DOI: 10.1111/eci.12256
REVIEW Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review Deborah Van Cauwenbergh*,†, Jo Nijs*,‡, Daphne Kos§, Laura Van Weijnen*, Filip Struyf*,† and Mira Meeus†,¶ *
Pain in Motion Research Group, Departments of Human Physiology and Rehabilitation Sciences, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussel, Belgium, †Pain in Motion Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium, ‡Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium, §Occupational therapy, Artesis Plantijn Antwerp & KU Leuven, University of Leuven, Leuven, Belgium, ¶Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Brussels, Belgium
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 714%. 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. Keywords Autonomic nervous system, dysautonomia, heart rate variability, marker, parasympathetic, stress, sympathetic. Eur J Clin Invest 2014; 44 (5): 516–526
Introduction Chronic fatigue syndrome (CFS) is a condition characterised by extreme fatigue not resolving with (bed) rest [1,2]. According to the Centre for Disease Control and Prevention (CDC), CFS is defined as clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset, should result in a substantial reduction in previous levels of occupational, educational, social or personal activities [3]. Furthermore, at least four of the following symptoms must have persisted or recurred during 6 or more consecutive months and must not have predated the fatigue: impairment in short-term memory or concentration, sore throat, tender cervical or
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axillary lymph nodes, muscle or multi-joint pain, headache, unrefreshing sleep and postexertional malaise that remains present for a period of more than 24 h [3]. Recently, a new set of diagnostic criteria have been proposed, emphasising the importance of postexertional malaise (i.e. the severe exacerbations following vigorous exercise) for the diagnosis of CFS [4]. The aetiology of the illness remains unclear, although various hypotheses exist encompassing immunological, virological, psychological and neuroendocrinological mechanisms [5]. There is a lack of conclusive evidence for any one of these hypotheses [5]. A prominent line of research had been dedicated to the role of stress as an aetiological and perpetuating factor in CFS [6]. Continuous stress might result in a
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deregulation of stress-responsive systems, such as the hypothalamic–pituitary–adrenal axis (HPA), the autonomic nervous system (ANS) and the immune system [7–9]. It has been suggested that this deregulation contributes to core symptoms of CFS, such as pain and fatigue [10–12]. Additionally, Dawson and his colleague [13] indicate that there is some evidence suggesting the involvement of the ANS in CFS as the ANS may play a role in many systemic diseases [14]. Malfunctioning of the autonomic nervous system would further substantiate the notion of CFS being a central nervous system disorder. The ANS is an efferent system transmitting impulses from the central nervous system to peripheral organs, as for example the heart, where it regulates the heart rate and contraction force. The ANS also controls contraction, constriction and dilatation of blood vessels, contraction and relaxation of smooth muscle in various organs and glandular secretions, but does not influence skeletal muscle [15,16]. It is a homoeostasis regulator [14]. According to Grubb et al. [16], the ANS is subdivided in three branches, namely (i) the sympathetic, (ii) parasympathetic and (iii) enteric nerve system. The ANS takes care, with the parasympathetic branch, of the routine maintenance/stress, for example during orthostatic stress. Persons with autonomic dysregulation can experience symptoms such as severe light-headiness or syncope [17]. Commonly seen symptoms in CFS possibly related to autonomic dysfunction are as follows: dizziness (common), palpitations, diarrhoea, urinary frequency and nocturia [18]. Also fever, sore throat, headache, muscle weakness, myalgia, postexertional malaise, sleep and cognitive disturbances and fatigue might be attributed to dysfunctioning of the ANS [19]. Additionally, heart rate (HR) and blood pressure variations are often seen in CFS, which also suggest a role for the ANS in the pathophysiology of CFS. It has been shown that between 13% and 29% of patients with CFS have postural orthostatic tachycardia syndrome [20,21], a form of dysautonomia implying that when patients change their body position from supine to upright, their heart rate will increase abnormally (tachycardia), which could be due to abnormalities in the baroreceptor reflex [22]. Postural orthostatic tachycardia syndrome is associated with several symptoms often seen in patients with CFS, such as fatigue, light-headedness, dizziness, neurocognitive deficits and exercise intolerance [22]. The goal of this study was to systematically review the scientific literature addressing the reactivity of the autonomic nervous system in patients with CFS compared with healthy controls. It is hypothesised that the autonomic nervous system responds differently to various stressors in patients with CFS compared with healthy controls.
Material and methods Literature search The following databases were screened up to January 2014: PubMed (National Library of Medicine) and Web of Science. Keywords were used to obtain articles which described the ANS and the differences between patients with CFS and healthy persons by means of autonomic testing. A combination of keywords and MeSH terms addressing CFS and autonomic testing was entered with Boolean operators at the search engines. The complete search strategy was the following: (‘myalgic encephalomyelitis’ OR ‘fatigue syndrome, Chronic’) AND (‘Sympathetic nervous system’ OR ‘Parasympathetic nervous system ’ OR ‘Heart Rate’ OR ‘Heart Rate’ AND ‘variability’ OR ‘Skin conductance’ OR ‘Regional Blood Flow’ OR ‘Skin Temperature’ OR ‘Blood Pressure’ OR ‘Head-up tilt’ OR ‘Tilt table’ OR ‘Autonomic Pathways’ OR ‘autonomic dysfunction’ OR ‘Autonomic nerve system’ OR ‘Autonomic Nervous System Diseases’ OR ‘vascular system abnormalities’ OR ‘pathogenic mechanism’ OR ‘orthostatic stress’ OR ‘orthostatic instability’ OR ‘Orthostatic dysregulation’ OR ‘posture change’ OR ‘orthostatic postural tachycardia’ OR ‘Dysautonomia’ OR ‘cardiovascular responses’ OR ‘hemodynamic instability score’ OR ‘Cardiovascular autonomic control’ OR ‘Baroreflex’ OR ‘Stress response’ OR ‘Orthostatic challenge’) NOT (‘review’) NOT (‘children’ OR ‘adolescents’) NOT (‘sleep’).
Inclusion and exclusion criteria Eligibility assessment of the search results was performed according to the inclusion and exclusion criteria presented in Table 1. After entering the keywords, the titles and abstracts were read and screened for these selection criteria. If the articles met the selection criteria during the first screening phase, full texts were retrieved. If full texts also fulfilled the selection criteria in the 2nd phase, the reference was added to the bibliography and screened on quality.
Data extraction Data regarding the comparison of autonomous response between patients with CFS and healthy persons were extracted from the included papers by L.V.W. There were no restrictions for the outcomes (e.g. blood pressure and heart rate). The results section organised according to the different outcomes.
