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Supplements Understanding the Diagnosis, Management, and Treatment Options for Neurogenic Orthostatic Hypoten

Neurogenic Orthostatic Hypotension: Pathophysiology and Diagnosis

Phillip A. Low, MD
During evaluation at the Mayo Autonomic Reflex Laboratory, symptoms and aggravating factors were characterized in 90 patients with severe NOH. Three diseases were responsible for 90% of cases in this group: PAF, MSA, and autonomic neuropathy, including diabetic neuropathy. Based on a mean Composite Autonomic Symptom Score (CASS) of 6.9, patients had moderate to severe autonomic failure and the severity of NOH symptoms correlated with the severity of autonomic failure.38 These patients tended to be in grades III and IV on the SGOI.37

The most commonly reported symptoms of orthostat-ic intolerance included lightheadedness (88%), weakness (72%), impaired cognition (47%), blurred vision (47%), tremulousness (38%), and vertigo (37%).38 Half of patients developed symptoms within less than 1 minute of stand-ing and 75% of patients developed symptoms within 5 minutes of standing. Orthostatic stressors that exacerbated OH included prolonged standing (58%), exercise (53%), warm temperatures (32%), and eating (24%). Symptoms of autonomic hyperactivity (palpitations, tremulousness, anxiety, and nausea) occurred in patients who were younger or had autonomic neuropathies, like-ly because they suffered from partial autonomic failure. Syncope was not a predominant symptom, with 58% of patients reporting that they had never lost conscious-ness completely, 28% reporting syncope less than once a month, and 14% reporting it more frequently. Although about half of patients reported that their symptoms were not worse at a particular time of day, 34% had exacerba-tion early in the morning.38 Other nonspecific symptoms of NOH include fatigue, leg buckling, orthostatic dyspnea, and chest pain.1

In the Mayo Autonomic Reflex Laboratory study, about half of patients with NOH reported difficulty concentrating.38 This symptom was most common in patients older than 70 years, and it was the only symptom of orthostatic intolerance in some patients.41 Identifying NOH as the cause of atypical symptoms such as this is especially important, both to avoid an incorrect diagnosis of possible dementia and to offer access to drug therapy that can dramatically improve cognition.38

In NOH, a characteristic form of pain affects the back of the head and muscles in the neck in a coat-hanger distribu-tion and may be due to ischemia of large neck muscles.42 In a study in 22 patients with severe adrenergic impairment, almost 60% reported experiencing a coat-hanger ache during daily activities.43 Pain would typically occur with 3 to 5 minutes of standing, had a slower onset during sitting, and was relieved within 5 to 20 minutes of lying down.

Patients with NOH become symptomatic when standing SBP falls below the range of cerebrovascular autoregulation.44 In the autoregulated range of SBP, which is typically between 80 and 150 mm Hg, cerebral blood flow remains constant in spite of changes in blood pressure. Some patients with NOH have expansion of this range with lower pressures down to about 60 mm Hg and may be asymptomatic in spite of large falls in blood pressure.45,46

Quality of Life With NOH

Considering that NOH is an orphan disease, it is not surprising that studies have not formally assessed QOL in patients who have NOH. Nonetheless, the majority of reports allude to impairment of QOL.2,6,47 One can safely estimate that QOL is poor for many patients because they may be wheelchair-bound, disabled by their symp-toms, and have difficulty completing activities of daily living without assistance.

QOL has been found to be substantially impaired in patients with postural tachycardia syndrome, another disorder that is characterized by orthostatic intolerance and autonomic dysfunction.48 Patients reported impairment across multiple domains of the short form (SF)-36, including physical functioning, role functioning, bodily pain, general health, vitality, and social functioning. Another study reported low QOL in patients with MSA, with patients reporting life satisfaction as low (mean score of 39 on a 100-point visual analog scale).49 The average Physical Component Score on the SF-36 was 26.0 ± 8.7, 1.5 standard deviations below the mean for a cohort of healthy people of an equivalent age.

Supine Hypertension in NOH

Approximately half of patients with NOH also have supine hypertension (SH).10,50 Consensus has not been reached about the level of blood pressure that defines SH, but studies on NOH and SH have defined SH as 150 to 180/≥90 mm Hg.6,50 The baseline blood pressure determines the size of the fall in orthostatic blood pressure; therefore, a reduction in SBP of at least 30 mm Hg may be a more appropriate criterion for OH than at least 20 mm Hg in patients with SH.1

Patients with SH experience a pressure diuresis if they lie flat at night. The resulting volume depletion worsens orthostatic symptoms in the morning.51 The clinical sig-nificance of SH has not been established in longitudinal studies, but in cross-sectional studies of patients with autonomic faxilure, it has been linked to renal impair-ment and left ventricular hypertrophy.52-54 Avoiding a supine blood pressure ≥180/110 mm Hg is a practical management goal for patients with SH.2 First-line man-agement of SH includes raising the head of the bed by inches, if necessary by 6 to 9 inches (10° to 20°), and avoiding the supine position during the day.10

