Page 408 – American ME and CFS Society

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Abstract:

BACKGROUND: Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls. Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors.

RESULTS: CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4(+)T and CD8(+)T cells. Moderate CFS/ME patients had increased CD8(+) CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5(+) on CD4(+)T cells and BTLA4(+) on CD4(+)T central memory cells. Moderate CFS/ME patients also had reduced CD8(+)T central memory LFA-1, total CD8(+)T KLRG1, naïve CD4(+)T KLRG1 and CD56(dim)CD16(-) NK cell CD2(+) and CD18(+)CD2(+). Severe CFS/ME patients had increased CD18(+)CD11c(-) in the CD56(dim)CD16(-) NK cell phenotype and reduced NKp46 in CD56(bright)CD16(dim) NK cells.

CONCLUSIONS: This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

Source: Hardcastle SL, Brenu EW, Johnston S, Nguyen T, Huth T, Wong N, Ramos S, Staines D, Marshall-Gradisnik S. Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). BMC Immunol. 2015 Jun 2;16:35. doi: 10.1186/s12865-015-0101-4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450981/ (Full article)

Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition

Abstract:

Current case definitions of Myalgic Encephalomyelitis (ME) and chronic fatigue syndrome (CFS) have been based on consensus methods, but empirical methods could be used to identify core symptoms and thereby improve the reliability. In the present study, several methods (i.e., continuous scores of symptoms, theoretically and empirically derived cut off scores of symptoms) were used to identify core symptoms best differentiating patients from controls. In addition, data mining with decision trees was conducted. Our study found a small number of core symptoms that have good sensitivity and specificity, and these included fatigue, post-exertional malaise, a neurocognitive symptom, and unrefreshing sleep. Outcomes from these analyses suggest that using empirically selected symptoms can help guide the creation of a more reliable case definition.

Source: Jason LA, Kot B, Sunnquist M, Brown A, Evans M, Jantke R, Williams Y, Furst J, Vernon SD. Chronic Fatigue Syndrome and Myalgic Encephalomyelitis: Toward An Empirical Case Definition. Health Psychol Behav Med. 2015;3(1):82-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443921/ (Full article)

Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case-control study

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating illness. Symptoms include profound fatigue and distinctive post-exertional malaise (PEM). We asked whether a submaximal exercise test would prove useful for identifying different patterns of tissue oxygen utilization in individuals with ME/CFS versus healthy subjects. Such a test has potential to aid with ME/CFS diagnosis, or to characterize patients’ illness.

METHODS: A case-control study of 16 patients with ME/CFS compared to 16 healthy controls completing a 3-min handgrip protocol was performed. Response was measured using near-infrared spectroscopy, resulting in measurements of oxygenated (O2Hb) and deoxygenated hemoglobin (HHb) over wrist extensors and flexors. Changes in O2Hb (delta (d)O2Hb) and HHb (dHHb) absorbance between the first and last contraction were calculated, as were the force-time product of all contractions, measured as tension-time index (TTI), and ratings of perceived exertion (RPE).

RESULTS: Individuals with ME/CFS demonstrated smaller dO2Hb and dHHb than controls. However, after adjusting for TTI and change in total hemoglobin (delta (d)tHb), differences in dO2Hb and dHHb were reduced, with large overlapping variances. RPE was significantly higher for cases than controls, particularly at rest.

CONCLUSIONS: Relative to controls, participants with ME/CFS demonstrated higher RPE, lower TTI, and reduced dO2Hb and dHHb during repetitive handgrip exercise, although considerable variance was observed. With further study, submaximal exercise testing may prove useful for stratifying patients with a lower propensity for inducing PEM, and have the ability to establish baseline intensities for exercise prescription.

Source: Miller RR, Reid WD, Mattman A, Yamabayashi C, Steiner T, Parker S, Gardy J, Tang P, Patrick DM. Submaximal exercise testing with near-infrared spectroscopy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients compared to healthy controls: a case-control study. J Transl Med. 2015 May 20;13:159. doi: 10.1186/s12967-015-0527-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4438583/ (Full article)

Working with uncertainty: A grounded theory study of health-care professionals’ experiences of working with children and adolescents with chronic fatigue syndrome

Abstract:

This grounded theory study explores conceptualisations of chronic fatigue syndrome/myalgic encephalomyelitis from semi-structured interviews with 10 health-care professionals working with children and adolescents. The findings suggest that a lack of a clear empirical understanding of chronic fatigue syndrome/myalgic encephalomyelitis leads to ‘working with uncertainty’, whereby health-care professionals utilise previous experiences to make sense of the condition and inform their clinical practice. How health-care professionals make sense of chronic fatigue syndrome/myalgic encephalomyelitis may influence the labels given to young people and the interventions they receive. The findings provide insight into a currently understudied area, and highlight potential avenues for further research and clinical practice.

Source: Marks MR, Huws JC, Whitehead L. Working with uncertainty: A grounded theory study of health-care professionals’ experiences of working with children and adolescents with chronic fatigue syndrome. J Health Psychol. 2015 May 8. pii: 1359105315583367. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/25957226

A critical analysis of the proposal of the Institute of Medicine to replace myalgic encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion intolerance disease

Abstract:

The Institute of Medicine (IOM) recently published their report in response to an assignment “to define diagnostic criteria for Myalgic Encephalomyelitis (ME)/chronic fatigue syndrome (CFS), to propose a process for reevaluation of these criteria in the future, and to consider whether a new name for this disease is warranted”.

