eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Multiple System Atrophy

André Diedrich, MD, PhD, Research Associate Professor of Medicine, Research Assistant Professor of Biomedical Engineering, Autonomic Dysfunction Center, Vanderbilt University School of Medicine
David Robertson, MD, Director, Clinical Research Center, Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University

Updated: Sep 4, 2009

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
 

MSA is defined as a sporadic, progressive, neurodegenerative disease of undetermined etiology, characterized clinically by extrapyramidal, pyramidal, cerebellar, and autonomic dysfunction in any combination (definition by the Consensus Committees representing the American Autonomic Society and the American Academy of Neurology in 1996 and 1998).²³ MSA is characterized pathologically by cell loss, gliosis, and GCIs in several brain and spinal cord structures.

MSA can be ascertained as possible, probable, or definite based on the features and criteria in the 3 clinical domains: (1) autonomic and/or urinary dysfunction, (2) parkinsonism, and (3) cerebellar dysfunction (Table 2, Table 3, Table 4, Table 5, Table 6). The nomenclature is based on features, which define the disease characteristic, and criterion, which is the defining feature. Possible MSA can be diagnosed when 1 criterion and 2 features separate from other clinical domains are found. The diagnosis of probable MSA requires the criterion of autonomic and/or urinary dysfunction and the presence of poorly levodopa-responsive parkinsonism or cerebellar ataxia. Only pathologic findings, a high density of alpha-synuclein-positive GCIs degenerative changes in the nigrostriatal or olivopontocerebellar pathways, can confirm the diagnosis of MSA.

When autonomic failure predominates, MSA is sometimes termed Shy-Drager syndrome. When extrapyramidal features predominate, the term striatonigral degeneration, parkinsonian variant, or MSA-P is sometimes used. When cerebellar features predominate, MSA is sometimes termed sporadic olivopontocerebellar atrophy or MSA-C.

The clinical and diagnostic distinctions between MSA and pure autonomic dysfunction are reviewed in Table 7.

*Incidence of clinical features recorded during the lifetimes of 203 patients.

Adapted from Gilman et al.²³

Table 3. Exclusion Criteria for Diagnosis of MSA

Table 4. Diagnostic Categories of MSA*

*Features and criteria for each clinical domain are defined in Table 2.

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 (Table 5).

Researchers initially assumed that gray-matter damage caused MSA. The discovery of oligodendroglial cytoplasmic inclusions (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.

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 25,000-100,000 Americans have MSA. Most 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 rapidly 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 ratios of 1:3-9 are 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. About a 57% increase of UMSARS motor scores in 1 year indicates rapid decline in motor function. 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 2 provides an overview of the clinical domains and their 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.
• Orthostatic hypotension: Orthostatic hypotension, defined as a reduction of systolic blood pressure (BP) of at least 20 mm Hg or of diastolic BP of at least 10 mm Hg within 3 minutes of standing, is common and present in at least 68% of patients. Most patients do not respond with an adequate heart rate increase.
  • 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 few 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 40 bpm and maintained BP.
• 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 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. No other environmental factors could be established to increase the risks to develop MSA.

Differential Diagnoses

Other Problems to Be Considered

Differentials to other diseases

• MSA and Parkinson disease
  • Parkinsonian symptoms can occur frequently in MSA. Approximately 10% of patients with a diagnosis of Parkinson disease are found to have MSA at autopsy. About 29-33% of patients with isolated late-onset cerebellar ataxia will eventually develop MSA.
  • Clinical differentiation of Parkinson disease and MSA is extremely difficult. MSA is suggested when (1) disability progresses rapidly,(2) patients are poorly responsive to levodopa,(3) autonomic features such as urinary retention or incontinence or orthostatic hypotension are pronounced,(4) rigidity and bradykinesia are out of proportion to tremor,(5) speech is affected severely (dysarthrophonia, severe dysarthria), and(6) abnormal aspiration, inspiratory gaps, and stridor are present.
  • Table 6 outlines some distinctive features. 
  • Wenning et al developed a predictive model based on established pathologic data from patients with MSA and Parkinson disease.⁸³ The new model contains the following features: poor response to levodopa, autonomic features, speech or bulbar dysfunction, absence of dementia, absence of levodopa-induced confusion, and falls. Preliminary results of an ongoing  comparison study indicate that autonomic indices are highly significantly more abnormal in MSA than in Parkinson disease.⁹¹

