eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases
Multiple System Atrophy
Updated: Aug 27, 2007
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
Open table in new window
Table
| 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 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 one 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 Committees | Classification of MSA based on clinical domains and features and neuropathology |
| United MSA Rating Scaling (UMSARS) | 2003 | European MSA Study Group | United MSA Rating Scale as a standard to define MSA symptoms |
| 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 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 one 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 Committees | Classification of MSA based on clinical domains and features and neuropathology |
| United MSA Rating Scaling (UMSARS) | 2003 | European MSA Study Group | United MSA Rating Scale as a standard to define MSA symptoms |
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 MSAOpen table in new window
Table
| Clinical Domain, %* | Feature (Characteristic of the Disease) | Criterion (Defining Feature) |
| Autonomic and urinary dysfunction | Orthostatic hypotension with blood pressure falling by 20 mm Hg systolic and 10 mm Hg diastolic within 3 min of standing | Orthostatic hypotension with blood pressure falling by 30 mm Hg systolic and 15 mm Hg diastolic within 3 min of standing and/or u rinary incontinence as persistent, involuntary, partial or total bladder emptying, accompanied by erectile dysfunction in men |
| Urinary incontinence or incomplete bladder emptying | ||
| Parkinsonism (87% incidence) | Bradykinesia - Slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions | Bradykinesia plus at least 1 parkinsonian feature |
| Rigidity | ||
| Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction | ||
| Tremor - Postural, resting, or both | ||
| Cerebellar dysfunction (54% incidence) | Gait ataxia (wide-based stance with steps of irregular length and direction) | Gait ataxia plus at least 1 cerebellar feature |
| Ataxic dysarthria | ||
| Limb ataxia | ||
| Sustained gaze-evoked nystagmus | ||
| Corticospinal tract dysfunction (49% incidence) | Extensor plantar response with hyperreflexia (pyramidal sign) | Not used as criterion in defining diagnosis of MSA |
| Clinical Domain, %* | Feature (Characteristic of the Disease) | Criterion (Defining Feature) |
| Autonomic and urinary dysfunction | Orthostatic hypotension with blood pressure falling by 20 mm Hg systolic and 10 mm Hg diastolic within 3 min of standing | Orthostatic hypotension with blood pressure falling by 30 mm Hg systolic and 15 mm Hg diastolic within 3 min of standing and/or u rinary incontinence as persistent, involuntary, partial or total bladder emptying, accompanied by erectile dysfunction in men |
| Urinary incontinence or incomplete bladder emptying | ||
| Parkinsonism (87% incidence) | Bradykinesia - Slowness of voluntary movement with progressive reduction in speed and amplitude during repetitive actions | Bradykinesia plus at least 1 parkinsonian feature |
| Rigidity | ||
| Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction | ||
| Tremor - Postural, resting, or both | ||
| Cerebellar dysfunction (54% incidence) | Gait ataxia (wide-based stance with steps of irregular length and direction) | Gait ataxia plus at least 1 cerebellar feature |
| Ataxic dysarthria | ||
| Limb ataxia | ||
| Sustained gaze-evoked nystagmus | ||
| Corticospinal tract dysfunction (49% incidence) | Extensor plantar response with hyperreflexia (pyramidal sign) | Not used as criterion in defining 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
Open table in new window
Table
| Procedure | Findings |
| History taking | Symptomatic onset at <30 years Family history of similar disorder Systemic diseases or other identifiable causes for features listed in Table 2 Hallucinations unrelated to medication |
| Physical examination | Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction such as aphasia, alien limb syndrome, and parietal dysfunction (Diagnostic and Statistic Manual for Mental Disorders, Fourth Edition criteria for dementia) |
| Laboratory study | Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2 |
| Procedure | Findings |
| History taking | Symptomatic onset at <30 years Family history of similar disorder Systemic diseases or other identifiable causes for features listed in Table 2 Hallucinations unrelated to medication |
| Physical examination | Prominent slowing of vertical saccades or vertical supranuclear gaze palsy Evidence of focal cortical dysfunction such as aphasia, alien limb syndrome, and parietal dysfunction (Diagnostic and Statistic Manual for Mental Disorders, Fourth Edition criteria for dementia) |
| Laboratory study | Metabolic, molecular genetic, and imaging evidence of alternative cause of features listed in Table 2 |
Table 4. Diagnostic Categories of MSA*
Open table in new window
Table
| Category | Definition |
| Possible MSA | One criterion plus 2 features from separate other domains* When criterion is parkinsonism, a poor levodopa response qualifies as 1 feature (hence only 1 additional feature required) |
| Probable MSA | One criterion for autonomic failure and urinary dysfunction* plus p oorly levodopa-responsive parkinsonism or cerebellar dysfunction |
| Definitive MSA | Pathologically confirmed by presence of high density of GCIs in association with degenerative changes in nigrostriatal and olivopontocerebellar pathways |
| Category | Definition |
| Possible MSA | One criterion plus 2 features from separate other domains* When criterion is parkinsonism, a poor levodopa response qualifies as 1 feature (hence only 1 additional feature required) |
| Probable MSA | One criterion for autonomic failure and urinary dysfunction* plus p oorly levodopa-responsive parkinsonism or cerebellar dysfunction |
| Definitive MSA | Pathologically confirmed by presence of high density of GCIs in association with degenerative changes in nigrostriatal and olivopontocerebellar pathways |
*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 CorrelationsOpen table in new window
Table
| 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 ambiguous or biochemical defect causing atrophy of posterior cricoarytenoid muscles |
| 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 ambiguous or biochemical defect causing atrophy of posterior cricoarytenoid muscles |
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
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.
