2016 – Page 9 – American ME and CFS Society

Unexpected findings and promoting monocausal claims, a cautionary tale

Abstract:

Stories of serendipitous discoveries in medicine incorrectly imply that the path from an unexpected observation to major discovery is straightforward or guaranteed. In this paper, I examine a case from the field of research about chronic fatigue syndrome (CFS).

In Norway, an unexpected positive result during clinical care has led to the development of a research programme into the potential for the immunosuppressant drug rituximab to relieve the symptoms of CFS. The media and public have taken up researchers’ speculations that their research results indicate a causal mechanism for CFS – consequently, patients now have great hope that ‘the cause’ of CFS has been found, and thus, a cure is sure to follow.

I argue that a monocausal claim cannot be correctly asserted, either on the basis of the single case of an unexpected, although positive, result or on the basis of the empirical research that has followed up on that result. Further, assertion and promotion of this claim will have specific harmful effects: it threatens to inappropriately narrow the scope of research on CFS, might misdirect research altogether, and could directly and indirectly harm patients. Therefore, the CFS case presents a cautionary tale, illustrating the risks involved in drawing a theoretical hypothesis from an unexpected observation.

Further, I draw attention to the tendency in contemporary clinical research with CFS to promote new research directions on the basis of reductive causal models of that syndrome. Particularly, in the case of CFS research, underdetermination and causal complexity undermine the potential value of a monocausal claim. In sum, when an unexpected finding occurs in clinical practice or medical research, the value of following up on that finding is to be found not in the projected value of a singular causal relationship inferred from the finding but rather in the process of research that follows.

Source: Copeland SM.Unexpected findings and promoting monocausal claims, a cautionary tale. J Eval Clin Pract. 2016 Jun 10. doi: 10.1111/jep.12584. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27283254

Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients

Abstract:

BACKGROUND: No epidemiological investigations have previously been conducted in Australia according to the current clinical definitions of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to describe sociodemographic and illness characteristics of Australian patients with CFS/ME.

METHODS: A cross-sectional survey on the medical history of patients enrolled in an Australian CFS/ME research database between April 2013 and April 2015. Participants were classified according to Fukuda criteria and International Consensus Criteria.

RESULTS: A total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. The mean age of all patients was 46.4 years (standard deviation 12.0); the majority were female (78.61%), Caucasian, and highly educated. Of these, 30.28% met Fukuda criteria. A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress. Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified.

CONCLUSION: This is the first study to summarize sociodemographic and illness characteristics of a cohort of Australian CFS/ME patients. This is vital for identifying potential risk factors and predictors associated with CFS/ME and for guiding decisions regarding health care provision, diagnosis, and management.

Source: Johnston SC, Staines DR, Marshall-Gradisnik SM. Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients. Clin Epidemiol. 2016 May 17;8:97-107. doi: 10.2147/CLEP.S96797. ECollection 2016. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4878662/ (Full article)

A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest.

This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting.

Source: Navaneetharaja N, Griffiths V, Wileman T, Carding SR. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)? J Clin Med. 2016 Jun 6;5(6). pii: E55. doi: 10.3390/jcm5060055. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929410/ (Full article)

Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients

Abstract:

BACKGROUND: Transient receptor potential melastatin 3 (TRPM3) cation channels are ubiquitously expressed by multiple cells and have an important regulatory role in calcium-dependent cell signalling to help maintain cellular homeostasis. TRPM3 protein expression has yet to be determined on Natural Killer (NK) cells and B lymphocytes. Multiple single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) patients and have been proposed to correlate with illness presentation. The object of the study was to assess TRPM3 surface expression on NK and B lymphocytes from healthy controls, followed by a comparative investigation examining TRPM3 surface expression, and cytoplasmic and mitochondrial calcium influx in CD19(+) B cells, CD56(bright) and CD56(dim) cell populations from CFS/ME patients.

