Multiple system atrophy
By
Lawrence I Golbe
Disclosures:
Dr. Golbe has no relevant financial relationships to disclose.
Last reviewed
April 20, 2007
ICD codes
ICD-9:
Other degenerative diseases of the basal ganglia: 333.0
ICD-10:
Other specified degenerative diseases of basal ganglia: G23.8
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 Déjerine and Thomas (Dejerine and Thomas 1900). The dysautonomia-predominant type was described much later (Shy and Drager 1960), as was the parkinsonism-predominant variety, striatonigral degeneration (van der Eecken et al 1960; Adams et al 1964; Adams and Salam-Adams 1986). No less historic a contribution was the recent observation that all varieties of multiple system atrophy share a specific glial cytoplasmic inclusion (Papp et al 1989) and that these inclusions are principally composed of alpha-synuclein (Gai et al 1998; Dickson et al 1999).
The term "olivopontocerebellar atrophy" has also been applied to part of the spectrum of the hereditary spinocerebellar degenerations. Modern understanding of these disorders and multiple system atrophy as separate entities suggests that the term "olivopontocerebellar atrophy" should be abandoned as a formal disease name (Harding 1987). The term olivopontocerebellar atrophy, however, may still be appropriate for disorders that do not fit the nosology of multiple system atrophy, such as some sporadic or autosomal dominant ataxias and other disorders such as certain hereditary, metabolic, or degenerative disorders with pathological features of olivopontocerebellar atrophy (Berciano et al 2006). This review uses the nosology "multiple system atrophy, olivopontocerebellar atrophy type;" "multiple system atrophy, dysautonomic type;" and "multiple system atrophy, striatonigral degeneration type."
Parkinsonism (rigidity, bradykinesia, and postural instability) occurs in at least 90% of all 3 types of multiple system atrophy (Wenning et al 1994). Unlike Parkinson disease, however, multiple system atrophy rarely receives sustained benefit from levodopa and exhibits rest tremor in fewer than 10% of cases (compared with 60% to 70% in Parkinson disease). The progression of parkinsonian motor features of multiple system atrophy, as measured by the motor score (Part III) of the Unified Parkinson's Disability Rating Scale, averages 28% per year, whereas untreated early Parkinson disease progresses less than 4% per year (Seppi 2005).
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 (Wenning et al 1994).
Rapid eye movement behavioral disorder occurs in 69% of patients by history and in 90% of patients by polysomnography (Plazzi et al 1997). The condition occurs earlier and more intensely than in Parkinson disease (Iranzo et al 2005) and its violent, even aggressive motor outbursts can injure the patient or bed partner.
Even more dangerous is obstructive sleep apnea, which occurs in the later stages in a majority of patients with dysautonomic multiple system atrophy and may produce sudden death (Munschauer et al 1990). It may be related either to central alveolar hypoventilation caused by loss of brainstem ventilatory drive centers or to obstructive sleep apnea caused by laryngeal dystonia (Vetrugno et al 2007) producing upper airway obstruction (Iranzo 2005).
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 (Okuma 2005), large-amplitude myoclonus, respiratory stridor, polyneuropathy, amyotrophy, distal cyanosis, and Raynaud phenomenon. Dementia and pain occur no more commonly than in Parkinson disease (Quinn et al 1989; Tison et al 1996). There is often a mild normocytic/normochromic anemia that may be caused by loss of sympathetic stimulation of renal erythropoietin production (Winkler et al 2001).
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, constipation, and impotence. Bladder emptying function may also be severely impaired. This usually starts with urgency, but later in the course of many cases simulates prostatic enlargement in men and stress incontinence in women (Beck et al 1994).
No information was provided by the author.
One study has shown an association of multiple system atrophy with various exogenous exposures such as solvents, pesticides, metals, and components of plastics (Vanacore et al 2001). Another showed an association with farming experience (Vanacore et al 2005). There appears to be an inverse association with smoking, as occurs in Parkinson disease, that is independent of the farming association (Vanacore et al 2000; 2005). A greater than expected exposure of patients to occupational toxins and frequent occurrence of minor dysautonomic symptoms in their relatives suggest that multiple system atrophy may be caused by a hereditary predisposition to an exogenous chemical toxicant (Nee et al 1991). Fewer than 1% of patients have a family history of progressive supranuclear palsy (Soma et al 2006). A hint of a specific genetic factor is the unconfirmed association of multiple system atrophy with a specific allele in the genes for interleukin 1-beta (Nishimura et al 2002) and alpha-1-antichymotripsin (Furiya et al 2005). No mutations have been found in LRRK2, the gene presently considered to be the most commonly mutated in Parkinson disease (Tan et al 2006).
