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clinical practice Neurogenic Orthostatic Hypotension Roy Freeman, M.B., Ch.B.
This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the author's clinical recommendations. A 65-year-old man reports a 6-month history of dizziness, light-headedness, weak-
ness, and fatigue while upright. He takes no medication and has no personal or fam-
ily history of neurologic disease. On physical examination, his supine blood pressure
is 160/100 mm Hg, with a heart rate of 72 beats per minute; on standing, his blood
pressure falls to 70/40 mm Hg, with no change in heart rate. The results of the re-
mainder of the examination, including neurologic examination, are normal. How
should he be evaluated and treated?
The Clinical Problem Orthostatic hypotension, defined as a reduction in systolic blood pressure of at least From the Department of Neurology, Beth 20 mm Hg or a reduction in diastolic blood pressure of at least 10 mm Hg during Israel Deaconess Medical Center, Har- the first 3 minutes of standing or a head-up tilt on a tilt table,1 is a classic manifes- vard Medical School, Boston. Address reprint requests to Dr. Freeman at the tation of sympathetic vasoconstrictor (autonomic) failure. In many (but not all) cases, Center for Autonomic and Peripheral there is no compensatory increase in the heart rate, despite hypotension; with milder Nerve Disorders, Department of Neurol- autonomic failure, the heart rate may increase, but not to a rate sufficient to main- ogy, Beth Israel Deaconess Medical Cen- ter, 1 Deaconess Rd., Boston, MA 02215, tain blood pressure. A variant of orthostatic hypotension is delayed orthostatic hypo- or at [email protected].
tension, which occurs after 3 minutes of standing; this condition may represent a mild or early form of sympathetic adrenergic dysfunction.2 In some cases, orthostatic hy- N Engl J Med 2008;358:615-24.
Copyright 2008 Massachusetts Medical Society. potension occurs within 15 seconds of standing (so-called initial orthostatic hy- potension); this may represent a transient mismatch between cardiac output and peripheral vascular resistance rather than autonomic failure.3 Orthostatic hypotension increases in prevalence with age; aging is associated with reduced baroreflex responsiveness, decreased cardiac compliance, and attenuation of the vestibulosympathetic reflex. Orthostatic hypotension is more common in elderly people living in care facilities (54 to 68%) than in those living in the community (6%),4 an observation most likely explained by the greater prevalence of predisposing neurologic disorders, physiological impairment, and medication use among people living in care facilities.
Physiological and Clinical Features
Standing results in pooling of 500 to 1000 ml of blood in the lower extremities and
splanchnic circulation. There is a decrease in venous return to the heart and reduced ventricular filling, resulting in diminished cardiac output and blood pressure. These hemodynamic changes provoke a compensatory reflex response, initiated by the barore- ceptors in the carotid sinus and aortic arch, that results in increased sympathetic outflow and decreased vagal-nerve activity (Fig. 1). This reflex increases peripheral resistance, venous return to the heart, and cardiac output, thereby limiting the fall in blood pres- sure. If this response fails, orthostatic hypotension and cerebral hypoperfusion occur.5 Characteristic symptoms of orthostatic hypotension include light-headedness, dizzi- ness, presyncope, and syncope in response to sudden postural change. However, symp- n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. Figure 1. The Baroreflex.
A decrease in arterial pressure unloads the baroreceptors — the terminals of afferent fibers of the glossopharyngeal and vagus nerves
— that are situated in the carotid sinus and aortic arch. Th C
uction in the afferent impulses that are relayed from these mechanoreceptors through the glossopharyngeal and vDargafut 4 s nerves to t 01/22/07 he nucleus of the tractus solitarius (NTS) in the dorsomedial me- dulla. The reduced baroreceptor afferent activity produces a decrease in vagal nerve input to the sinus node that is mediated by the neu- roanatomical connections of the NTS to the nucleus ambiguus (NA). There is an increase in sympathetic efferent activity that is mediat- ed by the NTS projections to the caudal ventrolat Title eral medulla (CVLM) (an excitatory pathway) and from there to the rostral ventrolateral medulla (RVLM) (an inhibitory pathway). The actiME vation of RVLM presympathetic neurons in response to hypotension is thus predomi- nantly due to disinhibition. In response to a sust DE ained fall in blood pressure, vasopressin release is mediated by projections from the A1 noradrenergic cell group in the ventrolateral med A pBrLojection activates vasopressin-synthesizing neurons in the magnocellular portion of the paraventricular nucleus (PVN) and the suprAUTHOR PLEASE NOTE: aoptic nucleus (SON) of the hypothalamus. Blue denotes sympathetic neu- Figure has been redrawn and type has been reset rons and green parasympathetic neurons.
