(See also Overview of the Autonomic Nervous System.)
Pure autonomic failure (also called idiopathic orthostatic hypotension) denotes generalized autonomic failure without central nervous system (CNS) involvement (1). The lack of motor involvement in this disorder distinguishes it from multiple system atrophy. Pure autonomic failure affects both women and men, tends to begin during a person’s 40s or 50s, and does not typically result in death.
Pure autonomic failure is a synucleinopathy (due to synuclein deposition); alpha-synuclein also accumulates in patients with Parkinson disease, multiple system atrophy, or dementia with Lewy bodies . (Alpha-synuclein is a neuronal and glial cell protein that can aggregate into insoluble fibrils and form Lewy bodies.) Some patients with pure autonomic failure later develop motor or cognitive impairment, consistent with conversion to multiple system atrophy, Parkinson disease, or dementia with Lewy bodies (2).
General references
1. Coon EA, Singer W, Low PA. Pure Autonomic Failure. Mayo Clin Proc 2019;94(10):2087-2098. doi:10.1016/j.mayocp.2019.03.009
2. Millar Vernetti P, Norcliffe-Kaufmann L, Palma JA, et al. Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study. Brain 2024;147(7):2440-2448. doi:10.1093/brain/awae033
Symptoms and Signs of Pure Autonomic Failure
The main symptom is:
There may be other autonomic symptoms, such as decreased sweating, heat intolerance, urinary retention, bladder spasms (possibly causing urinary incontinence), sexual dysfunction (including male erectile dysfunction), fecal incontinence or constipation, dry eyes and/or mouth, and pupillary abnormalities.
Rapid eye movement (REM) sleep behavior disorder (eg, acting out of dreams due to speech or skeletal muscle movement during REM sleep) may occur.
Diagnosis of Pure Autonomic Failure
History and physical examination (including orthostatic blood measurement)
Diagnosis of pure autonomic failure is based on clinical findings and requires orthostatic hypotension (1). The supine norepinephrine level is usually < 100 pg/mL (590 pmol/L) and does not increase with standing. Postural orthostatic tachycardia syndrome (POTS) can be differentiated because, with standing, POTS does not usually cause hypotension, the norepinephrine level increases, and heart rate increases by > 30 beats/minutes or to 120 beats/minutes within 10 minutes. Skin biopsy to detect alpha-synuclein deposition may be used in some circumstances.
Diagnosis reference
1. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Neurology 1996;46(5):1470. doi:10.1212/wnl.46.5.1470
Treatment of Pure Autonomic Failure
Symptomatic treatment
Treatment of pure autonomic failure is symptomatic:
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 and 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., can also be used and 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.
Constipation: A high-fiber diet and stool softeners are recommended. Sometimes enemas are needed.
Bladder spasms: Oxybutynin or tolterodine can be used to treat bladder spasms but can worsen orthostatic hypotension. For urinary urgency, tamsulosin or the beta-3 adrenergic agonist mirabegron may be given. Unlike tamsulosin, Oxybutynin or tolterodine can be used to treat bladder spasms but can worsen orthostatic hypotension. For urinary urgency, tamsulosin or the beta-3 adrenergic agonist mirabegron may be given. Unlike tamsulosin,mirabegron does not worsen orthostatic hypotension.
Urinary incontinence: If the cause is detrusor hyperreflexia, oxybutynin or tolterodine may be used. Tamsulosin may be effective for urinary urgency. Alternatively, mirabegron can be used. If the cause is detrusor hyperreflexia, oxybutynin or tolterodine may be used. Tamsulosin may be effective for urinary urgency. Alternatively, mirabegron can be used.
Urinary retention: Self-catheterization of the bladder may be needed. Sometimes medications that induce bladder contraction (eg, bethanechol) are given.Self-catheterization of the bladder may be needed. Sometimes medications that induce bladder contraction (eg, bethanechol) are given.
Sweating abnormalities: Hot conditions should be avoided.
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.
Key Points
Pure autonomic failure, like Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, is a synucleinopathy.
The main symptom is orthostatic hypotension.
Diagnose by confirming orthostatic hypotension with supporting features.
Use treatments specific for the symptoms present.
Drugs Mentioned In This Article
