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1.  Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study 
Chronic Fatigue Syndrome (CFS) is characterized by severe impairment and multiple symptoms. Autonomic dysregulation has been demonstrated in several studies. We aimed at exploring the relationship between indices of autonomic cardiovascular control, the case definition from Centers for Disease Control and Prevention (CDC criteria), important clinical symptoms, and disability in adolescent chronic fatigue syndrome. 38 CFS patients aged 12–18 years were recruited according to a wide case definition (ie. not requiring accompanying symptoms) and subjected to head-up tilt test (HUT) and a questionnaire. The relationships between variables were explored with multiple linear regression analyses. In the final models, disability was positively associated with symptoms of cognitive impairments (p<0.001), hypersensitivity (p<0.001), fatigue (p=0.003) and age (p=0.007). Symptoms of cognitive impairments were associated with age (p=0.002), heart rate (HR) at baseline (p=0.01), and HR response during HUT (p=0.02). Hypersensitivity was associated with HR response during HUT (p=0.001), high-frequency variability of heart rate (HF-RRI) at baseline (p=0.05), and adherence to the CDC criteria (p=0.005). Fatigue was associated with gender (p=0.007) and adherence to the CDC criteria (p=0.04). In conclusion, a) The disability of CFS patients is not only related to fatigue but to other symptoms as well; b) Altered cardiovascular autonomic control is associated with certain symptoms; c) The CDC criteria are poorly associated with disability, symptoms, and indices of altered autonomic nervous activity.
doi:10.1186/1751-0759-7-5
PMCID: PMC3570350  PMID: 23388153
Adolescents; Chronic fatigue syndrome; Autonomic cardiovascular control; Diagnostic criteria
2.  Effects of low-dose clonidine on cardiovascular and autonomic variables in adolescents with chronic fatigue: a randomized controlled trial 
BMC Pediatrics  2015;15:117.
Background
Chronic Fatigue Syndrome (CFS) is a common and disabling condition in adolescence with few treatment options. A central feature of CFS is orthostatic intolerance and abnormal autonomic cardiovascular control characterized by sympathetic predominance. We hypothesized that symptoms as well as the underlying pathophysiology might improve by treatment with the alpha2A–adrenoceptor agonist clonidine.
Methods
A total of 176 adolescent CFS patients (12–18 years) were assessed for eligibility at a single referral center recruiting nation-wide. Patients were randomized 1:1 by a computer system and started treatment with clonidine capsules (25 μg or 50 μg twice daily, respectively, for body weight below/above 35 kg) or placebo capsules for 9 weeks. Double-blinding was provided. Data were collected from March 2010 until October 2012 as part of The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL). Effect of clonidine intervention was assessed by general linear models in intention-to-treat analyses, including baseline values as covariates in the model.
Results
A total of 120 patients (clonidine group n = 60, placebo group n = 60) were enrolled and started treatment. There were 14 drop-outs (5 in the clonidine group, 9 in the placebo group) during the intervention period. At 8 weeks, the clonidine group had lower plasma norepinephrine (difference = 205 pmol/L, p = 0.05) and urine norepinephrine/creatinine ratio (difference = 3.9 nmol/mmol, p = 0.002). During supine rest, the clonidine group had higher heart rate variability in the low-frequency range (LF-HRV, absolute units) (ratio = 1.4, p = 0.007) as well as higher standard deviation of all RR-intervals (SDNN) (difference = 12.0 ms, p = 0.05); during 20° head-up tilt there were no statistical differences in any cardiovascular variable. Symptoms of orthostatic intolerance did not change during the intervention period.
Conclusions
Low-dose clonidine reduces catecholamine levels in adolescent CFS, but the effects on autonomic cardiovascular control are sparse. Clonidine does not improve symptoms of orthostatic intolerance.
Trial registration
Clinical Trials ID: NCT01040429, date of registration 12/28/2009.
doi:10.1186/s12887-015-0428-2
PMCID: PMC4566847  PMID: 26357864
3.  Self-reported post-exertional fatigue in Gulf War veterans: roles of autonomic testing 
To determine if objective evidence of autonomic dysfunction exists from a group of Gulf War veterans with self-reported post-exertional fatigue, we evaluated 16 Gulf War ill veterans and 12 Gulf War controls. Participants of the ill group had self- reported, unexplained chronic post-exertional fatigue and the illness symptoms had persisted for years until the current clinical study. The controls had no self-reported post-exertional fatigue either at the time of initial survey nor at the time of the current study. We intended to identify clinical autonomic disorders using autonomic and neurophysiologic testing in the clinical context. We compared the autonomic measures between the 2 groups on cardiovascular function at both baseline and head-up tilt, and sudomotor function. We identified 1 participant with orthostatic hypotension, 1 posture orthostatic tachycardia syndrome, 2 distal small fiber neuropathy, and 1 length dependent distal neuropathy affecting both large and small fiber in the ill group; whereas none of above definable diagnoses was noted in the controls. The ill group had a significantly higher baseline heart rate compared to controls. Compound autonomic scoring scale showed a significant higher score (95% CI of mean: 1.72–2.67) among ill group compared to controls (0.58–1.59). We conclude that objective autonomic testing is necessary for the evaluation of self-reported, unexplained post-exertional fatigue among some Gulf War veterans with multi-symptom illnesses. Our observation that ill veterans with self-reported post-exertional fatigue had objective autonomic measures that were worse than controls warrants validation in a larger clinical series.
doi:10.3389/fnins.2013.00269
PMCID: PMC3882719  PMID: 24431987
self-reported symptom; post-exertional fatigue; objective testing; autonomic; Gulf War veteran
4.  The Effect of Acclydine in Chronic Fatigue Syndrome: A Randomized Controlled Trial 
PLoS Clinical Trials  2007;2(5):e19.
Objectives:
It is unclear whether insulin-like growth factor (IGF) function is involved in the pathophysiology of chronic fatigue syndrome (CFS). Unpublished data and reports in patient organization newsletters suggest that Acclydine, a food supplement, could be effective in the treatment of CFS by increasing biologically active IGF1 levels. Here we aimed to measure the IGF1 and IGF binding protein (IGFBP) 3 status of CFS patients compared to age- and gender-matched neighborhood controls, and to assess the effect of Acclydine on fatigue severity, functional impairment, and biologically active IGF1 level (IGFBP3/IGF1 ratio).
