Neurogenic Orthostatic Hypotension

Educational Objectives

The goal of this program is to improve clinical diagnosis, differential diagnosis, and medical management of orthostatic hypotension. After hearing and assimilating this program, the clinician will be better able to:

1. Identify patients with orthostatic hypotension.
2. Distinguish neurogenic orthostatic hypotension from non-neurogenic orthostatic hypotension.
3. Carry out the appropriate bedside tests to identify patients with neurogenic orthostatic hypotension.
4. Recognize symptoms that are likely to progress to full-blown synucleinopathies.
5. Provide appropriate medical treatment to patients with orthostatic hypotension.

Summary

Definition: orthostatic hypotension (OH) is a sustained decrease of ≥20 mm Hg in systolic blood pressure (SBP) or 10 mm Hg of diastolic blood pressure (DBP), usually within 3 min of standing

Accurate measurement of BP: crossing the legs or incorrect placement of the cuff can raise SBP by 3 to 8 mm Hg; to correctly measure BP, ask the patient to lie down, place the BP cuff over the brachial artery, and use the correct cuff size; have the patient relax for ≈5 min, measure BP and heart rate (HR) in the supine position at least once, then ask the patient to stand without leaning on anything; wait 1 min and measure BP and HR again; repeat standing BP and HR measurements 3 times at intervals of 1 min

Diagnosis: sophisticated equipment and tests are not required to diagnose OH; OH is a sign, not a symptom; it may be symptomatic or asymptomatic, depending on several factors; although unnecessary for diagnosing OH, HR should be measured

Clinical features and differential diagnosis: measure orthostatic BP in all patients with Parkinson disease (PD), particularly those with specific symptoms of dizziness, a peculiar sensation of lightheadedness, presyncope (or, when the decrease in BP is pronounced, syncope), blurred vision, shortness of breath occurring only when standing, “coat hanger pain” (a peculiar sensation of pressure or soreness in the area of the neck and shoulders), or a sensation of generalized weakness or fatigue; all symptoms should occur only when standing; OH can be a factor in falls not associated with PD and otherwise unexplained; unexplained cognitive changes that occur when standing and improve in the supine position also suggest OH (directly related to cerebral hypoperfusion); always measure BP in the standing position for persons >70 yr of age

OH mimics: dizziness and lightheadedness when standing is not always OH; other nonmotor symptoms unrelated to autonomic dysfunction can produce these symptoms; orthostatic tremor or myoclonus, vestibular dysfunction, side effects of medications, or severe anxiety producing hyperventilation are possible causes; inebriation-like syndrome in PD — related to basal ganglia function; there is no treatment

Medications that cause hypotension: include opioids, diuretics, tricyclic antidepressants, benzodiazepines, α-blockers, nitrates, and phosphodiesterase type 5 inhibitors (eg, sildenafil); may cause hypotension even in patients who have no autonomic failure; α-blockers are one of the most common causes of syncope in elderly men (particularly in those with PD)

Anemia: should always prompt assessment; for anemia that is idiopathic or associated with mild renal insufficiency (ie, “anemia of chronic disease”), treatment with recombinant erythropoietin may be considered; several studies have shown that, in patients with OH and anemia, recombinant erythropoietin can increase standing BP without significant increase of supine BP

Common causes of OH: include medications, volume depletion, anemia, severe heart failure, and adrenal insufficiency; medications, particularly polypharmacy, are the most common cause; autonomic dysfunction, also referred to as neurogenic OH (nOH), requires specific treatment

Neurogenic OH vs non-neurogenic OH (non-nOH): nOH results from nerve dysfunction; in nOH, BP falls because release of norepinephrine is impaired (a disorder of noradrenergic neurotransmission; sympathetic postganglionic nerves (SPN) do not appropriately release norepinephrine); non-nOH is extremely common, particularly in the elderly, while nOH is relatively rare; non-nOH has variable onset; nOH is usually chronic; non-nOH is caused by medications, dehydration, anemia, and (often) physical deconditioning; even a short period of bedrest in an elderly person can result in non-nOH; nOH can be worsened by non-neurogenic factors; with non-nOH, outcomes are good when the cause is resolved; nOH can be treated but not cured; in non-nOH, there are usually no other signs of autonomic dysfunction; nOH is usually associated with other signs, eg, constipation, erectile dysfunction, bladder problems, decreased sweating, suggesting a more generalized autonomic problem; in most cases of non-nOH, there are no neurologic problems; in nOH, there may be no apparent central neurologic deficit, or there may be clear parkinsonism, cerebellar ataxia, or a sensory neuropathy; nOH is the hallmark of neurologic disorders that affect the autonomic nervous system, specifically the sympathetic neurons