Table 6. Differential Diagnosis of MSA and Parkinson Disease

Characteristic	MSA	Parkinson Disease
Response to chronic levodopa therapy	Poor or unsustained motor response because of loss of postsynaptic dopamine receptors Initial improvement in 30% of patients with MSA, but 90% were unresponsive over longer time of intake; 50% develop L-dopa induced dyskinesia of orofacial and neck muscles	Good response
Effects on nigrostriatal transmission	Both presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum and their striatal target cells have reduced dopamine receptors	Presynaptic
Symmetry of movement disorder	Possibly asymmetric	No data
Progression of symptoms	Rapid	Slow
Instability and falling	Early	Late
Progress of disability	Relatively fast disability; 30% decrease of activities of daily living in 1 year; 40% of patients in a wheelchair within 5 years (wheel chair sign)	Relatively slow disability
Abnormal speech	Severely affected speech in 30% of patients with MSA Dysarthrophonia and severe dysarthria are common	Less affected
Abnormal Respiration	Abnormal aspiration, inspiratory gaps, and stridor in 60% of patients with MSA Stridor caused by paralysis of vocal cord occurs especially at night but is also present during day	Less common
Lewy bodies (hyaline eosinophilic cytoplasmic neuronal inclusions)	Not present*	Primarily in substantia nigra
Cytoplasmic inclusions (immunocytochemical reaction with antibodies to anti-alpha-synuclein)	Glial inclusions; argyrophilic cellular inclusions in oligodendrocytes	Absent
Thermoregulation, skin perfusion	Cold hands and decrease of warm-up after cold-pack stimulus	Normal
Caudate-putamen index of dopamine uptake (on positron emission tomography [PET])	Decreased in putamen and caudate	Decreased in putamen with smaller decrease in caudate
Growth hormone release with intravenous injection of clonidine	No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)	Increase of growth hormone, intact function

*

Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling proposed criteria for the striatonigral form of MSA.⁵⁸

• MSA and PAF
  • Patients with MSA who present with only autonomic and urinary dysfunction can be incorrectly identified as having PAF.
  • Bradbury and Eggleston first described PAF as idiopathic hypotension in 1925,⁸ but current criteria imply failure of the autonomic nervous system in the absence of extrapyramidal, pyramidal, or cerebellar abnormalities. MSA is distinct from PAF.
  • The sympathetic and parasympathetic systems are centrally impaired in MSA, whereas the involvement is peripheral in PAF.
  • The progression of MSA is faster than that of PAF, and the prognosis is poor.
  • Lewy bodies are common in PAF at many sites, even occasionally in the heart, but they are not present in MSA. (Exception: In 1999, Pakiam et al reported 1 case in which a patient with diffuse Lewy-body disease presented with parkinsonism and prominent autonomic dysfunction, fulfilling proposed criteria for the striatonigral form of MSA.⁵⁸ )
  • Instead of Lewy bodies, patients with MSA have oligodendroglial cytoplasmic inclusions.
  • Low plasma norepinephrine levels usually indicate PAF.
  • Vasopressor response to tilt also can assist in making the diagnosis.
  • Table 7 summarizes the distinctive features of MSA and PAF. Early (eg, years 1-2) in the disease process, the distinction may be difficult, but distinguishing findings are usually evident during follow-up care.
    
    Table 7. Differential Diagnosis in MSA and PAF

    Characteristic	MSA	Pure Autonomic Failure
    CNS involvement	Multiple involvement	Unaffected
    Site of lesion	Mainly preganglionic, central; degeneration of intermediolateral cell columns; ganglionic neurons relatively intact	Mainly postganglionic; loss of ganglionic neurons
    Progression	Fast, median survival 6.5-9.5 years	Slow, some patients survive >10-15 years
    Prognosis	Poor	Good
    Extrapyramidal involvement	Common	Not present
    Cerebellar involvement	Common	Not present
    Gastrointestinal symptoms	Uncommon	Absent, except constipation
    Plasma supine norepinephrine level	Normal	Reduced
    Antidiuretic hormone (ADH) response to tilt	Impaired because of catecholaminergic denervation of hypothalamus (but normal ADH response to osmotic stimuli	Maintained
    Adrenocorticotropic hormone and beta-endorphin response to hypoglycemia	Impaired because of central cholinergic dysfunction or dysfunction of adrenergic input to paraventricular nucleus	Normal
    Growth hormone release with clonidine intravenous injection	No release, dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)	Increase of growth hormone; intact function
    Substance P, catecholamine, 5-HT, and acetylcholine markers in cerebrospinal fluid	Decreased levels	No data
    Lewy bodies	Mostly absent	Present in autonomic neurons
    BP response to oral water intake	Increased	Increased but variable
    BP response to ganglionic blockade	Profound decrease	Modest decrease

• MSA and progressive supranuclear palsy (PSP), or Steele-Richardson-Olszewski syndrome
  • Progressive supranuclear palsy (PSP), also known as the Steele-Richardson-Olszewski syndrome, is characterized by neuronal degeneration and neurofibrillary tangles affecting the pons and mid brain.
  • The clinical picture of PSP may be similar to that of MSA.
  • Analysis of the horizontal and vertical eye movements may help to distinguish PSP and MSA.
    • Patients with PSP demonstrate slowing of saccades, which is not the situation in MSA.
    • The trajectories of saccades made to diagonal target jumps are deviated toward the horizontal plane; because of the vertical hypometria, this is more pronounced in patients with PSP than in those with MSA.
  • The patient with PSP may be prone to falls because of impaired downward gaze.
  • PSP subjects and MSA subjects demonstrated different responses to pharmacologic and physiologic stimuli in autonomic function tests.⁴¹
  • Cardiovascular autonomic dysfunction should be an exclusionary feature in the diagnosis of PSP.⁴¹
• MSA and corticobasal ganglionic degeneration
  • Corticobasal ganglionic degeneration is pathologically characterized by enlarged achromatic neurons in cortical areas and nigral and striatal neuronal degeneration.
  • The onset is typically unilateral, with marked rigidity-dystonia of the involved arm, which differs from MSA.
  • Cortical signs of apraxia, alien-limb phenomena, cortical sensory loss, and cortical reflex myoclonus are helpful to distinguish between corticobasal ganglionic degeneration and MSA.
• Differential of MSA and cerebrovascular syndromes
  • Cerebrovascular syndromes (eg, multi-infarct lesions in the brain) may demonstrate features similar to those of MSA.
  • Dementia is not common in MSA.
  • Brain MRI helps to exclude cerebrovascular diseases.

