The cardinal symptom of PAF is orthostatic hypotension, which is defined as a reduction of systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg within 3 minutes of standing [1]. PAF patients typically present during mid-adulthood and experience lightheadedness, nausea, and syncopes [2]. They may report that fainting can be prevented if they squat, sit, or lie down. The same applies to other symptoms triggered by the hypoperfusion of tissues situated above the heart. For instance, insufficient blood supply to the neck musculature may induce postural coat-hanger headaches [3].

Patients may also have a slow, unchanging pulse rate and suffer from anhidrosis, xerostomia, constipation or diarrhea, and erectile dysfunction. Urinary symptoms are not usually observed until advanced stages of the disease and may comprise recurrent urinary tract infections and nocturia [4] [5]. Sleep apnea and respiratory disorders, as commonly observed in multiple system atrophy and Parkinson’s disease with autonomic features, are rarely seen in PAF patients [5].

There are no associated cognitive, motor, or sensory deficits.

• Pain

  Chest pain occurred mainly in patients with PAF (44% PAF, 13% MSA). Improvement occurred with sitting or lying flat. [ncbi.nlm.nih.gov]

  Chest pain, fatigue and sexual dysfunction are less common symptoms that may also occur. Symptoms are worse when standing; sometimes one may relieve symptoms by lying down. [psychology.wikia.org]

  focal brain disorders; focal spinal cord disorders; and chronic pain disorders with autonomic manifestations. [books.google.com]

• Weakness

  Abstract We wished to determine whether ibopamine, a dopaminergic prodrug with weak agonist activity on alpha- and beta-adrenoceptors, improves orthostatic tolerance in autonomic insufficiency. [ncbi.nlm.nih.gov]

  Monitor for signs of weakness and light-headedness at home.... 2 Thaisetthawatkul P. Pure autonomic failure. Curr Neurol Neurosci Rep. 2016;16... [5minuteconsult.com]

  There is a gradual onset of symptoms that include orthostatic weakness, urinary incontinence or retention, sexual problems, and sometimes inability to sweat, bowel problems, and dry mouth. [njfaint.com]

• Asymptomatic

  […] with a large range of manifestations including neonatal hyperammonemic encephalopathy with lethargy, seizures and coma; hepatic dysfunction in all age groups; episodes of hyperammonemia and neuropsychiatric symptoms in children or adults, or, can be asymptomatic [orpha.net]

  There are even milder forms with only mildly increased citrulline that might remain asymptomatic for life (periodic monitoring without therapy is recommended in these forms). [medicalhomeportal.org]

  The condition, which may be symptomatic or asymptomatic, is encountered commonly in family medicine. [aafp.org]

  OH may be asymptomatic or symptomatic. Clinical manifestations of OH are reported in table 1. [karger.com]

  Asymptomatic patients were not under treatment with fludrocortisone and midodrine; ACE-inhibitors were more frequently used in the asymptomatic group (72%) than in the symptomatic one (25%) (p=0.001). [functionalneurology.com]

• Amyloidosis

  Research affiliations include the Functional Imaging Laboratory at the ION, the ICN, the Department of Medicine at UCL, and the National Amyloidosis Centre at the Royal Free Hospital. [uclh.nhs.uk]

  […] beta-hydroxylase deficiency (see this term), which is ruled out by the presence of plasma noradrenaline in patients affected by orthostatic hypotension that is considered idiopathic, primary or secondary peripheral polyneuropathy (including diabetes, amyloidosis [orpha.net]

  It may result from a primary disturbance of autonomic regulation or more commonly as a secondary effect of another systemic disorder (eg, diabetes, amyloidosis). [emedicine.medscape.com]

  Other cases of autonomic failure may be secondary to other illnesses, such as diabetes, kidney failure, and amyloidosis. [njfaint.com]

• Anemia

  Other drugs are subject to ongoing trials (pyridostigmine, droxidopa) or are designed for particular situations such as anemia (erythropoietin) or postprandial hypotension (octreotide). [orpha.net]

  True anemia: incidence and significance in the elderly. Geriatrics. 1989; 44: 33–36.Google Scholar [ahajournals.org]

