2010 – Page 9 – American ME and CFS Society

Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways

Abstract:

BACKGROUND: In a recently published paper, Harvey and Wessely put forward a ‘biopsychosocial’ explanatory model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), which is proposed to be applicable to (chronic) fatigue even when apparent medical causes are present.

METHODS: Here, we review the model proposed by Harvey and Wessely, which is the rationale for behaviourally oriented interventions, such as cognitive behaviour therapy (CBT) and graded exercise therapy (GET), and compare this model with a biological model, in which inflammatory, immune, oxidative and nitrosative (IO&NS) pathways are key elements.

DISCUSSION: Although human and animal studies have established that the pathophysiology of ME/CFS includes IO&NS pathways, these abnormalities are not included in the model proposed by Harvey and Wessely. Activation of IO&NS pathways is known to induce fatigue and somatic (F&S) symptoms and can be induced or maintained by viral and bacterial infections, physical and psychosocial stressors, or organic disorders such as (auto)immune disorders. Studies have shown that ME/CFS and major depression are both clinical manifestations of shared IO&NS pathways, and that both disorders can be discriminated by specific symptoms and unshared or differentiating pathways. Interventions with CBT/GET are potentially harmful for many patients with ME/CFS, since the underlying pathophysiological abnormalities may be intensified by physical stressors.

CONCLUSIONS: In contrast to Harvey and Wessely’s (bio)psychosocial model for ME/CFS a bio(psychosocial) model based upon IO&NS abnormalities is likely more appropriate to this complex disorder. In clinical practice, we suggest physicians should also explore the IO&NS pathophysiology by applying laboratory tests that examine the pathways involved.

Source: Maes M, Twisk FN. Chronic fatigue syndrome: Harvey and Wessely’s (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15;8:35. doi: 10.1186/1741-7015-8-35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901228/ (Full article)

Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract

Abstract:

Various putative theories involved in the development of chronic fatigue syndrome revolve around the role of stress, infection and oxidative stress. Scientific evidence highlighting the protective role of nutritional supplements in chronic fatigue syndrome is lacking.

Based on these assumptions, the present study was designed to evaluate the effect of olive extract in a mouse model of immunologically-induced fatigue, wherein purified lipopolysaccharide (LPS) and Brucella abortus (BA) antigen were used as immunogens. The assessment of chronic fatigue syndrome was based on immobility period during chronic water-immersion stress test for 10 min daily. The stress-induced hyperalgesia was measured by tail withdrawal latency.

Mice challenged with LPS or BA for 19 days showed significant increase in the immobility time, hyperalgesia and oxidative stress on the 19th day. Serum tumor necrosis factor-alpha (TNF-α) levels were also markedly increased with LPS or BA challenge.

Concurrent treatment with olive extract resulted in a significant decrease in the immobility time as well as hyperalgesia. There was significant attenuation of oxidative stress as well as serum TNF-α levels. The results of the present study strongly indicate the role of oxidative stress and immunological activation in the pathophysiology of chronic fatigue syndrome and highlight the valuable role of olive extract in combating chronic fatigue syndrome.

Source: Gupta A, Vij G, Chopra K. Possible role of oxidative stress and immunological activation in mouse model of chronic fatigue syndrome and its attenuation by olive extract. J Neuroimmunol. 2010 Sep 14;226(1-2):3-7. doi: 10.1016/j.jneuroim.2010.05.021. Epub 2010 May 26. https://www.ncbi.nlm.nih.gov/pubmed/20537729

Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management

Abstract:

OBJECTIVES: To establish the relationship between the functional impairment experienced by Chronic fatigue syndrome (CFS) patients and the symptoms frequently experienced by those with CFS; specifically cognitive impairment, fatigue and orthostatic symptoms.

DESIGN: Cross sectional questionnaire survey.

SETTING: Specialist CFS Clinical Service.

SUBJECTS: Ninety-nine Fukuda diagnosed CFS and 64-matched controls.

MAIN OUTCOME MEASURES: Symptom and functional assessment tools completed and returned by post included; PROMIS HAQ (Patient-Reported Outcomes Measurement Information System, Health Assessment Questionnaire), CFQ (Cognitive Failures Questionnaire), FIS (Fatigue Impact Scale) and OGS (Orthostatic Grading Scale) assessment tools.

RESULTS: CFS patients experience greater functional impairment than controls [mean (95% CI) PROMIS HAQ scores CFS 36 (31-42) vs. controls 6 (2-10); P < 0.0001], especially in the functional domains of activities and reach. Poorer functional ability impairment is significantly associated with greater cognitive impairment (P = 0.0002, r = 0.4), fatigue (P < 0.0001, r = 0.5) and orthostatic symptoms (P < 0.0001, r = 0.6). However, only orthostatic symptoms (OGS) independently associated with functional impairment (beta = 0.4, P = 0.01).