There is loss of neurons and gliosis most prominently in the substantia nigra, caudate, and putamen; cerebellar cortex; pyramidal tract; Edinger-Westphal nucleus; locus ceruleus; inferior olives; dorsal motor nucleus of the vagus; intermediolateral cell column of the spinal cord; and Onuf nucleus. Reduced dopamine or norepinephrine levels occur in the nigra, nucleus accumbens, septum, hypothalamus, and locus ceruleus. The tremendous variability of emphasis of the anatomical and biochemical damage accounts for the clinical variability of multiple system atrophy.
In multiple system atrophy with dysautonomia, central control of sympathetic function is defective, whereas in progressive autonomic failure the defect occurs in the peripheral sympathetic neurons.
The pathognomonic oligodendroglial inclusions of multiple system atrophy, like the Lewy bodies of neurons in Parkinson disease, stain heavily for alpha-synuclein (Gai et al 1998). Their distribution relative to that of the neuronal pathology suggests that the glial defect may be the primary event in multiple system atrophy (Papp and Lantos 1994). Regardless of the initial cell locus, abnormal alpha-synuclein liberated by cell death appears to be taken up by nearby cells to perpetuate the degenerative process (Wenning and Jellinger 2005). The subcellular events leading to cell loss are not known, but an important clue is the observation that alpha-synuclein aggregates impair the function of the proteasome (Lindersson et al 2004).
Transgenic mouse models in which alpha-synuclein is overexpressed in oligodendroglia, forming aggregates and causing neuronal loss, have recently been reported (Shults et al 2005; Stefanova et al 2005; Yazawa et al 2005) .
At 1 large referral center, 100 patients with multiple system atrophy reported a median onset age of 53 years (range 33 to 76 years) (Wenning et al 1994). In Jellinger's unpublished series of 600 autopsied brains from patients with parkinsonian disorders, multiple system atrophy occurred in 5.1% (Quinn et al 1989). The sexes appear to be affected equally. The incidence in the 50- to 99-year age group has been measured at 3.0 new cases per 100,000 person-years (Bower et al 1997), and the prevalence in a medically-based series in London was 4.4 per 100,000 population (Schrag et al 1999), about 3% of that of Parkinson disease. The annual incidence of new cases is about 0.6 per 100,000 population (Vanacore et al 2001). Multiple system atrophy of the cerebellar type comprises 29% of the cases of sporadic, adult-onset ataxia (Abele et al 2002).
Also see the clinical summary: Epidemiology of movement disorders.
Not applicable.
Cases of Parkinson disease without the typical rest tremor are typically difficult to distinguish during life from multiple system atrophy, striatonigral degeneration type. The latter usually enjoys less or briefer relief from levodopa, progresses more rapidly, features earlier postural instability ("wheelchair sign"), and is more often symmetric. Cerebellar or pyramidal signs not explained by an anatomic lesion on MRI in a parkinsonian patient should direct suspicion from Parkinson disease toward multiple system atrophy. Dysautonomia disproportionate to the parkinsonism or severe autonomic side effects of levodopa (nausea, dizziness) in the mildly affected parkinsonian patient should do the same (Quinn and Wenning 1996). Symptomatic orthostatic hypotension occurred in the first year of illness in 76% of patients with multiple system atrophy and in much lower fractions in those with other parkinsonian disorders (Wenning et al 1999).
Progressive supranuclear palsy shares many features with multiple system atrophy, but dysautonomia is virtually never important in progressive supranuclear palsy. Multiple system atrophy may have supranuclear gaze abnormalities, but they are more often horizontal rather than vertical. Also, the saccades in multiple system atrophy are not slowed as in progressive supranuclear palsy (Rottach et al 1996). Startle responses are usually hypoactive in progressive supranuclear palsy but hyperactive in multiple system atrophy (Kofler et al 2003).
Corticobasal degeneration may be confused with multiple system atrophy, but the former is highly asymmetric and always shows important apraxia and cortical sensory loss. The multiple system atrophy with a predominance of dysautonomia may be confused with progressive autonomic failure. However, the dysautonomic features in multiple system atrophy typically start with bladder and erectile dysfunction, proceeding to thermoregulatory difficulty and orthostatic hypotension, and finally to ventilatory dysrhythmias. Progressive autonomic failure, on the other hand, begins with thermoregulatory and blood pressure dysregulation, bladder dysfunction occurs last, and ventilatory arrhythmias do not occur (Mabuchi 2005).
In a large series of patients carrying a diagnosis of multiple system atrophy of the cerebellar type, 4% (3 of 76 patients) had a permutation in the FMR1 gene, suggesting that fragile-X-associated tremor-ataxia syndrome must be considered in the differential diagnosis (Kamm et al 2005).
Multi-infarct states may mimic multiple system atrophy and many other degenerative disorders, but are usually identified by vascular lesions on MRI scan, arteriosclerotic risk factors, and a history of step-wise progression.