  True anemia: incidence and significance in the elderly. Geriatrics. 1989 ; 44 : 33–36. Google Scholar [hyper.ahajournals.org]

• Hypotension

  Ratna Bhavaraju-Sanka Other names: Idiopathic orthostatic hypotension, Bradbury-Eggleston Syndrome, Neurogenic orthostatic hypotension Cardinal Features: • Idiopathic orthostatic hypotension (Drop in BP by 20 mm Hg systolic or 10 mm diastolic) within [americanautonomicsociety.org]

  All patients had severe symptomatic postural hypotension, without neurological deficits. [ncbi.nlm.nih.gov]

  The overall prevalence of orthostatic hypotension in patients aged >65 years has been estimated at 20%, yet neurogenic orthostatic hypotension due to synucleinopathies is an orphan condition. [symptoma.com]

• Orthostatic Hypotension

  Ratna Bhavaraju-Sanka Other names: Idiopathic orthostatic hypotension, Bradbury-Eggleston Syndrome, Neurogenic orthostatic hypotension Cardinal Features: • Idiopathic orthostatic hypotension (Drop in BP by 20 mm Hg systolic or 10 mm diastolic) within [americanautonomicsociety.org]

  Lack of these features does not exclude the need to assess and investigate orthostatic hypotension and possible autonomic failure. [ncbi.nlm.nih.gov]

  The overall prevalence of orthostatic hypotension in patients aged >65 years has been estimated at 20%, yet neurogenic orthostatic hypotension due to synucleinopathies is an orphan condition. [symptoma.com]

  Idiopathic orthostatic hypotension, sometimes also referred to as Bradbury-Eggleston syndrome, falls into this general category. [emedicine.medscape.com]

• Heart Failure

  failure hospitalization Increase in death/MI/stroke; death; CV death; non-fatal MI; heart failure hospitalization Increase in death/MI/stroke; non-fatal stroke; heart failure hospitalization Not evaluated Increase in death/MI/stroke; non-fatal stroke [academic.oup.com]

  Thus, the use of spironolactone has been associated with better prognosis in patients with heart failure,4 while it has been pointed out that treatment with doxazosin has been related with a higher incidence of heart failure, although it seems that this [revespcardiol.org]

  Abnormalities of the QT interval in primary disorders of autonomic failure. Am Heart J 1998;136:664-671 32 Goldstein DS. Cardiac ectopy in chronic autonomic failure. Clin Auton Res 2010;20:85-92 [functionalneurology.com]

  failure, myocardial infarction, arrhythmia, pericarditis, or myocarditis Swollen extremities, edema Congestive heart failure, venous obstruction, prolonged sitting or standing (resulting in venous pooling) Symptoms on awakening or after a meal Venous [aafp.org]

• Palpitations

  Compensatory autonomic symptoms, such as palpitations and sweating, did not occur in either group. [ncbi.nlm.nih.gov]

  After the death of her father, clinical manifestations such as warm sensations all over the body, trembles, dizziness, palpitations and feeling of "needles pricking her skin" emerged. [mathewsopenaccess.com]

  This can cause lightheadedness, fainting, and heart palpitations. Injury to nerves from conditions like diabetes and Parkinson’s disease can cause episodes of orthostatic hypotension due to autonomic dysfunction. [healthline.com]

  Nausea, headaches, pain, palpitations, were all a daily part of life. My feet and legs would turn a deep red and ache. My eyes would hurt and vision became strained. [dinet.org]

  Other orthostatic symptoms ( for example, nausea, palpitations, light-headedness, tinnitus, shortness of breath). Syncope (may occur with micturition, defecation). Inability to stand without syncope (severe cases). Arrhythmias. Supine hypertension. [patient.info]

• Decreased Sweating

  She also had constipation, decreased sweating, and urinary disturbance. Despite treatment with ephedrine and fludrocortisone acetate, her symptoms worsened dramatically at age 78 years while she was bedridden because of a vertebral fracture. [jamanetwork.com]

  Signs and symptoms Symptoms of decreased sympathetic function may include the following: Orthostatic hypotension Decreased sweating Ejaculatory dysfunction Ptosis associated with Horner syndrome Symptoms of decreased parasympathetic function may include [emedicine.medscape.com]

