ANS dysfunction/Dysautonomia

<p>From: <a class="null" href="https://s3.amazonaws.com/academia.edu.documents/42338292/Malfunctioning_of_the_autonomic_nervous_20160207-32480-9ctx5z.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1534977267&Signature=Yd2lyD7G9EfiOawUGwEJOneupGY%3D&response-content-disposition=inline%3B%20filename%3DMalfunctioning_of_the_autonomic_nervous.pdf">https://s3.amazonaws.com/academia.edu.documents/42338292/Malfunctioning_of_the_autonomic_nervous_20160207-32480-9ctx5z.pdf?AWSAccessKeyId=AKIAIWOWYYGZ2Y53UL3A&Expires=1534977267&Signature=Yd2lyD7G9EfiOawUGwEJOneupGY%3D&response-content-disposition=inline%3B%20filename%3DMalfunctioning_of_the_autonomic_nervous.pdf</a><a id="null" class="null" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256">https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256</a></p>

<p> Taken together, the heart rate dynamic response to an upright lift (i.e. the head-up tilt test) differs between patients with CFS and healthy controls, resulting in an increased prevalence of postural orthostatic tachycardia syndrome in CFS. Electrodermal dissociation as a measurement for revealing autonomic dysfunction in CFS requires further study. There is some evidence that the autonomic reactivity is useful for the diagnosis of CFS. We can conclude with prudence (i) that in most cases, patients with CFS showed different responses of the ANS to the different applied tests and (ii) that there are probably subgroups in the CFS population, explaining the differences in the test findings. Finally, future work in this area should examine various autonomous variables concomitantly, to obtain an overall picture of (dys)autonomia in patients with CFS.</p>

<h2 class="citation__title">Malfunctioning of the autonomic nervous system in patients with chronic fatigue syndrome: a systematic literature review</h2>

<div class="accordion-tabbedtab-mobile accordionclosed"><a id="a1_Ctrl" class="author-name accordion-tabbed__control" href="https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Cauwenbergh%2C+Deborah" data-id="a1" data-db-target-for="a1">Deborah Van Cauwenbergh</a> </div>

<div class="accordion-tabbedtab-mobile accordionclosed"><a id="a3_Ctrl" class="author-name accordion-tabbed__control" href="https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Kos%2C+Daphne" data-id="a3" data-db-target-for="a3">Daphne Kos</a> </div>

<div class="accordion-tabbedtab-mobile accordionclosed"><a id="a4_Ctrl" class="author-name accordion-tabbed__control" href="https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Weijnen%2C+Laura" data-id="a4" data-db-target-for="a4">Laura Van Weijnen</a> </div>

<div class="accordion-tabbedtab-mobile accordionclosed"><a id="a5_Ctrl" class="author-name accordion-tabbed__control" href="https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Struyf%2C+Filip" data-id="a5" data-db-target-for="a5">Filip Struyf</a> </div>

<div class="accordion-tabbedtab-mobile accordionclosed"><a id="a6_Ctrl" class="author-name accordion-tabbed__control" href="https://onlinelibrary.wiley.com/action/doSearch?ContribAuthorStored=Meeus%2C+Mira" data-id="a6" data-db-target-for="a6">Mira Meeus</a></div>

</div>

<div class="epub-section"><span class="epub-state">First published: </span><span class="epub-date">07 March 2014</span></div>

<div class="epub-section"><a class="epub-doi" href="https://doi.org/10.1111/eci.12256">https://doi.org/10.1111/eci.12256</a></div>

<div class="epub-section cited-by-count">Cited by: <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#citedby-section">19</a></div>

</div>

</div>

<div class="coolBarsection coolBar--sections"><a id="sections_Ctrl" class="coolBarctrl" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256" data-db-target-for="sections" data-db-switch="icon-close_thin">SECTIONS</a></div>

</div>

<div class="relative"><a id="0e406ce9-5c43-4e2d-b741-e0b43d1f1865_Ctrl" class="article-tools__ctrl" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256" data-db-target-for="0e406ce9-5c43-4e2d-b741-e0b43d1f1865" data-db-switch="icon-close_thin">TOOLS</a></div>

