Pure Autonomic Failure
Introduction
Pure autonomic failure (PAF), or Bradbury-Eggleston syndrome, is a degenerative disorder of the autonomic nervous system presenting in middle to late life, affecting men more often than women. The disorder appears to be confined to the sympathetic and parasympathetic nervous systems. The adrenal medulla is relatively spared.
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Clinical Features
The initial feature in men is impotence, but the symptom that usually brings patients to the physician is orthostatic hypotension, or a fall in blood pressure with standing. The orthostatic hypotension may be described as unsteadiness, dizziness, or faintness upon standing. It is worse in the morning, after meals or exercise, or in hot weather. Patients also complain of pain in the neck or back of the head, relieved by lying down. The definitive diagnosis of hypotension as the cause of orthostatic symptoms is usually made by the demonstration of a decline in systolic blood pressure of 20 mm Hg and diastolic blood pressure of 10 mm Hg after at least one minute of standing. However, a decrease in systolic blood pressure by 50 mm Hg or greater is not unusual in these patients. This hypotension may be so severe that seizures supervene in perhaps 3% of affected patients. A diagnosis of PAF cannot be excluded on the basis of a single measurement of upright blood pressure that does not meet the above criteria. Several measurements of orthostatic blood pressure should be made. About 5% of PAF patients have angina pectoris, usually in the absence of significant angiographically demonstrable coronary atherosclerosis. PAF patients tolerate high altitude very poorly, perhaps because they hyperventilate in this situation.The orthostatic hypotension is usually accompanied by supine hypertension, or increased blood pressure while lying, even when the patient is on no medications to raise blood pressure. Yet, even when the supine hypertension is quite severe, cardiac function is well-preserved and contractility may even be raised. There is usually hypohidrosis or at least an asymmetrical distribution of sweating. Nocturia is an invariable accompaniment of dysautonomic orthostatic hypotension, and may cause the patient to get up as many as five to eight times per night to pass substantial amounts of urine. Urinary hesitancy, urgency, dribbling, and occasional incontinence might also occur. Some patients develop signs of neurogenic urinary retention and these individuals may have repeated urinary tract infections in consequence. It is noteworthy that patients with PAF do not usually have fevers as high as healthy subjects; nevertheless, any fever will significantly lower their blood pressure and consequently decrease their functional capacity. A sudden decline in functional mobility in a patient with PAF is suggestive of an intercurrent infection, usually of the urinary tract. A reduced basal metabolic rate is typical. Evidence of normal sympathetic and parasympathetic activity, such as nausea and pallor, may not occur when expected.
Pathology
The pathology of PAF has not been completely elucidated, but there is known to be a loss of cells in the intermediolateral column of the spinal cord and a loss of catecholamine uptake and catecholamine fluorescence in sympathetic postganglionic neurons. Autonomic failure should be distinguished from two other disorders classified as primary autonomic failure: Multiple System Atrophy (MSA) and idiopathic Parkinsons Disease (PD). PAF is less progressive and generally induces less disabling symptoms than do these other syndromes. In PAF, there should be no indication from the history or physical examination of cerebellar, striatal, pyramidal, and extrapyramidal dysfunction. Hoarseness and sleep apnea are two unusual symptoms highly suggestive of Multiple System Atrophy. Alpha-synuclein accumulates in cytoplasmic inclusions in affected brain areas in patients with MSA and PD. Alpha-synuclein accumulation in cytoplasmic inclusions in brainstem nuclei and in pre- and postganglionic sympathetic and parasympathetic nerves was recently demonstrated in a case of PAF. The role of alpha-synuclein accumulation in neuronal death has yet to be determined.Catecholamine levels
Autonomic failure patients have greatly reduced levels of catecholamines. These levels are very low while lying down, and have little increase upon standing. This is an important diagnostic test. Plasma and urinary norepinephrine levels are usually greatly reduced, sometimes to 10% of normal. Plasma norepinephrine is virtually always under 200 pg/ml and often under 100 pg/ml. Plasma levels of epinephrine are also reduced but usually to a lesser extent than norepinephrine. Dopamine levels in urine are usually about 50% of normal values. There is marked hypersensitivity to all pressor and depressor stimuli, especially sympathomimetic amines.Treatment
An important aspect of treatment in this patient population centers on patient education. Patients should understand the relatively benign nature of PAF but need to learn to live within the limitations imparted by their symptoms. Some patients find that leg-crossing helps to maintain upright posture. Other nonpharmacological treatment options include squatting, abdominal compression, bending forward and compression stockings. Pharmacological options include fludrocortisone, midodrine, somatostatin, erythropoietin, and other vasopressor agents. Finally, a recently discovered treatment option is water. Sixteen ounces of water can raise blood pressure as much as 40 mm Hg, with a peak at 30 minutes after ingestion.Outlook
Patients with PAF have a generally good outlook; many live for 20 years or more after the onset of their disease. The most common cause of death in these patients is pulmonary embolus or recurrent infection. The incidence of both myocardial infarction and stroke appears to be significantly reduced.Participate in Research Protocols
Click here to find details about how to become a Vanderbilt ADC Research Volunteer and about ongoing studies designed to better understand this disorder.
