Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review

Abstract:

OBJECTIVE: To identify case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), and explore how the validity of case definitions can be evaluated in the absence of a reference standard.

DESIGN: Systematic review.

SETTING: International.

PARTICIPANTS: A literature search, updated as of November 2013, led to the identification of 20 case definitions and inclusion of 38 validation studies.

PRIMARY AND SECONDARY OUTCOME MEASURE: Validation studies were assessed for risk of bias and categorised according to three validation models: (1) independent application of several case definitions on the same population, (2) sequential application of different case definitions on patients diagnosed with CFS/ME with one set of diagnostic criteria or (3) comparison of prevalence estimates from different case definitions applied on different populations.

RESULTS: A total of 38 studies contributed data of sufficient quality and consistency for evaluation of validity, with CDC-1994/Fukuda as the most frequently applied case definition. No study rigorously assessed the reproducibility or feasibility of case definitions. Validation studies were small with methodological weaknesses and inconsistent results. No empirical data indicated that any case definition specifically identified patients with a neuroimmunological condition.

CONCLUSIONS: Classification of patients according to severity and symptom patterns, aiming to predict prognosis or effectiveness of therapy, seems useful. Development of further case definitions of CFS/ME should be given a low priority. Consistency in research can be achieved by applying diagnostic criteria that have been subjected to systematic evaluation.

 

Source: Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 2014 Feb 7;4(2):e003973. doi: 10.1136/bmjopen-2013-003973. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918975/ (Full article)

 

Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial

Abstract:

IMPORTANCE: Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options.

OBJECTIVE: To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function.

DESIGN, SETTING, AND PARTICIPANTS: Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 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.

INTERVENTIONS: Clonidine hydrochloride capsules (25 µg or 50 µg twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks.

MAIN OUTCOMES AND MEASURES: Number of steps per day.

RESULTS: At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, -637 steps; P = .07), lower plasma norepinephrine level (mean difference, -42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group.

CONCLUSIONS AND RELEVANCE: Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus-pituitary-adrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01040429.

 

Source: Sulheim D, Fagermoen E, Winger A, Andersen AM, Godang K, Müller F, Rowe PC, Saul JP, Skovlund E, Øie MG, Wyller VB. Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial. JAMA Pediatr. 2014 Apr;168(4):351-60. doi: 10.1001/jamapediatrics.2013.4647. https://www.ncbi.nlm.nih.gov/pubmed/24493300

 

Living with the unexplained: coping, distress, and depression among women with chronic fatigue syndrome and/or fibromyalgia compared to an autoimmune disorder

Abstract:

Chronic fatigue syndrome (CFS) and fibromyalgia are disabling conditions without objective diagnostic tests, clear-cut treatments, or established etiologies. Those with the disorders are viewed suspiciously, and claims of malingering are common, thus promoting further distress. It was hypothesized in the current study that levels of unsupportive social interactions and the coping styles used among those with CFS/fibromyalgia would be associated with perceived distress and depressive symptoms.

Women with CFS/fibromyalgia (n=39), in fact, reported higher depression scores, greater perceived distress and more frequent unsupportive relationships than healthy women (n=55), whereas those with a chronic, but medically accepted illness comprising an autoimmune disorder (lupus erythematosus, multiple sclerosis, rheumatoid arthritis; n=28), displayed intermediate scores. High problem-focused coping was associated with low levels of depression and perceived distress in those with an autoimmune condition.

In contrast, although CFS/fibromyalgia was also accompanied by higher depression scores and higher perceived distress, this occurred irrespective of problem-focused coping. It is suggested that because the veracity of ambiguous illnesses is often questioned, this might represent a potent stressor in women with such illnesses, and even coping methods typically thought to be useful in other conditions, are not associated with diminished distress among those with CFS/fibromyalgia.

