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Multiple system atrophy: Prognosis and treatment

Multiple system atrophy: Prognosis and treatment
Authors:
Stewart A Factor, DO
Christine Doss Esper, MD
Section Editor:
Howard I Hurtig, MD
Deputy Editor:
April F Eichler, MD, MPH
Literature review current through: Feb 2022. | This topic last updated: Feb 17, 2022.

INTRODUCTION — Multiple system atrophy (MSA) is a unifying term that brings together a group of rare, fatal neurodegenerative syndromes that used to be referred to as olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager syndrome. They have similar pathology and are characterized by various degrees of autonomic dysfunction, cerebellar abnormalities, parkinsonism, and corticospinal degeneration.

This topic will review the prognosis and management of MSA. Other clinical aspects of MSA are reviewed separately. (See "Multiple system atrophy: Clinical features and diagnosis".)

PROGNOSIS — Disease progression in MSA usually occurs over 1 to 18 years, and is often faster than that of idiopathic Parkinson disease [1].

In mainly retrospective studies, the median times from disease onset to disability milestones in MSA were as follows:

Development of autonomic dysfunction, 2.5 years [2]

Need for walking aid, 3 years [3]

Wheelchair confinement, 3.5 to 5 years [2,3]

Bedridden state, 5 to 8 years [2,3]

The median time from MSA onset to death is 6 to 10 years [2-9]. However, survival is quite variable, and some patients with MSA live for 15 years or more after symptom onset [7,10,11]. In particular, patients with a disease onset before age 40 years, also known as young-onset MSA, may have a longer survival than typically reported for MSA more generally [12].

In various studies, risk factors for shorter survival include the following [2,3,5,7,8,11,13-18]:

A diagnosis of the parkinsonian variant of MSA (MSA-P)

Incomplete bladder emptying

Older age at disease onset

Early or severe autonomic failure

Early stridor onset (eg, within three years from motor or autonomic symptom onset)

Female sex

A short time from disease onset to the first clinical milestone of disability (frequent falling, cognitive disability, unintelligible speech, severe dysphagia, wheelchair dependence, urinary catheter use)

MANAGEMENT — No effective disease-modifying or neuroprotective treatment is available for MSA [19-21]. Management, limited as it is, is primarily symptomatic.

The main clinical features of MSA are parkinsonism, autonomic failure, cerebellar ataxia, and pyramidal signs in varying combinations. Additional manifestations can include sleep disorders, breathing disorders, and depression. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Clinical characteristics'.)

The motor symptoms in MSA are highly resistant to pharmacologic treatment. However, the autonomic symptoms may respond to pharmacotherapy. Physical, occupational, and speech therapy are helpful for the supportive care of patients with MSA.

Levodopa and dopaminergic therapy — The main role of levodopa in patients with suspected MSA is diagnostic; a poor or unsustained response to levodopa therapy is generally observed in patients with MSA and can help to distinguish the parkinsonian variant of MSA (MSA-P) from idiopathic Parkinson disease. However, some patients with clinically probable MSA do better on levodopa treatment than off it. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Levodopa responsiveness'.)

Therefore, we suggest a trial of levodopa for patients with suspected MSA. Levodopa is given with a peripheral decarboxylase inhibitor (eg, levodopa-carbidopa) in escalating doses up to 1000 mg of levodopa daily as necessary and tolerated over a three-month period. The total daily dose must be increased to 900 or 1000 mg before a trial of levodopa can be declared a failure. Clinical improvement is characterized as a 30 percent decrease in the Unified MSA Rating Scale (UMSARS) [10].

Amantadine has been used in doses up to 300 mg per day to treat MSA, but it is no more effective than levodopa [22].

The role for dopamine agonists is limited, both for the older (pergolide and bromocriptine) and newer agents (pramipexole and ropinirole). They rarely lead to motor benefit and frequently exacerbate orthostatic hypotension, gastrointestinal symptoms, and sleep disorders that are prevalent in MSA. Patients who do not respond to levodopa are unlikely to respond to dopamine agonists, so their use should be avoided in this situation.

Motor symptoms — There are no effective medications for the ataxia and gait abnormalities that predominate in the cerebellar subtype of MSA [10]. Furthermore, the parkinsonian manifestations of bradykinesia and rigidity in MSA are often but not always resistant to treatment. Approximately 30 to 50 percent of MSA-P patients have some response.  

Physical therapy is important for fall prevention, reduction in contractures, and maintenance of mobility while possible. Therapists are also helpful in determining requirements for and facilitating walker and wheelchair use when a patient becomes nonambulatory. Randomized controlled trials support occupational therapy in mild to moderate MSA [23], and it may promote longer independence in performing activities of daily living. Additionally, in-home visits for safety evaluation and driving evaluations are beneficial.