Workup

Laboratory Studies

• The diagnosis of MSA is based mainly on clinical features (see Table 2, Table 3, Table 4).
• Definite MSA can be established only on postmortem examination. MSA is confirmed by the presence of a high density of GCIs in association with degenerative changes in the nigrostriatal and olivopontocerebellar pathway.
• The combination of a normal supine norepinephrine level and a low upright norepinephrine level can assist in the diagnostic process.

Imaging Studies

• Iodine-123 (¹²³ I) metaiodobenzylguanidine (MIBG) scintigraphy
  • Scintigraphy with¹²³ I MIBG appears to be a useful tool for differentiation between Parkinson disease and MSA early after onset of autonomic dysfunction (90% sensitivity and 95% specificity).
  • Patients with Parkinson disease have cardiac¹²³ I MIBG uptake significantly lower than that of patients with MSA and controls.
• Neuroimaging to exclude other conditions - MRI and proton magnetic resonance (MR) study
  • Brain images may be normal in MSA. OPCA, and cerebellar atrophy, and the putaminal lesions of striatonigral degeneration are often detected by using MR techniques.
  • The slight hyperintensity of the lateral margin of the putamen on T2-weighted MRI is a characteristic finding in patients with MSA involving the extrapyramidal system.
  • MRI findings can help to exclude cerebrovascular diseases, such as multi-infarct syndromes.
  • Expected findings are as follows:
    • Atrophy of cerebellum and brainstem in OPCA and SND
    • No vascular damage
    • No multi-infarct pattern in brain
    • No other lesions
    • Hyperintensity in pons, peduncles, and cerebellum on T2-weighted and proton density–weighted MRIs
    • Slitlike hyperintensity on T2-weighted and proton density–weighted MRIs; a cruciform hyperintensity in the pons on T2-weighted MRI, known as the hot cross bun sign, is not specific to MSA.⁹⁴

• In a study comparing the results of diffusion-weighted MRI in MSA-P patients, MSA-C patients, and normal controls, Pellecchia et al found that MSA-P patients had significantly higher Trace (D) values in the entire and anterior putamen, whereas MSA-C patients had significantly higher Trace (D) values in the cerebellum and middle cerebellar peduncle. Furthermore, increased disease duration correlated significantly with increased Trace (D) values in the pons of MSA-P patients and in cerebellum and middle cerebellar peduncle of MSA-C patients.⁹³

Positron emission tomography

• 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) PET can be used to differentiate MSA and Parkinson disease.
• The caudate-putamen index, which is calculated by using a formula based on the difference in the uptakes in the caudate and putamen divided by the caudate uptake, is lower in patients with MSA than in patients with Parkinson disease.
• Expected findings are as follows:
  • Reduced putaminal FDG uptake
  • Reduced [¹¹ C]raclopride and [¹¹ C]diprenorphine levels
  • Reduced cerebellar glucose metabolism in OPCA

Other Tests

• Autonomic function testing - Evaluation of the distribution and severity of parasympathetic and sympathetic dysfunction
  • Diminished respiratory sinus arrhythmia
  • Abnormal response to Valsalva maneuver (no BP recovery in late phase II and/or no overshoot in phase IV, reduced Valsalva ratio for heart rate)
  • Reduced response to isometric exercise (handgrip)
  • Diminished response to cold pressor stimuli
• Sphincter electromyography (EMG) - Hyperreflexia of detrusor

Histologic Findings

Neuropathologic changes consist of a high density of GCIs in association with degenerative changes in some or all of the following structures. Table 5 provides an overview of the clinicopathologic correlation.

• Putamen
• Caudate nucleus
• Globus pallidus
• Thalamus
• Subthalamic nucleus
• Substantia nigra
• Locus ceruleus
• Dorsal vagal nucleus
• Vestibular nuclei
• Pontine nuclei
• Inferior olives
• Pontine nuclei
• Cerebellar Purkinje cells
• Autonomic nuclei of the brain stem
• Intermediolateral cell columns
• Anterior horn cells
• Onuf nuclei in the spinal cord and pyramidal tracts

GCIs can be stained by using the Gallyas silver technique and are a hallmark of MSA. They range from sickle-to-flame shaped to ovoid, on occasion, superficially resembling neurofibrillary tangles. GCIs are loosely aggregated filaments with cross-sectional diameters of 20-30 nm. These filaments often entrap cytoplasmic organelles (eg, mitochondria, secretory vesicles), have no limiting membrane, and are reported to have tubular profiles and electrodense granules along much of their lengths. GCIs are ubiquitin-positive, tau-positive, and alpha-synuclein-positive oligodendroglial inclusions. They are different from Lewy bodies and neurofibrillary structures in Alzheimer disease (Table 8).