 

Source: McInnis OA, Matheson K, Anisman H. Living with the unexplained: coping, distress, and depression among women with chronic fatigue syndrome and/or fibromyalgia compared to an autoimmune disorder. Anxiety Stress Coping. 2014;27(6):601-18. doi: 10.1080/10615806.2014.888060. Epub 2014 Mar 3. https://www.ncbi.nlm.nih.gov/pubmed/24479644

 

Diagnosing Chronic Fatigue Syndrome in South Asians: Lessons from a Secondary Analysis of a UK Qualitative Study

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalitis (CFS/ME) is rarely diagnosed in South Asia (SA), although the symptoms of this condition are seen in the population. Lessons from UK based South Asian, Black and Minority Ethnic (BME) communities may be of value in identifying barriers to diagnosis of CFS/ME in SA.

OBJECTIVES: To explore why CFS/ME may not be commonly diagnosed in SA.

SETTINGS AND DESIGN: A secondary analysis of qualitative data on the diagnosis and management of CFS/ME in BME people of predominantly South Asian origin in the UK using 27 semi-structured qualitative interviews with people with CFE/ME, carers, general practitioners (GPs), and community leaders.

RESULTS: CFS/ME is seen among the BME communities in the UK. People from BME communities in the UK can present to healthcare practitioners with vague physical complaints and they can hold a biomedical model of illness. Patients found it useful to have a label of CFS/ME although some GPs felt it to be a negative label. Access to healthcare can be limited by GPs reluctance to diagnose CFS/ME, their lack of knowledge and patients negative experiences. Cultural aspects among BME patients in the UK also act as a barrier to the diagnosis of CFS/ME.

CONCLUSION: Cultural values and practices influence the diagnosis of CFS/ME in BME communities. The variations in the perceptions around CFS/ME among patients, carers, and health professionals may pose challenges in diagnosing CFS/ME in SA as well. Raising awareness of CFS/ME would improve the diagnosis and management of patients with CFS/ME in SA.

 

Source: De Silva RE, Bayliss K, Riste L, Chew-Graham CA.Diagnosing Chronic Fatigue Syndrome in South Asians: Lessons from a Secondary Analysis of a UK Qualitative Study. J Family Med Prim Care. 2013 Jul;2(3):277-82. Doi: 10.4103/2249-4863.120765. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902687/ (Full article)

 

Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study

Abstract:

OBJECTIVE: Unsuspected idiopathic intracranial hypertension (IIH) is found in a significant minority of patients attending clinics with named headache syndromes, if it is specifically sought out. Chronic fatigue syndrome is frequently associated with headache. Could the same be true of chronic fatigue? Moreover, there are striking similarities between the two conditions. Could they be related? Attempting to answer these questions, we describe the results of a change in clinical practice aimed at capturing patients with chronic fatigue who might have IIH.

DESIGN: Cross-sectional.

SETTING: Hospital outpatient and radiology departments.

PARTICIPANTS: Patients attending a specialist clinic with chronic fatigue syndrome and headache who had lumbar puncture to exclude raised intracranial pressure.

MAIN OUTCOME MEASURES: Intracranial pressure measured at lumbar puncture and the effect on headache of cerebrospinal fluid drainage.

RESULTS: Mean cerebrospinal fluid pressure was 19 cm H2O (range 12-41 cm H2O). Four patients fulfilled the criteria for IIH. Thirteen others did not have pressures high enough to diagnose IIH but still reported an improvement in headache after drainage of cerebrospinal fluid. Some patients also volunteered an improvement in other symptoms, including fatigue. No patient had any clinical signs of raised intracranial pressure.

CONCLUSIONS: An unknown, but possibly substantial, minority of patients with chronic fatigue syndrome may actually have IIH. An unknown, but much larger, proportion of patients with chronic fatigue syndrome do not have IIH by current criteria but respond to lumbar puncture in the same way as patients who do. This suggests that the two conditions may be related.

