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Medication

Medication Summary

As previously mentioned, pharmacologic therapy for multiple system atrophy (MSA) is directed mainly toward alleviation of symptoms of the movement disorder and orthostatic hypotension (see Table 9, below). Medications can also be used to treat urinary incontinence, constipation, erectile dysfunction, and supine hypertension. In recent years, neuroprotective therapy has been successfully applied in the mouse model.^[39]But studies in humans (e.g., rifampicin rasagiline) did not show beneficial effects on slowing down the disease.^{[40, 41]}Transgenic MSA mouse models do not have the same human phenotype but may be the best choice to explore new therapies.^[42]

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.

Drugs that now are not commonly used in patients with MSA include 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, below, shows some of the most widely used drugs. However, drug therapy of orthostatic hypotension is limited by supine hypertension, which affects about 60% of patients with MSA.^[43]

In February 2014, droxidopa was approved by the FDA for the treatment of orthostatic hypotension. It is a synthetic amino precursor prodrug and is converted to norepinephrine.^[44]

Water is a uniquely powerful pressor agent in the management of orthostatic hypotension in patients with MSA. It acts by increasing sympathetic activity. On average, 16 ounces of water will raise BP about 30 mm Hg. Patients may understandably be skeptical that something so commonplace could help raise their BP, so it does require patient education. No other beverage (not juice or coffee or even Gatorade) is as good as a pressor agent as water in patients with autonomic dysfunction. Its major limitations are a short (1-hour) half-life and increased urination (inconvenient when autonomic impairment makes urination difficult).

Patients should drink 16 ounces of water on awakening each morning, even before they get out of bed. Patients should learn to use water prophylactically; they will be able to do much more in the hour after ingesting water than at other times. A repeat dosing midmorning or at lunch and at midafternoon may give the patient additional capacity for activity during this part of the day. Conversely, since patients with autonomic failure commonly have supine hypertension, we discourage them from drinking large amounts of water within the 2 hours prior to bedtime, although we allow them to drink when they are thirsty.

Table 9. Drugs Used to Manage Orthostatic Hypotension in MSA (Open Table in a new window)

Class	Drug	Description or Mechanism
Corticosteroids	Fludrocortisone (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	Alpha1-adrenoreceptor agonist acts directly on vasculature, causes venous and arteriolar vasoconstriction
Sympathomimetic amines	Droxidopa	Droxidopa is a synthetic precursor of norepinephrine. It acts by conversion to norepinephrine in the body.
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	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	Yohimbine	Alpha2-adrenoreceptor antagonist
Other sympathomimetics	Caffeine	Adenosine receptor antagonist

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 night. 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 by combining the nonpharmacologic approach, as previously described, with the following medications:

Nitrates, transdermal nitroglycerin (0.1–0.2 mg/h)
Hydralazine (50 mg)
Nifedipine; short-acting calcium blocker (10-30 mg)
Clonidine (0.1 mg), early in the evening^[45]

Class Summary

Patients with MSA may have an initial response to levodopa, but this response usually diminishes over time. Withdrawal of levodopa can cause a 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, Parcopa)

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In this combination, levodopa is administered with a dopa decarboxylase inhibitor. When levodopa is administered alone, it is largely decarboxylated by the intestinal mucosa or other peripheral sites rich in monoamine oxidase (MAO), and little reaches the cerebral circulation and CNS.

Class Summary

These agents are used as 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 through which dopaminergic agonists act is independent of the functional capacities of the striatonigral neurons and may be more effective than those of other drugs.

Bromocriptine (Parlodel, Cycloset)

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Bromocriptine is a strong agonist of D2 and a partial agonist of D1 striatal dopamine receptors.

Amantadine

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Amantadine may alter dopamine release or reuptake and actions at glutamate receptors.

Class Summary

These agents were widely used before levodopa was discovered.

Trihexyphenidyl

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Trihexyphenidyl is an anticholinergic receptor agent affecting structures in the neostriatum.

Benztropine mesylate (Cogentin)

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Benztropine mesylate is an anticholinergic receptor agent affecting structures in the neostriatum.

