≡ Menu

Orthostatic Intolerance in Chronic Fatigue Syndrome (ME/CFS) IV: A Biomarker? plus Conclusions, Link, etc. (Feb 2004/2007)

A Biomarker for Chronic Fatigue Syndrome (ME/CFS?)

Naschitz and colleagues in Israel noticed in 2000 – to their surprise – that CFS patients had a specific pattern of ‘cardiovascular reactivity’ in response to tilt tests. They used statistical analyses of common measures of autonomic function (heart rate, blood pressure) obtained during tilt table testing to create a ‘hemodynamic instability score’. These scores enabled researchers to differentiate CFS patients from a wide variety of control groups. This study was notable in the large number of control groups tested.

The authors posit that the very complex interactions between the heart and the neuro-endocrine systems that are involved in baroreflex activation give rise to specific disease patterns in certain illnesses.

CFS patients versus

Sensitivity %


All groups



Non-CFS but fatigued






Mediterranean fever






Neurally mediated syncope (fainting)



Healthy controls



Generalized anxiety disorder


Not significant


With the notable (and rather surprising?) exception of the patients with generalized anxiety disorder, this test was remarkably effective. Forty-five percent of patients with the anxiety disorder had similar HIS scores. The authors gave no indication why CFS patients had similar scores to anxiety patients. Since anxiety disorder is linked to over activity of the sympathetic nervous system perhaps this is not a surprising finding.

In another study a specific cutoff point for fractal HRV had a high sensitivity (90%) and specificity (72%) when it was used to discriminate CFS patients from controls. It appears that measures of ANS function during tilt may have a high discriminatory value; i.e. may provide a biomarker and possibly – dare one say it? – afford CFS some legitimacy.

One interesting and very promising side notes of this study was its restriction to patients with mild to moderate CFS. Patients with more severe CFS were unable to complete the 30 minute Tilt table test without fainting. Thus this finding is probably quite robust.


The extent and significance of orthostatic intolerance in CFS is still unclear. With some exceptions we find the same heterogeneity in test results that plagues other research efforts into CFS. The rapidly evolving nature of the field of orthostatic intolerance and the heterogeneous nature of the CFS patient population guarantee a  certain lack of clarity will prevail. In particular, tests of BP and the Valsalva maneuver have differed between groups.

Estimates of orthostatic intolerance (neurally mediated hypotension, POTS, etc.) in CFS patients have ranged from over 90% to less than 20%. The latest research indicates approximately 40% of CFS patients are believed to fulfill the parameters for POTS.

Perhaps the most significant finding regarding OI prevalence in CFS, however, was the increased rate of symptoms for all CFS patients undergoing TILT tests regardless of whether they meet the stated definition of OI (Poole et. al. 2000). As in other fields of CFS research, studies have been plagued by small sizes, different methodologies and parameters and poorly defined CFS and control patient sets.

Some consistencies have, however, emerged. CFS typically display ANS abnormalities when challenged, not at rest. CFS patients also consistently display significantly increased heart rates and significantly decreased heart rate variability.

These findings suggest over activation of the sympathetic nervous system (‘fight or flight’) and under activation of the parasympathetic nervous system (rest and digest) is occurring. A subset of CFS patients appear to have reduced blood volumes. When CFS patients have orthostatic intolerance it is generally in the form of POTS.

The splintering of the POTS patients into three coherent subsets – all of which occur in CFS – further refines (and complicates) our understanding of the orthostatic dysfunction occurring. It is generally agreed POTS occurs when insufficient venous flows of blood to the heart during standing triggers a compensatory response consisting of an increased heart beat.

The proximate causes of the increased blood pooling are varied; they include inadequate peripheral vasoconstriction in the legs possibly caused by denervation; increased local blood blows in the legs caused by increased levels of a local vasodilating agent such as NO or acetylcholine and inadequate vaso and venoconstriction in the abdomen. Symptoms appear to be exacerbated by reduced blood volume in a subset of CFS patients.

The ultimate causes of these dysfunctions are unknown but may include pathogen induced vasodilation of the peripheral blood vessels, endothelial dysfunction, blunted HPA axis activity or others. While deconditioning can cause POTS, no studies indicate deconditioning plays a major role in the orthostatic intolerance seen in CFS.

A most promising development in this field is the possible development of a biomarker created using heart rate and blood pressure changes during a tilt test. This test, which was surprisingly effective in differentiating CFS patients from a variety of control groups, suggested a distinctive pattern of ANS dysfunction occurred in CFS patients.

While orthostatic intolerance does not appear to be primary in CFS, its prevalence in CFS and similar symptoms indicate it is an integral part of it. It is likely the disruptions underlying OI will be found to some extent in most CFS patients whether they meet the standards for OI or not.