<div class="relative"><a id="sharectrl" class="sharectrl" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256" data-db-target-for="dff42abe-4b17-4fe9-a9c5-625405cd1007" data-db-switch="icon-close_thin">SHARE</a></div>

</div>

</nav>

<h2 id="d28736571" class="article-sectionheader sectiontitle main main">Abstract</h2>

<h3 class="article-section__sub-title section1">Introduction</h3>

<p>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.</p>

</div>

<h3 class="article-section__sub-title section1">Materials and methods</h3>

<p>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.</p>

</div>

<h3 class="article-section__sub-title section1">Results</h3>

<p>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.</p>

</div>

<h3 class="article-section__sub-title section1">Conclusion</h3>

<p>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.</p>

</div>

</section>

<h2 id="eci12256-sec-0005-title" class="article-sectiontitle sectiontitle section1">Introduction</h2>

<p>Chronic fatigue syndrome (CFS) is a condition characterised by extreme fatigue not resolving with (bed) rest <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0001" data-tab="pane-pcw-references">1</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0002" data-tab="pane-pcw-references">2</a>. 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0003" data-tab="pane-pcw-references">3</a>. 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 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0003" data-tab="pane-pcw-references">3</a>. 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0004" data-tab="pane-pcw-references">4</a>.</p>

<p>The aetiology of the illness remains unclear, although various hypotheses exist encompassing immunological, virological, psychological and neuroendocrinological mechanisms <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0005" data-tab="pane-pcw-references">5</a>. There is a lack of conclusive evidence for any one of these hypotheses <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0005" data-tab="pane-pcw-references">5</a>. A prominent line of research had been dedicated to the role of stress as an aetiological and perpetuating factor in CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0006" data-tab="pane-pcw-references">6</a>. Continuous stress might result in a deregulation of stress‐responsive systems, such as the hypothalamic–pituitary–adrenal axis (HPA), the autonomic nervous system (ANS) and the immune system <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0007" data-tab="pane-pcw-references">7</a>-<a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0009" data-tab="pane-pcw-references">9</a>. It has been suggested that this deregulation contributes to core symptoms of CFS, such as pain and fatigue <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0010" data-tab="pane-pcw-references">10</a>-<a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0012" data-tab="pane-pcw-references">12</a>.</p>

<p>Additionally, Dawson and his colleague <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0013" data-tab="pane-pcw-references">13</a> 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0014" data-tab="pane-pcw-references">14</a>.</p>

<p>Malfunctioning of the autonomic nervous system would further substantiate the notion of CFS being a central nervous system disorder.</p>

<p>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.</p>

<p>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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0015" data-tab="pane-pcw-references">15</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0016" data-tab="pane-pcw-references">16</a>. It is a homoeostasis regulator <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0014" data-tab="pane-pcw-references">14</a>. According to Grubb <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0016" data-tab="pane-pcw-references">16</a>, 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.</p>

<p>Persons with autonomic dysregulation can experience symptoms such as severe light‐headiness or syncope <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0017" data-tab="pane-pcw-references">17</a>. Commonly seen symptoms in CFS possibly related to autonomic dysfunction are as follows: dizziness (common), palpitations, diarrhoea, urinary frequency and nocturia <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>. Also fever, sore throat, headache, muscle weakness, myalgia, postexertional malaise, sleep and cognitive disturbances and fatigue might be attributed to dysfunctioning of the ANS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0019" data-tab="pane-pcw-references">19</a>.</p>

<p>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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0020" data-tab="pane-pcw-references">20</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0021" data-tab="pane-pcw-references">21</a>, 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0022" data-tab="pane-pcw-references">22</a>. 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0022" data-tab="pane-pcw-references">22</a>.</p>

<p>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.</p>

</div>

<h2 id="eci12256-sec-0006-title" class="article-sectiontitle sectiontitle section1">Material and methods</h2>

<h3 class="article-section__sub-title section2">Literature search</h3>

<p>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: <em>(‘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’)</em>.</p>

</div>

<h3 class="article-section__sub-title section2">Inclusion and exclusion criteria</h3>

