Adam P.J. Younger
David S. Younger, MD
DESCRIPTION
It is valuable to diagnose variable degrees of autonomic failure that may present as orthostatic intolerance (OI), postural tachycardia syndrome (POTS), or syncope. Orthostatic hypotension (OH) is a dominant feature of severe autonomic failure. The clinician must rely upon the history and observations of patients of any age, from childhood to older age, as autonomic failure can affect all age groups. The history of rapid-onset, short-lived dizziness, and other symptoms upon assuming the upright position that abates and resolves usually over seconds to minutes is suggestive of OH and OI. It is defined as (a) symptoms triggered by standing and relieved in supine position, (b) heart rate increase >30 beats per minutes (bpm) or >120 bpm, and (c) blood pressure is normal or increased. OH is defined as (a) blood pressure fall >20/10 mm Hg for 3 minutes, (b) with or without symptoms of cerebral hypoperfusion, and (c) loss of heart rate increase indicating severe autonomic failure. Neurogenic syncope is triggered by reflex mechanism and may occur with both conditions. The syndrome of POTS is defined as symptoms of OI usually of greater than 6 months’ duration, accompanied by a rise in the heart rate of at least 30 bpm or exceeds 120 bpm, within the first 10 minutes of the upright position or upon head-up tilting.
EPIDEMIOLOGY
In the US, 500,000 patients have OI.
- Race
- Age
- OI may affect all ages. OH is more common in the middle aged and the elderly.
- Sex
- Female > male; multiple system atrophy (MSA) male > female.
RISK FACTORS
Falls, injury.
Pregnancy Considerations
- OI—generally improvement during pregnancy
- OH—determined by primary diagnosis
Genetics
Unknown, except for familial dysautonomia [Riley–Day syndrome in Ashkenazi Jews on chromosome 9 (q31)].
COMMONLY ASSOCIATED CONDITIONS
- OI
- Small fiber neuropathy
- Excessive venous pooling/deconditioning/prolonged bed rest/weightlessness
- Hypovolemia
- β-receptor supersensitivity
- Brainstem dysregulation, Arnold–Chiari malformation
- OH
- Primary autonomic failure
- Pure autonomic failure (PAF)
- MSA with parkinsonian, cerebellar, and pyramidal features
- Acute and subacute pandysautonomia
- Secondary autonomic failure
- Peripheral autonomic neuropathy (diabetes, amyloidosis)
- Dopamine-β-hydroxylase (DBH) deficiency
- Guillain–Barré syndrome
- Paraneoplastic (Lambert–Eaton syndrome—small cell lung carcinoma)
- Brain tumors—posterior fossa
- Autoimmune and collagen disorders (Sjögren's syndrome)
- Tabes dorsalis
- HIV infection
- Familial dysautonomia (Riley–Day)
- Lyme neuroborreliosis
- Psychotropic medications in elderly
DIAGNOSTIC TESTS AND INTERPRETATION
Lab
- ECG normal; Holter monitoring shows episodes of sinus tachycardia.
- Standing plasma catecholamines are increased in some OI patients but reduced in OH.
- Reduced adrenocorticotropic hormone and β-endorphin can distinguish OH due to MSA vs. PAF (normal).
- Reduced growth hormone and melatonin in DBH deficiency.
- Screening metabolic, parainfectious, and autoimmune serology.
Imaging
- OI—MRI typically normal.
- OH—MSA—T2-weighted images show putamen hypointensity, olivopontocerebellar atrophy (OPCA). Positron emission tomography shows reduced reuptake of F-dopa in MSA.
Diagnostic Procedures/Other
Diagnosis of autonomic failure is made using a battery of autonomic tests:
- Tilt table testing is done at 60–80 degrees for 5–10 minutes without medications. OI shows sinus tachycardia (>100 bpm) for at least 5 minutes with normal or increased blood pressure. POTS is severe form of OI with orthostatic heart rate >120 bpm. OH shows sustained blood pressure drop >20/10 mm Hg for 3 minutes. Loss of heart rate increment indicates severe autonomic failure. Isoproterenol/nitroprusside infusions are used for evaluation of syncope.
- Heart rate variation to deep breathing and bradycardia/tachycardia ratio during Valsalva maneuver is typically reduced.
- Quantitative sudomotor axon reflex test (QSART)—stimulation of postganglionic sudomotor fibers using iontophoresis of 10% acetylcholine chloride. QSART may be normal in OI but is typically reduced with OH due to peripheral neuropathy.
- Thermoregulatory sweat test—body is covered by alizarin powder and temperature is raised by 1°C. Sweating is indicated by red coloration. Typically, in diabetic neuropathy, sweating is lost in stocking/glove distribution.
