Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review

Abstract:

INTRODUCTION: It is hypothesised that the autonomic nervous system responds differently to various stressors in patients with chronic fatigue syndrome (CFS) compared with healthy controls. The goal is to systematically review the scientific literature addressing the functioning of the autonomic nervous system in patients with CFS.

MATERIALS AND METHODS: All studies that were identified through electronic databases (PubMed and Web of Science) were screened for eligibility based on the selection criteria and assessed (two independent raters) for methodological quality using a methodological checklist for case-control studies.

RESULTS: Twenty-seven case-control studies were included. The methodological quality varied between 50% and 71·4%. Some studies showed different responses to head-up tilt and other autonomous testing.

CONCLUSION: Although comparison between the included case-control studies was difficult, we can conclude that there are differences in autonomous response between patients with CFS and healthy controls. The heart rate dynamic response during the head-up tilt test differs between patients with CFS and healthy controls, supporting the increased prevalence of postural orthostatic tachycardia syndrome. The autonomic response can be useful for the diagnosis of CFS.

© 2014 Stichting European Society for Clinical Investigation Journal Foundation.

 

Source: Van Cauwenbergh D, Nijs J, Kos D, Van Weijnen L, Struyf F, Meeus M. Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review. Eur J Clin Invest. 2014 May;44(5):516-26. doi: 10.1111/eci.12256. https://www.ncbi.nlm.nih.gov/pubmed/24601948

 

Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study

Abstract:

Chronic Fatigue Syndrome (CFS) is characterized by severe impairment and multiple symptoms. Autonomic dysregulation has been demonstrated in several studies. We aimed at exploring the relationship between indices of autonomic cardiovascular control, the case definition from Centers for Disease Control and Prevention (CDC criteria), important clinical symptoms, and disability in adolescent chronic fatigue syndrome.

38 CFS patients aged 12-18 years were recruited according to a wide case definition (ie. not requiring accompanying symptoms) and subjected to head-up tilt test (HUT) and a questionnaire. The relationships between variables were explored with multiple linear regression analyses. In the final models, disability was positively associated with symptoms of cognitive impairments (p<0.001), hypersensitivity (p<0.001), fatigue (p=0.003) and age (p=0.007).

Symptoms of cognitive impairments were associated with age (p=0.002), heart rate (HR) at baseline (p=0.01), and HR response during HUT (p=0.02). Hypersensitivity was associated with HR response during HUT (p=0.001), high-frequency variability of heart rate (HF-RRI) at baseline (p=0.05), and adherence to the CDC criteria (p=0.005). Fatigue was associated with gender (p=0.007) and adherence to the CDC criteria (p=0.04).

In conclusion, a) The disability of CFS patients is not only related to fatigue but to other symptoms as well; b) Altered cardiovascular autonomic control is associated with certain symptoms; c) The CDC criteria are poorly associated with disability, symptoms, and indices of altered autonomic nervous activity.

 

Source: Wyller VB, Helland IB. Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study. Biopsychosoc Med. 2013 Feb 7;7(1):5. doi: 10.1186/1751-0759-7-5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570350/ (Full article)

 

Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial

Abstract:

BACKGROUND: This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.

FINDINGS: Five adolescent CFS patients (14-19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.

CONCLUSION: Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

 

Source: Fagermoen E, Sulheim D, Winger A, Andersen AM, Vethe NT, Saul JP, Thaulow E, Wyller VB. Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Res Notes. 2012 Aug 7;5:418. doi: 10.1186/1756-0500-5-418. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461473/ (Full article)

 

Impaired cardiovascular response to standing in chronic fatigue syndrome

Abstract:

BACKGROUND: Impaired skeletal muscle metabolism is recognized in chronic fatigue syndrome (CFS). This study examined the relationship between skeletal and cardiac muscle function and symptoms on standing in CFS using magnetic resonance spectroscopy (MRS) and impedance cardiography.

MATERIALS AND METHODS: Phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio by cardiac MRS, PCr/ADP and proton efflux by muscle MRS were performed in 12 CFS (Fukuda) and 8 controls. Head up tilt (HUT) and cardiac contractility (left ventricular work index, LVWI) (n = 64 CFS and matched controls) were found. Fatigue impact was accessed by Fatigue Impact Scale and orthostatic symptoms by Orthostatic Grading Scale (OGS).