Design:
A randomized, placebo-controlled, double-blind clinical trial.
Setting:
Radboud University Nijmegen Medical Centre, The Netherlands.
Participants:
Fifty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention criteria for CFS. IGF status of 22 CFS patients was compared to that of 22 healthy age- and gender-matched neighborhood control individuals.
Intervention:
Acclydine or placebo for 14 wk.
Outcome measures:
Outcomes were fatigue severity (Checklist Individual Strength, subscale fatigue severity [CIS-fatigue]), functional impairment (Sickness Impact Profile-8 [SIP-8]), and biologically active IGF1 serum concentrations. Analyses were on an intention-to-treat basis.
Results:
There was no difference in IGF status in 22 CFS patients compared to healthy age- and gender-matched control individuals. Treatment with Acclydine did not result in significant differences compared with the placebo group on any of the outcome measures: CIS-fatigue +1.1 (95% CI −4.4 to +6.5, p = 0.70), SIP-8 +59.1 (95% CI −201.7 to +319.8, p = 0.65), and IGFBP3/IGF1 ratio −0.5 (95% CI −2.8 to +1.7, p = 0.63).
Conclusion:
We found no differences in IGF1 status in CFS patients compared to healthy matched neighborhood controls. In addition, the results of this clinical trial do not demonstrate any benefit of Acclydine over placebo in the treatment of CFS.
Editorial Commentary
Background: Chronic fatigue syndrome is a complicated and poorly understood illness. People with the condition experience tiredness that carries on for a long period of time and does not get better with rest. Other symptoms include sleeping problems, muscle and joint pains, concentration difficulties, and headaches. The causes of chronic fatigue syndrome are not known. There is evidence for the effectiveness of certain behavioral interventions, such as exercise therapy and cognitive behavioral therapy, in improving certain symptoms. However, some doctors are concerned that a food supplement called Acclydine, derived from a plant called Solanum dulcamara, is being used and promoted as a treatment for chronic fatigue syndrome when there is little evidence about the efficacy or safety of this supplement.
The researchers here carried out a randomized trial in The Netherlands, recruiting adult patients who met the internationally accepted criteria for chronic fatigue syndrome. The participants were allocated by chance to receive either 14 weeks of treatment with Acclydine together with amino acid supplements or, alternatively, placebo versions of the Acclydine and amino acid tablets. The researchers then measured participants' responses with respect to two primary outcome measures. One of these was how tired participants felt, which was measured using a subscale on a questionnaire called the Checklist Individual Strength scale (CIS-fatigue). The other primary outcome measure was “functional impairment,” which examines how well someone carries out their daily life, using the Sickness Impact Profile (SIP-8) scale. The secondary outcome measures included physical activity levels, day-to-day fatigue levels, and the levels of insulin-like growth factor 1 (IGF1) in blood, a hormone that's thought by some researchers to be related to the severity of chronic fatigue.
What the trial shows: In the trial, 57 people were randomized to receive either Acclydine plus amino acid supplements, or placebo tablets. When comparing scores on the primary outcome measures at the end of the trial, the researchers did not see significant differences between the treatment and placebo groups. Similarly, the results for secondary outcome measures in this trial did not show any significant differences between the treatment and placebo groups.
Strengths and limitations: Strengths of this study include the fact that it is one of the few properly designed studies of a product for which claims have been made of effectiveness in chronic fatigue syndrome. The study was designed as a double-blind trial, in which participants and investigators (those collecting the outcome data) did not know whether an individual received Acclydine or placebo. This procedure should help to minimize bias in assessing outcomes. A key limitation of this study is the relatively small number of participants. However, the investigators considered it unlikely that a larger trial would detect a clinically meaningful effect of Acclydine on these outcome measures for patients with chronic fatigue syndrome.
Contribution to the evidence: Systematic reviews of interventions for the treatment of chronic fatigue syndrome have found evidence for the efficacy of exercise therapy and cognitive behavioral therapy. This trial shows no evidence of efficacy of Acclydine plus amino acid supplements for the treatment of chronic fatigue.
doi:10.1371/journal.pctr.0020019
PMCID: PMC1876596  PMID: 17525791
5.  Primary Sjögrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure 
Background: Symptoms in keeping with autonomic dysfunction are commonly described by primary Sjögrens syndrome patients (pSS); whether objective abnormalities of autonomic function occur is unclear. This study set out to explore dynamic cardiovascular autonomic responses in pSS and their relationship with symptoms and quality of life.
Methods: Twenty-one people from the UK pSS registry, 21 community controls and 21 patients with the autoimmune liver disease primary biliary cirrhosis (PBC) (matched case-wise for age and sex) attended for assessment of autonomic responses to orthostasis and Valsalva manoeuvre (VM). pSS patients also completed EULAR Sjögrens Syndrome patient-reported index (ESSPRI), EULAR Sjögren’s syndrome disease activity index (ESSDAI), fatigue impact scale and EURO-QOL 5-dimension (EQ-5D).
Results: Compared with controls, pSS patients had significantly lower baseline systolic blood pressure (SBP) (114 ± 13 vs. 127 ± 20; P = 0.02), which dropped to a significantly lower value (98 ± 22 vs. 119 ± 24, P = 0.009). When area under the curve (AUC) was calculated for when the SBP was below baseline this was significantly greater in pSS compared to both control groups (pSS vs. control vs. PBC: 153 ± 236 vs. 92 ± 85 vs. 1.2 ± 0.3, P = 0.005). Peak phase IV SBP during the VM was significantly lower in pSS (P = 0.007) indicating early sympathetic failure. Increased heart rate associated with fatigue (P = 0.02; r2 = 0.2) and EQ-5D. A shift in sympathetic-vagal balance associated with overall symptom burden (ESSPRI) (P = 0.04, r2 = 0.3) and EULAR sicca score (P = 0.016; r2 = 0.3), the latter also correlated with baroreceptor effectiveness (P = 0.03; r2 = 0.2) and diastolic blood pressure variability (P = 0.003; r2 = 0.4).
Conclusion: pSS patients have impaired blood pressure response to standing. Dysautonomia correlates with PSS-associated symptoms and quality of life.
doi:10.1093/qjmed/hcs172
PMCID: PMC3508582  PMID: 22976617
6.  High flow variant postural orthostatic tachycardia syndrome amplifies the cardiac output response to exercise in adolescents 
Physiological Reports  2014;2(8):e12122.
