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Diagnosis: Orthostatic Intolerance (OI)

Orthostatic intolerance (OI) is the development of symptoms while standing or sitting upright.1 It has been associated with chronic fatigue and immune dysfunction syndrome (CFIDS) in both adults and children.2,3,4,5,6,7

The connection between OI and CFIDS was first introduced in 1995,8 by Rowe and associates at Johns Hopkins University, who identified neurally mediated hypotension (NMH) in CFIDS patients. Since 1995, scientists have learned much more about the broader problem of OI in CFIDS, of which NMH is just one form. It is now thought that many CFIDS patients (up to 97% in some studies) have some form of OI and it seems to be a particular problem in youth with CFIDS. 7,8,9,10

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Types of OI
There are many types of OI, but two forms have been linked with CFIDS in research studies: NMH and postural orthostatic tachycardia syndrome (POTS).

NMH is a precipitous drop (at least 20-25 mm Hg) in systolic blood pressure when standing. The blood pressure drop is accompanied or preceded by an increase in symptoms.2

POTS is a rapid increase in heart rate (pulse) of more than 30 beats per minute (bpm) from baseline, or to more than 120 bpm total, during the first 10 minutes of standing.1 It is also known as chronic orthostatic intolerance, or COI.11

The blood pressure and heart rate changes in NMH and POTS are accompanied by orthostatic symptoms such as lightheadedness, dizziness, nausea, fatigue, tremors, breathing or swallowing difficulties, headache, visual disturbances, sweating and pallor. Many patients develop swollen, bluish legs, providing evidence of blood pooling in the lower part of the body.10

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Most doctors are familiar with orthostatic hypotension (OH), which can result in fainting (or syncope, pronounced "sin-coh-pee") very quickly after standing, and can be diagnosed with a simple in-office test of taking the blood pressure first while lying down and again upon standing.

Unlike those with OH, which occurs within the first three minutes of standing,12 CFIDS patients with NMH or POTS often have a delayed form13,14 of orthostatic intolerance, meaning that heart rate and blood pressure changes don't develop for many minutes after standing, making the standard in-office test for acute orthostatic hypotension ineffective in diagnosis. A tilt table test in CFS is considered to be positive if a patient experiences orthostatic symptoms and blood pressure and/or heart rate changes, whether or not he or she faints.2 Patients typically undergo a head-up tilt table test (HUT)15 as an outpatient in a hospital or cardiology office to get a definitive diagnosis. Since the HUT reproduces the symptoms of NMH and POTS, patients often feel worse during and after the test. Some testers administer IV saline following the test to reduce the occurrence of prolonged symptoms.

Dr. David Streeten, a researcher who studied circulatory problems, and who collaborated with CFIDS clinician Dr. David S. Bell, favored the use of a prolonged standing test as more representative of a patient's daily symptoms and experiences than the HUT.16 Blood pressure and heart rate are measured every few minutes while patients lie quietly for 30 minutes and again as they stand quiet and motionless for 60 minutes, or until severe symptoms develop. It is very important that either this test or the HUT be done under close medical supervision, as serious complications, including brief periods of very slow heart rate, can occur during the test.

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There are several hypothesized causes of NMH and POTS relevant to CFIDS; regardless of the cause, all lead to inadequate blood circulation that may reduce the amount of blood getting back to the heart and brain. Patients may have low blood volume throughout the body17,18,19 or their blood may pool excessively in the extremities10,11 or both.

When healthy people stand, gravity causes about 750 ml of blood to fall to the abdomen and legs, resulting in a decrease in blood flow to the brain.20 In patients with POTS, cerebral blood flow decreases more prominently while standing.21 In one study of adolescents, the amount of blood that pooled in the legs was highest in CFIDS patients and second highest in POTS patients, as determined by measuring the circumference of their calves while lying down and again while standing.7

When the heart receives less blood from the limbs during standing, the brain releases chemicals and alters the pulse and blood pressure in an effort to get the blood flowing upwards again. When this chemical response is accentuated, as in NMH and POTS, patients can develop a rapid heart rate (tachycardia), low blood pressure (hypotension) and orthostatic symptoms (see "Types of OI" above). CFIDS patients can have either NMH or POTS, and some have both conditions.

Researchers have identified several physiological abnormalities in CFIDS patients that are consistent with autonomic nervous system problems such as NMH and POTS. In five studies, adults and adolescents with CFIDS had elevated heart rates at rest compared to healthy and sedentary controls,5,7,9,22,23, although two studies found no difference.2,24Heart rate further increased when patients underwent a tilt test, a finding consistent with POTS.5,7,23

In addition, three studies - one in adults5 and two in adolescents11,6 - found that heart rate variability is significantly reduced in CFS compared to controls. This means that instead of having a heart rate that changes appropriately when faced with orthostatic stress, many CFS patients have reduced modulation of their heart rate, suggesting impairment of the autonomic nervous system.11 In contrast, one study of adults with CFS found that heart rate variability is similar to that in controls.25

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Effective treatment for NMH and POTS in CFIDS must be individualized. In general, treatment for POTS and NMH helps greatly to alleviate some symptoms, but rarely fully resolves the CFIDS.

The first line of treatment should be non-medical interventions, such as increasing fluids and salt, tilting the head of the bed up a few degrees, wearing compression garments (such as support hose, girdles or abdominal binders), and learning to avoid and cope with things that can make OI worse (such as standing in long lines, being in warm environments and eating large, heavy meals).