Quality assessment Each study was assessed for methodological quality. As only diagnostic case–control studies were included, the National Institute for Health and Clinical Excellence’s ‘Methodology checklist for case-control studies’ was used for all studies (NIS: http://www.nice.org.uk/aboutnice/). Methodological quality
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Table 1 Inclusion and exclusion criteria
Table 2 Methodological quality criteria
Inclusion
Exclusion
0
Not applicable
Population: adults with a diagnosis of CFS based on any official criteria (i.e. CDC criteria, Oxford criteria and Canadian criteria)
Population: patients younger than 18 years old or having dementia, psychiatric disorder or fibromyalgia without CFS comorbidity
1
Not reported (mentioned with insufficient detail to allow assessment)
2
Not addressed (not mentioned/this aspect was ignored)
3
Poorly addressed (when it was not completely satisfying)
4
Adequately addressed (satisfying)
Test: patients should undergo a headup tilt or another autonomous testing
5
Well covered (very good explained)
Outcomes: ANS parameters in patients with CFS
Four of the 31 articles scored less than 50% and were excluded. A summary of the applied searching strategy can be retrieved in Fig. 1. In the end, the literature review produced a total of 27 studies which were qualified for inclusion.
Controls: healthy controls Language articles: Dutch or English
Study design: meeting report, editorial, letter, review, pilot studies or prognostic studies or randomised controlled trials (intervention studies)
was assessed by two independent raters/reviewers (L.V.W., Master student Physiotherapy and Rehabilitation Sciences; D.V.C., PhD candidate). In this review, only studies of good or excellent quality were included (i.e. only studies scoring at least 50% on the quality assessment). In this review, we considered a quality score between 50 and 5999% of moderate quality, articles between 60 and 6999% of good quality and studies above the 70% of very good quality. The questions of the ‘Methodology checklist for case-control studies’ are aimed at establishing the internal validity of the study under review. The following items are assessed in the checklist: the research question, the selection of participants, the assessment (measures were taken to prevent knowledge of primary exposure influencing case ascertainment, and exposure status is measured in a standard, valid and reliable way), the identification of confounding factors (the main potential confounders are identified and taken into account in the design and analysis) and the statistical analysis. A five-point scale was used, resulting in a final percentage (the points were added up and converted to 100%). In Table 2, the different points are explained.
Results The literature search using the two databases resulted in 31 hits. A methodological assessment of 31 articles gave us the possibility to include only articles of good or excellent quality.
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The methodological quality of the selected articles The included articles were assessed on their methodological quality. A comprehensive view on the methodological quality of each case–control studies is shown in Table 3. The excluded articles are presented in bold. These articles had a score below 50%. The most common shortcomings in the case–control studies were a lack of information addressing the eligible population group, inadequate or missing information about the blinding of the patients; assessors and impact assessors; statistical analyses and confounders. Four studies were excluded because they had a score below 50%. Ten studies had a moderate quality (score between 50 and 5999%), 14 studies had a good quality (score between 60 and 6999%), and three study had a very good quality (score ≥ 70%).
Analysis of literature: The autonomic nervous system in patients with CFS The result of the 27 included studies, extendedly described below, is summarised in a table that can be retrieved in Appendix S1. Head-up tilt test – Capnography head-up tilt test. Eleven studies [18,23,27,29–31,33,39,43,44] described the responses to head-up tilt test. La Manca et al. [30] showed a higher heart rate and a lower pulsative systolic area for the patients with CFS at baseline, and 11 of the 39 patients with CFS had an abnormal tilt response. Timmers et al. [43] observed a higher heart rate in the CFS group, and 10 of the 36 patients with CFS showed an abnormal tilt response. When a subdivision of these patients was made, in patients with or without an abnormal response, La Manca et al. [30] observed a lower pulse pressure and lower pulsative systolic area in the CFS group having an abnormal
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371 of records identified through database searching
Included
Eligibility
Screening
Identification
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Figure 1
312 of records after duplicates removed
312 of records screened
284 of records excluded
31 of full-text articles assessed for eligibility
4 of full-text articles excluded
27 studies included in qualitative synthesis
Flowchart of the search strategy.
head-up tilt response. Timmers et al. [43] observed a higher amount of patients with CFS with orthostatic intolerance, however, not significant at the .05 level. In the negative tilt groups, La Manca et al. [30] found no differences in blood pressure, but a lower pulsative systolic area and stoke volumes, and a significantly higher heart rate for CFS. The results of Timmers et al. [43] showed (i) a smaller increase in systolic blood pressure, (ii) a similar increase in diastolic blood pressure and arterial blood pressure and (iii) a relatively higher decrease in stroke volume and cardiac output for the CFS group. One-way comparison in the supine baseline phase in the study of Yamamoto et al. [44] showed only a lower mean respiration rate interval for patients with CFS. During the upright tilt the respiration rate interval, standard deviation of the respiration rate interval, amplitude of low frequency (AHF = 004– 015 Hz) and a periodic fractal spectral components were lower. When comparing the baseline data versus the data posthead-up tilt between the two groups, only the aperiodic fractal spectral components were significantly lower for the patients with CFS. In the studies of Naschitz et al. [31,33], no differences were found in the supine position between patients with CFS and controls. During tilt, Naschitz et al. [31] showed, with the capnography head-up tilt test, differences between the both groups for diastolic blood pressure, heart rate, systolic blood pressure, respiration rate/min, end tidal CO2 and reached end points.
Controls did not reach any of the predefined end points. At the end of the head-up tilt, systolic blood pressure and diastolic blood pressure were significant lower, while the heart rate was significantly higher in patients with CFS compared with healthy controls [33]. De Becker et al. [18] found no differences during the supine position; only in the tilt position, there were higher heart rates, changes in heart rate and low-frequency power. The study of Duprez et al. [26] found significant lower BP variability (total, low-frequency and high-frequency variances) in CFS in supine position. In standing position, the differences disappeared. Analysis of RR interval variability could not detect major alterations in autonomic function in CFS. Schondorf et al. [39] identified a higher resting heart rate, but no other differences. Sixty per cent of the patients with CFS did not have orthostatic intolerance and the control group showed a lower diastolic blood pressure in the female participants. Jones et al. [29] saw no differences in orthostatic instability between patients with CFS and controls. Allen et al. [23] found a significant lower pulse amplitude in the CFS group at the ear site in the supine position. At tilted, the pattern was similar to baseline with significant differences found (P = 0014) between subject groups at the ear site for the pulse amplitude measure only. A significant reduction (P = 0002) in the overall pulse timing response to controlled standing was found for the CFS group.
