Annals of Movement Disorders

: 2019  |  Volume : 2  |  Issue : 3  |  Page : 91--97

Clinical management of neurogenic orthostatic hypotension

Malligurki Raghurama Rukmani1, Ravi Yadav2, Pramod K Pal2, Talakad N Sathyaprabha1,  
1 Department of Neurophysiology, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bengaluru, Karnataka, India
2 Department of Neurology, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bengaluru, Karnataka, India

Correspondence Address:
Dr. Ravi Yadav
Department of Neurology, National Institute of Mental Health and Neuro-Sciences (NIMHANS), Bengaluru 560029, Karnataka.


Neurogenic orthostatic hypotension is a common disorder often seen in elderly patients affected with neurodegenerative disorders and peripheral neuropathies. Defective baroreflex-mediated sympathetic activation in response to standing results in neurogenic orthostatic hypotension. Lightheadedness, dizziness, blurring of vision, palpitations, and/or recurrent syncope in response to sudden postural change or prolonged standing are the characteristic symptoms presented by patients with orthostatic hypotension. Orthostatic symptoms may be further aggravated by certain medications, fluid depletion, food intake, increased temperature, or physical deconditioning. Bedside orthostatic test, head-up tilt table test, and 24-h ambulatory blood pressure monitoring are the important tests to diagnose orthostatic hypotension. Discontinuation of medications that cause or exacerbate orthostatic hypotension and non-pharmacological approaches should be initially tried to treat neurogenic orthostatic hypotension. If the patient does not have significant improvement, add-on pharmacotherapy should be administered. Midodrine, droxidopa, and fludrocortisone are the commonly administered medications for treating neurogenic orthostatic hypotension. Systematic reviews have shown that there is moderate level of evidence that droxidopa and midodrine improve orthostatic hypotension in the short term. Fludrocortisone is included in the treatment guidelines based on expert opinion, despite having low level of evidence. However, there is no much evidence for the long-term efficacy of any pharmacological agent used to treat orthostatic hypotension. Treatment of neurogenic orthostatic hypotension should be periodically assessed. Predominantly, it involves measuring symptomatic benefit including impact on activities of daily living as well as blood pressure monitoring.

How to cite this article:
Rukmani MR, Yadav R, Pal PK, Sathyaprabha TN. Clinical management of neurogenic orthostatic hypotension.Ann Mov Disord 2019;2:91-97

How to cite this URL:
Rukmani MR, Yadav R, Pal PK, Sathyaprabha TN. Clinical management of neurogenic orthostatic hypotension. Ann Mov Disord [serial online] 2019 [cited 2023 May 28 ];2:91-97
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Full Text


Orthostatic hypotension (OH) is a common disorder in the elderly population with a pooled prevalence of 22.2%.[1] It is defined as “a sustained reduction of systolic blood pressure (SBP) of at least 20mm Hg or diastolic BP (DBP) of 10mm Hg, or both, within 3min of standing or head-up tilt to at least 60° on a tilt table” according to consensus statement by the American Autonomic Society and the American Academy of Neurology, and endorsed by the European Federation of Autonomic Societies and the World Federation of Neurology.[2] Patients with neurogenic OH should also have autonomic dysfunction characterized by failure to provide adequate postural responses.[3]Neurogenic OH is often seen in patients affected with neurodegenerative disorders and peripheral neuropathies.[4],[5] It carries a significant morbidity, mortality, and can have a profound impact on the quality of life.[6],[7]

Postural change induces gravitational redistribution of blood volume, which in turn changes the BP levels. Under normal conditions, pooling of venous blood in the legs during standing is countered by the normal sympathetic nervous system to maintain standing BP. Norepinephrine is the major neurotransmitter responsible for this. Whenever an individual stands up, there is sympathetic activation (release of norepinephrine from sympathetic nerve terminals). This leads to venoconstriction with increased venous return, increase in heart rate (HR), and myocardial contractility with increased cardiac output; and vasoconstriction with increased BP. These changes brought about by autonomic nervous system along with sufficient circulating blood volume will prevent the gravity induced fall in standing BP and ensure optimal perfusion of brain and other vital organs. In patients with neurogenic OH, defective baroreflex-mediated sympathetic activation will result in OH.[7],[8],[9]