RESULTS: Cardiac PCr/ATP correlated with measures of muscle bioenergetic function (half-time PCr recovery [kappa = -0.71, P = 0.005] and half-time ADP recovery [kappa = -0.60, P = 0.02]) suggesting that the muscle and cardiac bioenergetic function correlate in CFS. Four of 12 (33.3%) CFS patients had PCr/ATP values consistent with significant cardiac impairment. Those with impaired cardiac energy metabolism had significantly reduced maximal and initial proton efflux rates (P < 0.05). Cardiac PCr/ATP ratio correlated with myocardial contractility (LVWI) in response to standing (P = 0.03). On HUT, LVWI on standing was significantly higher in CFS (P = 0.05) with symptoms on standing (OGS) occurring in 61/64 (95%) (vs. 25/64 [39%] controls; P < 0.0001). OGS scores were significantly higher in those with abnormal LVWI responses to standing (P = 0.04), with the LVWI on standing correlating with OGS scores (r(2) = 0.1; P = 0.03). HUT was positive in 19 (32%).

CONCLUSIONS: Skeletal muscle and cardiac bioenergetic abnormalities associate in CFS. Cardiac bioenergetic metabolism associates with increase in cardiac contractility on standing. Haemodynamic assessment in CFS is well tolerated and safe with a high diagnostic yield comparable with unexplained syncope.

 

Source: Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL. Impaired cardiovascular response to standing in chronic fatigue syndrome. Eur J Clin Invest. 2010 Jul;40(7):608-15. doi: 10.1111/j.1365-2362.2010.02310.x. Epub 2010 May 23. https://www.ncbi.nlm.nih.gov/pubmed/20497461

 

A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome

Abstract:

This study aimed to define cardiovascular and heart rate variability (HRV) changes following head-up tilt (HUT) in children/adolescents with chronic fatigue syndrome (CFS) in comparison to age- and gender-matched controls.

Twenty-six children/adolescents with CFS (11-19 y) and controls underwent 70-degree HUT for a maximum of 30 min, but returned to horizontal earlier at the participant’s request with symptoms of orthostatic intolerance (OI) that included lightheadedness.

Using electrocardiography and beat-beat finger blood pressure, a positive tilt was defined as OI with 1) neurally mediated hypotension (NMH); bradycardia (HR <75% of baseline), and hypotension [systolic pressure (SysP) drops >25 mm Hg)] or 2) postural orthostatic tachycardia syndrome (POTS); HR increase >30 bpm, or HR >120 bpm (with/without hypotension).

Thirteen CFS and five controls exhibited OI generating a sensitivity and specificity for HUT of 50.0% and 80.8%, respectively. POTS without hypotension occurred in seven CFS subjects but no controls. POTS with hypotension and NMH occurred in both. Predominant sympathetic components to HRV on HUT were measured in CFS tilt-positive subjects.

In conclusion, CFS subjects were more susceptible to OI than controls, the cardiovascular response predominantly manifest as POTS without hypotension, a response unique to CFS suggesting further investigation is warranted with respect to the pathophysiologic mechanisms involved.

 

Source: Galland BC, Jackson PM, Sayers RM, Taylor BJ. A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome. Pediatr Res. 2008 Feb;63(2):196-202. https://www.ncbi.nlm.nih.gov/pubmed/18091356

 

Sympathetic predominance of cardiovascular regulation during mild orthostatic stress in adolescents with chronic fatigue

Abstract:

Haemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular control. This study was designed to explore the pathophysiology in adolescent CFS-patients by analysing RR-interval (RRI) variability and diastolic blood pressure (DBP) variability during mild orthostatic stress, using an algorithm which accounts for non-stationary biosignals.

A total of 27 adolescents with CFS and 33 healthy control subjects having equal age- and sex distribution underwent 15 min of 20 degrees head-up tilt (HUT). The spectral power densities of RRI and DBP were computed in the low-frequency (LF) band (0.04-0.15 Hz) and the high-frequency (HF) band (0.15-0.4 Hz) using an adaptive autoregressive algorithm to obtain a time-varying spectrum. RMSSD, a time domain index of RRI variability, was also computed. At rest, all indices of variability were similar in the two groups. During tilt, CFS patients had a larger increase in the LF/HF ratio (P<or=0.001) and normalized LF power of RRI (P<or=0.01), and a larger decrease in normalized HF power (P<or=0.01) of RRI than controls. CFS patients also had trends towards a larger decrease in absolute HF power of RRI and a larger increase in normalized LF power of DBP.

These findings suggest that adolescents with CFS have sympathetic predominance of cardiovascular regulation during very mild orthostatic stress. Possible underlying mechanisms are moderate hypovolemia, abnormalities of reflex control or physical de-conditioning.

