(See also Overview of the Autonomic Nervous System.)
Multiple system atrophy affects men and women equally. Mean age at onset is 53 years; after symptoms appear, patients live approximately 10 years (1, 2, 3).
There are 2 types of multiple system atrophy (MSA); types are based on the initial symptoms that predominate:
MSA-C: Characterized by cerebellar ataxia and postural instability (cerebellar dysfunction)
MSA-P: Similar to Parkinson disease but often without tremor and often unresponsive to levodopa (MSA-P: Similar to Parkinson disease but often without tremor and often unresponsive to levodopa (parkinsonian symptoms)
Both types involve autonomic nervous system dysfunction. Although multiple system atrophy begins as one type, symptoms of the other type frequently develop. After approximately 5 years, symptoms tend to be similar regardless of which disorder developed first.
General references
1. Krismer F, Fanciulli A, Meissner WG, Coon EA, Wenning GK. Multiple system atrophy: advances in pathophysiology, diagnosis, and treatment. Lancet Neurol 2024;23(12):1252-1266. doi:10.1016/S1474-4422(24)00396-X
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. doi:10.1016/S1474-4422(15)00058-7
3. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013;12(3):264-274. doi:10.1016/S1474-4422(12)70327-7
Etiology of Multiple System Atrophy
Etiology of multiple system atrophy is unknown, but neuronal degeneration occurs in several areas of the brain; the area and amount of cellular damage determine initial symptoms. A characteristic finding is cytoplasmic inclusion bodies containing alpha-synuclein within oligodendroglial cells. Synuclein is a neuronal and glial cell protein that can aggregate into insoluble fibrils and form Lewy bodies or glial cytoplasmic inclusions.
Multiple system atrophy is a synucleinopathy (due to synuclein deposition); synuclein can also accumulate in patients with Parkinson disease, pure autonomic failure, or dementia with Lewy bodies.
Symptoms and Signs of Multiple System Atrophy
Initial symptoms of multiple system atrophy vary but include a combination of:
Parkinsonism, partially or unresponsive to levodopaParkinsonism, partially or unresponsive to levodopa
Cerebellar ataxia
Symptoms due to autonomic insufficiency
Parkinsonian symptoms
Parkinsonian symptoms predominate in MSA-P (previously called striatonigral degeneration). They include rigidity, bradykinesia, postural instability, and jerky postural tremor. High-pitched, strained dysarthria is common.
In contrast to Parkinson disease, multiple system atrophy usually does not cause resting tremor or severe dyskinesia, and symptoms respond poorly and transiently to levodopa. In contrast to Parkinson disease, multiple system atrophy usually does not cause resting tremor or severe dyskinesia, and symptoms respond poorly and transiently to levodopa.
Cerebellar abnormalities
Cerebellar abnormalities predominate in MSA-C (previously called olivopontocerebellar atrophy). They include ataxia, dysmetria, dysdiadochokinesia (difficulty performing rapidly alternating movements), poor coordination, and abnormal eye movements.
Autonomic symptoms
Typically, autonomic failure causes orthostatic hypotension (symptomatic fall in blood pressure when a person stands, often with syncope), urinary retention, urinary incontinence, constipation, and sexual dysfunction, including male erectile dysfunction.
Other autonomic symptoms, which may occur early or late, include decreased sweating, difficulty breathing and swallowing, and fecal incontinence.
Rapid eye movement (REM) sleep behavior disorder (eg, acting out of dreams due to speech or skeletal muscle movement during REM sleep), respiratory stridor, and sleep apnea are common. Patients are often unaware of sleep-related symptoms.
Patients may have nocturnal polyuria; contributing factors may include a circadian decrease in argininevasopressin, supine hypertension, and treatments used to increase blood volume.
Diagnosis of Multiple System Atrophy
History and physical examination to confirm autonomic insufficiency plus parkinsonism or cerebellar symptoms that respond poorly to levodopaHistory and physical examination to confirm autonomic insufficiency plus parkinsonism or cerebellar symptoms that respond poorly to levodopa
MRI of brain and possibly spinal cord
Autonomic tests
Diagnosis of multiple system atrophy is suspected clinically, based on the combination of autonomic failure and parkinsonism or cerebellar symptoms (1). Similar symptoms may result from Parkinson disease, dementia with Lewy bodies, pure autonomic failure, autonomic neuropathies, progressive supranuclear palsy, multiple cerebral infarcts, or medication-induced parkinsonism.
No diagnostic test is definitive, but some (eg, MRI, nuclear imaging with 123I-metaiodobenzylguanidine [MIBG], autonomic tests) help confirm clinical suspicion of multiple system atrophy—for example, if:
MRI shows characteristic changes in the midbrain, pons, or cerebellum.