Class Summary

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

Oxybutynin chloride (Ditropan XL, Gelnique, Oxytrol)

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Oxybutynin chloride, a tertiary amine muscarinic receptor antagonist, is a nonspecific relaxant on smooth muscles.

Tolterodine (Detrol, Detrol LA)

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Tolterodine is a competitive muscarinic receptor antagonist for overactive bladder. It differs from other anticholinergics by being selective for the urinary bladder over the salivary glands. Tolterodine has high specificity for muscarinic receptors and has minimal activity or affinity for other neurotransmitter receptors and other potential targets (eg, calcium channels).

Propantheline

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Propantheline blocks the action of acetylcholine at postganglionic parasympathetic receptor sites.

Class Summary

If a special bulk-forming diet fails, lactulose occasionally is helpful. In rare cases, cisapride (Propulsid) may promote bowel movements, but this agent has been removed from the US market because of risk of cardiac rhythm disturbances.

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

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Erythromycin is a macrolide antibiotic that duplicates the action of motilin. By binding to and activating motilin receptors, it is responsible for migrating motor complex activity. IV administration enhances the emptying rate of liquids and solids. The effect can also be seen with oral erythromycin. The enteric-coated form may be the most tolerable. However, erythromycin's benefit as a prokinetic agent is usually marginal in MSA.

Class Summary

MSA may respond to yohimbine with BP elevation, but male erectile dysfunction only occasionally improves. Yohimbine (Yohimex, Yocon) should be given at a dose of 5.4 mg 3 times a day for the purposes of blood pressure elevation. Yohimbine has a very limited ability to improve erectile dysfunction in MSA and can dangerously elevate blood pressure when given with acetylcholinesterase inhibitors such as pyridostigmine. If adverse effects are a problem, the dose can be reduced to half a tablet 3 times a day and gradually increased to 1 tablet 3 times a day. The effect of sildenafil (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)

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Yohimbine blockades alpha2 receptors in the pontomedullary region of the CNS, increasing sympathetic outflow.

Class Summary

Specific agents in this class have salt-retaining (mineralocorticoid) properties.

Fludrocortisone

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Fludrocortisone has been a mainstay of pressor therapy for the last 50 years. It is a powerful mineralocorticoid that is largely devoid of a glucocorticoid effect when it is administered in low to moderate doses (0.1-0.3 mg). This agent can initially increase blood volume, which tends to normalize after the first week. Most patients gradually (over 2 wk) gain weight (usually 5-8 lb), with mild ankle edema occurring as a result of sodium retention, primarily in the extravascular compartment.

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

Class Summary

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

Midodrine

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Midodrine is a prodrug with activity as an alpha1-adrenoreceptor agonist. This agent is widely used to treat orthostatic hypotension in MSA. Midodrine acts directly on the vasculature to increase BP and avoids electrolyte abnormalities associated with fludrocortisone. However, supine hypertension is a significant problem and limits the enhancement of functional capacity in MSA. Midodrine has often caused an unpleasant sensation in the scalp (due to piloerection).

Class Summary

These agents augment coronary and cerebral blood flow. Agents such as ephedrine have been used in patients with MSA and share with midodrine the possible complication of excessive supine hypertension. The advantage of these short-acting vasopressors is that they can be given during the day if the patient does not lie down for 3-4 hours after taking them. A late-afternoon dose should be avoided if possible.

Droxidopa (Northera)

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Droxidopa is an oral norepinephrine precursor that is directly metabolized to norepinephrine by dopa-decarboxylase which is extensively distributed throughout the body. Peak droxidopa plasma concentrations are associated with increases in systolic and diastolic blood pressures. Droxidopa has no clinically significant effect on standing or supine heart rates in patients with autonomic failure. It is indicated for symptomatic neurogenic orthostatic hypotension (NOH) in patients with primary autonomic failure caused by diseases and conditions (eg, Parkinson disease, multiple system atrophy, and pure autonomic failure, dopamine beta-hydroxylase deficiency, and nondiabetic autonomic neuropathy).