Botulinum toxin injection is often useful in alleviating symptoms from focal dystonias that occur in MSA, such as cervical dystonia and blepharospasm. Caution is advised when injecting an MSA patient for cervical dystonia, given the risk of potentially exacerbating underlying dysphagia often associated with the disease [24]. (See "Treatment of dystonia in children and adults", section on 'Focal dystonia'.)

For patients with anterocollis, it is important to differentiate dystonia from myopathy as the cause. This should be done before using botulinum toxin, which may worsen symptoms when myopathy is the cause. Electromyography usually clarifies the picture, although biopsy may be necessary when the diagnosis is uncertain.

Speech therapy referral early in the course of disease allows objective determination of the progression of dysphagia. The need for percutaneous gastrostomy tube placement should be assessed by videofluoroscopic swallow evaluation and barium swallow studies.

Orthostatic hypotension — The treatment of orthostatic hypotension is reviewed here briefly and discussed in detail separately. (See "Treatment of orthostatic and postprandial hypotension".)

The plasma volume expander fludrocortisone acetate is the medication of first choice for chronic orthostatic hypotension due to autonomic dysfunction (table 1). This agent has a long duration of action and is well tolerated by most patients with chronic autonomic failure. Patients treated with fludrocortisone must be monitored for the development of edema and worsening seated or supine hypertension. These side effects may necessitate discontinuation or dose reduction. Potassium supplementation is usually required, particularly when higher doses are used. (See "Treatment of orthostatic and postprandial hypotension", section on 'Fludrocortisone'.)

Second-line agents for orthostatic hypotension include the alpha-1 adrenergic agonist, midodrine, and the norepinephrine precursor, droxidopa. The efficacy of droxidopa was demonstrated in two small studies that included patients with MSA [25,26]; however, long-term efficacy has not been demonstrated [27,28]. In addition, there is emerging evidence supporting the use of atomoxetine, a norepinephrine transport inhibitor, for neurogenic orthostatic hypotension [29,30]. Supine hypertension can be a significant side effect with these medications. Raising the head of the bed by 30 to 45 degrees may help ameliorate this problem. (See "Treatment of orthostatic and postprandial hypotension", section on 'Pharmacotherapy'.)

Supplementary agents for orthostatic hypotension include pyridostigmine, nonsteroidal anti-inflammatory drugs, caffeine, and erythropoietin. These agents may be used in combination therapy with first- or second-line agents in patients with persistent symptoms. However, there are anecdotal reports suggesting that pyridostigmine causes worsening parkinsonism [31,32].

Nonpharmacologic measures are important components of the therapy of chronic orthostatic hypotension. These include removal of offending medications, patient education and physical maneuvers (eg, arising slowly from supine to sitting, raising the head of the bed 10 to 20 degrees, custom-fitted elastic stockings that extend to the waist, abdominal binders), increased salt and water intake, and avoidance of precipitating factors.

Postprandial hypotension — The management of postprandial hypotension is reviewed here briefly and discussed in detail separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Postprandial hypotension'.)

Optimal therapy of symptomatic postprandial hypotension has not been defined. The following general suggestions may be helpful in selected patients:

Eat small meals

Eat low carbohydrate meals

Avoid salt restriction

Avoid standing up suddenly or standing still after meals

Walk between meals; if walking is not tolerated, lie semirecumbent for 90 minutes after meals

The somatostatin analogue octreotide can minimize postprandial hypotension. However, octreotide must be given subcutaneously 30 minutes before each meal. It is expensive, and often leads to side effects such as diarrhea and pain at the injection site. Therefore, it should be reserved for the most severely symptomatic patients.

Urogenital symptoms — For detrusor hyperreflexia, the muscarinic acetylcholine receptor antagonists oxybutynin (2.5 to 5 mg two or three times daily) or tolterodine (2 to 4 mg daily) may prevent overactive bladder. However, these drugs can cause confusion in susceptible patients and can worsen constipation.

For bladder atony, intermittent self-catheterization should be used for retention or residual volume >100 mL.

The treatment of erectile dysfunction is discussed elsewhere. (See "Treatment of male sexual dysfunction".)

Depression — Depression is a common problem in patients with MSA, often requiring psychiatric treatment with counseling for the patient and family, and in some cases antidepressant pharmacotherapy. (See "Unipolar major depression in adults: Choosing initial treatment" and "Diagnosis and management of late-life unipolar depression".)

Stridor — Laryngeal stridor in patients with MSA typically occurs during sleep, although daytime symptoms can emerge in advanced cases. Stridor during sleep warrants further evaluation.