MIBG scans show intact innervation of the heart (because the lesion is preganglionic in multiple system atrophy)
Autonomic tests indicate generalized autonomic failure.
Biomarker testing of tissue or fluid is consistent with multiple system atrophy.
Diagnosis reference
1. Wenning GK, Stankovic I, Vignatelli L, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord 2022;37(6):1131-1148. doi:10.1002/mds.29005
Treatment of Multiple System Atrophy
Supportive care
There is no specific treatment for multiple system atrophy, but symptoms are managed as follows (1):
Orthostatic hypotension: Volume expansion, vasopressors, and compression garments are used. Raising the head of the bed about 10 cm reduces nocturnal polyuria and supine hypertension and may reduce morning orthostatic hypotension. Sometimes fludrocortisone and/or alpha-adrenoreceptor stimulation with midodrine is given, but Volume expansion, vasopressors, and compression garments are used. Raising the head of the bed about 10 cm reduces nocturnal polyuria and supine hypertension and may reduce morning orthostatic hypotension. Sometimes fludrocortisone and/or alpha-adrenoreceptor stimulation with midodrine is given, butmidodrine may increase supine blood pressure, causing supine hypertension. Droxidopa, a drug that is metabolized to may increase supine blood pressure, causing supine hypertension. Droxidopa, a drug that is metabolized tonorepinephrine, can also be used. It has a longer duration of action than midodrine. Pyridostigmine increases acetylcholine, which is thought to increase traffic through the autonomic ganglia, which can help stabilize blood pressure without causing supine hypertension, and it may be used in conjunction with other medications. . Pyridostigmine increases acetylcholine, which is thought to increase traffic through the autonomic ganglia, which can help stabilize blood pressure without causing supine hypertension, and it may be used in conjunction with other medications.
Parkinsonism: Levodopa/carbidopa may be tried to relieve rigidity and other parkinsonian symptoms but may be ineffective or provide only modest benefit and cause dyskinesias.
Urinary incontinence: If the cause is detrusor hyperreflexia, oxybutynin or tolterodine may be used, but either can significantly worsen orthostatic hypotension. Tamsulosin may be effective for urinary urgency but worsens orthostatic hypotension. Alternatively, the beta-3 adrenergic agonist mirabegron can be used and does not worsen orthostatic hypotension.If the cause is detrusor hyperreflexia, oxybutynin or tolterodine may be used, but either can significantly worsen orthostatic hypotension. Tamsulosin may be effective for urinary urgency but worsens orthostatic hypotension. Alternatively, the beta-3 adrenergic agonist mirabegron can be used and does not worsen orthostatic hypotension.
Decreased sweating: If sweating is reduced or absent, patients are advised to avoid warm environments and overheating the body.
Urinary retention: Many patients must self-catheterize their bladder or require an indwelling urinary catheter or suprapubic catheter. Sometimes medications that induce bladder contraction (eg, bethanechol) are used.Many patients must self-catheterize their bladder or require an indwelling urinary catheter or suprapubic catheter. Sometimes medications that induce bladder contraction (eg, bethanechol) are used.
Constipation: A high-fiber diet and stool softeners can be used; for refractory cases, enemas may be necessary.
Erectile dysfunction: Medications such as sildenafil or tadalafil can be used, but these medications may worsen orthostatic hypotension.Medications such as sildenafil or tadalafil can be used, but these medications may worsen orthostatic hypotension.
Patients require supportive therapy and can benefit from multidisciplinary care; physical therapy, occupational therapy, and speech therapy are vital. Palliative medicine specialists can be helpful for supportive care and to guide patients in preparing advance directives as the disorder is progressive. Many people are confined to a wheelchair or are otherwise severely disabled within 5 years after symptoms begin. The disorder results in death approximately 10 years after symptoms begin (2).
Treatment references
1. Krismer F, Fanciulli A, Meissner WG, Coon EA, Wenning GK. Multiple system atrophy: advances in pathophysiology, diagnosis, and treatment. Lancet Neurol 2024;23(12):1252-1266. doi:10.1016/S1474-4422(24)00396-X
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. doi:10.1016/S1474-4422(15)00058-7
Key Points
Multiple system atrophy can include parkinsonian symptoms, cerebellar abnormalities, and autonomic impairment in various degrees of severity.
Diagnosis is based on clinical, autonomic, and MRI findings, but consider Parkinson disease, dementia with Lewy bodies, pure autonomic failure, autonomic neuropathies, progressive supranuclear palsy, cerebrovascular disease, and medication-induced parkinsonism, which can cause similar symptoms.
Use treatments specific for the symptoms present.
Drugs Mentioned In This Article