Please check carefully toms may be absent or nonspecific, such as gener- coronary arteries). One or more of these nonspe- alized weakness, fatigue, nausea, cognitive slowing, cific symptoms may be the presenting or only symp- leg buckling, or headache. Visual blurring may oc- tom of orthostatic hypotension. Symptoms may cur, probably because of retinal or occipital-lobe be exacerbated by exertion, prolonged standing, ischemia. Neck pain may occur, typically in the increased ambient temperature, or eating. Syncope suboccipital, posterior cervical, and shoulder re- is usually preceded by warning symptoms but may gion (called the coat-hanger headache), which is occur suddenly, suggesting the possibility of a sei- most likely due to ischemia in the trapezius and zure or cardiac cause.
neck muscles.6 Patients may report orthostatic dys- Supine hypertension is common in patients pnea (thought to reflect ventilation–perfusion mis- with orthostatic hypotension, affecting more than match due to inadequate perfusion of ventilated 50% of patients in some series. Orthostatic hypo- lung apexes)7 or angina (attributed to impaired tension may occur after therapy for hypertension, myocardial perfusion even in patients with normal and supine hypertension may follow treatment of n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. clinical practice hypointensity to uptake particularly uptake particularly SPECT sympathomimetic SPECT sympathomimetic SPECT sympathomimetic Diagnostic
change cerebellar normalities, putaminal taminal relative T 2 like posterolateral margin, nal dle and with amine MIBG paired, autonomic scanning shows with amine shows is with with amine MIBG paired, autonomic positron-emission in postganglionic autonomic precipitation cytoplasmic and neurons, neocortical glia clusions) neurons Lewy of nent limbic dominantly in peripheral rons parasympathetic system cognitive visual sleep Prominent
Other Clinical
tures ticularly sleep dementia cedes parkinsonism, alertness impairment, nations, ior Hypotension
manifestations, progression I-MIBG tomography.
in bellar dominant tients), abnormalities motor rare Parkinson's mentia Orthostatic
therapy; progno better with clinical associated autonomic disorders Disorders
dysfunction later dysfunction early Autonomic
develops course most feature 7 occurs course, with antiparkinsonism tions; as atrophy nomic responds quality sis than other degenerative single-photon-emission Autonomic
1. Primary
with (Shy–Drager rapid-eye Symptoms n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. orthostatic hypotension. In other cases, however, mocytoma), and excessive vasodilatation (e.g., the association of the two conditions is unrelated systemic mastocytosis and the carcinoid syn- to therapy and may be explained in part by baro- drome). The history taking should address other reflex dysfunction in the presence of residual sym- features suggestive of central or peripheral auto- pathetic outflow, particularly in patients with cen- nomic dysfunction, such as gastrointestinal, uri- tral autonomic degeneration.8 nary, sexual, and sudomotor dysfunction; motor system dysfunction, such as parkinsonism, pyra- Causes of Neurogenic Orthostatic Hypotension
midal tract dysfunction, and cerebellar ataxia; and Causes of neurogenic orthostatic hypotension in- peripheral neuropathy (Tables 1 and 2).
clude central and peripheral autonomic nervous Blood pressure should be measured while the system diseases or disorders. Autonomic dysfunc- patient is in the supine position and at least 3 min- tion of varying severity in other organ systems utes after the patient stands up. In the absence of (including the bladder, bowels, sexual organs, and an apparent cause of symptoms, screening blood sudomotor system) frequently accompanies or- tests typically include a complete blood count, thostatic hypotension in these disorders.
electrolyte assessment, blood glucose level, serum The primary autonomic degenerative disorders immunoelectrophoresis, vitamin B12 level, and a are multiple-system atrophy (the Shy–Drager syn- morning cortisol level.