We refer patients with symptomatic stridor to otolaryngology and sleep medicine for overnight polysomnography. For most patients, initial symptomatic therapy consists of nocturnal continuous positive airway pressure (CPAP). Adaptive servo-ventilation (ASV) is sometimes used instead of CPAP when there is concurrent central sleep apnea [33]. Based on small short-term retrospective studies, CPAP often eliminates stridor [34-37]. Long-term symptomatic effects are not well studied. A 2019 systematic review and consensus statement concluded that the impact of CPAP on overall survival is uncertain [38].

Patients with persistent and severe stridor that does not respond to CPAP or ASV or in whom these are not feasible may require tracheostomy for symptomatic control. Tracheostomy for stridor typically involves placement of a fenestrated cannula, which is maintained in a closed position during the day to allow for phonation and opened at night to bypass airway obstruction at the larynx and relieve distressing stridor [38]. Whether tracheostomy prevents sudden death in sleep due to airway obstruction is not known. Small retrospective studies have suggested that tracheostomy may be associated with longer survival in patients with MSA, but the evidence is of very low quality [2,15,39]. There have been reports of worsening central sleep apnea after tracheostomy in MSA [40], and patients who undergo tracheostomy should be followed by a pulmonary and/or sleep specialist.

Rapid eye movement sleep behavior disorder — Patients with rapid eye movement sleep behavior disorder and their bed partners should be counseled on ways to alter the sleeping environment to prevent injury (algorithm 1). Effective pharmacotherapy options include melatonin and clonazepam (table 2). Treatment is reviewed in detail separately. (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)

Support groups — Local, regional, and national associations can play an integral role to benefit lives of patients, family members, and caregivers. These groups include:

The American Parkinson Disease Association

The Parkinson's Foundation

The Multiple System Atrophy Coalition

INVESTIGATIONAL THERAPIES — There is currently no effective disease-modifying or neuroprotective treatment for MSA. Several therapies have failed in phase III trials [20]. Some strategies currently under investigation in clinical trials include reducing alpha-synuclein aggregation using serotonin specific reuptake inhibitors such as sertraline, inhibiting neuroinflammatory response with intravenous immunoglobulins and other agents, and infusing autologous mesenchymal stem cells, which theoretically may have a neuroprotective effect [41-44]. Emerging studies include a phase I study of active vaccination against an epitope similar to alpha-synuclein [45,46].

Verdiperstat, an oral, brain-penetrant, irreversible inhibitor of myeloperoxidase (MPO; which is an enzyme that impels oxidative and neuroinflammatory processes that underlie neurodegeneration), has received orphan drug designation from the US Food and Drug Administration (FDA). In phase I clinical trials, after 12 weeks of treatment, placebo-treated patients worsened by 4.6 points on the Unified MSA Rating Scale (UMSARS), while verdiperstat-treated patients worsened by 3.7 points at the 300 mg twice-daily dose and by 2.6 points at the 600 mg twice-daily dose [47]. More research needs to be done and a phase III trial is underway, but this is a promising development for MSA patients.

There is a growing list of agents in the preclinical treatment pipeline [20,48].

SUMMARY AND RECOMMENDATIONS

Cardinal features – Multiple system atrophy (MSA) is a rare neurodegenerative movement disorder characterized by parkinsonism, autonomic failure, cerebellar ataxia, and pyramidal signs in varying combinations. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Clinical characteristics'.)

Prognosis – There is no effective disease-modifying or neuroprotective treatment for MSA. Management focuses on symptom control and quality of life.

Disease progression in MSA is often faster than in idiopathic Parkinson disease, as illustrated by median times from MSA symptom onset to autonomic dysfunction (2.5 years), wheelchair confinement (3.5 to 5 years), and bedridden state (5 to 8 years). The median time from MSA onset to death is 6 to 10 years. (See 'Prognosis' above.)

Anticipatory care

Physical therapy is important for fall prevention, reduction in contractures, and maintenance of mobility. (See 'Motor symptoms' above.)

Occupational therapy may promote longer independence in performing activities of daily living.

Speech therapy referral early in the course of disease allows objective determination of the progression of dysphagia.

Depression is a common problem in MSA. It should be identified early and treated appropriately. (See 'Depression' above and "Unipolar major depression in adults: Choosing initial treatment" and "Diagnosis and management of late-life unipolar depression".)

Symptomatic therapies

Parkinsonism – Although a poor or unsustained response to levodopa therapy is generally observed in patients with MSA, some patients with clinically probable MSA do better with levodopa treatment than without it. The total daily dose of levodopa should be increased to 900 or 1000 mg daily before a trial of levodopa can be declared a failure. (See 'Levodopa and dopaminergic therapy' above.)

Dopamine agonists (pergolide, bromocriptine, pramipexole, and ropinirole) rarely lead to motor benefit and frequently exacerbate orthostatic hypotension, gastrointestinal symptoms, and sleep disorders that are prevalent in MSA.

