Last updated:
8/13/2025
Years published: 2018, 2025
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Caroline Kim, NORD Editorial Intern from the Keck Graduate Institute and Italo Biaggioni, MD, Professor of Medicine and Pharmacology, Associate Director, Clinical Research Center, Vanderbilt Autonomic Dysfunction Center, Vanderbilt University Medical Center, for assistance in the preparation of this report.
Summary
Pure autonomic failure (PAF) is a rare, sporadic neurodegenerative disorder characterized by neurogenic orthostatic hypotension (OH) without other central neurological signs at onset.
This condition is mainly caused by the buildup of a protein called alpha-synuclein in the nerves of the autonomic nervous system, the part of the nervous system that controls automatic body functions such blood pressure, heart rate, digestion, body temperature and bladder function. When the alpha-synuclein accumulates in the nerves, it disrupts how this system works, leading to autonomic dysfunction.
The main symptom is orthostatic hypotension, which is a sudden and significant drop in blood pressure when standing up from a lying or sitting position, often causing dizziness or fainting. The autonomic dysfunction can also affect other body systems, leading to symptoms such as urinary problems (like urgency, frequency, or difficulty emptying the bladder), digestive issues (such as constipation), problems with temperature regulation (like heat intolerance or unusual sweating) and others. There is no cure yet. Treatment involves managing the specific symptoms that the affected person has.
Introduction
PAF is classified under α-synucleinopathies, and, although traditionally viewed as a peripheral disorder, in some cases PAF may evolve into central nervous system (CNS) synucleinopathies such as Parkinson’s disease (PD), multiple system atrophy (MSA), or dementia with Lewy bodies (DLB). For this reason, some researchers think that PAF isn’t a distinct disease, but rather an early stage or precursor to these other conditions.
Pure autonomic failure (PAF) is characterized by orthostatic hypotension, typically in the context of more widespread autonomic failure, without other neurological features.
The first and most noticeable symptom is orthostatic hypotension, defined as a drop in systolic BP ≥ 20 mmHg or diastolic BP ≥ 10 mmHg within 3 minutes of standing. Systolic pressure is the maximum blood pressure during contraction of the ventricles; diastolic pressure is the minimum pressure recorded just prior to the next contraction. The blood pressure is usually described as the systolic pressure over the diastolic pressure (e.g., 120/80 mm Hg).
Due to the drop in blood pressure, people can have dizziness or faintness including syncope (loss of consciousness) in severe cases.
Additional symptoms may include:
Symptoms worsen with prolonged standing, warm environments, postprandial states and in the mornings. Relief is usually achieved by lying down.
Pure autonomic failure (PAF) is a condition linked to the buildup of a protein called alpha-synuclein in the autonomic nerves, which are nerves outside the brain and spinal cord. This same protein is involved in other neurological disorders like Parkinson’s disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB). The difference is in where and how the protein builds up.
In PAF, the abnormal protein mainly affects the autonomic nervous system, which controls automatic body functions like blood pressure, digestion and temperature regulation. This is different from MAS, where the protein builds up mostly in support cells in the brain and from Parkinson’s disease and Lewy Body Dementia, where it affects the central nervous system (brain and spinal cord) early and progressively.
Although PAF starts in the peripheral (outside the brain) nervous system, about 12–34% of people with PAF may later develop more widespread brain involvement. This change is called phenoconversion, meaning that the disease may progress into other synucleinopathies such as multiple system atrophy (MSA), Parkinson’s disease, or dementia with Lewy bodies. This can take 10 or more years to happen.
Studies have identified possible signs of phenoconversion, which include the development of subtle motor signs (like mild slowness or tremor), urinary or sexual dysfunction, changes on speech or swallowing, changes on smell sense, cognitive decline, neuropsychiatric symptoms (such as hallucinations), or REM sleep behavior disorder.
People who convert to MSA tend to be younger and have higher noradrenaline levels early on. Those who develop Lewy body dementia are usually older at the time of diagnosis. People who later developed Parkinson’s disease had a more severely blunted heart rate response to standing, while those who developed MSA had more intense symptoms related to urination and sweating. Recognizing these signs early may help guide monitoring and care and could be important in identifying people who might benefit from future treatments aimed at slowing or preventing progression.
The worldwide prevalence of PAF is not known. The age of onset is during adulthood usually in individuals over 60 years. It is more common in males than females.
Pure autonomic failure is diagnosed only after other possible conditions, especially those affecting movement, memory, or thinking, have been ruled out. This is known as a “diagnosis of exclusion.” To confirm PAF, doctors look for a few key findings.
First, the patient must have consistent orthostatic hypotension, which means a significant drop in blood pressure when standing up, but without signs of brain or spinal cord involvement like tremors, difficulty moving, or memory problems. Blood tests often show that levels of norepinephrine, a chemical that helps regulate blood pressure, are low and do not increase as they should when the person stands. Imaging of the brain using a DaTscan (an image test which shows dopamine activity) is usually normal early on, helping to rule out Parkinson’s disease.