Table 8. Differences Between GCIs in MSA and Other Pathologic Inclusions and Structures

	GCIs in MSA	Lewy Bodies in Parkinson Disease	Neurofibrillary Pathology in Alzheimer Disease	Glial Lesions in Corticobasal and Progressive Supranuclear Palsy
Shape	Sickle-to-flame shaped to ovoid, various neurofibrillary tangles	Target-shaped inclusions	Tangles	Tufted astrocytes, coiled bodies
Membrane	No limiting membrane; tubular profiles and electrodense granules	Present	Present	Present
Ultrastructure	Loosely aggregated filaments	No data	No data	Astrocytic plaques
Immunocytochemistry	Ubiquitin positive, alpha-B-crystallin (synuclein) positive, alpha- and beta-tubulin positive, tau-protein positive	Hyaline eosinophilic cytoplasmic neuronal inclusions, ubiquitin	No data	Absence from phosphorylated tau
Localization	In oligodendroglial cells and neurons	In neuronal cells and oligodendroglial cells	No data	No data

Treatment

Medical Care

The cause of MSA remains unknown, and no current therapy can reverse or halt progression of the disease. The extrapyramidal and cerebellar aspects of the disease are debilitating and difficult to treat, but the earliest symptom that brings patients to medical attention usually is orthostatic hypotension. Orthostatic hypotension leads to curtailing of physical activity, with all the attendant problems of deconditioning that occur in consequence. Without an adequate upright BP, keeping patients active and on an exercise regimen is extremely difficult; therefore, management of orthostatic hypotension is one of the major tasks in the treatment of patients with MSA.

• Nonpharmacologic management in MSA
  • Orthostatic hypotension: Mechanical maneuvers, such as leg-crossing, squatting, abdominal compression, bending forward, and placing 1 foot on a chair, can be effective to prevent episodes of orthostatic hypotension. Wearing a tight-waisted external support garment improves venous return and preload to the heart during standing but loses effectiveness if the patient is supine. Increased salt and fluid intake and tilted sleeping with the head elevated increase the circulatory plasma volume.
  • Postprandial hypotension: Small, frequent meals prevent BP drop after eating. Intake of water half an hour before meals or drinking coffee can counteract postprandial hypotension.
  • Supine hypertension: The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate blood pressure control is often achieved following the treatment strategy:
    • Use of over-the-counter medication with pressor effects.
    • Avoid fluid intake at bedtime.
    • Avoid using elastic stockings when supine.
    • Avoid the use of pressor agents before bedtime.
    • Raise the head of the bed 6-9 inches.
    • Rest on a semirecumbent chair with feet on the floor during the day.
    • Snacks before bedtime are encouraged.
  • Urinary incontinence: Intermittent self-catheterization or suprapubic or urethral catheterization can improve symptoms of urinary incontinence.
  • Constipation: A high-fiber diet, bulk laxative, lactulose, and suppositories can prevent constipation.
  • Stridor: Speech therapy is often useful to improve swallowing and communication.
  • Deconditioning: Physical therapy and an aquatic exercise program (hypotension does not occur while patients are in water) prevent physical deconditioning of the patient unless the movement disorder aspect of the illness so impairs balance that this is not advisable.
• Pharmacologic management in MSA: Please see the Medication section for a discussion of pharmacologic management.

Surgical Care

Surgical care may be necessary.

• An atrial pacemaker rarely benefits patients but may be tried in patients with profound bradycardia to prevent orthostatic hypotension.
• Consider tracheostomy with the utmost care for intermittent respiratory stridor.
• Cricopharyngeal myotomy or gastrostomy has been used in patients with severe dysphagia, but its value is uncertain.

Consultations

Physical therapists, occupational therapists, speech therapists, and social works offer considerable practical help.

Diet

An essentially normal diet is recommended, with the following guidelines:

• Increased salt and fluid intake maintains plasma volume.
• Frequent and small meals may help those for whom postprandial hypotension is a significant problem.
• A high-fiber diet, bulk laxatives, and suppositories prevent constipation.

Activity

Exercise of muscles of the lower extremities and abdomen, water aerobics at hip level (not swimming, as it causes polyuria), and postural training, in combination with drug therapy, are useful.

Medication

Drug therapy is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension (see also Table 9). Medical therapy can be also applied for urinary incontinence, constipation, erectile dysfunction, and supine hypertension. Medical Therapy of Movement Disorder

The movement-disorder component of MSA is usually treated with levodopa, dopaminergic agonists, anticholinergic agents, or amantadine, but results are rarely as favorable in MSA as in classic Parkinson disease.

Other classes of drugs now uncommonly used are nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, somatostatin analogues, and caffeine.

Medical therapy of orthostatic hypotension

Many agents have been advocated for the management of orthostatic hypotension. Table 9 shows some of the most widely used approaches. However, drug therapy of orthostatic hypotension is limited by supine hypertension, which affects about 60% of patients with MSA.

Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA

Class	Drug	Description or Mechanism
Fludrocortisone	Fludrocortisone acetate (Florinef)	Mineralocorticoid; sodium retention, primarily in extravascular compartment, causes tissue edema to venous capacitance bed in lower extremity. With this edema, venous bed accommodates decreased volume of blood in an upright posture (high doses, late effect); increases sensitivity to norepinephrine (even with small doses)
Sympathomimetic amines	Midodrine, dihydroxyphenylserine	Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction
Recombinant erythropoietin (EPO)	Epoetin alfa	Increases sensitivity to pressor effects of angiotensin II; increases plasma endothelin level; increases cytosolic free calcium in vascular smooth muscle; increases intravascular volume
NSAIDs	Indomethacin, ibuprofen	Inhibition of vasodilator prostaglandins proposed but not proven
Antihistamines	Diphenhydramine, cimetidine	Reduce vasodilatation caused by histamine release
Somatostatin analogs	Somatostatin, octreotide	Reduce splanchnic capacitance
Vasopressin agonists	Desmopressin (DDAVP)	Vasopressin analogs; no effect on V1 receptors, which are responsible for vasopressin-induced vasoconstriction; acts on V2 receptors on renal tubuli, which are responsible for antidiuretic effect; prevents nocturnal diuresis, raises BP in morning
Other sympathomimetics Other sympathomimetics	Yohimbine	Alpha2-adrenoreceptor antagonist, sympathomimetic
	Caffeine	Adenosine receptor antagonist, sympathomimetic

Medical therapy of supine hypertension

The presence of supine hypertension can complicate the pharmacologic management of patients with MSA, but a rational approach to its treatment is often successful. Simply avoiding the supine position is often enough to control hypertension during the day. Treatment of supine hypertension is required at nighttime. Elevating the head of the bed is useful but rarely sufficient. Short-acting vasodilators are effective in controlling hypertension. The management of patients with orthostatic hypotension and supine hypertension can be challenging, but adequate BP control is often achieved following the nonpharmacologic approach as described above combined with following medication:

• Nitrates, transdermal nitroglycerin (0.1–0.2 mg/h)
• Hydralazine (50 mg)
• Nifedipine; short-acting calcium blocker (30 mg)
• Minoxidil (2.5 mg)
• Clonidine (0.1 mg), early in the evening

Drug List

The following drug list is categorized and compiled for MSA treatments.

Antiparkinson agents

Patients with MSA may have an initial response to levodopa. This response usually diminishes over time. Withdrawal of levodopa can cause the patient's condition to deteriorate, but this is much more prominent in Parkinson disease than in MSA. In modern practice, levodopa is administered in combination with a dopa decarboxylase inhibitor.

Levodopa/Carbidopa (Sinemet)

Levodopa plus dopa decarboxylase inhibitor. Levodopa administered alone, largely decarboxylated by intestinal mucosa or other peripheral sites rich in MAO, and little reaches cerebral circulation and CNS.

Dosing

Adult

25/100 mg PO hs; increase q3-7d to total 100 mg/d levodopa or until adverse effects occur

Pediatric

Not established

Interactions

Hydantoins, pyridoxine, phenothiazines, and hypotensive agents may decrease effects; antacids and MAOIs increase toxicity

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; malignant melanoma; undiagnosed skin lesions

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

With SR form, certain CNS adverse effects (eg, dyskinesias) may occur early and at low doses; caution with history of myocardial infarction, arrhythmias, asthma, or peptic ulcer disease; sudden discontinuation of levodopa may cause worsening of Parkinson disease; high-protein meals should be distributed throughout day to prevent fluctuations in levodopa absorption

These agents are alternatives to levodopa therapy in the late phase of the movement disorder. They selectively act on different subtypes of dopamine receptors throughout the brain. The mechanism is independent of the functional capacities of the nigrostriatal neurons and may be more effective than other drugs.

Pergolide (Permax)

Pergolide was withdrawn from the US market March 29, 2007, because of heart valve damage resulting in cardiac valve regurgitation. It is important not to abruptly stop pergolide. Health care professionals should assess patients' need for dopamine agonist (DA) therapy and consider alternative treatment. If continued treatment with a DA is needed, another DA should be substituted for pergolide. For more information, see FDA MedWatch Product Safety Alert and Medscape Alerts: Pergolide Withdrawn From US Market.

May exert therapeutic effect by directly stimulating postsynaptic dopamine receptors in nigrostriatal system. Agonist of D1 and D2 striatal dopamine receptors.

Dosing

Adult

0.75-3 mg PO qd

Pediatric

Not established

Interactions

Dopamine antagonists (eg, neuroleptics, phenothiazines, butyrophenones, thioxanthenes, metoclopramide) may diminish effectiveness; because >90% bound to plasma proteins, caution if coadministered with drugs known to affect protein binding

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May cause valvular heart disease (yearly echocardiograms recommended for patients on chronic therapy); inhibits secretion of prolactin; causes transient rise in serum concentrations of growth hormone and decrease in serum concentrations of luteinizing hormone; adverse effects include nausea, hypotension, hallucinations, and somnolence; use caution in patients who have been treated for cardiac dysrhythmias; may cause or exacerbate preexisting states of confusion and hallucinations or dyskinesia

Bromocriptine (Parlodel)

Strong agonist of D2 and partial agonist of D1 striatal dopamine receptors.

Dosing

Adult

2.5-40 mg PO qd

Pediatric

Not established

Interactions

Ergot alkaloids may increase toxicity; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic disease

These agents were widely used before levodopa was discovered.

Trihexyphenidyl (Artane)

Anticholinergic receptor agent affecting structures in neostriatum.

