Autonomic Disorders Information for Healthcare Professionals

The Autonomic Disorders Consortium joins with patient support groups to harness the knowledge and energies of physicians and investigators in the major centers where these patients are cared for, so that they can discover ways to treat and to cure these diseases. The greater the collaboration between doctors and patients, the more we can learn about these disorders. This important first step is necessary if we are ever to find genuinely effective and curative treatments. All consortium sites (Mayo, Harvard, New York University, The National Institutes of Health and Vanderbilt) have long traditions in discovery and treatment of autonomic disorders.

Several members of the ADC (representing Vanderbilt University, the Mayo Clinic and the NIH) were featured speakers at the Dysautonomia International Conference in July 2014 in Washington DC. This event was sold-out, with over 400 patients and family members attending from around the US, reflecting the interest among patients with these disorders in learning more about how to apply the state of the art knowledge in the field of autonomic rare disorders. Multiple lectures have been captured on video and are available from Dysautonomia International (www.dysautonomiainternational.org), one of our partnering Patient Advocacy Groups. Interested clinicians and patients can "stream" these talks at their convenience. Based on informal feedback, these have been well received and have had a wide reach.

  • Autoimmune Autonomic Ganglionopathy
  • Baroreflex Failure
  • Dopamine Beta-Hydroxylase Deficiency (DBH)
  • Familial Dysautonomia (FD)
  • Hypovolemic Postural Tachycardia Syndrome
  • Multiple System Atrophy
  • Neurally Mediated Syncope (NMS)
  • Pure Autonomic Failure

Autoimmune Autonomic Ganglionopathy

Introduction

Autoimmune autonomic ganglionopathy (AAG) is a rare disorder characterized by the presence of autonomic failure in association with specific antibodies directed against the α3 subunit of the neuronal nicotinic acetylcholine receptor (AChR) of the autonomic ganglia. The cause is unknown.

Symptoms

  • Severe orthostatic hypotension (lasting weeks to years)
  • Syncope
  • Constipation
  • Urinary retention
  • Fixed and dilated pupils
  • Dry mouth and eyes

Treatment

  • For mild cases, treatment is centered around symptom management.
  • Many patients remain incapacitated and disease modifying therapy may help.
  • There is no established therapeutic regimen.
  • A therapeutic trial in autoimmune autonomic ganglionopathy is being conducted by the Autonomic Disorders Consortium.

Baroreflex Failure

Introduction

Baroreflex failure, a rare disorder due to a damaged baroreflex arc, prevents the body’s buffering of high and low blood pressures. It is characterized by marked lability of BP with episodic severe hypertension and increased heart rate during stress and hypotension and normal or reduced heart rate during rest. There is often also headache, diaphoresis, emotional lability, and refractoriness of heart rate in response to exogenous vasoactive substances. It may resemble another rare disorder, pheochromocytoma, a catecholamine-secreting tumor.

Etiologies may include:

  • Surgery and irradiation for cancer of the throat.
  • Injury to the glossopharyngeal and vagus nerves.
  • Cell loss bilaterally in the nuclei of the solitary tract in the setting of a degenerative neurologic disease of medullary and higher structures.
  • For many of those who suffer from baroreflex failure, an etiology remains unknown.

Symptoms

  • Baroreflex failure has a range of presentations, varying from the acute onset of a hypertensive crisis to a chronically volatile blood pressure and heart rate with hypertensive surges in response to stress, punctuated by periods of normal or even low blood pressure during rest. Differentiating this syndrome from other causes of labile hypertension is essential in devising effective treatment.
  • Patients with baroreflex failure may present with severe hypertension, either sustained or episodic. Blood pressures can reach 170-320/110-135.
  • Accompanying tachycardia may suggest the diagnosis of pheochromocytoma, which is supported by sensations of warmth and or flushing, palpitations, and headache.

Management

  • Clonidine or methyldopa suppresses pressor and tachycardic surges.
  • Diazepam reduces stress.

