Selena Nicholas-Bublick, MD, MHS
Lawrence W. Elmer, MD, PhD
DESCRIPTION 
- Multiple system atrophy (MSA) belongs to a family of disorders termed α-synucleinopathies which include idiopathic Parkinson's disease (IPD) and dementia with Lewy bodies. Whereas in these latter disorders the histological hallmark of α-synuclein inclusions are found in the cytoplasm, axons, and dendrites of neurons, in MSA the abnormal α-synuclein inclusions are found within the cytoplasm of glial cells in the CNS. These groups of disorders share common clinical features and may initially appear very similar, but with time MSA patients develop a characteristic constellation of symptoms. Two main subtypes are described on the basis of whether the most predominant clinical features include cerebellar dysfunction or parkinsonism. A patient with MSA may be considered as having possible, probable, or definite MSA based on the criteria outlined in the second consensus statement on the diagnosis of MSA (1).
- MSA-P: This designation is given to those patients who present with predominantly parkinsonian features (bradykinesia, rigidity, postural instability, and/or rest tremor). This syndrome is notoriously difficult to distinguish from IPD at initial evaluation; however, in contrast to IPD, a sustained and robust benefit is not achieved from treatment with conventional anti-parkinsonian therapies.
- MSA-C: Cerebellar dysfunction is the major clinical feature of this subtype and may be manifested through one or more of the following: Ataxia of limb movement, ataxia of gait and speech, dysrhythmia, dysdiadochokinesia, titubation, impaired check response, eye movement abnormalities including nystagmus, square-wave jerks, overshoot/undershoot dysmetria, saccadic pursuits, and slowed pursuits. Bulbar symptoms may also develop, increasing the risk of dysphagia.
- Autonomic dysfunction is a required criterion for both subtypes and may include: Otherwise unexplained urinary urgency, frequency or incomplete bladder emptying, erectile dysfunction in males, or significant orthostatic blood pressure (BP) decline. The severity of orthostatic BP decline differs between possible or probable MSA with the latter requiring a decrease of BP within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic.
- Older literature described patients with combinations of the above clinical findings as three separate syndromes: Striatonigral degeneration, olivopontocerebellar atrophy, and Shy–Drager syndrome. This terminology for classification of MSA is now obsolete.
EPIDEMIOLOGY
Prevalence
- The prevalence of MSA has been estimated at 2–5 per 100,000 in the general population. Incidence in individuals past the age of 50 may approach 3/100,000 (2).
- Race: No known ethnic predilection has been noted; however, the phenotype with more predominant parkinsonism features (MSA-P) appears more commonly in the Western Hemisphere and MSA-C appears to be the more frequent phenotype in the Eastern Hemisphere (3).
- Age: The mean age of onset is around the early to mid-fifties, slightly earlier than idiopathic PD.
- Sex: No clear difference in gender shown.
PATHOPHYSIOLOGY
Neuropathological changes in MSA include α-synuclein positive glial cytoplasmic inclusions (GCIs) and widespread neurodegeneration of the cerebral white matter including, but not limited to the following structures: The pons, medulla, putamen, substantia nigra pars compacta, cerebellum, and preganglionic autonomic structures (4).
ETIOLOGY
There are no clear genetic or environmental causes of MSA. The cerebellar variant must be distinguished from hereditary multiple system degenerations (Machado–Joseph disease [SCA3] and occasionally SCA1 and SCA2 mutations).
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DIAGNOSTIC TESTS AND INTERPRETATION
Lab
Initial Lab Tests
Bloodwork: There are no specific blood tests to diagnose MSA, but the following tests should be considered to identify potential secondary causes of parkinsonism: Thyroid function tests, serum vitamin E, B12 and ceruloplasmin levels, and 24-hour urine copper excretion.
Imaging
Initial Approach
- Functional neuroimaging by PET and SPECT scanning using markers for neuronal activity (fluorodeoxyglucose), dopaminergic terminals (β-CIT, DTBZ, and others) and dopamine receptors (IBZD) may distinguish MSA from idiopathic PD, but does not distinguish MSA from other parkinsonism syndromes such as PSP. These methods are not widely implemented.
- There is evidence to suggest that MRI imaging can assist in the diagnosis of MSA. Brain MRI imaging may reveal changes in imaging intensity and/or atrophy in the putamen, cerebellum and/or brainstem. Some investigators are attempting to define MRI rating scales in order to help diagnose and follow the progression of MSA; however, at this time these are not widely used (5). MRI imaging may also reveal evidence of other causes of parkinsonism such as vascular insults, mass lesions, calcium or iron deposition in the striatum, and cortical atrophy patterns suggestive of other dementing illnesses.
Diagnostic Procedures/Other
Routine studies of autonomic function may distinguish MSA from cases of primary autonomic failure. Cardiac imaging studies visualizing the autonomic innervation of the heart using a SPECT ligand has consistently distinguished MSA from IPD with autonomic involvement.
DIFFERENTIAL DIAGNOSIS
- Idiopathic Parkinson's disease
- Dementia with Lewy bodies
- Corticobasal ganglionic degeneration
- Progressive supranuclear palsy
- Hereditary ataxias
Signs and Symptoms
Differentiating MSA in its early stages from other akinetic-rigid syndromes such as IPD is difficult, even for specialists. The clinical diagnosis relies on the development of distinct signs and symptoms, none of which are unique to MSA. However, consensus criteria have been developed which allow for some degree of confidence in making the diagnosis in an adult who presents with a sporadic progressive disease onset (1). The criteria are as follows.