Ephedrine

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Ephedrine is a sympathomimetic amine. It is an alpha- and a beta-adrenergic agonist and a peripheral vasoconstrictor.

Class Summary

These agents correct anemia associated with MSA.

Epoetin alfa (Epogen, Procrit)

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This is a recombinant EPO that has been shown to increase the functional capacity of patients with MSA, particularly those with characteristic mild anemia. Up to 38% of patients with severe autonomic failure have anemia. A lack of sympathetic stimulation may lead to decreased EPO production and anemia. Sympathetic impairment and low plasma norepinephrine levels are correlated with the severity of anemia.

Even low doses (25-50 U/kg SC 3 times weekly) of epoetin alfa have successfully corrected anemia and improved upright BP. The drug's biologic activity mimics that of human urinary EPO, which stimulates the division and differentiation of committed erythroid progenitor cells and induces the release of reticulocytes from bone marrow into the bloodstream.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase 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)

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Indomethacin inhibits vasodilator prostaglandin synthesis.

Class Summary

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, Diphenhist)

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Diphenhydramine is a first-generation antihistamine with anticholinergic effects that binds to H1 receptors in the CNS and body. It competitively blocks histamine from binding to H1 receptors.

Diphenhydramine affects structures in the neostriatum. It has significant antimuscarinic activity and penetrates the CNS, giving the drug a pronounced tendency to induce sedation. Approximately half of patients treated with conventional doses have some somnolence.

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Author

André Diedrich, MD, PhD Research Professor of Medicine, Adjunct Research Professor of Biomedical Engineering, Director of the Analytical and Phenotyping Core, Autonomic Dysfunction Center, Vanderbilt University School of Medicine

André Diedrich, MD, PhD is a member of the following medical societies: American Autonomic Society

Disclosure: Nothing to disclose.

Coauthor(s)

David Robertson, MD Director, Clinical and Translational Research Center, Vanderbilt Institute for Clinical and Translational Research, Principal Investigator, Autonomic Rare Disease Clinical Research Consortium, Elton Yates Professor of Medicine, Pharmacology, and Neurology, Vanderbilt University School of Medicine

David Robertson, MD is a member of the following medical societies: American Heart Association, Association of American Physicians

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

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, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK life science, Sunovion, Takeda, UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Aquestive, Bioserenity, Eisai, Jazz, LivaNova, Neurelis, SK life science, Stratus, Sunovion, UCB<br/>Received research grant from: Cerevel Therapeutics, Ovid Therapeutics, Neuropace, Greenwich Jazz, SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Neuroelectrics Corporation, Longboard, Janssen, Equilibre Biopharmaceuticals.

Acknowledgements

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.

Christopher Luzzio, MD Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison School of Medicine and Public Health

Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Term	Period	Authors	Comments
Olivopontocerebellar atrophy (OPCA)	1900	Dejerine and Thomas	Introduction of the term olivopontocerebellar atrophy
Orthostatic hypotension (OH)	1925	Bradbury and Eggleston	Introduction of autonomic failure as a clinical syndrome
Shy-Drager syndrome (SDS)	1960	Shy and Drager	Origin of this term as a neuropathologic entity with parkinsonism and autonomic failure with OH
Striatonigral degeneration (SND)	1960	Van der Eecken et al	Description of SND
Multiple system atrophy (MSA)	1969	Graham and Oppenheimer	Introduction of the term MSA, which represents SDS, SND, and OPCA as 1 entity
Glial cytoplasmic inclusions (GCIs)	1989	Papp et al, Matsuo et al	Discovery of GCIs as hallmark of MSA
Alpha-synuclein inclusion	1998	Spillantini et al, Wakabayashi et al	Alpha-synuclein immunostaining as a sensitive marker of MSA
MSA classification	1996-1999	Consensus Committee	Classification of MSA based on clinical domains and features and neuropathology
Unified MSA Rating Scale (UMSARS)	2003	European MSA Study Group	Unified MSA Rating Scale as a standard to define MSA symptoms^{[5, 6]}
Second consensus for MSA	2007	Consensus Committee	New definition of MSA with simplified criteria