RESULTS: TRPM3 cell surface expression was identified for NK and B lymphocytes in healthy controls (CD56(bright) TRPM3 35.72 % ± 7.37; CD56(dim) 5.74 % ± 2.00; B lymphocytes 2.05 % ± 0.19, respectively). There was a significant reduction of TRPM3 surface expression on CD19(+) B cells (1.56 ± 0.191) and CD56(bright) NK cells (17.37 % ± 5.34) in CFS/ME compared with healthy controls. Anti-CD21 and anti-IgM conjugated biotin was cross-linked with streptavidin,and subsequently treatment with thapsigargin. This showed a significant reduction in cytoplasmic calcium ion concentration in CD19(+) B lymphocytes. CD56(bright) NK cells also had a significant decrease in cytoplasmic calcium in the presence of 2-APB and thapsigargin in CFS/ME patients.

CONCLUSIONS: The results from this preliminary investigation identify, for the first time, TRPM3 surface expression on both NK and B lymphocytes in healthy controls. We also report for the first time, significant reduction in TRPM3 cell surface expression in NK and B lymphocytes, as well as decreased intracellular calcium within specific conditions in CFS/ME patients. This warrants further examination of these pathways to elucidate whether TRPM3 and impaired calcium mobilisation has a role in CFS/ME.

Source: Nguyen T, Staines D, Nilius B, Smith P, Marshall-Gradisnik S. Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients. Biol Res. 2016 May 31;49(1):27. doi: 10.1186/s40659-016-0087-2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888729/ (Full article)

A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

PURPOSE: The pathogenesis of chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is complex and remains poorly understood. Evidence regarding the use of drug therapies in CFS/ME is currently limited and conflicting. The aim of this systematic review was to examine the existing evidence on the efficacy of drug therapies and determine whether any can be recommended for patients with CFS/ME.

METHODS: MEDLINE, EMBASE, and PubMed databases were searched from the start of their records to March 2016 to identify relevant studies. Randomized controlled trials focusing solely on drug therapy to alleviate and/or eliminate chronic fatigue symptoms were included in the review. Any trials that considered graded exercise therapy, cognitive behavior therapy, adaptive pacing, or any other nonpharmaceutical treatment plans were excluded. The inclusion criteria were examined to ensure that study participants met specific CFS/ME diagnostic criteria. Study size, intervention, and end point outcome domains were summarized.

FINDINGS: A total of 1039 studies were identified with the search terms; 26 studies met all the criteria and were considered suitable for review. Three different diagnostic criteria were identified: the Holmes criteria, International Consensus Criteria, and the Fukuda criteria. Primary outcomes were identified as fatigue, pain, mood, neurocognitive dysfunction and sleep quality, symptom severity, functional status, and well-being or overall health status. Twenty pharmaceutical classes were trialed. Ten medications were shown to be slightly to moderately effective in their respective study groups (P < 0.05).

IMPLICATIONS: These findings indicate that no universal pharmaceutical treatment can be recommended. The unknown etiology of CFS/ME, and complications arising from its heterogeneous nature, contributes to the lack of clear evidence for pharmaceutical interventions. However, patients report using a large number and variety of medications. This finding highlights the need for trials with clearly defined CFS/ME cohorts. Trials based on more specific criteria such as the International Consensus Criteria are recommended to identify specific subgroups of patients in whom treatments may be beneficial.

Source: Collatz A, Johnston SC, Staines DR, Marshall-Gradisnik SM. A Systematic Review of Drug Therapies for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. Clin Ther. 2016 Jun;38(6):1263-1271.e9. doi: 10.1016/j.clinthera.2016.04.038. Epub 2016 May 24. https://www.ncbi.nlm.nih.gov/pubmed/27229907

The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is comparable to multiple sclerosis, diabetes or rheumatoid arthritis in prevalence (∼0.2% to 1%), long-term disability, and quality of life,[1–5] yet the scale of biomedical research and funding has been pitifully limited, as the recent National Institutes of Health (NIH) and Institute of Medicine reports highlight.[6,7] Recently in the USA, NIH Director Francis Collins has stated that the NIH will be ramping up its efforts and levels of funding for ME/CFS,[8] which we hope will greatly increase the interest in, and resources for researching this illness. Despite scant funding to date, researchers in the field have generated promising leads that throw light on this previously baffling illness. We suggest the key elements of a concerted research programme and call on the wider biomedical research community to actively target this condition.