MRI will help rule out a multi-infarct state or normal-pressure hydrocephalus as a cause of dopa-unresponsive parkinsonism and will also rule out an anatomical lesion of the cerebellum. Cerebellar and brainstem atrophy on MRI or CT are highly variable in multiple system atrophy, olivopontocerebellar atrophy type.
Two moderately specific MRI features of multiple system atrophy are signal on T2 or FLAIR in the lateral putamen (indicating iron deposition) and a high-T2 "slit" at the posterolateral border of the putamen (indicating gliosis) (Konagaya et al 1994). These are especially common in the striatonigral degeneration type (Macia et al 2001). The combination of the 2 findings provides a 97% sensitivity for multiple system atrophy (von Lewinski et al 2007). Another characteristic, but not very specific, MRI finding is the “hot cross bun” sign, present on MRI in 63% of patients with multiple system atrophy (Watanabe et al 2002).
Diffusion-weighted imaging shows an elevated striatal apparent diffusion coefficient relative to Parkinson disease in initial studies (Seppi et al 2005). However, the diagnostic value of these findings has not been convincingly demonstrated in early or diagnostically equivocal cases but is reported to have good sensitivity and excellent specificity in clinically diagnosed cases (Schrag et al 1998; Kraft et al 1999; Seppi et al 2005). Diffusion-weighted imaging also shows abnormal signal in the middle cerebellar peduncle in multiple system atrophy of the cerebellar type but not in progressive supranuclear palsy or Parkinson disease (Nicoletti et al 2006; Paviour et al 2007).
Diagnostic tests other than MRI remain largely investigational.
Positron emission tomography may be a more sensitive, but less practical, means of distinguishing multiple system atrophy from Parkinson disease or other conditions. 18-F-dopa imaging of dopaminergic presynaptic terminal function shows decreased activity only in the posterior putamen in Parkinson disease, but in most of the caudate and putamen in multiple system atrophy (Brooks et al 1990). 11-C-raclopride imaging of D2 receptors shows only a 10% decrease in multiple system atrophy and normal results in Parkinson disease (Brooks et al 1992). Its utility in discriminating these 2 conditions is unproved but may be enhanced by concomitant imaging with 18-F fluorodeoxyglucose (Antonini et al 1997).
SPECT imaging using the dopamine reuptake binding ligand beta-CIT has corroborated the 18-F-dopa PET results (Brucke et al 1997) and may become more readily available as a clinical tool. Similar results are reported for SPECT using the D2 receptor ligand [(123)I]iodo-benzoaminde (Seppi et al 2005).
Perfusion studies using SPECT to differentiate multiple system atrophy from Parkinson disease show small differences in means, but the wide overlap degrades the clinical utility of this procedure (Matsui et al 2005).
Nerve conduction and EMG studies may show subclinical polyneuropathy in multiple system atrophy. External urethral sphincter EMG shows denervation in almost all patients with multiple system atrophy (Paviour et al 2005), but not in Parkinson disease or in other cerebellar degenerations (Kirby et al 1986; Wenning et al 1997). The ability of this procedure to distinguish multiple system atrophy from Parkinson disease has, however, been disputed (Giladi et al 2000) and false positives arise from many nonneurologic causes of sphincter denervation such as multiparity or pelvic surgery.
Transcranial ultrasound, a modality requiring careful training but no equipment beyond that available at any medical center, has been reported to differentiate Parkinson disease, where the substantia nigra gives a hyperechogenic signal, from multiple system atrophy, where that signal is normal but the lentiform nucleus may be hyperechogenic (Behnke 2005).
In multiple system atrophy, dysautonomia is the result of central neuronal loss, therefore, the resting supine norepinephrine level is normal or slightly elevated. In pure autonomic failure or Parkinson disease, where dysautonomia arises from postsynaptic sympathetic neuronal loss, the levels are decreased. In neither case does the level show its normal increase on standing (Polinsky 1993).
Another neuron-endocrinologic test, an elevation in growth hormone after a dose of arginine, shows poor responsivity in multiple system atrophy but not in Parkinson disease or controls, with a positive predictive value for multiple system atrophy in 1 study of 97% (Pellecchia et al 2006).
A set of diagnostic criteria proposed by Quinn (Quinn 1989) was modified and operationalized by a Consensus Conference (Gilman et al 1999) but its validity has not yet been adequately demonstrated prospectively (Litvan et al 2003). It delineates 4 “domains”: autonomic/urinary dysfunction, parkinsonism, cerebellar dysfunction, and corticospinal dysfunction. “Possible multiple system atrophy” requires 1 of these plus 2 features from other domains. “Probable multiple system atrophy” requires autonomic dysfunction plus either parkinsonism that is poorly responsive to levodopa or cerebellar dysfunction. For both “possible” and “probable” diagnoses, there must be absence of onset before age 30, positive family history, hallucinations unrelated to medication, dementia, vertical supranuclear gaze dysfunction, focal cortical dysfunction, and clinical or radiographic evidence for alternative diagnoses.
