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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.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  Chronic fatigue syndrome 
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
16.  Chronic fatigue syndrome 
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
17.  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
18.  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
19.  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
20.  Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial 
BMC Research Notes  2012;5:418.
Background
This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects.
Findings
Five adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire.
After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered.
Conclusion
Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).
doi:10.1186/1756-0500-5-418
PMCID: PMC3461473  PMID: 22871021
Chronic fatigue syndrome; Adolescents; Clonidine; Adverse effects; Head-up tilt test; Autonomic nervous system
21.  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
22.  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
23.  Endovascular Laser Therapy for Varicose Veins 
Executive Summary
Objective
The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost–effectiveness of endovascular laser therapy (ELT) for the treatment of primary symptomatic varicose veins (VV).
Background
The Ontario Health Technology Advisory Committee (OHTAC) met on November 27, 2009 to review the safety, effectiveness, durability and cost-effectiveness of ELT for the treatment of primary VV based on an evidence-based review by the Medical Advisory Secretariat (MAS).
Clinical Condition
VV are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins).
Symptoms typically affect the lower extremities and include (but are not limited to): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI).
A number of complications are associated with untreated venous reflux: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI.
CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad or worse as other chronic diseases such as back pain and arthritis.
Lower limb VV is a common disease affecting adults and estimated to be the seventh most common reason for physician referral in the US. There is a strong familial predisposition to VV with the risk in offspring being 90% if both parents affected, 20% when neither is affected, and 45% (25% boys, 62% girls) if one parent is affected. Globally, the prevalence of VV ranges from 5% to 15% among men and 3% to 29% among women varying by the age, gender and ethnicity of the study population, survey methods and disease definition and measurement. The annual incidence of VV estimated from the Framingham Study was reported to be 2.6% among women and 1.9% among men and did not vary within the age range (40-89 years) studied.
Approximately 1% of the adult population has a stasis ulcer of venous origin at any one time with 4% at risk. The majority of leg ulcer patients are elderly with simple superficial vein reflux. Stasis ulcers are often lengthy medical problems and can last for several years and, despite effective compression therapy and multilayer bandaging are associated with high recurrence rates. Recent trials involving surgical treatment of superficial vein reflux have resulted in healing and significantly reduced recurrence rates.
Endovascular Laser Therapy for VV
ELT is an image-guided, minimally invasive treatment alternative to surgical stripping of superficial venous reflux. It does not require an operating room or general anesthesia and has been performed in outpatient settings by a variety of medical specialties including surgeons (vascular or general), interventional radiologists and phlebologists. Rather than surgically removing the vein, ELT works by destroying, cauterizing or ablating the refluxing vein segment using heat energy delivered via laser fibre.
Prior to ELT, colour-flow Doppler ultrasonography is used to confirm and map all areas of venous reflux to devise a safe and effective treatment plan. The ELT procedure involves the introduction of a guide wire into the target vein under ultrasound guidance followed by the insertion of an introducer sheath through which an optical fibre carrying the laser energy is advanced. A tumescent anesthetic solution is injected into the soft tissue surrounding the target vein along its entire length. This serves to anaesthetize the vein so that the patient feels no discomfort during the procedure. It also serves to insulate the heat from damaging adjacent structures, including nerves and skin. Once satisfactory positioning has been confirmed with ultrasound, the laser is activated. Both the laser fibre and the sheath are simultaneously, slowly and continuously pulled back along the length of the target vessel. At the end of the procedure, homeostasis is then achieved by applying pressure to the entry point.
Adequate and proper compression stockings and bandages are applied after the procedure to reduce the risk of venous thromboembolism, and to reduce postoperative bruising and tenderness. Patients are encouraged to walk immediately after the procedure and most patients return to work or usual activity within a few days. Follow-up protocols vary, with most patients returning 1-3 weeks later for an initial follow-up visit. At this point, the initial clinical result is assessed and occlusion of the treated vessels is confirmed with ultrasound. Patients often have a second follow-up visit 1-3 months following ELT at which time clinical evaluation and ultrasound are repeated. If required, sclerotherapy may be performed during the ELT procedure or at any follow-up visits.
Regulatory Status
Endovascular laser for the treatment of VV was approved by Health Canada as a class 3 device in 2002. The treatment has been an insured service in Saskatchewan since 2007 and is the only province to insure ELT. Although the treatment is not an insured service in Ontario, it has been provided by various medical specialties since 2002 in over 20 private clinics.
Methods
Literature Search
The MAS evidence-based review was performed as an update to the 2007 health technology review performed by the Australian Medical Services Committee (MSAC) to support public financing decisions. The literature search was performed on August 18, 2009 using standard bibliographic databases for studies published from January 1, 2007 to August 15, 2009. Search alerts were generated and reviewed for additional relevant literature up until October 1, 2009.