Uncovering the source of the OI seen in CFS will undoubtedly contribute greatly to our understanding of the pathophysiology of CFS. Thankfully this is one of the few areas of ‘CFS’ research that has some funding; several projects are underway that should illuminate this most intriguing aspect of CFS in the near future.>

(Produced Fall 2004, brief update 2007)


Bonyhay, I and R. Freeman. 2004. Sympathetic nerve activity in response to hypotensive str essin the postural tachycardia syndrome. Circulation 110: 3193-3198.

Carson, R., Diedrich, A. and D. Robertson. 2002. Autonomic control after blockade of the norepinephrine transporter: a model of orthostatic intolerance. J. Appl. Physiol 93: 2192-2198.

Chalmers RA, Jones MG, Goodwin CS, Amjad S. 2005. CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts. Clin Chim Acta. Aug 8 [Epub ahead of print]

De Becker, P., Dendale, P., De Meirleir K., Campine, I., Vandenborne, K. and Y. Hagers. 1998. Autonomic testing in patients with chronic fatigue syndrome. The American Journal of Medicine 105 (3A) 22S-26S.

Dunn, A. Interactions between the nervous system and the immune system: implications for psychopharmacology.

Farquhar, W., Hunt, B., Taylor, J., Darling, S. and R Freeman. 2002. Blood volume and its relation to peak O2 consumption and physical activity in patients with chronic fatigue. Am J. Heart Physiol. Circ. Phsyiol.282: H66-71.

Freeman, R. and A. Komaroff. 1997. Does the chronic fatigue syndrome involve the autonomic nervous system? American Journal of Medicine 102, 357-364.

Goldstein, D., Robertson, D., Esler, M., Straus, S. and G. Eisenhofer. 2002. NIH Conference: Dysautonomias: clinical disorders of the autonomic nervous system. Annals of Internal Medicine 137 (9)753-767.

Hageberg, J., Goldberg, A., Lakatta, L., O’Conner, F., Becker, L., Lakatta, E. and J. Fleg. 1998. Expanded blood volumes contribute to the increased cardiovascular performance of endurance-trained older men. Journal of Applied Physiology 85: 484-489.

Jacob, G., Robertson, R., Mosqueda-Garcia, R., Ertl, A., Robertson, R. and I. Biaggioni. 1997. Hypovolemia in syncope and orthostatic intolerance. Role of the Renin-angiotensin system. Am. Jour. Med. 128-133.

Jacob, G., Shannon, J., Costa, F., Rurlan, R., Biaggioni, I., Mosqueda-Garcia, R., Robertson, R. and D. Robertson. 1999. Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance. Circulation 99: 1706-1712.

Jacob, G., Costa, F., Shannon, J., Robertson, R., Wathen,M., Stein, M., Biaggioni, I., Ertl, A., Black, B and D. Robertson. 2000. The neuropathic postural tachycardia syndrome. New England Journal of Medicine 343: 1008-14.

Kavelaars, A., Kuis, W., Knook, L., Sinnema, G. and C. Heijnen. 2000. Disturbed neuroendocrine-immune interactions in chronic fatigue syndrome. The Journal of Clinical Endocrinology and Metabolism 85 (2) 696-696.

Khan, F., Spence, V, Kennedy, G. and J. Belch. 2002 Prolonged acetylcholine-induced vasodilation in the peripheral microcirculation of patients with chronic fatigue syndrome. Clin Physiol Func Imaging 23; 282-5.

Kimberly, D. and K. Shoemaker. 2002. Hypovolemia and neurovascular control during orthostatic stress. Am J. Physiol. Heart Circ. Physiol. 282: H645-H655.

Licino, J. and P. Frost. 2000. The neuroimmune-endocrine axis: pathyphsiological implications for the central nervous system cytokines and hypothalamus-pituitary-adrenal hormone dynamics. Brazilian Journal of Medical and Biological Research 33: 1141-1148.

Naschitz, J. E., Rosner, I, Rozenbaum, M., Naschitz, S., Musafia-Priselac, R., Shaviv, N., Fields, M., Isseroff, H., Zuckerman, E., Yeshurun, D and E. Sabo. 2003. The head-up tilt test with haemodynamic instability score in diagnosing chronic fatigue syndrome. Q. J. Med 96: 133-142.

Padzerka-Robinson, H., Morrison, J. and P. Flor-Henry. 2004. Electrodermal dissociation of chronic fatigue and depression: evidence for distinct physiological mechanisms. International Journal of Psychophysiology 53, 171-182.

