PATHOPHYSIOLOGY OF NEUROGENIC ORTHOSTATIC HYPOTENSION (nOH)

nOH IS A SUBSET OF ORTHOSTATIC HYPOTENSION CAUSED BY AUTONOMIC DYSFUNCTION

nOH is a failure of the autonomic nervous system to respond to a gravity-induced drop in blood pressure due to pooling of blood in splanchnic circulation and lower extremities upon standing. Patients with Parkinson's disease (PD), pure autonomic failure (PAF), multiple system atrophy (MSA), or autonomic neuropathies may experience nOH.1,2

nOH MAY OCCUR WHEN THE AUTONOMIC NERVOUS SYSTEM RELEASES AN INSUFFICIENT LEVEL OF NOREPINEPHRINE

When a healthy individual stands, approximately 500–1000 mL of blood pools in the lower extremities and splanchnic circulation.2,3 Arterial baroreceptors detect the increased volume in the capacitance vessels and norepinephrine is released from sympathetic nerves. This, in turn, normalizes blood pressure by increasing heart rate, vascular tone, and cardiac contractility.4-6

In patients with nOH, a baroreflex failure results in a norepinephrine deficiency. This leads to inadequate vasoconstriction and no compensatory heart rate increase. As a result of cerebral hypoperfusion, symptoms such as dizziness and lightheadedness may occur, increasing the risk of falls and other serious consequences.2,7-10

BLOOD VOLUME WITH POSTURAL CHANGE IN nOH

Sitting Down Blood Pressure Graphic

SITTING

Blood volume throughout the body is at an equilibrium.1,8

Postural Change Blood Pressure Graphic

POSTURAL CHANGE

Begins to pool in splanchnic circulation and lower extremities. Impaired norepinephrine release results in vasoconstrictive failure and cerebral hypoperfusion.4,11

Standing Blood Pressure Graphic

STANDING

Patients experience symptoms such as dizziness, lightheadedness, and syncope. Symptoms abate when patients return to sitting or lying down.2,4,11

Falls caused by the symptoms of nOH may be associated with serious consequences, including hip fracture and subdural hematoma. As such, managing these symptoms is warranted.8,12,13

nOH IS A NEUROTRANSMITTER DISORDER, MAKING IT DISTINCT FROM OH

While symptoms of neurogenic and non-neurogenic OH may be similar, the insufficient release of norepinephrine at the root of nOH is the chief distinction between the two disorders.4,11,14,15

Differentiating features of nOH

nOH

Non-neurogenic OH

Prevalence

~1/3 of patents with OH11,16

~2/3 of patents with OH11,16

Causes

Autonomic nervous system dysfunction4,8

Medications2,8,14

Intravascular volume loss11,14

Vascular disease17

Vasovagal syncope4,8

Cardiomyopathy15,17

Physical deconditioning8,11

Heart rate response following postural changes

Inadequate compensatory increase (<15 bpm)8,11

Compensatory increase (>15 bpm)7,8,15

Associated supine hypertension

Common (up to 70%)18

Not present15,19,20

Prognosis

Chronic disorder (symptom management is the main focus)11

Typically resolves when underlying cause is corrected11

Differentiating features of nOH

nOH

Prevalence

~1/3 of patents with OH11,16

Causes

Autonomic nervous system dysfunction4,8

Heart rate response following postural changes

Inadequate compensatory increase (<15 bpm)8,11

Associated supine hypertension

Common (up to 70%)18

Prognosis

Chronic disorder (symptom management is the main focus)11

Differentiating features of nOH

Non-neurogenic OH

Prevalence

~2/3 of patents with OH11,16

Causes

Medications2,8,14

Intravascular volume loss11,14

Vascular disease17

Vasovagal syncope4,8

Cardiomyopathy15,17

Physical deconditioning8,11

Heart rate response following postural changes

Compensatory increase (>15 bpm)7,8,15

Associated supine hypertension

Not present15,19,20

Prognosis

Typically resolves when underlying cause is corrected11

NEURODEGENERATIVE DISORDERS CAN IMPACT NOREPINEPHRINE MODULATION IN PATIENTS WITH nOH

Due to the inadequate release of peripheral norepinephrine in patients with autonomic dysfunction, blood pressure is not properly regulated upon standing.4,8 With exposure to orthostatic triggers throughout the day, and consequent fluctuations in blood pressure, symptomatic episodes of nOH can occur at any time and also vary from day to day.1,4,8,21,22