Inclusion Criteria
English language full-reports and human studies
Original reports with defined study methodology
Reports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction
Reports involving ELT for VV (great or small saphenous veins)
Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Cohort and controlled clinical studies involving > 1 month ultrasound imaging follow-up
Exclusion Criteria
Non systematic reviews, letters, comments and editorials
Reports not involving outcome events such as safety, effectiveness, durability, or patient satisfaction following an intervention with ELT
Reports not involving interventions with ELT for VV
Pilot studies or studies with small samples ( < 50 subjects)
Summary of Findings
The MAS evidence search identified 14 systematic reviews, 29 cohort studies on safety and effectiveness, four cost studies and 12 randomized controlled trials involving ELT, six of these comparing endovascular laser with surgical ligation and saphenous vein stripping.
Since 2007, 22 cohort studies involving 10,883 patients undergoing ELT of the great saphenous vein (GSV) have been published. Imaging defined treatment effectiveness of mean vein closure rates were reported to be greater than 90% (range 93%- 99%) at short term follow-up. Longer than one year follow-up was reported in five studies with life table analysis performed in four but the follow up was still limited at three and four years. The overall pooled major adverse event rate, including DVT, PE, skin burns or nerve damage events extracted from these studies, was 0.63% (69/10,883).
The overall level of evidence of randomized trials comparing ELT with surgical ligation and vein stripping (n= 6) was graded as moderate to high. Recovery after treatment was significantly quicker after ELT (return to work median number of days, 4 vs. 17; p= .005). Major adverse events occurring after surgery were higher [(1.8% (n=4) vs. 0.4% (n = 1) 1 but not significantly. Treatment effectiveness as measured by imaging vein absence or closure, symptom relief or quality of life similar in the two treatment groups and both treatments resulted in statistically significantly improvements in these outcomes. Recurrence was low after both treatments at follow up but neovascularization (growth of new vessels, a key predictor of long term recurrence was significantly more common (18% vs. 1%; p = .001) after surgery. Although patient satisfaction was reported to be high (>80%) with both treatments, patient preferences evaluated through recruitment process, physician reports and consumer groups were strongly in favour of ELT. For patients minimal complications, quick recovery and dependability of outpatient scheduling were key considerations.
As clinical effectiveness of the two treatments was similar, a cost-analysis was performed to compare differences in resources and costs between the two procedures. A budget impact analysis for introducing ELT as an insured service was also performed. The average case cost (based on Ontario hospital costs and medical resources) for surgical vein stripping was estimated to be $1,799. Because of the uncertainties with resources associated with ELT, in addition to the device related costs, hospital costs were varied and assumed to be the same as or less than (40%) those for surgery resulting in an average ELT case cost of $2,025 or $1,602.
Based on the historical pattern of surgical vein stripping for varices a 5-year projection was made for annual volumes and costs. In Ontario in 2007/2008, 3481 surgical vein stripping procedures were performed, 28% for repeat procedures. Annual volumes of ELT currently being performed in the province in over 20 private clinics were estimated to be approximately 840. If ELT were publicly reimbursed, it was assumed that it would capture 35% of the vein stripping market in the first year and increase to 55% in subsequent years. Based on these assumptions if ELT were not publicly reimbursed, the province would be paying approximately $5.9 million and if ELT were reimbursed the province would pay $8.2 million if the hospital costs for ELT were the same as surgery and $7.1 million if the hospital costs were less (40%) than surgery.
The conclusions on the comparative outcomes between laser ablation and surgical ligation and saphenous vein stripping are summarized in the table below (ES Table 1).
Outcome comparisons of ELT vs. surgery for VV
The outcomes of the evidence-based review on these treatments based on three different perspectives are summarized below:
Patient Outcomes – ELT vs. Surgery
ELT has a quicker recovery attributable to the decreased pain, lower minor complications, use of local anesthesia with immediate ambulation.
ELT is as effective as surgery in the short term as assessed by imaging anatomic outcomes, symptomatic relief and HRQOL outcomes.
Recurrence is similar but neovascularization, a key predictor of long term recurrence, is significantly higher with surgery.
Patient satisfaction is equally high after both treatments but patient preference is much more strongly for ELT. Surgeons performing ELT are satisfied with treatment outcomes and regularly offer ELT as a treatment alternative to surgery.
Clinical or Technical Advantages – ELT Over Surgery
An endovascular approach can more easily and more precisely treat multilevel disease and difficult to treat areas
ELT is an effective and a less invasive treatment for the elderly with VV and those with venous leg ulcers.
System Outcomes – ELT Replacing Surgery
ELT may offer system advantages in that the treatment can be offered by several medical specialties in outpatient settings and because it does not require an operating theatre or general anesthesia.
The treatment may result in ↓ pre-surgical investigations, decanting of patients from OR, ↓ demand on anesthetists time, ↓ hospital stay, ↓decrease wait time for VV treatment and provide more reliable outpatient scheduling.