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867862/

Source: Edwards JC, McGrath S, Baldwin A, Livingstone M, Kewley A. The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue. 2016 Apr 2;4(2):63-69. Epub 2016 Apr 28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867862/

Simon McGrath 2016 May 30 4:05 p.m.

Authors’ abstract

(An abstract wasn’t required for this editorial, but the authors felt it would be helpful to add this one for PubMed. I am one of the authors.)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is as prevalent and disabling as multiple sclerosis, diabetes and rheumatoid arthritis but biomedical research into the condition has been grossly underfunded. However, the NIH is committed to ramping up funding for this illness and there are now promising research leads. We indicate clues to the biological mechanisms that may perpetuate the condition and suggest the key elements of a concerted research programme. In the absence of effective treatments, study of mechanism remains a key priority including the possible role of stochastic factors.

We identify the three most interesting major categories of causal model: (1) the brain is responding normally and symptoms are due to persistent signal input from peripheral tissues, such as cytokines or metabolites; (2) there is a persistent abnormality of ‘housekeeping’ processes in the brain, such as an increase in activation of microglia; and (3) there is a persistent abnormality in neural signalling in sensory pathways.

We recommend seven important, practical steps to make progress towards effective treatments: (1) build research infrastructure, including population-based cohorts with close attention to diagnostic criteria; (2) use new, developing techniques for brain imaging; (3) pursue promising immunological leads, such as natural killer cell abnormalities, cytokine shifts, auto-antibodies, and immune responses to viruses such as Epstein-Barr virus; (4) further explore autonomic/endocrine regulation; (5) extend the research on post-exertional changes in physiology; (6) attempt to replicate key findings to determine which are robust; and (7) present data in a way that allows subgroup analysis, and always provide raw data.

We conclude that the problem of ME/CFS now looks solvable and we call on the wider biomedical research community to target the condition.

A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity

Abstract:

We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions.

We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls.

Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls.

Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.

Source: Fukuda S, Nojima J, Motoki Y, Yamaguti K, Nakatomi Y, Okawa N, Fujiwara K, Watanabe Y, Kuratsune H. A potential biomarker for fatigue: Oxidative stress and anti-oxidative activity. Biol Psychol. 2016 Jul;118:88-93. doi: 10.1016/j.biopsycho.2016.05.005. Epub 2016 May 17. https://www.ncbi.nlm.nih.gov/pubmed/27224647

Chronic fatigue syndrome in adolescents

Dear Editor:

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a rare disease in adolescents, in whom the incidence is 0.5%. In adults, it has a multifactorial aetiology with no determining factor, primarily affects women (ratio, 2–3:1) aged 20–40 years, and in some cases its onset is associated with an infectious cause (usually viral). In adulthood, CFS is diagnosed based on clinical manifestations and is a diagnosis of exclusion (Table 1),1 and while the literature includes descriptions of differences in the paediatric population, few series present data on its particular features in this age group. The management is symptomatic with the goal of improving quality of life. Treatment with selective serotonin reuptake inhibitors (SSRIs), melatonin, methylphenidate, cognitive-behavioural therapy (CBT) and graded exercise has been proven to be effective in these patients.

You can read the full letter here: http://www.analesdepediatria.org/en/chronic-fatigue-syndrome-in-adolescents/articulo/S2341287916301168/

Source: Calle Gómez Á, Delgado Díez B, Campillo I López F, Salmerón Ruiz MA, Casas Rivero J. Chronic fatigue syndrome in adolescents. An Pediatr (Barc). 2016 Dec;85(6):318-320. doi: 10.1016/j.anpedi.2016.03.010. Epub 2016 May 20. [Article in Spanish] http://www.analesdepediatria.org/en/chronic-fatigue-syndrome-in-adolescents/articulo/S2341287916301168/ (Full article)

A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: An estimated 10% of children and adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) experience eating difficulties; however, little is known about why these difficulties develop, what the impact is or how to manage them.