Abstract
Postural orthostatic tachycardia syndrome (POTS) is characterized by chronic fatigue and dizziness and affected individuals by definition have orthostatic intolerance and tachycardia. There is considerable overlap of symptoms in patients with POTS and chronic fatigue syndrome (CFS), prompting speculation that POTS is akin to a deconditioned state. We previously showed that adolescents with postural orthostatic tachycardia syndrome (POTS) have excessive heart rate (HR) during, and slower HR recovery after, exercise – hallmarks of deconditioning. We also noted exaggerated cardiac output during exercise which led us to hypothesize that tachycardia could be a manifestation of a high output state rather than a consequence of deconditioning. We audited records of adolescents presenting with long‐standing history of any mix of fatigue, dizziness, nausea, who underwent both head‐up tilt table test and maximal exercise testing with measurement of cardiac output at rest plus 2–3 levels of exercise, and determined the cardiac output () versus oxygen uptake () relationship. Subjects with chronic fatigue were diagnosed with POTS if their HR rose ≥40 beat·min−1 with head‐up tilt. Among 107 POTS patients the distribution of slopes for the , relationship was skewed toward higher slopes but showed two peaks with a split at ~7.0 L·min−1 per L·min−1, designated as normal (5.08 ± 1.17, N = 66) and hyperkinetic (8.99 ± 1.31, N = 41) subgroups. In contrast, cardiac output rose appropriately with in 141 patients with chronic fatigue but without POTS, exhibiting a normal distribution and an average slope of 6.10 ± 2.09 L·min−1 per L·min−1. Mean arterial blood pressure and pulse pressure from rest to exercise rose similarly in both groups. We conclude that 40% of POTS adolescents demonstrate a hyperkinetic circulation during exercise. We attribute this to failure of normal regional vasoconstriction during exercise, such that patients must increase flow through an inappropriately vasodilated systemic circulation to maintain perfusion pressure.
e12122
Forty percent of postural orthostatic tachycardia syndrome (POTS) adolescents who, by definition have abnormal sympathetic control of HR and BP, demonstrate a hyperkinetic circulation during exercise. We attribute this to failure of normal regional vasoconstriction during exercise, such that patients must increase flow through an inappropriately vasodilated systemic circulation to maintain perfusion pressure.
doi:10.14814/phy2.12122
PMCID: PMC4246579  PMID: 25168872
Cardiac output; exercise; hyperkinetic circulation; orthostatic intolerance; sympathetic nervous system
7.  Mild autonomic dysfunction in primary Sjögren's syndrome: a controlled study 
Introduction
The aim of this study was to compare cardiovascular autonomic nervous system function in patients with primary Sjögren's syndrome (pSS) with that in control individuals, and to correlate the findings with autonomic symptoms and the presence of exocrine secretory dysfunction.
Methods
Twenty-seven female patients with pSS and 25 control individuals completed the COMPASS (Composite Autonomic Symptom Scale) self-reported autonomic symptom questionnaire. Beat-to-beat heart rate and blood pressure data in response to five standard cardiovascular reflex tests were digitally recorded using a noninvasive finger pressure cuff and heart rate variability was analyzed by Fourier spectral analysis. Analysis was performed by analysis of variance (ANOVA), multivariate ANOVA and repeated measures ANOVA, as indicated. Factor analysis was utilized to detect relationships between positive autonomic symptoms in pSS patients.
Results
Multiple, mild autonomic disturbances were observed in pSS patients relating to decreased heart rate variability, decreased blood pressure variability and increased heart rate, which were most evident in response to postural change. There was a strong trend toward an association between decreased heart rate variability and increased severity of the secretomotor, orthostatic, bladder, gastroparesis and constipation self-reported autonomic symptom cluster identified in pSS patients. This symptom cluster was also associated with fatigue and reduced unstimulated salivary flow, and therefore may be an important component of the clinical spectrum of this disease.
Conclusion
There was evidence of mild autonomic dysfunction in pSS as measured with both cardiovascular reflex testing and self-reported symptoms. Pathogenic autoantibodies targeting M3 muscarinic receptors remain a strong candidate for the underlying pathophysiology, but practical assays for the detection of this autoantibody remain elusive.
doi:10.1186/ar2385
PMCID: PMC2453776  PMID: 18328102
8.  A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis 
Nmr in Biomedicine  2011;24(10):1302-1312.
To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel-based regressions against clinical scores. Using SPM5 we performed voxel-based morphometry (VBM) and analysed T1- and T2-weighted spin-echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24-h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS). © 2011 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.
doi:10.1002/nbm.1692
PMCID: PMC4369126  PMID: 21560176
voxel based; CFS; MRI; regression; interaction; brainstem; homeostasis; autonomic nervous system
9.  Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes 
Brain  2014;138(1):43-52.
Treatment induced neuropathy of diabetes is an iatrogenic neuropathy that develops in the setting of a rapid improvement in glycaemic control. Through retrospective review of case records, Gibbons and Freeman reveal that symptom severity and the risk of developing the disorder correlate strongly with the magnitude of glycaemic change.
See Low and Singer (10.1093/brain/awu327) for a scientific commentary on this article.
The neural substrate of Gilles de la Tourette syndrome is unknown. Worbe et al. use probabilistic tractography to demonstrate widespread structural abnormalities in cortico-striato-pallido-thalamic white matter pathways—likely arising from abnormal brain development—in patients with this syndrome.