Distinguishing nOH from non-nOH via laboratory testing: in non-nOH, the plasma norepinephrine level significantly increases upon moving from supine to standing; in nOH, the norepinephrine level may be normal or slightly low in the supine position and does not increase on rising from supine to standing

Distinguishing nOH from non-nOH via bedside testing: study — documented HR changes in patients with autonomic failure caused by neurodegenerative synucleinopathies; showed a pronounced increase in HR upon standing in patients with non-nOH; patients with nOH had a much smaller increase in HR; the absolute value of HR had a sensitivity of 79% and a specificity of 87% for distinguishing nOH from non-nOH

Gain: the ratio of the increase in HR with standing to the decrease in systolic BP (ΔHR/ΔSBP); gain is much more pronounced in patients with non-nOH than in those with nOH, with a sensitivity of >91% and a specificity of 88%

Conclusions: a blunted increase in HR during hypotension suggests neurogenic cause; a specific ratio of 0.5 bpm/mm Hg of decrease is diagnostic of neurogenic OH; therefore, in addition to measuring BP, it is important to measure HR in supine and standing positions when assessing orthostatic vital statistics

Importance of identifying nOH: the most common cause is diabetic autonomic neuropathy (affects ≈10 million people in the United States); the second most common cause is neurodegenerative synucleinopathies (including PD); ≈0.5 million people with synucleinopathies have treatable nOH; many patients with nOH may have neurogenerative disease that has not yet been diagnosed

Synucleinopathies

Definition: disorders caused by abnormal accumulation of misfolded phosphorylated α-synuclein; synuclein accumulation affects autonomic neurons centrally and peripherally

Clinical phenotypes: clinical symptoms and survival depend on the cell type in which α-synuclein initially aggregates; 1) accumulation primarily in neurons — results in Lewy bodies or Lewy neurites, which are the hallmark of PD, dementia with Lewy bodies (DLB), or pure autonomic failure (PAF); characterized by slow progression; 2) accumulation primarily in oligodendroglia — results in glial cytoplasmic inclusions, which are the hallmark of multiple system atrophy (MSA); associated with rapid progression

PD: α-synuclein accumulates in the brainstem and midbrain, and continues to the cortex; in addition, there is dramatic accumulation of α-synuclein in peripheral sympathetic neurons, specifically in the PSN that innervate the heart, gut, bladder, and sexual organs; the same occurs in DLB or PD dementia (ie, PD may be considered an autonomic peripheral neuropathy)

MSA: characterized by accumulation of α-synuclein centrally in the brain and spinal cord, particularly the intermediolateral columns; initially, it does not affect the peripheral autonomic neurons; PSN are mostly spared

PAF: considered an incidental Lewy body disease; most cases of PAF are prodromal parkinsonism; clinically, accumulation of α-synuclein is peripheral only (if present, accumulation in the central nervous system [CNS] is not clinically evident)

Rapid eye movement behavior disorder (RBD): a prodromal form of parkinsonism or MSA; accumulation of α-synuclein occurs mainly in the brainstem, but also is found in the peripheral sympathetic neurons

Spectrum of synucleinopathies: although symptoms vary among the synucleinopathy phenotypes, autonomic dysfunction (particularly OH) is usually present to some degree in all; synucleinopathies can be divided into those with motor or cognitive deficit (PD and DLB) and those without motor or cognitive deficits (PAF and isolated RBD); synucleinopathies without motor or cognitive deficit at presentation may evolve over time to full-blown synucleinopathies (ie, phenoconversion [the phenotype converts])