drome), Parkinson's disease, dementia with Lewy Autonomic testing is often performed in special- bodies, and pure autonomic failure. These disor- ized centers to uncover any asymptomatic abnor- ders are often referred to collectively as synucle- malities.31 Testing includes functional assessments inopathies because of the presence of α-synuclein, of the parasympathetic nervous system (e.g., heart a small protein that precipitates predominantly rate variability with deep respiration and during a in the cytoplasm of neurons in the Lewy-body Valsalva maneuver), the sympathetic cholinergic disorders (Parkinson's disease, dementia with system (e.g., thermoregulatory sweat response and Lewy bodies, and pure autonomic failure) and in quantitative sudomotor axon reflex test), and the the glia in multiple-system atrophy.1,9,10 Charac- sympathetic adrenergic system (e.g., blood-pressure teristic features of these disorders are summa- response to a Valsalva maneuver and a tilt-table test rized in Table 1.
with beat-to-beat measurement of blood pressure). Peripheral autonomic dysfunction may also Autonomic testing may be useful in distinguish- accompany small-fiber peripheral neuropathies, ing orthostatic hypotension due to autonomic such as those seen in diabetes, amyloidosis, im- failure from neurally mediated syncope.
mune-mediated neuropathies, hereditary sensory The primary autonomic degenerative disorders and autonomic neuropathies (particularly heredi- (Tables 1 and 2) can be differentiated accord- tary sensory and autonomic neuropathy type III, ing to clinical criteria, although imaging stud- also called familial dysautonomia), and inflam- ies may be helpful when the diagnosis remains matory neuropathies (Table 2). Less frequently, unclear. Characteristic findings on magnetic res- orthostatic hypotension is associated with the onance imaging13 and single-photon-emission peripheral neuropathies that accompany vitamin computed tomographic scanning (with the radio- B12 deficiency, exposure to neurotoxins, neuropa- labeled sympathomimetic amine 123I-metaiodo- thies due to infections, including human immu- benzylguanidine)16 in the various disorders are nodeficiency virus, and porphyria.29,30 noted in Table 1.
S tr ategies and Ev idence Treatment
Neurogenic orthostatic hypotension is usually the
most incapacitating symptom of autonomic fail- Dehydration and acute blood loss should be ruled ure, but the quality of life of affected patients can out in patients presenting with orthostatic hypo- be improved substantially with nonpharmacologic tension, and other non-neurogenic causes should or, when necessary, pharmacologic interventions.
also be considered. These include drugs (e.g., an- tihypertensive agents and antidepressants), reduced Nonpharmacologic Interventions cardiac output (e.g., constrictive pericarditis, car- Patients with orthostatic hypotension should be diomyopathy, and aortic stenosis), endocrine dis- educated about simple measures they can use in orders (e.g., adrenal insufficiency and pheochro- situations that typically precipitate symptoms (Ta- n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. clinical practice glucose-tolerance Diagnostic
fat specimen testing immunoelectrophoresis val-biopsy its, urine for kinase–associated (IKBKAP patients for receptor some neuronal which Purkinje-cell lapsin (CRMP-5), non–small-cell gastrointestinal Comments
immunoglobulin light immunomodulating by cells; proteins cancer; cancer, prostate, acterized fibrillar um, sues, mon thyretin; mutations protein gelsolin caused monoclonal (M ments) marrow fibrillar um, sues, autosomal primarily lung lung tract, pancreas, abnor increased pupils 20% easy nephrotic Orthostatic
pain visceral hypoactive Associated
e, features of dysautonom autonomic gastroparesis, urinary Associated
alized tension other clude tion, function ropathy, and sociated syndrome cardiomyopathy malities, intraocular may are ent ropathy, and sociated syndrome cardiac tooth tients), organomegaly, drome, but (alacrima), reflexes, papillae than orthostatic hypotension m Gastrointestinal Commonly
Disorders
amyloidosis; (AL Autonomic
2. Peripheral
n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. Table 3. Nonpharmacologic Interventions Used in the Treatment of Orthostatic Hypotension.
Perform gradual staged movements with postural change. Time should be allowed for autonomic adaptation.
Avoid straining, coughing, and other maneuvers that in- These maneuvers decrease venous return to the heart and crease intrathoracic pressure.
thereby reduce cardiac output.
Avoid prolonged recumbency.
Deconditioning exacerbates orthostatic hypotension.
Perform isotonic exercise.
The straining associated with isometric exercise decreases venous return to the heart.
Perform physical counter-maneuvers, such as crossing These maneuvers reduce peripheral pooling and increase legs, stooping, squatting. and tensing muscles.
venous return to the heart.
Raise the head of the bed by 10–20 degrees.