A validated disability rating scale is now available (Wenning et al 2004).
As a heterogeneous group, autopsy-proven cases of multiple system atrophy survived a mean of 8.0 years in an autopsy series (Hughes et al 1992). A meta-analysis of 433 cases gave a mean survival of only 6.2 years (Ben-Shlomo et al 1997), with no difference between the parkinsonian type and cerebellar type. In 1 recent, large series, median intervals from onset to the need for gait assistance was 3 years, to wheelchair confinement 5 years, to a bedbound state 8 years, and to death 9 years (Watanabe et al 2002). In the final stage, all 3 variants will produce a rigid, bradykinetic state leading eventually to a bed-bound existence with aphagia and its complications. Some patients with Shy-Drager syndrome are confined to bed long before this stage by orthostatic hypotension and this form of multiple system atrophy confers the worst prognosis in terms of time to disability milestones and death (Tada et al 2007). Levodopa may induce disabling confusion and psychosis and may cause dyskinesias without concomitant motor benefit (Hughes et al 1992). Sudden death is over 7 times as common in patients with dysautonomic predominance than in other forms of multiple system atrophy (Tada et al 2007).
Levodopa may provide a few years' benefit for the rigidity, bradykinesia, and postural instability, but is effective in only about half of cases and rarely more than moderately so (Hughes et al 1992; Parati et al 1993). Treatment may be initiated with carbidopa/levodopa 25/100 0.5 to 1 tablet twice a day and increased every few days to efficacy or toxicity. Patients with multiple system atrophy may require and tolerate far larger dosages than do patients with Parkinson disease, but because some are sensitive to dopaminergic side effects, particularly nausea and dyskinesias, treatment should begin conservatively. Ancillary antiparkinson agents have not added importantly to the efficacy of levodopa, but adequate studies are lacking.
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 has been found to ameliorate otherwise intractable hypotension in multiple system atrophy (Deguchi et al 2007).
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 (Jankovic et al 1993). Treatment starts with 2.5 mg 3 times a day increasing to 10 mg 3 times a day. Supine hypertension is an uncommon but important adverse effect that may be lessened by raising the head of the bed. If these drugs are unsuccessful, inhibition of vasodilator prostaglandin synthesis may be initiated with indomethacin 25 mg 3 times a day with meals increasing to 50 mg 3 times a day. Alternatives include the alpha-adrenergic agonist clonidine 0.1 mg twice a day increasing to 0.3 mg twice a day, and the peripheral vasoconstrictors ephedrine starting at 25 mg 3 times a day and propranolol starting at 20 mg twice a day.
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 (Singer et al 2006).
Urinary frequency or incontinence may respond to a peripherally acting anticholinergic agent such as oxybutynin 5 to 10 mg at bedtime, tolterodine 2 mg at bedtime, or propantheline 15 to 30 mg at bedtime, if the pathophysiology is detrusor hyperreflexia. However, anticholinergic treatment may worsen the constipation of multiple system atrophy. The impotence of multiple system atrophy may respond to yohimbine 5.6 mg 1 to 3 times daily (Robertson and Davis 1995). Sildenafil, although efficacious, often exacerbates the orthostatic hypotension of multiple system atrophy (Hussain et al 2001).
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.
Rapid eye movement behavioral disorder usually responds well to clonazepam 0.5 mg at bedtime. Sleep apnea caused by upper airway obstruction with daytime stridor is best managed with tracheostomy. For nocturnal stridor, continuous positive airway pressure, if accepted by the patient, has the virtues of being noninvasive and more efficacious and should be tried before tracheostomy (Iranzo 2005).
There is no known treatment for the ataxia of multiple system atrophy, olivopontocerebellar atrophy type.
No information was provided by the author.
Patients with any form of parkinsonism should avoid neuroleptic tranquilizers. Hypotension may be aggravated by opiates or other sedatives. The dysphagia of some patients with multiple system atrophy dictates careful postoperative airway management.
Obstructive sleep apnea
Rapid eye movement behavioral disorder
Advanced Parkinson disease
Epidemiology of movement disorders
Myoclonus
Neurochemical and functional imaging of movement disorders
Obstructive sleep apnea
Parkinson disease
Rapid eye movement sleep behavior disorder
Sleep disorders associated with parkinsonism
Parkinson disease
progressive supranuclear palsy
corticobasal degeneration
progressive autonomic failure
fragile-X-associated tremor-ataxia syndrome
multi-infarct states
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.