Study: follows the natural history of patients who present with autonomic abnormalities only, particularly neurogenic OH, and no signs of CNS dysfunction (no motor signs); by 4 yr, 34% of patients had phenoconverted to DLB, PD, or MSA; among patients initially diagnosed with PAF, the cumulative risk of progressing to a CNS synucleinopathy was 14%/yr; among patients who phenoconverted to MSA, this diagnosis typically was reached within 5 yr of the onset of autonomic failure (for PD or DLB, phenoconversion occurred in ≈9 yr); patients who present free of cognitive and motor signs develop full-blown synucleinopathies in an average of 12 yr, but the process may take ≤25 yr; studies have reported similar findings for RBD; these findings are critical to developing criteria for prodromal PD

Management of OH

General principles: patients who are asymptomatic should not be treated; the first step is to eliminate aggravating factors (eg, medication, anemia, dehydration)

Nonpharmacologic treatment: increase sodium intake using binders; reassess BP after increasing salt and water intake; if symptoms persist despite nonpharmacologic treatment, consider pharmacologic treatment

Pharmacologic treatment: there are 2 mechanisms (volume expansion and vasoconstriction); volume expansion — achieved with fludrocortisone, a mineralocorticoid; vasoconstriction — midodrine, a direct adrenergic agonist, produces direct vasoconstriction of the blood vessels; droxidopa, a synthetic amino acid, is transformed into norepinephrine inside neurons and in non-neuronal tissues (acts on α-adrenergic receptors in the blood vessels to increase BP); a newer approach uses norepinephrine transporter (NET) inhibitors; NET is responsible for recycling of released norepinephrine; therefore, blocking NET increases the level of norepinephrine in the neurovascular junction

Fludrocortisone: increases sodium reabsorption and intravascular volume; effective at low doses (no more than 0.1-0.2 mg/day) and is long acting; clinical effects are seen after 3 to 5 days (after volume expansion has occurred); adverse effects — hypokalemia is most common and can result in arrhythmias (prescribe potassium supplements or periodically check serum potassium); edema, heart failure, left ventricular hypertrophy, and renal fibrosis are other possible effects; a population study showed that, compared with midodrine, use of fludrocortisone is associated with higher risk for all-cause hospitalization in patients with OH

Midodrine: a selective α-1 agonist; does not cross the blood-brain barrier, so it does not have a stimulant effect or cause insomnia; has predictable effect 1 hr after administration; the duration of action is ≈3 hr; usual dose is 2.5 to 10 mg, ≤3 times/day (with higher doses given earlier in the day, when OH is more pronounced; avoid dosing at bedtime); adverse effects — include supine hypertension, piloerection, and (rarely) urinary retention

Droxidopa: a newer drug; shown to increase BP and improve symptom burden in a large international phase 3 trial and several other studies; effective in patients with PD; a synthetic precursor of norepinephrine (converted to norepinephrine by a single decarboxylation step, without the need for dopamine β-hydroxylase); peak plasma concentration is reached 1 hr after administration; dose is 100 to 600 mg, 3 times/day; as with midodrine, dosing should be at the time of greatest need, rather than at fixed intervals; surprisingly, in ≈30% of patients with nOH, BP does not increase and there is no symptomatic improvement in response to droxidopa

Study: hypothesized that the degree of denervation supersensitivity predicts the response to droxidopa; found nonresponders had a significantly higher concentration of norepinephrine when supine before receiving droxidopa, compared with responders; plotting the increase in BP against the plasma concentration of norepinephrine showed that only the patients with low plasma concentrations of norepinephrine had a significant increase in BP (patients with high norepinephrine levels had almost no response); a supine plasma norepinephrine level <219 pg/mL predicted a good response to droxidopa; conclusion — the level of peripheral denervation, rather than the primary diagnosis, predicts the response to droxidopa; this finding allows for phenotype-driven treatment of nOH

Norepinephrine transporter inhibitors: response is the exact opposite of that to droxidopa, ie, NET inhibitors increase BP only in patients with higher levels of norepinephrine; atomoxetine (Strattera) — a NET inhibitor that is approved for treatment of attention-deficit disorder; increases BP in patients with higher levels of norepinephrine

Conclusions: patients with peripheral involvement, with or without involvement of the CNS, have significant denervation; those with central involvement have decentralization rather than denervation; determining whether nOH is central vs peripheral is key to personalization of treatment