Dystonia – Focal dystonia may be alleviated by botulinum toxin injection. (See 'Motor symptoms' above.)

Orthostatic hypotensionFludrocortisone acetate is the medication of first choice for chronic orthostatic hypotension due to autonomic dysfunction (table 1). The optimal therapy of symptomatic postprandial hypotension has not been defined. (See 'Orthostatic hypotension' above and 'Postprandial hypotension' above and "Treatment of orthostatic and postprandial hypotension".)

Laryngeal stridor – Patients with nocturnal stridor may benefit from nocturnal positive pressure ventilation; severe cases may necessitate tracheostomy. (See 'Stridor' above.)

Sleep disturbances – Rapid eye movement (REM) sleep behavior disorder is common in patients with MSA and can lead to injury to the patient and bed partner. Treatment is reviewed in the algorithm and discussed separately (algorithm 1 and table 2). (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)

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Topic 4891 Version 25.0

References

1 : Clinical features and natural history of multiple system atrophy. An analysis of 100 cases.

2 : Early development of autonomic dysfunction may predict poor prognosis in patients with multiple system atrophy.

3 : Progression and prognosis in multiple system atrophy: an analysis of 230 Japanese patients.

4 : Survival in multiple system atrophy.

5 : Survival of patients with pathologically proven multiple system atrophy: a meta-analysis.

6 : Incidence and prevalence of multiple system atrophy: a nationwide study in Iceland.

7 : The natural history of multiple system atrophy: a prospective European cohort study.

8 : Natural history of multiple system atrophy in the USA: a prospective cohort study.

9 : Survival in synucleinopathies: A prospective cohort study.

10 : Multiple system atrophy.

11 : Multiple system atrophy-parkinsonism with slow progression and prolonged survival: a diagnostic catch.

12 : Young-onset multiple system atrophy: Clinical and pathological features.

13 : Clinical outcomes of progressive supranuclear palsy and multiple system atrophy.

14 : Clinical features and autonomic testing predict survival in multiple system atrophy.

15 : Early stridor onset and stridor treatment predict survival in 136 patients with MSA.

16 : Predictors of survival in progressive supranuclear palsy and multiple system atrophy: a systematic review and meta-analysis.

17 : Multiple system atrophy with prolonged survival: is late onset of dysautonomia the clue?

18 : Disease progression and prognostic factors in multiple system atrophy: A prospective cohort study.

19 : Multiple system atrophy: an update.

20 : Multiple System Atrophy: Recent Developments and Future Perspectives.

21 : Current Management and Emerging Therapies in Multiple System Atrophy.

22 : The symptomatic treatment of multiple system atrophy.

23 : Occupational therapy in multiple system atrophy: a pilot randomized controlled trial.

24 : Severe dysphagia after botulinum toxin injection for cervical dystonia in multiple system atrophy.

25 : Norepinephrine precursor therapy in neurogenic orthostatic hypotension.

26 : L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: a multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure.

27 : Meta-analysis of the safety and efficacy of droxidopa for neurogenic orthostatic hypotension.

28 : Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension.

29 : Evaluating the effectiveness of atomoxetine for the treatment of primary orthostatic hypotension in adults.

30 : Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure.

31 : Parkinsonism induced by pyridostigmine.

32 : Coexistence of Parkinson's disease and myasthenia gravis: a case report.

33 : Stridor combined with other sleep breathing disorders in multiple system atrophy: a tailored treatment?

34 : Long-term effect of CPAP in the treatment of nocturnal stridor in multiple system atrophy.

35 : Continuous positive airway pressure for sleep-related breathing disorders in multiple system atrophy: long-term acceptance.

36 : Continuous positive air pressure eliminates nocturnal stridor in multiple system atrophy. Barcelona Multiple System Atrophy Study Group.

37 : Stridor during sleep: description of 81 consecutive cases diagnosed in a tertiary sleep disorders center.

38 : Stridor in multiple system atrophy: Consensus statement on diagnosis, prognosis, and treatment.

39 : Stridor and death in multiple system atrophy.

40 : Tracheostomy can fatally exacerbate sleep-disordered breathing in multiple system atrophy.

41 : A randomized trial of mesenchymal stem cells in multiple system atrophy.

42 : Novel therapeutic approaches in multiple system atrophy.

43 : Toward disease modification in multiple system atrophy: Pitfalls, bottlenecks, and possible remedies.

44 : Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.

45 : Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.

46 : Current Treatment of Multiple System Atrophy.

47 : Current Treatment of Multiple System Atrophy.

48 : Current Symptomatic and Disease-Modifying Treatments in Multiple System Atrophy.