This positioning decreases supine hypertension and mini- mizes pressure diuresis. Discontinue or reduce hypotensive and antihypertensive It may be necessary to accept some supine hypertension in order to maintain orthostatic tolerance.
Wear custom-fitted elastic stockings and abdominal Wearing these reduces peripheral pooling in the lower limbs and splanchnic circulation.
Minimize postprandial hypotension.
Small meals, low in carbohydrates, are recommended. Alcohol should be avoided.
Increase intake of fluid and salt.
A daily dietary intake of up to 10 g of sodium per day and a fluid intake of 2.0 to 2.5 liters per day is recommended.
Drink water rapidly.
Rapid ingestion of approximately 0.5 liter of tap water raises blood pressure within 5–15 minutes.
ble 3). Patients should be advised to move from a occurs in the splanchnic circulation. Abdominal supine to a standing position in gradual stages, binders that compress the splanchnic circulation particularly in the morning, when orthostatic with an application pressure of about 20 mm Hg tolerance is lowest, owing to the nocturnal diure- may provide an additional benefit.34 The long- sis induced by supine hypertension and fluid re- term benefit of these interventions is uncertain.
distribution.32 It is also advisable to raise the head Patients with autonomic failure and even healthy of the bed. In addition, several physical counter- elderly persons are susceptible to substantial drops maneuvers — including crossing the legs, stoop- in blood pressure after eating.35 Postprandial hy- ing, squatting, and tensing the muscles of the leg, potension can be minimized by avoiding large abdomen, or buttock or of the whole body — can meals, eating foods that are low in carbohydrates, help maintain blood pressure during daily activi- and minimizing alcohol intake. Patients should be ties. These maneuvers reduce venous pooling and advised against sudden standing or physical ac- thus increase central blood volume and cardiac tivity immediately after eating.
filling, with resultant increases in cardiac out- The recognition and removal (when possible) of put, blood pressure, and cerebral perfusion.33 reversible causes of orthostatic hypotension are Physical activity and exercise should be en- also important. Diuretics, antihypertensive agents, couraged to avoid deconditioning, which is known antianginal agents, α-adrenoreceptor antagonists to exacerbate orthostatic intolerance. Because the for the treatment of benign prostatic hyperplasia, intramuscular vasodilatation that accompanies antiparkinsonism agents, and antidepressants are exercise may exacerbate orthostatic hypotension, the most common offending agents.
recumbent or seated exercise may be preferable. Adequate plasma volume is essential for ortho- During exercise, patients should avoid straining, static tolerance. In patients with supine hyper- which can result in reduced venous return to the tension, elevated nocturnal blood pressure causes a pressure diuresis, resulting in volume depletion. The use of custom-fitted elastic stockings, Raising the head of the bed 10 to 20 degrees (6 to which apply graded pressure to the lower extremi- 10 in.) reduces supine hypertension and decreases ties and abdomen, may also be beneficial. These nocturnal diuresis.36 stockings minimize peripheral-blood pooling in Central blood volume can be augmented by the lower extremities and in the splanchnic cir- increasing the intake of sodium (with high-so- culation. It is preferable for compression to ex- dium foods or salt tablets) and fluid.5 Patients' tend to the waist, since most peripheral pooling daily dietary intake should include up to 10 g of n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. clinical practice sodium and 2.0 to 2.5 liters of fluid. Urinary so- vasodilatory effects may attenuate their pressor ef- dium excretion that exceeds 170 mmol and uri- fects.42 There have been few studies comparing the nary volume greater than 1500 ml over a 24-hour effects of different α-adrenoreceptor agonists. In a period are considered to indicate adequate salt small trial, midodrine (mean dose, 8.4 mg three and fluid intake.37 times a day) improved standing blood pressure and Rapid ingestion (e.g., over a period of 3 to orthostatic tolerance significantly more than ephed- 4 minutes) of approximately 0.5 liter of tap water rine (mean dose, 22.3 mg three times a day).43 elicits a marked pressor response and improve- Other agents may be considered for cases in ment in symptoms in many, but not all, patients which symptoms do not respond to the above in- with autonomic failure. The pressor response, a terventions. Data supporting the use of many of systolic blood pressure increase of more than 30 these agents are from small, single-center trials.
