Currently Viewing:
Supplements Understanding the Diagnosis, Management, and Treatment Options for Neurogenic Orthostatic Hypoten

Neurogenic Orthostatic Hypotension: Pathophysiology and Diagnosis

Phillip A. Low, MD
Several factors may contribute to the diag-nosis of NOH being missed. One reason is that symptoms of lightheadedness may be absent. Additionally, patients may instead have subtle symptoms, such as cognitive slowing.38 Another reason is that a patient may truly be asymptomatic, due to expansion of the autoregulated range.46 Awareness of this rare disease also presents a problem because it is understandably low among both clinicians and patients. In addition, patients may attribute NOH symptoms to their primary disorder. An online survey collected data from 178 patients with disorders that may be affected by NOH (PD, MSA, PAF, dopamine beta-hydrox-ylase deficiency, and nondiabetic autonomic neuropathy) and their caregivers (n = 180).68 Although most patients reported experiencing at least 1 symptom of NOH, 24% of patients and 22% of caregivers had never heard of NOH.

Tools for Assessing NOH Symptoms

Two self-report questionnaires have been developed specifically to assess symptoms in patients with NOH: the Orthostatic Grading Scale (OGS; Table 337) and the Orthostatic Hypotension Questionnaire (OHQ; Figure 1a, 1b, 1c69).37,69 These instruments may be used in diagnosis to assess progres-sion of NOH and to assess the response to pharmaco-therapy in clinical practice.41 The OHQ has been used to evaluate the clinical efficacy of droxidopa and midodrine for NOH in clinical trials.70,71 The OGS, which was adapted from the autonomic symptom profile, has 5 items that address the frequency and severity of orthostatic symptoms, relationship of symptoms to orthostatic stressors, and impact of symptoms on activities of daily living and standing time.2,37 Scores for each item are summed to provide a total score for the instrument, ranging from 0 for no impairment to 20 for maximal impairment. The OGS robustly correlated with autonomic deficits on the CASS in patients undergoing full autonomic laboratory evaluation. Using a CASS adrenergic subscore of at least 3, an OGS score of at least 9 had sensitivity of 65.6% and specificity of 69.2%.37

The OHQ has 2 domains: OH symptoms and their impact on walking.69 The 6-item Orthostatic Hypotension Symptom Assessment (OHSA) asks about dizziness/ lightheadedness, vision disturbance, weakness, fatigue, trouble concentrating, and head or neck discomfort. The 4-item Orthostatic Hypotension Daily Activity Scale (OHDAS) assesses the interference of NOH with daily activities: standing a short time, standing a long time, walking a short time, and walking a long time. Patients score items on a scale of 0 to 10 for the average severity of symptoms over the past week. Two factors raise questions about content validity of the OHQ: the questionnaire asks patients to rate only symptoms related to their low blood pressure problem and to average the severity of their symptoms over the past week.72 An improvement of 0.8 to 1.0 units is considered a minimal important change on the OHSA, OHDAS, and OHQ composite score.69

A study in 201 patients with PD evaluated the rela-tionship between the orthostatic drop, standing blood pressure, and symptoms of OH as characterized by the OHQ. Using the criteria of a 20/10 mm Hg drop in blood pressure for the diagnosis of NOH, 50% of patients in the cohort met the diagnosis and 33% of them were symptom-atic. Using the criteria of a 30/15 mm Hg drop in blood pressure, 30% of patients met the diagnosis and 44% were symptomatic. A mean standing blood pressure lower than 75 mm Hg had 97% sensitivity and 98% specificity for detecting symptomatic OH. The authors propose a mean standing blood pressure lower than 75 mm Hg as a marker for determining if OH symptoms are substantial enough for pharmacotherapy.73

Author affiliation: Mayo Clinic.

Funding source: This activity is supported by an educational grant from Lundbeck, LLC. Author disclosure: Dr. Low has no relevant commercial financial relationships or affiliations to disclose.

Authorship information: Concept and design, analysis and interpreta-tion of data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, statistical analysis, and supervision.

Address correspondence to:
1. 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.

2. Low PA, Singer W. Management of neurogenic orthostatic hypotension: an update. Lancet Neurol. 2008;7(5):451-458.

3. Freeman R. Clinical practice. Neurogenic orthostatic hypoten-sion. N Engl J Med. 2008;358(6):615-624.

4. Low PA, Denq JC, Opfer-Gehrking TL, Dyck PJ, O’Brien PC, Slezak JM. Effect of age and gender on sudomotor and cardiova-gal function and blood pressure response to tilt in normal sub-jects. Muscle Nerve. 1997;20(12):1561-1568.

5. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypotension: a pathophysiological approach. Circulation. 2009;119(1):139-146.

6. Arnold AC, Shibao C. Current concepts in orthostatic hypoten-sion management. Curr Hypertens Rep. 2013;15(4):304-312.

7. Poon IO, Braun U. High prevalence of orthostatic hypotension and its correlation with potentially causative medications among elderly veterans. J Clin Pharm Ther. 2005;30(2):173-178.

8. Perez-Lloret S, Rey MV, Fabre N, et al. Factors related to ortho-static hypotension in Parkinson’s disease. Parkinsonism Relat Disord. 2012;18(5):501-505.

9. Milazzo V, Stefano CD, Servo S, et al. Drugs and orthostatic hypotension: evidence from literature. J Hypertens. 2012;1(2):1-8.

10. Shibao C, Lipsitz LA, Biaggioni I. Evaluation and treatment of orthostatic hypotension. J Am Soc Hypertens. 2013;7(4):317-324.

11. Low PA, Tomalia VA, Park KJ. Autonomic function tests: some clinical applications. J Clin Neurol. 2013;9(1):1-8.

12. Gugger JJ. Antipsychotic pharmacotherapy and orthostatic hypotension: identification and management. CNS Drugs. 2011;25(8):659-671.

13. Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension. 1992;19(6 pt 1):508-519.

14. Mader SL, Josephson KR, Rubenstein LZ. Low prevalence of postural hypotension among community-dwelling elderly. JAMA. 1987;258(11):1511-1514.

15. Ooi WL, Hossain M, Lipsitz LA. The association between orthostatic hypotension and recurrent falls in nursing home resi-dents. Am J Med. 2000;108(2):106-111.

16. National Organization for Rare Diseases. Orthostatic hypo-tension. NORD website. orthostatic-hypotension/. Accessed June 19, 2015.

17. Chelsea Therapeutics. Northera (droxidopa) for the treatment of neurogenic orthostatic hypotension. FDA website. www.fda. gov/downloads/advisorycommittees/committeesmeetingma-terials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ ucm294077.pdf. Accessed July 3, 2015.

18. Low PA, Reich SG, Jankovic J, et al. Natural history of mul-tiple system atrophy in the USA: a prospective cohort study. Lancet Neurol. 2015;14(7):710-719.

19. Thaisetthawatkul P, Boeve BF, Benarroch EE, et al. Autonomic dysfunction in dementia with Lewy bodies. Neurology. 2004;62(10):1804-1809.

20. Low PA. Prevalence of orthostatic hypotension. Clin Auton Res. 2008;18(suppl 1):8-13.

21. Ha AD, Brown CH, York MK, Jankovic J. The prevalence of symptomatic orthostatic hypotension in patients with Parkinson’s disease and atypical parkinsonism. Parkinsonism Relat Disord. 2011;17(8):625-628.

22. Velseboer DC, de Haan RJ, Wieling W, Goldstein DS, de Bie RM. Prevalence of orthostatic hypotension in Parkinson’s dis-ease: a systematic review and meta-analysis. Parkinsonism Relat Disord. 2011;17(10):724-729.

23. Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27(12):2942-2947.

24. Wang AK, Fealey RD, Gehrking TL, Low PA. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc. 2008;83(11):1226-1230.

25. Mussi C, Ungar A, Salvioli G, et al; Evaluation of Guidelines in Syncope Study 2 Group. Orthostatic hypotension as cause of syncope in patients older than 65 years admitted to emergency departments for transient loss of consciousness. J Gerontol A Biol Sci Med Sci. 2009;64(7):801-806.

26. Franceschini N, Rose KM, Astor BC, Couper D, Vupputuri S. Orthostatic hypotension and incident chronic kidney disease: the atherosclerosis risk in communities study. Hypertension. 2010;56(6):1054-1059.

27. Jones CD, Loehr L, Franceschini N, et al. Orthostatic hypoten-sion as a risk factor for incident heart failure: the atherosclerosis risk in communities study. Hypertension. 2012;59(5):913-918.

28. Chou RH, Liu CJ, Chao TF, et al. Association between ortho-static hypotension, mortality, and cardiovascular disease in Asians. Int J Cardiol. 2015;195:40-44.

