What is the pathophysiology of multiple system atrophy (MSA)?

Updated: Oct 17, 2018
  • Author: André Diedrich, MD, PhD; Chief Editor: Selim R Benbadis, MD  more...
  • Print
Answer

MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the central nervous system (CNS). The cause of MSA remains unclear, 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] Autoimmune mechanisms have also been suggested as potential causes of MSA, but evidence for these is weak.

There is some evidence of genetic predispositions in Japanese cohorts. Autosomal recessive inheritance [9] and genetic alterations with abnormal expansion of 1 allele of the SCA type 3 gene has been reported. [10] Single nucleotide polymorphisms (SNPs) at the SNCA locus coding for alpha-synuclide have been identified. G51D mutation in the SNCA locus has been described, but a connection between SCNA locus and MSA disease could not be confirmed. Associations with COQ2 and C9orf72 have been reported. [11, 12]

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)

Clinical Symptom

Pathologic Findings and Location of Damage or Cell Loss

Orthostatic hypotension

Primary preganglionic damage of intermediolateral cell columns

Urinary incontinence (not retention)

Preganglionic cell loss in spinal cord (intermediolateral cell columns), related to detrusor hyperreflexia caused mainly by loss of inhibitory input to pontine micturition center (rather than to external urethral sphincter denervation alone)

Urinary retention caused by detrusor atonia

Sacral intermediolateral cell columns

Cerebellar ataxia

Cell loss in inferior olives, pontine nuclei, and cerebellar cortex

Pyramidal signs

Pyramidal tract demyelination

Extensor plantar response

Pyramidal tract lesion

Hyperreflexia

Pyramidal tract lesion

Motor abnormalities

GCIs in cortical motor areas or basal ganglia

Akinesia

Putamen, globus pallidus

Rigidity

Putaminal (not nigral) damage

Limb and gait ataxia

Inferior olives, basis pontis

Decreased or absent levodopa responsiveness

Striatal cell loss, loss of D1 and D2 receptors in striatum or impaired functional coupling of D1 and D2 receptors

Nystagmus

Inferior olives, pontine nuclei

Dysarthria

Pontine nuclei

Laryngeal stridor

Severe cell loss in nucleus ambiguus or biochemical defect causing atrophy of posterior cricoarytenoid muscles

Excessive daytime sleepiness

Loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons [13]

Adapted from Wenning et al and other sources.


Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!