Supine hypertension, nocturnal hypertension, and postprandial hypotension (PPH) are also commonly observed in patients with neurogenic OH. Supine hypertension is defined as SBP ≥ 150mm Hg and DBP ≥ 90mm Hg during supine position. Nocturnal hypertension is defined as nocturnal BP ≤ 10% with respect to daytime mean BP values. PPH is defined as a mean BP drop ≥ 20mm Hg within 2h after a meal.[9],[10],[11]

Lightheadedness, dizziness, blurring of vision, palpitations, and/or recurrent syncope in response to sudden postural change or prolonged standing are the characteristic symptoms presented by patients with OH.[4],[9] Orthostatic cognitive dysfunction (as a result of transient frontal lobe hypoperfusion), mental dulling, generalized weakness, coat hanger pain (discomfort or pain in the suboccipital and paracervical region because of ischemia of the strap muscles of the neck), and/or platypnea (dyspnea as a result of inadequate perfusion of ventilated lung apices) are the less commonly reported symptoms by the patients with OH.[12],[13],[14] Patients are symptomatic only when standing BP falls below the lower limit of cerebral auto regulatory range.[9],[11] Reshaping of cerebral autoregulation may take place in some of the long-standing dysautonomia patients (such as multiple system atrophy patients) to maintain adequate brain perfusion even during severe OH. Such patients remain asymptomatic.[11]

Orthostatic symptoms may be further aggravated by certain medications, fluid depletion, food intake, increased temperature, or physical deconditioning.[4],[11],[15],[16],[17] Patients suspected of, or diagnosed with neurodegenerative disorders associated with dysautonomia (Parkinson’s disease, multiple system atrophy, pure autonomic failure, dementia with Lewy bodies), peripheral neuropathies (diabetes mellitus), and elderly patients who are on multiple medications are at an increased risk for OH.[4],[18] These patients should be routinely screened for OH.[4],[11],[18]


Clinicians should ask the patients about the cardinal symptoms of OH; how frequent and severe they are and the effect of these symptoms on activities of daily living (ADL). It is important to note the time of the symptom occurrence, in addition to aggravating and relieving factors. Orthostatic symptoms typically improve or disappear on lying down. Clinician should review the current medications because certain medications can cause OH or exacerbate the symptoms of OH. These include dopaminergic agents, tricyclic antidepressants, anti-cholinergics, diuretics, nitrates, α-1 adrenergic antagonists, β-adrenergic blockers, calcium channel blockers, central sympatholytic agents, and Renin-angiotensin system antagonist. If the patient is taking medications that exacerbate OH, the clinician should either reduce the dose or prescribe alternative equivalent medication. When the history or screening questions suggest that the patient might be at risk for OH, a more complete evaluation needs to be done to confirm the diagnosis of OH. Clinician should do detailed physical examination to identify underlying neurological or systemic illness, if any.[4],[5],[7],[11],[15],[16],[17]

OH should be investigated first by recording supine BP and HR (after 5-min rest) followed by BP and HR testing after 3min of standing in the clinic.[4] Current guidelines for the diagnosis of OH are a sustained fall of SBP of at least 20mm Hg or a diastolic BP of at least 10mm Hg within 3min of standing. However, in patients with supine hypertension, a more appropriate criterion might be sustained fall of SBP of at least 30mm Hg or a DBP of at least 15mm Hg within 3min of standing. This is because the magnitude of orthostatic fall in BP is dependent on baseline BP.[2]