mm Hg in some patients, is evident within 5 min- The postural release of arginine–vasopressin utes of water ingestion, peaks at 20 to 30 min- is reduced in some patients with autonomic fail- utes, and lasts for up to 1 hour. The mechanisms ure49 (particularly when autonomic failure is due underlying the pressor effect are not established. to a central neurodegenerative process in which The observation that venous plasma norepineph- there may be loss of vasopressin neurons in the rine increases after water ingestion suggests that suprachiasmatic nucleus of the hypothalamus). activation of the sympathetic nervous system may The vasopressin analogue desmopressin acetate can be used to supplement volume expansion and reduce nocturnal diuresis.44 Erythropoietin increases standing blood pres- Table 4 lists doses and side effects of medica- sure, and controlled trials have shown that it tions used for orthostatic hypotension. The aim improves orthostatic tolerance in patients with of therapy is to control symptoms, not to restore orthostatic hypotension and anemia45; normo- chromic normocytic anemia is frequently associ- Administration of 9-α-fluorohydrocortisone ated with autonomic failure. The mechanism for (fludrocortisone acetate), a synthetic mineralo- the pressor effect has not been determined but corticoid, may be helpful for patients in whom may involve increases in red-cell mass and cen- plasma volume cannot be adequately increased tral blood volume, alterations in blood viscosity, with fluid and salt.36 Sodium retention and plas- and neurohumoral effects on the vascular wall.45 ma volume return to normal with long-term use, Pyridostigmine, the acetylcholinesterase in- although the pressor effect persists because of hibitor, has been shown in controlled trials to increased peripheral vascular resistance.39 cause a modest increase in blood pressure in pa- Since neurogenic orthostatic hypotension is in tients with neurogenic orthostatic hypotension. large part a consequence of the failure to release The associated increase in supine blood pressure the norepinephrine from sympathetic neurons, the may not be as great as that seen with other pres- administration of sympathomimetic medications sors. The therapeutic rationale is that inhibition is central to the care of patients whose symptoms of acetylcholinesterase enhances sympathetic gan- are not controlled with other measures. Mido- glionic neurotransmission and that the effect is drine, a peripheral, selective, direct α1-adrenore- maximal when the patient is upright, since sympa- ceptor agonist, is the only medication approved thetic-nerve traffic is greatest in this position.48 by the Food and Drug Administration for the treat- Other agents that have been used to treat or- ment of orthostatic hypotension.40 Double-blind, thostatic hypotension include cyclooxygenase in- multicenter, placebo-controlled trials have shown hibitors, β-adrenoreceptor antagonists, clonidine, that midodrine is associated with significantly yohimbine, somatostatin, dihydroergotamine, and increased standing blood pressures and reduced dopamine antagonists. Clinical experience and symptoms of orthostatic intolerance.40,41 small controlled trials of these agents have yield- The mixed α-adrenoreceptor agonists — which ed inconsistent results.50 act directly on the α-adrenoreceptor and release norepinephrine from the postganglionic sympa- Ar e as of Uncertaint y thetic neurons — include ephedrine and pseudo- ephedrine (a stereoisomer of ephedrine).42 Both Among the agents used to treat orthostatic hypo- agents stimulate α, β1, and β2 receptors; their β2 tension, only midodrine has been subjected to a n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. an sympathetic- greatest duration supplementation treatment tension; active be fore supplementation required edema, and, failure tremulous intracere tremulous intracere sympathomimetic (e.g., in sympathomimetic (e.g., in salivation, nausea, hypokalemia, rarely, pine gastrointestinal urinary central effects ness); bral rhythmias, events; central effects ness); bral rhythmias, disease; long-term diovascular population stalsis, stomach weight, 3 approaches maintenance used absorption kidney (releases presynaptic (releases presynaptic Orthostatic
Mechanism
α1-adrenoreceptor α1-adrenoreceptor α1-adrenoreceptor distal enhance sels amines V2 of volume nocturnal the anemia creasing tral rect lar Neurogenic
Acetylcholinesterase Treatment
n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. clinical practice large, multicenter, placebo-controlled trial. There be focused on ruling out non-neurologic causes have been few head-to-head comparisons of agents (e.g., blood loss, dehydration, and cardiovascular and no long-term assessments of efficacy and safe- or endocrine disorders) and determining whether ty. Multicenter, controlled trials assessing dihy- other features of primary autonomic degenera- droxyphenylserine, a synthetic precursor of nor- tive disorders or autonomic peripheral neuropa- epinephrine, are currently in progress.51,52 thies are present. If the diagnosis remains un- Although severe supine hypertension may lim- clear, additional testing, including autonomic it therapeutic intervention, many patients appear testing and imaging studies, may be useful. to tolerate elevations in supine blood pressures In the case presented in the vignette, the ab- without untoward effects, perhaps because su- sence of another apparent cause of symptoms pine hypertension is accompanied by orthostatic and of neurologic findings on examination sug- hypotension. Myocardial hypertrophy is observed gests a diagnosis of pure autonomic failure. None- in some patients53; the incidence of hypertensive theless, because orthostatic hypotension may be end-organ damage, such as cerebrovascular dis- the first manifestation of multiple-system atrophy ease, nephropathy, and cardiomyopathy, has not or autonomic neuropathy, follow-up is essential.