Dosing

Adult

2-4 mg PO tid

Pediatric

Not established

Interactions

Amantadine may increase anticholinergic adverse effects (resolve when dose reduced); haloperidol may worsen schizophrenic symptoms; may decrease haloperidol serum concentrations; may reduce pharmacologic and/or therapeutic actions of phenothiazines

Contraindications

Documented hypersensitivity; glaucoma; peptic ulcers; pyloric or duodenal obstruction; stenosing prostatic hypertrophy or bladder neck obstructions; achalasia; toxic megacolon

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Dose adjustment may be required in elderly patients; caution in tachycardia, cardiac hypotension, prostatic hypertrophy, arrhythmias, hypertension, or any tendency toward urinary retention, liver or kidney disorders, or obstructive disease of GI or GU tract; if dry mouth severe and impairs swallowing or speaking or if loss of appetite and weight, reduce dose or discontinue temporarily

Benztropine mesylate (Cogentin)

Anticholinergic receptor agent affecting structures in neostriatum.

Dosing

Adult

2-4 mg PO tid

Pediatric

Not established

Interactions

Decreases effects of levodopa; increases effects of narcotic analgesics, phenothiazines, quinidine, TCAs, and anticholinergics

Contraindications

Documented hypersensitivity; angle-closure glaucoma; stenosing peptic ulcers; prostatic hypertrophy; bladder neck obstructions; myasthenia gravis; pyloric or duodenal obstruction; achalasia (megaesophagus); megacolon

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate hypertension, tachycardia, cardiac arrhythmias, liver or kidney disorders, hypotension, prostatic hypertrophy, urinary retention, and obstructive disease of GI and/or GU tract; toxic psychosis may occur in extrapyramidal reactions due to phenothiazine to treat psychiatric conditions

Diphenhydramine hydrochloride (Benadryl)

Affects structures in neostriatum.

Dosing

Adult

25-50 mg PO tid/qid

Pediatric

Not established

Interactions

Potentiates effect of CNS depressants; because of alcohol content, do not give syrup to patient taking medications that can cause disulfiram-like reactions

Contraindications

Documented hypersensitivity; MAOIs

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia

Amantadine (Symmetrel)

May alter dopamine release or reuptake and actions at glutamate receptors.

Dosing

Adult

100 mg PO bid

Pediatric

Not established

Interactions

Drugs with anticholinergic or CNS stimulant activity increase toxicity; hydrochlorothiazide plus triamterene may increase plasma concentrations

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in liver disease, uncontrolled psychosis, eczematoid dermatitis, seizures, and use of CNS stimulants; reduce dose in renal disease in treating Parkinson disease; do not discontinue abruptly

Urinary antispasmodic agents

When detrusor hyperreflexia is the cause of the patient's urinary incontinence, peripherally acting anticholinergic agents (eg, oxybutynin chloride [Ditropan], tolterodine [Detrol], propantheline [Pro-Banthine]) can be applied.

Oxybutynin chloride (Ditropan)

Tertiary amine muscarinic receptor antagonist. Nonspecific relaxant on smooth muscles.

Dosing

Adult

5-10 mg PO hs

Pediatric

Not established

Interactions

CNS effects increase with concurrent CNS depressants

Contraindications

Documented hypersensitivity; glaucoma; partial or complete GI obstruction; myasthenia gravis; ulcerative colitis; toxic megacolon

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in urinary tract obstruction, reflux esophagitis, and heart disease; may worsen constipation

Tolterodine (Detrol)

Competitive muscarinic receptor antagonist for overactive bladder. Selective for urinary bladder over salivary glands; therefore, differs from other anticholinergics. High specificity for muscarinic receptors, minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).

Dosing

Adult

2 mg PO hs

Pediatric

Not established

Interactions

Patients treated with macrolide antibiotics or antifungals should not receive >1.0 mg bid

Contraindications

Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not give dosages >1.0 mg bid to patients with significantly reduced hepatic function; caution in renal impairment

Propantheline (Pro-Banthine)

Blocks action of acetylcholine at postganglionic parasympathetic receptor sites.

Dosing

Adult

15-30 mg PO hs

Pediatric

Not established

Interactions

Antacids decrease effects; disopyramide, tricyclic antidepressants, phenothiazines, corticosteroids, and bretylium increase toxicity

Contraindications

Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI or urinary tract

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or hepatic disease; may worsen constipation

Gastroprokinetic agents

If a special bulk-forming diet fails, lactulose occasionally is helpful. In rare cases, cisapride (Propulsid) may promote bowel movements.

Erythromycin (E.E.S., E-Mycin)

Macrolide antibiotic that duplicates action of motilin and is responsible for migrating motor complex activity, by binding to and activating motilin receptors. IV administration enhances emptying rate of liquids and solids. Effect can be seen with oral erythromycin. Enteric-coated form may be most tolerable.

Dosing

Adult

250 mg PO 30 min ac initially

Pediatric

Not established

Interactions

Theophylline, digoxin, carbamazepine, and cyclosporine may increase toxicity; may potentiate anticoagulant effects of warfarin; lovastatin and simvastatin increase risk of rhabdomyolysis

Contraindications

Documented hypersensitivity; hepatic impairment

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in liver disease; estolate formulation may cause cholestatic jaundice; GI side effects are common (give pc); discontinue use if nausea, vomiting, malaise, abdominal colic, or fever occur

Agents for erectile dysfunction

MSA may respond to yohimbine with BP elevation; male erectile dysfunction occasionally improves. Yohimbine (Yohimex, Yocon) should be given 5.6 mg qd/tid. The effect of Viagra has not been determined in patients with autonomic failure. Other approaches include the use of mechanical devices, pumps, penile prostheses, or implants.

