Multiple System Atrophy

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Definition/Description

Multiple System Atrophy (MSA) is defined as a sporadic, progressive, neurodegenerative adult-onset disorder that can affect the autonomic system, basal ganglia causing parkinsonism, and/or cerebellum causing ataxia in any combination.(Lundy-Eckman)

This disorder is called Multiple System Atrophy, because there is a combination of symptoms arising from each system just mentioned (autonomic system, basal gangila, and cerebellum).  In order for a patient to be diagnosed with MSA, there have to be at least two systems involved. There can be any combination of symptoms present from the three systems. (Swan)

• In MSA, patients often have symptoms that are characteristic of autonomic dysfunction, parkinsonism, or cerebellar dysfunction. As the disease progresses, additional symptoms emerge (Swan).
• Some patients may initially have autonomic features and may be diagnosed with pure autonomic failure. (Swan)
  o Patients who are initially misdiagnosed with PAF may later be correctly diagnosed with MSA as the neurological symptoms of parkinsonism and/or cerebellar ataxia appear. (Swan).

There are three different categories or types of MSA, based upon what areas of the nervous system or autonomic system are affected and to what degree:

• Clinically, MSA is dominated by autonomic failure (MSA-A subtype) (also referred to as Shy Drager Syndrome), which may be associated with either:
• the movement dysfunction of parkinsonism (MSA-P subtype) (also referred to as Striatonigral degeneration) in 80% of cases. 2,3
• or with cerebellar ataxia (MSA-C subtype) (also referred to as Sporadic Olivopontocerebellar atrophy OPCA), which will result in difficulty with postural control and coordination in 20-50% of cases. 2,3,

Prevalence

The prevalence of MSA has been estimated to be 4.4 per 100,000 people. (Diedrich).

The mean age at onset has been reported to be between 52.5 and 55 years (Diedrich).

MSA is found more often in men than in women (Diedrich).

Wenning et al- completed an analysis of 100 patients with MSA and measured their disability. They found that patients with MSA become disabled at a faster rate than patients with Parkinson's Disease.

Characteristics/Clinical Presentation

MSA is classified by the most dominant symptom exhibited by the patient.

• When Parkinson-like movement dysfunction is the more prominent feature, the disease is categorized as MSA-P. Parkinsonism has been identified as the initial feature in 46% of patients with MSA, but eventually over 80% of patients with MSA will develop parkinsonian features.(wedge)
• Characteristics of parkinsonism include bilateral involvement, bradykinesia, impaired writing, slurred speech, and rigidity (Swan), postural and rest tremor disequilibrium and gait unsteadiness (Diedrich).

• When cerebellar dysfunction is more prominent, the disease is labeled as MSA-C.  Over 50% of individuals with MSA will present with cerebellar dysfunction. (wedge)
• Cerebellar features that are characteristic of MSA have their initial manifestations in the trunk and lower extremities, leading to disturbances in gait. (Swan). Also display limb kinetic ataxia and scanning dysarthria as well as cerebellar oculomotor disturbances. (Diedrich).

• Autonomic dysfunction, primarily orthostatic hypotension, is present in approximately 75% of people with MSA. (Wedge)
• Autonomic dysfunction commonly appears as postural/orthostatic hypotension associated with impaired or absent reflex tachycardia upon standing, bowel and bladder incontinence, impotence, hypohydrosis. (Swan and Diedrich).

• Dysfunction to the pyramidal/corticospinal tracts can also occur, but does not have its own subtype. This will often result in impaired muscle performance. (Wedge).
•  Signs of corticospinal tract dysfunction (hyperreflexia, spasticity, and a positive Babinski sign) are features characteristic of MSA, but are not used as criteria for diagnosis. (Swan).

There is no “typical” presentation of this disorder, which makes it hard to pick up, and patients often go misdiagnosed. MSA may also goes misdiagnosed because the disorder initially (as mentioned previously) manifests with S/S of only one system. (Lundy-Eckman)

• Parkinson’s is the most common misdiagnosis. About 1/3 of people with MSA die while still misdiagnosed. (Lundy-Eckman).
• Only 25% of patients with MSA are correctly diagnosed at their first neurological visit. The correct diagnosis is usually established on average 4 to 5 years after disease onset (Wenning).

It is important to differentiate MSA from pure autonomic failure (PAF) and pure Parkinsonism.

• According to Lundy-Eckman, the distinction between MSA and Parkinsonism is made by exclusion.  If no autonomic or cerebellar signs are present, then the patient has pure Parkinsonism.
• It is also important to note that up to 90% of patients with MSA-P treated with levodopa (L-Dopa) fail to show a sustained, long-term response. (Wenning) This is a sign that this patient does not have pure Parkinsonism, as L-Dopa is not effective.
• In addition, orthostatic hypotension, difficulty urinating, rapid progression of functional limitations, loud breathing,and impotence indicate that MSA is a more likely Dx than Parkinson’s Disease.
• According to Lundy-Eckman, a patient has pure autonomic failure if ANS signs (such as orthostatic hypotension) are present, but signs of parkinsonism or cerebellar are not, then most likely PAF.
  