been prospectively studied. The use of short-acting Reversible causes of orthostatic hypotension oral antihypertensive agents at bedtime should be (in particular, the use of hypotensive medications) considered in patients with severe, sustained su- should be addressed as soon as possible. Patients pine hypertension. Because patients with auto- should be counseled regarding nonpharmacologic nomic failure cannot generate the appropriate strategies that can reduce symptoms, such as per- compensatory reflexes, treatment of supine hyper- forming physical counter-maneuvers (e.g., cross- tension, even with short-acting agents, may in- ing the legs, stooping, and tensing muscles), crease the likelihood of syncope and falls. These raising the head of the bed, and ingesting ade- risks must be balanced against the potential ben- quate salt and fluid. If symptoms persist, a low efits of treatment.
dose of fludrocortisone (0.05 or 0.1 mg daily) should be considered. If these approaches do not Guidelines from Professional control symptoms, an α-adrenoreceptor agonist can be added (e.g., midodrine, at an initial dose of 2.5 mg two or three times a day, with a grad- The European Federation of Neurological Societ- ual increase to 10 mg three times a day), with ies has published guidelines for the treatment of use avoided in the 4-hour period before recum- orthostatic hypotension.54 The recommendations bency. Supplementary agents are sometimes need- in this article are generally consistent with these ed. Patients should maintain a blood-pressure diary, measuring blood pressure and noting any accompanying symptoms while supine or stand- ing or after meals, and they should understand that the aim of therapy is to minimize symptoms, not to restore normotension.
A fall in systolic blood pressure of at least 20 Dr. Freeman reports receiving consulting fees from and hon- mm Hg or in diastolic blood pressure of at least oraria for participating in a symposium for Chelsea Pharmaceu- 10 mm Hg within 3 minutes after standing, as in ticals. No other potential conflict of interest relevant to this ar- ticle was reported.
the case in the vignette, is diagnostic of ortho- static hypotension. The history and physical ex- An audio version of this article is available at www.nejm.org.
amination, as well as laboratory testing, should References
1. The definition of orthostatic hypoten-
Linzer M, Tschakovsky ME. Initial ortho- ing W. Pathophysiological basis of ortho- sion, pure autonomic failure, and multiple static hypotension: review of a forgotten static hypotension in autonomic failure. system atrophy. J Auton Nerv Syst 1996; condition. Clin Sci (Lond) 2007;112:157- J Physiol 1999;519:1-10.
6. Robertson D, Kincaid DW, Haile V,
2. Gibbons CH, Freeman R. Delayed or-
4. Shibao C, Grijalva CG, Raj SR, Biag-
Robertson RM. The head and neck dis- thostatic hypotension: a frequent cause of gioni I, Griffin MR. Orthostatic hypoten- comfort of autonomic failure: an unrec- orthostatic intolerance. Neurology 2006;67: sion-related hospitalizations in the United ognized aetiology of headache. Clin Au- States. Am J Med 2007;120:975-80.
ton Res 1994;4:99-103.
3. Wieling W, Krediet CT, van Dijk N, 5. Smit AA, Halliwill JR, Low PA, Wiel-
7. Gibbons CH, Freeman R. Orthostatic
n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. clinical practice dyspnea: a neglected symptom of ortho- autonomic neuropathies: familial dysau- multicenter study. JAMA 1997;277:1046- static hypotension. Clin Auton Res 2005; tonomia and other HSANs. Clin Auton 51. [Erratum, JAMA 1997;278:388.] Res 2002;12:Suppl 1:I2-I14.
