The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with Joint Hypermobility Show Larger Cerebral Blood Flow Reductions during Orthostatic Stress Testing Than Patients without Hypermobility: A Case Control Study Hypermobility in ME/CFS: effect on cerebral blood flow

Main Article Content

Linda M.C. van Campen Peter C Rowe, mr Frans C Visser, mr


Aims: An abnormal reduction in cerebral blood flow (CBF) during orthostatic stress is common in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a condition with more prevalent joint hypermobility than in the healthy population. As one of proposed underlying mechanisms of orthostatic intolerance in hypermobile patients is vessel laxity, reducing the normal return of blood to the heart during orthostatic stress, we hypothesized that the CBF reduction during tilt-testing would be larger in ME/CFS patients with joint hypermobility than in patients without hypermobility.

Methods: In this case-control study, 100 female ME/CFS cases with joint hypermobility, who had undergone tilt-testing with CBF measurements, were compared to 100 female ME/CFS patients without joint hypermobility, matched by age and disease duration.

Results: No differences in baseline characteristics were found between groups. The hypermobile patients had significantly more postural orthostatic tachycardia syndrome (POTS) during tilt testing than the non-hypermobile ones. Compared to supine CBF, the degree of CBF reduction during the tilt was significantly larger in hypermobile cases than in the non-hypermobile controls: -32 (6)% vs -23 (7)% (p<0.0001) The larger CBF reduction in hypermobile patients was not only present in POTS patients: -33 (6)% vs -24 (4)%, but also in patients with a normal heart rate and blood pressure response to tilt testing: -31 (6)% vs -22 (9)%: (both p<0.0001).

Conclusions: ME/CFS patients with joint hypermobility syndromes have larger CBF reductions during orthostatic stress testing than patients without hypermobility. This larger CBF reduction is independent of the heart rate and blood pressure results of the orthostatic stress test.

Article Details

How to Cite
VAN CAMPEN, Linda M.C.; ROWE, Peter C; VISSER, Frans C. The Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients with Joint Hypermobility Show Larger Cerebral Blood Flow Reductions during Orthostatic Stress Testing Than Patients without Hypermobility: A Case Control Study. Medical Research Archives, [S.l.], v. 9, n. 6, june 2021. ISSN 2375-1924. Available at: <>. Date accessed: 03 dec. 2022. doi:
Research Articles


1. Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. J Pediatr. Oct 1999;135(4):494-499. doi:10.1016/s0022-3476(99)70173-3
2. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognised cause of chronic fatigue? Lancet. 3/11/1995 1995;345(8950):623-624. Not in File. doi:10.1016/s0140-6736(95)90525-1
3. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 9/27/1995 1995;274(12):961-967. Not in File.
4. Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med. Apr 1997;102(4):357-364. doi:10.1016/s0002-9343(97)00087-9
5. Furlan R, Jacob G, Snell M, et al. Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation. Nov 17 1998;98(20):2154-2159. doi:10.1161/01.cir.98.20.2154
6. Grubb BP, Kosinski DJ, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing. Pacing Clin Electrophysiol. Sep 1997;20(9 Pt 1):2205-2212. doi:10.1111/j.1540-8159.1997.tb04238.x
7. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. Jan 1999;103(1):116-121. doi:10.1542/peds.103.1.116
8. Institute Of Medicine (IOM), ed. Beyond mayalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. The National Academies Press; 2015.
9. van Campen CLMC, Verheugt FWA, Rowe PC, Visser FC. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography. Clin Neurophysiol Pract. 2020;5:50-58. doi:10.1016/j.cnp.2020.01.003
10. van Campen CLMC, Rowe PC, Visser FC. Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Healthcare. 2020;8:394. doi:10.3390/healthcare8040394
11. van Campen CLMC, Rowe PC, Visser FC. Cerebral Blood Flow Is Reduced in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing. Healthcare (Basel). Jun 13 2020;8(2):169. doi:10.3390/healthcare8020169
12. Nijs J, Aerts A, de Meirleir K. Generalized joint hypermobility is more common in chronic fatigue syndrome than in healthy control subjects. J Manipulative Physiol Ther. 1/2006 2006;29(1):32-39. Not in File. doi:10.1016/j.jmpt.2005.11.004
13. Bragee B, Michos A, Drum B, Fahlgren M, Szulkin R, Bertilson BC. Signs of Intracranial Hypertension, Hypermobility, and Craniocervical Obstructions in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Neurol. 2020;11:828. doi:10.3389/fneur.2020.00828
14. Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC. Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls. J Pediatr. 9/2002 2002;141(3):421-425. Not in File. doi:10.1067/mpd.2002.127496
15. Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. Jul 2003;115(1):33-40. doi:10.1016/s0002-9343(03)00235-3
16. Cazzato D, Castori M, Lombardi R, et al. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. Jul 12 2016;87(2):155-9. doi:10.1212/WNL.0000000000002847
17. De Wandele I, Rombaut L, Leybaert L, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Semin Arthritis Rheum. Aug 2014;44(1):93-100. doi:10.1016/j.semarthrit.2013.12.006
18. Mathias CJ, Low DA, Iodice V, Owens AP, Kirbis M, Grahame R. Postural tachycardia syndrome--current experience and concepts. Nat Rev Neurol. Dec 6 2011;8(1):22-34. doi:10.1038/nrneurol.2011.187
19. Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 12/15/1994 1994;121(12):953-959. Not in File. doi:10.7326/0003-4819-121-12-199412150-00009
20. Carruthers BM, van de Sande MI, DE Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 10/2011 2011;270(4):327-338. Not in File. doi:10.1111/j.1365-2796.2011.02428.x
21. Beighton P, Solomon L, Soskolne CL. Articular mobility in an African population. Ann Rheum Dis. Sep 1973;32(5):413-418. doi:10.1136/ard.32.5.413
22. Cooper DJ, Scammell BE, Batt ME, Palmer D. Development and validation of self-reported line drawings of the modified Beighton score for the assessment of generalised joint hypermobility. BMC Med Res Methodol. Jan 17 2018;18(1):11. doi:10.1186/s12874-017-0464-8
23. Wolfe F, Clauw DJ, Fitzcharles MA, et al. 2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. Dec 2016;46(3):319-329. doi:10.1016/j.semarthrit.2016.08.012
24. van Campen CLMC, Verheugt FWA, Visser FC. Cerebral blood flow changes during tilt table testing in healthy volunteers, as assessed by Doppler imaging of the carotid and vertebral arteries. Clin Neurophysiol Pract. 2018;3:91-95. doi:10.1016/j.cnp.2018.02.004
25. van Campen CLMC, Visser FC. Validation of Stroke volume measured with suprasternal aortic Doppler imaging: comparison to transthoracic Stroke Volume measurements. research article. Journal Of Thrombosis and Circulation. 2018;(2):1-5. doi:10.29011/ JTC -106. 000006
26. van Campen CLMC, Visser FC, de Cock CC, Vos HS, Kamp O, Visser CA. Comparison of the haemodynamics of different pacing sites in patients undergoing resynchronisation treatment: need for individualisation of lead localisation. Heart. Dec 2006;92(12):1795-1800. doi:10.1136/hrt.2004.050435
27. Kusumoto F, Venet T, Schiller NB, Sebastian A, Foster E. Measurement of aortic blood flow by Doppler echocardiography: temporal, technician, and reader variability in normal subjects and the application of generalizability theory in clinical research. J Am Soc Echocardiogr. Sep-Oct 1995;8(5 Pt 1):647-53. doi:10.1016/s0894-7317(05)80378-5
28. Freeman R, Wieling W, Axelrod FB, et al. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci. 4/26/2011 2011;161(1-2):46-48. Not in File. doi:10.1016/j.autneu.2011.02.004
29. Sheldon RS, Grubb BP, 2nd, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. Jun 2015;12(6):e41-63. doi:10.1016/j.hrthm.2015.03.029
30. Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS Guideline for the Evaluation and Management of Patients With Syncope: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. Aug 1 2017;70(5):620-663. doi:10.1016/j.jacc.2017.03.002
