Diagnosis and Management of Orthostatic Hypotension in Individuals with Parkinson Disease

Orthostatic hypotension (OH) is a common but underrecognized symptom associated with Parkinson disease (PD). OH is estimated to occur in 30% to 58% of people with PD and is a major underlying cause of falls and syncope (ie, fainting or passing out) in this population.¹ OH may occur in the prodromal stage of PD or after the diagnosis has been made,² but may be overlooked given the many other obvious motor and nonmotor features associated with PD. The neurogenic OH syndrome was identified in the 1960s on the basis of its relationship to multiple system atrophy disorders, such as the neurologic syndrome associated with OH described by Shy and Drager,³ wherein OH is a central feature. Over time, advances have been made in the medical management of neurogenic OH. This review article addresses the physiology of blood pressure (BP) control in relation to neurogenic OH, detection of OH, and management of OH in people with PD. 

Physiology of BP Control and Detection of OH 

Definition of OH
Arterial hypotension may arise when there is reduction of blood volume, impairment of nervous system or hormonal control of the systemic circulation, or disease of the heart.⁴ The term “orthostatic” stems from the Greek words “orthos,” meaning straight or upright, and “statikos,” meaning causing to stand.⁴ By convention, OH is defined as a reduction in systolic BP of ≥20 mm Hg or diastolic BP of ≥10 mm Hg within the first 3 minutes of standing or during a head-up tilt on a tilt table.⁵

Key Neuroanatomic Structures and Regulation of BP
Regulation of arterial BP may be thought of as primarily a sympathetic nervous system (SNS) noradrenergic function whereby α1 receptors in skeletal muscle and mesenteric blood vessels are driven by premotor neurons in the rostral ventrolateral medulla (RVLM).^6,7 The paraventricular nucleus of the hypothalamus may also participate in the process of SNS arterial BP regulation. 

The RVLM plays a pivotal role in the regulation of BP. Stimulation or inhibition of the RVLM will be associated with a rise or fall in BP, respectively. Short-term or moment-to-moment BP control is regulated by baroreceptors in the carotid sinus, which is innervated by the glossopharyngeal nerve, and the aortic arch, which is innervated by the vagal nerve.^6,7 The latter nerves connect to the nucleus solitarius in the lower brainstem, which provides inhibitory stimuli to the RVLM. Thus, OH may result from failure of the SNS when there are lesions affecting the RVLM or its projections to the intermediolateral cell column of the spinal cord located at the T1–L3 levels. Other neuroanatomic structures involved in the OH pathway include preganglionic sympathetic neurons, sympathetic ganglia, postganglionic axons, or noradrenergic neurotransmission.^6,7 Further details of neurogenic regulation of BP are found in references 6, 7. 

Detection of OH
OH is frequently encountered in older people with intravascular volume depletion, blood pooling related to varicose veins, anemia, treatment with antihypertensive medications, deconditioned states, or other medical conditions.⁸ Correction of the medical conditions usually improves or resolves OH.⁸ However, a minority of OH cases are deemed neurogenic, wherein there is reduction in the release of norepinephrine from postganglionic sympathetic nerves leading to impairment of vasoconstriction upon standing or rising.⁸ Neurogenic OH may be associated with medical conditions such as diabetes, disorders associated with α-synuclein accumulation (eg, PD), small-fiber neuropathies (eg, amyloid, immune or paraneoplastic disorders), and high spinal cord lesions. Paradoxically in neurogenic OH, about one-half of individuals have supine hypertension.⁸

People with neurogenic OH may experience symptoms consistent with hypoperfusion of the brain, such as dizziness, lightheadedness, and syncope.⁸ Other general symptoms (eg, cognitive slowing, blurring or dimming of vision, fatigue, muscle pain, angina pectoris) also may be present.⁸ If BP is not demonstrated to fall within 3 minutes of standing, a tilt-table test is indicated to obtain and record a more prolonged stimulus for detection of OH. Performance of a comprehensive neurologic examination is imperative because there may be subtle signs of a central or peripheral nervous system disorder associated with autonomic failure.⁸ It is useful to determine whether variability in heart rate with BP change or a history of postprandial hypotension exists.⁸