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Table 3 Risk of bias assessment scores for the selected studies Autor/Year
An appropriate and clearly question
Selection of patients
Assessment
Confounding factors
Statistic analysis
Score (%)
Level of evidence
1
Allen J. et al. (2012) [23]
60
55
70
60
80
65
B
2
Boneva R.S. et al. (2007) [24]
70
40
60
0
80
50
B
3
Bouholaigah et al. (1995) [17]
80 80
67 67
50 50
60 60
100 100
71 71
B
4
Burton A.R. et al. (2010) [25]
80
80
70
0
80
62
B
5
De Becker P. et al. (1998) [18]
100 80
45 50
30 20
80 80
60 60
63 58
B
6
Duprez D.A. et al. (1998) [26]
60
50
60
0
80
50
B
7
Freeman R et al. (1997)*
80 80
40 40
20 20
60 60
40 40
48 48
B
8
Frith J. et al. (2012)[27]
80
65
70
60
80
71
B
9
Hoad A et al. (2008) [21]
60 60
75 80
60 60
80 80
40 40
63 64
B
10
Hollingsworth KG et al. (2010) [28]
60 60
45 40
50 50
80 80
60 60
59 58
B
11
Jones JF et al.(2005) [29]
80 80
65 60
30 30
80 80
60 60
63 62
B
12
LaManca JJ et al.(1999) [30]
100 100
25 30
30 35
40 40
60 60
51 53
B
13
Naschitz J.E. et al. (2000) [31]
80 80
50 40
80 80
40 40
60 60
62 60
B
14
Naschitz JE et al. (2001) [32]
80 80
80 80
70 80
0 25
60 70
58 67
B
15
Naschitz JE; et al. (2001) [33]
80 80
55 60
40 50
40 40
60 60
55 58
B
16
Naschitz J.E. et al. (2002) [34]
80 90
65 60
50 60
40 50
40 50
55 62
B
17
Naschitz JE, et al. (2002)[35]
80 80
45 50
20 30
60 60
60 60
53 56
B
18
Naschitz J.E. et al. (2003) [36]
80 80
70 60
60 60
80 60
40 40
66 60
B
19
Naschitz J.E. et al. (2004) [37]
60 80
65 70
50 60
60 65
60 60
59 67
B
20
Naschitz JE et al. (2006)*
80 80
45 50
70 70
40 40
0 0
47 48
C
21
Pazderka-Robinson H. et al. (2004) [19]
80 80
75 80
0 30
60 65
100 80
63 67
B
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Table 3 Continued Autor/Year
An appropriate and clearly question
Selection of patients
Assessment
22
Peckerman et al. (2003)* [22]
80 80
55 60
40 50
23
Razumovsky A.Y. et al. (2003) [38]
80 80
45 50
24
Schondorf R et al. (1999) [39]
80 80
25
Sisto SA et al. (1995) [40]
26
Confounding factors
Statistic analysis
Score (%)
Level of evidence
0 0
60 50
47 48
C
50 50
60 65
80 80
63 65
B
45 40
40 35
60 60
60 60
57 55
B
100 100
35 40
20 30
60 60
60 60
55 58
B
Soetekouw PM et al. (1999) [41]
80 80
80 80
60 60
40 40
60 60
64 64
B
27
Strahler J et al. (2013) [42]
80
80
70
60
60
70
B
28
Timmers HJ et al.(2002) [43]
80 80
80 75
50 50
80 75
60 60
70 68
B
29
Winkler A.S. et al. (2004)*
80 70
40 40
40 30
40 40
40 45
48 45
C
30
Yamamoto Y et al. (2003)[44]
80 70
65 60
30 30
100 100
60 70
67 66
B
31
Yataco A et al. (1997) [45]
80 80
75 60
20 20
80 60
60 60
63 56
B
*Excluded articles.
Frith et al. [27] showed a significant higher resting heart rate (P = 0006) and diastolic blood pressure (0003) in the supine position in the CFS group. There were no differences in the systolic blood pressure. In the tilted position, they saw a significant lower systolic blood pressure in the CFS group (P = 00001). In supine condition, good evidence is available for no differences in heart rate between patients with CFS and controls. Good evidence indicates a higher heart rate in the tilt position in patients with CFS. Due to the lack of consistency across studies, it is hard to draw firm conclusions regarding the other parameters. Isoproterenol infusion – more stage head-up tilt test. Yataco et al. [45], Bou-holaigah et al. [17] and Razumovsky et al. [38] used all isoproterenol infusion for their study of ANS in CFS. An abnormal response was retrieved in most CFS cases. At the end of the upright tilt, Yataco et al. [45] found differences in heart rate, heart rate variability and in patients with positive tilt between the supine position and the first 5 min and 10–15 min. Only a higher heart rate and lower blood pressure were found between the groups at the end of the tilt. They concluded, using heart rate variability as assessment, that the autonomic function
does not differ between both groups. Bou-holaigah et al. [17] found only at the end of the tilt a lower heart rate, systolic blood pressure and diastolic blood pressure. They concluded that CFS is closely associated with neural mediated hypotension and that this could be an important implication for the management of CFS. Razumovsky et al. [38] found a higher baseline heart rate and higher heart and symptoms of orthostatic intolerance during tilt in patients with CFS. Controls had a shorter time to orthostatic symptoms and a greater increase in end tidal CO2. In comparison with the baseline, a higher increase in pulsatility index and cardiovascular resistance and a decrease in cerebral blood flow velocity were seen. There were no differences in end tidal CO2 (first 10 min), blood pressure, Sa02, CBFV, respiration rate, cardiovascular resistance and heart rate at the end of tilt and respiration rate during the entire study. The three studies all showed a different heart rate at the end of the tilt, using an isoproterenol infusion. Good evidence supports decreased blood pressure at the end of the tilt. Autonomic tests. In addition to the head-up tilt test, three studies [18,29,39] used other autonomic tests, as for example rhythmic deep breathing and the Valsalva manoeuver. The
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results of the three studies showed no differences in rhythmic deep breathing between patients with CFS and healthy controls. Sisto et al. [40] found a higher vagal power with a lower breathing rate in both sitting and standing position, which followed a same decrease for patients with CFS as controls. This decrease was lower in patients with CFS, with the exception at a rate of 18 breaths per minute in the standing position. Jones et al. [29] showed a higher diastolic blood pressure in the supine position in the CFS group, a lower diastolic blood pressure in neural mediated hypotension patients after immediate standing, in comparison with postural orthostatic tachycardia and subjects with normal tilt tests. In addition, a greater heart rate variability was found in individuals susceptible to neural mediated hypotension. In the study of Hoad et al. [21], patients with CFS had a higher maximal heart rate on standing and a higher amount of postural orthostatic tachycardia syndrome. Hollingsworth et al. [28] found a higher rate of loss of consciousness, positive tilt, postural orthostatic tachycardia syndrome and Orthostatic Grading Scale (OGS) scores in the CFS group. The OGS score was higher in the subdivision group ‘abnormal left ventricular work index’, who were more present in the CFS group, than the ‘normal left ventricular work index’. The paper of Soetekouw et al. [41] was the only study who saw a higher diastolic and systolic blood pressure in the CFS group in the implementation of the Valsalva manoeuver. The handgrip and cold pressure test gave no significant differences for systolic blood pressure and diastolic blood pressure, but a trend to significance for an increased maximal heart rate during the cold pressure procedure. The mental arrhythmic test gave a lower increase in heart rate (i.e. difference between the maximal and minimal heart rate) in the CFS group. The results of the studies showed no differences in rhythmic deep breathing between patients with CFS and healthy controls. There is some moderate evidence that patients with CFS had a higher amount of postural orthostatic tachycardia syndrome on standing. Electrodermal dissociation. The topic electrodermal dissociation was described by Pazderka-Robinson et al. [19] and accomplished in patients with CFS who complied with the 1994 CDC criteria. They measured three autonomic functions, namely (i) phase skin conductance response, defined by an increase of ≥ 005 microsiemens (lS) in 1 or 4 s poststimulus (=‘intensity of reaction’ and ‘habituation, initial response’), (ii) the tonic skin conductance (Sc) level data, composed by a mean prestimulus Sc for 5 s each time before a trial.(=‘physiological level at rest’) and (ii) skin temperature levels, measured by a commercial temperature transducers on the volar surface of the