- Associated symptoms include the following:
- 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.
More on Multiple System Atrophy |
 Overview: Multiple System Atrophy |
| Differential Diagnoses & Workup: Multiple System Atrophy |
| Treatment & Medication: Multiple System Atrophy |
| Follow-up: Multiple System Atrophy |
| References |
| Next Page » |
References
Albanese A, Colosimo C, Lees AJ, Tonali P. The clinical diagnosis of multiple system atrophy presenting as pure parkinsonism. Adv Neurol. 1996;69:393-8. [Medline].
Anonymous. The definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. J Auton Nerv Syst. Apr 20 1996;58(1-2):123-4. [Medline].
Antonini A, Leenders KL, Vontobel P, et al. Complementary PET studies of striatal neuronal function in the differential diagnosis between multiple system atrophy and Parkinson''s disease. Brain. Dec 1997;120 ( Pt 12):2187-95. [Medline].
Bannister R, Oppenheimer DR. Degenerative diseases of the nervous system associated with autonomic failure. Brain. 1972;95(3):457-74. [Medline].
Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology. Feb 1997;48(2):384-93. [Medline].
Biaggioni I, Onrot J, Stewart CK, Robertson D. The potent pressor effect of phenylpropanolamine in patients with autonomic impairment. JAMA. Jul 10 1987;258(2):236-9. [Medline].
Biaggioni I, Robertson D, Krantz S, et al. The anemia of primary autonomic failure and its reversal with recombinant erythropoietin. Ann Intern Med. Aug 1 1994;121(3):181-6. [Medline].
Bradbury S, Eggleston C. Postural hypotension: a report of three cases. Am Heart J. 1925;1:73-85.
Burn DJ, Sawle GV, Brooks DJ. Differential diagnosis of Parkinson''s disease, multiple system atrophy, and Steele-Richardson-Olszewski syndrome: discriminant analysis of striatal 18F-dopa PET data. J Neurol Neurosurg Psychiatry. Mar 1994;57(3):278-84. [Medline].
Castellani R. Multiple system atrophy: clues from inclusions. Am J Pathol. Sep 1998;153(3):671-6. [Medline].
Chin SS, Goldman JE. Glial inclusions in CNS degenerative diseases. J Neuropathol Exp Neurol. May 1996;55(5):499-508. [Medline].
Chobanian AV, Volicer L, Tifft CP, et al. Mineralocorticoid-induced hypertension in patients with orthostatic hypotension. N Engl J Med. Jul 12 1979;301(2):68-73. [Medline].
Colosimo C, Tiple D, Wenning GK. Management of multiple system atrophy: state of the art. J Neural Transm. Dec 2005;112(12):1695-704. [Medline].
Daniel SE. The neuropathology and neurochemistry of multiple system atrophy. In: Bannister R, Mathias C, eds. Autonomic Failure: A Textbook of Clinical Disorders. 3rd ed. Oxford, England: Oxford University Press; 1992:564-85.
Davie CA, Wenning GK, Barker GJ, et al. Differentiation of multiple system atrophy from idiopathic Parkinson''s disease using proton magnetic resonance spectroscopy. Ann Neurol. Feb 1995;37(2):204-10. [Medline].
Diedrich A, Robertson D. Shy-Drager syndrome. In: Encyclopedia of the Neurological Science. San Diego, CA: Academic; 2003:264-70.
Duvoisin R. Progressive supranuclear palsy. In: Rowland LP, ed. Merritt's Textbook of Neurology. 8th ed. Baltimore, MD: Lippincott William & Wilkins; 1995:730-6.
