Multiple System Atrophy: A Common Form of Atypical Parkinsonism

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Multiple system atrophy is thought to be associated with glial cytoplasmic inclusions with α-synuclein, as well as pathologic modifications in selected neurons.
Multiple system atrophy is thought to be associated with glial cytoplasmic inclusions with α-synuclein, as well as pathologic modifications in selected neurons.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder with an unknown cause. Previously known as Shy-Drager syndrome, MSA is a form of atypical parkinsonism that primarily affects the autonomic nervous system and movement. With onset in adulthood, the prevalence of MSA in the United States is estimated to be 2 to 5 cases per 100,000 people.1 Despite MSA being a rare disease process, it is important for healthcare providers to be aware of its presentation due to its significant morbidity and mortality.

MSA is thought to be associated with glial cytoplasmic inclusions with α-synuclein, as well as pathologic modifications in selected neurons.2 MSA cases are usually sporadic, and a distinguishing feature of the disease is the accumulation of α-synuclein in glial cells, which support neurons. α-Synuclein mainly deposits in oligodendrocytes, which are glial cells that produce myelin.3 Myelin is an insulating substance that wraps around the axons of most neurons and helps increase the speed at which a nerve impulse travels. A proposed mechanism posits that MSA involves “prion-like spreading of aberrant α-synuclein from neurons to glia through functionally connected networks, thereby leading to glial and myelin dysfunction and an inflammatory cascade that promotes secondary neurodegeneration.”1 This suggests that MSA is primarily a disorder of the glia and that myelin degeneration is characteristic of it.1

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Symptoms of MSA result from loss of nerve cells in various areas of the brain and spinal cord, and the loss of these nerve cells may be due to the accumulation of α-synuclein. Because MSA has this accumulation of α-synuclein, it is also known as a synucleinopathy. A possible risk factor for MSA is abnormalities in the synuclein gene SNCA, which is responsible for the instructions to create α-synuclein.3

A meta-analysis of 433 patients with a definitive diagnosis of MSA identified a mean age of onset at 54 years.4 This study showed that MSA affected both men and women about the same, with no gender differences in survival. MSA has been documented in white, Asian, and African populations with no preference for a particular race.1

Clinical Findings of MSA

The major clinical features of MSA are autonomic failure and motor dysfunction (Figure 1). Autonomic signs and symptoms can include “orthostatic hypotension, bowel and bladder disturbances, and sexual dysfunction.”5 The motor features classify MSA into 2 subtypes: MSA-P has predominant parkinsonism, and MSA-C has predominant cerebellar ataxia. Signs and symptoms that characterize MSA-P include postural instability, bradykinesia, irregular postural tremor, rigidity, and hypophonia. Signs and symptoms characterizing MSA-C include “gait ataxia, limb ataxia, ataxic dysarthria, and cerebellar disturbances of eye movements.”1

Another symptom that is common in MSA is anterocollis, which is anterior flexion of the neck. Dysphagia and dysautonomia are clinical features of both types of MSA. Urogenital dysfunction and orthostatic hypotension are the most common symptoms of dysautonomia in MSA. Urogenital dysfunction includes erectile dysfunction, urinary incontinence, frequency, and urgency. Sleep and breathing disorders common in MSA include REM sleep behavior disorder, nocturnal stridor, obstructive sleep apnea, restless leg syndrome, and excessive daytime sleepiness.

Although cognitive function in MSA remains fairly intact, it can be impaired. However, unimpaired cognitive function does not rule out MSA in patients with classic signs and symptoms. Many patients with MSA tend to have depression and anxiety.1

Work-up of MSA

MSA is a clinical diagnosis; there are no imaging studies or laboratory tests that are diagnostic. Responsiveness to levodopa may be used to differentiate MSA-P from idiopathic Parkinson disease as there is usually a poor response to levodopa in patients with MSA-P; however, this may be ineffective in the early stages of MSA-P. Diagnostic criteria for MSA include a sporadic, progressive onset and age >30 years. Additional diagnostic criteria include autonomic failure with either orthostatic hypotension (as reflected by a reduction in blood pressure of ≥30 mm Hg systolic or ≥15 mm Hg diastolic within 3 minutes of standing) or urinary incontinence.  Poor responsiveness to levodopa when parkinsonism is present may be diagnostic for MSA, as may be the presence of a cerebellar syndrome.1

Neuroimaging lacks sufficient sensitivity or specificity to be used to diagnose MSA. Even so, there are diagnostic criteria that show “atrophy of putamen, middle cerebellar peduncle, or pons [on magnetic resonance imaging] as supportive features for possible MSA-P or MSA-C.”1 Hypometabolism of the cerebellum, putamen, or brainstem has been demonstrated on (18F)fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with MSA-P . In patients with MSA-C, hypometabolism of the putamen has been demonstrated on FDG-PET, as has presynaptic dopaminergic denervation in the striatum on PET or single-photon emission computed tomography (SPECT).1