 

Source: Higgins N, Pickard J, Lever A. Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study. JRSM Short Rep. 2013 Nov 21;4(12):2042533313507920. doi: 10.1177/2042533313507920. eCollection 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899735/ (Full article)

 

Rebuttal to Ickmans et al. association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome

Dear Editor:

In a study recently published in Journal of Rehabilitation Research and Development, Ickmans et al. [1] found a substantially deteriorated physical exercise capacity in myalgic encephalopathy/chronic fatigue syndrome (ME/CFS), as established by a cardiopulmonary exercise test (peak oxygen uptake [VO2max]: 19.1 ± 4.6 mL/min/kg, peak heart rate: 145.1 ± 22.4 beats per minute [bpm], peak workload: 114.2 ± 31.3 W, compared with 27.2 ± 5.6 mL/min/ kg, 170.0 ± 36.2 bpm, and 114.2 ± 31.3 W, respectively, in sedentary controls). Ickmans et al. Also observed various cognitive deficits in ME/CFS, e.g., prolonged choice and simple reaction times in various Stroop subtests and the psychomotor vigilance task test (PVT), more errors of omission in the PVT, and worse letter recall scores on the operation span task test, indicative for working memory impairment and reduced psychomotor speed.

You can read the rest of this letter here:  http://www.rehab.research.va.gov/jour/2013/509/pdf/pagevii.pdf 

Comment on: Association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome. [J Rehabil Res Dev. 2013]

 

Source: Twisk F. Rebuttal to Ickmans et al. association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome. J Rehabil Res Dev. 2013;50(9):vii-viii. http://www.rehab.research.va.gov/jour/2013/509/pdf/pagevii.pdf (Full article)

 

Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: The insufficient metabolic adaptation to exercise in Chronic Fatigue Syndrome (CFS) is still being debated and poorly understood.

METHODS: We analysed the cardiopulmonary exercise tests of CFS patients, idiopathic chronic fatigue (CFI) patients and healthy visitors. Continuous non-invasive measurement of the cardiac output by Nexfin (BMEYE B.V. Amsterdam, the Netherlands) was added to the cardiopulmonary exercise tests. The peak oxygen extraction by muscle cells and the increase of cardiac output relative to the increase of oxygen uptake (ΔQ’/ΔV’O₂) were measured, calculated from the cardiac output and the oxygen uptake during incremental exercise.

RESULTS: The peak oxygen extraction by muscle cells was 10.83 ± 2.80 ml/100ml in 178 CFS women, 11.62 ± 2.90 ml/100 ml in 172 CFI, and 13.45 ± 2.72 ml/100 ml in 11 healthy women (ANOVA: P=0.001), 13.66 ± 3.31 ml/100 ml in 25 CFS men, 14.63 ± 4.38 ml/100 ml in 51 CFI, and 19.52 ± 6.53 ml/100 ml in 7 healthy men (ANOVA: P=0.008).The ΔQ’/ΔV’O₂ was > 6 L/L (normal ΔQ’/ΔV’O₂ ≈ 5 L/L) in 70% of the patients and in 22% of the healthy group.

CONCLUSION: Low oxygen uptake by muscle cells causes exercise intolerance in a majority of CFS patients, indicating insufficient metabolic adaptation to incremental exercise. The high increase of the cardiac output relative to the increase of oxygen uptake argues against deconditioning as a cause for physical impairment in these patients.

 

Source: Vermeulen RC, Vermeulen van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014 Jan 23;12:20. doi: 10.1186/1479-5876-12-20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3903040/ (Full article)’

 

Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome

Abstract:

Epstein-Barr virus (EBV) has long been discussed as a possible cause or trigger of Chronic Fatigue Syndrome (CFS). In a subset of patients the disease starts with infectious mononucleosis and both enhanced and diminished EBV-specific antibody titers have been reported.

In this study, we comprehensively analyzed the EBV-specific memory B- and T-cell response in patients with CFS. While we observed no difference in viral capsid antigen (VCA)-IgG antibodies, EBV nuclear antigen (EBNA)-IgG titers were low or absent in 10% of CFS patients.