  • Symptoms associated with nOH may appear when a patient's blood pressure falls below the lower limit of cerebral autoregulation1,11 
  • Patients may feel symptomatic within 30 minutes of eating a meal because of associated postprandial splanchnic vasodilation1,4,11,20  
  • The morning may be especially problematic for patients due to nocturnal diuresis1,2  
  • At night, healthy individuals experience a decrease or dip in blood pressure23,24  
    –However, in patients with nOH, blood pressure may spike into the hypertensive range while supine (known as reverse dipping)
Graph of Blood Pressure Changes Throughout the Day
  • In nOH, the compensatory increase in heart rate upon standing is inadequate8  
  • If a symptomatic patient experiences an increase in heart rate less than 15 bpm within 3 minutes, nOH is a possible diagnosis7,8,11,15 
    –However, an increase of more than 15 bpm within 3 minutes may suggest non-neurogenic orthostatic hypotension
  • Orthostatic measurements of blood pressure and heart rate while a patient is supine as well as standing may help identify nOH in at-risk patients7,11,25

MANY nOH PATIENTS ALSO EXPERIENCE SUPINE HYPERTENSION

Up to 70% of patients with nOH will also experience supine hypertension.18 The association of supine hypertension with nOH stems from the autonomic dysfunction in patients with a neurodegenerative disorder. Patients with autonomic failure lack the normal blood pressure buffering mechanisms that offset both hypo- and hypertension.1,15,20

REFERENCES
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  2. Freeman R. Neurogenic orthostatic hypotension. N Engl J Med. 2008;358(6):615-624. 
  3. Robertson D. The pathophysiology and diagnosis of orthostatic hypotension. Clin Auton Res. 2008;18(suppl 1):s2-s7. 
  4. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Auton Res. 2011;21(2):69-72. 
  5. Charkoudian N, Rabbitts JA. Sympathetic neural mechanisms in human cardiovascular health and disease. Mayo Clin Proc. 2009;84(9):822-830. 
  6. Stewart JM. Mechanisms of sympathetic regulation in orthostatic intolerance. J Appl Physiol. 2012;113(10):1659-1668. 
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  8. Low PA. Neurogenic orthostatic hypotension: pathophysiology and diagnosis. Am J Manag Care. 2015;21(suppl 13):s248-s257. 
  9. Figueroa JJ, Basford JR, Low PA. Preventing and treating orthostatic hypotension: as easy as A, B, C. Cleve Clin J Med. 2010;77(5):298-306. 
  10. Rascol O, Perez-Lloret S, Damier P, et al. Falls in ambulatory non-demented patients with Parkinson's disease. J Neural Transm (Vienna). 2015;122(10):1447-1455. 
  11. Palma JA, Kaufmann H. Epidemiology, diagnosis, and management of neurogenic orthostatic hypotension. Mov Disord Clin Pract. 2017;4(3):298-308. 
  12. Isaacson SH. Managed care approach to the treatment of neurogenic orthostatic hypotension. Am J Manag Care. 2015;21(suppl 13):s258-s268. 
  13. Goldstein DS, Pechnik S, Holmes C, et al. Association between supine hypertension and orthostatic hypotension in autonomic failure. Hypertension. 2003;42(2):136-142. 
  14. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation. 2009;119(1):139-146. 
  15. Gibbons CH, Schmidt P, Biaggioni I, 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;264(8):1567-1582. 
  16. Robertson D, Robertson RM. Causes of chronic orthostatic hypotension. Arch Intern Med. 1994;154(14):1620-1624. 
  17. Bradley JG, Davis KA. Orthostatic hypotension. Am Fam Physician. 2003;68(12):2393-2398. 
  18. Berganzo K, Diez-Arrola B, Tijero B, et al. Nocturnal hypertension and dysautonomia in patients with Parkinson's disease: are they related? J Neurol. 2013;260(7):1752-1756. 
  19. Jordan J, Biaggioni I. Diagnosis and treatment of supine hypertension in autonomic failure patients with orthostatic hypotension. J Clin Hypertens. 2002;4(2):139-145. 
  20. Naschitz JE, Slobodin G, Elias N, et al. The patient with supine hypertension and orthostatic hypotension: a clinical dilemma. Postgrad Med J. 2006;82(966):246-253. 
  21. Mathias CJ. Autonomic diseases: clinical features and laboratory evaluation. J Neurol Neurosurg Psychiatry. 2003;74(suppl 3):iii31-iii41. 
  22. Kaufmann H, Palma JA. Neurogenic orthostatic hypotension: the very basics. Clin Auton Res. 2017;27(suppl 1):39-43. 
  23. Voichanski S, Grossman C, Leibowitz A, et al. Orthostatic hypotension is associated with nocturnal change in systolic blood pressure. Am J Hypertens. 2012;25(2):159-164. 
  24. Stuebner E, Vichayanrat E, Low DA, et al. Twenty-four hour non-invasive ambulatory blood pressure and heart rate monitoring in Parkinson's disease. Front Neurol. 2013;4:49. 
  25. Centers for Disease Control and Prevention. Measuring orthostatic blood pressure. https://www.cdc.gov/steadi/pdf/STEADI-Assessment-MeasuringBP-508.pdf. Accessed January 25, 2019.