The “hot cross bun sign” is a nonspecific finding signifying T2 hypersensitivity that forms a cross through the pons as a result of degeneration of pontocerebellar fibers (Figure 2). This sign can be seen on imaging of patients with various causes of parkinsonism.1

A definitive diagnosis of MSA results from postmortem pathology “showing α-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures.”1 Striatonigral degeneration is indicative of MSA-P, and olivopontocerebellar atrophy is indicative of MSA-C.1

Management of MSA

Currently no disease-modifying or neuroprotective treatments exist for MSA, nor are there effective medications to treat the cerebellar ataxia in MSA-C or the parkinsonian features in MSA-P. Physical therapy can be encouraged to enhance mobility and prevent falls. Occupational therapy can assist with activities of daily living, and speech therapy can also be beneficial if done in the early stages of MSA. Continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) can be used to treat obstructive sleep apnea or stridor.

The use of levodopa in MSA is primarily diagnostic. Although fludrocortisone acetate is the first-line medication for chronic orthostatic hypotension that results from autonomic failure, nonpharmacologic interventions are essential for managing chronic orthostatic hypotension. These include raising the head of the bed, removing medications that could be worsening the hypotension, instructing patients to rise slowly from supine to sitting, encouraging increased salt and water intake, and wearing elastic stockings that go up to the waist.6

Urinary symptoms associated with MSA can be treated with the muscarinic acetylcholine receptor antagonists oxybutynin or tolterodine. Multiple options are available for treatment of erectile dysfunction. Treatments for REM-sleep behavior disorder include tricyclic antidepressants, clonazepam, and melatonin. Depression can be treated with counseling and antidepressant medications. Support groups also provide benefit for individuals with MSA, as well as their families and caregivers.  A number of treatment interventions are currently under investigation, including sertraline to reduce α-synuclein aggregation, infusing autologous mesenchymal stem cells for a possible neuroprotective effect, and intravenous immunoglobulins to stop the neuroinflammatory response.6

Prognosis for MSA

Progression of MSA can occur over 1 to 18 years, and the disease has a fatal course with 6 to 10 years as the median time from onset to death. Survival can be longer in some patients, and risk factors have been identified that predict shorter survival. These risk factors include early or severe autonomic failure, incomplete bladder emptying, and female gender.7

Causes of death include aspiration pneumonia or acute aspiration during sleep, sudden death due to cardiac arrest or unknown etiology, sudden death from laryngeal stridor and acute airway obstruction, or complications resulting from recurrent urinary tract infections.7

The effects of MSA subtype on prognosis were studied in the first prospective cohort study of MSA in the United States.2 No significant difference was identified between MSA-C and MSA-P in length of survival. Median survival was measured from onset of symptoms to death; median survival for MSA-C was 9.9 years and for MSA-P was 9.6 years.2 MSA-P has been found to predominate in Europe and North America, while MSA-C has been found to predominate in Japan.8

Sudhisha Jala, PA-C, is employed by Gastroenterology Associates of Atlanta, Georgia, and Lisa Daitch, PA-C is associate professor and director of admissions for the physician assistant program at Georgia Regents University, in Augusta, Georgia.

References

  1. Factor S, Esper CD. Multiple system atrophy: clinical features and diagnosis. Available at: https://www.uptodate.com/contents/multiple-system-atrophy-clinical-features-and-diagnosis. Updated June 8, 2018. Accessed October 14, 2018.
  2. Low PA, Reich SG, Jankovic J, et al. Natural history of multiple system atrophy in the usa: a prospective cohort study. Lancet Neurol. 2015;14(7):710-719.
  3. Multiple system atrophy fact sheet.  Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Multiple-System-Atrophy. Modified July 24, 2018. Accessed October 4, 2018.
  4. Ben-Shlomo Y, Wenning GK, Tison F, Quinn NP. Survival of patients with pathologically proven multiple system atrophy: a meta-analysis. Neurology. 1997;48(2):384-393.
  5. Coon EA, Sletten DM, Suarez MD, et al. Clinical features and autonomic testing predict survival in multiple system atrophy. Brain. 2015;138(Pt 12):3623-3631.
  6. Factor SA, Esper CD. Multiple system atrophy: prognosis and treatment. Available at: https://www.uptodate.com/contents/multiple-system-atrophy-prognosis-and-treatment. Updated May 9, 2017. Accessed October 4, 2018.
  7. Papapetropoulos S, Tuchman A, Laufer D, Papatsoris AG, Papapetropoulos N, Mash DC. Causes of death in multiple system atrophy. J Neurol Neur0surg Psychiatry. 2007;78(3):327-329.
  8. Ozawa T, Onodera O. Multiple system atrophy: clinicopathological characteristics in Japanese patients. Proc Japan Acad. 2017;93(5):251-258.
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