<p>Eligibility assessment of the search results was performed according to the inclusion and exclusion criteria presented in Table <a class="tableLink scrollableLink" title="Link to table" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-tbl-0001">1</a>.</p>

<div id="eci12256-tbl-0001" class="article-table-content"><header class="article-table-caption"><span class="table-caption__label">Table 1. </span>Inclusion and exclusion criteriaInclusionExclusionPopulation</header>

<thead>

<tr>

</tr>

</thead>

<tbody>

<tr>

<td class="right-bordered-cell left-aligned">: adults with a diagnosis of CFS based on any official criteria (i.e. CDC criteria, Oxford criteria and Canadian criteria)</td>

<td class="left-aligned">Population: patients younger than 18 years old or having dementia, psychiatric disorder or fibromyalgia without CFS comorbidityTest</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">: patients should undergo a head‐up tilt or another autonomous testing</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Outcomes: ANS parameters in patients with CFS</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Controls: healthy controls</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Language articles: Dutch or EnglishStudydesign</td>

<td class="left-aligned">: meeting report, editorial, letter, review, pilot studies or prognostic studies or randomised controlled trials (intervention studies)</td>

</tr>

</tbody>

</table>

</div>

<p>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.</p>

</div>

<h3 class="article-section__sub-title section2">Data extraction</h3>

<p>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.</p>

</div>

<h3 class="article-section__sub-title section2">Quality assessment</h3>

<p>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<em>:</em><a class="linkBehavior" href="http://www.nice.org.uk/aboutnice/">http://www.nice.org.uk/aboutnice/</a>). Methodological quality was assessed by two independent raters/reviewers (L.V.W., Master student Physiotherapy and Rehabilitation Sciences; D.V.C., PhD candidate).</p>

<p>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 59·99% of moderate quality, articles between 60 and 69·99% of good quality and studies above the 70% of very good quality.</p>

<p>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 <a class="tableLink scrollableLink" title="Link to table" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-tbl-0002">2</a>, the different points are explained.</p>

<div id="eci12256-tbl-0002" class="article-table-content"><header class="article-table-caption"><span class="table-caption__label">Table 2. </span>Methodological quality criteria0Not</header>

<thead>

<tr>

<th class="bottom-bordered-cell left-aligned">applicable1Not</th>

</tr>

</thead>

<tbody>

<tr>

<td class="left-aligned">reported (mentioned with insufficient detail to allow assessment)</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">2Notaddressed</td>

<td class="left-aligned">(not mentioned/this aspect was ignored)</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">3Poorlyaddressed</td>

<td class="left-aligned">(when it was not completely satisfying)</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">4Adequatelyaddressed</td>

<td class="left-aligned">(satisfying)</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">5Wellcovered</td>

<td class="left-aligned">(very good explained)</td>

</tr>

</tbody>

</table>

</div>

<h2 id="eci12256-sec-0011-title" class="article-sectiontitle sectiontitle section1">Results</h2>

<p>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. Four of the 31 articles scored less than 50% and were excluded. A summary of the applied searching strategy can be retrieved in Fig. <a href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-fig-0001">1</a>. In the end, the literature review produced a total of 27 studies which were qualified for inclusion.</p>

<div class="figurecaptionheader"><strong class="figure-title">Figure 1</strong>

<div class="figure-extra"><a class="open-figure-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256">Open in figure viewer</a><a class="ppt-figure-link" href="https://onlinelibrary.wiley.com/action/downloadFigures?id=eci12256-fig-0001&doi=10.1111%2Feci.12256">PowerPoint</a></div>

</div>

<div>Flowchart of the search strategy.</div>

</figcaption>

</figure>

</section>

<h3 class="article-section__sub-title section2">The methodological quality of the selected articles</h3>

<p>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 <a class="tableLink scrollableLink" title="Link to table" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-tbl-0003">3</a>. The excluded articles are presented in bold. These articles had a score below 50%.</p>

<div id="eci12256-tbl-0003" class="article-table-content"><header class="article-table-caption"><span class="table-caption__label">Table 3. </span>Risk of bias assessment scores for the selected studies</header>

<thead>

<tr>

<th class="bottom-bordered-cell left-aligned">Autor/YearAnappropriate</th>

<th class="bottom-bordered-cell left-aligned">and clearly questionSelectionof</th>

