Former author(s)
Lawrence I Golbe MD
Publication dates
Originally released October 4, 1993; last updated June 7, 2010; expires June 7, 2013
Synonyms
Shy-Drager syndrome
Historical note and nomenclature
Like many heterogeneous disorders, multiple system atrophy was described piecemeal over a period of decades and engenders nosologic controversy. The sporadic form of "olivopontocerebellar atrophy," a term often applied to the cerebellar-predominant variety of multiple system atrophy, was first described by Dejerine and Thomas
The current classification scheme based on the first consensus statement on the diagnosis of multiple system atrophy divides the disorder into a parkinsonian type (

Parkinsonism (
Autonomic insufficiency is a more prominent part of most cases of multiple system atrophy than of Parkinson disease. Cerebellar features are early and important in many patients and predominate in some. Parkinsonism predominates in others. Because there is considerable pathologic and clinical overlap among the 3 varieties of multiple system atrophy, there is no need for formal criteria differentiating them. A few patients with multiple system atrophy have isolated dysautonomia, cerebellar dysfunction, or parkinsonism
Rapid eye movement behavioral disorder occurs in 69% of patients by history and in 90% of patients by polysomnography
Even more dangerous is
Less frequent or severe features of multiple system atrophy include emotional lability, pyramidal signs, contractures, a tendency to lean laterally while seated (the “Pisa syndrome”), supranuclear ophthalmoplegia, antecollis, an irregular or jerky myoclonic action tremor that is of cortical origin
Most prominent among the dysautonomic findings is orthostatic hypotension, but other important defects are postprandial hypotension, supine hypertension, anhidrosis with thermoregulatory disturbance, poor lacrimation and salivation,
Olfactory function remains preserved in multiple system atrophy as tested via the University of Pennsylvania Smell Identification Test (UPSIT)
Gastrointestinal symptoms, pain, urinary problems, and postural instability due to orthostatic hypotension are reported more frequently in multiple system atrophy than in Parkinson disease,

A 57-year-old right-handed bookkeeper, on disability, complained of a 6-year history of
On physical examination, there was mild saccadic pursuit with saccadic hypometria. Gait was both broad-based and shuffling. There was mild dysmetria on finger-to-nose testing, which was worse on the left side. The patient also had

One study has shown an association of multiple system atrophy with various exogenous exposures such as solvents, pesticides, metals, and components of plastics
Fewer than 1% of patients have a family history of

Pathogenesis and pathophysiology
The hallmark of multiple system atrophy pathology is the presence of glial cytoplasmic inclusions
Glial cytoplasmic inclusions include hyperphosphorylated alpha-synuclein, ubiquitin, LRRK2, as well as other proteins
Dysfunction of the ubiquitin proteasome system has been reported in multiple system atrophy
In MSA-P, there is cell type-specific neuronal loss, with calcineurin-positive medium spiny neurons depleted in the posterior
Lewy body pathology has been found in submandibular glands of
A rare association of multiple system atrophy with
Transcranial magnetic stimulation with triple stimulation technique detects corticospinal tract involvement in multiple system atrophy
High levels of
Neuronal cell loss has been reported in the Onufrowicz nucleus and the intermediolateral cell column, as well as a portion of the intermediate reticular formation, dorsal motor nucleus of vagus, nucleus ambiguus, caudal raphe nucleus, arcuate nucleus, pontine micturition center, and locus ceruleus
Growth hormone release in response to arginine is impaired in multiple system atrophy, but not in Parkinson disease
In a study, multiple system atrophy patients were found to have pupillary sympathetic dysfunction from an early stage, whereas in Parkinson disease patients, it tended to gradually accelerate at a more advanced stage of the disease
Blunted heart rate
In an electromyography study, the mean duration of motor unit potentials recorded from the external anal sphincter was significantly longer in patients with multiple system atrophy and progressive supranuclear palsy compared with motor unit potentials recorded from patients with Parkinson disease (P < 0.005 for both)
Chronic orthostatic hypotension in multiple system atrophy patients leads to structural remodeling of veins and reduced venous compliance, which actually serves to counteract excessive venous pooling in the lower extremities

At a large referral center, 100 patients with multiple system atrophy reported a median age at onset of 53 years (range 33 to 76 years)
Also see the clinical summary:

Not applicable.

Clinical and imaging findings of sporadic adult-onset
Spinocerebellar ataxia type 2 may present with a parkinsonian or cerebellar phenotype and should be considered in the differential diagnosis, especially if an autosomal dominant inheritance pattern is established
“Red flags” with greater than 95% specificity for MSA-P as opposed to
The presence of excessive square-wave jerks, mild to moderate hypometria of
Differentiation of MSA-P from the subset of Parkinson disease patients with prominent autonomic failure is a profound diagnostic challenge. In a prospective study of multiple system atrophy and Parkinson disease patients, scores on self-report questionnaires of
Although progressive supranuclear palsy parkinsonism (
Corticobasal degeneration may be confused with multiple system atrophy, but the former is highly asymmetric and always shows important
In a large series of patients carrying a diagnosis of multiple system atrophy of the cerebellar type, 4% (3 of 76 patients) had a mutation in the
Multi-infarct states may mimic multiple system atrophy and many other degenerative disorders but are usually identified by vascular lesions on