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digital phalange of the 5th finger (left and right), each time before a trial. CFS showed the lowest response amplitude and habituation rate. They made a discriminant analysis of the three variables to see which one was the most important. Between the three groups, the tonic level came out as the most important variable. For the peripheral skin temperature, they reported a higher peripheral skin temperature for the patients with CFS compared with the other groups. A submaximal cycle ergometry (ERGO) and insulin tolerance test (ITT). The study of Strahler et al. [42] implemented a submaximal cycle ergometer test and a pharmacological test (insulin tolerance test) in 21 patients with CFS and 20 age-, sexand body mass index-matched controls. Plasma norepinephrine and epinephrine were collected once before and twice after the tests. Significant lower baseline levels (P = 0012) and attenuated responses of epinephrine to exercise (P = 0040) were found in patients with CFS compared with controls, while the groups did not differ in their responses to the insulin tolerance test. Monitoring during sleep. Two studies measured the autonomic function in CFS during sleep. The study by Boneva et al. [24] found a significant increased HR (P < 00004), a shorter mean RRI (P < 00004) and a reduced HRV in CFS during sleep with higher norepinephrine (P = 005). Burton et al. [25] found a significant lower HRV (P < 0006) in patients with CFS during sleep. There is moderate evidence that patients with CFS have a lower HRV during sleep. Autonomic reactivity for the (differential) diagnosis of CFS and likelihood ratio. Naschitz et al. [32] aimed at examining the cardiovascular response to postural challenge and determined whether the degree of instability of this response can aid in the diagnosis of CFS. In one of the later studies [35], they aimed at examining the differences in hemodynamic instability score (=HIS) between patients with CFS, healthy controls and non-CFS persons. The study of 2001 [32] found a different HIS value in patients with CFS in comparison with the healthy controls, patients with fibromyalgia and hypotension. They concluded that the HIS value adds objective criteria to confirm the diagnosis of CFS. The 2002 study [35] showed no differences in the supine position, but showed a lower diastolic blood pressure in the CFS group in the tilt position. The patients with CFS showed higher rates of following end points: (i) pre- or postsyncopes, (ii) more classic end points, (iii) HIS values with a score > 098 and (4) a higher rate of patients with CFS with the combination of the last two items. They suggested again that the HIS value
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can be a reinforcement in the clinical diagnosis of CFS, by providing objective criteria. These findings were further confirmed by the same researchers [34,36,37]. They investigated whether the ‘Fractal & Recurrence Analysis –based Scores’ can be used to recognise phenotypes of diseases, in this case cardiovascular reactivity. Because Fractal and Recurrence Analysis-based scores provide objective criteria, which could become valuable in the assessment of CFS, a Fractal and Recurrence Analysis-based score of > +022 has been suggested as a cut-off value for the diagnosis of CFS [34]. The paper published in 2003 [36] used the Fractal and Recurrence Analysis-based scores to compare persons with hypertension with controls and patients with CFS. Using univariate analysis, 13 variables showed significant differences between patients with CFS and controls. These included six fractal parameters, five recurrence quantitative analyses parameters and two parameters derived from summary statistical analysis. The authors themselves indicated that the HIS score, as studied earlier [32,35], is analogous to the Fractal and Recurrence Analysis-based Score value. Both methods are good to identify the autonomic reactivity of patients with CFS. The HIS value distinguished CFS from healthy subjects with 97% sensitivity and 97% specificity. The study of 2004 [37] found, out of multivariate analysis, four predictors of what discriminant scores were calculated. The discriminant score cut-off for patients with CFS was > 005 and differentiated them from all other study groups with 90% specificity and 60% sensitivity. Based on the sensitivity and specificity data retrieved in the articles, the positive and negative likelihood ratios were calculated (Table 4). All studies, except that of the Naschitz et al. in
2003 [36], had a higher specificity. The more the likelihood scores approaches 1, the less false-negative and false-positive results were observed. A high amount of false-positive scores would decrease the specificity of the test. The most ideal result would be, when patients with CFS have autonomous abnormalities and the healthy controls do not have any abnormality. This happens rarely in reality. Moderate evidence is available that HIS and FRAS are valid for identifying dysfunctional autonomic reactivity in patients with CFS.
Discussion The goal of the present study was to systematically review the scientific literature addressing the functioning of the ANS in patients with CFS. Based on the available literature data, it can be concluded that evidence for autonomic dysfunctions in patients with CFS is cumulating.
Head-up tilt test We can conclude with some prudence that in the most cases (7/ 8 studies), significant differences were found between patients with CFS and controls during the head-up tilt test and that this may suggest a malfunctioning of the ANS in patients with CFS. In supine condition, good evidence is available for no differences in heart rate between patients with CFS and controls. Good evidence indicates a higher heart rate in the tilt position in patients with CFS. The literature study by Meeus et al. [46] reported heart rate variability (HRV) differences at night in patients with CFS compared with controls suggestive of increased sympathetic activity.