Clinical Domain	Feature	Comment
Autonomic dysfunction	Severe orthostatic hypotension (OH) Asymptomatic Symptomatic	OH is defined as blood pressure fall by at least 30mm Hg systolic and 15mm Hg diastolic within 3 minutes of standing from a previous 3-minute interval in the recumbent position.**
Urogenital dysfunction	Urinary incontinence (UI) or incomplete bladder emptying	UI is defined as persistent, involuntary, partial or total bladder emptying. ED usually occurs before symptomatic OH.***
Urogenital dysfunction	Erectile dysfunction (ED) in men
Parkinsonian features (87% incidence *)	Bradykinesia (BK)	BK is slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions. PI not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction.
	Rigidity
	Postural instability (PI)
	Tremor - Postural, resting, or both
Cerebellar dysfunction (54% incidence *)	Gait ataxia (GA)	GA is a wide-based stance with steps of irregular length and direction. Sustained gaze-evoked nystagmus
	Ataxic dysarthria
	Limb ataxia
	Oculomotor dysfunction
Coritcospinal tract dysfunction	Extensor plantar response with hyperreflexia	Babinsky sign, Pyramidal sign
Incidence of clinical features recorded during the lifetimes of 203 patients (Gilman et al^[3]). OH caused by drugs, food, temperature, deconditioning, or diabetes are excluded. **ED does not count in the definition of onset of disease, because it is a general feature in older people.

Category	Additional Features
Possible MSA-P Possible MSA-C	Babinski sign with hyperreflexia Stridor
Possible MSA-P	Rapidly progressive parkinsonism Poor response to levodopa Postural instability within 3 years of motor onset Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction Dysphagia within 5 years of motor onset Atrophy on magnetic resonance imaging (MRI) of putamen, middle cerebellar peduncle, pons, or cerebellum Hypometabolism on 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) scanning in putamen, brainstem, or cerebellum
Possible MSA-C	Parkinsonism (bradykinesia and rigidity) Atrophy on MRI of the putamen, middle cerebellar peduncle, or pons Hypometabolism on FDG-PET in the putamen Presynaptic striatonigral dopaminergic denervation on single-photon emission computed tomography (SPECT) or PET scanning
*Modified from second consensus^[7]

Procedure	Nonsupporting Features
History taking	Symptomatic onset at < 30 years Onset after age 75 years Family history of ataxia or parkinsonism Systemic diseases or other identifiable causes for features listed in Table 2a Hallucinations unrelated to medication Dementia
Physical examination	Classic parkinsonian pill-rolling rest tremor Clinically significant neuropathy Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction, such as aphasia, alien limb syndrome, and parietal dysfunction
Laboratory study	Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2a White matter lesions suggesting multiple sclerosis

Category	Definition
Possible MSA	A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Parkinsonism or cerebellar syndrome At least 1 feature of autonomic or urogenital dysfunction At least 1 of the additional features from Table 2b
Probable MSA	A sporadic, progressive, adult (>30y) with onset disease* characterized by the following: Autonomic failure involving urinary dysfunction Poorly levodopa-responsive parkinsonism or cerebellar dysfunction
Definitive MSA	A sporadic, progressive, adult (>30y) with onset disease pathologically confirmed by presence of high density GCIs in association with degenerative changes in striatonigral and olivopontocerebellar pathways
*Disease onset is defined as the initial presentation of any parkinsonian or cerebellar motor problems or autonomic features (except erectile dysfunction).