  The syndrome is a sporadic neurodegenerative disorder which is characterized by symptoms like orthostatic hypotension, syncope, light headedness, dizziness or faintness ,decreased sweating and erectile dysfunction. [medium.com]

  Orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweating abnormalities (increased or decreased sweating) are common problems. [ 7 ] History Autonomic nerve fibres are affected in most symmetrical peripheral neuropathies; [patient.info]

• Neck Pain

  In MSA, despite substantial orthostatic hypotension, fewer patients had syncope, visual disturbance and neck pain; the reasons for this are unclear. [ncbi.nlm.nih.gov]

  For example, if your condition causes high blood pressure and neck pain, then the VA will rate both. The DoD will only rate the symptoms that interfere with your ability to do your job. [blog.militarydisabilitymadeeasy.com]

  Dizziness or near syncope within seconds after standing, after a large meal (especially carbohydrate heavy), or in hot weather Hypertension when lying flat Neck pain in coat hanger dist... Encourage physical exercise; avoid immobility. [5minuteconsult.com]

  SymptomsEdit A degenerative disease of the autonomic nervous system, symptoms include dizziness and fainting (caused by orthostatic hypotension), visual disturbances and neck pain. [psychology.wikia.org]

  Symptoms A degenerative disease of the peripheral nervous system, symptoms include dizziness and fainting (caused by orthostatic hypotension ), visual disturbances and neck pain. [dysautonomiaconnection.org]

• Myalgia

  […] intestinal issues (reflux, nausea, constipation, diarrhea), slow or rapid heartbeat (tachycardia), excessive sweating (hyperhidrosis), perspiration depletion (anhidrosis), nerve pain or numbness (paresthesia or neuropathy), and joint pain (arthralgia or myalgia [clinicalposters.com]

• Dizziness

  Postural symptoms (mainly dizziness and neck pain) were worse in the morning and with warm temperature, straining, exertion, arm movements and food ingestion; they were more common in PAF. [ncbi.nlm.nih.gov]

  […] upright position by 30 mm Hg systolic • No history of Parkinsonism • May have problems with bladder and sexual function • Commonly seen in mid-late adulthood • Synucleopathy with synuclein deposits in lewy bodies found in autonomic ganglia Symptoms: • Dizziness [americanautonomicsociety.org]

  The condition usually causes a person to feel dizzy or lightheaded. Sometimes, orthostatic hypotension can cause a person to faint. [nyulangone.org]

• Headache

  Periodic Fevers & Flare-ups Often, NOMID syndrome causes bouts of fevers (starting in infancy), accompanied by flare-ups of the rash, increased pain in the joints, headaches, red eyes and other symptoms. [autoinflammatory.org]

  Neurocardiogenic Syncope response. i have some neuropathy as mentioned but whatever has caused the autonomic failing which triggered the PTS has likely also caused some neuropathy. and i am doing much much better today, but not before things got worse. the headaches [medhelp.org]

  Acrocyanosis is present in 40-50% of patients, headaches malaise, and cognitive impairment. [clinicalposters.com]

  Central nervous system involvement is revealed by chronic headaches due to chronic meningitis with granulocytes. In the severe forms, intellectual deficit can occur. [orpha.net]

  Over half of these patients experience migraine headaches as well as a significant increase in urinary output after being upright for only a short period of time. [justmildlymedicated.com]

• Tremor

  Three years later, he developed resting tremor in the right limbs, associated with bradykinesia. Brain DAT-SCAN was altered and a diagnosis of PD was made. [mdsabstracts.org]

  A type of tremor of the hands that is characteristic of Parkinson’s disease, known as a pill-rolling tremor, does not occur in MSA patients1. [multiplesystematrophy.org]

  […] hypotension predominates, patients with Multiple System Atrophy can develop muscular stiffness / rigidity (similar to Parkinson’s Disease), and other patients can become uncoordinated with difficulty standing and walking, slurred speech, and at times a tremor [njfaint.com]