CONCLUSION: Treatment of orthostatic symptoms in CFS has the potential to improve functional capacity and so improve quality of life.

Source: Costigan A, Elliott C, McDonald C, Newton JL. Orthostatic symptoms predict functional capacity in chronic fatigue syndrome: implications for management. QJM. 2010 Aug;103(8):589-95. doi: 10.1093/qjmed/hcq094. Epub 2010 Jun 9. http://qjmed.oxfordjournals.org/content/103/8/589.long (Full article)

Illness duration and coping style in chronic fatigue syndrome

Abstract:

A sample of patients with chronic fatigue syndrome was recruited to assess coping strategies and illness duration. It was hypothesized that adaptive coping strategies would be higher among those with longer illness duration.

Those in the longer illness duration group reported higher use of active coping, positive reframing, planning, and acceptance, and lower use of behavioral disengagement than those in the shorter illness duration group. No significant differences were found between the two illness duration groups for physical impairment or symptom severity, but the long duration group revealed a lower percentage of participants who were working than the short duration group.

These findings suggest that individuals with longer or shorter duration of the illness have differences in coping styles but not differences in physical impairment or symptom severity.

Source: Brown MM, Brown AA, Jason LA. Illness duration and coping style in chronic fatigue syndrome. Psychol Rep. 2010 Apr;106(2):383-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036543/ (Full article)

Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) studies from our laboratory and others described decreased natural killer cell cytotoxicity (NKCC) and elevated proportion of lymphocytes expressing the activation marker, dipeptidyl peptidase IV (DPPIV) also known as CD26. However, neither these assays nor other laboratory tests are widely accepted for the diagnosis or prognosis of CFS. This study sought to determine if NKCC or DPPIV/CD26 have diagnostic accuracy for CFS.

METHODS/RESULTS: Subjects included female and male CFS cases and healthy controls. NK cell function was measured with a bioassay, using K562 cells and (51)Cr release. Lymphocyte associated DPPIV/CD26 was assayed by qualitative and quantitative flow cytometry. Serum DPPIV/CD26 was measured by ELISA. Analysis by receiver operating characteristic (ROC) curve assessed biomarker potential. Cytotoxic function of NK cells for 176 CFS subjects was significantly lower than in the 230 controls. According to ROC analysis, NKCC was a good predictor of CFS status. There was no significant difference in NK cell counts between cases and controls. Percent CD2+ lymphocytes (T cells and NK cells) positive for DPPIV/C26 was elevated in CFS cases, but there was a decrease in the number of molecules (rMol) of DPPIV/C26 expressed on T cells and NK cells and a decrease in the soluble form of the enzyme in serum. Analyses by ROC curves indicated that all three measurements of DPPIV/CD26 demonstrated potential as biomarkers for CFS. None of the DPPIV/C26 assays were significantly correlated with NKCC.

CONCLUSIONS: By ROC analysis, NKCC and three methods of measuring DPPIV/C26 examined in this study had potential as biomarkers for CFS. Of these, NKCC, %CD2+CD26+ lymphocytes and rMol CD26/CD2+ lymphocyte, required flow cytometry, fresh blood and access to a high complexity laboratory. Soluble DPPIV/C26 in serum is done with a standard ELISA assay, or with other soluble factors in a multiplex type of ELISA. Dipeptidyl peptidase IV on lymphocytes or in serum was not predictive of NKCC suggesting that these should be considered as non-redundant biomarkers. Abnormalities in DPPIV/CD26 and in NK cell function have particular relevance to the possible role of infection in the initiation and/or the persistence of CFS.

Source: Fletcher MA, Zeng XR, Maher K, Levis S, Hurwitz B, Antoni M, Broderick G, Klimas NG. Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 2010 May 25;5(5):e10817. doi: 10.1371/journal.pone.0010817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2876037/ (Full article)

A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes

Abstract:

Participants with CFS were grouped into viral and non-viral onset fatigue categories and assessed for differential immunological marker expression. Peripheral Blood Mononuclear Cells were assessed for differential phenotypic expression of surface adherence glycoproteins on circulating lymphocytes. The flow cytometric analysis employed fluorescent monoclonal antibody labeling.

The viral in comparison to the non-viral group demonstrated significant elevations in several Th1 type subsets including: the percentage and number of CD4+ cells, the percentage and number of CD2+CD26+ cells, the percentage and number of CD2+CD4+CD26+ cells, the percentage and number of CD4+ CD26+ cells, and the percentage of Th2 naïve cells (CD4+ CD45RA+CD62L+).