<th class="bottom-bordered-cell left-aligned">patientsAssessmentConfounding</th>

<th class="bottom-bordered-cell left-aligned">factorsStatisticanalysisScore</th>

<th class="bottom-bordered-cell left-aligned">Level of evidence1Allen</th>

</tr>

</thead>

<tbody>

<tr>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">2BonevaR.S.et</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">3Bouholaigahet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">4BurtonA.R.et</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">5DeBecker</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">6DuprezD.A.et</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">7FreemanR</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">8FrithJ.</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">9HoadA</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">10HollingsworthKG</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">11JonesJFet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">12LaMancaJJet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">13NaschitzJ.E.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">14NaschitzJEet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">15NaschitzJE</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">16NaschitzJ.E.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">17NaschitzJE</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">18NaschitzJ.E.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">19NaschitzJ.E.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">20NaschitzJEet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">21Pazderka‐RobinsonH.</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">22Peckermanet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">23RazumovskyA.Y.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">24SchondorfR</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">25SistoSA</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">26SoetekouwPM</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">27StrahlerJ</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">28TimmersHJet</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">29WinklerA.S.et</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">30YamamotoY</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">31YatacoA</td>

</td>

</td>

</td>

</td>

</td>

</td>

</tr>

</tbody>

</table>

</div>

<ul>

<li id="eci12256-note-0001"><span class="number">a </span>Excluded articles.</li>

</ul>

</div>

<p>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.</p>

<p>Four studies were excluded because they had a score below 50%. Ten studies had a moderate quality (score between 50 and 59·99%), 14 studies had a good quality (score between 60 and 69·99%), and three study had a very good quality (score ≥ 70%).</p>

</div>

<h3 class="article-section__sub-title section2">Analysis of literature: The autonomic nervous system in patients with CFS</h3>

<p>The result of the 27 included studies, extendedly described below, is summarised in a table that can be retrieved in Appendix S1.</p>

<h4 class="article-section__sub-title section3">Head‐up tilt test – Capnography head‐up tilt test</h4>

<p>Eleven studies <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0023" data-tab="pane-pcw-references">23</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0027" data-tab="pane-pcw-references">27</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0029" data-tab="pane-pcw-references">29</a>-<a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0031" data-tab="pane-pcw-references">31</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0033" data-tab="pane-pcw-references">33</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0043" data-tab="pane-pcw-references">43</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0044" data-tab="pane-pcw-references">44</a> described the responses to head‐up tilt test. La Manca <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0043" data-tab="pane-pcw-references">43</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a> observed a lower pulse pressure and lower pulsative systolic area in the CFS group having an abnormal head‐up tilt response. Timmers <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0043" data-tab="pane-pcw-references">43</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0043" data-tab="pane-pcw-references">43</a> 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.</p>

<p>One‐way comparison in the supine baseline phase in the study of Yamamoto <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0044" data-tab="pane-pcw-references">44</a>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 = 0·04–0·15 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.</p>

<p>In the studies of Naschitz <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0031" data-tab="pane-pcw-references">31</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0033" data-tab="pane-pcw-references">33</a>, no differences were found in the supine position between patients with CFS and controls. During tilt, Naschitz <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0031" data-tab="pane-pcw-references">31</a> 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0033" data-tab="pane-pcw-references">33</a>.</p>

<p>De Becker <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0026" data-tab="pane-pcw-references">26</a> 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.</p>

<p>Schondorf <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0029" data-tab="pane-pcw-references">29</a> saw no differences in orthostatic instability between patients with CFS and controls.</p>

<p>Allen <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0023" data-tab="pane-pcw-references">23</a> 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 (<em>P</em> = 0·014) between subject groups at the ear site for the pulse amplitude measure only. A significant reduction (<em>P</em> = 0·002) in the overall pulse timing response to controlled standing was found for the CFS group.</p>

<p>Frith <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0027" data-tab="pane-pcw-references">27</a> showed a significant higher resting heart rate (<em>P</em> = 0·006) and diastolic blood pressure (0·003) 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 (<em>P</em> = 0·0001).</p>