  He was managed with midodrine 15 mg daily and fludrocortisone 0.1 mg daily. 3 years later, he developed resting tremor in the right hand and foot associated with mild bradykinesia. [onlinelibrary.wiley.com]

  They could confirm that the presence of subtle motor signs as slight gait imbalance or subtle tremor at the time of PAF diagnosis were risk factors for a phenoconversion to both, MSA or PD/DLB even if those findings at the time of study entry were too [ean.org]

• Polyneuropathy

  Abstract The haemodynamic and catecholamine responses to supine exercise, and the effect on standing blood pressure (BP), were studied in three groups with peripheral autonomic dysfunction; insulin-dependent diabetes mellitus (IDDM), familial amyloid polyneuropathy [ncbi.nlm.nih.gov]

  In our case of a female patient aged 75 years with recurrent syncopes, detection of reversed sympathetic innervation in MIBG-SPECT, pathological quantitative sudomotor axon reflex test, small fiber polyneuropathy in skin biopsy, and evidence of severe [thieme-connect.com]

  […] orthostatic hypotension, dopamine beta-hydroxylase deficiency (see this term), which is ruled out by the presence of plasma noradrenaline in patients affected by orthostatic hypotension that is considered idiopathic, primary or secondary peripheral polyneuropathy [orpha.net]

  A rare but dramatic presentation is known as Acute Autonomic Failure or “acure panautonomic polyneuropathy.” [njfaint.com]

• Vertigo

  Such tests have the goal of ruling out Ménière Disease (with a series of hearing tests) to focus on Benign Positional Proximal Vertigo (BPPV). A gastroenterologist performs an endoscopy to identify obstructions or ulcers. [clinicalposters.com]

  Common symptoms include: an inability to stay upright dizziness, vertigo, and fainting fast, slow, or irregular heartbeat chest pain low blood pressure problems with the gastrointestinal system nausea disturbances in the visual field weakness breathing [medicalnewstoday.com]

  I was dismissed as probably having some vertigo again. I went back twice to the doctor to tell them this was different. The doctor finally agreed to run some tests, but it was too late! [dinet.org]

  As a result, symptoms of central nervous system hypoperfusion may occur, including feelings of weakness, nausea, headache, neck ache, lightheadedness, dizziness, blurred vision, fatigue, tremulousness, palpitations, and impaired cognition. 1 Vertigo also [aafp.org]

• Sexual Dysfunction

  dysfunction like impotence, erectile and ejaculatory problems Signs: • Fall in blood pressure by >20 mm systolic or 10 mm diastolic after at least 1 minute of standing. • Abnormal autonomic testing showing autonomic insufficiency. • low supine norepinephrine [americanautonomicsociety.org]

  These diseases are pure autonomic failure, in which autonomic impairment (that is, orthostatic hypotension and bladder and sexual dysfunction) occurs alone; Parkinson disease, in which autonomic failure is combined with an extrapyramidal movement disorder [annals.org]

  Chest pain, fatigue and sexual dysfunction are less common symptoms that may also occur. Symptoms are worse when standing; sometimes one may relieve symptoms by lying down. [psychology.wikia.org]

  The second section focuses on the pathophysiology and management of orthostatic hypotension, postural tachycardia, baroreflex failure; syncope, disorders of sweating, neurogenic bladder and sexual dysfunction, gastrointestinal dysmotility, and autonomic [books.google.com]

• Nocturia

  Changes in urination including nocturia (the need to urinate during the night), urinary hesitancy (difficulty starting or maintaining a urinary stream), urgency, dribbling, and occasional incontinence. [mc.vanderbilt.edu]

  Urinary symptoms are not usually observed until advanced stages of the disease and may comprise recurrent urinary tract infections and nocturia. [symptoma.com]

  She described other dysautonomic symptoms such as constipation and voiding problems: tenesmus and nocturia. She also presented a decrease in olfaction (7/12 in the BSIT). [elsevier.es]

• Kidney Failure

  Other cases of autonomic failure may be secondary to other illnesses, such as diabetes, kidney failure, and amyloidosis. [njfaint.com]