Dopamine Beta-Hydroxylase Deficiency (DBH)

Introduction

Norepinephrine and epinephrine are crucial determinants of minute-to-minute neural regulation of blood pressure and are also present at central nervous system sites likely to be involved in a variety of behaviors. Norepinephrine and epinephrine thus seem so important to human beings that it seemed unlikely for many years that subjects without these catecholamines would survive the perinatal period and develop to adulthood.
This view changed with recognition of a congenital syndrome of severe orthostatic hypotension, noradrenergic failure, and ptosis of the eyelids in two young adults. The syndrome differs from familial dysautonomia and various autonomic disorders seen in adults in that the defect can be localized to the noradrenergic and adrenergic tissues. There is virtual absence of norepinephrine, epinephrine, and their metabolites. However, there is greatly increased dopamine in plasma, cerebrospinal fluid, and urine.

Symptoms

  • As children, DBH deficient patients have had a markedly reduced ability to exercise, perhaps because of hypotension engendered by the physical exertion. Because of occasional syncope, anticonvulsive medications have been given in some patients, even though no abnormality was seen on the electroencephalogram.
  • Symptoms have generally worsened in late adolescence and by early adulthood, patients complain of profound orthostatic hypotension, especially early in the day and during hot weather or after alcohol ingestion.
  • In addition to ptosis of the eyelids, there is a tendency for nasal stuffiness to occur, especially in the supine posture.
  • A male patient had appropriate erectile function, but retrograde rather than antegrade ejaculation.
  • Presyncopal symptoms in these patients have included dizziness, blurred vision, dyspnea, nuchal discomfort, and occasionally chest pain.

Physical Examination

  • The physical examination usually includes a normal or low normal supine blood pressure and a normal heart rate but a standing blood pressure that is less than 80 mmHg systolic.
  • Heart rate rises on standing but appears to have an attenuated elevation given the very low blood pressure with upright posture.
  • Pupils are somewhat small but respond to light and accommodation. Parasympatholytics dilate the eye appropriately.

Testing

  • Many specialized tests differentiate these patients from those with familial dysautonomia. Cholinergic sensitivity as assessed by conjunctival methacholine is normal, and intradermal histamine evokes a typical flare reaction in DBH deficiency, whereas this does not occur in familial dysautonomia. These patients are further distinguished from familial dysautonomia in having normal tearing, intact corneal and deep tendon reflexes, normal sensory function and normal senses of taste and smell. Also, subjects thus far recognized have not been of Ashkenazi Jewish extraction.
  • Atrial fibrillation occasionally occurs in adults.
  • These patients have no response even to high doses of tyramine, which normally increases blood pressure by releasing neuronal norepinephrine. Central autonomic regulation and catecholamine release mechanisms are intact, but dopamine, rather than norepinephrine, levels increase on assumption of the upright posture, during sustained handgrip, and after tyramine administration, while they decrease after clonidine administration.
  • Muscle sympathetic nerve traffic, as measured by direct intraneuronal recordings, is present in excess under basal conditions but is otherwise normally modulated by baroreflex mechanisms in these patients. Therefore, primary autonomic neuronal pathways are intact and respond to appropriate stimuli, but dopamine instead of norepinephrine is present in noradrenergic nerve terminals. The excessive microneurographic sympathetic nerve traffic appears to be due to insufficient central alpha-2 adrenoreceptor stimulation.
  • Sympathetic cholinergic function is intact, as assessed by normal sweating.
  • Parasympathetic function is also preserved, as assessed by intact sinus arrhythmia, normal heart rate increase during Valsalva, and tachycardia after atropine.
  • A diagnosis of DBH deficiency is based on the characteristic plasma catecholamine pattern of absent norepinephrine and epinephrine and elevated dopamine.

Genetics

The DBH gene is located at 9q34. In 2000, the genomic basis of DBH deficiency was elucidated. Kim et al. identified seven novel variants, including four potentially pathogenic mutations, in the human DBH gene of two unrelated DBH deficient patients and their families. Both patients had an intronic mutation that can lead to aberrant splicing. However, this mutation generates both aberrant and properly spliced DBH messages, and patients with DBH deficiency have no DBH gene product, even when a polyclonal antibody against DBH is used to measure it. It is possible that another variant at DBH is necessary to produce the DBH deficiency phenotype.