<p>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.</p>

</div>

<h4 class="article-section__sub-title section3">Isoproterenol infusion – more stage head‐up tilt test</h4>

<p>Yataco <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0045" data-tab="pane-pcw-references">45</a>, Bou‐holaigah <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0017" data-tab="pane-pcw-references">17</a> and Razumovsky <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0038" data-tab="pane-pcw-references">38</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0045" data-tab="pane-pcw-references">45</a> 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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0017" data-tab="pane-pcw-references">17</a> 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.</p>

<p>Razumovsky <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0038" data-tab="pane-pcw-references">38</a> 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.</p>

<p>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.</p>

</div>

<h4 class="article-section__sub-title section3">Autonomic tests</h4>

<p>In addition to the head‐up tilt test, three studies <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0029" data-tab="pane-pcw-references">29</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a> used other autonomic tests, as for example rhythmic deep breathing and the Valsalva manoeuver. The results of the three studies showed no differences in rhythmic deep breathing between patients with CFS and healthy controls.</p>

<p>Sisto <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0040" data-tab="pane-pcw-references">40</a> 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.</p>

<p>Jones <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0029" data-tab="pane-pcw-references">29</a> 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.</p>

<p>In the study of Hoad <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0021" data-tab="pane-pcw-references">21</a>, patients with CFS had a higher maximal heart rate on standing and a higher amount of postural orthostatic tachycardia syndrome. Hollingsworth <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0028" data-tab="pane-pcw-references">28</a>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’.</p>

<p>The paper of Soetekouw <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0041" data-tab="pane-pcw-references">41</a> 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.</p>

<p>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.</p>

</div>

<h4 class="article-section__sub-title section3">Electrodermal dissociation</h4>

<p>The topic electrodermal dissociation was described by Pazderka‐Robinson <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0019" data-tab="pane-pcw-references">19</a> 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 ≥ 0·05 microsiemens (μS) 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 digital phalange of the 5th finger (left and right), each time before a trial.</p>

<p>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.</p>

</div>

<h4 class="article-section__sub-title section3">A submaximal cycle ergometry (ERGO) and insulin tolerance test (ITT)</h4>

<p>The study of Strahler <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0042" data-tab="pane-pcw-references">42</a> implemented a submaximal cycle ergometer test and a pharmacological test (insulin tolerance test) in 21 patients with CFS and 20 age‐, sex‐ and body mass index‐matched controls. Plasma norepinephrine and epinephrine were collected once before and twice after the tests. Significant lower baseline levels (<em>P</em> = 0·012) and attenuated responses of epinephrine to exercise (<em>P</em> = 0·040) were found in patients with CFS compared with controls, while the groups did not differ in their responses to the insulin tolerance test.</p>

</div>

<h4 class="article-section__sub-title section3">Monitoring during sleep</h4>

<p>Two studies measured the autonomic function in CFS during sleep.</p>

<p>The study by Boneva <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0024" data-tab="pane-pcw-references">24</a> found a significant increased HR (<em>P</em> < 0·0004), a shorter mean RRI (<em>P</em> < 0·0004) and a reduced HRV in CFS during sleep with higher norepinephrine (<em>P</em> = 0·05). Burton <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0025" data-tab="pane-pcw-references">25</a> found a significant lower HRV (<em>P</em> < 0·006) in patients with CFS during sleep.</p>

<p>There is moderate evidence that patients with CFS have a lower HRV during sleep.</p>

</div>

<h4 class="article-section__sub-title section3">Autonomic reactivity for the (differential) diagnosis of CFS and likelihood ratio</h4>

<p>Naschitz <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0032" data-tab="pane-pcw-references">32</a> 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0035" data-tab="pane-pcw-references">35</a>, 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0032" data-tab="pane-pcw-references">32</a> 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.</p>

<p>The 2002 study <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0035" data-tab="pane-pcw-references">35</a> 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 > −0·98 and (4) a higher rate of patients with CFS with the combination of the last two items. They suggested again that the HIS value can be a reinforcement in the clinical diagnosis of CFS, by providing objective criteria.</p>