  Resistant hypertension substantially increases the risk of heart attack, stroke and kidney failure. What You Need to Know Twenty percent of patients with hypertension are resistant. [hopkinsmedicine.org]

  Kidney-failure risk projection for the living kidney-donor candidate.N Engl J Med. 2016; 374:411–421. doi: 10.1056/NEJMoa1510491CrossrefMedlineGoogle Scholar 301. Kuznik A, Mardekian J, Tarasenko L. [ahajournals.org]

• Renal Insufficiency

  Renal artery stenosis is recognized to produce a wide spectrum of manifestations ranging from an incidental, asymptomatic finding to accelerated hypertension and renal insufficiency. [ahajournals.org]

The diagnosis of PAF is based on clinical findings and is not usually confirmed until symptoms have persisted for a minimum of 5 years [5]. As the disease name implies, these symptoms are confined to the autonomic nervous system, and PAF does not affect sensory or motor skills. Indeed, the absence of non-autonomic neurological deficits has been defined as a major diagnostic criterion for PAF and helps to distinguish PAF from other diseases of the nervous system that may present with autonomic features [1].

Various neurophysiological tests may be conducted to demonstrate dysfunctions of the autonomic nervous system [5]:

• The quantitative sudomotor axon reflex test is a useful tool in the evaluation of postganglionic sympathetic function and sudomotor activity. In patients suffering from PAF and other diseases that interfere with the postganglionic part of the sudomotor pathway, the sweating response is delayed.
• The thermoregulatory sweat test provides a quantitative measure of the patient's ability to respond to heat and humidity by sweating. Abnormalities in sweating, namely in sweat patterns, are often seen in PAF patients and in individuals with other small fiber neuropathies.
• Cardiovagal tests such as the heart-rate response to deep breathing may reveal anomalies in the parasympathetic control of cardiac function. Under physiological conditions, variations of the heart rate can be observed between inspiration and expiration. The difference is reduced in patients with PAF, with other synucleinopathies or neuropathies.
• Valsalva maneuvers increase and subsequently ease the intrathoracic pressure and should be followed by adjustments of the heart rate and blood pressure. The Valsalva ratio is defined as the ratio between the maximum and minimum heart rates registered during specific phases of the Valsalva maneuver and allows for conclusions regarding the possibly dysfunctions of the autonomic nervous system.
• The vascular response to head-up tilt helps to evaluate the integrity of the cardiovascular functions of the autonomic nervous system.

Findings can be related to deficiencies in norepinephrine release by measuring plasma concentrations of catecholamines in the supine and standing position: PAF is characterized by low supine plasma norepinephrine levels that barely increase on standing. Interestingly, PAF patients may be hypertensive when in a supine position and may experience considerable increases of blood pressure upon fluid intake and exposure to pressor agents [3]. Both increased vascular resistance from loss of adequate baroreceptor reflex buffering and postsynaptic adrenoceptor hypersensitivity have been suggested as possible explanations for this phenomenon.

Furthermore, 123I-MIBG single-photon emission computed tomography and 6-[18F] fluorodopamine positron emission tomography may show decreased sympathetic innervation of the heart [4]. Nerve conduction studies, on the other hand, will yield no evidence of any sensory-motor neuropathy.

Skin biopsy samples may be obtained and examined for the presence of α-synuclein aggregates in nerve fibers innervating the sweat glands. These insoluble deposits result in neuronal cytoplasmic inclusions called Lewy bodies and are considered the neuropathological hallmark of PAF [3]. Histological analyses account for the formation of Lewy bodies in the vast majority of patients, although a lack thereof has been described in isolated cases [6]. This adds to the confusion as to the pathophysiological role of α-synuclein and stresses the need for a correlated interpretation of all findings.

There is no causal treatment. Patients must be provided supportive care including physical therapy, counseling regarding dietary and environmental adjustments, and medication. In general, it is important to alleviate daytime hypotension without exacerbating supine hypertension at night, which may require the combination of vasopressor and antihypertensive treatment in a rigorously time-dependent regimen [3].