Fahn S. Parkinsonism. In: Rowland LP, ed. Merritt's Textbook of Neurology. 8th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1995:713-30.
Fearnley JM, Lees AJ. Striatonigral degeneration: a clinicopathological study. Brain. Dec 1990;113 (pt 6):1823-42. [Medline].
Freeman R, Landsberg L, Young J. The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo- dihydroxyphenylserine: a randomized, placebo-controlled, crossover trial. Neurology. Dec 10 1999;53(9):2151-7. [Medline].
Geser F, Wenning GK. The diagnosis of multiple system atrophy. J Neurol. Aug 2006;253 Suppl 3:iii2-iii15. [Medline].
Geser F, Wenning GK, Seppi K. Progression of multiple system atrophy (MSA): a prospective natural history study by the European MSA Study Group (EMSA SG). Mov Disord. Feb 2006;21(2):179-86. [Medline].
Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. American Autonomic Society and American Academy of Neurology. Clin Auton Res. Dec 1998;8(6):359-62. [Medline].
Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Auton Nerv Syst. Dec 11 1998;74(2-3):189-92. [Medline].
Gilman S, Low PA, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. Feb 1 1999;163(1):94-8. [Medline].
Gilman S, Koeppe RA, Junck L, et al. Decreased striatal monoaminergic terminals in multiple system atrophy detected with positron emission tomography. Ann Neurol. Jun 1999;45(6):769-77. [Medline].
Goldberg MR, Robertson D, FitzGerald GA. Prostacyclin biosynthesis and platelet function in autonomic dysfunction. Neurology. Jan 1985;35(1):120-3. [Medline].
Goldstein DS, McRae A, Holmes C, Dalakas MC. Autoimmune autonomic failure in a patient with myeloma-associated Shy-Drager syndrome. Clin Auton Res. Feb 1996;6(1):17-21. [Medline].
Goldstein DS. Dysautonomia in Parkinson''s disease: neurocardiological abnormalities. Lancet Neurol. Nov 2003;2(11):669-76. [Medline].
Goldstein DS. Orthostatic hypotension.
Goodman LS, Gilman A. The pharmacological basis of therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996.
Hoeldtke RD, Streeten DH. Treatment of orthostatic hypotension with erythropoietin. N Engl J Med. Aug 26 1993;329(9):611-5. [Medline].
Hoeldtke RD, Israel BC. Treatment of orthostatic hypotension with octreotide. J Clin Endocrinol Metab. Jun 1989;68(6):1051-9. [Medline].
Horimoto Y, Aiba I, Yasuda T, et al. Cerebral atrophy in multiple system atrophy by MRI. J Neurol Sci. Feb 15 2000;173(2):109-12. [Medline].
Hughes AJ, Colosimo C, Kleedorfer B, et al. The dopaminergic response in multiple system atrophy. J Neurol Neurosurg Psychiatry. Nov 1992;55(11):1009-13. [Medline].
Jankovic J, Gilden JL, Hiner BC, et al. Neurogenic orthostatic hypotension: a double-blind, placebo-controlled study with midodrine. Am J Med. Jul 1993;95(1):38-48. [Medline].
Jordan J, Shannon JR, Black BK, et al. The pressor response to water drinking in humans : a sympathetic reflex?. Circulation. Feb 8 2000;101(5):504-9. [Medline].
Jordan J, Shannon JR, Diedrich A, et al. Mechanism of supine hypertension in autonomic failure [abstract]. Circulation. 1998;17:I-337.
Jordan J, Shannon JR, Black BK, et al. N(N)-nicotinic blockade as an acute human model of autonomic failure. Hypertension. May 1998;31(5):1178-84. [Medline].
Kaplan MR, Meyer-Franke A, Lambert S, et al. Induction of sodium channel clustering by oligodendrocytes. Nature. Apr 17 1997;386(6626):724-8. [Medline].
Kimber J, Mathias CJ, Lees AJ, et al. Physiological, pharmacological and neurohormonal assessment of autonomic function in progressive supranuclear palsy. Brain. Jul 2000;123 ( Pt 7):1422-30. [Medline].
Kimber JR, Watson L, Mathias CJ. Distinction of idiopathic Parkinson''s disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine. Lancet. Jun 28 1997;349(9069):1877-81. [Medline].
Klein C, Brown R, Wenning G, Quinn N. The "cold hands sign" in multiple system atrophy. Mov Disord. Jul 1997;12(4):514-8. [Medline].