Diagnosis of NOH

The initial diagnosis of NOH is based on blood pres-sure and heart rate measurements taken after the patient has been supine for at least 5 minutes, and then after 1 and 3 minutes of active standing.10 In addition to the substantial reductions in blood pressure when standing, as specified in the definition of OH, the diagnosis of NOH is likely when the associated increase in heart rate is less than 15 beats per minute.55 The initial diagnosis can be based on auscultatory or oscillometric measurements during active standing in the clinic or in an auto-nomic laboratory, where patients are placed on a tilt table in the head-up position at an angle of at least 60°.39 HUT, which evaluates the blood pressure and heart rate response to tilt, can help distinguish between NOH and postural tachycardia syndrome.11 European guidelines recommend HUT if the active standing test is negative, especially if the patient’s history suggests OH.56

It should be noted that patients with milder NOH may have a normal or exaggerated heart rate increment.57 The latter is due to a preserved and increased sympathetic response, which can manifest as orthostatic tachycardia and increased orthostatic plasma norepinephrine. These patients typically also have symptom of sympathetic activation, such as palpitations, tremulousness, sweatiness, and nausea.58

Patients may be asked to maintain a diary documenting supine and standing blood pressures throughout the day, as well as their symptoms and blood pressure response to orthostatic stressors (eating, exercise, etc). Sensitivity may be increased by obtaining blood pressure measurements in the morning, when NOH may be worst.10 Diaries like these help physicians to determine a patient’s level of impairment and orthostatic stressors that patients need to avoid or minimize. These diaries also provide a good opportunity to educate patients about strategies to help manage their exposure to orthostatic stressors.

Autonomic testing confirms the clinical diagnosis (see Table 211). During continuous blood pressure monitoring of the Valsalva maneuver, a diagnosis of NOH is indicated by an exaggerated and sustained decrease in blood pres-sure without a compensatory increase in heart rate during straining (phase 2), a lack of reflex vasoconstriction shown through a loss of late phase 2 and blood pressure over-shoot, and delayed blood pressure recovery.59,60 By determining the distribution, severity, and progres-sion of autonomic dysfunction with autonomic testing, a physician can distinguish between the synuceinopathies.11 Such tests include the auto-nomic reflex screen, thermoregulatory sweat test, measurement of supine and standing norepinephrine, and 24-hour urinary sodium.

The autonomic reflex screen includes the quantitative sudomotor axon reflex tests of cardiovagal function (heart rate variability and Valsalva ratio), and tests of adrenergic reflex function (beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver and HUT). The 24-hour urinary sodium helps determine if the patient is drinking enough fluids and ingesting enough salt. Urine volume of 1500 to 2500 mL in 24 hours indicates adequate fluid intake, while urinary sodium excretion of more than 170 mmol/24 hours indicates adequate salt intake.61

The diagnosis of NOH should consider 2 variants: initial and delayed OH.1 In initial OH, a transient drop in blood pressure (≥40 mm Hg SBP or ≥20 mm Hg DBP) occurs within about 15 seconds of standing. Initial OH can cause syncope and may be caused by a transient mismatch between cardiac output and peripheral vascular resistance. Patients may report that, when standing up quickly, they experience transient orthostatic symptoms and feel normal immedi-ately afterward. Continuous beat-to-beat blood pressure monitoring is used to detect initial OH because blood pressure changes are too fleeting to be detected with auscultatory or oscillometric measurements.62

Delayed OH is defined as a drop in blood pressure that does not occur until after at least 3 minutes of standing.1 One study found that patients with delayed NOH were younger and had smaller drops in blood pressure during the Valsalva maneuver, suggesting that delayed OH may represent earlier or less severe autonomic failure63; however, longitudinal studies have not been performed to confirm this. A study in more than 600 patients undergoing prolonged tilt testing used logistic regression to determine the minimum duration of testing needed to detect delayed OH.64 The study results showed that 30 minutes was long enough to detect delayed OH in patients aged at least 65 years, while 40 minutes was necessary in younger patients.

Ambulatory blood pressure monitoring (ABPM) can capture the wide fluctuations in blood pressure experienced by patients with NOH. It can help confirm the diagnosis in patients who report OH symptoms but have equivocal blood pressure measurements in the office or on the tilt test.65 ABPM records only blood pressure and not posture, so its utility can be enhanced by documenting the patient’s posture during monitoring.10 It also has a role in the diagnosis and monitoring of SH.66 A study that compared ABPM with office tilt test measurements found that supine office blood pressure values were pre-dictive of nocturnal SH.65 A study that enrolled 74 patients with MSA or PD with and without autonomic failure compared 24-hour ABPM with HUT to diagnose OH.67 Using the standing test during 24-hour ABPM, a reduction in SBP of at least 20 mm Hg had sensitivity and specificity of 82% and 100% (area under the curve 0.91; 95% CI, 0.84-0.98), respectively, in differentiating between patients with and without OH.

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