Table 4 Positive and negative likelihood ratios (LR) Study
Sensitivity/specificity
LR + (> 1)/LR- (
REVIEW Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review Deborah Van Cauwenbergh*,†, Jo Nijs*,‡, Daphne Kos§, Laura Van Weijnen*, Filip Struyf*,† and Mira Meeus†,¶ *
Pain in Motion Research Group, Departments of Human Physiology and Rehabilitation Sciences, Faculty of Physical Education & Physiotherapy, Vrije Universiteit Brussel, Brussel, Belgium, †Pain in Motion Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium, ‡Department of Physical Medicine and Physiotherapy, University Hospital Brussels, Brussels, Belgium, §Occupational therapy, Artesis Plantijn Antwerp & KU Leuven, University of Leuven, Leuven, Belgium, ¶Department of Rehabilitation Sciences and Physiotherapy, Faculty of Medicine and Health Sciences, Ghent University, Brussels, Belgium
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 714%. 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. Keywords Autonomic nervous system, dysautonomia, heart rate variability, marker, parasympathetic, stress, sympathetic. Eur J Clin Invest 2014; 44 (5): 516–526
Introduction Chronic fatigue syndrome (CFS) is a condition characterised by extreme fatigue not resolving with (bed) rest [1,2]. According to the Centre for Disease Control and Prevention (CDC), CFS is defined as clinically evaluated, unexplained, persistent or relapsing chronic fatigue that is of new or definite onset, should result in a substantial reduction in previous levels of occupational, educational, social or personal activities [3]. Furthermore, at least four of the following symptoms must have persisted or recurred during 6 or more consecutive months and must not have predated the fatigue: impairment in short-term memory or concentration, sore throat, tender cervical or
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axillary lymph nodes, muscle or multi-joint pain, headache, unrefreshing sleep and postexertional malaise that remains present for a period of more than 24 h [3]. Recently, a new set of diagnostic criteria have been proposed, emphasising the importance of postexertional malaise (i.e. the severe exacerbations following vigorous exercise) for the diagnosis of CFS [4]. The aetiology of the illness remains unclear, although various hypotheses exist encompassing immunological, virological, psychological and neuroendocrinological mechanisms [5]. There is a lack of conclusive evidence for any one of these hypotheses [5]. A prominent line of research had been dedicated to the role of stress as an aetiological and perpetuating factor in CFS [6]. Continuous stress might result in a
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deregulation of stress-responsive systems, such as the hypothalamic–pituitary–adrenal axis (HPA), the autonomic nervous system (ANS) and the immune system [7–9]. It has been suggested that this deregulation contributes to core symptoms of CFS, such as pain and fatigue [10–12]. Additionally, Dawson and his colleague [13] indicate that there is some evidence suggesting the involvement of the ANS in CFS as the ANS may play a role in many systemic diseases [14]. Malfunctioning of the autonomic nervous system would further substantiate the notion of CFS being a central nervous system disorder. The ANS is an efferent system transmitting impulses from the central nervous system to peripheral organs, as for example the heart, where it regulates the heart rate and contraction force. The ANS also controls contraction, constriction and dilatation of blood vessels, contraction and relaxation of smooth muscle in various organs and glandular secretions, but does not influence skeletal muscle [15,16]. It is a homoeostasis regulator [14]. According to Grubb et al. [16], the ANS is subdivided in three branches, namely (i) the sympathetic, (ii) parasympathetic and (iii) enteric nerve system. The ANS takes care, with the parasympathetic branch, of the routine maintenance/stress, for example during orthostatic stress. Persons with autonomic dysregulation can experience symptoms such as severe light-headiness or syncope [17]. Commonly seen symptoms in CFS possibly related to autonomic dysfunction are as follows: dizziness (common), palpitations, diarrhoea, urinary frequency and nocturia [18]. Also fever, sore throat, headache, muscle weakness, myalgia, postexertional malaise, sleep and cognitive disturbances and fatigue might be attributed to dysfunctioning of the ANS [19]. Additionally, heart rate (HR) and blood pressure variations are often seen in CFS, which also suggest a role for the ANS in the pathophysiology of CFS. It has been shown that between 13% and 29% of patients with CFS have postural orthostatic tachycardia syndrome [20,21], a form of dysautonomia implying that when patients change their body position from supine to upright, their heart rate will increase abnormally (tachycardia), which could be due to abnormalities in the baroreceptor reflex [22]. Postural orthostatic tachycardia syndrome is associated with several symptoms often seen in patients with CFS, such as fatigue, light-headedness, dizziness, neurocognitive deficits and exercise intolerance [22]. The goal of this study was to systematically review the scientific literature addressing the reactivity of the autonomic nervous system in patients with CFS compared with healthy controls. It is hypothesised that the autonomic nervous system responds differently to various stressors in patients with CFS compared with healthy controls.
Material and methods Literature search The following databases were screened up to January 2014: PubMed (National Library of Medicine) and Web of Science. Keywords were used to obtain articles which described the ANS and the differences between patients with CFS and healthy persons by means of autonomic testing. A combination of keywords and MeSH terms addressing CFS and autonomic testing was entered with Boolean operators at the search engines. The complete search strategy was the following: (‘myalgic encephalomyelitis’ OR ‘fatigue syndrome, Chronic’) AND (‘Sympathetic nervous system’ OR ‘Parasympathetic nervous system ’ OR ‘Heart Rate’ OR ‘Heart Rate’ AND ‘variability’ OR ‘Skin conductance’ OR ‘Regional Blood Flow’ OR ‘Skin Temperature’ OR ‘Blood Pressure’ OR ‘Head-up tilt’ OR ‘Tilt table’ OR ‘Autonomic Pathways’ OR ‘autonomic dysfunction’ OR ‘Autonomic nerve system’ OR ‘Autonomic Nervous System Diseases’ OR ‘vascular system abnormalities’ OR ‘pathogenic mechanism’ OR ‘orthostatic stress’ OR ‘orthostatic instability’ OR ‘Orthostatic dysregulation’ OR ‘posture change’ OR ‘orthostatic postural tachycardia’ OR ‘Dysautonomia’ OR ‘cardiovascular responses’ OR ‘hemodynamic instability score’ OR ‘Cardiovascular autonomic control’ OR ‘Baroreflex’ OR ‘Stress response’ OR ‘Orthostatic challenge’) NOT (‘review’) NOT (‘children’ OR ‘adolescents’) NOT (‘sleep’).
Inclusion and exclusion criteria Eligibility assessment of the search results was performed according to the inclusion and exclusion criteria presented in Table 1. After entering the keywords, the titles and abstracts were read and screened for these selection criteria. If the articles met the selection criteria during the first screening phase, full texts were retrieved. If full texts also fulfilled the selection criteria in the 2nd phase, the reference was added to the bibliography and screened on quality.
Data extraction Data regarding the comparison of autonomous response between patients with CFS and healthy persons were extracted from the included papers by L.V.W. There were no restrictions for the outcomes (e.g. blood pressure and heart rate). The results section organised according to the different outcomes.
