Background
Multiple system atrophy (MSA) is defined as an adult-onset, sporadic, rapidly progressive, multisystem, neurodegenerative fatal disease of undetermined etiology, characterized clinically by varying severity of parkinsonian features; cerebellar, autonomic, and urogenital dysfunction; and corticospinal disorders. Neuropathological hallmarks of MSA are 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 primary alpha-synucleinopathy). (See Etiology and Pathophysiology, History and Physical Examination, and Workup.)
A consensus statement by the American Autonomic Society and American Academy of Neurology in 2007
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 as olivopontocerebellar atrophy (OPCA) about a century ago. The Shy-Drager syndrome with features of parkinsonism and autonomic failure with OH was described in 1960. The term MSA was introduced to unify different forms of MSA in 1996. 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).
Table 1. Historical Milestones in the Definition of Terms for MSA (Open Table in a new window)
|
Term |
Period |
Authors |
Comments |
|
Olivopontocerebellar atrophy (OPCA) |
1900 |
Dejerine and Thomas |
Introduction of the term olivopontocerebellar atrophy |
|
Orthostatic hypotension (OH) |
1925 |
Bradbury and Eggleston |
Introduction of autonomic failure as a clinical syndrome |
|
Shy-Drager syndrome (SDS) |
1960 |
Shy and Drager |
Origin of this term as a neuropathologic entity with parkinsonism and autonomic failure with OH |
|
Striatonigral degeneration (SND) |
1960 |
Van der Eecken et al |
Description of SND |
|
Multiple system atrophy (MSA) |
1969 |
Graham and Oppenheimer |
Introduction of the term MSA, which represents SDS, SND, and OPCA as 1 entity |
|
Glial cytoplasmic inclusions (GCIs) |
1989 |
Papp et al, Matsuo et al |
Discovery of GCIs as hallmark of MSA |
|
Alpha-synuclein inclusion |
1998 |
Spillantini et al, Wakabayashi et al |
Alpha-synuclein immunostaining as a sensitive marker of MSA |
|
MSA classification |
1996-1999 |
Consensus Committee |
Classification of MSA based on clinical domains and features and neuropathology |
|
Unified MSA Rating Scale (UMSARS) |
2003 |
European MSA Study Group |
Unified MSA Rating Scale as a standard to define MSA symptoms |
|
Second consensus for MSA |
2007 |
Consensus Committee |
New definition of MSA with simplified criteria |
A consensus conference in 2007
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
—and incorporated current knowledge for a better assessment of the disease.
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)
|
Clinical Domain |
Feature |
Comment |
|
Autonomic dysfunction |
Severe orthostatic hypotension (OH) Asymptomatic Symptomatic |
OH is defined as blood pressure fall by at least 30mm Hg systolic and 15mm Hg diastolic within 3 minutes of standing from a previous 3-minute interval in the recumbent position.** |
|
Urogenital dysfunction |
Urinary incontinence (UI) or incomplete bladder emptying |
UI is defined as persistent, involuntary, partial or total bladder emptying. ED usually occurs before symptomatic OH.*** |
|
Erectile dysfunction (ED) in men |
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|
Parkinsonian features (87% incidence *) |
Bradykinesia (BK) |
BK is slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions. PI not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction. |
|
Rigidity |
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|
Postural instability (PI) |
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Tremor – Postural, resting, or both |
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|
Cerebellar dysfunction (54% incidence *) |
Gait ataxia (GA) |
GA is a wide-based stance with steps of irregular length and direction. Sustained gaze-evoked nystagmus |
|
Ataxic dysarthria |
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Limb ataxia |
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Oculomotor dysfunction |
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|
Coritcospinal tract dysfunction |
Extensor plantar response with hyperreflexia |
Babinsky sign, Pyramidal sign |
|
*Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al **OH caused by drugs, food, temperature, deconditioning, or diabetes are excluded. ***ED does not count in the definition of onset of disease, because it is a general feature in older people. |
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Table 2b. Additional Features for the Diagnosis of Possible MSA* (Open Table in a new window)
|
Category |
Additional Features |
|
Possible MSA-P Possible MSA-C |
Babinski sign with hyperreflexia Stridor |
|
Possible MSA-P |
Rapidly progressive parkinsonism Poor response to levodopa Postural instability within 3 years of motor onset Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 years of motor onset Atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle, pons, or cerebellum Hypometabolism on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scanning in putamen, brainstem, or cerebellum |
|
Possible MSA-C |
Parkinsonism (bradykinesia and rigidity) Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons Hypometabolism on FDG-PET in the putamen Presynaptic striatonigral dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET scanning |
|
*Modified from second consensus |
|
Table 3. Characteristics That Do Not Support the Diagnosis of MSA (Open Table in a new window)
|
Procedure |
Nonsupporting Features |
|
History taking |
Symptomatic onset at < 30 years Onset after age 75 years Family history of ataxia or parkinsonism Systemic diseases or other identifiable causes for features listed in Table 2a Hallucinations unrelated to medication Dementia |
|
Physical examination |
Classic parkinsonian pill-rolling rest tremor Clinically significant neuropathy Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction |
|
Laboratory study |
Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2a White matter lesions suggesting multiple sclerosis |
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)
|
Category |
Definition |
|
Possible MSA |
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Parkinsonism or cerebellar syndrome At least 1 feature of autonomic or urogenital dysfunction At least 1 of the additional features from Table 2b |
|
Probable MSA |
A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Autonomic failure involving urinary dysfunction Poorly levodopa-responsive parkinsonism or cerebellar dysfunction |
|
Definitive MSA |
A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in striatonigral and olivopontocerebellar pathways |
|
*Disease onset is defined as the initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction). |
|
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 Multiple System Atrophy Coalitions, Autonomic Disorder Consortium of the Clinical Rare Diseases Research Network, and Vanderbilt Autonomic Dysfunction Center.