As there is no “typical” presentation for this disorder, and MSA can often be masked by other diagnoses, it is important if one has a patient with pure Parkinson’s, PAF, etc to keep a watchful eye of any suspicious S/S that are not associated with that system alone. This is pertinent so that these patients do not go misdiagnosed.

Associated Co-morbidities

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Medications

Since MSA is a variable disorder and can present in many different ways, treatment is symptomatic.

Pharmacological Treatment:

MSA-A

• To treat orthostatic hypotension: (is defined as a fall in BP on standing of more than 20mmHg systolic or 10 mmHg diastolic) (Hardy) Drugs can be prescribed to enhance vasoconstriction and increase the blood volume, which will increase the blood pressure (Fludrocortisone and Midodrine) (Lundy-Eckman).
• To treat constipation: Stool softener medications
• To treat urinary dysfunction: Pharmacological intervention does not adequately reduce post-void residual volume in patients with MSA, but anticholinergic agents like Oxybutynin can improve symptoms of hyper-reflexia. (Wenning).
• To treat impotence: Sildenafil (25 to 75mg) may be successful in treating erectile failure. (Wenning).

MSA-C

• There are no currently established pharmacological treatment strategies for cerebellar ataxia and pyramidal dysfunction (Wenning).

MSA-P

• Dopamimetics (Levodopa, Dopamine Agonists) and Anticholinergics/Amantadine. (Wenning).

Diagnostic Tests/Lab Tests/Lab Values

A definite diagnosis of MSA is only made on autopsy where degenerative changes characterized by cell loss, gliosis, and the presence of cytoplasmic inclusions in the oligodendrocytes are apparent on tissue examination. (Wedge).

In order to better predict the diagnosis of MSA, the Consensus Committees representing the American Autonomic Society and the American Academy of Neurology developed a series of tables, which will help decipher if a patient is a possible, probable, or definite candidate for MSA. (Diedrich)

Table I defines the diagnostic categories of MSA, which are possible, probable, and definite.  Table II displays what clinical features (additional S/S that are often present with that particular domain) and criterion (S/S that are required to be present in order to be diagnosed under that particular domain) are required for the diagnosis of each clinical domain. Table III includes exclusion criterion for each clinical domain. (Diedrich)

Table I. Diagnostic categories of MSA

I. Possible MSA	One criterion plus two features from separate other domains. When the criterion is parkinsonism, a poor levodopa response qualifies as one feature (hence only one additional feature is required)
II. Probable MSA	Criterion for: autonomic failure/urinary dysfunction plus poorly levodopa-responsive parkinsonism or cerebellar dysfunction
III. Definite MSA	Pathologically confirmed by the presence of a high density of glial cytoplasmic inclusions in association with a combination of degenerative changes in the nigrostriatal and olivopontocerebellar pathways

Table II. Clinical domains, features and criteria used in the diagnosis of MSA

Clinical Domain	Feature (Characteristic of the Disease)	Criterion (Defining Feature)
Autonomic       Dysfunction	• Orthostatic hypotension with blood pressure falling by 20 mm Hg systolic and 10 mm Hg diastolic within 3 min of standing • Urinary incontinence or incomplete bladder emptying	Orthostatic hypotension with blood pressure falling by 30 mm Hg systolic and 15 mm Hg diastolic within 3 min of standing and/or u rinary incontinence as persistent, involuntary, partial or total bladder emptying, accompanied by erectile dysfunction in men
Parkinsonism	• Bradykinesia - Slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions • Rigidity • Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction • Tremor - Postural, resting, or both	Bradykinesia plus at least 1 parkinsonian feature
Cerebellar Dysfunction	• Gait ataxia (wide-based stance with steps of irregular length and direction) • Ataxic dysarthria • Limb ataxia • Sustained gaze-evoked nystagmus	Gait ataxia plus at least 1 cerebellar feature
Corticospinal Tract Dysfunction	• Extensor plantar response with hyperreflexia (pyramidal sign)	Not used as criterion in defining diagnosis of MSA

Table III. Exclusion criteria for the diagnosis of MSA

Procedure	Findings
History Taking	• Symptomatic onset at <30 years • Family history of similar disorder • Systemic diseases or other identifiable causes for features listed in Table II  • Hallucinations unrelated to medication
Physical Examination	• 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 II

Causes

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Systemic Involvement

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Medical Management (current best evidence)

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Physical Therapy Management (current best evidence)

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Alternative/Holistic Management (current best evidence)

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Differential Diagnosis

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Case Reports

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Resources

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Recent Related Research (from Pubmed)

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References

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