Yohimbine (Yohimex)

Blockade of alpha2-receptors in pontomedullary region of CNS increases sympathetic outflow.

Dosing

Adult

2.7 -5.4 mg PO tid

Pediatric

Not established

Interactions

Increases toxicity of antidepressants

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Adverse effects include anxiety, tremor, palpitation, diarrhea, supine hypertension; not for use in patients with cardiorenal conditions

Mineralocorticoids

These agents have salt-retaining (mineralocorticoid) properties.

Fludrocortisone acetate (Florinef acetate)

Mainstay of therapy for last 40 years. Powerful mineralocorticoid largely devoid of glucocorticoid effect when administered in low-to-moderate doses (0.1-0.3 mg). Can initially increase blood volume, which tends to normalize after first week. Most patients gradually (over 2 wk) gain weight (usually 5-8 lb), with mild ankle edema, because of sodium retention, primarily in extravascular compartment.

Much benefit depends on support from tissue edema to venous capacitance bed in lower extremities. With edema, venous bed accommodates only low volume of blood in upright posture. Effect in turn improves blood return to heart and therefore functional capacity. In addition to direct effect of extravascular fluid accumulation, increases alpha1-adrenoreceptor sensitivity by about 50%. During therapy, renin-angiotensin system suppressed (as expected).

Dosing

Adult

0.1-0.4 mg PO qd

Pediatric

Not established

Interactions

Antagonizes effects of anticholinergics; rifampin, hydantoins, and barbiturates decrease effects of fludrocortisone; decreases salicylate levels

Contraindications

Documented hypersensitivity; systemic fungal infections; supine hypertension (eg, systolic BP >200 mm Hg)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hypokalemia, hypomagnesemia, gain of weight, excessive fluid accumulation with excessive BP elevation in supine posture; supine hypertension in most patients, even without therapy (limits degree to which BP can be increased with drug); supine hypertension may increase risk of hemorrhage in MSA (reliable studies lacking)

Alpha-adrenergic agonists

These agents may reduce sympathetic outflow, which may reduce muscle tone.

Midodrine (Pro- Amatine)

Prodrug with activity as alpha1-adrenoreceptor agonist that acts directly on vasculature. Also widely used to treat orthostatic hypotension in MSA. Acts directly on vasculature to increase BP and avoids electrolyte abnormalities associated with fludrocortisone. However, supine hypertension significant problem and limits enhancement of functional capacity in MSA.

Dosing

Adult

10 mg PO tid

Pediatric

Not established

Interactions

Drugs that stimulate alpha-adrenergic agonists may enhance or potentiate pressor effects; coadministration with cardiac glycosides may enhance or precipitate bradycardia, psychopharmacologic agents or beta-blockers, AV block, or arrhythmia

Contraindications

Documented hypersensitivity; supine hypertension (eg, systolic BP >200 mm Hg)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in diabetes or visual complications; discontinue and reevaluate if signs or symptoms of bradycardia occur

Sympathomimetics

These agents augment both coronary and cerebral blood flow. Agents such as phenylpropanolamine, ephedrine, and dihydroxyphenylserine have also been in MSA and share with midodrine the possible complication of excessive supine hypertension. The advantage of these short-acting pressors is that they can be given during the day if the patient does not lie down for the next 3-4 h. A late-afternoon dose should be avoided if possible.

Phenylpropanolamine (Propagest)

Recalled from US market. Sympathomimetic amine. Acts to directly release noradrenaline

Dosing

Adult

12.5-25 mg PO bid with 12 oz of water

Pediatric

Not established

Interactions

Theophylline, atropine, or MAO inhibitors may increase toxicity

Contraindications

Documented hypersensitivity; supine hypertension (eg, systolic BP >200 mm Hg)

Precautions

Pregnancy

C-Safety for use during pregnancy has not been established.

Precautions

Reduced appetite, nervousness, tachycardia, supine hypertension, tachyphylaxis

Ephedrine (Ephedrine sulfate)

Sympathomimetic amine. Alpha- and beta-adrenergic agonist; peripheral vasoconstrictor

Dosing

Adult

Starting: 25 mg PO tid

Pediatric

Not established

Interactions

Theophylline, atropine, or MAO inhibitors may increase toxicity; alpha- and beta-blockers decrease vasopressor effects of ephedrine; cardiac glycosides and general anesthetics increase cardiac stimulation of ephedrine

Contraindications

Documented hypersensitivity; angle-closure glaucoma, and cardiac arrhythmias

Precautions

Pregnancy

C-Safety for use during pregnancy has not been established.

Precautions

Caution in elderly, diabetes mellitus, hyperthyroidism, hypertension, cardiovascular disease, prostatic hypertrophy, or cerebrovascular insufficiency

Dihydroxyphenylserine (L-DOPS)

Sympathomimetic amine. Direct synthesis of NE from this drug in absence of dopamine beta- hydroxylase.