If the person also has REM sleep behavior disorder, acting out dreams during sleep, along with low blood pressure when standing, this may support a diagnosis of PAF. However, because this sleep disorder is also linked to other brain-related diseases, close monitoring over time is important.
To fully assess the autonomic nervous system, the part that controls automatic functions like blood pressure, heart rate, sweating and digestion, doctors use a range of tests. These may include continuous blood pressure monitoring throughout the day, tilt table testing (which measures blood pressure changes with position) and tests that track how the heart responds to deep breathing or to pressure changes created by blowing into a tube.
Sweating function is also tested, since impaired sweat response is a common feature in PAF. One test uses heat to trigger full-body sweating, while another uses a mild electrical stimulus to check how individual areas of skin respond. These tests help show whether the problem lies in the nerves that directly control sweat glands.
Blood samples may be taken while lying down and standing to measure levels of stress hormones like norepinephrine and adrenaline. In PAF, these levels tend to stay low, even when standing, suggesting the nerves involved in blood pressure control are damaged.
Imaging tests like the MIBG heart scan can reveal if the nerves that regulate heart function are impaired, which is common in PAF. A skin biopsy might be done in rare cases to look for abnormal protein deposits and bladder testing may be used if the person has urinary symptoms. Spinal fluid testing can sometimes identify warning signs for progression to more serious conditions like multiple system atrophy, though it’s not part of routine diagnosis.
Other optional evaluations include tests that look at how blood pressure changes after meals or exercise.
Since certain medications can interfere with test results, like blood pressure drugs, antihistamines, or opioids, people might need to stop taking them temporarily before testing.
In complex cases, a combination of tests such as measuring eye reflexes, sweat responses and hormone levels, can help distinguish PAF from other similar neurological conditions like Parkinson’s disease or multiple system atrophy.
Treatment
There is currently no specific treatment for PAF and treatment focuses on decreasing the effects of the symptoms.
Non-medical measures for sudden changes in blood pressure include tight compression stockings, standing up slowly, increase in salt and water intake and abdominal binders. These measures are taken to stabilize the sudden changes in blood pressure. Consuming more salt and water may increase the volume of blood and thus help increase blood pressure. Standing up slowly may prevent blood pressure from decreasing too much or too fast. Wearing compression stockings or abdominal binders helps maintain blood pressure by promoting blood flow from the legs to the heart and prevents too much blood from staying in the low parts of the body. Raising the head of the bed by about 4 inches can help prevent blood pressure from increasing too much when lying down.
Symptoms of constipation can be managed with high-fiber diet and stool softeners. Problems with urination can be resolved by insertion of a thin rubber tube (catheter) into the bladder.
Several medications are used to help raise blood pressure and reduce symptoms like dizziness or fainting:
Supine hypertension can be managed with medications such as nifedipine, captopril, losartan, transdermal nitroglycerine, hydralazine and clonidine.
Finding the right balance between treating low and high blood pressure is one of the biggest challenges in managing PAF. Medications may need to be carefully timed or adjusted throughout the day.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Coon EA, Badihian N, McCarter SJ, et al. The phenotype of “pure” autonomic failure. Clin Auton Res. 2025;35(3):477-485. doi:10.1007/s10286-025-01121-z
Koay S, Vichayanrat E, Bremner F, et al. Multimodal Autonomic Biomarkers Predict Phenoconversion in Pure Autonomic Failure. Ann Clin Transl Neurol. Published online July 22, 2025. doi:10.1002/acn3.70140
Pavy-Le Traon A, Foubert-Samier A, Fabbri M. An overview on pure autonomic failure. Rev Neurol (Paris). 2024;180(1-2):94-100. doi:10.1016/j.neurol.2023.11.003
Bhattacharjee S, Alsukhni RA. Pure Autonomic Failure-A Localized Alpha Synucleinopathy with a Potential for Conversion to More Extensive Alpha Synucleinopathies. Ann Indian Acad Neurol. 2022;25(3):340-346. doi:10.4103/aian.aian_1078_21
Mabuchi N. Progression and prognosis in pure autonomic failure (PAF): comparison with multiple system atrophy. Journal of Neurology, Neurosurgery & Psychiatry. 2005;76(7):947-952. doi:10.1136/jnnp.2004.049023
Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. The Journal of Clinical Hypertension 2002;4(2):139-145. doi:10.1111/j.1524-6175.2001.00516.x
Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology. 1996;46(5):1470-1470. doi:10.1212/wnl.46.5.1470
Bradbury S, Eggleston C. Postural hypotension. American Heart Journal. 1927;3(1):105-106. doi:10.1016/s0002-8703(27)90177-x
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