Measurement of plasma norepinephrine levels may be beneficial to determine whether the disorder involves the peripheral or central nervous system.⁸ Norepinephrine is released from postganglionic sympathetic neurons; therefore, low norepinephrine levels may signify a peripheral lesion, whereas high or normal levels may suggest an underlying central nervous system condition.⁸

Management of OH in PD
Guidance for the management of OH in PD is generally centered around correction of aggravating factors (eg, medical conditions), nonpharmacologic treatments (eg, increasing salt intake, hydration, sleeping with the head of the bed raised, compression stockings), and pharmacologic management.⁸ However, evidence-based criteria suggest that the quality of evidence to support such management recommendations generally falls within the inconsistent or consensus-based categories rather than deriving from consistent, higher-quality evidence.⁹

Correction of Underlying Disorders
Medications, such as opioids, psychoactive agents, dopaminergic drugs (eg, dopamine agonists, levodopa), antihypertensives, and anticholinergics can exacerbate symptomology⁹ and should be considered for substitution or dose adjustments at time of diagnosis of OH. For example, if OH symptoms occur during the day, individuals may benefit from taking their antihypertensive drugs at night. 

Other medical conditions will affect symptoms, especially when there is an increase in blood viscosity and a propensity for blood pooling. People with varicose veins are advised to use compression garments or receive surgical intervention to increase circulating blood volume and avoid organ hypoperfusion. The organs in people with anemia may not be provided with sufficient oxygen supply. Erythropoietin administration and blood transfusion may be considered depending on the underlying etiology of the anemic condition. 

Diabetes is the largest contributor to the development of OH by causing both peripheral and autonomic neuropathy. Strict glucose control remains imperative as a preventative measure because damage resulting from diabetes is irreversible. 

Nonpharmacologic Measures
Volume expansion is a mainstay of treatment for OH. Recommendations include liberal use of salt (2 to 3 g/d) and increase in fluid intake (2 to 3 L/d), including boluses of 500 mL of water taken orally.⁹

OH is affected by redistribution of blood volume. Individuals may experience postprandial hypotension due to the change of blood flow to the digestive system. Low glycemic index carbohydrate meals and frequent small meals are recommended measures to counterbalance this effect. Sleeping with the head of the bed elevated at 30 to 45 degrees is encouraged to avoid the potential for a rapid change in BP upon sitting or standing from a supine position. Waist-high compression stockings and inflatable abdominal binders assist with prevention of blood pooling. Alternate or counterpositional changes (eg, crossing one’s legs while sitting, squatting, buttock clenching, standing on one’s tiptoes) may encourage blood flow. A summary of nonpharmacologic measures to be encouraged or avoided is listed in the Table.⁸

Pharmacologic Management
Fludrocortisone.^8–10 The synthetic mineralocorticoid, fludrocortisone, expands vascular volume by reabsorbing sodium in the renal system in addition to promoting vasoconstriction with increasing α-adrenergic receptor sensitivity. During a 2-week study, participants with PD treated with fludrocortisone demonstrated significant improvement in orthostatic vital signs; however, no change in symptoms was noted.¹⁰ The recommended dosing is .05 to .2 mg/d once or twice daily. Fludrocortisone treatment should be avoided in individuals with heart failure or cirrhosis. Adverse effects associated with fludrocortisone treatment include hypokalemia, left ventricular hypertrophy, and renal failure. 

Droxidopa.^8,9,11 The synthetic norepinephrine precursor, droxidopa, increases peripheral vascular resistance by inducing both arterial and venous vasoconstriction. Droxidopa is approved by the Food and Drug Administration (FDA) for use in individuals with OH. A meta-analysis of studies examining 1 to 8 weeks of droxidopa treatment in individuals with neurogenic OH reported significant improvement in quality of life and performance of activities of daily living.¹¹ The recommended dosing is 100 to 600 mg 3 times daily administered at least 3 hours before bedtime, and individuals should avoid lying flat immediately after dosing. Caution must be exercised when treating individuals with a history of congestive heart failure or chronic renal failure. Adverse effects associated with droxidopa treatment include supine hypertension, headache, nausea, and dizziness. 