Dosing

Adult

250-500 mg PO bid

Pediatric

Not established

Interactions

Theophylline, atropine, or MAO inhibitors may increase toxicity

Contraindications

Documented hypersensitivity; severe hypertension or ventricular tachycardia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

May not work in patients taking carbidopa (Sinemet) or benserazide

Colony-stimulating factor

These agents correct anemia associated with MSA.

Epoetin alfa (Epogen, Procrit)

Recombinant EPO recently shown to increase functional capacity of patients with MSA, particularly those with characteristic mild anemia. Up to 38% of patients with severe autonomic failure have anemia. Lack of sympathetic stimulation may lead to decreased EPO production and anemia. Sympathetic impairment and low plasma norepinephrine levels correlated with severity of anemia. Even low doses (25-50 units/kg SC 3 times/wk) successfully corrected anemia and improved upright BP. Biologic activity mimics human urinary EPO, which stimulates division and differentiation of committed erythroid progenitor cells and induces release of reticulocytes from bone marrow into bloodstream.

Dosing

Adult

25-50 U/kg body wt SC 3 times/wk

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity; uncontrolled hypertension

Precautions

Pregnancy

C Safety for use during pregnancy has not been established.

Precautions

Caution in porphyria, hypertension, history of seizures; decrease dose if increase in hematocrit > 4 U in any 2-wk period; multidose preserved formulation contains benzyl alcohol and may increase risk of neurologic toxicity in infants (use preservative-free formulation); treatment results depend on adequate iron supplementation

Nonsteroidal Anti-inflammatory Drug (NSAID), Oral

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation and various cell-membrane functions.

Indomethacin (Indocin)

Inhibits vasodilator prostaglandin synthesis.

Dosing

Adult

25 mg PO tid ac; increase to 50 mg tid

Pediatric

Not established

Interactions

Coadministration with aspirin increases risk of serious NSAID-related adverse effects; probenecid may increase concentrations and possibly toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when patient taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may increase when administered concurrently

Contraindications

Documented hypersensitivity; GI bleeding or renal insufficiency

Precautions

Pregnancy

B-Usually safe but benefits must outweigh the risks

Precautions

Acute renal insufficiency, hyperkalemia, hyponatremia, interstitial nephritis, and renal papillary necrosis may occur; increases risk of acute renal failure in patients with preexisting renal disease or compromised renal perfusion; reversible leukopenia may occur (discontinue if persistent leukopenia, granulocytopenia, or thrombocytopenia present)

Antihistamine

These agents prevent histamine response in sensory nerve endings and blood vessels. They are more effective in preventing histamine response than in reversing it.

Diphenhydramine (Benadryl, Benylin)

First-generation antihistamine with anticholinergic effects that binds to H1 receptors in CNS and body. Competitively blocks histamine from binding to H1 receptors. Significant antimuscarinic activity and penetrates CNS, which causes pronounced tendency to induce sedation. Approximately half of patients treated with conventional doses have some somnolence.

Dosing

Adult

25-50 mg PO q6-8h prn; not to exceed 400 mg/d
10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d

Pediatric

Not established

Interactions

Potentiates effect of CNS depressants; due to alcohol content, do not give syrup to patient taking medications that can cause disulfiram-like reactions

Contraindications

Documented hypersensitivity; MAO inhibitors

Precautions

Pregnancy

C Safety for use during pregnancy has not been established.

Precautions

May exacerbate angle closure glaucoma, hyperthyroidism, peptic ulcer, or urinary-tract obstruction; xerostomia may occur

Follow-up

Further Inpatient Care

Inpatient evaluation and tailoring of therapy are often important. However, if patients are restricted to bedrest, their functional mobility can decrease rapidly. Therefore, initiate physical therapy if the patient must remain in the hospital for longer than 2 days.

Prognosis

No current therapeutic modality reverses or halts the progress of this disease.

Patient Education

• A variety of resources are now available for patient education. These include the Web site of the MSA Shy-Drager Support Group.
• An email list is available for patients, spouses, and caregivers throughout the world to use to communicate with each other about their experiences with this disease. The list is sponsored by the Vanderbilt Autonomic Dysfunction Center. Interested persons should follow directions on the Web site to subscribe.

Miscellaneous

Medicolegal Pitfalls

• MSA is a difficult diagnosis, especially early in the clinical course, and the initial physician often misdiagnoses the condition. The most common initial diagnosis is idiopathic Parkinson disease.
• As the disease progresses, the risk of falls increases. Proper gait instruction and precautions are critical to prevent falls and resultant injury.
• The incidence of medication-related adverse effects is increased, especially as the number and dosages of medications increase.

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Keywords

MSA, multiple-system atrophy, multisystem atrophy, Shy-Drager syndrome, striatonigral degeneration, MSA-P, sporadic olivopontocerebellar atrophy, MSA-C

Contributor Information and Disclosures

Author

André Diedrich, MD, PhD, Research Associate Professor of Medicine, Research Assistant Professor of Biomedical Engineering, Autonomic Dysfunction Center, Vanderbilt University School of Medicine
André Diedrich, MD, PhD is a member of the following medical societies: American Autonomic Society and American Heart Association
Disclosure: Nothing to disclose.

Coauthor(s)

David Robertson, MD, Director, Clinical Research Center, Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University
David Robertson, MD is a member of the following medical societies: American Heart Association and Association of American Physicians
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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