extensor plantar response with hyperreflexia [pyramidal sign] is not used to categorize MSA.) (See DDx.)

Table 2a. Main Features for the Diagnosis of MSA (Open Table in a new window)

Table 2b. Additional Features for the Diagnosis of Possible MSA* (Open Table in a new window)

Table 3. Characteristics That Do Not Support the Diagnosis of MSA (Open Table in a new window)

levels of certainty of MSA

MSA can be ascertained as possible, probable, or definite MSA (see Table 4, below), based on autonomic and urogenital features, on the presence of parkinsonism, and on cerebellar dysfunction, as well as on additional features (see tables 2a and 2b, above).

Only pathologic findings of high density of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) and degenerative changes in the striatonigral or olivopontocerebellar pathways can definitively confirm the diagnosis of MSA. (See Workup.)

Table 4. Diagnostic Categories of MSA (Open Table in a new window)

Red flags supporting the diagnosis of MSA include the following:

• Orofacial dystonia
• Disproportionate antecollis
• Severe anterior flexion of the spine (camptocormia)
• Severe lateral flexion of the spine (Pisa syndrome)
• Contractures of hands and feet
• Inspiratory sighs
• Severe dysphonia
• Severe dysarthria
• New or increased snoring
• Cold hands and feet
• Pathologic laughter or crying
• Jerky myoclonic postural/action tremor

Patient education

A variety of resources are available for patient education. These include the Web sites of the MSA Shy-Drager Support Group and the Vanderbilt Autonomic Dysfunction Center.

MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the central nervous system (CNS). The cause of MSA is unknown, although a history of trauma has been suggested. Pesticide exposure as a causative factor in MSA has been suggested but has not been confirmed statistically.^[8] In addition, no other environmental factors have been established as risk factors for MSA. Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak.

Autosomal recessive inheritance^[9] and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported.^[10]

Researchers initially assumed that gray-matter damage caused MSA. However, the discovery of oligodendroglial glial cytoplasmic inclusions (GCIs) (see 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. The clinical symptoms of MSA correlate with cell loss in different CNS sites. (See Table 5, below.)

Table 5. Clinicopathologic Correlations (Open Table in a new window)

Occurrence in the United States

The prevalence of MSA is reported to be between 1.9-4.9 cases per 100,000 population. An estimated 25,000-75,000 Americans have MSA. Many 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 occurrence

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

Race-, sex-, and age-related demographics

MSA has been encountered in Caucasian, African, and Asian populations. In Western countries, MSA-P predominates, occurring in 66-82% of patients. In Eastern countries, MSA-C is common, occurring in 67% of patients.

The disease more often affects men than women. The female-to-male ratio is around 1:2. (A ratio of 1:3-9 has also been reported.) However, the early and easy diagnosis of impotence may have led to the male statistical predominance of MSA. The mean age at onset in MSA is 52.5-55 years. The disease progresses over intervals of 1-18 years.

Patients with MSA have a poor prognosis. The disease progresses rapidly. Median survivals of 6.2-9.5 years from the onset of first symptoms have been reported since the late 20th century. No current therapeutic modality reverses or halts the progress of this disease. MSA-P and MSA-C have the same survival times, but MSA-P shows more rapid dysfunctional progression.

An older age at onset has been associated with shorter duration of survival in MSA. The overall striatonigral cell loss is correlated with the severity of disease at the time of death.

Bronchopneumonia (48%) and sudden death (21%) are common terminal conditions in MSA. Urinary dysfunction in MSA often leads to lower urinary tract infections (UTIs); more than 50% of patients with MSA suffer from recurrent lower UTIs and a significant number die of related complications.^[12]