Some patients with dysautonomia might have delayed OH (orthostatic drop in BP beyond 3min of standing).[19] It is advisable to refer the patients to the autonomic laboratory for cardiac autonomic function testing including head-up tilt table testing (HUTT).[20],[21] Assessment of severity of cardiac autonomic dysfunction aids in treatment planning and assessing the prognosis. If orthostatic test or tilt table test does not reveal OH in individuals with unexplained postural symptoms or syncopal attack, extended at-home BP monitoring with results recorded by the caregiver or 24-h ambulatory BP monitoring (where the patient can annotate times when supine or standing) might be advisable to understand BP fluctuations. Extended at-home BP monitoring includes BP/HR monitoring early in the morning before arising from the bed or after 5min of supine rest, repeat BP/HR monitoring after 3min of standing, and repeat BP/HR monitoring while standing whenever patient is symptomatic. The patient or caregiver should maintain a BP diary and note these recordings on a regular basis.[4] The diagnostic approach to patient suspected of neurogenic OH is summarized in [Figure 1].{Figure 1}

Clinician should also include workup to rule out non-neurogenic causes of OH. These include electrocardiography (ECG) to evaluate cardiac electrical activity; complete blood count to evaluate anemia or infections; serum electrolytes, blood urea nitrogen, and creatinine to look for electrolyte imbalance, blood volume depletion, and/or renal dysfunction; fasting blood glucose and glycosylated hemoglobin (HbA1c) to look for diabetes mellitus, thyroid stimulating hormone (TSH) to evaluate for thyroid dysfunction; and vitamin B12 level to evaluate B12 deficiency.[4],[5],[7],[11],[15-17]

It is important to grade the severity of neurogenic OH, once the diagnosis is made. American Autonomic Society and the National Parkinson Foundation consensus panel has proposed a grading scale for neurogenic OH based on the total drop in SBP, duration of orthostasis (ability to stand), and the number and severity of symptoms that affect ADL. Grade 1: Infrequent symptoms/unrestricted standing time AND mild OH (20–30mm Hg drop in SBP during supine-to-standing test); Grade 2: More than 5-min standing time (but not unrestricted) AND (30mm Hg drop in SBP OR moderate impact on ADL); Grade 3: Less than 5-min standing time AND (30mm Hg drop in SBP OR severe impact on ADL); Grade 4: Less than 1-min standing time AND (30mm Hg drop in SBP OR incapacitated).[4]


Therapeutic strategies to address neurogenic OH should principally focus on reducing the symptom burden, prolong the standing time and improve the physical capabilities of the patient to make him/her independent for ADL, prevent severe drop in standing BP, and minimize the risk of supine hypertension. Individually tailored therapy is the key to managing neurogenic OH. Patients and the caregivers should be educated about OH, trained to recognize pre-syncopal symptoms, and take appropriate precautions.[4],[5],[7],[11],[15-17] Firstly, the clinician should identify the medications that can cause or exacerbate OH and adjust the dose or replace them with equivalent alternative medications; wait for 2-week period and review the patient again. Discontinuation of such medications or lowering the dose might be sufficient to give symptomatic relief in some patients.[4]

Non-pharmacological approaches. If the patient is still symptomatic, clinician should then use non-pharmacological approaches. These patients should be trained to recognize pre-syncopal symptoms and to promptly apply counterpressure maneuvers.[4],[5],[7],[11],[15-17] The counterpressure maneuvers increase the BP by raising vascular resistance or by increasing venous return. Some of the commonly advised counterpressure maneuvers include leg crossing with active tensing of the lower extremities, isometric handgrip with arm tensing, bending forward, whole body tensing, squatting, putting the head between the knees, clenching the buttocks or fists, step-up, toe raises, and genuflection contraction.[4],[11],[16],[22] However, counterpressure maneuvers are difficult in patients with advanced Parkinson’s disease or multiple system atrophy for they have postural instability and motor impairment.[11] Wearing waist-high or thigh high elastic compression stockings (compression of 30–40mm Hg) or abdominal binders may ameliorate OH by reducing venous pooling. An increased water (2–2.5 liters/day) and salt intake (>8g of salt/day) effectively improves OH by volume expansion. However, clinician should make sure these patients do not have a history of heart failure, hepatic or renal insufficiency before advising increased salt and fluid intake. Acute water ingestion is recommended for syncope caused by neurogenic OH for occasional, temporary relief. Drinking 500mL of water raises the BP and improves orthostatic tolerance within 5–10min and peaks at around 30min but is short lived. This might be probably due to induction of hypoosmolality in the portal vein that triggers a spinal sympathetic reflex/noradrenaline-mediated increase in systemic vascular resistance.[4],[5],[7],[11],[15],[16],[17],[22],[23] Physical deconditioning exacerbates the magnitude of OH. Hence, lower body strength training, moderate, non-strenuous, non-gravitationally challenging exercises such as a stationery recumbent bicycle, rowing machine, or water-based activities are advocated in these patients to improve physical conditioning.[4],[11],[22],[23]