 

Source: Wyller VB, Saul JP, Amlie JP, Thaulow E. Sympathetic predominance of cardiovascular regulation during mild orthostatic stress in adolescents with chronic fatigue. Clin Physiol Funct Imaging. 2007 Jul;27(4):231-8. https://www.ncbi.nlm.nih.gov/pubmed/17564672

 

Treatment of chronic fatigue and orthostatic intolerance with propranolol

Abstract:

We describe the effect of propranolol in an adolescent with chronic fatigue syndrome and orthostatic intolerance. Our observations suggest that the head-up tilt-test and beta-blocker treatment might be considered in patients with chronic fatigue syndrome and that enhanced sympathetic nervous activity might be part of the underlying pathophysiology.

 

Source: Wyller VB, Thaulow E, Amlie JP. Treatment of chronic fatigue and orthostatic intolerance with propranolol. J Pediatr. 2007 Jun;150(6):654-5. https://www.ncbi.nlm.nih.gov/pubmed/17517256

 

Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls

Abstract:

Hemodynamic dysfunction is documented in chronic fatigue syndrome (CFS). This study was conducted to investigate cardiovascular responses to orthostatic stress in adolescents with CFS, using a novel procedure for tilt-table testing.

A total of 27 adolescents with CFS and 33 healthy control subjects with equal age and gender distribution underwent 15 minutes of 20 degrees head-up tilt testing. Heart rate, systolic blood pressure (BP), mean BP, diastolic BP, stroke index, total peripheral resistance index, end-diastolic volume index, and acceleration index were continuously and noninvasively recorded.

At rest, patients with CFS had higher total peripheral resistance index values (p<0.01) and lower stroke index and end-diastolic volume index values (p<0.05) than controls. During 20 degrees head-up tilt testing, patients with CFS had greater increases in heart rate, diastolic BP (p<0.001), mean BP (p<0.01), and total peripheral resistance index (p<0.05) than controls and greater decreases in stroke index (p<0.05). Syncope or near syncope was not observed.

In conclusion, this study found that adolescents with CFS have significant abnormalities of cardiovascular regulation in response to mild orthostatic stress, differentiating them from healthy controls.

 

Source: Wyller VB, Due R, Saul JP, Amlie JP, Thaulow E. Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls. Am J Cardiol. 2007 Apr 1;99(7):997-1001. Epub 2007 Feb 16. https://www.ncbi.nlm.nih.gov/pubmed/17398200

 

Continuous measurement of BRSI in chronic fatigue syndrome

Abstract:

This paper discusses the development of a system to measure continuous cardiac baroreceptor measurement during a 45-minute 70-degree head-up tilt (HUT) of five groups of subjects suffering the following: chronic fatigue syndrome (CFS), CFS with fibromyalgia (CFS-FM), CFS with postural orthostatic tachycardia syndrome (CFS-POTS), controls with POTS (CON-POTS), and controls (CON). The duration of the test was 56-minutes, which included a five-minute supine baseline, a 45-minute HUT and a six-minute recovery period. The system was developed in LabView, and can provide a comparative time analyses of weighted BRSI averages. Baroreflex effectiveness index (BEI) was also investigated over the course of lags 0, 1 and 2 as well as an assessment of overall BEI performance between groups.

 

Source: Donnelly DL, Rockland RH, Reisman SS, Quigley KS. Continuous measurement of BRSI in chronic fatigue syndrome. Conf Proc IEEE Eng Med Biol Soc. 2004;2:906-8. https://www.ncbi.nlm.nih.gov/pubmed/17271825

 

Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome

Abstract:

PURPOSE: Because autonomic nervous functioning is frequently abnormal in chronic fatigue syndrome (CFS), we examined whether the corrected QT interval (QTc) in CFS differs from QTc in other populations.

METHODS: The QTc was calculated at the end of 10 minutes of recumbence and the end of 10 minutes of head-up tilt. In a pilot study, groups of 15 subjects, CFS, and controls, matched for age and sex, were investigated. In a second phase of the study, the QTc was measured in larger groups of CFS (n = 30) and control patients (n = 96) not matched for demographic features.

RESULTS: In the pilot study, the average supine QTc in CFS was 0.371 +/- 0.02 seconds and QTc on tilt, 0.385 +/- 0.02 seconds, significantly shorter than in controls (P = .0002 and .0003, respectively). Results of phase II confirmed this data.

CONCLUSIONS: Relative short QTc intervals are features of the CFS-related dysautonomia. The significance of this finding is discussed.

 

Source: Naschitz J, Fields M, Isseroff H, Sharif D, Sabo E, Rosner I. Shortened QT interval: a distinctive feature of the dysautonomia of chronic fatigue syndrome. J Electrocardiol. 2006 Oct;39(4):389-94. Epub 2006 Feb 28. https://www.ncbi.nlm.nih.gov/pubmed/16895768