Neurogenic Orthostatic Hypotension: Pathophysiology and Diagnosis

Published Online: October 30, 2015
Phillip A. Low, MD

Although orthostatic hypotension in elderly patients is common, neurogenic orthostatic hypotension (NOH) is a condition with substantial morbidity and a variable prognosis. Patients with severe NOH have difficulty standing for any period of time and must scrupulously avoid orthostatic stressors that exacerbate their condition. In about half of patients, supine hypertension complicates management. The diagnosis is based on measurements of supine and standing blood pressures or head-up tilt testing and is confirmed by autonomic testing. Two self-report questionnaires, the Orthostatic Hypotension Questionnaire and the Orthostatic Grading Scale, can help evaluate a patient’s level of impairment, document progression, and assess the response to pharmacotherapy in clinical practice. There are many gaps in our knowledge of this rare disorder; this review summarizes what is currently known about the pathophysiology, epidemiology, progno-sis, signs and symptoms, and the diagnosis of NOH.
Am J Manag Care. 2015;21:S248-S257
When an individual stands up, the auto- nomic nervous system ensures that ade-quate blood flow keeps the heart pumping and the brain perfused, in addition to preventing almost a liter of blood from pooling in the abdomen and lower extremities. The cardiac output that is caused by standing and the drop in blood pressure stimulates a reflex response by baroreceptors that increases sympathetic outflow and decreases vagal nerve activity.1 Baroreflex path-ways send coordinated signals to the heart to increase heart rate and cardiac output. The coordinated signals are also sent to arterioles and venules to increase systemic vascular resistance. Vasoconstriction of the splanchnic-mesenteric bed in the abdomen, mediated by alpha-adrenergic receptors, plays an important role because this vascular bed accounts for up to 30% of total blood volume.2

In the normal body, these complex actions maintain a similar level of blood pressure whether supine, sitting, or standing.2,3 Orthostatic hypotension (OH) occurs when the body is unable to maintain the same blood pressure when standing. A consensus statement, developed and endorsed by international experts, defines OH as a sustained reduction of systolic blood pressure (SBP) of at least 20 mm Hg or diastolic blood pressure (DBP) of at least 10 mm Hg within 3 minutes of standing. However, with the head-up tilt (HUT) test, a decrement of 30 mm Hg is more appropriate.1,4

Pathophysiology of Orthostatic Hypotension

OH has both non-neurogenic and neurogenic causes that can be acute or chronic.5 It can be multifactorial, with non-neurogenic causes more common than neurogenic causes. For example, dehydration and drug therapy can contribute to the development of OH in an elderly patient.6 Non-neurogenic causes of OH fall into 3 categories: hypovolemia, cardiac pump failure, and venous pool-ing. Hypovolemia has myriad causes, ranging from acute dehydration due to nausea and vomiting to chronic blood loss from colon cancer or gastric ulcers. Cardiac pump failure can be caused by bradycardia, tachyarrhythmia, aortic stenosis, myocardial infarction (MI), or pericarditis. Venous pooling can be caused by prolonged standing, such as when a soldier faints while standing in formation; however, it can also be caused by fever, severe varicose veins, postprandial dilation of splanchnic blood vessels, and heat exposure.5

Drugs cause or exacerbate OH through a variety of mechanisms that mimic the primary non-neurogenic causes of OH: hypovolemia, cardiac pump failure, and venous pooling. Classes of drugs that commonly cause OH include diuretics (ie, hypovolemia) and alpha1-adren-ergic antagonists (reduced systemic vascular resistance).7,8 OH with the nondihydropyridine calcium channel block-ers diltiazem and verapamil is attributed to their negative inotropic and chronotropic effects.9 Nitrates induce OH by causing vasodilation.9

In neurogenic orthostatic hypotension (NOH), impaired vasoconstriction is caused by inadequate release of norepinephrine from sympathetic vasomotor neu-rons.1 In addition to having inadequate vasoconstriction, patients with NOH may have an inadequate increase in heart rate when they stand up.1 This stands in contrast to the exaggerated increase in heart rate that occurs with OH due to hypovolemia.10 NOH occurs primarily in autonomic degenerative disorders that are characterized by abnormal accumulation of alpha-synuclein. The synucleinopathies include Parkinson’s disease (PD), mul-tiple system atrophy (MSA), Lewy body dementia, and pure autonomic failure (PAF). In addition to experiencing NOH, patients with these conditions experience other forms of autonomic dysfunction, including erectile dys-function, neurogenic bladder, and constipation.11