Treatment-induced neuropathy in diabetes (also referred to as insulin neuritis) is considered a rare iatrogenic small fibre neuropathy caused by an abrupt improvement in glycaemic control in the setting of chronic hyperglycaemia. The prevalence and risk factors of this disorder are not known. In a retrospective review of all individuals referred to a tertiary care diabetic neuropathy clinic over 5 years, we define the proportion of individuals that present with and the risk factors for development of treatment-induced neuropathy in diabetes. Nine hundred and fifty-four individuals were evaluated for a possible diabetic neuropathy. Treatment-induced neuropathy in diabetes was defined as the acute onset of neuropathic pain and/or autonomic dysfunction within 8 weeks of a large improvement in glycaemic control—specified as a decrease in glycosylated haemoglobin A1C (HbA1c) of ≥2% points over 3 months. Detailed structured neurologic examinations, glucose control logs, pain scores, autonomic symptoms and other microvascular complications were measured every 3–6 months for the duration of follow-up. Of 954 patients evaluated for diabetic neuropathy, 104/954 subjects (10.9%) met criteria for treatment-induced neuropathy in diabetes with an acute increase in neuropathic or autonomic symptoms or signs coinciding with a substantial decrease in HbA1c. Individuals with a decrease in HbA1c had a much greater risk of developing a painful or autonomic neuropathy than those individuals with no change in HbA1c (P < 0.001), but also had a higher risk of developing retinopathy (P < 0.001) and microalbuminuria (P < 0.001). There was a strong correlation between the magnitude of decrease in HbA1c, the severity of neuropathic pain (R = 0.84, P < 0.001), the degree of parasympathetic dysfunction (R = −0.52, P < 0.01) and impairment of sympathetic adrenergic function as measured by fall in blood pressure on tilt-table testing (R = −0.63, P < 0.001). With a decrease in HbA1c of 2–3% points over 3 months there was a 20% absolute risk of developing treatment-induced neuropathy in diabetes, with a decrease in HbA1c of >4% points over 3 months the absolute risk of developing treatment-induced neuropathy in diabetes exceeded 80%. Treatment-induced neuropathy of diabetes is an underestimated iatrogenic disorder associated with diffuse microvascular complications. Rapid glycaemic change in patients with uncontrolled diabetes increases the risk of this complication.
doi:10.1093/brain/awu307
PMCID: PMC4285188  PMID: 25392197
diabetic neuropathy; painful neuropathy; autonomic neuropathy; insulin neuritis
10.  Orthostatic responses in adolescent chronic fatigue syndrome: contributions from expectancies as well as gravity 
Background
Orthostatic intolerance is common in chronic fatigue syndrome (CFS), and several studies have documented an abnormal sympathetic predominance in the autonomic cardiovascular response to gravitational stimuli. The aim of this study was to explore whether the expectancies towards standing are contributors to autonomic responses in addition to the gravitational stimulus itself.
Methods
A total of 30 CFS patients (12–18 years of age) and 39 healthy controls underwent 20° head-up tilt test and a motor imagery protocol of standing upright. Beat-to-beat cardiovascular variables were recorded.
Results
At supine rest, CFS patients had significantly higher heart rate, diastolic blood pressure, and mean arterial blood pressure, and lower stroke index and heart rate variability (HRV) indices. The response to 20° head-up tilt was identical in the two groups. The response to imaginary upright position was characterized by a stronger increase of HRV indices of sympathetic predominance (power in the low-frequency range as well as the ratio low-frequency: high-frequency power) among CFS patients.
Conclusions
These results suggest that in CFS patients expectancies towards orthostatic challenge might be additional determinants of autonomic cardiovascular modulation along with the gravitational stimulus per se.
doi:10.1186/1751-0759-8-22
PMCID: PMC4166398  PMID: 25237387
Adolescence; Autonomic nervous system; Chronic fatigue syndrome; Expectancies; Orthostatic intolerance
11.  Spectral analysis of heart rate and blood pressure variability in primary Sjögren's syndrome 
Annals of the Rheumatic Diseases  2002;61(3):232-236.
Background: Autonomic dysfunction has been described in primary Sjögren's syndrome (SS).
Objective: To investigate the circulatory autonomic regulation in patients with primary SS by power spectral analysis of heart rate and blood pressure variability.
Methods: Forty three (42 female) patients with primary SS, mean age 52 years (range 23–80), with a mean disease duration of eight years (range 1–30) and 30 (15 female) healthy controls, mean age 43 years (range 21–68) were studied. In each patient blood pressure, heart rate, and respiration were measured continuously during supine rest and orthostatic challenge (60° head-up tilt). Power spectral analysis was performed to determine possible differences in short term sympathetic and parasympathetic autonomic regulation between patients and controls. Furthermore, spectral parameters were studied in relation to illness severity and disease duration of the patients with primary SS.
Results: After controlling for differences in age, heart rate variability of the mid-frequency band and the variation coefficient of systolic blood pressure were significantly lower in patients with primary SS than in controls during supine rest. During 60° tilt patients with primary SS showed a significantly higher mean heart rate, mean systolic blood pressure, and variation coefficient of diastolic blood pressure, and a significantly lower baroreflex index than controls. After controlling for age, no differences were found either in heart rate variability, blood pressure results, and baroreflex sensitivity during supine rest and tilt between the subgroups divided according to disease duration, Schirmer test results, or between the subgroups with different fatigue scores. No differences were found in spectral data between the groups with and without positive antinuclear antibody serology.
Conclusion: For the group no differences in sympathetic and parasympathetic cardiac control were seen between patients with primary SS and controls, as assessed by spectral techniques, although some cardiovascular differences were found, particularly during orthostatic challenge.
doi:10.1136/ard.61.3.232
PMCID: PMC1754013  PMID: 11830428
12.  Cerebral vascular control is associated with skeletal muscle pH in chronic fatigue syndrome patients both at rest and during dynamic stimulation☆ 
NeuroImage : Clinical  2013;2:168-173.
Cerebral blood flow (CBF) is maintained despite changing systemic blood pressure through cerebral vascular control, with such tight regulation believed to be under local tissue control. Chronic fatigue syndrome (CFS) associates with a wide range of symptoms, including orthostatic intolerance, skeletal muscle pH abnormalities and cognitive impairment. CFS patients are known to have reduced CBF and orthostatic intolerance associates with abnormal vascular regulation, while skeletal muscle pH abnormalities associate with autonomic dysfunction. These findings point to autonomic dysfunction as the central feature of CFS, and cerebral vascular control being influenced by factors outside of the brain, a macroscopic force affecting the stability of regional regulation. We therefore explored whether there was a physiological link between cerebral vascular control and skeletal muscle pH management in CFS.
Seventeen consecutive CFS patients fulfilling the Fukuda criteria were recruited from our local CFS clinical service. To probe the static scenario, CBF and skeletal muscle pH were measured at rest using MRI and 31P magnetic resonance spectroscopy (31P-MRS).
To examine dynamic control, brain functional MRI was performed concurrently with Valsalva manoeuvre (VM), a standard autonomic function challenge, while 31P-MRS was performed during plantar flexion exercise.
Significant inverse correlation was seen between CBF and skeletal muscle pH at rest (r = − 0.67, p < 0.01). Prolonged cerebral vascular constriction during the sympathetic phase of VM was associated with higher pH in skeletal muscle after plantar flexion exercise (r = 0.69, p < 0.008).