Quality assessment Each study was assessed for methodological quality. As only diagnostic case–control studies were included, the National Institute for Health and Clinical Excellence’s ‘Methodology checklist for case-control studies’ was used for all studies (NIS: http://www.nice.org.uk/aboutnice/). Methodological quality
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Table 1 Inclusion and exclusion criteria
Table 2 Methodological quality criteria
Inclusion
Exclusion
0
Not applicable
Population: adults with a diagnosis of CFS based on any official criteria (i.e. CDC criteria, Oxford criteria and Canadian criteria)
Population: patients younger than 18 years old or having dementia, psychiatric disorder or fibromyalgia without CFS comorbidity
1
Not reported (mentioned with insufficient detail to allow assessment)
2
Not addressed (not mentioned/this aspect was ignored)
3
Poorly addressed (when it was not completely satisfying)
4
Adequately addressed (satisfying)
Test: patients should undergo a headup tilt or another autonomous testing
5
Well covered (very good explained)
Outcomes: ANS parameters in patients with CFS
Four of the 31 articles scored less than 50% and were excluded. A summary of the applied searching strategy can be retrieved in Fig. 1. In the end, the literature review produced a total of 27 studies which were qualified for inclusion.
Controls: healthy controls Language articles: Dutch or English
Study design: meeting report, editorial, letter, review, pilot studies or prognostic studies or randomised controlled trials (intervention studies)
was assessed by two independent raters/reviewers (L.V.W., Master student Physiotherapy and Rehabilitation Sciences; D.V.C., PhD candidate). In this review, only studies of good or excellent quality were included (i.e. only studies scoring at least 50% on the quality assessment). In this review, we considered a quality score between 50 and 5999% of moderate quality, articles between 60 and 6999% of good quality and studies above the 70% of very good quality. The questions of the ‘Methodology checklist for case-control studies’ are aimed at establishing the internal validity of the study under review. The following items are assessed in the checklist: the research question, the selection of participants, the assessment (measures were taken to prevent knowledge of primary exposure influencing case ascertainment, and exposure status is measured in a standard, valid and reliable way), the identification of confounding factors (the main potential confounders are identified and taken into account in the design and analysis) and the statistical analysis. A five-point scale was used, resulting in a final percentage (the points were added up and converted to 100%). In Table 2, the different points are explained.
Results The literature search using the two databases resulted in 31 hits. A methodological assessment of 31 articles gave us the possibility to include only articles of good or excellent quality.
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The methodological quality of the selected articles The included articles were assessed on their methodological quality. A comprehensive view on the methodological quality of each case–control studies is shown in Table 3. The excluded articles are presented in bold. These articles had a score below 50%. The most common shortcomings in the case–control studies were a lack of information addressing the eligible population group, inadequate or missing information about the blinding of the patients; assessors and impact assessors; statistical analyses and confounders. Four studies were excluded because they had a score below 50%. Ten studies had a moderate quality (score between 50 and 5999%), 14 studies had a good quality (score between 60 and 6999%), and three study had a very good quality (score ≥ 70%).
Analysis of literature: The autonomic nervous system in patients with CFS The result of the 27 included studies, extendedly described below, is summarised in a table that can be retrieved in Appendix S1. Head-up tilt test – Capnography head-up tilt test. Eleven studies [18,23,27,29–31,33,39,43,44] described the responses to head-up tilt test. La Manca et al. [30] showed a higher heart rate and a lower pulsative systolic area for the patients with CFS at baseline, and 11 of the 39 patients with CFS had an abnormal tilt response. Timmers et al. [43] observed a higher heart rate in the CFS group, and 10 of the 36 patients with CFS showed an abnormal tilt response. When a subdivision of these patients was made, in patients with or without an abnormal response, La Manca et al. [30] observed a lower pulse pressure and lower pulsative systolic area in the CFS group having an abnormal
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371 of records identified through database searching
Included
Eligibility
Screening
Identification
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Figure 1
312 of records after duplicates removed
312 of records screened
284 of records excluded
31 of full-text articles assessed for eligibility
4 of full-text articles excluded
27 studies included in qualitative synthesis
Flowchart of the search strategy.
head-up tilt response. Timmers et al. [43] observed a higher amount of patients with CFS with orthostatic intolerance, however, not significant at the .05 level. In the negative tilt groups, La Manca et al. [30] found no differences in blood pressure, but a lower pulsative systolic area and stoke volumes, and a significantly higher heart rate for CFS. The results of Timmers et al. [43] showed (i) a smaller increase in systolic blood pressure, (ii) a similar increase in diastolic blood pressure and arterial blood pressure and (iii) a relatively higher decrease in stroke volume and cardiac output for the CFS group. One-way comparison in the supine baseline phase in the study of Yamamoto et al. [44] showed only a lower mean respiration rate interval for patients with CFS. During the upright tilt the respiration rate interval, standard deviation of the respiration rate interval, amplitude of low frequency (AHF = 004– 015 Hz) and a periodic fractal spectral components were lower. When comparing the baseline data versus the data posthead-up tilt between the two groups, only the aperiodic fractal spectral components were significantly lower for the patients with CFS. In the studies of Naschitz et al. [31,33], no differences were found in the supine position between patients with CFS and controls. During tilt, Naschitz et al. [31] showed, with the capnography head-up tilt test, differences between the both groups for diastolic blood pressure, heart rate, systolic blood pressure, respiration rate/min, end tidal CO2 and reached end points.
Controls did not reach any of the predefined end points. At the end of the head-up tilt, systolic blood pressure and diastolic blood pressure were significant lower, while the heart rate was significantly higher in patients with CFS compared with healthy controls [33]. De Becker et al. [18] found no differences during the supine position; only in the tilt position, there were higher heart rates, changes in heart rate and low-frequency power. The study of Duprez et al. [26] found significant lower BP variability (total, low-frequency and high-frequency variances) in CFS in supine position. In standing position, the differences disappeared. Analysis of RR interval variability could not detect major alterations in autonomic function in CFS. Schondorf et al. [39] identified a higher resting heart rate, but no other differences. Sixty per cent of the patients with CFS did not have orthostatic intolerance and the control group showed a lower diastolic blood pressure in the female participants. Jones et al. [29] saw no differences in orthostatic instability between patients with CFS and controls. Allen et al. [23] found a significant lower pulse amplitude in the CFS group at the ear site in the supine position. At tilted, the pattern was similar to baseline with significant differences found (P = 0014) between subject groups at the ear site for the pulse amplitude measure only. A significant reduction (P = 0002) in the overall pulse timing response to controlled standing was found for the CFS group.