Midodrine.^8,9,12The direct α1-adrenergic receptor agonist, midodrine, increases peripheral vascular resistance by constricting both arteriolar and venous vessels. In addition to droxidopa, midodrine is FDA-approved for use in individuals with OH. In a study by Byun and colleagues, a total of 78.3% of study participants no longer met criteria for OH after 1 month of midodrine treatment and showed significant improvement in symptoms at 3 months.¹² The recommended dosing is 2.5 to 10 mg 3 times daily. Caution must be exercised in individuals with a history of congestive heart failure or chronic renal failure. Adverse effects associated with midodrine treatment include supine hypertension, bradycardia, pruritic scalp, paresthesias, and dysuria. Administration should be avoided within 4 hours of sleep, and individuals should avoid lying flat immediately after dosing. 

Atomoxetine.^8,9,12This norepinephrine reuptake inhibitor, atomoxetine, leads to an increase in norepinephrine levels within the synaptic cleft. Results of a study by Byun and colleagues showed that 68.4% of study participants no longer met criteria for OH after 1 month of atomoxetine treatment. In addition, atomoxetine treatment was associated with a significant improvement in symptoms and performance of activities of daily living (ADL).¹² The recommended dosing is 10 to 18 mg twice daily. Adverse effects associated with atomoxetine treatment include aggressive behavior, acute myocardial infarct, stroke, tachycardia, hepatic toxicity, and corrected QT interval (QTc) prolongation. 

Pyridostigmine.^8,9,10,13Pyridostigmine reversibly binds and inhibits acetylcholinesterase from breaking down acetylcholine in the synaptic cleft. In a study by Byun and colleagues, a total of 46.2% and 52.4% of study participants continued to meet criteria for OH at 1 and 3 months, respectively.¹³ Participants noted significant improvement in quality of life and performance of ADL at 3 months. The recommended dosing is 30 mg twice daily up to 60 mg 3 times daily. Adverse effects associated with pyridostigmine treatment include bradycardia, atrioventricular block, diarrhea, and bronchoconstriction. 

Approach to the Management of OH
A reasonable approach to OH management is to correct aggravating conditions and institute nonpharmacologic treatments.¹⁰ If pharmacologic therapies are needed, clinicians should consider prescribing droxidopa or midodrine if there is deficiency of plasma norepinephrine, or a norepinephrine reuptake inhibitor if the former drug therapies fail. Treatment with fludrocortisone should be considered if there is blood volume depletion.¹⁰ Combination therapy may also be tried. For example, pyridostigmine modestly increases systolic BP (~4 mm Hg), but in combination with atomoxetine it may produce a synergistic effect leading to a greater increase in systolic BP. In addition, pyridostigmine plus midodrine may be a more effective treatment option than pyridostigmine alone.¹⁰ Denervation supersensitivity may be observed when there is peripheral denervation, resulting in a hypertensive response caused by exaggerated vasoconstriction with low-dose sympathomimetic agents.⁶

Key Points

1. OH is defined as a reduction of ≥20 mm Hg systolic BP or ≥10 mm Hg diastolic BP within 3 minutes of standing or during a tilt-table test.
2. OH is associated with falls, increased risk of cardiovascular events, and all-cause mortality. 
3. Neurogenic OH is characterized by a substantial drop in blood pressure when standing or changing positions without an appropriate compensatory increase in heart rate, is caused by reduction in norepinephrine release, and can be seen in a variety of disease processes, including PD.
4. Conservative management of OH includes increasing fluid and salt intake, physical maneuvers, compression garments, and lifestyle adaptations (eg, low glycemic index diet). 
5. Midodrine and droxidopa are the only FDA-approved medications for management of OH. 

For Further Reading

Benarroch EE. Physiology and pathophysiology of the autonomic nervous system. Continuum (Minneap Minn). 2020;26(1):12-24. doi:10.1212/CON.0000000000000817

Kim MJ, Farrell J. Orthostatic hypotension: a practical approach. Am Fam Physician. 2022;105(1):39-49.

Palma J-A, Kaufmann H. Management of orthostatic hypotension. Continuum (Minneap Minn). 2020;26(1):154-177. doi:10.1212/CON.0000000000000816