In conclusion, cerebral vascular control is closely related to skeletal muscle pH both at rest and after dynamic stimulation in CFS.
Highlights
► Cerebral vascular control in CFS is affected by factors external to the brain. ► Valsalva manoeuvre performed during fMRI probes cerebral vascular control. ► Cerebral blood flow is associated with skeletal muscle pH at rest in CFS. ► Cerebral vascular control relates to skeletal pH recovery after stimulation in CFS. ► Our results point towards a peripheral or systemic cause for CFS.
doi:10.1016/j.nicl.2012.12.006
PMCID: PMC3777833  PMID: 24179772
Autonomic function; Chronic fatigue syndrome; 31P MR spectroscopy; Cerebral blood flow; Arterial spin labelling (ASL); Dual echo fMRI
13.  Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population 
Background
Scant research has adequately addressed the impact of chronic fatigue syndrome on patients' daily activities and quality of life. Enumerating specific problems related to quality of life in chronic fatigue syndrome patients can help us to better understand and manage this illness. This study addresses issues of functional status in persons with chronic fatigue syndrome and other fatiguing illnesses in a population based sample, which can be generalized to all persons with chronic fatigue.
Methods
We conducted a random telephone survey in Wichita, Kansas to identify persons with chronic fatigue syndrome and other fatiguing illnesses. Respondents reporting severe fatigue of at least 1 month's duration and randomly selected non-fatigued respondents were asked to participate in a detailed telephone interview. Participants were asked about symptoms, medical and psychiatric illnesses, and about physical, social, and recreational functioning. Those meeting the 1994 chronic fatigue syndrome case definition, as determined on the basis of their telephone responses, were invited for clinical evaluation to confirm a diagnosis of chronic fatigue syndrome. For this analysis, we evaluated unemployment due to fatigue, number of hours per week spent on work, chores, and other activities (currently and prior to the onset of fatigue), and energy level.
Results
There was no difference between persons with chronic fatigue syndrome and persons with a chronic fatigue syndrome-like illness that could be explained by a medical or psychiatric condition for any of the outcomes we measured except for unemployment due to fatigue (15% vs. 40%, P < .01). Persons with chronic fatigue syndrome and other fatiguing illnesses had substantially less energy and spent less time on hobbies, schooling, or volunteer work than did non-fatigued controls (P < .01).
Conclusions
Persons with chronic fatigue syndrome are as impaired as persons whose fatigue could be explained by a medical or psychiatric condition, and they have less energy than non-fatigued controls.
doi:10.1186/1477-7525-1-48
PMCID: PMC239865  PMID: 14577835
chronic fatigue syndrome; CFS; fatigue; function; disability
14.  The definition of disabling fatigue in children and adolescents 
BMC Family Practice  2005;6:33.
Background
Disabling fatigue is the main illness related reason for prolonged absence from school. Although there are accepted criteria for diagnosing chronic fatigue in adults, it remains uncertain as to how best to define disabling fatigue and Chronic Fatigue Syndrome (CFS) in children and adolescents. In this population-based study, the aim was to identify children who had experienced an episode of disabling fatigue and examine the clinical and demographic differences between those individuals who fulfilled a narrow definition of disabling fatigue and those who fulfilled broader definitions of disabling fatigue.
Methods
Participants (aged 8–17 years) were identified from a population-based twin register. Parent report was used to identify children who had ever experienced a period of disabling fatigue. Standardised telephone interviews were then conducted with the parents of these affected children. Data on clinical and demographic characteristics, including age of onset, gender, days per week affected, hours per day spent resting, absence from school, comorbidity with depression and a global measure of impairment due to the fatigue, were examined. A narrow definition was defined as a minimum of 6 months disabling fatigue plus at least 4 associated symptoms, which is comparable to the operational criteria for CFS in adults. Broader definitions included those with at least 3 months of disabling fatigue and 4 or more of the associated symptoms and those with simply a minimum of 3 months of disabling fatigue. Groups were mutually exclusive.
Results
Questionnaires were returned by 1468 families (65% response rate) and telephone interviews were completed on 99 of the 129 participants (77%) who had experienced fatigue. There were no significant differences in demographic and clinical characteristics or levels of impairment between those who fulfilled the narrower definition and those who fulfilled the broader definitions. The only exception was the reported number of days per week that the child was affected by the fatigue. All groups demonstrated evidence of substantial impairment associated with the fatigue.
Conclusion
Children and adolescents who do not fulfil the current narrow definition of CFS but do suffer from disabling fatigue show comparable and substantial impairment. In primary care settings, a broader definition of disabling fatigue would improve the identification of impaired children and adolescents who require support.
doi:10.1186/1471-2296-6-33
PMCID: PMC1192794  PMID: 16091130
15.  Blood pressure variability and closed-loop baroreflex assessment in adolescent chronic fatigue syndrome during supine rest and orthostatic stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS. We included a consecutive sample of 14 adolescents 12–18 years old with CFS diagnosed according to a thorough and standardized set of investigations and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of –20 mmHg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high–frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm. Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP, compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control. CFS in adolescents is characterized by reduced systolic blood pressure variability and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; Baroreflex sensitivity; Chronic fatigue syndrome; Autonomic nervous system; Cardiovascular regulation
16.  Blood Pressure Variability and Closed-loop Baroreflex Assessment in Adolescent Chronic Fatigue Syndrome during Supine Rest and Orthostatic Stress 
Hemodynamic abnormalities have been documented in the chronic fatigue syndrome (CFS), indicating functional disturbances of the autonomic nervous system responsible for cardiovascular regulation. The aim of this study was to explore blood pressure variability and closed-loop baroreflex function at rest and during mild orthostatic stress in adolescents with CFS.
We included a consecutive sample of 14 adolescents 12 to 18 years old with CFS diagnosed according to a thorough and standardized set of investigations, and 56 healthy control subjects of equal sex and age distribution. Heart rate and blood pressure were recorded continuously and non-invasively during supine rest and during lower body negative pressure (LBNP) of −20 mm Hg to simulate mild orthostatic stress. Indices of blood pressure variability and baroreflex function (α-gain) were computed from monovariate and bivariate spectra in the low-frequency (LF) band (0.04–0.15 Hz) and the high-frequency (HF) band (0.15–0.50 Hz), using an autoregressive algorithm.
