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multiple system atrophy

Tuesday 14 April 2009

While the designation multiple system atrophy (MSA) originally applied to a wide spectrum of neurodegenerative disorders affecting multiple neural "systems," it is now used to describe a group of disorders characterized by the presence of glial cytoplasmic inclusions (GCIs), typically within the cytoplasm of oligodendrocytes.

With recognition of GCIs, the three clinicopathologic entities of striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy were gathered into a single pathologic category.

Subsequently, the identification of α-synuclein (SNA) as the major component of the inclusions has resulted in this disorder being considered as a synucleinopathy.

Unlike Parkinson disease, with which it shares the feature of α-synuclein-containing inclusions, no mutations in the gene for this synaptic protein have been found in cases of MSA.

Clinical synopsis

The two principal symptoms of MSA are parkinsonism and autonomic dysfunction, particularly orthostatic hypotension. When these are present in relative isolation, the syndromes may be referred to as striatonigral degeneration and Shy-Drager syndrome, respectively.

Presentation as an isolated ataxic disorder with cerebellar dysfunction (olivopontocerebellar atrophy) is much rarer.

In general, patients have clinical signs and symptoms that represent a combination of these entities, corresponding to a combination of anatomic sites of pathology.

Parkinsonism (akinesia and rigidity) can be related to the degree of cell loss from the substantia nigra and striatum; ataxia with changes in the circuits involving the pons, cerebellum, and inferior olive; and autonomic symptoms with cell loss from the catecholaminergic nuclei of the medulla and the intermediolateral cell column of the spinal cord.

Morphology

On macroscopic examination, there is typically atrophy of the cerebellum, including the cerebellar peduncles, pons (especially the basis pontis), medulla (especially the inferior olive), substantia nigra, and striatum (especially putamen). These brain regions show evidence of neuronal loss as well as variable numbers of neuronal cytoplasmic and nuclear inclusions.

The shared diagnostic feature of these disorders, the cytoplasmic inclusions, were originally demonstrated with silver impregnation methods and by immunostaining have been shown to contain α-synuclein (SNA) as well as ubiquitin and αB-crystallin.

Tau may be present in the inclusions but is not hyperphosphorylated as compared with other diseases marked by tau inclusions.

The inclusions are ultrastructurally distinct from those found in other neurodegenerative diseases and are composed primarily of 20- to 40-nm tubules. Similar inclusions may also be found in the cytoplasm of neurons, sometimes in neuronal and glial nuclei, and in axons.

It appears that glial cytoplasmic inclusions can occur in the absence of neuronal loss, suggesting that they may represent a primary pathologic event.