Patients with neurogenic OH should avoid orthostatic stressors such as sudden postural changes, prolonged recumbency, straining during micturition or defecation, exposure to hot temperatures, excessive high-intensity physical activity, refined carbohydrate rich diet, and alcohol.[4],[11],[15],[23] Straining during micturition and defecation in dysautonomia patients might result in Valsalva maneuver being performed, resulting in substantial reduction in BP without recovery mechanisms that normally come in to play. When a patient with dysautonomia is exposed to hot temperatures, their core temperature can rise for they lack the ability to sweat. This might result in lowering of BP because of uncompensated vasodilatation. During high-intensity exercise, hypotension occurs in patients with autonomic dysregulation. This is presumably as a result of vasodilatation in exercising muscles that is not accompanied by adequate compensatory changes in different vascular regions. Refined carbohydrate rich diet leads to release of insulin and other gastrointestinal hormones resulting vasodilatation in the gut, which is not compensated for by the defective sympathetic reflexes. Alcohol has the potential to lower BP by causing mesenteric vasodilatation.[15],[23]

Add-on pharmacotherapy. If the patient does not show significant symptomatic improvement with 2 weeks of non-pharmacological approaches, add-on pharmacological treatment should be initiated. If the patient with OH has recurrent syncopal attacks and recurrent falls, add-on pharmacotherapy in combination with non-pharmacological approaches should be the first line of therapy. Clinician should individualize the treatment based on the urgency of the symptoms and their consequences. The step-by-step approach for treating neurogenic OH is summarized in [Figure 2]. Add-on pharmacological measures for OH include plasma volume expanders and vasoconstrictive agents. Plasma volume expanders include fludrocortisone (0.1–0.4mg o.i.d.) and desmopressin (10–40 µg/nasal spray or 100–400µg/tablet). Vasoconstrictive agents include midodrine (2.5–10mg t.i.d.), etilefrine (25mg ER o.i.d. or b.i.d.), droxidopa (100–600mg t.i.d.), and pyridostigmine (30–60mg o.i.d to and droxidopa are the only FDA-approved drugs for the treatment of OH, whereas the other drugs have been used off-label. Pharmacological intervention should be used with caution, especially when the patients have comorbid cardiac, hepatic or renal dysfunction. One of the major challenges associated with pharmacological intervention for neurogenic OH is the limited availability of the clinical evidence and lack of studies that assess the comparative effectiveness. Fludrocortisone, midodrine, and droxidopa are the commonly prescribed drugs for neurogenic OH.[4],[5],[7],[11],[15],[16],[17],[23],[24]{Figure 2}