DIFFERENTIAL DIAGNOSIS
- Non-neurogenic OI
- Non-neurogenic OH
- Cardiac impairment (myocardial infarction, myocarditis)
- Impaired cardiac filling/output (e.g., aortic stenosis, cardiomyopathy, heart failure)
- Nephrogenic (nephropathy, hemodialysis)
- Blood/plasma loss—hemorrhage, burns, sepsis
- Fluid/electrolyte loss—vomiting, diarrhea, fluid loss
- Increased intracranial pressure
- Drug induced—centrally acting agents that reduce sympathetic activity (clonidine, methyldopa, reserpine, barbiturates, anesthetics)
MEDICATION
- Orthostatic intolerance
- Fludrocortisone 0.05 mg PO b.i.d.; weekly increase to 0.1–0.3 mg PO b.i.d
- 3- to 6-lb weight gain is desirable
- Side effects: 50% hypokalemia, 50% hypomagnesemia, peripheral edema
- Sodium chloride (salt tablets): 50 mEq or 1,200 mg PO t.i.d.
- Side effects: Peripheral edema
- Propranolol (Inderal) 10–40 mg PO q.i.d.
- Pindolol (Visken) 2.5–5.0 mg bid to t.i.d.
- Orthostatic hypotension
- Fludrocortisone (Florinef) 0.05 mg PO b.i.d.; weekly increase to 0.1–0.3 mg PO
- Side effects: See above
- Sodium chloride: See above
- Midodrine (ProAmatine): Starting dose 5 mg t.i.d. up to 40 mg/day, last dose before supper
- Side effects: Sensation of goose flesh (chills), scalp pruritus, urinary retention, supine hypertension, may increase urinary Na+ loss
- Caffeine 250 mg (2 cups) in the morning and 1 cup with meals (postprandial hypotension)
- Erythropoietin (epoetin alfa) 25–75 mg U/kg IV or SC 3 times weekly (only for severe autonomic failure)
- Octreotide (somatostatin) 25 µg SC b.i.d. with increase to 100–200 µg t.i.d.
- Clonidine (Catapres—α2-agonists) 0.1–0.3 mg given as 0.2–0.8 mg b.i.d. to t.i.d.
- Indications: Autonomic failure due to efferent sympathetic lesion. Note that patients with peripheral lesion become hypotensive
- Contraindications
- Fludrocortisone, ProAmatine—congestive heart failure
- Erythropoietin—hypersensitivity to human albumin
- Clonidine—caution with β-blockers; tricyclic antidepressants may cause rebound hypertension
- Precautions: Monitor supine hypertension, peripheral edema, and congestive heart failure
- Alternative drugs
ADDITIONAL TREATMENT
General Measures
Treatment of OH includes a combination of volume expansion, pressor agents, and supportive measures.
COMPLEMENTARY AND ALTERNATIVE THERAPIES
- Symptomatic treatment
- Liberalize fluid and salt intake.
- Review all medications to determine if any that might be contributing to orthostasis may be discontinued, especially diuretics, antihypertensive agents, antianginal agents, and antidepressants.
- Have patient move from supine to sitting and standing positions in gradual stages.
- Head-up tilt bed—elevation of bed to 20-degree angle activates the renin–angiotensin–aldosterone system and decreases nocturnal diuresis.
- Elastic body garments (custom-fitted stockings with graded pressure, abdominal binder inflatable, or easy-wraps
- Adjunctive treatment
SURGERY/OTHER PROCEDURES
- Tumor removal
- Brainstem decompression in Arnold–Chiari malformation
IN-PATIENT CONSIDERATIONS
Admission Criteria
Frequent loss of consciousness/improvement of orthostatic tolerance.
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- If no improvement of symptoms is there, repeat tilt study on medications.
- Monitor supine hypertension (24-hour BP monitoring might be useful).
DIET
High sodium and 2–2.5 L of fluids; small, more frequent, low-carbohydrate meals.
PATIENT EDUCATION
- Activities
- Countermaneuvers (squatting, leg crossing, toe raising, marching, bending forward, abdominal contraction); supine exercise (leg lifting, weight pressing), swimming; relaxation. Avoid overheating and straining maneuvers. Schedule activities for the afternoon since the symptoms are typically worse in the morning.
- Organizations
- The National Dysautonomia Research Foundation, contact person: Linda J. Smith (Email: ndrf@ndrf.org, phone: 715-594-3140; fax: 715-594-3140; website: http://www.ndrf.org)
PROGNOSIS
- OI
- Good prognosis—majority of patients improve over time.
- Orthostatic hypotension
- Knowing precise diagnosis is important for prognosis
- Diabetic neuropathy—increased risk for death/arrhythmias
- MSA survival: 5 years from diagnosis
- PAF survival >10 years