The basic pre-assumption of the IOM committee for the development of evidence-based diagnostic criteria for ME/CFS was that ME and CFS denote conditions with similar symptoms, hence ME/CFS. The IOM committee recommends: (1) that ME/CFS will be renamed ‘systemic exertion intolerance disease’ (SEID); and that a new code should be assigned to SEID in the International Classification of Diseases (ICD), replacing the existing codes for ME (a neurological disease: G93.3) and CFS (‘signs, symptoms, and abnormal clinical and laboratory findings, not elsewhere classified’: R53.82); (2) that a diagnosis of SEID should be made if the new diagnostic criteria are met; (3) that the Department of Health and Human Services develops a toolkit appropriate for screening and diagnosing patients; and (4) that a multidisciplinary group re-examines the new diagnostic criteria when necessary.

This editorial reviews the working procedure of the IOM and two of the outcomes: the recommendation to introduce a new clinical entity (SEID) and new diagnostic criteria. Based upon the contents of the report, and the arguments of the IOM, a search of PubMed and the archive of the Journal of Chronic Fatigue Syndrome using the search terms ME (and old synonyms) and CFS, and a search of PubMed related to the five core symptoms of SEID was conducted.

Reviewing the working method and the recommendations, it is concluded that the new diagnostic criteria for SEID are based upon important methodological shortcomings and that the introduction of SEID to replace both ME and CFS has several profound negative consequences outweighing the advantages.

Source: Twisk FN. A critical analysis of the proposal of the Institute of Medicine to replace myalgic encephalomyelitis and chronic fatigue syndrome by a new diagnostic entity called systemic exertion intolerance disease. Curr Med Res Opin. 2015;31(7):1333-47. doi: 10.1185/03007995.2015.1045472. Epub 2015 May 29. https://www.ncbi.nlm.nih.gov/pubmed/25912615 (Full article)

Chronic Fatigue Syndrome

Excerpt:

Fatigue is a universal symptom, occurring in all individuals after prolonged exertion or lack of sleep. However, when fatigue is persistently present, without adequate environmental or medical explanation, fatigue has been recognised as the hallmark of a frequent and enigmatic clinical syndrome. Although difficult to precisely define and measure, fatigue is a pervasive sense of tiredness or lack of energy, that is not related exclusively to exertion. Fatigue may be appreciated centrally in terms of concentration, memory and motivation, or appreciated peripherally, where symptoms are often referred to the muscles. Chronic Fatigue Syndrome (CFS) is a term that was chosen and defined by Holmes et al., in 1988 to describe a combination of non-specific symptoms including profound fatigue, weakness, malaise and cognitive impairment with a remarkable lack of objective physical or laboratory abnormalities (1).

This syndrome had previously been known as “Chronic Epstein-Barr Virus Syndrome” and “Chronic Mononucleosis”. The terminology “CFS” was widely accepted because it implies no aetiology or specific pathological process. Several definitions of CFS have been developed, primarily to standardise research (2,3). It was not intended that they be used for clinical diagnosis. The Canadian Clinical Working Case Definition of Chronic Fatigue Syndrome was developed in response to an increasing need for such a definition for practising clinicians (4). It is the first definition that was created primarily to aid in clinical diagnosis, by encompassing many of the positive signs and symptoms of CFS, in order that it can be recognised as a distinct entity and distinguished from other clinical syndromes that have overlapping symptoms.

Source: Torpy BDJ, Saranapala M. Chronic Fatigue Syndrome. In: De Groot LJ, Chrousos G, Dungan K, Feingold KR, Grossman A, Hershman JM, Koch C, Korbonits M, McLachlan R, New M, Purnell J, Rebar R,Singer F, Vinik A, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. 2014 Nov 20. https://www.ncbi.nlm.nih.gov/books/NBK279099/ (Full article)

Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia

Abstract:

BACKGROUND: Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders.

OBJECTIVE: To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years.

METHODS: 38 patients were included in a cross-sectional survey. Based on a validated observer’s rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects.

RESULTS: Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as “very much” or “much” improved, while Mild responders rated “much” or “minimally” improved.

CONCLUSIONS: Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It’s important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed.

Source: Regland B, Forsmark S, Halaouate L, Matousek M, Peilot B, Zachrisson O, Gottfries CG. Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia. PLoS One. 2015 Apr 22;10(4):e0124648. doi: 10.1371/journal.pone.0124648. ECollection 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406448/ (Full article)

In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients.

To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

Source: Lengert N, Drossel B. In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome. Biophys Chem. 2015 Jul;202:21-31. doi: 10.1016/j.bpc.2015.03.009. Epub 2015 Apr 4. https://www.ncbi.nlm.nih.gov/pubmed/25899994

The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

Abstract:

BACKGROUND: Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson’s disease, schizophrenia, depression, autism, and chronic fatigue syndrome.

DISCUSSION: While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson’s disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines.

SUMMARY: This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.

Source: Morris G, Berk M. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 2015 Apr 1;13:68. doi: 10.1186/s12916-015-0310-y. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382850/ (Full article)