Treatment

  • Fludrocortisone at relatively high doses has successfully raised blood pressure with some benefit. Indomethacin has also been of modest benefit in raising blood pressure, but one patient had aggressive ideation while receiving this drug.
  • The monoamine oxidase inhibitor tranylcypromine also produced paranoid thinking in one patient.
  • There has been a reasonable pressor response to phenylpropanolamine (25 and 50 mg), perhaps because of the hypersensitive alpha-adrenoreceptors in these patients.
  • Once the specific enzymatic defect had been elucidated, investigators knew that a better treatment for DBH deficiency could be devised. DBH deficient patients possessed all the machinery to handle neurotransmitters effectively, but simply had a 'false neurotransmitter', dopamine, instead of the physiological neurotransmitter, norepinephrine. Their alternative therapeutic approaches were to reduce the former (with metyrosine) or increase the latter (with dihydroxyphenylserine).
  • Metyrosine is an inhibitor of tyrosine hydroxylase and reduces the synthesis of catecholamines, both in the periphery and in the central nervous system. Metyrosine significantly reduces urinary and plasma dopamine levels in DBH deficiency.
  • A more favorable long-term result has been achieved with L-dihydroxyphenylserine (droxidopa or L-DOPS). This agent is a prodrug acted upon by endogenous dopa decarboxylase to yield norepinephrine. DBH is not required for the conversion of DOPS to norepinephrine and, thus, this defective enzyme can be bypassed. The administration of DOPS to these patients results in dramatic increases in blood pressure and in the restoration of plasma and urinary levels of norepinephrine toward normal. Long-term experience with this drug indicates continued efficacy at the 250 mg or 500 mg tid regimen.

Prospectus

DBH deficiency and its successful treatment by DOPS has provided valuable lessons in catecholamine pharmacology and encourages us to hope that other autonomic disorders may one day also yield to genuinely effective therapeutic intervention. Indeed, other newly recognized genetic autonomic and catecholamine disorders are now being recognized, including tetrahydrobiopterin deficiency, dopa decarboxylase deficiency. Menkes disease, monoamine oxidase deficiency and other disorders of dopamine metabolism.

Familial Dysautonomia (FD)

What is Familial Dysautonomia (FD)?

Familial Dysautonomia - pronounced "dys-auto-NO-mia" - is a genetic disease present at birth in male and female Ashkenazi Jews, primarily causing dysfunction of the autonomic and sensory nervous systems. Dysfunction is a result of an incomplete development of the neurons (nerve fibers) of these systems.

The prognosis of the disease depends on early detection, severity of symptoms, and the individual response to therapeutic treatment for this disorder. Supportive treatment can enhance quality of life and promote better survival.

What are the symptoms of FD?

The lack of tears is the landmark symptom of FD. Children with FD have an absence of overflow tears with emotional crying. That is why a tear appears in the Dysautonomia Foundation's FD logo.

Symptoms displayed by a baby with FD might include:

  • High prevalence of breech presentation births
  • Poor muscle tone - "Floppy Baby"
  • Weak or absent suck
  • Respiratory congestion due to misdirected swallowing
  • Blotching of skin
  • Difficulty in maintaining temperature

Symptoms in an older child with FD might include:

  • Delay in developmental milestones such as walking and speech
  • Poor balance and unsteady gait
  • Scoliosis (spinal curvature). 90% of children with FD have scoliosis before 13 years of age
  • Orthostatic hypotension - extreme drop in blood pressure with change in posture
  • Breath holding in early years to the point of fainting
  • Episodic vomiting
  • Excessive drooling and sweating
  • A smooth tongue and decrease in sense of taste
  • Inappropriate temperature control with very high to very low temperatures
  • Poor weight gain and growth
  • Frequent lung infections
  • Decreased reaction to pain or no reaction at all
  • Cold, puffy hands and feet
  • Extremes in blood pressure
  • Corneal abrasions and dry eyes
  • Gastric dysmotility
  • Dysautonomic "crisis"

A crisis is an incident of extreme physiologic response of the FD child’s body to stress. This stress may be triggered by something physical, such as an infection, or by something causing emotional stress, such as an upcoming medical exam. Whatever the catalyst, the child will become nauseated, usually accompanied by retching or vomiting, have a marked increase in blood pressure, sweating, drooling, increased heart rate, and blotching of the skin. Irritability and a negative personality change accompany these symptoms. Episodes can occur as frequently as daily; some patients will never experience a "crisis."