Koeppen AH. Consensus statement on the diagnosis of multiple system atrophy. J Neurol Sci. Feb 1 1999;163(1):4-5. [Medline].
Konagaya M, Sakai M, Matsuoka Y, et al. [Patho-MR imaging study in the putaminal margin in multiple system atrophy]. No To Shinkei. Apr 1998;50(4):383-5. [Medline].
Köllensperger M, Stampfer-Kountchev M, Seppi K, Geser F, Frick C, Del Sorbo F. Progression of dysautonomia in multiple system atrophy: a prospective study of self-perceived impairment. Eur J Neurol. Jan 2007;14(1):66-72. [Medline].
Lahrmann H, Cortelli P, Hilz M. EFNS guidelines on the diagnosis and management of orthostatic hypotension. Eur J Neurol. Sep 2006;13(9):930-6. [Medline].
Matsuo A, Akiguchi I, Lee GC, et al. Myelin degeneration in multiple system atrophy detected by unique antibodies. Am J Pathol. Sep 1998;153(3):735-44. [Medline].
McTavish D, Goa KL. Midodrine. A review of its pharmacological properties and therapeutic use in orthostatic hypotension and secondary hypotensive disorders [published erratum appears in Drugs 1990 Feb;39(2):following Table of Contents]. Drugs. Nov 1989;38(5):757-77. [Medline].
Mitsky VP, Workman RJ, Nicholson WE, et al. A sensitive radioimmunoassay for fludrocortisone in human plasma. Steroids. Sep 1994;59(9):555-8. [Medline].
Munschauer FE, Loh L, Bannister R, Newsom-Davis J. Abnormal respiration and sudden death during sleep in multiple system atrophy with autonomic failure. Neurology. Apr 1990;40(4):677-9. [Medline].
Nee LE, Gomez MR, Dambrosia J, et al. Environmental-occupational risk factors and familial associations in multiple system atrophy: a preliminary investigation. Clin Auton Res. Mar 1991;1(1):9-13. [Medline].
Onrot J, Goldberg MR, Hollister AS, et al. Management of chronic orthostatic hypotension. Am J Med. Mar 1986;80(3):454-64. [Medline].
Onrot J. Pharmacological treatment of orthostatic hypotension. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. Luxembourg: Harwood Academic Publisher GmbH; 1995:419-435.
Onrot J, Goldberg MR, Biaggioni I, et al. Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for postprandial hypotension. N Engl J Med. Aug 29 1985;313(9):549-54. [Medline].
Onrot J, Goldberg MR, Biaggioni I, et al. Oral yohimbine in human autonomic failure. Neurology. Feb 1987;37(2):215-20. [Medline].
Otsuka M, Kuwabara Y, Ichiya Y, et al. Differentiating between multiple system atrophy and Parkinson''s disease by positron emission tomography with 18F-dopa and 18F-FDG. Ann Nucl Med. Aug 1997;11(3):251-7. [Medline].
Pakiam AS, Bergeron C, Lang AE. Diffuse Lewy body disease presenting as multiple system atrophy. Can J Neurol Sci. May 1999;26(2):127-31. [Medline].
Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the CNS of patients with multiple system atrophy (striatonigral degeneration, olivopontocerebellar atrophy and Shy-Drager syndrome). J Neurol Sci. Dec 1989;94(1-3):79-100. [Medline].
Perera R, Isola L, Kaufmann H. Effect of recombinant erythropoietin on anemia and orthostatic hypotension in primary autonomic failure. Clin Auton Res. Sep 1995;5(4):211-3. [Medline].
Quinn N. Multiple system atrophy--the nature of the beast. J Neurol Neurosurg Psychiatry. Jun 1989;Suppl:78-89. [Medline].
Reinhardt MJ, Jungling FD, Krause TM, Braune S. Scintigraphic differentiation between two forms of primary dysautonomia early after onset of autonomic dysfunction: value of cardiac and pulmonary iodine-123 MIBG uptake. Eur J Nucl Med. May 2000;27(5):595-600. [Medline].
Robertson D, Davis TL. Recent advances in the treatment of orthostatic hypotension. Neurology. Apr 1995;45(4 Suppl 5):S26-32. [Medline].
Robertson D, Goldberg MR, Tung CS, et al. Use of alpha 2 adrenoreceptor agonists and antagonists in the functional assessment of the sympathetic nervous system. J Clin Invest. Aug 1986;78(2):576-81. [Medline].
Rottach KG, Riley DE, DiScenna AO, et al. Dynamic properties of horizontal and vertical eye movements in parkinsonian syndromes. Ann Neurol. Mar 1996;39(3):368-77. [Medline].
