Cerebral blood flow remains reduced after tilt testing in myalgic encephalomyelitis/chronic fatigue syndrome patients
C Linda M C van Campen, Peter C Rowe, Frans C Visser, C Linda M C van Campen, Peter C Rowe, Frans C Visser
Abstract
Objective: Orthostatic symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may be caused by an abnormal reduction in cerebral blood flow. An abnormal cerebral blood flow reduction was shown in previous studies, without information on the recovery pace of cerebral blood flow. This study examined the prevalence and risk factors for delayed recovery of cerebral blood flow in ME/CFS patients.
Methods: 60 ME/CFS adults were studied: 30 patients had a normal heart rate and blood pressure response during the tilt test, 4 developed delayed orthostatic hypotension, and 26 developed postural orthostatic tachycardia syndrome (POTS) during the tilt. Cerebral blood flow measurements, using extracranial Doppler, were made in the supine position pre-tilt, at end-tilt, and in the supine position at 5 min post-tilt. Also, cardiac index measurements were performed, using suprasternal Doppler imaging, as well as end-tidal PCO2 measurements. The change in cerebral blood flow from supine to end-tilt was expressed as a percent reduction with mean and (SD). Disease severity was scored as mild (approximately 50% reduction in activity), moderate (mostly housebound), or severe (mostly bedbound).
Results: End-tilt cerebral blood flow reduction was -29 (6)%, improving to -16 (7)% at post-tilt. No differences in either end-tilt or post-tilt measurements were found when patients with a normal heart rate and blood pressure were compared to those with POTS, or between patients with normocapnia (end-tidal PCO2 ≥ 30 mmHg) versus hypocapnia (end-tidal PCO2 < 30 mmHg) at end-tilt. A significant difference was found in the degree of abnormal cerebral blood flow reduction in the supine post-test in mild, moderate, and severe ME/CFS: mild: cerebral blood flow: -7 (2)%, moderate: -16 (3)%, and severe :-25 (4)% (p all < 0.0001). Cardiac index declined significantly during the tilt test in all 3 severity groups, with no significant differences between the groups. In the supine post-test cardiac index returned to normal in all patients.
Conclusions: During tilt testing, extracranial Doppler measurements show that cerebral blood flow is reduced in ME/CFS patients and recovery to normal supine values is incomplete, despite cardiac index returning to pre-tilt values. The delayed recovery of cerebral blood flow was independent of the hemodynamic findings of the tilt test (normal heart rate and blood pressure response, POTS, or delayed orthostatic hypotension), or the presence/absence of hypocapnia, and was only related to clinical ME/CFS severity grading. We observed a significantly slower recovery in cerebral blood flow in the most severely ill ME/CFS patients.
Significance: The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.
Keywords: BMI, Body Mass Index; BSA, Body Surface Area; CBF, Cerebral blood flow; CI, Cardiac Index; Cardiac Index; Cerebral blood flow; DBP, Diastolic Blood pressure; Extracranial Doppler echography; HR, Heart rate; ICC, International Consensus Criteria; ME/CFS; ME/CFS, Myalgic encephalomyelitis/chronic fatigue syndrome; NormHRBP, normal heart rate and blood pressure response; Normal heart rate and blood pressure response; Orthostatic intolerance; PET, end-tidal pressure; POTS, Postural orthostatic tachycardia syndrome; Post exertional malaise; Postural Orthostatic Tachycardia Syndrome; Recovery; SBP, Systolic Blood pressure; Tilt table testing; VTI, Time velocity integral; dOH, delayed orthostatic hypotension.
© 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.
Figures
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- Reductions in Cerebral Blood Flow Can Be Provoked by Sitting in Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.Campen CLMV, Rowe PC, Visser FC. Campen CLMV, et al. Healthcare (Basel). 2020 Oct 11;8(4):394. doi: 10.3390/healthcare8040394. Healthcare (Basel). 2020. PMID: 33050553 Free PMC article.
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-
- Barde P.B., Deepak K.K. Effect of postural challenges on non-invasive cardiac output measurement with impedance cardiography in young healthy adults using new horizontal electrode placement method. IJBAR. 2012;3(11):806–809.
-
- Bou-Holaigah I., Rowe P.C., Kan J., Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274(12):961–967. - PubMed
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References
- Barde P.B., Deepak K.K. Effect of postural challenges on non-invasive cardiac output measurement with impedance cardiography in young healthy adults using new horizontal electrode placement method. IJBAR. 2012;3(11):806–809.
- Bola R.A., Kiyatkin E.A. Inflow of oxygen and glucose in brain tissue induced by intravenous norepinephrine: relationships with central metabolic and peripheral vascular responses. J Neurophysiol. 2018;119(2):499–508.
- Bou-Holaigah I., Rowe P.C., Kan J., Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA. 1995;274(12):961–967.
- Carruthers B.M., van de Sande M.I., De Meirleir K.L., Klimas N.G., Broderick G., Mitchell T. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011;270(4):327–338.