<p>These findings were further confirmed by the same researchers <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0034" data-tab="pane-pcw-references">34</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0036" data-tab="pane-pcw-references">36</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0037" data-tab="pane-pcw-references">37</a>. 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 > +0·22 has been suggested as a cut‐off value for the diagnosis of CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0034" data-tab="pane-pcw-references">34</a>.</p>

<p>The paper published in 2003 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0036" data-tab="pane-pcw-references">36</a> 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0032" data-tab="pane-pcw-references">32</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0035" data-tab="pane-pcw-references">35</a>, 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 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0037" data-tab="pane-pcw-references">37</a> found, out of multivariate analysis, four predictors of what discriminant scores were calculated. The discriminant score cut‐off for patients with CFS was > 0·05 and differentiated them from all other study groups with 90% specificity and 60% sensitivity.</p>

<p>Based on the sensitivity and specificity data retrieved in the articles, the positive and negative likelihood ratios were calculated (Table <a class="tableLink scrollableLink" title="Link to table" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-tbl-0004">4</a>). All studies, except that of the Naschitz <em>et al.</em> in 2003 <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0036" data-tab="pane-pcw-references">36</a>, 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.</p>

<div id="eci12256-tbl-0004" class="article-table-content"><header class="article-table-caption"><span class="table-caption__label">Table 4. </span>Positive and negative likelihood ratios (LR)</header>

<thead>

<tr>

<th class="bottom-bordered-cell right-bordered-cell left-aligned">StudySensitivity</th>

<th class="bottom-bordered-cell left-aligned">/specificityLR</th>

</tr>

</thead>

<tbody>

<tr>

<td class="right-bordered-cell left-aligned">Naschitz <em>et al.</em> (2001) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0032" data-tab="pane-pcw-references">32</a></td>

<p>Sensitivity: 97%</p>

<p>Specificity: 97%</p>

</td>

</td>

</tr>

<tr>

<p>Sensitivity: 84%</p>

<p>Specificity: 96·6%</p>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Naschitz <em>et al.</em> (2002) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0034" data-tab="pane-pcw-references">34</a></td>

<p>Sensitivity: 70%</p>

<p>Specificity: 88%</p>

</td>

</td>

</tr>

<tr>

<p>Sensitivity: 97%</p>

<p>Specificity: 97%</p>

</td>

</td>

</tr>

<tr>

<p>Naschitz <em>et al.</em> (2003) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0036" data-tab="pane-pcw-references">36</a></p>

<p><em>NOT given for FRAS →</em></p>

<p><em>For HIS out of other study</em></p>

</td>

<p>Sensitivity: 91·4%</p>

<p>Specificity: 85·1%</p>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Naschitz <em>et al.</em> (2004) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0037" data-tab="pane-pcw-references">37</a></td>

<p>Sensitivity: 50%</p>

<p>Specificity: 90%</p>

</td>

</td>

</tr>

<tr>

<td class="right-bordered-cell left-aligned">Yamamoto <em>et al.</em> (2003) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0044" data-tab="pane-pcw-references">44</a></td>

<p>Sensitivity: 90%</p>

<p>Specificity: 72%</p>

</td>

</td>

</tr>

</tbody>

</table>

</div>

<p>Moderate evidence is available that HIS and FRAS are valid for identifying dysfunctional autonomic reactivity in patients with CFS.</p>

</div>

<h2 id="eci12256-sec-0021-title" class="article-sectiontitle sectiontitle section1">Discussion</h2>

<p>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.</p>

<p>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 <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0046" data-tab="pane-pcw-references">46</a> reported heart rate variability (HRV) differences at night in patients with CFS compared with controls suggestive of increased sympathetic activity.</p>

<p>The heart rate dynamic response to an upright tilt, reflected as a lower aperiodic fractal spectral component (A<sub>FR</sub>)<sub>,</sub> can possibly be used to differentiate patients with CFS from controls <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0044" data-tab="pane-pcw-references">44</a>. In addition, it has been suggested that several subgroups exist within the CFS population <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a>.</p>

</div>

<h3 class="article-section__sub-title section2">Isoproterenol infusion – more stage head‐up tilt test</h3>