Possible MSA
This includes parkinsonism or a cerebellar syndrome and at least one feature suggesting autonomic dysfunction. At least one additional feature from Table 1 should be present. For either phenotype, a Babinski sign with hyperreflexia or stridor may count as an additional feature.
See also Table 2: Items that May Indicate Autonomic Failure
Probable MSA
Parkinsonism meeting the criteria for possible MSA-C or MSA-P in association with autonomic failure involving urinary incontinence or an orthostatic decrease of BP within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm Hg diastolic. Notice the stricter criteria for orthostatic BP in this category.
Definite MSA
- Pathological confirmation of neurodegenerative changes in striatonigral or olivopontocerebellar structures in association with abundant GCIs.
- Other associated clinical features that support the diagnosis of MSA include: Orofacial dystonia, anterocollis, camptocormia and/or Pisa syndrome, contractures of and/or cold hands and feet, inspiratory sighs, severe dysphonia and/or dysarthria, pathologic laughter or crying and a jerky, myoclonic postural/action tremor. Clinical features that should cue the clinician to consider other neurodegenerative disorders include: Classic pill rolling rest tremor, significant neuropathy, unexplained hallucinations, age >75 years old, relatives with ataxia or parkinsonian syndromes, dementia, and/or suspicious white matter lesions on brain imaging.
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MEDICATION
First Line
- Rarely, extrapyramidal symptoms seen in MSA may respond to carbidopa/levodopa, sometimes requiring supratherapeutic (i.e., >600–800 mg levodopa per day) doses. Anticholinergic agents and amantadine may also be of limited usefulness. Responses are usually minimal and short-lived.
- Orthostatic hypotension may be treated with increased salt intake, fludrocortisone (0.1–0.4 mg/day in two divided doses), midodrine (5–10 mg up to 3×/day), and/or pyridostigmine (30–60 mg up to 3×/day-off label use).
- Urinary incontinence may be treated with peripheral anticholinergic therapy (oxybutinin 5–10 mg at bedtime, and other formulations). Constipation is treated with advancing doses of fiber supplements, stool softeners, fruit and vegetable preparations, and/or lactulose.
- The ataxia seen in MSA sometimes responds to clonazepam 0.5–1.0 mg at bedtime.
- Antidepressants, especially SSRI agents, have helped in cases of depression associated with the progression of this illness.
- Contraindications: Individuals with a history ofcongestive heart failure and/or renal insufficiency should not be prescribed a high salt diet and should be carefully monitored if given a volume expanding agent such as fludrocortisone.
- Precautions: Severe hypertension can result from aggressive treatment with volume expanding or vasoactive therapies. Monitor BP carefully during titration of these agents.
ADDITIONAL TREATMENT
General Measures
There is no effective treatment for MSA. Management is aimed at alleviating consequences of the motor and autonomic changes.
Additional Therapies
The extrapyramidal symptoms of bradykinesia and resultant loss of mobility may be overcome by the use of 4-wheeled walkers, but the tendency of patients with MSA, especially MSA-C to fall usually limits the effective duration of this intervention. Percutaneous endoscopic gastrostomy (PEG) may be performed to provide life-sustaining nutrition. Dysarthria/dysphagia may benefit from speech pathology intervention.
SURGERY/OTHER PROCEDURES
Patients with MSA are at risk of vocal cord abductor paralysis (VCAP). VCAP involves dysfunction of the vocal cords that worsens during sleep and may result in sudden death. Definite diagnosis is through fiberoptic laryngoscopy and treatment options include nasal CPAP, laryngosurgery for glottal opening, botulinum toxin injection, and tracheostomy for severe cases. At this time no definite treatment paradigm exists (6).
IN-PATIENT CONSIDERATIONS
Admission Criteria
MSA is usually managed in an outpatient setting. Rarely, concomitant illnesses, especially aspiration pneumonia, can lead to an acute exacerbation of MSA symptoms, requiring hospitalization for dysphagia, airway management, and issues of decreased mobility.
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PATIENT MONITORING
Like other parkinsonism syndromes, the progression of MSA is relentless and refractory to most common treatment modalities, resulting in death within an average of 6–9 years after time of symptom onset. Patients are monitored in the outpatient setting, usually at 4–6 month intervals. Judicious use of antidepressant medications and timely discussion of PEG tube placement are recommended to assist patients and their families prepare for future decline.
PATIENT EDUCATION
The postural instability characteristic of MSA prevents the use of ambulatory exercise, although stretching and strengthening exercises in a sitting position may be useful. Aquatic therapy with close supervision may help forestall some of the immobility issues associated with this illness. Speech therapy is useful for speech and swallowing disturbances. Frequently, patients continue to be classified as IPD patients, confounding their understanding and expectations of treatment options and prognosis.
PROGNOSIS
Due to its progressive nature, the symptoms of MSA always worsen with time. Over time, the limited responsiveness of MSA patients to dopaminergic therapy typically deteriorates. Death usually occurs as a consequence of cardiac arrhythmia or aspiration pneumonia.
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ICD9
333.0 Other degenerative diseases of the basal ganglia
“PD with autonomic insufficiency equals MSA” is no longer true (see chapter on “Parkinson's Disease”), but poor response to levodopa and/or early gait and balance disturbance–think “Possible MSA” and refer to a specialist early!