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Table 3 Risk of bias assessment scores for the selected studies Autor/Year
An appropriate and clearly question
Selection of patients
Assessment
Confounding factors
Statistic analysis
Score (%)
Level of evidence
1
Allen J. et al. (2012) [23]
60
55
70
60
80
65
B
2
Boneva R.S. et al. (2007) [24]
70
40
60
0
80
50
B
3
Bouholaigah et al. (1995) [17]
80 80
67 67
50 50
60 60
100 100
71 71
B
4
Burton A.R. et al. (2010) [25]
80
80
70
0
80
62
B
5
De Becker P. et al. (1998) [18]
100 80
45 50
30 20
80 80
60 60
63 58
B
6
Duprez D.A. et al. (1998) [26]
60
50
60
0
80
50
B
7
Freeman R et al. (1997)*
80 80
40 40
20 20
60 60
40 40
48 48
B
8
Frith J. et al. (2012)[27]
80
65
70
60
80
71
B
9
Hoad A et al. (2008) [21]
60 60
75 80
60 60
80 80
40 40
63 64
B
10
Hollingsworth KG et al. (2010) [28]
60 60
45 40
50 50
80 80
60 60
59 58
B
11
Jones JF et al.(2005) [29]
80 80
65 60
30 30
80 80
60 60
63 62
B
12
LaManca JJ et al.(1999) [30]
100 100
25 30
30 35
40 40
60 60
51 53
B
13
Naschitz J.E. et al. (2000) [31]
80 80
50 40
80 80
40 40
60 60
62 60
B
14
Naschitz JE et al. (2001) [32]
80 80
80 80
70 80
0 25
60 70
58 67
B
15
Naschitz JE; et al. (2001) [33]
80 80
55 60
40 50
40 40
60 60
55 58
B
16
Naschitz J.E. et al. (2002) [34]
80 90
65 60
50 60
40 50
40 50
55 62
B
17
Naschitz JE, et al. (2002)[35]
80 80
45 50
20 30
60 60
60 60
53 56
B
18
Naschitz J.E. et al. (2003) [36]
80 80
70 60
60 60
80 60
40 40
66 60
B
19
Naschitz J.E. et al. (2004) [37]
60 80
65 70
50 60
60 65
60 60
59 67
B
20
Naschitz JE et al. (2006)*
80 80
45 50
70 70
40 40
0 0
47 48
C
21
Pazderka-Robinson H. et al. (2004) [19]
80 80
75 80
0 30
60 65
100 80
63 67
B
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Table 3 Continued Autor/Year
An appropriate and clearly question
Selection of patients
Assessment
22
Peckerman et al. (2003)* [22]
80 80
55 60
40 50
23
Razumovsky A.Y. et al. (2003) [38]
80 80
45 50
24
Schondorf R et al. (1999) [39]
80 80
25
Sisto SA et al. (1995) [40]
26
Confounding factors
Statistic analysis
Score (%)
Level of evidence
0 0
60 50
47 48
C
50 50
60 65
80 80
63 65
B
45 40
40 35
60 60
60 60
57 55
B
100 100
35 40
20 30
60 60
60 60
55 58
B
Soetekouw PM et al. (1999) [41]
80 80
80 80
60 60
40 40
60 60
64 64
B
27
Strahler J et al. (2013) [42]
80
80
70
60
60
70
B
28
Timmers HJ et al.(2002) [43]
80 80
80 75
50 50
80 75
60 60
70 68
B
29
Winkler A.S. et al. (2004)*
80 70
40 40
40 30
40 40
40 45
48 45
C
30
Yamamoto Y et al. (2003)[44]
80 70
65 60
30 30
100 100
60 70
67 66
B
31
Yataco A et al. (1997) [45]
80 80
75 60
20 20
80 60
60 60
63 56
B
*Excluded articles.
Frith et al. [27] showed a significant higher resting heart rate (P = 0006) and diastolic blood pressure (0003) in the supine position in the CFS group. There were no differences in the systolic blood pressure. In the tilted position, they saw a significant lower systolic blood pressure in the CFS group (P = 00001). In supine condition, good evidence is available for no differences in heart rate between patients with CFS and controls. Good evidence indicates a higher heart rate in the tilt position in patients with CFS. Due to the lack of consistency across studies, it is hard to draw firm conclusions regarding the other parameters. Isoproterenol infusion – more stage head-up tilt test. Yataco et al. [45], Bou-holaigah et al. [17] and Razumovsky et al. [38] used all isoproterenol infusion for their study of ANS in CFS. An abnormal response was retrieved in most CFS cases. At the end of the upright tilt, Yataco et al. [45] found differences in heart rate, heart rate variability and in patients with positive tilt between the supine position and the first 5 min and 10–15 min. Only a higher heart rate and lower blood pressure were found between the groups at the end of the tilt. They concluded, using heart rate variability as assessment, that the autonomic function
does not differ between both groups. Bou-holaigah et al. [17] found only at the end of the tilt a lower heart rate, systolic blood pressure and diastolic blood pressure. They concluded that CFS is closely associated with neural mediated hypotension and that this could be an important implication for the management of CFS. Razumovsky et al. [38] found a higher baseline heart rate and higher heart and symptoms of orthostatic intolerance during tilt in patients with CFS. Controls had a shorter time to orthostatic symptoms and a greater increase in end tidal CO2. In comparison with the baseline, a higher increase in pulsatility index and cardiovascular resistance and a decrease in cerebral blood flow velocity were seen. There were no differences in end tidal CO2 (first 10 min), blood pressure, Sa02, CBFV, respiration rate, cardiovascular resistance and heart rate at the end of tilt and respiration rate during the entire study. The three studies all showed a different heart rate at the end of the tilt, using an isoproterenol infusion. Good evidence supports decreased blood pressure at the end of the tilt. Autonomic tests. In addition to the head-up tilt test, three studies [18,29,39] used other autonomic tests, as for example rhythmic deep breathing and the Valsalva manoeuver. The
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results of the three studies showed no differences in rhythmic deep breathing between patients with CFS and healthy controls. Sisto et al. [40] found a higher vagal power with a lower breathing rate in both sitting and standing position, which followed a same decrease for patients with CFS as controls. This decrease was lower in patients with CFS, with the exception at a rate of 18 breaths per minute in the standing position. Jones et al. [29] showed a higher diastolic blood pressure in the supine position in the CFS group, a lower diastolic blood pressure in neural mediated hypotension patients after immediate standing, in comparison with postural orthostatic tachycardia and subjects with normal tilt tests. In addition, a greater heart rate variability was found in individuals susceptible to neural mediated hypotension. In the study of Hoad et al. [21], patients with CFS had a higher maximal heart rate on standing and a higher amount of postural orthostatic tachycardia syndrome. Hollingsworth et al. [28] found a higher rate of loss of consciousness, positive tilt, postural orthostatic tachycardia syndrome and Orthostatic Grading Scale (OGS) scores in the CFS group. The OGS score was higher in the subdivision group ‘abnormal left ventricular work index’, who were more present in the CFS group, than the ‘normal left ventricular work index’. The paper of Soetekouw et al. [41] was the only study who saw a higher diastolic and systolic blood pressure in the CFS group in the implementation of the Valsalva manoeuver. The handgrip and cold pressure test gave no significant differences for systolic blood pressure and diastolic blood pressure, but a trend to significance for an increased maximal heart rate during the cold pressure procedure. The mental arrhythmic test gave a lower increase in heart rate (i.e. difference between the maximal and minimal heart rate) in the CFS group. The results of the studies showed no differences in rhythmic deep breathing between patients with CFS and healthy controls. There is some moderate evidence that patients with CFS had a higher amount of postural orthostatic tachycardia syndrome on standing. Electrodermal dissociation. The topic electrodermal dissociation was described by Pazderka-Robinson et al. [19] and accomplished in patients with CFS who complied with the 1994 CDC criteria. They measured three autonomic functions, namely (i) phase skin conductance response, defined by an increase of ≥ 005 microsiemens (lS) in 1 or 4 s poststimulus (=‘intensity of reaction’ and ‘habituation, initial response’), (ii) the tonic skin conductance (Sc) level data, composed by a mean prestimulus Sc for 5 s each time before a trial.(=‘physiological level at rest’) and (ii) skin temperature levels, measured by a commercial temperature transducers on the volar surface of the
