eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases
Multiple System Atrophy
Updated: Mar 4, 2010
Introduction
Background
The concept of multiple system atrophy (MSA) as a unitary diagnosis encompassing several clinical syndromes has a long history. The first cases of MSA were presented 106 years ago. The term MSA was introduced in 1969. The discovery of glial cytoplasmic inclusions (GCIs) and alpha-synuclein immunostaining as a sensitive marker of MSA was the major milestone in the definition of MSA as a clinicopathological entity (Table 1). Table 1. Historical Milestones in the Definition of Terms for MSA
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Table
| 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 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 one 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 |
| United MSA Rating Scaling (UMSARS) | 2003 | European MSA Study Group | United MSA Rating Scale as a standard to define MSA symptoms |
| Second consensus for MSA | 2008 | Consensus Committee | New definition of MSA with simplified criteria |
| 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 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 one 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 |
| United MSA Rating Scaling (UMSARS) | 2003 | European MSA Study Group | United MSA Rating Scale as a standard to define MSA symptoms |
| Second consensus for MSA | 2008 | Consensus Committee | New definition of MSA with simplified criteria |
The second consensus conference in 200795 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 199823 ) and incorporated current knowledge for a better assessment of the disease as follows:
- Clinical definition of MSA: 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.
- Neuropathological definition of MSA: MSA is characterized neuropathologically by cell loss in striatonigral and olivopontocerebellar structures of the brain and spinal cord accompanied by profuse distinctive glia cytoplasmic inclusions formed by fibrillized alpha-synuclein proteins defined as alpha-synucleinpathy of unknown etiology.
- Definition of categories of MSA: The 2 categories of MSA are (1) with predominant parkinsonism (MSA-P) and (2) with cerebellar features (MSA-C).
- MSA-P is the category of MSA where extrapyramidal features predominate. The term striatonigral degeneration, parkinsonian variant is sometimes used. See eMedicine article Striatonigral Degeneration.
- MSA-C is the category when cerebellar ataxia predominates. It is sometimes termed sporadic olivopontocerebellar atrophy. See eMedicine article Olivopontocerebellar Atrophy.
- The designation to a category MSA-P or MSA-C depends on the dominant feature at the time of evaluation, which can change with time.
When autonomic failure predominates, MSA was sometimes termed Shy-Drager syndrome (not defined in the present consensus anymore).
Following main and additional features (Table 2a and 2b), nonsupporting features (Table 3) are used in the definition of MSA.
Table 2a. Main Features for the Diagnosis of MSA
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Table
| Clinical Domain, %* | Feature | Comment |
| Autonomic dysfunction | Severe orthostatic hypotension (OH)
| OH is defined as blood pressure fall by at least 30 mm Hg systolic and 15 mm Hg diastolic within 3 min 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 | ||
| 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 | ||
| Postural instability (PI) | ||
| Tremor - Postural, resting, or both | ||
| 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 | ||
| Limb ataxia | ||
| Oculomotor dysfunction |
| Clinical Domain, %* | Feature | Comment |
| Autonomic dysfunction | Severe orthostatic hypotension (OH)
| OH is defined as blood pressure fall by at least 30 mm Hg systolic and 15 mm Hg diastolic within 3 min 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 | ||
| 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 | ||
| Postural instability (PI) | ||
| Tremor - Postural, resting, or both | ||
| 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 | ||
| Limb ataxia | ||
| Oculomotor dysfunction |
*Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al23 ).
**OH caused by drugs, food, temperature, deconditioning, diabetes are excluded.
***ED does not count in the definition of onset of disease because it is a general feature in older people.
Corticospinal tract dysfunction with extensor plantar response with hyperreflexia (pyramidal sign) are not used to categorize MSA.