Passatore, M., Hellstrom, I and S. Roatta. The role of the sympathetic nervous system in stress and pain.

Pawelczyk, J., Zucherman, J., Blomqvist, C. and B Levine. 2001. Regulation of muscle sympathetic nerve activity after bed rest deconditioning. AM J. Physiol. Heart Circ. Physiol. 280: H2230- H2239.

Pociniki, A. 2004. Joint hypermobility and the link with CFIDS. Summer 2004 CFID Chronicle. CFIDS Association of America.

Poole, J. Herrell, R., Ashton, S., Goldberg, J. and D. Buchwald. 2000. Arch. Intern. Med. 160, 3461-3468.

Razumovsky, A., DeBusk, K., Calkins, H., Snader, S., Lucas, K., Vyas, P., Hanley, D. and P. Rowe. 2003. Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue syndrome. Journal of Neuroimaging 13 (1); 57-67.

Rivest, S. 2003. Immune function and regulation of the autonomic nervous system. In Handbook of the Autonomic Nervous System in Health and Disease. Ed. C. Bolis, J. Licinio, S. Govoni. 55-125. Marcel Dekker, New York.

Rowe, P., Barron, D., Calkins, H., Maumenee, I., Tong, P. and M. Geraghty. 1999. Orthostatic intolerance and chronic fatigue syndrome are associated with Ehlers-Danlos syndrome. J. Pediatr. 135: 494-9.

Rowe, P. 2002. Orthostatic intolerance and chronic fatigue syndrome: new light on a old problem. Journal of Pediatrics 140: 387-9.

Schondrof, R, Benoit, J., Wein, T., and D. Phaneuf. 1999. Orthostatic intolerance in the chronic fatigue syndrome. J. Auton. Nerv Syst. 75: 192-201.

Shibao, C., Arzubiaga, C., Roberts II, L. J., Raj, S., Black, B., Harris, P. and I. Biaggioni. 2005. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 45: 385-390.

Soetekouv, P., Lenders, J., Bleijenberg, G., Thien, T, and J. van der Meer. 1999. Autonomic function in patients with chronic fatigue syndrome. Clin Auton Res. 9: 334-340.

Stewart, J.M., Minor, J. and A. Weldon. 2002. Clinical and physiological effects of an acute a-1 adrenergic agonist and b-1 adrenergic antagonist in chronic orthostatic intolerance. Circulation 106, 2946-2954.

Stewart, J. and L. Montgomery. 2004 Regional blood volume and peripheral blood blood flow in postural tachycardia syndrome. Am. J. Physiol. Heart Circ. Physiol. 287; H1319-H1327.

Stewart, J. 2004. Chronic orthostatic intolerance and the postural tachycardia syndrome. J. Pediatrics 145: 725-30.

Stewart, J. 2003a. Orthostatic intolerance. In Handbook of Chronic Fatigue Syndrome. Ed. Jason, L., Fennell, P. and R. Taylor, 245-280. John Wiley and Sons.

Stewart, J. 2003b. Microvascular filtration is increased in postural tachycardia syndrome. Circulation 107: 2816-2822.

Stewart, J. 2000. Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated baroreflex and potentiated sympathetic vasomotion. Pediatric Research 48, 218-226.

Streeten, D., and D. Bell 1998. Circulating blood volume in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome.

Sztajzel, J. 2004. Heart rate variability: a non-invasive electrocardiographic method to measure the autonomic nervous system. Swiss Med Wkly: 514-522.

Tanaka, H., Matsuushima, R., Tamai, H. and Y. Kajimoto. 2002. Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance. J. Pediatr. 140: 412-417.

Timmers, H., Wieling, W., Soetekouw, P., Bleijenberg, G., Van Meer, J. and J. Lenders. 2002. Hemodynamic and neurohumoral responses to a head-up tilt in patients with chronic fatigue syndrome. Clin Auton. Res. 12: 273-80.

Tsuru, H., Tanimitsu, N. and T. Hirai. 2002 Role of perivascular sympathetic nerves and regional differences in the features of sympathetic innervaton of the vascular system. Japan Journal of Pharmacology 88, 9-13.

Winkler, A. S., Blair, D., Marsden, J., Peters, T., Wessely, S. and A. Cleare. 2004. Autonomic function and serum erythropoietin levels in chronic fatigue syndrome. Journal of Psychosomatic Research 56: 179-183.

Yamamoto, Y., LaManca, J. and B. Natelson 2002 A measure of heart rate variability is sensitive to orthostatic challenge in women with chronic fatigue syndrome. Exp. Biol. Med. 228: 167-174.

Our friendly, international forum is the busiest in the world with 400 new posts every day and over 13,000 members - join in!