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digital phalange of the 5th finger (left and right), each time before a trial. CFS showed the lowest response amplitude and habituation rate. They made a discriminant analysis of the three variables to see which one was the most important. Between the three groups, the tonic level came out as the most important variable. For the peripheral skin temperature, they reported a higher peripheral skin temperature for the patients with CFS compared with the other groups. A submaximal cycle ergometry (ERGO) and insulin tolerance test (ITT). The study of Strahler et al. [42] implemented a submaximal cycle ergometer test and a pharmacological test (insulin tolerance test) in 21 patients with CFS and 20 age-, sexand body mass index-matched controls. Plasma norepinephrine and epinephrine were collected once before and twice after the tests. Significant lower baseline levels (P = 0012) and attenuated responses of epinephrine to exercise (P = 0040) were found in patients with CFS compared with controls, while the groups did not differ in their responses to the insulin tolerance test. Monitoring during sleep. Two studies measured the autonomic function in CFS during sleep. The study by Boneva et al. [24] found a significant increased HR (P < 00004), a shorter mean RRI (P < 00004) and a reduced HRV in CFS during sleep with higher norepinephrine (P = 005). Burton et al. [25] found a significant lower HRV (P < 0006) in patients with CFS during sleep. There is moderate evidence that patients with CFS have a lower HRV during sleep. Autonomic reactivity for the (differential) diagnosis of CFS and likelihood ratio. Naschitz et al. [32] aimed at examining the cardiovascular response to postural challenge and determined whether the degree of instability of this response can aid in the diagnosis of CFS. In one of the later studies [35], they aimed at examining the differences in hemodynamic instability score (=HIS) between patients with CFS, healthy controls and non-CFS persons. The study of 2001 [32] found a different HIS value in patients with CFS in comparison with the healthy controls, patients with fibromyalgia and hypotension. They concluded that the HIS value adds objective criteria to confirm the diagnosis of CFS. The 2002 study [35] showed no differences in the supine position, but showed a lower diastolic blood pressure in the CFS group in the tilt position. The patients with CFS showed higher rates of following end points: (i) pre- or postsyncopes, (ii) more classic end points, (iii) HIS values with a score > 098 and (4) a higher rate of patients with CFS with the combination of the last two items. They suggested again that the HIS value
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can be a reinforcement in the clinical diagnosis of CFS, by providing objective criteria. These findings were further confirmed by the same researchers [34,36,37]. They investigated whether the ‘Fractal & Recurrence Analysis –based Scores’ can be used to recognise phenotypes of diseases, in this case cardiovascular reactivity. Because Fractal and Recurrence Analysis-based scores provide objective criteria, which could become valuable in the assessment of CFS, a Fractal and Recurrence Analysis-based score of > +022 has been suggested as a cut-off value for the diagnosis of CFS [34]. The paper published in 2003 [36] used the Fractal and Recurrence Analysis-based scores to compare persons with hypertension with controls and patients with CFS. Using univariate analysis, 13 variables showed significant differences between patients with CFS and controls. These included six fractal parameters, five recurrence quantitative analyses parameters and two parameters derived from summary statistical analysis. The authors themselves indicated that the HIS score, as studied earlier [32,35], is analogous to the Fractal and Recurrence Analysis-based Score value. Both methods are good to identify the autonomic reactivity of patients with CFS. The HIS value distinguished CFS from healthy subjects with 97% sensitivity and 97% specificity. The study of 2004 [37] found, out of multivariate analysis, four predictors of what discriminant scores were calculated. The discriminant score cut-off for patients with CFS was > 005 and differentiated them from all other study groups with 90% specificity and 60% sensitivity. Based on the sensitivity and specificity data retrieved in the articles, the positive and negative likelihood ratios were calculated (Table 4). All studies, except that of the Naschitz et al. in
2003 [36], had a higher specificity. The more the likelihood scores approaches 1, the less false-negative and false-positive results were observed. A high amount of false-positive scores would decrease the specificity of the test. The most ideal result would be, when patients with CFS have autonomous abnormalities and the healthy controls do not have any abnormality. This happens rarely in reality. Moderate evidence is available that HIS and FRAS are valid for identifying dysfunctional autonomic reactivity in patients with CFS.
Discussion The goal of the present study was to systematically review the scientific literature addressing the functioning of the ANS in patients with CFS. Based on the available literature data, it can be concluded that evidence for autonomic dysfunctions in patients with CFS is cumulating.
Head-up tilt test We can conclude with some prudence that in the most cases (7/ 8 studies), significant differences were found between patients with CFS and controls during the head-up tilt test and that this may suggest a malfunctioning of the ANS in patients with CFS. In supine condition, good evidence is available for no differences in heart rate between patients with CFS and controls. Good evidence indicates a higher heart rate in the tilt position in patients with CFS. The literature study by Meeus et al. [46] reported heart rate variability (HRV) differences at night in patients with CFS compared with controls suggestive of increased sympathetic activity.
Table 4 Positive and negative likelihood ratios (LR) Study
Sensitivity/specificity
LR + (> 1)/LR- (