41. Wright RA, Kaufmann HC, Perera R,
8. Shannon JR, Jordan J, Diedrich A, et al. 26. Vernino S, Low PA, Fealey RD, Stewart et al. A double-blind, dose-response study
Sympathetically mediated hypertension in JD, Farrugia G, Lennon VA. Autoantibod- of midodrine in neurogenic orthostatic autonomic failure. Circulation 2000;101: ies to ganglionic acetylcholine receptors hypotension. Neurology 1998;51:120-4.
in autoimmune autonomic neuropathies. 42. Jordan J, Shannon JR, Biaggioni I,
9. Kaufmann H, Biaggioni I. Autonomic N Engl J Med 2000;343:847-55.
Norman R, Black BK, Robertson D. Con- failure in neurodegenerative disorders. 27. Wright RA, Grant IA, Low PA. Auto- trasting actions of pressor agents in se-
Semin Neurol 2003;23:351-63.
nomic neuropathy associated with sicca vere autonomic failure. Am J Med 1998; 10. Gilman S, Low PA, Quinn N, et al. complex. J Auton Nerv Syst 1999;75:70-6.
Consensus statement on the diagnosis of 28. Rudnicki SA, Dalmau J. Paraneoplas- 43. Fouad-Tarazi FM, Okabe M, Goren H.
multiple system atrophy. J Auton Nerv tic syndromes of the peripheral nerves. Alpha sympathomimetic treatment of au- Curr Opin Neurol 2005;18:598-603.
tonomic insufficiency with orthostatic 11. Wenning GK, Tison F, Ben Shlomo Y, 29. Low PA, Vernino S, Suarez G. Auto-
hypotension. Am J Med 1995;99:604-10.
Daniel SE, Quinn NP. Multiple system at- nomic dysfunction in peripheral nerve 44. Sakakibara R, Matsuda S, Uchiyama
rophy: a review of 203 pathologically prov- disease. Muscle Nerve 2003;27:646-61.
T, Yoshiyama M, Yamanishi T, Hattori T. en cases. Mov Disord 1997;12:133-47.
30. Freeman R. Autonomic peripheral neu-
The effect of intranasal desmopressin on 12. Schrag A, Wenning GK, Quinn N, Ben ropathy. Lancet 2005;365:1259-70.
nocturnal waking in urination in multi- Shlomo Y. Survival in multiple system at- 31. Assessment: clinical autonomic test- ple system atrophy patients with noctur-
rophy. Mov Disord (in press).
ing report of the Therapeutics and Tech- nal polyuria. Clin Auton Res 2003;13:106- 13. Bhattacharya K, Saadia D, Eisenkraft nology Assessment Subcommittee of the 8.
B, et al. Brain magnetic resonance imag- American Academy of Neurology. Neurol- 45. Hoeldtke RD, Streeten DH. Treatment
ing in multiple-system atrophy and Par- ogy 1996;46:873-80.
of orthostatic hypotension with erythro- kinson disease: a diagnostic algorithm. 32. Omboni S, Smit AA, van Lieshout JJ, poietin. N Engl J Med 1993;329:611-5.
Arch Neurol 2002;59:835-42.
Settels JJ, Langewouters GJ, Wieling W. 46. Perera R, Isola L, Kaufmann H. Effect
14. Biaggioni I. Parkinson's disease: au-
Mechanisms underlying the impairment of recombinant erythropoietin on anemia tonomic neuronopathy with impaired car- in orthostatic tolerance after nocturnal and orthostatic hypotension in primary diovascular regulation. Hypertension 2007; recumbency in patients with autonomic autonomic failure. Clin Auton Res 1995; failure. Clin Sci (Lond) 2001;101:609- 5:211-3.
15. Senard JM, Brefel-Courbon C, Rascol 18.
47. Biaggioni I, Robertson D, Krantz S,
O, Montastruc JL. Orthostatic hypoten- 33. van Lieshout JJ, ten Harkel AD, Wiel- Jones M, Haile V. The anemia of primary
sion in patients with Parkinson's disease: ing W. Physical manoeuvres for combat- autonomic failure and its reversal with pathophysiology and management. Drugs ing orthostatic dizziness in autonomic recombinant erythropoietin. Ann Intern failure. Lancet 1992;339:897-8.
Med 1994;121:181-6.
