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.

• Wheelchair Bound

  […] of them were wheelchair bound and spent a considerable amount of their waking time lying down. [jnnp.bmj.com]

• Recurrent Urinary Tract Infection

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

• Hypotension

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

  Pure autonomic failure Other names Bradbury-Eggleston syndrome, idiopathic orthostatic hypotension Specialty Neurology Symptoms primarily the same as orthostatic hypotension Complications primarily the same as orthostatic hypotension; can convert to synucleinopathy [en.wikipedia.org]

• Orthostatic Hypotension

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

  Pure autonomic failure Other names Bradbury-Eggleston syndrome, idiopathic orthostatic hypotension Specialty Neurology Symptoms primarily the same as orthostatic hypotension Complications primarily the same as orthostatic hypotension; can convert to synucleinopathy [en.wikipedia.org]

• Eye Movements Abnormal

  The following neurologic features may also be present: Pyramidal or cerebellar abnormalities: Weakness, ataxia, incoordination, and eye-movement abnormalities may precede the autonomic features by as long as 2 years Variable parkinsonian findings: Found [emedicine.medscape.com]

• 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]

  Signs and symptoms[edit] A degenerative disease of the autonomic nervous system, symptoms include dizziness and fainting (caused by orthostatic hypotension), visual disturbances and neck pain. [en.wikipedia.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]

  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]

• Cerebellar Ataxia

  Cerebellar ataxia affects gait, though in a different way than the unsteady, shuffling gait of Parkinson’s disease. [multiplesystematrophy.org]

• Slow Speech

  She also had some depressive symptoms as: depressed mood for more than 6 months, an inability to experience pleasure in everyday activities, sad facial appearance, slow speech and inconsistent attention. [mathewsopenaccess.com]

• Dysmetria

  […] years Variable parkinsonian findings: Found in MSA parkinsonian variant; are unresponsive to levodopa; include rigidity, bradykinesia, tremor, and truncal instability Evidence of cerebellar dysfunction: Found in MSA cerebellar variant; includes ataxia, dysmetria [emedicine.medscape.com]

• Sexual Dysfunction

  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. [en.wikipedia.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 laying down. [dysautonomiaconnection.org]

  […] sitting or lying down position • Symptoms worse in morning, or after meals or after exercise/physical activity • reduced sweating, heat intolerance • urinary problems like hesitancy, urgency, incontinence, urinary retention and frequent infections • Sexual [americanautonomicsociety.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]

• Retrograde Ejaculation

  The disease badly hit his sex life leading him to a urologist and a thorough examination showed no “obvious cause” with an explanation that he had “retrograde ejaculation”. [medium.com]

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.

• White Matter Lesions

  KEYWORDS: Pure autonomic failure; Supine hypertension; White matter lesions [ncbi.nlm.nih.gov]

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.

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