<p>Three studies <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0017" data-tab="pane-pcw-references">17</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0038" data-tab="pane-pcw-references">38</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0045" data-tab="pane-pcw-references">45</a> used all isoproterenol infusion. The three studies showed all a different heart rate at the end of the tilt. Good evidence supports decreased blood pressure at the end of the tilt. Further research with isoproterenol and the same protocol is warranted.</p>

<p>The use of isoproterenol infusion could possibly influence the autonomic reaction or gave a misrepresent picture. These can possibly differ according to age, health situation, etc., which should be taken into account in future work.</p>

</div>

<h3 class="article-section__sub-title section2">Autonomic tests</h3>

<p>In people with neurally mediated hypotension, diastolic blood pressure was lower during the stand‐up tests in supine position and immediately after standing. However, neurally mediated hypotension was present in both patients with CFS and controls, indicating that it is a nonspecific finding in relation to the aim of the systematic literature review. Compared with healthy controls, postural orthostatic tachycardia syndrome is more prevalent in patients with CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0021" data-tab="pane-pcw-references">21</a>, possibly reflecting a dysfunction in the ANS in CFS. This important observation has recently been emphasised by Lewis <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0020" data-tab="pane-pcw-references">20</a>.</p>

<p>The response of the ANS to the <em>handgrip test or cold pressure test</em> did not differ between adult patients with CFS and healthy controls. However, adolescents with CFS show less reduction in acral skin blood flow, the occurrence of vasoconstrictor events at lower temperatures and more decreased tympanic temperature decreased compared with healthy controls <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0047" data-tab="pane-pcw-references">47</a>. Another study concluded that patients with CFS have a prolonged acetylcholine‐induced vasodilatation, suggestive of a disturbance in cholinergic pathways in the vascular endothelium of patients with CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0048" data-tab="pane-pcw-references">48</a>. Such a disturbed cholinergic pathway in the vascular endothelium might be associated with some of the vascular symptoms (hypotension and orthostatic intolerance) frequently seen in patients with CFS.</p>

<p>Taken together, the heart of patients with CFS fastens in response to standing, but the Valsalva manoeuver is not a valid tool to distinguish patients with CFS from controls.</p>

</div>

<h3 class="article-section__sub-title section2">Electrodermal dissociation</h3>

<p>Because electrodermal dissociation was studied only once in patients with CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0019" data-tab="pane-pcw-references">19</a>, there is only very limited evidence regarding electrodermal dissociation in CFS. It seems that patients with CFS have a higher peripheral skin temperature. Further research in this area is warranted.</p>

</div>

<h3 class="article-section__sub-title section2">A submaximal cycle ergometry (ERGO) and insulin tolerance test (ITT)</h3>

<p>During an exercise challenge, a relative hyporeactivity emerged in patients with CFS with regard to epinephrine (E), but not with regard to norepinephrine (NE). However, both groups returned to baseline levels for NE and E within 30 min postexercise. This indicates that patients with CFS are capable of establishing a counterregulatory response to physical exertion, albeit to a lower degree <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0042" data-tab="pane-pcw-references">42</a>. The same study showed that patients with CFS display a relatively normal catecholaminergic secretion in response to a standardised pharmological stimulus <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0042" data-tab="pane-pcw-references">42</a>.</p>

</div>

<h3 class="article-section__sub-title section2">Monitoring during sleep</h3>

<p>The multiple regression analyses of the study by Burton <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0025" data-tab="pane-pcw-references">25</a> revealed that HRV parameters were the best predictors of subjective sleep measures. Low HRV strongly predicted sleep quality, suggesting a pervasive state of nocturnal sympathetic hypervigilance in CFS.</p>

</div>

<h3 class="article-section__sub-title section2">Autonomic reactivity for the (differential) diagnosis of CFS</h3>

<p>Based on the reviewed studies, it is concluded that the Fractal and Recurrence Analyses‐based Scores (FRAS) and hemodynamic instability score (HIS) values are valuable assessment tools for the (differential) diagnosis of CFS <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0034" data-tab="pane-pcw-references">34</a>.</p>