Of the remaining significant findings, the non viral group demonstrated significant elevations in comparison to the viral group for the following Th1 type subsets: the percentage of CD8+ cells, the percentage of T-cytotoxic suppressor cells (CD3+8+), and the percentage and number of Th1 memory cells (CD8+CD45RA-CD62L-).

The viral group demonstrated a pattern of activation that differed from that of the group with a non-viral etiology, as evidenced by an elevated and out of range percentage and number of CD4+ cells, the percentage of CD2+CD26+, and the percentage of Th2 naïve cells (CD4+CD45RA+CD62L+). Both groups demonstrated reduced and out of range Natural Killer Cell Cytotoxicity and percentage of B-1 cells (CD5+CD19).

In addition, both groups demonstrated an elevated and out of range percentage of CD2+CD8+CD26+, percentage of the Th1 memory subset (CD4+CD45RA-CD62L-), the percentage of Th1 memory and naïve cells (CD8+CD45RA-CD62L-, CD8+CD45RA+CD62L-), the percentage and number of Th2 memory cells (CD4+CD45RA-CD62L+), and the percentage of Th2 memory and naïve cells (CD8+CD45RA-CD62L+, CD8+CD45RA+CD62L+).

These findings imply that the homeostatic mechanism responsible for the regulation of the Th1 (cell mediated) and Th2 (humoral) immune responses is disturbed in CFS. The implications of these findings are discussed.

Source: Porter N, Lerch A, Jason LA, Sorenson M, Fletcher MA, Herrington J. A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes. J Behav Neurosci Res. 2010 Jun 1;8(2):1-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951052/ (Full article)

Reduced heart rate variability predicts poor sleep quality in a case-control study of chronic fatigue syndrome

Abstract:

Parasympathetic function is important in the induction and maintenance of sleep. We examined whether nocturnal vagal modulation of heart rate is related to the poor sleep quality commonly reported in chronic fatigue syndrome (CFS).

Heart rate (HR, as R-R intervals) was continuously monitored during sleep in 20 patients with CFS and 20 matched control subjects. Questionnaires assessed demographic information, symptoms, functional impairment, and subjective sleep quality.

CFS was associated with more sleep problems in general and poorer subjective sleep quality on the study night (all p < 0.003), and reports of repeated awakening during the night were 7 times more likely compared to healthy subjects (p = 0.017). Time and frequency-domain parameters of HR variability during sleep were significantly lower in patients with CFS (all p < 0.006). Multiple regression analyses revealed that heart rate variability (HRV) parameters were the best predictors of subjective sleep measures.

This study identified significant reductions in vagal modulation of heart rate during sleep in CFS. Low HRV strongly predicted sleep quality-suggesting a pervasive state of nocturnal sympathetic hypervigilance in CFS.

Source: Burton AR, Rahman K, Kadota Y, Lloyd A, Vollmer-Conna U. Reduced heart rate variability predicts poor sleep quality in a case-control study of chronic fatigue syndrome. Exp Brain Res. 2010 Jul;204(1):71-8. doi: 10.1007/s00221-010-2296-1. Epub 2010 May 26. https://www.ncbi.nlm.nih.gov/pubmed/20502886

Possible detrimental effects of cognitive behaviour therapy for chronic fatigue syndrome

Abstract:

BACKGROUND: Cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) can decrease the level of fatigue and disabilities, but it has been suggested that during therapy some patients experience a deterioration of their symptoms rather than an improvement. The aim of this study is to examine the frequency and severity of symptom deterioration during CBT for CFS.

METHODS: Data from 3 randomised controlled trials on CBT for CFS were pooled and reanalysed. Symptom deterioration during the trial was rated by patients and measured as deterioration in fatigue, pain, functional impairment and psychological distress. Both the frequency and severity of deterioration in these domains were compared between the patients receiving CBT and those in the control group. Predictors of symptom deterioration were identified by comparing their means in patients with and without an increase in fatigue. Statistically significant predictors were then combined in a logistic regression model.

RESULTS: The frequency of symptom deterioration varied from 2 to 12% in patients receiving CBT and from 7 to 17% in the control group. None of the measures showed a significantly higher frequency of symptom deterioration in the CBT group. The severity of deterioration was also comparable in the CBT and in the control group. No predictors of symptom deterioration specific to CBT were found.

CONCLUSION: Patients receiving CBT do not experience more frequent or more severe symptom deterioration than untreated patients. The reported deterioration during CBT seems to reflect the natural variation in symptoms. Thus, CBT is not only a helpful, but also a safe treatment for CFS.

