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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

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

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