NOH can also be caused by peripheral neuropathies, such as diabetic neuropathy, amyloidosis, and Guillain-Barré syndrome; it also occurs with spinal cord injury.5 Just as drugs can mimic non-neurogenic causes of OH, they can exacerbate the defect in sympathetic nerve activity that is characteristic of NOH. For example, alpha-adrenergic agonists (ie, clonidine, guanfacine) reduce sympathetic out-flow from the central nervous system. Monoamine oxidase inhibitors may cause OH by depleting norepinephrine.12


OH is common in elderly patients and increases with age. In the longitudinal Cardiovascular Health Study, the prevalence of symptomatic OH increased from 14.8% in patients aged 65 to 69 years to 26% in patients 85 years or older.13 The incidence of OH is also greater in frail popula-tions, with a prevalence as high as 50% in nursing homes compared with 6.4% in community-living elderly.14,15 Common causes of OH in elderly patients include drugs, dehydration or volume depletion, and heart failure (HF).5

In contrast to OH in elderly patients, NOH is rare enough to be classified as an orphan disease in the United States.16 Symptomatic NOH is estimated to affect approximately 80,000 patients with PD, MSA, or PAF.17 NOH is present in approximately 80% of patients with MSA, occurring within the context of rapidly progressing autonomic failure, Parkinsonism, and cerebellar ataxia.18 It is present in about half of patients with Lewy body dementia.19 The reported prevalence of NOH in PD varies widely, with estimates ranging from 18% to 58%.20,21 The point prevalence of OH in PD was 30.1% (95% CI, 22.9%-38.4%) in a meta-analysis that pooled data from 25 studies.22 In the population-based Rochester Diabetic Neuropathy Study, the incidence of OH was 8.4% among patients with type 1 diabetes and 7.4% among patients with type 2 diabetes.23 In 65 patients with biopsy-proven amyloidosis, 74% had orthostatic intolerance.24

Prognosis and Associated Comorbidities

Epidemiologic studies suggest that OH in elderly patients increases the risk of frequent falling, syncope, chronic kidney disease, stroke, HF, coronary events, and all-cause mortality.13,25-32 In 2004, the rate of hospitalization associated with OH was 36 per 100,000 adults in the United States.33 In addition, among the approximately 80,000 admissions of patients with OH that year, 4% were associated with PD, 4% with autonomic neuropathy, and 0.9% with abnormal degeneration of basal ganglia. In con-trast to extensive data about the prognosis of OH in elderly patients, few studies describe the prognosis in NOH.

Maule and colleagues described the course of NOH in 104 patients (45 with MSA, 43 with PD, 9 with PAF, and 7 with other autonomic neuropathies) treated at an Italian center over 14 years. More than half of the patients either had comorbid cardiovascular disorders (primarily hypertension) or developed cardiac complica-tions (primarily HF) during the course of their disease. Forty-four (42.3%) had died by the end of follow-up, with the highest mortality in patients with MSA. The death rate was higher in patients with comorbid cardiovascular disease (53% vs 31%, P = .04). Infection, respiratory diseases, and cachexia were the most common causes of death. Patients with NOH had a 3-fold higher risk of death than the general population in that geographic area.34

A French treatment center followed 31 NOH patients with autonomic failure (7 with MSA, 10 with PD, and 7 with PAF) over successive 19-day periods in August 2003 and 2004.35 There was a dramatic heat wave in Europe during the observation period in August 2003, followed by a normal summer in 2004. The primary goal of the study was to document the effects of heat exposure, a factor known to exacerbate NOH. Clinical events were compared with a control group of PD patients who did not have NOH.

In 2003, 45.1% of NOH patients experienced at least 1 clinical adverse event compared with 11.5% of control patients. Ten events were severe in patients with NOH (6 fractures due to falls, 2 cases of head trauma due to syncope, 1 case of dehydration, and 1 hip fracture after discontinuation of midodrine) compared with none in control patients (P = .0025). During the year, 5 patients with NOH died (2 sudden deaths, 1 brain hemorrhage, 1 MI, and 1 respiratory event). During the second study period, in 2004, 42.3% of NOH patients experienced at least 1 clinical adverse event compared with 12% of control patients. These rates were similar to the summer before, but there were fewer severe events in NOH patients in the second year (2 cases of severe dehydration and 1 fall with head trauma). This study demonstrates the harmful effect of heat on patients with NOH. However, with 7 fractures due to falls, 3 cases of head trauma, and 5 deaths over 1 year in a cohort of 31 patients, it also documents substantial morbidity and mortality in patients with severe NOH.35

Signs and Symptoms of NOH

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