What are the differential diagnoses and treatment options for orthostatic hypotension?

Differential Diagnosis for Orthostatic Hypotension

Primary Diagnostic Categories

Orthostatic hypotension has three main etiologic categories: medication-induced (most common), neurogenic autonomic failure, and non-neurogenic causes including volume depletion and cardiovascular dysfunction. 1, 2

Medication-Induced Orthostatic Hypotension

• Diuretics are among the most frequent culprits, causing OH through volume depletion 3, 1, 2
• Vasodilators (including nitrates) directly reduce vascular tone and contribute to OH 2
• Alpha-adrenergic blockers impair vasoconstriction and are particularly problematic in initial orthostatic hypotension 2
• Beta-blockers can worsen orthostatic symptoms 2
• Psychotropic medications (antidepressants, antipsychotics) commonly cause OH 4
• Any vasoactive drugs can contribute to classical or delayed orthostatic hypotension 2

Neurogenic Orthostatic Hypotension (Primary Autonomic Failure)

Characterized by cardiovascular sympathetic fiber failure resulting in inadequate vasoconstriction and blunted heart rate response (typically <10 bpm increase) upon standing 2:

• Multiple system atrophy with widespread autonomic degeneration 3, 2
• Parkinson's disease with autonomic involvement 3, 1
• Pure autonomic failure affecting peripheral autonomic nerves 3, 2
• Dementia with Lewy bodies 3

Secondary Autonomic Failure

• Diabetic autonomic neuropathy is the most common endocrine cause, representing advanced autonomic dysfunction 3, 1, 2
• Amyloidosis with autonomic nerve infiltration 2
• Spinal cord injuries 3
• Autoimmune autonomic neuropathy 3
• Paraneoplastic autonomic neuropathy 3
• Kidney failure 3

Non-Neurogenic Causes

In non-neurogenic OH, heart rate response is preserved or enhanced (>10 bpm increase) 2:

• Volume depletion from dehydration, blood loss, or excessive diuresis 1, 2, 5
• Cardiac insufficiency with reduced cardiac output 5
• Impaired venous return from prolonged bed rest or deconditioning 5
• Severe arteriosclerosis causing pseudohypertension 2

Age-Related Physiologic Changes

• Cardiac stiffness with reduced responsiveness to preload changes 2
• Impaired compensatory vasoconstrictor reflexes 2
• Baroreflex dysfunction from age-related changes 2
• Reduced cerebral autoregulation 2

Differential Diagnoses to Exclude

Postural Tachycardia Syndrome (PoTS)

• Diagnosed by heart rate increase >30 bpm upon standing without significant blood pressure drop 3
• Requires detailed autonomic history and formal standing tests 3
• Negative standing test does not exclude PoTS; consider additional autonomic testing if clinical suspicion is high 3

Cervicogenic Headache

• Headache provoked by cervical movement rather than posture 3
• Reduced cervical range of motion and associated myofascial tenderness 3
• Presence of cervical pathology on examination 3

Migraine

• Headache provoked by movement rather than posture 3
• Establish migrainous biology including history, trajectory of episodes, presence of aura 3
• Vertigo rather than hearing impairment and tinnitus 3

Spontaneous Intracranial Hypotension

• Consider in patients with orthostatic headache (absent/mild on waking, onset within 2 hours of upright posture, >50% improvement within 2 hours of lying flat) 3
• "End of the day" headache with improvement on lying flat 3
• Thunderclap headache followed by orthostatic headache 3

Diagnostic Evaluation Approach

Essential Clinical Assessment

• Measure blood pressure after 5 minutes lying/sitting, then at 1 and 3 minutes after standing to document OH (≥20 mmHg systolic or ≥10 mmHg diastolic drop) 3, 1, 4
• In patients with supine hypertension, use ≥30 mmHg systolic drop as diagnostic threshold 2
• Comprehensive medication review focusing on all vasoactive agents 1, 4
• Volume status assessment including signs of dehydration or blood loss 1
• Neurological examination for signs of autonomic dysfunction (resting tachycardia, sudomotor dysfunction, gastroparesis symptoms, bladder dysfunction) 3, 1
• Cardiovascular assessment including evaluation for cardiac insufficiency 3