- Castle-Kirszbaum M., Parkin W.G., Goldschlager T., Lewis P.M. Cardiac output and cerebral blood flow: a systematic review of cardio-cerebral coupling. J Neurosurg Anesthesiol. 2021 doi: 10.1097/ANA.0000000000000768.
- Dave K.R., Christian S.L., Perez-Pinzon M.A., Drew K.L. Neuroprotection: lessons from hibernators. Comp Biochem Physiol B Biochem Mol Biol. 2012;162(1-3):1–9.
- De Lorenzo F., Hargreaves J., Kakkar V.V. Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res. 1997;7(4):185–190.
- Del Pozzi A.T., Pandey A., Medow M.S., Messer Z.R., Stewart J.M. Blunted cerebral blood flow velocity in response to a nitric oxide donor in postural tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2014;307(3):H397–H404.
- Duprez, D.A., De Buyzere, M.L., Drieghe, B., Vanhaverbeke, F., Taes ,Y., Michielsen, W., et al. Long- and short-term blood pressure and RR-interval variability and psychosomatic distress in chronic fatigue syndrome. Clin Sci (Lond) 1998;94(1):57-63.
- Fedorowski A., Burri P., Melander O. Orthostatic hypotension in genetically related hypertensive and normotensive individuals. J Hypertens. 2009;27(5):976–982.
- Freeman R., Wieling W., Axelrod F.B., Benditt D.G., Benarroch E., Biaggioni I. Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci. 2011;161(1-2):46–48.
- Fukuda K., Straus S.E., Hickie I., Sharpe M.C., Dobbins J.G., Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121(12):953–959.
- Hoiland R.L., Fisher J.A., Ainslie P.N. Regulation of the cerebral circulation by arterial carbon dioxide. Compr Physiol. 2019;9(3):1101–1154.
- Hollingsworth K.G., Jones D.E., Taylor R., Blamire A.M., Newton J.L. Impaired cardiovascular response to standing in chronic fatigue syndrome. Eur J Clin Invest. 2010;40(7):608–615.
- Immink R.V., Pott F.C., Secher N.H., van Lieshout J.J. Hyperventilation, cerebral perfusion, and syncope. J Appl Physiol. 2014;116(7):844–851.
- Institute Of Medicine (IOM). Beyond mayalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. Washington DC: The National Academies Press; 2015. p. 304.
- Jardine D.L., Melton I.C., Crozier I.G., Bennett S.I., Donald R.A., Ikram H. Neurohormonal response to head-up tilt and its role in vasovagal syncope. Am J Cardiol. 1997;79(9):1302–1306.
- Jones J.F., Nicholson A., Nisenbaum R., Papanicolaou D.A., Solomon L., Boneva R. Orthostatic instability in a population-based study of chronic fatigue syndrome. Am J Med. 2005;118(12):1415.e19–1415.e28.
- Kloner R.A. Stunned and hibernating myocardium: Where are we nearly 4 decades later? J Am Heart Assoc. 2020;9(3)
- Kusumoto F., Venet T., Schiller N.B., 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. 1995;8(5):647–653.
- Laffey J.G., Kavanagh B.P. Hypocapnia. N Engl J Med. 2002;347(1):43–53.
- LaManca J.J., Peckerman A., Walker J., Kesil W., Cook S., Taylor A. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999;19(2):111–120.
- Miyake T., Nakamura T., Kouda K., Uenishi H., Yamamoto Y., Kawasaki S. Carotid blood flow, cardiovascular and endocrine responses during head-up tilt in patients with acute cerebrovascular diseases. Springerplus. 2014;3(1):191.
- Moore R., Lum Y.W. Venous thoracic outlet syndrome. Vasc Med. 2015;20(2):182–189.
- Naschitz J.E., Rosner I., Rozenbaum M., Gaitini L., Bistritzki I., Zuckerman E. The capnography head-up tilt test for evaluation of chronic fatigue syndrome. Semin Arthritis Rheum. 2000;30(2):79–86.
- Naschitz J.E., Sabo E., Naschitz S., Rosner I., Rozenbaum M., Madelain F. Hemodynamics instability score in chronic fatigue syndrome and in non-chronic fatigue syndrome. Semin Arthritis Rheum. 2002;32(3):141–148.
- Newton D.J., Kennedy G., Chan K.K.F., Lang C.C., Belch J.J.F., Khan F. Large and small artery endothelial dysfunction in chronic fatigue syndrome. Int J Cardiol. 2012;154(3):335–336.
- Novak P. Orthostatic cerebral hypoperfusion syndrome. Front Aging Neurosci. 2016;8:22.
- Novak P., Gallyas F. Hypocapnic cerebral hypoperfusion: a biomarker of orthostatic intolerance. PLoS One. 2018;13(9):e0204419.
- Novak V., Spies J.M., Novak P., McPhee B.R., Rummans T.A., Low P.A. Hypocapnia and cerebral hypoperfusion in orthostatic intolerance. Stroke. 1998;29(9):1876–1881.