Comment in: Harms of cognitive behaviour therapy designed to increase activity levels in chronic fatigue syndrome: questions remain.[Psychother Psychosom. 2011]

Source: Heins MJ, Knoop H, Prins JB, Stulemeijer M, van der Meer JW, Bleijenberg G. Possible detrimental effects of cognitive behaviour therapy for chronic fatigue syndrome. Psychother Psychosom. 2010 Jun;79(4):249-56. doi: 10.1159/000315130. Epub 2010 May 25. https://www.ncbi.nlm.nih.gov/pubmed/20502065

Impaired cardiovascular response to standing in chronic fatigue syndrome

Abstract:

BACKGROUND: Impaired skeletal muscle metabolism is recognized in chronic fatigue syndrome (CFS). This study examined the relationship between skeletal and cardiac muscle function and symptoms on standing in CFS using magnetic resonance spectroscopy (MRS) and impedance cardiography.

MATERIALS AND METHODS: Phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio by cardiac MRS, PCr/ADP and proton efflux by muscle MRS were performed in 12 CFS (Fukuda) and 8 controls. Head up tilt (HUT) and cardiac contractility (left ventricular work index, LVWI) (n = 64 CFS and matched controls) were found. Fatigue impact was accessed by Fatigue Impact Scale and orthostatic symptoms by Orthostatic Grading Scale (OGS).

RESULTS: Cardiac PCr/ATP correlated with measures of muscle bioenergetic function (half-time PCr recovery [kappa = -0.71, P = 0.005] and half-time ADP recovery [kappa = -0.60, P = 0.02]) suggesting that the muscle and cardiac bioenergetic function correlate in CFS. Four of 12 (33.3%) CFS patients had PCr/ATP values consistent with significant cardiac impairment. Those with impaired cardiac energy metabolism had significantly reduced maximal and initial proton efflux rates (P < 0.05). Cardiac PCr/ATP ratio correlated with myocardial contractility (LVWI) in response to standing (P = 0.03). On HUT, LVWI on standing was significantly higher in CFS (P = 0.05) with symptoms on standing (OGS) occurring in 61/64 (95%) (vs. 25/64 [39%] controls; P < 0.0001). OGS scores were significantly higher in those with abnormal LVWI responses to standing (P = 0.04), with the LVWI on standing correlating with OGS scores (r(2) = 0.1; P = 0.03). HUT was positive in 19 (32%).

CONCLUSIONS: Skeletal muscle and cardiac bioenergetic abnormalities associate in CFS. Cardiac bioenergetic metabolism associates with increase in cardiac contractility on standing. Haemodynamic assessment in CFS is well tolerated and safe with a high diagnostic yield comparable with unexplained syncope.

Source: Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL. Impaired cardiovascular response to standing in chronic fatigue syndrome. Eur J Clin Invest. 2010 Jul;40(7):608-15. doi: 10.1111/j.1365-2362.2010.02310.x. Epub 2010 May 23. https://www.ncbi.nlm.nih.gov/pubmed/20497461

Physical and functional impact of chronic fatigue syndrome/myalgic encephalomyelitis in childhood

Abstract:

OBJECTIVE: The aim of this study was to compare self-reported and parent-reported quality of life for a group of pediatric patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME) and age- and gender-matched healthy control children, to determine the extent of functional and physical impairment.

METHODS: The Child Health Questionnaire was completed by 25 children with CFS/ME, who were recruited throughout the United Kingdom, and by 23 age-, gender-, and Tanner scale-matched control children. In addition, patients were asked questions about the background to their illness (ie, precipitating factors), the status of their illness, and school attendance.

RESULTS: The median illness duration for patients was 3 years. Sixty-eight percent of the children said that their illness developed quickly, and the illness had an infectious onset for 88%. Only 1 child (4%) attended school full-time, whereas 12 (48%) attended school part-time and 8 (32%) received home tuition only. Children with CFS/ME scored significantly lower for 10 of 14 Child Health Questionnaire concepts; the lowest scores were observed for global health (scores of 21.4 and 84.1 for patients and control subjects, respectively; P < .0001) and role/social limitations attributable to physical health problems (scores of 24.9 and 100, respectively; P < .0001). Quality of life for the children with CFS/ME compared unfavorably with previously published results for pediatric patients with type 1 diabetes mellitus or asthma.

CONCLUSION: The quality of life of children with CFS/ME was profoundly reduced, compared with that of their healthy counterparts.

Source: Kennedy G, Underwood C, Belch JJ. Physical and functional impact of chronic fatigue syndrome/myalgic encephalomyelitis in childhood. Pediatrics. 2010 Jun;125(6):e1324-30. doi: 10.1542/peds.2009-2644. Epub 2010 May 17. https://www.ncbi.nlm.nih.gov/pubmed/20478937