Depending on the reimbursement mechanism for the treatment, however, it may also result in closure of outpatient clinics with an increasingly centralization of procedures in selected hospitals with large capital budgets resulting in larger and longer waiting lists.
Procedure costs may be similar for the two treatments but the budget impact may be greater with insurance of ELT because of the transfer of the cases from the private market to the public payer system.
PMCID: PMC3377531  PMID: 23074409
24.  Fatigue in primary Sjögren's syndrome 
Annals of the Rheumatic Diseases  1998;57(5):291-295.
OBJECTIVE—To assess fatigue in relation to depression, blood pressure, and plasma catecholamines in patients with primary Sjögren's syndrome (SS), in comparison with healthy controls and patients with rheumatoid arthritis.
METHODS—For the assessment of fatigue the Multidimensional Fatigue Inventory (MFI) was used, a 20 item questionnaire, covering the following dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity. Furthermore, the Zung depression scale was used to quantify aspects of depression. Forty nine female primary SS patients, 44 female patients with rheumatoid arthritis (RA), and 32 healthy women filled in both questionnaires. In addition, supine values of blood pressure and plasma catecholamines were measured in the patients with primary SS.
RESULTS—Primary SS patients were more fatigued compared with the healthy controls on all the five dimensions of the MFI. When the analyses were repeated using depression as a covariate, group differences disappeared for the dimensions of reduced motivation and mental fatigue. In the primary SS patients, significant positive correlations between depression and the dimensions of reduced motivation and mental fatigue were found. Comparing patients with primary SS with those with RA, using depression as covariate, no statistically significant differences were found between these groups. No relation between fatigue and blood pressure was found, but a negative correlation was observed between the general fatigue subscale of the MFI and plasma noradrenaline.
CONCLUSION—Patients with primary SS report more fatigue than healthy controls on all the dimensions of the MFI and when controlling for depression significant differences remain on the dimensions of general fatigue, physical fatigue, and reduced activity. The negative correlations between levels of noradrenaline and general fatigue in patients with primary SS may imply the involvement of the autonomic nervous system in chronic fatigue.

 Keywords: Sjögren's syndrome; fatigue
PMCID: PMC1752605  PMID: 9741313
25.  Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes 
Several studies recognized an overlap between CFS (chronic fatigue syndrome) and POTS (postural tachycardia syndrome). We compared the autonomic and neurohormonal phenotype of POTS patients with CFS (CFS–POTS) to those without CFS (non-CFS–POTS), to determine whether CFS–POTS represents a unique clinical entity with a distinct pathophysiology. We recruited 58 patients with POTS, of which 47 were eligible to participate. A total of 93% of them reported severe fatigue [CIS (Checklist of Individual Strength), fatigue subscale >36], and 64% (n=30) fulfilled criteria for CFS (CFS–POTS). The prevalence of CFS symptoms (Centers for Disease Control and Prevention criteria) was greater in the CFS–POTS group, but the pattern of symptoms was similar in both groups. Physical functioning was low in both groups (RAND-36 Health Survey, 40±4 compared with 33±3; P=0.153), despite more severe fatigue in CFS–POTS patients (CIS fatigue subscale 51±1 compared with 43±3; P=0.016). CFS–POTS patients had greater orthostatic tachycardia than the non-CFS–POTS group (51±3 compared with 40±4 beats/min; P=0.030), greater low-frequency variability of BP (blood pressure; 6.3±0.7 compared with 4.8±1.0 mmHg2; P=0.019), greater BP recovery from early to late phase II of the Valsalva manoeuvre (18±3 compared with 11±2 mmHg; P=0.041) and a higher supine (1.5±0.2 compared with 1.0±0.3 ng/ml per·h; P=0.033) and upright (5.4±0.6 compared with 3.5±0.8 ng/ml per h; P=0.032) PRA (plasma renin activity). In conclusion, fatigue and CFS-defining symptoms are common in POTS patients. The majority of them met criteria for CFS. CFS–POTS patients have higher markers of sympathetic activation, but are part of the spectrum of POTS. Targeting this sympathetic activation should be considered in the treatment of these patients.
doi:10.1042/CS20110200
PMCID: PMC3203411  PMID: 21906029
autonomic nervous system; blood volume; chronic fatigue syndrome; orthostatic intolerance; postural tachycardia syndrome (POTS); renin; AFT, autonomic function test; AngI, angiotensin I; BMI, body mass index; BP, blood pressure; BV, blood volume; CDC, Centers for Disease Control and Prevention; CFS, chronic fatigue syndrome; CIS, Checklist of Individual Strength; HR, heart rate; POTS, postural tachycardia syndrome; PRA, plasma renin activity; PV, plasma volume; QSART, quantitative sudomotor axon reflex testing; RAAS, renin–angiotensin–aldosterone system

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