Questions and Answers

Orthostatic hypertension: also believed to have a neurogenic mechanism; occurs along a spectrum, ranging from severe anxiety to afferent baroreflex failure (ABF); ABF occurs when the vagal nerve and the glossopharyngeal nerve in the neck, which bring the information from the periphery, are affected (by, eg, cancer involving the neck); incidence has increased with that of human papillomavirus-related neck cancers; normal restraint of the baroreflex through the afferent limb is impaired; as a result, any stimulus can produce an increase in BP; in addition to an increase in BP upon standing or becoming excited, OH can occur when the patient becomes relaxed

Postprandial hypotension in patients with nOH: the main mechanism is release of insulin (a vasodilator); in the normal autonomic nervous system, rapid compensation for insulin that is released after eating prevents a decrease in BP; in elderly people and those with PD, the worsening of OH after meals is dramatic (postprandial hypotension may produce hypotension when the patient is supine); consistent decrease in BP after meals is diagnostic

Treatment: recommend small, frequent meals, with avoidance of carbohydrates that are easily absorbed (ie, these produce a high peak of insulin); acarbose — used for diabetes; inhibits carbohydrate absorption; when taken before meals, significantly reduces postprandial hypotension; often prescribed for patients with PD; safe; side effects are gastrointestinal (eg, flatulence)

Readings

Fanciulli A et al. Association of transient orthostatic hypotension with falls and syncope in patients with Parkinson disease. Neurology. 2020;95(21):e2854-e2865; Fanciulli A et al. Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS). Clin Auton Res. 2018 Aug;28(4):355-362; Fanciulli A et al. Validation of the neurogenic orthostatic hypotension ratio with active standing. Ann Neurol. 2020;88(3):643-645. doi:10.1002/ana.25834; Gibbons CH et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol. 2017 Aug;264(8):1567-1582; Idiaquez JF et al. Neurogenic orthostatic hypotension. Lessons from synucleinopathies. Am J Hypertens. 2021 Mar 11;34(2):125-133; Jellinger KA. Multiple system atrophy: an oligodendroglioneural synucleinopathy. J Alzheimers Dis. 2018;62(3):1141-1179. doi:10.3233/JAD-170397; Jones PK et al. Orthostatic hypotension: managing a difficult problem. Expert Rev Cardiovasc Ther. 2015;13(11):1263-1276. doi:10.1586/14779072.2015.1095090; Kaufmann H et al. Droxidopa in neurogenic orthostatic hypotension. Expert Rev Cardiovasc Ther. 2015;13(8):875–891; Kaufmann H et al. Natural history of pure autonomic failure: A United States prospective cohort. Ann Neurol. 2017;81(2):287-297. doi:10.1002/ana.24877; Mendoza-Velásquez JJ et al. Autonomic dysfunction in α-synucleinopathies. Front Neurol. 2019;10:363; Norcliffe-Kaufmann L et al. Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. Ann Neurol. 2018;83(3):522-531. doi:10.1002/ana.25170; Palma JA et al. An orthostatic hypotension mimic: The inebriation-like syndrome in Parkinson disease. Mov Disord. 2016;31(4):598-600. doi:10.1002/mds.26516; Palma JA et al. Management of orthostatic hypotension. Continuum (Minneap Minn). 2020 Feb;26(1):154-177; Palma JA et al. Orthostatic hypotension in Parkinson disease. Clin Geriatr Med. 2020 Feb;36(1):53-67; Park JW et al. Pharmacologic treatment of orthostatic hypotension. Auton Neurosci. 2020 Dec;229:102721; Ramirez CE et al. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2014;64(6):1235-1240. doi:10.1161/HYPERTENSIONAHA.114.04225.

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, members of the faculty and planning committee reported nothing to disclose. In his lecture, Dr. Kaufmann presents information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Kaufmann was recorded at Parkinson’s Disease and Beyond: An Update in Movement Disorders, presented virtually by Cedars-Sinai Medical Center, on October 24, 2020. Audio Digest thanks Dr. Kaufmann and Cedars-Sinai Medical Center for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

IM684601

Qualifies for:

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.