Multiple system atrophy: Prognosis and treatment

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)

Neurofilament light chain protein has been explored as a potential biomarker that correlates with clinical disease severity, progression, and prognosis [19].

MANAGEMENT — No effective disease-modifying or neuroprotective treatment is available for MSA [20-22]. 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 features'.)

The motor symptoms in MSA are generally 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, and some also develop motor fluctuations and dyskinesia. (See "Multiple system atrophy: Clinical features and diagnosis", section on 'Levodopa response assessment'.)

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]. For patients with advanced disease who have demonstrated oral levodopa responsiveness, levodopa-carbidopa intestinal gel (LCIG) is a device-assisted option that may improve global function scores and allow for discontinuation of oral antiparkinsonian drugs in some patients [23]. (See "Device-assisted and lesioning procedures for Parkinson disease", section on 'Continuous levodopa-carbidopa intestinal gel infusion'.)

Amantadine has been used in doses up to 300 mg per day to treat MSA, but it is no more effective than levodopa [24].

The role for dopamine agonists is limited. 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.

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 [25], 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 of 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 [26]. (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 — Symptomatic orthostatic hypotension due to neurodegenerative dysautonomia affects approximately three-quarters of patients with MSA. Recognition and treatment are key components of supportive care in an effort to prevent falls and other complications and to improve quality of life.

Treatment in patients with MSA is the same as for other causes of neurogenic orthostatic hypotension and includes nonpharmacologic (table 1) and pharmacologic measures (table 2) as well as avoidance of aggravating medications when possible (table 3). An approach to medication selection is presented in the algorithm (algorithm 1) and reviewed in detail separately. (See "Treatment of orthostatic and postprandial hypotension".)

Postprandial hypotension — Optimal therapy of symptomatic postprandial hypotension has not been defined. Modification of meals may be helpful in selected patients:

●Avoid large meals

●Eat low-carbohydrate meals

●Avoid salt restriction

●Drink water with meals

●Avoid standing up suddenly or standing still after meals

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

Several medications have been shown to improve blood pressure in postprandial hypotension and may be used in refractory cases, including somatostatin analogues. Supporting evidence and administration are reviewed separately. (See "Treatment of orthostatic and postprandial hypotension", section on 'Postprandial hypotension'.)

Urogenital symptoms — Overactive bladder symptoms due to detrusor overactivity (also referred to as detrusor hyperreflexia) are an early and common manifestation of autonomic dysfunction in patients with MSA [27,28]. Symptoms include urinary urgency, urinary frequency, nocturia, and urge incontinence. Patients with MSA are also at risk for urinary retention, and ultrasound to measure postvoid residual volumes should generally be performed before starting symptomatic medications and in patients with new or worsening urinary symptoms.

●Overactive bladder – For overactive bladder, the initial approach is similar to that in the general population, including education about lifestyle modifications (eg, reducing consumption of mild diuretics like caffeine and alcohol, avoiding fluids before bedtime), prompted/timed bladder emptying, and behavioral therapies such as pelvic floor muscle training. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Initial approach to treatment' and "Lower urinary tract symptoms in males", section on 'Patient evaluation'.)

Adjunctive medications for overactive bladder should be offered in patients with residual bothersome symptoms [27]. First-line therapies include beta-3 adrenergic agonists (eg, mirabegron, vibegron) and antimuscarinic drugs. All medications should be started at low doses and titrated slowly to reduce the risk of side effects.

Mirabegron may have the most favorable adverse event profile in patients with MSA and does not cause cognitive side effects. Emerging data support its efficacy and tolerability in patients with Parkinson disease [29-31]. The starting dose is one 25 mg extended-release tablet daily. Mirabegron can cause hypertension and should not be used in patients with severe or uncontrolled hypertension. Further details on administration and monitoring are provided separately. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Beta-3 adrenergic agonists'.)

Among the antimuscarinic agents, those with low central nervous system penetration (eg, darifenacin, solifenacin, trospium) are preferred due to lower risk of neurocognitive side effects. Solifenacin has been studied specifically in patients with Parkinson disease [32]. Older drugs like oxybutynin and tolterodine should be avoided if possible in patients with MSA due to higher risk of confusion and worsening constipation.