Schatz IJ. The non-pharmacological management of autonomic dysfunction. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. London, England: Harwood Academic; 1995:407-18.
Schrag A, Good CD, Miszkiel K, et al. Differentiation of atypical parkinsonian syndromes with routine MRI. Neurology. Feb 8 2000;54(3):697-702. [Medline].
Shannon JR, Jordan J, Diedrich A, et al. Sympathetically mediated hypertension in autonomic failure. Circulation. Jun 13 2000;101(23):2710-5. [Medline].
Shannon JR, Jordan J, Black BK, et al. Uncoupling of the baroreflex by N(N)-cholinergic blockade in dissecting the components of cardiovascular regulation. Hypertension. Jul 1998;32(1):101-7. [Medline].
Sharabi Y, Eldadah B, Li ST. Neuropharmacologic distinction of neurogenic orthostatic hypotension syndromes. Clin Neuropharmacol. May-Jun 2006;29(3):97-105. [Medline].
Shibao C, Gamboa A, Diedrich A, Biaggioni I. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. Apr 2005;45(4):469-76. [Medline].
Shibao C, Gamboa A, Diedrich A. Management of hypertension in the setting of autonomic failure: a pathophysiological approach. Hypertension. Apr 2005;45(4):469-76. [Medline].
Shibao C, Gamboa A, Abraham R. Clonidine for the treatment of supine hypertension and pressure natriuresis in autonomic failure. Hypertension. Mar 2006;47(3):522-6. [Medline].
Spillantini MG, Crowther RA, Jakes R. Filamentous alpha-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies. Neurosci Lett. Jul 31 1998;251(3):205-8. [Medline].
Stacpoole PW, Robertson D. Combination H1 and H2 receptor antagonist therapy in diabetic autonomic neuropathy. South Med J. May 1982;75(5):634-5. [Medline].
Takamori M, Hirayama M, Kobayashi R. Altered venous capacitance as a cause of postprandial hypotension in multiple system atrophy. Clin Auton Res. Feb 2007;17(1):20-5. [Medline].
Testa D, Filippini G, Farinotti M, et al. Survival in multiple system atrophy: a study of prognostic factors in 59 cases. J Neurol. May 1996;243(5):401-4. [Medline].
Wakabayashi K, Yoshimoto M, Tsuji S. Alpha-synuclein immunoreactivity in glial cytoplasmic inclusions in multiple system atrophy. Neurosci Lett. Jun 19 1998;249(2-3):180-2. [Medline].
Wenning GK, Tison F, Ben Shlomo Y, et al. Multiple system atrophy: a review of 203 pathologically proven cases. Mov Disord. Mar 1997;12(2):133-47. [Medline].
Wenning GK, Quinn NP. Parkinsonism. Multiple system atrophy. Baillieres Clin Neurol. Apr 1997;6(1):187-204. [Medline].
Wenning GK, Ben Shlomo Y, Magalhaes M, et al. Clinical features and natural history of multiple system atrophy. An analysis of 100 cases. Brain. Aug 1994;117 ( Pt 4):835-45. [Medline].
Wenning GK, Ben-Shlomo Y, Magalhaes M, et al. Clinicopathological study of 35 cases of multiple system atrophy. J Neurol Neurosurg Psychiatry. Feb 1995;58(2):160-6. [Medline].
Wenning GK, Ben-Shlomo Y, Hughes A, et al. What clinical features are most useful to distinguish definite multiple system atrophy from Parkinson''s disease?. J Neurol Neurosurg Psychiatry. Apr 2000;68(4):434-40. [Medline].
Wenning GK, Jellinger KA. The role of alpha-synuclein in the pathogenesis of multiple system atrophy. Acta Neuropathol. 2005;109:129-40. [Medline].
Wenning GK, Colosimo C, Geser F, Poewe W. Multiple System Atrophy. Lancet Neurol. 2004;3:93-103. [Medline].
Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord. Dec 2004;19(12):1391-402. [Medline].
Wenning GK, Geser F, Poewe W. Therapeutic strategies in multiple system atrophy. Mov Disord. Aug 2005;20 Suppl 12:S67-76. [Medline].
Wieling W. Nonpharmacological management of autonomic disorders. In: Robertson D, Low PA, Polinsky RJ, eds. Primer of the Autonomic Nervous System. San Diego, CA: Academic; 1996:319-24.
Further Reading
Keywords
MSA, multiple-system atrophy, multisystem atrophy, Shy-Drager syndrome, striatonigral degeneration, MSA-P, sporadic olivopontocerebellar atrophy, MSA-C