29. Fedorowski A, Stavenow L, Hedblad B, Berglund G, Nilsson PM, Melander O. Orthostatic hypotension predicts all-cause mortality and coronary events in middle-aged individuals (The Malmo Preventive Project). Eur Heart J. 2010;31(1):85-91.

30. Ricci F, Fedorowski A, Radico F, et al. Cardiovascular morbidity and mortality related to orthostatic hypotension: a meta-analysis of prospective observational studies. Eur Heart J. 2015;36(25):1609-1617.

31. Masaki KH, Schatz IJ, Burchfiel CM, et al. Orthostatic hypo-tension predicts mortality in elderly men: the Honolulu Heart Program. Circulation. 1998;98(21):2290-2295.

32. Angelousi A, Girerd N, Benetos A, et al. Association between orthostatic hypotension and cardiovascular risk, cerebrovascular risk, cognitive decline and falls as well as overall mortality: a sys-tematic review and meta-analysis. J Hypertens. 2014;32(8):1562-1571; discussion 1571.

33. Shibao C, Grijalva CG, Raj SR, Biaggioni I, Griffin MR. Orthostatic hypotension-related hospitalizations in the United States. Am J Med. 2007;120(11):975-980.

34. Maule S, Milazzo V, Maule MM, Di Stefano C, Milan A, Veglio F. Mortality and prognosis in patients with neurogenic orthostatic hypotension. Funct Neurol. 2012;27(2):101-106.

35. Pathak A, Lapeyre-Mestre M, Montastruc JL, Senard JM. Heat-related morbidity in patients with orthostatic hypotension and primary autonomic failure. Mov Disord. 2005;20(9):1213-1219.

36. FDA Cardiovascular and Renal Drugs Advisory Committee. Transcript for the January 14, 2014 meeting. FDA website. AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ CardiovascularandRenalDrugsAdvisoryCommittee/UCM396030. pdf. Accessed July 4, 2014.

37. Schrezenmaier C, Gehrking JA, Hines SM, Low PA, Benrud-Larson LM, Sandroni P. Evaluation of orthostatic hypotension: relationship of a new self-report instrument to laboratory-based measures. Mayo Clin Proc. 2005;80(3):330-334.

38. Low PA, Opfer-Gehrking TL, McPhee BR, et al. Prospective evaluation of clinical characteristics of orthostatic hypotension. Mayo Clin Proc. 1995;70(7):617-622.

39. 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.

40. Rascol O, Perez-Lloret S, Damier P, et al. Falls in ambula-tory non-demented patients with Parkinson’s disease. J Neural Transm. Published online: April 7, 2015.

41. Low PA, Fealey RD. Management of neurogenic orthostatic hypotension. In: Low PA, Benarroch EE, eds. Clinical Autonomic Disorders. Baltimore, MD: Lippincott Williams & Wilkins; 2008:547-559.

42. Humm AM, Bostock H, Troller R, Z’Graggen WJ. Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles. J Neurol Neurosurg Psychiatry. 2011;82(12):1394-1398.

43. Khurana RK. Coat-hanger ache in orthostatic hypotension. Cephalalgia. 2012;32(10):731-737.

44. Isaacson SH, Skettini J. Neurogenic orthostatic hypotension in Parkinson’s disease: evaluation, management, and emerging role of droxidopa. Vasc Health Risk Manag. 2014;10:169-176.

45. Arbogast SD, Alshekhlee A, Hussain Z, McNeeley K, Chelimsky TC. Hypotension unawareness in profound orthostatic hypoten-sion. Am J Med. 2009;122(6):574-580.

46. Novak V, Novak P, Spies JM, Low PA. Autoregulation of cere-bral blood flow in orthostatic hypotension. Stroke. 1998;29(1):104-111.

47. Mathias CJ. L-dihydroxyphenylserine (Droxidopa) in the treat-ment of orthostatic hypotension: the European experience. Clin Auton Res. 2008;18(suppl 1):25-29.

48. Benrud-Larson LM, Dewar MS, Sandroni P, Rummans TA, Haythornthwaite JA, Low PA. Quality of life in patients with pos-tural tachycardia syndrome. Mayo Clin Proc. 2002;77(6):531-537.

49. Benrud-Larson LM, Sandroni P, Schrag A, Low PA. Depressive symptoms and life satisfaction in patients with multiple system atrophy. Mov Disord. 2005;20(8):951-957.

50. Biaggioni I, Robertson RM. Hypertension in orthostatic hypo-tension and autonomic dysfunction. Cardiol Clin. 2002;20(2):291-301, vii.