MRI will help rule out a multi-infarct state or
The “hot cross bun” sign is a hyperintensity in the pons on T2
Putaminal atrophy can differentiate multiple system atrophy from
“Pointers” raising the possibility of multiple system atrophy also include hyperintensity of the middle cerebellar peduncle, pons, and cerebellum
Hypometabolism on fluorodeoxyglucose positron emission tomography (
Voxel-based morphometry as well as tractography are not appropriate for the diagnostic workup of individual patients, but they offer important research insights
Nerve conduction and
A set of diagnostic criteria proposed by Quinn
A validated disability rating scale is available
Table 1. Multiple System Atrophy Diagnostic Criteria
| Definite multiple system atrophy | Requires neuropathologic finding of widespread and abundant central nervous system glial cytoplasmic inclusions that are positive for alpha-synuclein, in association with neurodegeneration in striatonigral or olivopontocerebellar structures.
|
| Probable multiple system atrophy | A sporadic, progressive adult-onset (after age 30) disease characterized by autonomic failure involving urinary incontinence plus erectile dysfunction in males, or an orthostatic decrease of blood pressure within 3 minutes of standing by at least 30 mmHg systolic or 15 mmHg diastolic, and • poorly levodopa-responsive parkinsonism ( or • a cerebellar syndrome (gait ataxia with cerebellar
|
| Possible multiple system atrophy | A sporadic, progressive adult-onset (after age 30) disease characterized by parkinsonism or a cerebellar syndrome and • at least 1 feature suggesting autonomic dysfunction otherwise unexplained urinary urgency, frequency, or incomplete bladder emptying; erectile dysfunction in males; or significant orthostatic hypotension decline that does not meet the level requirements in probable multiple system atrophy, and • at least 1 additional feature from Table 2. |
Table 2. Additional Diagnostic Criteria for Possible Multiple System Atrophy
| Possible MSA-P or MSA-C | • Babinski sign with hyperreflexia • Stridor
|
| Possible MSA-P | • Rapidly progressive parkinsonism • Poor response to • Postural instability within 3 years of motor onset • Gait ataxia with cerebellar • Dysphagia within 5 years of motor onset • Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum • Hypometabolism on FDG-PET in putamen, brainstem, or cerebellum
|
| Possible MSA-C | • Parkinsonism • Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum • Hypometabolism on FDG-PET in putamen • Presynaptic nigrostriatal dopaminergic denervation in SPECT or PET |

As a heterogeneous group, autopsy-proven cases of multiple system atrophy survived a mean of 8.0 years in an autopsy series

Available treatments are primarily symptomatic
Treatment of symptomatic orthostatic hypotension starts with sodium and volume repletion, unless the patient is at risk of congestive heart failure or renal insufficiency. Patients with multiple system atrophy and dysautonomia should be informed that the frequent recommendation to minimize dietary sodium does not necessarily apply to them. Drinking 350 mL of tap water once daily in the early morning demonstrated a benefit in treating orthostatic hypotension in a group of multiple system atrophy patients without any adverse effects
Ancillary measures such as pressure stockings to increase central venous volume and elevating the head of the bed 6 inches to increase renin secretion may also be attempted, but often prove uncomfortable. It is also useful to avoid extreme heat with its reflex peripheral vasodilation and to avoid overeating and straining at stool, which increase vagal activity.
The mineralocorticoid fludrocortisone may be started at 0.1 mg daily and increased to a maximum of 4 tablets per day in 2 divided doses, given with fluid repletion. Midodrine, an alpha-adrenergic agonist, is a good alternative
Pyridostigmine has recently been found to ameliorate the hypotension of multiple system atrophy without causing supine hypertension, at least after a single 60 mg dose
Urinary frequency or incontinence may respond to a peripherally acting anticholinergic agent such as
The hallucinations caused by dopaminergic therapeutic agents usually respond to clozapine 6.25 to 50 mg or quetiapine 25 to 75 mg at bedtime. These must be used cautiously in patients with hypotension. All patients receiving clozapine must be monitored for agranulocytosis with weekly white blood cell counts.
There is no known treatment for the
Rapid eye movement behavior disorder usually responds well to clonazepam 0.5 mg at bedtime. Patients with multiple system atrophy have a higher risk of
Laryngoscopy under anesthesia may be useful for evaluating upper airway obstruction in multiple system atrophy
Deep brain stimulation of the internal pallidum remains ineffective for multiple system atrophy and may even be harmful
Nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to inhibit the formation of alpha-synuclein fibrils, which are involved in the pathogenesis of multiple system atrophy, and could serve as a potential drug development target for multiple system atrophy treatment

No information was provided by the author.

Patients with any form of parkinsonism should avoid

ICD-9:
Other degenerative diseases of the basal ganglia: 333.0
ICD-10:
Other specified degenerative diseases of basal ganglia: G23.8

Rapid eye movement behavioral disorder


fragile-X-associated tremor-
multi-infarct states
spinocerebellar ataxia

For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.
Age
19-44 years
45-64 years
65+ years
Population
None selectively affected.
Occupation
None selectively affected.
Sex
male=female
Family history
None
Heredity
None

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**References especially recommended by the author or editor for general reading.