Clinical Symptom	Pathologic Findings and Location of Damage or Cell Loss
Orthostatic hypotension	Primary preganglionic damage of intermediolateral cell columns
Urinary incontinence (not retention)	Preganglionic cell loss in spinal cord (intermediolateral cell columns), related to detrusor hyperreflexia caused mainly by loss of inhibitory input to pontine micturition center (rather than to external urethral sphincter denervation alone)
Urinary retention caused by detrusor atonia	Sacral intermediolateral cell columns
Cerebellar ataxia	Cell loss in inferior olives, pontine nuclei, and cerebellar cortex
Pyramidal signs	Pyramidal tract demyelination
Extensor plantar response	Pyramidal tract lesion
Hyperreflexia	Pyramidal tract lesion
Motor abnormalities	GCIs in cortical motor areas or basal ganglia
Akinesia	Putamen, globus pallidus
Rigidity	Putaminal (not nigral) damage
Limb and gait ataxia	Inferior olives, basis pontis
Decreased or absent levodopa responsiveness	Striatal cell loss, loss of D1 and D2 receptors in striatum or impaired functional coupling of D1 and D2 receptors
Nystagmus	Inferior olives, pontine nuclei
Dysarthria	Pontine nuclei
Laryngeal stridor	Severe cell loss in nucleus ambiguus or biochemical defect causing atrophy of posterior cricoarytenoid muscles
Excessive daytime sleepiness	Loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons^[15]
Adapted from Wenning et al and other sources.

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 a longer time; 50% develop levodopa-induced dyskinesia of orofacial and neck muscles	Good response
Effects on striatonigral transmission	Presynaptic and postsynaptic; dopaminergic cell bodies in substantia nigra and their terminals in striatum, as well as their striatal target cells, have reduced dopamine receptors	Presynaptic
Symmetry of movement disorder	Possibly asymmetrical	No data
Progression of symptoms	Rapid	Slow
Postural instability and falling**	Early Fast progression Worsen >20% of UPDRS scale**	Late Less progression (< 10%)
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 gasps, 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 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] scanning)	Decreased in putamen and caudate	Decreased in putamen with smaller decrease in caudate
Growth hormone release with intravenous (IV) injection of clonidine	No release; dysfunction of hypothalamic-pituitary pathway (alpha2-adrenoceptor-hypothalamic deficit)	Increase of growth hormone, intact function
^* A positive response to levodopa is defined as a significant improvement of motor features during 3 months’ application of escalating doses of levodopa with a peripheral decarboxylase inhibitor.^[7] ^ Postural instability as defined by item 30 of the Unified Parkinson's Disease Rating Scale (UPDRS) part III (motor examination).^[7] ^* Pakiam et al reported that patients with diffuse Lewy-body disease may present with parkinsonism and prominent autonomic dysfunction, fulfilling some proposed criteria for the striatonigral form of MSA.^[29]

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 >10-30 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 IV 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

	GCIs in MSA	Lewy Bodies in Parkinson Disease	Neurofibrillary Pathology in Alzheimer Disease	Glial Lesions in Corticobasal and Progressive Supranuclear Palsy
Shape	Sickle shaped 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 of phosphorylated tau
Localization	In oligodendroglial cells and neurons	In neuronal cells and oligodendroglial cells	No data	No data

Multiple System Atrophy Medication

Medication Summary

Antiparkinson Agents, COMT Inhibitors

Class Summary

Levodopa/Carbidopa (Sinemet, Parcopa)

Antiparkinson Agents, Dopamine Agonists

Class Summary

Bromocriptine (Parlodel, Cycloset)

Amantadine

Antiparkinson Agents, Anticholinergics

Class Summary

Trihexyphenidyl

Benztropine mesylate (Cogentin)

Urinary Antispasmodic Agents

Class Summary

Oxybutynin chloride (Ditropan XL, Gelnique, Oxytrol)

Tolterodine (Detrol, Detrol LA)

Propantheline

Prokinetic Agents

Class Summary

Erythromycin (E.E.S., Ery-Tab, Erythrocin)

Agents for Erectile Dysfunction

Class Summary

Yohimbine (Yohimex)

Corticosteroids

Class Summary

Fludrocortisone

Alpha1 Agonists

Class Summary

Midodrine

Alpha/Beta Adrenergic Agonists

Class Summary

Droxidopa (Northera)

Ephedrine

Hematopoietic Growth Factors

Class Summary

Epoetin alfa (Epogen, Procrit)

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Class Summary

Indomethacin (Indocin)

Antihistamines

Class Summary

Diphenhydramine (Benadryl, Diphenhist)

References

Tables

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