Fludrocortisone acetate is a synthetic mineralocorticoid, which increases renal reabsorption of sodium and water, and therefore expands plasma volume and increases BP. It might also sensitize α-adrenoceptors, thereby augmenting the action of noradrenaline. Fludrocortisone is readily absorbed after oral administration and reaches peak plasma levels within 45min. Elimination half-life of fludrocortisone is around 7h. Fludrocortisone reduces OH in a dosage between 0.1 and 0.4mg once daily. Higher doses of fludrocortisone (>0.2mg/day) can increase the risk of fluid overload, supine hypertension, headache, dependent ankle edema, and hypokalemia. It is advisable to take potassium-rich foods or potassium supplements to prevent hypokalemia, when an individual is prescribed fludrocortisone.[4],[5],[7],[11],[15-17],[23],[24] Although the level of evidence for treating OH is low (Level C: Expert opinion), fludrocortisone is included in the treatment guidelines based on expert opinion.[4],[11],[15]

Pyridostigmine is an acetylcholinesterase inhibitor, which potentiates neurotransmission at the peripheral cholinergic synapses including autonomic ganglia. It might amplify the increased sympathetic nerve activity in response to orthostatic stress, leading to increased vascular tone in the upright position. It is useful in mild dysautonomic patients with residual sympathetic function, at a dose of 30–60mg once to three times per day. The major advantage of pyridostigmine is that it does not worsen supine hypertension, unlike other drugs. Adverse side effects associated with pyridostigmine include abdominal cramps, diarrhea, sialorrhea, excessive sweating, and urinary incontinence.[4],[15] These side effects might worsen the non-motor symptoms of the patients affected with movement disorders. Hence, pyridostigmine should be prescribed with caution. Pyridostigmine treatment trial by Singer et al.[25] has reported a modest improvement in standing BP and orthostatic symptoms, without worsening the supine hypertension. However, there is no much evidence on the long-term efficacy and possible adverse effects of pyridostigmine.[4],[15]

Midodrine is a sympathomimetic, which is recommended for OH in a dosage between 2.5mg and 10mg orally two to three times daily. It is a prodrug with an active metabolite, desglymidodrine, a peripherally acting α-1 adrenoceptor agonist. It increases BP by inducing arterial and venous vasoconstriction and reducing venous blood pooling. Duration of action of desglymidodrine is around 4h. Its elimination half-life is 2–3h. Midodrine does not influence HR for it does not stimulate cardiac β-adrenergic receptors. It does not cross blood–brain barrier. Adverse effects of midodrine include supine hypertension, piloerection, scalp or general pruritis, general paresthesia, urinary retention, and chills. Patients should be advised to take their final dose of midodrine at least 3–4h before bedtime and sleep with head-elevation to reduce the risk of supine hypertension.[4],[5],[7],[11],[15-17],[23],[24] According to systematic review by Izcovich et al.,[26] there is moderate quality of evidence (Level B) that midodrine is effective for the management of OH. Most of the studies have assessed the efficacy of midodrine only for a short duration (less than 3 months). There is no much evidence for the long-term efficacy of midodrine (more than 3 months).[4]

Droxidopa (L-threo-dihydroxyphenylserine/L-DOPS) is a prodrug that is converted both peripherally and centrally into norepinephrine by dopadecarboxylase. It increases the norepinephrine levels in postganglionic sympathetic neurons and enhances central nervous system norepinephrine production, resulting in arterial and venous vasoconstriction. At 6h following droxidopa intake, increases in circulating plasma norepinephrine levels peak. Droxidopa reduces OH at a dose of 100–600mg thrice a day. It is short-acting drug. Commonly observed adverse reactions of droxidopa include headache, dizziness, nausea, and supine hypertension. Patients should be advised to take their final dose of droxidopa at least 4h before bedtime and sleep with head elevation to reduce the risk of supine hypertension.[4],[5],[7],[11],[15-17],[23],[24]According to systematic reviews and meta-analyses by Strassheim et al.,[27]Keating et al.,[28]Hauser et al.[29]Elgebaly et al.,[30]and Biaggioni et al.,[31]there is moderate level of evidence (Level B) that droxidopa improves OH in short term (less than 12 weeks). There is no much evidence for the long-term efficacy of any of the medications prescribed for OH. One clinical trial (NCT02586623) is underway to study the long-term effectiveness of droxidopa in patients with neurogenic OH for up to 36 weeks of treatment.[4]

