Multiple system atrophy: insights into a rare and debilitating movement disorder

Key Points

  • Multiple system atrophy (MSA) is a sporadic and rare neurodegenerative movement disorder with an estimated annual incidence of 0.6 per 100,000 (ORPHA102)

  • The clinical presentation is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common — and often debilitating — symptoms

  • α-Synuclein-immunoreactive (oligodendro)glial cytoplasmic inclusions are the neuropathological hallmark of MSA

  • Permissive templating ('prion-like' propagation) of misfolded α-synuclein is currently thought to be the key event in the pathophysiological cascade

  • No disease-modifying therapies are currently available; symptomatic treatment options are limited, and the therapeutic benefits of these therapies is often only transient

  • International collaboration is gaining momentum with the recent formation of international study groups and novel funding opportunities dedicated exclusively to MSA research

Abstract

Multiple system atrophy (MSA) is a devastating and fatal neurodegenerative disorder. The clinical presentation of this disease is highly variable, with parkinsonism, cerebellar ataxia and autonomic failure being the most common — and often debilitating — symptoms. These symptoms progress rapidly, and patients die from MSA-related complications after 9 years of symptom duration on average. Unfortunately, the course of the disease cannot be improved by drug or surgical treatment. In addition, symptomatic treatment options are currently limited, and therapeutic benefits are often only transient. Thus, further interventional studies of candidate disease-modifying and symptomatic therapies are essential to improve patient care. In the past 15 years, the understanding of MSA-specific requirements in trial methodology has improved, resulting in a substantial increase in high-quality interventional studies. In this Review, we discuss MSA risk factors, clinical presentation and neuropathology, and we provide a hypothesis on key pathophysiological events, a summary of recent randomized controlled trials, and an overview of ongoing international collaborations.

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Figure 1: Key events in the pathophysiological cascade of MSA.
Figure 2: Diagnostic scheme for MSA.
Figure 3: Common findings on routine MRI in patients with multiple system atrophy.
Figure 4: Flow chart of the MDS MSA Study Group aims.

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G.K.W and F.K. contributed equally to writing the article. G.K.W researched the data for the article, and provided a substantial contribution to discussions of the content and to review and editing of the manuscript before submission.

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Correspondence to Gregor K. Wenning.

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Glossary

Permissive templating

Also known as seeding, permissive templating is a phenomenon whereby some protein assemblies can induce folding of the same (or similar) protein into a disease-causing confirmation.

Orphan disease

A disease that affects fewer than 5 in 10,000 people (European Union) or fewer than 7.5 in 10,000 people (USA).

Argyrophilic

A histological term used to describe an affinity to silver, making the protein amenable to silver-staining techniques.

Dysarthria

Slurred or slow speech that can be difficult to understand.

Nystagmus

Involuntary, rapid and repetitive movement of the eyes.

Hypometric saccades

Saccades refer to conjugate and voluntary eye movements that shift the eyes from one target to another. A hypometric saccade is a undershoot movement of the eyes.

Neurogenic orthostatic hypotension

A sign of cardiovascular autonomic dysfunction with substantial blood pressure drops on postural challenge.

Anhidrosis

Inability to sweat.

Camptocormia

Abnormal forward flexion of the trunk that disappears when the patient is lying down.

Pisa syndrome

Lateral flexion of the trunk when sitting or standing.

Antecollis

Also known as dropped head sign: a marked forward flexion of the head and neck.

Polyminimyoclonus

Small-amplitude myoclonic movements of the hands and/or fingers.

Supranuclear gaze palsy

Inability to look in a particular direction, although reflex eye movements remain intact.

Focal dystonia

Involuntary muscular contractions affecting a muscle or a group of muscles in a circumscribed part of the body.

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Krismer, F., Wenning, G. Multiple system atrophy: insights into a rare and debilitating movement disorder. Nat Rev Neurol 13, 232–243 (2017). https://doi.org/10.1038/nrneurol.2017.26

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