<p>In a quick overview of the literature, we found differences in autonomic responses between studies. Some showed differences in heart rates and blood pressure at baseline, while others did not found these significant differences. A few of our included papers did not find significant differences for the baseline HR, as for example Bouholaigah <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0017" data-tab="pane-pcw-references">17</a>, De Becker <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>, and Naschitz <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0031" data-tab="pane-pcw-references">31</a>; while La Manca <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a>, Schondorf <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a> and Timmers <em>et al.</em> <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0043" data-tab="pane-pcw-references">43</a> did find such baseline differences. Also for diastolic blood pressure and systolic blood pressure and other parameters, differences were found.</p>

</div>

<h3 class="article-section__sub-title section2">Limitations and recommendations for further research</h3>

<p>In general, beside gender, age, the used tests or used diagnostic criteria for CFS, other factors can explain the discrepancy across studies. The lack of uniformity in the used protocols of the head‐up tilt test might preclude firm conclusions. Not to forget the different times at which the measurements were taken. In addition, the moderate methodological quality of the majority of the selected studies is an important restriction. Due to the large discrepancy of studied variables across studies, it is difficult to make an overall conclusion of autonomic (dys)functioning in people with CFS.</p>

<p>This review included only articles which scored at least 50% on the risk of bias assessment score. The following methodological flaws were observed most often and hence require attention in future studies: (i) confounding factors (they were poorly or not addressed) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a>-<a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0034" data-tab="pane-pcw-references">34</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0041" data-tab="pane-pcw-references">41</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0049" data-tab="pane-pcw-references">49</a>, (ii) selection of patients (the participation rate was not addressed) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0023" data-tab="pane-pcw-references">23</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0027" data-tab="pane-pcw-references">27</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0028" data-tab="pane-pcw-references">28</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0038" data-tab="pane-pcw-references">38</a>-<a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0040" data-tab="pane-pcw-references">40</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0049" data-tab="pane-pcw-references">49</a> and (iii) the assessment (the exposure status was not measured in a standard, valid and reliable way) <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0018" data-tab="pane-pcw-references">18</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0019" data-tab="pane-pcw-references">19</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0029" data-tab="pane-pcw-references">29</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0030" data-tab="pane-pcw-references">30</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0032" data-tab="pane-pcw-references">32</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0035" data-tab="pane-pcw-references">35</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0040" data-tab="pane-pcw-references">40</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0044" data-tab="pane-pcw-references">44</a>, <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0045" data-tab="pane-pcw-references">45</a>.</p>

<p>Future studies should take not only the heart rate changes and blood pressure into account, but also parameters as respiration rate and skin temperature. In this way, all the aspects of ANS are studied. Another aspect for future studies is the differences in responses between men and women. The only study in this review that examined gender differences found that healthy women had a different cardiovascular response to upright tilt in comparison with healthy men and that this could indicate a predisposition of women to postural insufficiency <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a>. Hence, pooling of gender data may account for the predominance of symptomatic women with clinically mild dysautonomia <a class="bibLink tab-link" href="https://onlinelibrary.wiley.com/doi/full/10.1111/eci.12256#eci12256-bib-0039" data-tab="pane-pcw-references">39</a>.</p>

<p>More sensitive and direct measurements of the autonomic activity may be necessary to establish whether slight autonomic dysfunction is involved in CFS.</p>

</div>

<h2 id="eci12256-sec-0030-title" class="article-sectiontitle sectiontitle section1">Conclusion</h2>

<p>Taken together, the heart rate dynamic response to an upright lift (i.e. the head‐up tilt test) differs between patients with CFS and healthy controls, resulting in an increased prevalence of postural orthostatic tachycardia syndrome in CFS. Electrodermal dissociation as a measurement for revealing autonomic dysfunction in CFS requires further study. There is some evidence that the autonomic reactivity is useful for the diagnosis of CFS.</p>

<p>We can conclude with prudence (i) that in most cases, patients with CFS showed different responses of the ANS to the different applied tests and (ii) that there are probably subgroups in the CFS population, explaining the differences in the test findings. Finally, future work in this area should examine various autonomous variables concomitantly, to obtain an overall picture of (dys)autonomia in patients with CFS.</p>

</div>

</section>

</article>

</div>