Table 2b. Additional Features for Diagnosis of Possible MSA*
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Table
| Category | Additional Features |
Possible MSA-P Possible MSA-C |
|
Possible MSA-P |
|
Possible MSA-C |
|
| Category | Additional Features |
Possible MSA-P Possible MSA-C |
|
Possible MSA-P |
|
Possible MSA-C |
|
Table 3. Features Against Diagnosis of MSA
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Table
| Procedure | Nonsupporting Features |
| History taking |
|
| Physical examination |
|
| Laboratory study |
|
| Procedure | Nonsupporting Features |
| History taking |
|
| Physical examination |
|
| Laboratory study |
|
Definition of levels of certainty of MSA
MSA can be ascertained as possible MSA, probable MSA, or definite MSA (see Table 4 below) based on main features in the clinical domain's autonomic, urogenital, parkinsonism, and cerebellar dysfunction and additional features (see Table 2a and 2b above).
Only pathologic findings of high density of alpha-synuclein-positive glial cytoplasmic inclusions (GCIs) degenerative changes in the nigrostriatal or olivopontocerebellar pathways can confirm the diagnosis of definite MSA.
Table 4. Diagnostic Categories of MSA
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Table
| Category | Definition |
| Possible MSA | A sporadic, progressive, adult (>30 y) with onset disease* characterized by the following:
|
| Probable MSA | A sporadic, progressive, adult (>30 y) with onset disease* characterized by the following:
|
| Definitive MSA | A sporadic, progressive, adult (>30 y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in nigrostriatal and olivopontocerebellar pathways |
| Category | Definition |
| Possible MSA | A sporadic, progressive, adult (>30 y) with onset disease* characterized by the following:
|
| Probable MSA | A sporadic, progressive, adult (>30 y) with onset disease* characterized by the following:
|
| Definitive MSA | A sporadic, progressive, adult (>30 y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in nigrostriatal and olivopontocerebellar pathways |
*Disease onset is defined as initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction).
Red flags supporting the diagnosis of MSA are 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.
Pathophysiology
MSA is characterized by progressive loss of neuronal and oligodendroglial cells in numerous sites in the CNS. The etiology of the cell loss is still unknown. Autoimmune mechanisms and toxic agents have been suggested as potential causes of MSA, but evidence for these etiologies is weak. No evidence of a genetic etiology has been found. The clinical symptoms of MSA correlate with cell loss in different CNS sites (see Table 5 below).
Researchers initially assumed that gray-matter damage caused MSA. 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.
Table 5. Clinicopathologic CorrelationsOpen table in new window
Table
| 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 90 |
| 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 90 |
Adapted from Wenning et al and other sources.
Frequency
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
In the United Kingdom, the prevalence is 0.9-8.4 cases per 100,000 population; in France, 1.8-2.7 per 100,000 population.
Mortality/Morbidity
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 in the last 2 decades.
- MSA-P and MSA-C have the same survival times, but MSA-P shows more rapid dysfunctional progression.
- Bronchopneumonia (48%) and sudden death (21%) are common terminal conditions.
- Urinary dysfunction in MSA often leads to lower urinary tract infections (UTIs); more than 50% of MSA patients suffer from recurrent lower UTIs and a significant number die of related complications.92
Race
MSA has been encountered in Caucasian, African, and Asian populations.
- In Western countries, MSA-P predominates with 66-82% of patients.
- In Eastern countries, MSA-C is common with 67% of patients.
Sex
The disease more often affects men than women.
- Female-to-male ratio is around 1:2. (Ratio of 1:3-9 is also reported.)
- Early and easy diagnosis of impotence may lead to the male predominance of MSA.
Age
The mean age at onset in MSA is 52.5-55 years. The disease progresses over intervals of 1-18 years.
- An older age at onset has been associated with shorter duration of survival.
- The overall nigrostriatal cell loss is correlated with the severity of disease at the time of death.
Clinical
History
Most patients with MSA develop the disease when they are older than 40 years (average 52-55 y), and they experience fast progression. Usually autonomic and/or urinary dysfunction develops first. Patients with MSA may have parkinsonian symptoms with poor or nonsustained response to levodopa therapy. Only 30% of MSA-P patients have an initial transient improvement. About 90% of patients are nonresponsive to long-term levodopa therapy. Typically, 60% of patients experience objective decline in motor function within 1 year. Motor impairment can be caused by cerebellar dysfunction. Corticospinal tract dysfunction also can occur but is not often a major symptomatic feature of MSA. Table 2a provides an overview of the clinical domains and their main features. More details are described in subsequent sections.