31. Fedorowski A, Burri P, Melander O. Orthostatic hypotension in genetically related hypertensive and normotensive individuals. J Hypertens. May 2009;27(5):976-982. doi:10.1097/hjh.0b013e3283279860
32. Maeland S, Assmus J, Berglund B. Subjective health complaints in individuals with Ehlers-Danlos syndrome: a questionnaire study. Int J Nurs Stud. Jun 2011;48(6):720-4. doi:10.1016/j.ijnurstu.2010.10.007
33. De Wandele I, Rombaut L, Malfait F, De Backer T, De Paepe A, Calders P. Clinical heterogeneity in patients with the hypermobility type of Ehlers-Danlos syndrome. Res Dev Disabil. Mar 2013;34(3):873-881. doi:10.1016/j.ridd.2012.11.018
34. Murray B, Yashar BM, Uhlmann WR, Clauw DJ, Petty EM. Ehlers-Danlos syndrome, hypermobility type: A characterization of the patients' lived experience. Am J Med Genet A. Dec 2013;161A(12):2981-8. doi:10.1002/ajmg.a.36293
35. Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet. Mar 2017;175(1):212-219. doi:10.1002/ajmg.c.31554
36. Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Comparative clinical profile of postural orthostatic tachycardia patients with and without joint hypermobility syndrome. Indian Pacing Electrophysiol J. 2010;10(4):173-178.
37. Wallman D, Weinberg J, Hohler AD. Ehlers-Danlos Syndrome and Postural Tachycardia Syndrome: a relationship study. J Neurol Sci. May 15 2014;340(1-2):99-102. doi:10.1016/j.jns.2014.03.002
38. Celletti C, Camerota F, Castori M, et al. Orthostatic Intolerance and Postural Orthostatic Tachycardia Syndrome in Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome, Hypermobility Type: Neurovegetative Dysregulation or Autonomic Failure? Biomed Res Int. 2017;2017:9161865. doi:10.1155/2017/9161865
39. Miller AJ, Stiles LE, Sheehan T, et al. Prevalence of hypermobile Ehlers-Danlos syndrome in postural orthostatic tachycardia syndrome. Auton Neurosci. Mar 2020;224:102637. doi:10.1016/j.autneu.2020.102637
40. Roma M, Marden CL, De Wandele I, Francomano CA, Rowe PC. Postural tachycardia syndrome and other forms of orthostatic intolerance in Ehlers-Danlos syndrome. Auton Neurosci. Dec 2018;215:89-96. doi:10.1016/j.autneu.2018.02.006
41. Shin KJ, Kim SE, Park KM, et al. Cerebral hemodynamics in orthostatic intolerance with normal head-up tilt test. Acta Neurol Scand. Oct 2 2015;134(2):108-115. doi:10.1111/ane.12516
42. Park J, Kim HT, Park KM, et al. Orthostatic dizziness in Parkinson's disease is attributed to cerebral hypoperfusion: A transcranial doppler study. J Clin Ultrasound. Jul 8 2017;45(6):337-342. doi:10.1002/jcu.22452
43. Novak P. Hypocapnic cerebral hypoperfusion: A biomarker of orthostatic intolerance. PLoS One. 2018;13(9):e0204419. doi:10.1371/journal.pone.0204419
44. Del Pozzi AT, Schwartz CE, Tewari D, Medow MS, Stewart JM. Reduced cerebral blood flow with orthostasis precedes hypocapnic hyperpnea, sympathetic activation, and postural tachycardia syndrome. Hypertension. Jun 2014;63(6):1302-1308. doi:10.1161/HYPERTENSIONAHA.113.02824
45. Stewart JM, Pianosi P, Shaban MA, et al. Hemodynamic characteristics of postural hyperventilation: POTS with hyperventilation versus panic versus voluntary hyperventilation. J Appl Physiol (1985). Nov 1 2018;125(5):1396-1403. doi:10.1152/japplphysiol.00377.2018
46. Stewart JM, Pianosi P, Shaban MA, et al. Postural Hyperventilation as a Cause of Postural Tachycardia Syndrome: Increased Systemic Vascular Resistance and Decreased Cardiac Output When Upright in All Postural Tachycardia Syndrome Variants. J Am Heart Assoc. Jun 30 2018;7(13):e008854. doi:10.1161/JAHA.118.008854
47. Novak V, Spies JM, Novak P, McPhee BR, Rummans TA, Low PA. Hypocapnia and cerebral hypoperfusion in orthostatic intolerance. Stroke. Sep 1998;29(9):1876-1881. doi:10.1161/01.str.29.9.1876
48. Laffey JG, Kavanagh BP. Hypocapnia. N Engl J Med. Jul 4 2002;347(1):43-53. doi:10.1056/NEJMra012457
49. Sato K, Sadamoto T, Hirasawa A, et al. Differential blood flow responses to CO(2) in human internal and external carotid and vertebral arteries. J Physiol. Jul 15 2012;590(14):3277-3290. doi:10.1113/jphysiol.2012.230425
50. Immink RV, Pott FC, Secher NH, van Lieshout JJ. Hyperventilation, cerebral perfusion, and syncope. J Appl Physiol (1985). Apr 1 2014;116(7):844-851. doi:10.1152/japplphysiol.00637.2013
51. Newton DJ, Kennedy G, Chan KK, Lang CC, Belch JJ, Khan F. Large and small artery endothelial dysfunction in chronic fatigue syndrome. Int J Cardiol. Feb 9 2012;154(3):335-336. doi:10.1016/j.ijcard.2011.10.030
52. Scherbakov N, Szklarski M, Hartwig J, et al. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. Jun 2020;7(3):1064-1071. doi:10.1002/ehf2.12633
53. Loebel M, Grabowski P, Heidecke H, et al. Antibodies to beta adrenergic and muscarinic cholinergic receptors in patients with Chronic Fatigue Syndrome. Brain Behav Immun. Feb 2016;52:32-39. doi:10.1016/j.bbi.2015.09.013
54. Scheibenbogen C, Loebel M, Freitag H, et al. Immunoadsorption to remove ss2 adrenergic receptor antibodies in Chronic Fatigue Syndrome CFS/ME. PLoS One. 2018;13(3):e0193672. doi:10.1371/journal.pone.0193672
55. Tanaka S, Kuratsune H, Hidaka Y, et al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med. 8/2003 2003;12(2):225-230. Not in File.
56. Yamamoto S, Ouchi Y, Nakatsuka D, et al. Reduction of [11C](+)3-MPB binding in brain of chronic fatigue syndrome with serum autoantibody against muscarinic cholinergic receptor. PLoS One. 2012 2012;7(12):e51515. Not in File. doi:10.1371/journal.pone.0051515
57. Cipolla MJ. The cerebral circulation. Integrated Systems Physiology: from molecule to function. Morgan & Claypool Life Sciences; 2010.