Treatment of supine hypertension/ nocturnal hypertension. Treatment of patients who have both supine hypertension and OH is clinically challenging. Most of the medications used to treat neurogenic OH can cause or exacerbate supine hypertension. OH and supine hypertension are hemodynamic opposites. Hence, improving one can worsen the other. However, prioritizing the treatment of OH over supine hypertension is important for symptomatic OH carries debilitating symptoms such as postural dizziness, syncope, and falls. Nocturnal hypertension causes pressure natriuresis (sodium and water loss) resulting in overnight depletion of intravascular volume, which further worsens OH in the morning. Patients with supine/nocturnal hypertension should not sleep for 4–5h after taking plasma expanders or vasoconstrictive agents prescribed for OH. They might be advised to have a light snack 1h before bedtime and sleep in a 30° head-up position (15–23cm higher than the feet). Head-up position during night reduces supine BP, which in turn reduces the nocturnal diuresis and natriuresis, thereby reducing overnight fluid loss and improving OH in the morning. Pharmacological treatments available for nocturnal/supine hypertension include short-acting calcium antagonists (nifedipine 30mg at night), losartan (50mg at night), or clonidine (100–150 µg at night) administered 1h before sleeping and transdermal nitroglycerine patch (0.1–0.2mg/h) to be worn exclusively during nighttime. Patients who are prescribed antihypertensives for supine/nocturnal hypertension should be warned about the increased risk of OH and syncopal attacks, when they arise in the night to urinate.[4],[5],[9],[10],[11],[23]

Treatment of Postprandial hypotension. Rapid water ingestion during meals and postprandial consumption of caffeine may ameliorate PPH symptoms in dysautonomia patients. They should also avoid alcohol and excessive single-meal refined carbohydrates intake. Octreotide (25–50 µg, subcutaneously before meals) might be administered. However, use of octreotide is limited by the parenteral administration and gastrointestinal side effects such as nausea and pain.[4],[11],[23]

Assessing therapeutic success. Treatment of neurogenic OH should be periodically assessed. Predominantly, it involves measuring symptomatic benefit including impact on ADL as well as BP monitoring. It is essential that patient/caregivers should be educated on the various orthostatic symptoms, precautions to be taken and conduct at-home BP monitoring.[4],[11] They should note the BP recordings (at bed time, before arising in the morning in supine position, in their normal head-up sleeping position, and after 3min of standing) on a regular basis in a BP diary and bring it to the clinician during the follow-up visit. Clinician should review the BP diary, ask questions related to the orthostatic symptoms and their effect on ADL, and perform bedside orthostatic test to assess the treatment success. The dose of the medication should be titrated until either symptomatic benefit is achieved, or the maximum tolerable dose of the therapy is reached.


Individually tailored therapy is the key to managing neurogenic OH. The goal of treatment should principally focus on improving the functional capacity, quality of life, and preventing injury rather than achieving a target BP. Patients and the caregivers should be educated about OH, trained to recognize pre-syncopal symptoms, and take appropriate precautions. They should be educated about the various factors that influence BP (fluid intake, foods, habits, body positions, and medications). Firstly, the clinician should identify the medications that can cause or exacerbate OH and adjust the dose or replace them with equivalent alternative medications; wait for 2-week period and review the patient again. If the patient is still symptomatic, clinician should then use non-pharmacological approaches; wait for 2-week period and review again. Add-on pharmacotherapy should be initiated only when the above measures do not improve the symptoms. The symptomatic benefit of available pharmacological agents is only partial in patients affected with severe neurogenic OH. There is a paucity of treatment options for this condition. In addition, there is no much evidence about the long-term efficacy and side effects of the medications prescribed for neurogenic OH. Ongoing and future long-term studies that evaluate the sustained efficacy, safety, and possible adverse side effects of the pharmacological agents will help in treatment planning and management of neurogenic OH.

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