Simple measures such as performing isometric exercises before standing, standing up slowly, and avoiding prolonged standing may help to alleviate the symptoms of orthostatic hypotension. The use of compressive garments such as support stockings and abdominal binders follows a similar purpose. Because symptoms tend to worsen with heat exposure and after the ingestion of larger meals, patients should be recommended to prefer small, frequent meals over larger portions, and to avoid warm and humid environments. They should be informed about the benefits of adequate hydration, drinking at least 3 liters of water per day, and the abstinence from alcohol. Moreover, patients should be advised to increase their salt intake and add about 500 mg of salt to each of their meals [7]. They should also elevate the head of their bed at night to avoid being in a supine position for an extended period of time [3].

If these measures prove to be insufficient, fludrocortisone and/or midodrine may be administered [8]. The former is a sodium-retaining, hypokalemic mineralocorticoid; the latter acts as an α1 adrenergic agonist and pressure agent. Beyond that, norepinephrine precursor droxidopa, cholinesterase inhibitor pyridostigmine, and somatostatin analog octreotide may be given to augment the standing blood pressure, to elevate diastolic blood pressure, and to prevent postprandial hypotension, respectively [3]. The treatment schedule must be adjusted to the individual needs of the patient, which, in turn, may vary according to the activities planned for every day [7].

PAF follows a progressive, yet generally indolent course. Patients are troubled by worsening orthostatic hypotension and other symptoms of sympathetic and parasympathetic dysregulation, which may leave them confined to their homes in a reclined position. Yet they may survive for 10-20 years after symptom onset [9].

PAF patients are at increased risks of cardiovascular pathologies, however, and these pathologies may reduce their life expectancy. This is due to the fact that supine hypertension predisposes to left ventricular hypertrophy and atherosclerosis [10]. The patients' prognosis also changes if additional symptoms develop that require a change of diagnosis: PAF may transform into dementia with Lewy bodies (18%), Parkinson's disease with autonomic features (8%), or multiple system atrophy (8%). This may occur at any time and cannot be predicted with any certainty, although very low plasma levels of norepinephrine, bradycardia, preserved smell, and the absence of any REM sleep behavior disorder have been named as favorable prognostic factors [5].

PAF develops sporadically and its causes remain unknown.

Orthostatic hypotension is a frequent and disabling problem in patients with synucleinopathies, but such conditions account for a minority of cases only. The overall prevalence of orthostatic hypotension in patients aged >65 years has been estimated at 20%, yet neurogenic orthostatic hypotension due to synucleinopathies is an orphan condition [8]. Beyond that, detailed information regarding the epidemiology of PAF cannot be provided.

Disease onset is usually in the fifth to seventh decade of life, and no significant differences by gender, race, or ethnicity have been reported.

PAF is related to the deposition of α-synuclein in the autonomic ganglia and axons of autonomic neurons, while peripheral tissues are affected to a lesser extent. To date, it remains unknown whether the presence of protein aggregates is the cause of progressive cellular dysfunction or merely a concomitant phenomenon, but neurodegeneration does occur and neurotransmitter release is increasingly disturbed in PAF patients. This is best demonstrated by their irresponsiveness to yohimbine, an antagonist to the α2 adrenergic receptor that inhibits the negative feedback on norepinephrine release by binding to presynaptic adrenoceptors: If there is no norepinephrine in the synaptic cleft - as is the case in PAF patients - blockage of the negative feedback loop must have little to no effect [5].

Symptoms like orthostatic hypotension mainly result from deficient neurotransmission in the sympathetic branch of the autonomic nervous system. In short, baroreceptors located in the carotid sinuses and aortic arch are activated at low blood pressure levels and send a signal to the brain demanding an increase of the heart rate, stroke volume, and vascular resistance. To accomplish this task, the sympathetic tone must be augmented while the parasympathetic tone must be reduced, and this information must be transmitted to the target organs. Due to deficiencies in sympathetic neurotransmission, however, this buffering system is lost in patients with PAF. The short-term regulation of low blood pressure is no longer possible, and affected individuals are unduly sensitive to any stressor that disturbs the delicate equilibrium of blood pressure [3].

Due to large knowledge gaps regarding the etiology of PAF, no recommendations can be given to prevent this disease. The triggers of transformation are not yet understood either, and no measures can be described to lower the individual risk of developing even more severe synucleinopathies.