Variability of systolic blood pressure in the HF range was lower among CFS patients as compared to controls both at rest and during LBNP. During LBNP compared to controls, α-gain HF decreased more, and α-gain LF and the ratio of α-gain LF/α-gain HF increased more in CFS patients, all suggesting greater shift from parasympathetic to sympathetic baroreflex control.
CFS in adolescents is characterized by reduced systolic blood pressure variability, and a sympathetic predominance of baroreflex heart rate control during orthostatic stress. These findings may have implications for the pathophysiology of CFS in adolescents.
doi:10.1007/s00421-010-1670-9
PMCID: PMC3037975  PMID: 20890710
Blood pressure variability; baroreflex sensitivity; chronic fatigue syndrome; autonomic nervous system; cardiovascular regulation
17.  The Effect of Ivabradine on the Heart Rate and Sympathovagal Balance in Postural Tachycardia Syndrome Patients 
Background
Postural tachycardia syndrome (POTS) is a common form of chronic orthostatic intolerance. The remarkable increase in heart rate (HR) upon standing is the hallmark of this syndrome. Treatment of POTS patients is challenging and includes drugs that slow the HR. Ivabradine is a selective If channel blocker designed to slow the HR, as an anti-anginal agent. In view of its ability to slow the HR, we posited that ivabradine may be an ideal medication for treating POTS patients. This report provides the results of an investigation in which we studied ivabradine’s effect on the hemodynamics and sympathovagal balance in POTS patients.
Methods
An open-label trial, without a placebo control, was performed in eight patients with POTS of two years’ standing. Characterization of symptoms, hemodynamics, autonomic function tests, and HR and blood pressure (BP) variability were determined while patients were in a supine position and during a 20-minute head-up tilt before and after a single oral dose of 7.5 mg ivabradine.
Results
Ivabradine slowed the HR of POTS patients at rest by 4±1 bpm (P<0.05). During a 5-minute head-up tilt, the HR decreased from 118±4 bpm to 101±5 bpm (P<0.01). Ivabradine did not affect the BP when patients were at rest in a supine position or in head-up tilt position. Cardiovascular vagal and sympathetic tone, extrapolated from the time and frequency domains of the HR and BP variability, were also not affected by ivabradine.
Conclusions
Ivabradine is an effective drug for slowing the HR of POTS patients at rest and during tilting, without producing significant adverse effects. Moreover, ivabradine exerts its effects without influencing the sympathovagal balance.
doi:10.5041/RMMJ.10213
PMCID: PMC4524401  PMID: 26241226
If channel blocker; postural tachycardia syndrome; orthostatic intolerance; sympathovagal balance
18.  Validation of the Fatigue Severity Scale in chronic hepatitis C 
Background
Fatigue is a common symptom of chronic hepatitis C virus (cHCV) infection and a common side effect of interferon-based treatment for cHCV. This study provides confirmatory evidence of the reliability and validity of the Fatigue Severity Scale (FSS) to document fatigue in cHCV research and identifies values that indicate clinically important differences in FSS to aid in interpreting fatigue in cHCV clinical trials.
Methods
The study used data from two double-blind, randomized, placebo-controlled, Phase IIb trials evaluating the efficacy and safety of simeprevir plus peginterferon-α/ribavirin in treatment-naïve (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) with cHCV infection. Patients completed the FSS and EuroQoL 5 dimension questionnaire (EQ-5D) at baseline and at regular intervals throughout both trials. Reliability was assessed using Cronbach’s coefficient α at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL hemoglobin [Hb] change between Weeks 12/24). Correlation with the EQ-5D visual analog scale (VAS) and “Usual Activity” domain score was used to assess concurrent validity. Clinical validity was evaluated using a case-control method to link spontaneously reported fatigue and anemia adverse events (AEs) during the study to FSS scores.
Results
FSS total scores demonstrated good reliability (Cronbach’s α: 0.95, 0.96; ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively) and concurrent validity (correlation with EQ-5D VAS: -0.63, -0.66) with a monotonic relationship between the EQ-5D “Usual Activities” item response and FSS. Clinical validity was confirmed by a significant difference between cases and controls for fatigue AEs (p < 0.05); however, anemia defined by AE or Hb abnormalities was only weakly related to FSS score. Analyses indicate that a change of 0.33–0.82 in mean FSS scores represents a meaningful improvement in fatigue, and a one-point change is a conservative indicator of an important change in individual FSS scores.
Conclusion
A difference of ≥0.7 in mean FSS scores can be considered a clinically important difference within groups over time or between groups. A one-point change or less in individual FSS scores indicates a clinically relevant change in fatigue.
doi:10.1186/1477-7525-12-90
PMCID: PMC4094687  PMID: 24915781
Chronic hepatits C; Psychometric validation; Fatigue Severity Scale; Health status; Fatigue
19.  Chronic fatigue syndrome 
BMJ Clinical Evidence  2008;2008:1101.
Introduction
Chronic fatigue syndrome (CFS) affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2007 (BMJ Clinical evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 45 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antidepressants, cognitive behavioural therapy (CBT), corticosteroids, dietary supplements, evening primrose oil, galantamine, graded exercise therapy, homeopathy, immunotherapy, intramuscular magnesium, oral nicotinamide adenine dinucleotide, and prolonged rest.
Key Points
Chronic fatigue syndrome (CFS) is characterised by severe, disabling fatigue, and other symptoms including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches. CFS affects between 0.006% and 3% of the population depending on the criteria used, with women being at higher risk than men.
Graded exercise therapy has been shown to effectively improve measures of fatigue and physical functioning. Educational interventions with encouragement of graded exercise (treatment sessions, telephone follow-ups, and an educational package explaining symptoms and encouraging home-based exercise) improve symptoms more effectively than written information alone.
CBT is also effective in treating chronic fatigue syndrome. CBT may also be beneficial when administered by therapists with no specific experience of chronic fatigue syndrome, but who are adequately supervised.In adolescents, CBT can reduce fatigue severity and improve school attendance compared with no treatment.
We don't know how effective antidepressants, corticosteroids, and intramuscular magnesium are in treating chronic fatigue syndrome. Antidepressants should be considered in people with affective disorders, and tricyclics in particular have potential therapeutic value because of their analgesic properties.
Interventions such as dietary supplements, evening primrose oil, oral nicotinamide adenine dinucleotide, homeopathy, and prolonged rest have not been studied in enough detail for us to draw conclusions on their efficacy.