Important notes

  • Not all children with FD have the same symptoms. The number and severity of symptoms are extremely variable. FD patients can be expected to function independently if treatment is begun early and major disabilities avoided.
  • FD children are usually of normal intelligence. There has been an increased frequency of learning disabilities in FD children, however. Early intervention and aggressive therapy in areas of language and learning have been extremely successful in prevention and treatment.

How is FD inherited?

It is estimated that one in 27 individuals of Eastern European Jewish ancestry is a carrier of the gene for FD. All parents of children with FD are carriers of the defective recessive gene that transmits the disease. A parent has no symptoms or warning signs of being a carrier. For individuals who have not been screened for the FD trait, the first clue that they are carriers is the birth of a child with FD.

How is FD diagnosed?

The diagnosis can be made through genetic testing or clinical evaluation. The clinical diagnosis of FD is based upon a constellation of criteria:

  • Parents of Ashkenazi Jewish Background
  • Absence of fungiform papillae on the tongue [Compare NORMAL and FD tongue images].
  • Decreased deep tendon reflexes
  • Lack of an axon flare following intradermal histamine
  • No overflow tears with emotional crying

A definitive diagnosis can be made with a blood test that will show mutations in the IKBKAP gene in an affected individual. Over 99% of affected individuals will have two copies of the most common mutation.

Genetic testing -- Is there a prenatal or carrier test for FD?

Thankfully, there are prenatal and carrier tests for FD for the general population.

FD was once thought of as a fatal childhood disease, with most children expected to live, on average, only to five years of age. Advances in treatment have dramatically extended life expectancy, but children with FD still suffer from chronic and often debilitating symptoms that prevent them from leading normal lives.

Hypovolemic Postural Tachycardia Syndrome (POTS)

Introduction

When a patient’s heart rate speeds up 30 beats per minute or more without much change in blood pressure on standing, the patient may have orthostatic intolerance (OI). This disorder is heterogeneous and has had many different names, including neurasthenia, soldier’s heart, mitral valve prolapse syndrome, vasoregulatory asthenia, neurocirculatory asthenia, and and effort syndrome. Because upright heart rate is usually greatly increased, the more common term used now is Postural Tachycardia Syndrome (POTS). The increase in heart rate may be a sign that the cardiovascular system is working hard to maintain blood pressure and blood flow to the brain. Orthostatic intolerance affects an estimated 500,000 Americans and causes a wide range of disabilities. It is most frequently seen in young women, often less than 35 years of age.

Symptoms & Signs (for at least 6 months)

  • Lightheadedness, palpitations and tremulousness during standing
  • Other upright posture symptoms may include:
    • Visual changes
    • Discomfort in the head and neck
    • Throbbing of the head
    • Poor concentration
    • Tiredness
    • Weakness
    • Occasionally fainting
    • Nausea
    • Chest discomfort
    • Shortness of breath

Etiology

The etiology of POTS is unknown. The onset of POTS is sometimes predated by a recent viral infection. Patients can undergo extensive clinical evaluation without identification of a specific abnormality, and therefore most patients remain undiagnosed. These difficulties are compounded by the heterogeneity of disease states in patients with orthostatic symptoms, spontaneous fluctuations in disease severity, and no uniformity in nomenclature of disease classification. Another problem in the diagnosis of OI is its overlap with other conditions such as Chronic Fatigue Syndrome (CFS), Neurally Mediated Syncope (NMS), physical deconditioning, etc.  Improving characterization of the underlying circulatory responses may lead to a clarification of some of those issues, and will facilitate the discovery of the pathophysiologies of POTS.

The Role of Hypovolemia in POTS

Hypovolemia is an abnormal decrease in blood volume, or more specifically an abnormal decrease in the volume of blood plasma. This sometimes occurs in POTS patients. The patients may have a reduced blood volume throughout their body, or the hypovolemia may occur due to blood pooling in the abdomen and legs. Reduced plasma renin activity often accompanies the low blood volume. Reduced levels of renin release consequently result in reduced secretion of aldosterone. This would be expected to impair renal sodium conservation thereby contributing to hypovolemia. Findings suggest that the impaired renin release may possibly result from sympathetic denervation. Abnormalities in the kidney are also suspected of causing the reduced renin and aldosterone levels. Physicians believe hypovolemia and inappropriately low levels of plasma renin activity may be important pathophysiological components of orthostatic intolerance. The findings in hypovolemic POTS patients have been dubbed the "renin-aldosterone paradox" and are explained as follows:

Under normal circumstances, low plasma volume is sensed in the kidney (and in the heart and aorta) and stimulates an increase in plasma renin activity (renin), and aldosterone (ALDO). The increase in plasma renin activity and aldosterone promotes salt and water retention, which leads to an increase in extracellular fluid volume and plasma volume. In POTS, there is a failure to sense and appropriately respond to low plasma volume. There is no appropriate increase in plasma renin activity and aldosterone given the hypovolemia. Because plasma renin activity and aldosterone are not increased, salt and water retention is not increased, and plasma volume is not increased.