PAF has first been described by Bradbury and Eggleston in 1925, and it remains poorly understood until today. It is a rare neurodegenerative disease of insidious onset that is generally associated with the formation of Lewy bodies in sympathetic ganglia and postganglionic sympathetic axons, although aggregates of α-synuclein have also been found in the substantia nigra and locus ceruleus. Little is known about the causes of these anomalies. What's more, the fact that PAF may transform into other synucleinopathies with central nervous system involvement raises the question whether PAF is indeed an autonomic-specific synucleinopathy or rather an early stage of even more complex disorders [11]. Additional research is required to better understand the etiology of PAF and to identify its true position in the spectrum of synucleinopathies. This way, new therapeutic targets could be identified and treatment strategies developed to relieve affected individuals from their often disabling orthostatic hypotension and other symptoms of autonomic nervous system dysfunction.

Pure autonomic failure (PAF) is a rare neurodegenerative disorder of unknown cause. It is associated with the dysregulation of many processes controlled by the autonomic nervous system, especially the sympathetic branch. The latter is essential for the short-term regulation of low blood pressure, and deficiencies in sympathetic neurotransmission leave patients prone to orthostatic hypotension and cerebral hypoperfusion. PAF patients thus experience lightheadedness, nausea, and tend to faint when standing up, and they have exaggerated responses to common stimuli such as food or fluid intake, environmental heat, exercise, and medications. They may also suffer from an inability to sweat normally, a dry mouth, excessively hard stools or diarrhea, and erectile dysfunction.

There is no causal therapy. Symptoms may improve, however, by adopting simple measures such as performing isometric exercises before standing, standing up slowly, and avoiding prolonged standing, or the use of compressive stockings and abdominal binders. PAF patients should drink at least 3 liters a day and increase their salt intake, and they are advised to prefer small, frequent meals over large ones that are rich in carbohydrates. If these and additional measures recommended by the treating physician prove to be insufficient, drug therapy must be considered. There are distinct agents that may help to alleviate the complaints of the individual patient, whereby the treatment regimen must be adjusted to their specific needs.

1. The Consensus Committee of the American Autonomic Society and the American Academy of Neurology. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. J Neurol Sci. 1996; 144(1-2):218-219.
2. Claassen DO, Adler CH, Hewitt LA, Gibbons C. Characterization of the symptoms of neurogenic orthostatic hypotension and their impact from a survey of patients and caregivers. BMC Neurol. 2018; 18(1):125.
3. Brown TP. Pure autonomic failure. Pract Neurol. 2017; 17(5):341-348.
4. Fanciulli A, Stefanova N, Scherfler C, et al. Very late-onset pure autonomic failure. Mov Disord. 2017; 32(7):1106-1108.
5. Kabir MA, Chelimsky TC. Pure autonomic failure. Handb Clin Neurol. 2019; 161:413-422.
6. Isonaka R, Holmes C, Cook GA, Sullivan P, Sharabi Y, Goldstein DS. Pure autonomic failure without synucleinopathy. Clin Auton Res. 2017; 27(2):97-101.
7. Mader SL. Identification and management of orthostatic hypotension in older and medically complex patients. Expert Rev Cardiovasc Ther. 2012; 10(3):387-395.
8. Palma JA, Kaufmann H. Epidemiology, Diagnosis, and Management of Neurogenic Orthostatic Hypotension. Mov Disord Clin Pract. 2017; 4(3):298-308.
9. Goldstein DS, Holmes C, Sharabi Y, Wu T. Survival in synucleinopathies: A prospective cohort study. Neurology. 2015; 85(18):1554-1561.
10. Milazzo V, Maule S, Di Stefano C, et al. Cardiac Organ Damage and Arterial Stiffness in Autonomic Failure: Comparison With Essential Hypertension. Hypertension. 2015; 66(6):1168-1175.
11. Muppidi S, Miglis MG. Is pure autonomic failure an early marker for Parkinson disease, dementia with Lewy bodies, and multiple system atrophy? And other updates on recent autonomic research. Clin Auton Res. 2017; 27(2):71-73.