Remarkably, when analyzing the EBV-specific memory B-cell reservoir in vitro a diminished or absent number of EBNA-1- and VCA-antibody secreting cells was found in up to 76% of patients. Moreover, the ex vivo EBV-induced secretion of TNF-α and IFN-γ was significantly lower in patients. Multicolor flow cytometry revealed that the frequencies of EBNA-1-specific triple TNF-α/IFN-γ/IL-2 producing CD4(+) and CD8(+) T-cell subsets were significantly diminished whereas no difference could be detected for HCMV-specific T-cell responses. When comparing EBV load in blood immune cells, we found more frequently EBER-DNA but not BZLF-1 RNA in CFS patients compared to healthy controls suggesting more frequent latent replication.

Taken together, our findings give evidence for a deficient EBV-specific B- and T-cell memory response in CFS patients and suggest an impaired ability to control early steps of EBV reactivation. In addition the diminished EBV response might be suitable to develop diagnostic marker in CFS.

 

Source: Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, Thomas S, Unterwalder N, von Baehr V, Reinke P, Knops M, Hanitsch LG, Meisel C, Volk HD, Scheibenbogen C. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS One. 2014 Jan 15;9(1):e85387. doi: 10.1371/journal.pone.0085387. ECollection 2014. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893202/ (Full article)

 

Chronic fatigue syndrome: a personalized integrative medicine approach

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a relatively common illness, yet despite considerable investigation, current treatments have modest benefits, and the prognosis remains poor. Because CFS/ME is a heterogeneous disorder with diverse etiological factors and pathological features, a patient-centered integrative framework based on modifiable physiological and environmental factors may offer hope for more effective management and better clinical outcomes. An individualized approach may also help target interventions for subgroups most likely to respond to specific treatments. This review summarizes a number of avenues for integrative management, including dietary modification, functional nutritional deficiencies, physical fitness, psychological and physical stress, environmental toxicity, gastrointestinal disturbances, immunological aberrations, inflammation, oxidative stress, and mitochondrial dysfunction. A personalized, integrative approach to CFS/ME deserves further consideration as a template for patient management and future research.

 

Source: Brown B. Chronic fatigue syndrome: a personalized integrative medicine approach. Altern Ther Health Med. 2014 Jan-Feb;20(1):29-40. https://www.ncbi.nlm.nih.gov/pubmed/24445354

 

Valacyclovir treatment of chronic fatigue in adolescents

Abstract:

Chronic fatigue syndrome (CFS) presents with fatigue, low motivation, diminished mood, and reduced activity, all symptoms having extensive diagnostic overlaps with depression. Studies have linked chronic viral infections with CFS, and antiviral therapy has effectively treated CFS in adult patients.

In a retrospective case series, 15 adolescents and preteens referred to the author for treatment-resistant depression or mood disorder were evaluated and found to have met the Fukuda diagnostic criteria for CFS. While a subset (4/15) had been diagnosed in the past with CFS, the majority had a current diagnosis of depression or a mood disorder. The Diagnostic and Statistical Manual-IV Text Revision (DSM-IV TR) criteria for depression were not met in all patients, although 3 cases of mood disorder not otherwise specified (MD-NOS) and 1 case of Tourette syndrome (TS) plus MD-NOS were diagnosed. Baseline scores on the Children’s Depression Inventory (CDI) were below the cutoff for depression in all but 1 patient. Baseline self-assessment scales for CFS or fatigue were obtained and sleep was evaluated with sleep logs.

All patients were treated subsequently with valacyclovir, with 93% having a positive response. At the end of treatment, scores on fatigue self-assessment scales improved significantly (P < .001). Vigor subscale scores also improved significantly (P < .001). Some patients experienced complete resolution of symptoms. Although not every patient was tested, available laboratory testing revealed increased counts of natural killer (NK) cells and decreased human herpesvirus 6 (HHV-6) antibody titers in all patients who responded to valacyclovir.

This article discusses the significance of infectious agents in the pathogenesis of psychiatric symptoms. The study’s data support an intriguing hypothesis that a portion of treatment-resistant depression in fact may be undiagnosed CFS or other chronic viral infection.

 

Source: Henderson TA. Valacyclovir treatment of chronic fatigue in adolescents. Adv Mind Body Med. 2014 Winter;28(1):4-14. https://www.ncbi.nlm.nih.gov/pubmed/24445302