Physical
- Autonomic and/or urinary dysfunction: Autonomic symptoms are the initial feature in 41-74% of patients with MSA but ultimately develop in 97%. Genitourinary dysfunction is the most frequent initial complaint in women, and erectile dysfunction is the most frequent initial complaint in men.
- Severe orthostatic hypotension: Severe orthostatic hypotension, defined as a reduction of systolic blood pressure (BP) of at least 30 mm Hg or of diastolic BP of at least 15 mm Hg within 3 minutes of standing from a previous 3-minute interval in the recumbent position is common and present in at least 68% of patients. Most patients do not respond with an adequate heart rate increase. The definition of severe orthostatic blood pressure fall as a diagnostic criterion for MSA is more strict than the definition of orthostatic hypotension as a physical finding as defined by the American Autonomic Society.
- Associated symptoms include the following:
- Light-headedness
- Dizziness
- Dimming of vision
- Head, neck, or shoulder pain
- Altered mentation
- Weakness, especially of legs
- Fatigue
- Yawning
- Slurred speech
- Syncope
- Some patients have fewer orthostatic symptoms. In 51% of patients with MSA, syncope is reported at least once. In 18% of patients with severe hypotension, more than 1 syncopal episode is documented. Because of dysautonomia-mediated baroreflex impairment and consequent debuffering, patients respond in an exaggerated fashion to drugs that raise or lower their BP.
- Orthostatic hypotension must be distinguished from postural tachycardia syndrome, which is defined as an increase in heart rate of greater than 30 bpm and maintained BP (absence of orthostatic hypotension).
- Associated symptoms include the following:
- Postprandial hypotension: Patients are also susceptible to postprandial hypotension. Altered venous capacitance and baroreflex dysfunction have been reported as a cause.
- Supine hypertension: Approximately 60% of patients with MSA have orthostatic hypotension and supine hypertension, which is sometimes severe (>190/110 mm Hg) and which complicates the treatment of orthostatic hypotension.
- Parkinsonism: Parkinsonism can be the initial feature in 46% of MSA-P patients and ultimately develops in 91%.
- Although akinesia and rigidity predominate, tremor is present at rest in 29% of patients; however, a classic pill-rolling parkinsonian rest tremor is recorded in only 8-9%. Patients with MSA have a poor response to levodopa.
- About 28-29% of patients have a good or even excellent levodopa response early in their disease. However, only 13% maintain this response. Patients with early-onset (at <49 y) MSA tend to have a good levodopa response.
- Patients sometimes complain of stiffness, clumsiness, or a change in their handwriting at the onset of MSA.
- Cerebellar dysfunction: Cerebellar symptoms or signs are the only initial feature in 5% of patients. MSA-C most commonly causes gait and limb ataxia; tremor, pyramidal signs, and myoclonus are less common findings.
- Other symptoms are based on mixed dysfunction.
- When the disorder results in nonautonomic features, imbalance caused by cerebellar or extrapyramidal abnormalities is the most common feature.
- If the cerebellar, extrapyramidal, and pyramidal systems are involved, the movement disorder is usually the most profound disability.
- Vocal cord paralysis may lead to hoarseness and stridor. A neurogenic and obstructive mixed form of sleep apnea can occur.
Causes
The cause of MSA is unknown. Environmental toxins or a history of trauma has been suggested. A trend that environmental (pesticide) exposure is a factor causing MSA has been suggested but cannot be confirmed statistically.52 No other environmental factors could be established to increase the risks to develop MSA. Autosomal recessive inheritance97 and genetic alterations with abnormal expansion of one allele of the SCA type 3 gene has been reported98 .
More on Multiple System Atrophy |
 Overview: Multiple System Atrophy |
| Differential Diagnoses & Workup: Multiple System Atrophy |
| Treatment & Medication: Multiple System Atrophy |
| Follow-up: Multiple System Atrophy |
| References |
| Next Page » |
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Further Reading
Keywords
MSA, multiple-system atrophy, multisystem atrophy, Shy-Drager syndrome, striatonigral degeneration, MSA-P, sporadic olivopontocerebellar atrophy, MSA-C