Alpha-adrenergic blockers (eg, tamsulosin, silodosin) can exacerbate orthostatic hypotension and should be used very cautiously, if at all, for urinary symptoms [27].

Patients with refractory symptoms may be referred to urology for consideration of options such as implantable stimulators (sacral nerve and tibial nerve) and intramural botulinum toxin injections. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Patients with continued symptoms' and "Lower urinary tract symptoms in males", section on 'Refractory OAB'.)

●Urinary retention – For bladder atony, intermittent self-catheterization should be used for retention or residual volume >100 mL. As the severity of bladder dysfunction progresses, a permanent transcutaneous suprapubic catheter may be required [33,34]. (See "Placement and management of urinary bladder catheters in adults", section on 'Clean intermittent catheterization'.)

●Erectile dysfunction – 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. Sleep dysfunction is a major cause of death in MSA [35,36] and 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 [37]. Based on small short-term retrospective studies, CPAP often eliminates stridor [38-41]. 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 [42].

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 [42]. Whether tracheostomy prevents sudden death in sleep due to airway obstruction is not known, but observational studies have suggested that tracheostomy may prolong survival in patients with MSA [2,15,43,44]. In one retrospective study of 75 patients with MSA and stridor, 22 patients were treated with tracheostomy, 29 with CPAP, and 24 with no treatment. Tracheostomy was associated with longer survival compared with CPAP or no treatment (incidence rate of death 12 versus 21 versus 23 per 100 person-years, respectively). Tracheostomy remained an independent predictor of longer survival after adjustment for confounders. There have been reports of worsening central sleep apnea after tracheostomy in MSA [45], 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 2). Effective pharmacotherapy options include melatonin and clonazepam (table 4). 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 early therapeutic attempts with general neuroprotective drugs such as rasagiline, coenzyme Q10, riluzole, and others failed in phase III trials [21]. Strategies currently under investigation include reducing alpha-synuclein aggregation and pathology as well as modulating neuroinflammation [46].

Disease-specific strains of alpha-synuclein exist in MSA compared with Parkinson disease and dementia with Lewy bodies, indicating the possible need for individualized approaches of the therapies targeting alpha-synuclein. A majority of the developed therapeutic approaches have focused on enhancing alpha-synuclein degradation and preventing or disrupting its aggregation.

●Enhanced alpha-synuclein degradation – Initial studies were based on inducing alpha-synuclein degradation by stimulating macro-autophagy using agents such as rapamycin, lithium, sirolimus, and the c-Abl inhibitor nilotinib; all of these were found to be ineffective [21,47]. Other approaches include increasing the extracellular alpha-synuclein clearance to promote its degradation by microglial cells such as toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA).

●Reduced alpha-synuclein aggregation – Small molecules such as Anle138b have shown promise in preventing alpha-synuclein accumulation or disrupting the formation of toxic oligomeric species. The small molecule ATH434 is a moderate iron chelator shown to reduce alpha-synuclein accumulation by redistributing labile iron in the brain.

Another approach is the use of anti-alpha-synuclein immunotherapies (both passive and active) with specific binding of the antigen alpha-synuclein and its respective antibody, followed by clearance of the complexes. Lu AF82422 is one anti-alpha-synuclein human immunoglobulin G1 monoclonal antibody being examined. Such vaccination studies are in early-phase trials. Active immunotherapies develop antibodies against an epitope similar to alpha-synuclein [48,49].

Antisense oligonucleotides are an alternative therapeutic approach to suppress the production of alpha-synuclein and therefore reduce its intracellular toxic accumulation. Infusing autologous mesenchymal stem cells may theoretically have a neuroprotective effect [50-53]. These treatments are currently in preclinical or early-phase clinical development.

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 [54]. A phase III trial was unfortunately reported to be negative. The details of the study have not been published.

There is a growing list of agents in the preclinical treatment pipeline [21,55].

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 features'.)

●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 (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 hypotension – Treatment of orthostatic hypotension includes nonpharmacologic and pharmacologic measures (algorithm 1) as well as avoidance of aggravating medications when possible (table 3). An approach to medication selection is presented in the algorithm (algorithm 1) and reviewed in detail separately. (See "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 2 and table 4). (See "Rapid eye movement sleep behavior disorder", section on 'Management'.)