METHODS: Semi-structured interviews were conducted with adolescents (aged 12-17 years) attending a specialist service who have a primary diagnosis of CFS/ME and experience nausea, abdominal pain and/or eating difficulties. A total of 11 adolescents were interviewed (eight female, mean age: 15 years). Transcripts were analysed thematically using techniques of constant comparison which commenced soon after data collection and informed further interview protocols.

RESULTS: Adolescents perceived their eating difficulties were caused by abdominal symptoms, being too fatigued to eat and changes to their senses of taste and smell. Some of the adolescents recognised how their eating difficulties were exacerbated and maintained by psychological factors of low mood and anxiety. The adolescents eating difficulties had a negative impact on their weight, fatigue, socialising and family life. They perceived helpful interventions to include modifying their diets, families adjusting and also medical interventions (e.g. medication). Adolescents identified that early education and support about diet and eating habits would have been helpful.

CONCLUSIONS: If adolescents diagnosed with CFS/ME develop eating difficulties, this has a significant impact on their quality of life, illness and on their families. Not eating increases fatigue, low mood and anxiety which further exacerbates the eating difficulties. Clinicians should screen for eating difficulties in those with symptoms of nausea and abdominal pain, warn adolescents and their families of the risk of developing eating difficulties and provide interventions and support as early as possible.

Source: Harris S, Gilbert M, Beasant L, Linney C, Broughton J, Crawley E. A qualitative investigation of eating difficulties in adolescents with chronic fatigue syndrome/myalgic encephalomyelitis. Clin Child Psychol Psychiatry. 2017 Jan;22(1):128-139. doi: 10.1177/1359104516646813. Epub 2016 Jul 26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207298/ (Full article)

Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis

Abstract:

PURPOSE: A prominent symptom of myalgic encephalomyelitis, chronic fatigue syndrome, or systemic exertion intolerance disease (ME/CFS/SEID) is persistent fatigue that is worsened by physical exertion. Here the population effect of a single bout of exercise on fatigue symptoms in people with ME/CFS/SEID was estimated and effect moderators were identified.

METHODS: Google Scholar was systematically searched for peer-reviewed articles published between February 1991 and May 2015. Studies were included where people diagnosed with ME/CFS/SEID and matched control participants completed a single bout of exercise and fatigue self-reports were obtained before and after exercise. Fatigue means, standard deviations, and sample sizes were extracted to calculate effect sizes and the 95% confidence interval. Effects were pooled using a random-effects model and corrected for small sample bias to generate mean Δ. Multilevel regression modeling adjusted for nesting of effects within studies. Moderators identified a priori were diagnostic criteria, fibromyalgia comorbidity, exercise factors (intensity, duration, and type), and measurement factors.

RESULTS: Seven studies examining 159 people with ME/CFS/SEID met inclusion criteria, and 47 fatigue effects were derived. The mean fatigue effect was Δ = 0.73 (95% confidence interval = 0.24-1.23). Fatigue increases were larger for people with ME/CFS/SEID when fatigue was measured 4 h or more after exercise ended rather than during or immediately after exercise ceased.

CONCLUSIONS: This preliminary evidence indicates that acute exercise increases fatigue in people with ME/CFS/SEID more than that in control groups, but effects were heterogeneous between studies. Future studies with no-exercise control groups of people with ME/CFS/SEID are needed to obtain a more precise estimate of the effect of exercise on fatigue in this population.

Source: Loy BD, O’Connor PJ, Dishman RK. Effect of Acute Exercise on Fatigue in People with ME/CFS/SEID: A Meta-analysis. Med Sci Sports Exerc. 2016 Oct;48(10):2003-12. doi: 10.1249/MSS.0000000000000990. https://www.ncbi.nlm.nih.gov/pubmed/27187093