16. Orimo S, Amino T, Uchihara T, et al. 34. Smit AA, Wieling W, Fujimura J, et al. 48. Singer W, Sandroni P, Opfer-Gehr-
Decreased cardiac uptake of MIBG is a Use of lower abdominal compression to king TL, et al. Pyridostigmine treatment potential biomarker for the presence of combat orthostatic hypotension in pa- trial in neurogenic orthostatic hypoten- Lewy bodies. J Neurol 2007;254:Suppl 4: tients with autonomic dysfunction. Clin sion. Arch Neurol 2006;63:513-8.
Auton Res 2004;14:167-75.
49. Kaufmann H, Oribe E, Miller M, Knott
17. Goldstein DS. Functional neuroimag-
35. Lipsitz LA, Ryan SM, Parker JA, Free-
P, Wiltshire-Clement M, Yahr MD. Hypo- ing of sympathetic innervation of the heart. man R, Wei JY, Goldberger AL. Hemody- tension-induced vasopressin release distin- Ann N Y Acad Sci 2004;1018:231-43.
namic and autonomic nervous system re- guishes between pure autonomic failure 18. Thaisetthawatkul P, Boeve BF, Benar-
sponses to mixed meal ingestion in and multiple system atrophy with auto- roch EE, et al. Autonomic dysfunction in healthy young and old subjects and dysau- nomic failure. Neurology 1992;42:590-3.
dementia with Lewy bodies. Neurology tonomic patients with postprandial hypo- 50. Freeman R. Treatment of orthostatic
tension. Circulation 1993;87:391-400.
hypotension. Semin Neurol 2003;23:435- 19. Freeman R. Pure autonomic failure: 36. van Lieshout JJ, ten Harkel AD, Wiel-
an immaculate misconception? Neurolo- ing W. Fludrocortisone and sleeping in 51. Freeman R, Landsberg L, Young J. The
gy 2004;63:953-4.
the head-up position limit the postural treatment of neurogenic orthostatic hy- 20. Kaufmann H, Nahm K, Purohit D, decrease in cardiac output in autonomic potension with 3,4-DL-threo-dihydroxy-
Wolfe D. Autonomic failure as the initial failure. Clin Auton Res 2000;10:35-42.
phenylserine: a randomized, placebo-con- presentation of Parkinson disease and de- 37. Wieling W, van Lieshout JJ, Hains- trolled, crossover trial. Neurology 1999;
mentia with Lewy bodies. Neurology worth R. Extracellular fluid volume ex- 53:2151-7.
pansion in patients with posturally related 52. Kaufmann H, Saadia D, Voustianiouk
21. Low PA, Benrud-Larson LM, Sletten syncope. Clin Auton Res 2002;12:242-9.
A, et al. Norepinephrine precursor thera- DM, et al. Autonomic symptoms and dia- 38. Jordan J, Shannon JR, Black BK, et al. py in neurogenic orthostatic hypotension.
betic neuropathy: a population-based The pressor response to water drinking in Circulation 2003;108:724-8.
study. Diabetes Care 2004;27:2942-7.
humans: a sympathetic reflex? Circula- 53. Vagaonescu TD, Saadia D, Tuhrim S,
22. Benson MD, Kincaid JC. The molecular tion 2000;101:504-9.
Phillips RA, Kaufmann H. Hypertensive biology and clinical features of amyloid 39. Chobanian AV, Volicer L, Tifft CP, cardiovascular damage in patients with
neuropathy. Muscle Nerve 2007;36:411-23.
Gavras H, Liang CS, Faxon D. Mineralo- primary autonomic failure. Lancet 2000; 23. Falk RH, Comenzo RL, Skinner M. corticoid-induced hypertension in patients 355:725-6.
The systemic amyloidoses. N Engl J Med with orthostatic hypotension. N Engl J 54. Lahrmann H, Cortelli P, Hilz M,
Med 1979;301:68-73.
Mathias CJ, Struhal W, Tassinari M. EFNS 24. Adams D. Hereditary and acquired 40. Low PA, Gilden JL, Freeman R, Sheng guidelines on the diagnosis and manage-
amyloid neuropathies. J Neurol 2001;248: KN, McElligott MA. Efficacy of midodrine ment of orthostatic hypotension. Eur J vs placebo in neurogenic orthostatic hy- Neurol 2006;13:930-6.
25. Axelrod FB. Hereditary sensory and potension: a randomized, double-blind Copyright 2008 Massachusetts Medical Society.
n engl j med 358;6 www.nejm.org february 7, 2008 Downloaded from www.nejm.org by KAREN G. KELLY MD on September 26, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

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