A large study has found that galantamine is no better than placebo at improving symptoms of chronic fatigue syndrome.
Although there is some evidence that immunotherapy can improve symptoms compared with placebo, it is associated with considerable adverse effects, and should therefore probably not be offered as a treatment for chronic fatigue.
PMCID: PMC2907931  PMID: 19445810
20.  Chronic fatigue syndrome 
BMJ Clinical Evidence  2011;2011:1101.
Introduction
Chronic fatigue syndrome (CFS) affects between 0.006% and 3% of the population depending on the criteria of definition used, with women being at higher risk than men.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for chronic fatigue syndrome? We searched: Medline, Embase, The Cochrane Library, and other important databases up to March 2010 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 46 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antidepressants, cognitive behavioural therapy (CBT), corticosteroids, dietary supplements, evening primrose oil, galantamine, graded exercise therapy, homeopathy, immunotherapy, intramuscular magnesium, oral nicotinamide adenine dinucleotide, and prolonged rest.
Key Points
Chronic fatigue syndrome is characterised by severe, disabling fatigue, and other symptoms including musculoskeletal pain, sleep disturbance, impaired concentration, and headaches. CFS affects between 0.006% and 3% of the population depending on the criteria used, with women being at higher risk than men.
Graded exercise therapy has been shown to effectively improve measures of fatigue and physical functioning. Educational interventions with encouragement of graded exercise (treatment sessions, telephone follow-ups, and an educational package explaining symptoms and encouraging home-based exercise) improve symptoms more effectively than written information alone.
CBT is effective in treating chronic fatigue syndrome in adults. CBT may also be beneficial when administered by therapists with no specific experience of chronic fatigue syndrome, but who are adequately supervised.In adolescents, CBT can reduce fatigue severity and improve school attendance compared with no treatment.
We don't know how effective antidepressants, corticosteroids, and intramuscular magnesium are in treating chronic fatigue syndrome. Antidepressants should be considered in people with affective disorders, and tricyclics in particular have potential therapeutic value because of their analgesic properties.
Interventions such as dietary supplements, evening primrose oil, oral nicotinamide adenine dinucleotide, homeopathy, and prolonged rest have not been studied in enough detail in RCTs for us to draw conclusions on their efficacy.
Based on a single large RCT galantamine seems no better than placebo at improving symptoms of chronic fatigue syndrome.
Although there is some RCT evidence that immunotherapy can improve symptoms compared with placebo, it is associated with considerable adverse effects, and should therefore probably not be offered as a treatment for chronic fatigue.
PMCID: PMC3275316  PMID: 21615974
21.  Autonomic Modulation and Health-Related Quality of Life among Schizophrenic Patients Treated with Non-Intensive Case Management 
PLoS ONE  2011;6(11):e26378.
Background
Schizophrenia is associated with autonomic dysfunction and this may increase cardiovascular mortality. Past studies on autonomic modulation of schizophrenic patients focused on inpatients rather than individuals in a community setting, especially those receiving non-intensive case management (non-ICM). Besides, autonomic modulation and its association with health-related quality of life (HRQoL) in this population remain unexplored.
Methods
A total of 25 schizophrenic patients treated by non-ICM and 40 healthy volunteers were matched by age, gender and body mass index; smokers were excluded. Between the two groups, we compared the individuals' 5 min resting assessments of heart rate variability and their HRQoL, which was measured using EuroQoL-5D (EQ-5D). Patients with schizophrenia were assessed for psychopathology using the Positive and Negative Syndrome Scale for Schizophrenia (PANSS). We examined the relationship between heart rate variability measurements, HRQoL scores, PANSS scores, and other clinical variables among the schizophrenic patients treated by non-ICM.
Results
Compared to the controls, patients with schizophrenia showed a significant impairment of autonomic modulation and a worse HRQoL. Cardiovagal dysfunction among the schizophrenic patients could be predicted independently based on lower educational level and more negative symptoms. Sympathetic predominance was directly associated with anticholinergics use and EQ-5D using a visual analogue scale (EQ-VAS).
Conclusion
Patients with schizophrenia treated by non-ICM show a significant impairment of their autonomic function and HRQoL compared to the controls. Since the sympathovagal dysfunction is associated with more negative symptoms or higher VAS score, the treatment of the negative symptoms as well as the monitoring of HRQoL might help to manage cardiovascular risk among these individuals. In addition, EQ-VAS scores must be interpreted more cautiously in such a population.
doi:10.1371/journal.pone.0026378
PMCID: PMC3208549  PMID: 22073161
22.  Effects of a Supervised Exercise Intervention on Recovery From Treatment Regimens in Breast Cancer Survivors 
Oncology Nursing Forum  2008;35(6):909-915.
Purpose/Objectives
To investigate the effects of supervised exercise training on cardiopulmonary function and fatigue in cancer survivors undergoing various clinical treatments.
Design
Pretest and post-test quasiexperimental.
Setting
Outpatient oncology rehabilitation center.
Sample
96 breast cancer survivors undergoing various clinical treatments.
Methods
Subjects were divided into four groups based on the specific type of clinical treatment: surgery alone (n = 22); surgery and chemotherapy (n = 30); surgery and radiation (n = 17); and surgery, chemotherapy, and radiation (n = 27). Following a comprehensive screening and medical examination, cardiovascular endurance, pulmonary function, and fatigue were assessed, leading to the development of an individualized exercise prescription and a six-month exercise intervention. Repeated-measures analysis of variance and covariance were used to compare the effectiveness of the intervention and differences among treatment groups.
Main Research Variables
Systolic and diastolic blood pressure, resting heart rate, forced vital capacity, forced expiratory volume, predicted oxygen consumption, time on treadmill, and fatigue.
Findings
Cardiopulmonary function (predicted maximal oxygen consumption and time on treadmill) significantly increased in all groups after exercise training. In addition, resting heart rate and forced vital capacity significantly improved in those receiving surgery, chemotherapy, and radiation. Psychologically, the exercise intervention resulted in significant reductions in behavioral, affective, sensory, cognitive and mood, and total fatigue scale scores in all three groups who received treatment with surgery. The breast cancer survivors in the surgery-alone group showed significant reductions in behavioral, affective, and total fatigue scale scores but not in sensory and cognitive and mood fatigue scale scores.