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Long-Term Outlook for Patients with POTS

The majority of patients with POTS have a relatively mild disorder which improves over succeeding weeks and months. Most patients will eventually be free of symptoms. However, in some patients, the symptoms are more severe, the duration of the illness may be longer, and the expected recovery may not occur.

Therapy

In individual patients, different therapeutic regimens may result in improvement of symptoms. These include:

  • Orthostatic “exercise”
  • Low dose beta blockade
  • Water
  • Salt and /or fludrocortisones
  • Low dose alpha 2 agonist (clonidine)
  • Low dose alpha-1 agonist (midodrine)
  • Alpha-Methyldopa (Aldomet)

Multiple System Atrophy  (MSA) / Shy-Drager Syndrome

Introduction

In Multiple System Atrophy, there is widespread autonomic failure associated with impairment in other neurological systems. The other neurological systems may be cerebellar, extrapyramidal, neuromuscular, or pyramidal. The pathological hallmark of MSA is glial cytoplasmic inclusions, neuronal loss and gliosis within multiple sites in the brain.

Clinical Manifestations

  • The average age of onset is in the sixth decade of life. Men are affected slightly more than women.
  • In some patients, chronic orthostatic hypotension may be a presenting symptom, but in other cases, extrapyramidal symptoms or cerebellar symptoms may predominate in the early stages. When the chronic orthostatic hypotension antedates other neurological involvement, it may be very difficult to differentiate MSA from the more benign pure autonomic failure (PAF).
  • Patients complain of male erectile dysfunction, change in writing, slurred speech, sleep apnea, difficulty with urination, frequent urinary tract infections, a hoarse voice, passing out, headache, neck pain, dimming of vision and yawning.
  • Syncope, or passing out, is most frequently associated with orthostatic hypotension, or a low blood pressure with standing, even though blood pressure while lying down may be very high.
  • Patients frequently note emotional lability, with short (sometimes only one or two minutes) episodes of crying due to happiness or sadness in response to relatively minor environmental stimulus, such as a song, a television program, or a movie. This is usually self-limited, but may be a harbinger of depression.
  • Patients sometimes have periodic gasping respirations punctuating the medical interview. They only last a second or two, are not generally deep, but seem labored.
  • Many patients will discontinue the use of nicotine-containing products at the onset of their disease. Ultimately, nicotine may provoke worsened tremor in some of these patients.
  • A symptom which occasionally occurs in patients with MSA is diplopia, not unlike that seen in multiple sclerosis.
  • Pathologically, there is involvement of multiple sites within the brain and spinal cord. A glial cytoplasmic inclusion has been found to occur intracellularly in both glial cells and neurons of involved portions of the brain.
  • Blood and urinary levels of norepinephrine are often near normal in the unstimulated state in patients with MSA, but they do not rise appropriately on assumption of the upright posture. Peripheral norepinephrine levels tend to be higher in MSA than in PAF. Catecholamine metabolites reflect the central nature of the neurological defect.
  • There is also biochemical evidence of central abnormalities in the dopamine, acetylcholine and serotonin systems.

Diagnosis

  • In order to diagnose multiple system atrophy, thoughtful and careful evaluation should be undertaken.
  • Posture studies with blood pressure and heart rate monitoring with catecholamine levels in the supine and upright position should be done.
  • Other potential evaluations include autonomic function testing, MRI, consultation by physicians that specialize in movement and/or blood pressure disorders, a sleep study, urodynamic testing, and blood pressure monitoring throughout sleep to evaluate for supine hypertension, or a high blood pressure with lying.
  • True diagnosis can only be accomplished by examination of the brain post-mortem.