- Park J., Kim H.T., Park K.M., Ha S.Y., Kim S.E., Shin K.J. Orthostatic dizziness in Parkinson's disease is attributed to cerebral hypoperfusion: a transcranial doppler study. J Clin Ultrasound. 2017;45(6):337–342.
- Poole J., Herrell R., Ashton S., Goldberg J., Buchwald D. Results of isoproterenol tilt table testing in monozygotic twins discordant for chronic fatigue syndrome. Arch Intern Med. 2000;160(22):3461–3468.
- Razumovsky, A.Y., DeBusk, K., Calkins, H., Snader, S., Lucas, K.E., Vyas, P., et al. Cerebral and systemic hemodynamics changes during upright tilt in chronic fatigue syndrome. J Neuroimaging 2003;13(1):57-67.
- Sato, K., Sadamoto, T., Hirasawa, A., Oue, A., Subudhi, A.W., Miyazawa, T., et al. Differential blood flow responses to CO(2) in human internal and external carotid and vertebral arteries. J Physiol 2012;590(14):3277-3290.
- Scherbakov N., Szklarski M., Hartwig J., Sotzny F., Lorenz S., Meyer A. Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome. ESC Heart Fail. 2020;7(3):1064–1071.
- Schondorf R., Benoit J., Wein T., Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst. 1999;75(2-3):192–201.
- Sheldon R.S., Grubb B.P., 2nd, Olshansky B., Shen W.K., Calkins H., Brignole M. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12(6):e41–e63.
- Shen W.K., Sheldon R.S., Benditt D.G., Cohen M.I., Forman D.E., Goldberger Z.D. 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. 2017;70(5):620–663.
- Shin K.J., Kim S.E., Park K.M., Park J., Ha S.Y., Kim S.E. Cerebral hemodynamics in orthostatic intolerance with normal head-up tilt test. Acta Neurol Scand. 2015;134(2):108–115.
- Statistics L. Leard Statistics. Multiple regression using SPSS Statistics. Statistical tutorials and software guides. Retrieved from . 2015.
- Stewart J.M., Pianosi P., Shaban M.A., Terilli C., Svistunova M., Visintainer P. Hemodynamic characteristics of postural hyperventilation: POTS with hyperventilation versus panic versus voluntary hyperventilation. J Appl Physiol. 2018;125(5):1396–1403.
- Stewart J.M., Pianosi P., Shaban M.A., Terilli C., Svistunova M., Visintainer P. 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. 2018;7(13) doi: 10.1161/JAHA.118.008854.
- Streeten D.H.P., Thomas D., Bell D.S. 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):1–8.
- Timmers H.J.L.M., Wieling W., Soetekouw P.M.M.B., Lenders J.W.M., Bleijenberg G., van der Meer J.W.M. Hemodynamic and neurohumoral responses to head-up tilt in patients with chronic fatigue syndrome. Clin Auton Res. 2002;12(4):273–280.
- Toska K., Walløe L. Dynamic time course of hemodynamic responses after passive head-up tilt and tilt back to supine position. J Appl Physiol. 2002;92(4):1671–1676.
- van Campen C(L)MC, Rowe PC, Verheugt FWA, Visser FC. Numeric rating scales show prolonged post-exertional symptoms after orthostatic testing of adults with myalgic encephalomyelitis/chronic fatigue syndrome. Front Med 2021;7:10.
- van Campen C(L)MC, 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) 2020a;8(2):169.
- van Campen C(L)MC, Rowe PC, Visser FC. Reductions in cerebral blood flow can be provoked by sitting in severe myalgic encephalomyelitis/chronic fatigue syndrome patients. Healthcare 2020b;8:394.
- van Campen C.M.C., Verheugt F.W.A., Rowe P.C., Visser F.C. 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.
- van Campen C.M.C., Verheugt F.W.A., Rowe P.C., Visser F.C. Comparison of the finger plethysmography derived stroke volumes by Nexfin CO Trek and suprasternal aortic Doppler derived stroke volume measurements in adults with myalgic encephalomyelitis/chronic fatigue syndrome and in healthy controls. Techn. Health Care. 2021;29(4):629–642.
- van Campen C.M.C., Verheugt F.W.A., Visser F.C. 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.
- van Campen C(L)MC, Visser FC. The abnormal Cardiac Index and Stroke Volume Index changes during a normal Tilt Table Test in ME/CFS patients compared to healthy volunteers, are not related to deconditioning. J. Thromb. Circ. 2018;JTC -107:1-8.
- van Campen C(L)MC, Visser FC. Validation of Stroke volume measured with suprasternal aortic Doppler imaging: comparison to transthoracic Stroke Volume measurements. J Thromb Circ 2018;JTC -106:1-5.
- van Campen C.M.C., Visser F.C., de Cock C.C., Vos H.S., Kamp O., Visser C.A. Comparison of the haemodynamics of different pacing sites in patients undergoing resynchronisation treatment: need for individualisation of lead localisation. Heart. 2006;92(12):1795–1800.
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