Conclusions
The results suggest that moderate intensity, individualized, prescriptive exercise maintains or improves cardiopulmonary function with concomitant reductions in fatigue regardless of treatment type. Moreover, cancer survivors receiving combination chemotherapy and radiotherapy following surgery appear to benefit to a greater extent as a result of an individualized exercise intervention.
Implications for Nursing
Clinicians need to be aware of adjuvant therapies such as moderate exercise that attenuate negative side effects of cancer treatments. Symptom management recommendations should be given to cancer survivors concerning the effectiveness of exercise throughout the cancer continuum and the importance of participating in a cancer rehabilitation exercise program.
doi:10.1188/08.ONF.909-915
PMCID: PMC3040031  PMID: 18980921
23.  Structural and Functional Small Fiber Abnormalities in the Neuropathic Postural Tachycardia Syndrome 
PLoS ONE  2013;8(12):e84716.
Objective
To define the neuropathology, clinical phenotype, autonomic physiology and differentiating features in individuals with neuropathic and non-neuropathic postural tachycardia syndrome (POTS).
Methods
Twenty-four subjects with POTS and 10 healthy control subjects had skin biopsy analysis of intra-epidermal nerve fiber density (IENFD), quantitative sensory testing (QST) and autonomic testing. Subjects completed quality of life, fatigue and disability questionnaires. Subjects were divided into neuropathic and non-neuropathic POTS, defined by abnormal IENFD and abnormal small fiber and sudomotor function.
Results
Nine of 24 subjects had neuropathic POTS and had significantly lower resting and tilted heart rates; reduced parasympathetic function; and lower phase 4 valsalva maneuver overshoot compared with those with non-neuropathic POTS (P<0.05). Neuropathic POTS subjects also had less anxiety and depression and greater overall self-perceived health-related quality of life scores than non-neuropathic POTS subjects. A sub-group of POTS patients (cholinergic POTS) had abnormal proximal sudomotor function and symptoms that suggest gastrointestinal and genitourinary parasympathetic nervous system dysfunction.
Conclusions and Relevance
POTS subtypes may be distinguished using small fiber and autonomic structural and functional criteria. Patients with non-neuropathic POTS have greater anxiety, greater depression and lower health-related quality of life scores compared to those with neuropathic POTS. These findings suggest different pathophysiological processes underlie the postural tachycardia in neuropathic and non-neuropathic POTS patients. The findings have implications for the therapeutic interventions to treat this disorder.
doi:10.1371/journal.pone.0084716
PMCID: PMC3874039  PMID: 24386408
24.  Postural Tachycardia Syndrome: A Heterogeneous and Multifactorial Disorder 
Mayo Clinic Proceedings  2012;87(12):1214-1225.
Postural tachycardia syndrome (POTS) is defined by a heart rate increment of 30 beats/min or more within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. POTS manifests with symptoms of cerebral hypoperfusion and excessive sympathoexcitation. The pathophysiology of POTS is heterogeneous and includes impaired sympathetically mediated vasoconstriction, excessive sympathetic drive, volume dysregulation, and deconditioning. POTS is frequently included in the differential diagnosis of chronic unexplained symptoms, such as inappropriate sinus tachycardia, chronic fatigue, chronic dizziness, or unexplained spells in otherwise healthy young individuals. Many patients with POTS also report symptoms not attributable to orthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia, and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated with anxiety, depression, and behavioral amplification contribute to symptom chronicity. The aims of evaluation in patients with POTS are to exclude cardiac causes of inappropriate tachycardia; elucidate, if possible, the most likely pathophysiologic basis of postural intolerance; assess for the presence of treatable autonomic neuropathies; exclude endocrine causes of a hyperadrenergic state; evaluate for cardiovascular deconditioning; and determine the contribution of emotional and behavioral factors to the patient's symptoms. Management of POTS includes avoidance of precipitating factors, volume expansion, physical countermaneuvers, exercise training, pharmacotherapy (fludrocortisone, midodrine, β-blockers, and/or pyridostigmine), and behavioral-cognitive therapy. A literature search of PubMed for articles published from January 1, 1990, to June 15, 2012, was performed using the following terms (or combination of terms): POTS; postural tachycardia syndrome, orthostatic; orthostatic; syncope; sympathetic; baroreceptors; vestibulosympathetic; hypovolemia; visceral pain; chronic fatigue; deconditioning; headache; Chiari malformation; Ehlers-Danlos; emotion; amygdala; insula; anterior cingulate; periaqueductal gray; fludrocortisone; midodrine; propranolol; β-adrenergic; and pyridostigmine. Studies were limited to those published in English. Other articles were identified from bibliographies of the retrieved articles.
doi:10.1016/j.mayocp.2012.08.013
PMCID: PMC3547546  PMID: 23122672
EDS, Ehlers-Danlos syndrome; HUT, head-up tilt; NE, norepinephrine; NET, norepinephrine transporter; POTS, postural tachycardia syndrome
25.  Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study 
BMJ Open  2014;4(10):e005920.
Objectives
Although pain is a significant symptom in chronic fatigue syndrome (CFS), pain is poorly understood in adolescents with CFS. The aim of this study was to explore pain distribution and prevalence, pain intensity and its functional interference in everyday life, as well as pressure pain thresholds (PPT) in adolescents with CFS and compare this with a control group of healthy adolescents (HC).
Methods
This is a case–control, cross-sectional study on pain including 120 adolescents with CFS and 39 HCs, aged 12–18 years. We measured pain frequency, pain severity and pain interference using self-reporting questionnaires. PPT was measured using pressure algometry. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial.
Results
Adolescents with CFS had significantly lower PPTs compared with HCs (p<0.001). The Pain Severity Score and the Pain Interference Score were significantly higher in adolescents with CFS compared with HCs (p<0.001). Almost all adolescents with CFS experienced headache, abdominal pain and/or pain in muscles and joints. Moreover, in all sites, the pain intensity levels were significantly higher than in HCs (p<0.001).
Conclusions
We found a higher prevalence of severe pain among adolescents with CFS and lowered pain thresholds compared with HCs. The mechanisms, however, are still obscure. Large longitudinal population surveys are warranted measuring pain thresholds prior to the onset of CFS.
Trial registration number
Clinical Trials, NCT01040429; The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL) http://www.clinicaltrials.gov.
doi:10.1136/bmjopen-2014-005920
PMCID: PMC4187660  PMID: 25287104
PAIN MANAGEMENT; PUBLIC HEALTH

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