51. Ten Harkel AD, Van Lieshout JJ, Wieling W. Treatment of orthostatic hypotension with sleeping in the head-up tilt position, alone and in combination with fludrocortisone. J Intern Med. 1992;232(2):139-145.

52. Garland EM, Gamboa A, Okamoto L, et al. Renal impairment of pure autonomic failure. Hypertension. 2009;54(5):1057-1061.

53. Vagaonescu TD, Saadia D, Tuhrim S, Phillips RA, Kaufmann H. Hypertensive cardiovascular damage in patients with primary autonomic failure. Lancet. 2000;355(9205):725-726.

54. Maule S, Milan A, Grosso T, Veglio F. Left ventricular hyper-trophy in patients with autonomic failure. Am J Hypertens. 2006;19(10):1049-1054.

55. Biaggioni I. Treatment: special conditions: orthostatic hypotension. J Am Soc Hypertens. 2015;9(1):67-69; quiz 70.

56. Lahrmann H, Cortelli P, Hilz M, et al. Orthostatic hypotension. In: European Handbook of Neurological Management. Wiley-Blackwell; 2010:469-475.

57. Mar PL, Shibao CA, Garland EM, et al. Neurogenic hyperad-renergic orthostatic hypotension: a newly recognized variant of orthostatic hypotension in older adults with elevated norepineph-rine (noradrenaline). Clin Sci (Lond). 2015;129(2):107-116.

58. Suarez GA, Opfer-Gehrking TL, Offord KP, Atkinson EJ, O’Brien PC, Low PA. The Autonomic Symptom Profile: a new instrument to assess autonomic symptoms. Neurology. 1999;52(3):523-528.

59. Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva maneuver in patients with autonomic failure. Neurology. 2005;65(10):1533-1537.

60. Schrezenmaier C, Singer W, Swift NM, Sletten D, Tanabe J, Low PA. Adrenergic and vagal baroreflex sensitivity in autonomic failure. Arch Neurol. 2007;64(3):381-386.

61. Low PA, Tomalia VA. Orthostatic hypotension: mechanisms, causes, management. J Clin Neurol. 2015;11(3):220-226.

62. Stewart JM, Clarke D. “He’s dizzy when he stands up”: an introduction to initial orthostatic hypotension. J Pediatr. 2011;158(3):499-504.

63. Gibbons CH, Freeman R. Delayed orthostatic hypoten-sion: a frequent cause of orthostatic intolerance. Neurology. 2006;67(1):28-32.

64. Gurevich T, Machmid H, Klepikov D, Ezra A, Giladi N, Peretz C. Head-up tilt testing for detecting orthostatic hypotension: how long do we need to wait? Neuroepidemiology. 2014;43(3-4):239-243.

65. Norcliffe-Kaufmann L, Kaufmann H. Is ambulatory blood pres-sure monitoring useful in patients with chronic autonomic failure? Clin Auton Res. 2014;24(4):189-192.

66. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 2006;354(22):2368-2374.

67. Vichayanrat E, Low DA, Stuebner E, Iodice V, Mathias CJ. 24-hour ambulatory blood pressure monitoring in Parkinson’s disease and multipe system atrophy [abstract 1556]. Mov Disord. 2014;29(suppl 1):S571.

68. Chelsea Therapeutics. Neurogenic orthostatic hypotension (also known as neurogenic OH or NOH). MSA-AMS/NEWS-NIEUWSFLASH/Artikelen/2012/2/9_Neurogenic_ orthostatic_hypotension_(also_known_as_Neurogenic_OH_or_ NOH)..html. Accessed July 2, 2015.

69. Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R. The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale. Clin Auton Res. 2012;22(2):79-90.

70. Biaggioni I, Freeman R, Mathias CJ, Low P, Hewitt LA, Kaufmann H. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65(1):101-107.

71. Shire Pharmaceuticals. Clinical efficacy of midodrine in symp-tomatic orthostatic hypotension. website. https:// 6&term=midodrine&rank=12#outcome1. Accessed June 17, 2015.

72. NDA 203202 Study Endpoint Review: Orthostatic Hypotension Questionnaire. FDA website. Accessed July 8, 2015.

73. Palma JA, Gomez-Esteban JC, Norcliffe-Kaufmann L, et al. Orthostatic hypotension in Parkinson disease: how much you fall or how low you go? Mov Disord. 2015;30(5):639-645.
Copyright AJMC 2006-2017 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up

Sign In

Not a member? Sign up now!