Prognosis

The prognosis is more guarded in the multiple system atrophy patient than in pure autonomic failure. It is rare for a patient to survive beyond 10 years though cases of 16 years have been seen. The autonomic abnormalities are seldom the direct cause of death. A significant number of patients develop laryngeal stridor and difficulty swallowing, which can lead to pneumonia. In addition, many patients with MSA experience sleep apnea and in some cases this may lead to a critical loss of respiratory drive. Pulmonary hypertension may occur during apnea. The most common causes of death in patients with MSA are pulmonary embolus, apnea, and intercurrent infection.

Management

There is no known cure for MSA, so management involves treating specific problems in this patient population. This includes treatment of the depression, tremor and gait disturbances, supine hypertension, orthostatic hypotension, and possible self-catheterization.  

Neurally Mediated Syncope (NMS)

What is Neurally Mediated Syncope (NMS)?

Syncope (described as “fainting” or “passing out”) is a common problem, accounting for approximately 3% of emergency room visits. Neurally mediated syncope (NMS) is also called neurocardiogenic, vasovagal, vasodepressor or reflex mediated syncope.
Repeated episodes of NMS may be caused by a wide variety of medical problems, and require diagnosis and treatment. It is important to distinguish syncope from “dizziness”, which generally refers to an alteration in balance, vision, or perception of the environment, without the loss of consciousness.

What causes NMS?

NMS occurs when the part of the nervous system that regulates heart rate and blood pressure malfunctions, often in response to a trigger. The heart rate slows, and the blood vessels in the legs widen. This allows blood to pool in the legs, which lowers blood pressure. The drop in blood pressure and slowed heart rate quickly cause diminished blood flow to the brain, causing fainting.

How is NMS diagnosed?

The diagnosis of NMS often focuses on ruling out other potential causes of fainting - particularly heart-related problems. Tests may include:

  • Electrocardiogram
  • Echocardiogram
  • Exercise stress test
  • Blood tests
  • Tilt table tests to measure your blood pressure with changes in posture

What is the treatment for NMS?

In many cases, education about ways to avoid “triggers” may be enough to control NMS.

Treatment may require medications, therapies to increase blood pressure or decrease pooling of blood in the legs or the use of an electrical pace maker to regulate heartbeat. Other therapies include using compression stockings, sleeping with the head of the bed slightly elevated, and mild aerobic conditioning (especially in the water).

Pure Autonomic Failure (PAF)

Introduction

Pure autonomic failure (PAF), or Bradbury-Eggleston syndrome, is a peripheral degenerative disorder of the autonomic nervous system presenting in middle to late life, and affecting men more often than women. The disorder appears to be confined to the sympathetic and parasympathetic nervous systems.

Clinical Features

  • The initial feature in men is often erectile dysfunction.
  • 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.
  • Complaints of pain in the neck or back of the head, relieved by lying down are sometimes present.
  • The orthostatic hypotension is frequently 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 sometimes even be raised.
  • There is usually hypohidrosis or at least an asymmetrical distribution of sweating.
  • Nocturia is common and may cause the patient to get up as many as three or more 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.
  • Evidence of normal sympathetic and parasympathetic activity, such as nausea and pallor, may not occur when expected.

Pathology

There is 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 Parkinson’s Disease (PD). PAF generally induces fewer disabling symptoms than do these other syndromes. In PAF, there should be no indication from the history or physical examination of cerebellar, striatal, pyramidal or extrapyramidal dysfunction. Autonomic failure patients have greatly reduced levels of catecholamines and an impaired response to stimuli that normally raise plasma norepinephrine and DHPG. Plasma and urinary norepinephrine levels are sometimes only 10% of normal. There is marked hypersensitivity to all pressor and depressor stimuli, especially sympathomimetic amines.

Treatment

  • An important aspect of treatment is 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 droxidopa, fludrocortisone, midodrine, yohimbine, octreotide, erythropoietin, and other vasopressor agents.
  • Finally, an important treatment option is water. Sixteen ounces of water can raise blood pressure as much as 40 mm Hg for about 90 minutes, with a peak at 30 minutes after ingestion. Conversely, a carbohydrate-rich meal will lower blood pressure about the same amount over the same time course.

Outlook

Patients with PAF have a generally good outlook; many live normal life spans and sometimes well into their 80s.