If these are not effective, doctors may introduce pharmaceutical treatments such as fludrocortisone (Florinef) to treat low blood volume, and vasoconstrictor medications, including methylphenidate (Ritalin), dextroamphetamine (Dexedrine) and midodrine (ProAmatine) to treat blood pooling, and sometimes drugs to block the release or effect of epinephrine and norepinephrine. Selective serotonin reuptake inhibitors (SSRIs) have been used with some success in patients with POTS, and one randomized trial has demonstrated the efficacy of paroxetine (Paxil) for those with recurrent syncope due to NMH.26

Although randomized trials of treatment for POTS have not been performed, other randomized trials in those with recurrent syncope due to NMH have demonstrated efficacy for atenolol, midodrine and enalapril.27 It is unclear whether these medications will work in CFIDS. Intravenous saline can help reduce symptoms, especially following HUT or other acute exacerbations of symptoms. Common syncope treatments beta-blockers and clonidine may be less effective in POTS and may reflect different causes for POTS and simple fainting.

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Further research is required to determine how orthostatic intolerance is involved in CFIDS. It is clear from past studies that OI is associated with CFIDS, but the degree and meaning of that association is still a focus of vigorous research.

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1. Low PA, Opfer-Gehrking TL, Textor SC, et al. Postural tachycardia syndrome (POTS). Neurology. 1995;45:S19-25.
2. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274:961-7.
3. Calkins H, Rowe PC. Relationship Between Chronic Fatigue Syndrome and Neurally Mediated Hypotension. Cardiol Rev. 1998;6:125-134.
4. Schondorf R, Freeman R. The importance of orthostatic intolerance in the chronic fatigue syndrome. Am J Med Sci. 1999;317:117-23.
5. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. 1997;102:357-64.
6. Stewart JM. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res. 2000;48:218-26.
7. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999;103:116-21.
8. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue? Lancet. 1995;345:623-4.
9. Stewart J, Weldon A, Arlievsky N, Li K, Munoz J. Neurally mediated hypotension and autonomic dysfunction measured by heart rate variability during head-up tilt testing in children with chronic fatigue syndrome. Clin Auton Res. 1998;8:221-30.
10. Stewart JM, Gewitz MH, Weldon A, Munoz J. Patterns of orthostatic intolerance: the orthostatic tachycardia syndrome and adolescent chronic fatigue. J Pediatr. 1999;135:218-25.
11. Stewart J.M., Weldon A. Vascular perturbations in the chronic orthostatic intolerance of the postural orthostatic tachycardia syndrome. J Appl Physiol. 2000;89:1505-1512.
12. Bannister RH eal. Consensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Robertson D LPPRe. Primer on the Autonomic Nervous System. San Diego: Academic Press; 1996.
13. Streeten DH, Anderson GH Jr. Delayed orthostatic intolerance. [abstract on site] Arch Intern Med. 1992;152:1066-72.
14. Streeten DH, Anderson GH Jr. The role of delayed orthostatic hypotension in the pathogenesis of chronic fatigue. Clin Auton Res. 1998;8:119-24.
15. Benditt DG, Ferguson DW, Grubb BP, et al. Tilt table testing for assessing syncope. American College of Cardiology. J Am Coll Cardiol . 1996;28:263-75.
16. Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 2000;320:1-8.
17. Streeten D.H., Bell D.S. Circulating blood volume in chronic fatigue syndrome. J CFS. 1998;4:3-11.
18. Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann Intern Med. 1986;104:298-303.
19. Jacob G, Biaggioni I, Mosqueda-Garcia R, Robertson RM, Robertson D. Relation of blood volume and blood pressure in orthostatic intolerance. Am J Med Sci. 1998;315:95-100.
20. Jacob G, Atkinson D, Jordan J, et al. Effects of standing on cerebrovascular resistance in patients with idiopathic orthostatic intolerance. Am J Med. 1999;106:59-64.
21. Rowell LB. Human Cardiovascular Control. New York: Oxford; 1993.
22. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst. 1999;75:192-201.
23. LaManca JJ, Peckerman A, Walker J, et al. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999;19:111-20.
24. Alexander ME, Berde C, Triedman JK, Sundel R, Saul JP. Postural orthostatic tachycardia and chronic fatigue: a distinct subset of neurally-mediated syncope in adolescents (abstract). Proceedings of the Fourth International Conference of the American Association for Chronic Fatigue Syndrome: J CFS; 1999.
25. Yataco A, Talo H, Rowe P, Kass DA, Berger RD, Calkins H. Comparison of heart rate variability in patients with chronic fatigue syndrome and controls. Clin Auton Res. 1997;7:293-7.
26. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1999;33:1227-30.
27. Calkins H. Pharmacologic approaches to therapy for vasovagal syncope. Am J Cardiol. 1999;84:20Q-25Q.

The CFIDS Association of America, Inc.
PO Box 220398
Charlotte, NC 28222-0398

Copyright © 2004, The CFIDS Association of America, Inc.

Posted with permission from The CFIDS Association of America.

This article was originally posted at www.cfids.org/about-cfids/orthostatic-intolerance.asp

[Note: As of 2014, The CFIDS Association of America changed its name and website to Solve ME/CFS Initiative - https://solvecfs.org.]

Note: Dr. David H. Streeten died September of 2000. His research and understanding of Orthostatic Intolerance (OI) will always be greatly appreciated.

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