Distinguishing Neurogenic from Non-Neurogenic OH

• Neurogenic OH: Blunted heart rate increase (usually <10 bpm) upon standing 2
• Non-neurogenic OH: Preserved or enhanced heart rate increase (>10 bpm) upon standing 2

Specialized Testing When Indicated

For suspected neurogenic OH, the European guidelines recommend 3:

• Valsalva maneuver to assess autonomic function
• Deep-breathing testing for cardiovascular autonomic reflex testing
• Ambulatory and home blood pressure monitoring
• Referral for autonomic evaluation in patients with known or suspected neurodegenerative disease 3

Diabetic Patients

• Screen for orthostatic symptoms in any diabetic patient, with yearly OH testing recommended regardless of symptoms, particularly after age 50 1
• Perform cardiovascular autonomic reflex tests (CARTs) including heart rate variability, Valsalva maneuver, and deep breathing tests to confirm diabetic cardiovascular autonomic neuropathy 1
• Assess for associated autonomic symptoms: hypoglycemia unawareness, gastroparesis, constipation, diarrhea, erectile dysfunction, neurogenic bladder, sudomotor dysfunction 3

Treatment Principles

Non-Pharmacological Management (First-Line for All Patients)

• Discontinue or modify culprit medications as the primary intervention 3, 1, 4
• Increase fluid intake to 2-3 liters daily and salt consumption to 6-9g daily if not contraindicated by heart failure 3, 4
• Teach physical counter-maneuvers: leg crossing, squatting, stooping, muscle tensing during symptomatic episodes (particularly effective in patients <60 years with prodromal symptoms) 3, 4
• Use compression garments: waist-high stockings (30-40 mmHg) and abdominal binders to reduce venous pooling 3, 4
• Elevate head of bed by 10 degrees during sleep to prevent nocturnal polyuria and supine hypertension 4
• Acute water ingestion ≥480 mL for temporary relief (peak effect at 30 minutes) 4
• Smaller, more frequent meals to reduce post-prandial hypotension 3, 4
• Encourage physical activity and exercise to avoid deconditioning 3, 4

Pharmacological Management (When Non-Pharmacological Measures Insufficient)

First-line medications 3, 1, 4:

• Midodrine (FDA-approved): Start 2.5-5 mg three times daily, can increase to 10 mg three times daily; avoid last dose after 6 PM to prevent supine hypertension 3, 4, 6

  • Increases standing systolic BP by 15-30 mmHg for 2-3 hours 4, 6
  • Strongest evidence base among pressor agents 4

• Fludrocortisone: Start 0.05-0.1 mg daily, titrate to 0.1-0.3 mg daily 3, 1, 4

  • Acts through sodium retention and vessel wall effects 1, 4
  • Monitor for supine hypertension, hypokalemia, heart failure, peripheral edema 3, 4

• Droxidopa (FDA-approved): Particularly effective for neurogenic OH in Parkinson's disease, pure autonomic failure, and multiple system atrophy 3, 4

Second-line options for refractory cases 4:

• Pyridostigmine: May be beneficial in neurogenic OH refractory to other treatments, with favorable side effect profile 4
• Combination therapy: Midodrine plus fludrocortisone for non-responders to monotherapy 1

Critical Monitoring and Treatment Goals

• Treatment goal is minimizing postural symptoms and improving functional capacity, NOT restoring normotension 3, 1, 4, 6
• Balance increasing standing BP against risk of worsening supine hypertension 3, 1
• Monitor for supine hypertension development (can cause end-organ damage) 4, 6
• Regular electrolyte monitoring with fludrocortisone due to mineralocorticoid effects 4
• Measure BP supine and standing at each visit to assess treatment response and detect supine hypertension 4