AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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). 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.

Table 2. Clinical Domains and Features in the Diagnosis of MSA

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

Adapted from Gilman et al.

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.

Table 5. Clinicopathologic Correlations

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. Patients survive an average of 6-9 years after the onset of the illness.

• 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.

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.

• Median survivals of 6.2-9.5 years from the onset of first symptoms have been reported in the last 2 decades.
• 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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 response with 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 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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. 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.

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.

• 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, 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.)
  • 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 demonstrated different responses to pharmacologic and physiologic stimuli in autonomic function tests.
  • Cardiovascular autonomic dysfunction should be an exclusionary feature in the diagnosis of PSP.
• 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 on 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

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab 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 to evidence a presence of high density of GCIs in association with degenerative changes in nigrostriatal and olivopontocerebellar pathway.
• The following laboratory tests can assist in the diagnostic process:
• • Blood status - Normal supine norepinephrine level and low upright norepinephrine level
  • Response to levodopa - Poor or no response

Imaging Studies

• Iodine-123 (¹²³I) metaiodobenzylguanidine (MIBG) scintigraphy
• • Scintigraphy with ¹²³I 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 cardiac ¹²³I 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
• 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 [¹¹C]raclopride and [¹¹C]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

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

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.

Drug Category: 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.

Drug Category: Dopaminergic agonists

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.

Drug Name	Bromocriptine (Parlodel)
Description	Strong agonist of D2 and partial agonist of D1 striatal dopamine receptors.
Adult Dose	2.5-40 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Ergot alkaloids may increase toxicity; amitriptyline, butyrophenones, imipramine, methyldopa, phenothiazines, and reserpine may decrease effects
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

Drug Category: Anticholinergic agents (Muscarinic receptor agonists)

These agents were widely used before levodopa was discovered.

Drug Name	Benztropine mesylate (Cogentin)
Description	Anticholinergic receptor agent affecting structures in neostriatum.
Adult Dose	2-4 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; angle-closure glaucoma; stenosing peptic ulcers; prostatic hypertrophy; bladder neck obstructions; myasthenia gravis; pyloric or duodenal obstruction; achalasia (megaesophagus); megacolon
Interactions	Decreases effects of levodopa; increases effects of narcotic analgesics, phenothiazines, quinidine, TCAs, and anticholinergics
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

Drug Name	Diphenhydramine hydrochloride (Benadryl)
Description	Affects structures in neostriatum.
Adult Dose	25-50 mg PO tid/qid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; MAOIs
Interactions	Potentiates effect of CNS depressants; because of alcohol content, do not give syrup to patient taking medications that can cause disulfiram-like reactions
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

Drug Name	Amantadine (Symmetrel)
Description	May alter dopamine release or reuptake and actions at glutamate receptors.
Adult Dose	100 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Drugs with anticholinergic or CNS stimulant activity increase toxicity; hydrochlorothiazide plus triamterene may increase plasma concentrations
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

Drug Category: 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.

Drug Name	Tolterodine (Detrol)
Description	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).
Adult Dose	2 mg PO hs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; urinary retention; gastric retention; uncontrolled narrow-angle glaucoma
Interactions	Patients treated with macrolide antibiotics or antifungals should not receive >1.0 mg bid
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

Drug Name	Propantheline (Pro-Banthine)
Description	Blocks action of acetylcholine at postganglionic parasympathetic receptor sites.
Adult Dose	15-30 mg PO hs
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; ulcerative colitis; narrow-angle glaucoma; obstructive disease of GI or urinary tract
Interactions	Antacids decrease effects; disopyramide, tricyclic antidepressants, phenothiazines, corticosteroids, and bretylium increase toxicity
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

Drug Category: Gastroprokinetic agents

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

Drug Category: 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.

Drug Category: Mineralocorticoids

These agents have salt-retaining (mineralocorticoid) properties.

Drug Category: Alpha-adrenergic agonists

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

Drug Category: 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.

Drug Name	Ephedrine (Ephedrine sulfate)
Description	Sympathomimetic amine. Alpha- and beta-adrenergic agonist; peripheral vasoconstrictor
Adult Dose	Starting: 25 mg PO tid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; angle-closure glaucoma, and cardiac arrhythmias
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
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

Drug Name	Dihydroxyphenylserine (L-DOPS)
Description	Sympathomimetic amine. Direct synthesis of NE from this drug in absence of dopamine beta- hydroxylase.
Adult Dose	250-500 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe hypertension or ventricular tachycardia
Interactions	Theophylline, atropine, or MAO inhibitors may increase toxicity
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

Drug Category: Colony-stimulating Factor

These agents correct anemia associated with MSA.

Drug Category: 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.

Drug Category: 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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 M