ME and CFS References

Beqaj, SH., Lerner, AM and Fitzgerald, JT. Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detect active infection in patients with chronic fatigue syndrome. Journal of Clinical Pathology, 2007, Dec 5; [Epub ahead of print]. doi:10.1136/jcp.2007.050633.

The purpose of this study is to demonstrate that the use of recombinant early antigens for detection of antibodies to cytomegalovirus (HCMV) gene products CM2 (UL44, UL57) and p52 (UL44) is specific in the diagnosis and differentiation of active HCMV infection in a subset of patients with CFS which is often missed by the current ELISA assay that uses crude viral lysate antigen.

At a single clinic from 1999 – 2001, a total of 4,774 serologic tests were performed in 1135 patients with CFS (CDC criteria ’94) using two immunoassays; Copalis immunoassay and ELISA immunoassay. The Copalis immunoassay utilized HCMV early gene products of UL44 and UL57 recombinant antigens for detection of HCMV IgM antibody, and viral capsid antigen for detection of HCMV IgG antibody. The ELISA immunoassay utilized viral crude lysate as antigen for detection of both HCMV IgG and IgM.

Of the total, 1135 CFS patients, 517 patients (45.6%) were positive for HCMV IgG by both HCMV IgG by both assays. Of these, twelve CFS patients (2.2%) were positive for HCMV(V) IgM serum antibody by HCMV ELISA assay, and 61 CFS patients (11.8%) were positive for IgM HCMV serum antibody by Copalis assays. The Copalis assay that uses HCMV early recombinant gene products CM2 (UL44, UL57) and p52 (UL44) in comparison with ELISA was 98% specific.

Immunoassays that use Early Antigen recombinant HCMV CM2 and p52 are five times more sensitive than HCMV ELISA assay using viral lysate and are specific in the detection and differentiation of active HCMV infection in a subset of CFS patients.

[Ed. Note: Extracts: HCMV maintains infection in immunocompetent patients by its latency, awaiting an opportunity to reactivate infection... However, in CFS patients, who are otherwise immunocompetent, complete virus, or abortive multiplication may be present. In the CFS patient, herpes virus multiplication occurs in part without full virus assembly... Antiviral therapy is effective only during the viral replication as it impairs DNA synthesis. Therefore, virus may express some genes and make some protein products, but not fully replicate... Here, we demonstrate that use of recombinant antigens in detection of antibody to HCMV gene products is a significant improvement in detection and differentiation of HCMV infection in CFS patients. As demonstrated here, there was excellent correlation between ELISA and Copalis assays for HCMV IgG serum antibodies, indicating HCMV infection in these patients. However, significant differences were seen in detection of HCMV IgM antibodies in these patients.... The sensitivity of the recombinant assay is increased by use of the chimeric antigens, p52 and CM2 for detection of IgM antibody... Both p52 and CM2 antigens are non-structural products of HCMV genes UL44 and UL57, which are early HCMV genes... The central portion of p52 is a major reactive protein of acute HCMV infection. The antigen CM2 is a chimeric protein product of fused UL44 and UL57 genes, which markedly increases sensitivity of the assay. This is demonstrated here: of 61 serum HCMV recombinant IgM positive CFS patients, 9 patients were p52 positive, “40 patients were CM2 positive” and 12 patients were positive for both combined p52, and CM2 antigens. This use of recombinant HCMV p52 and CM2 antigens to detect IgM HCMV serum antibody is, thus, the best method to detect active HCMV infection in immunocompetent individuals... Abortive viral multiplication in immunocompetent CFS patients may be unique.]

Jason, L.A., Corradi, K., & Torres-Harding, S. Toward an empirical case definition of CFS. Journal of Social Service Research, 2007, 34, 43-54.

The current case definition of CFS was developed by consensus rather than empirical methods. From a practice point of view, if the case definition is not empirically based, it is possible that some individuals with this illness might not be diagnosed, and others who do not have the disorder might be diagnosed. In the present study, 114 individuals with CFS were provided a theoretically driven questionnaire that featured neuropsychiatric, vascular, inflammatory, muscle/joint, infectious, and other symptoms. When symptoms using this classification were factored analyzed, a more interpretable factor structure was identified than when using symptoms from traditional case definition criteria. Patients were also interviewed using the SCID and medically examined.

Factor scores from the new classification system were cluster analyzed, and four types of patient groups were identified. The field of CFS studies needs to be grounded in empirical methods for determining a case definition versus more consensus based efforts. Such efforts will ultimately help social service providers better diagnose and provide services to those with this chronic illness.

[Ed. Note: Cluster 1 seems consistent with the description of post viral fatigue. The results suggest identifying the acute onset patients may be useful. The diagnosis of post-exertional fatigue might not be precise enough to identify patients with ME.]

Smith, AK., Dimulescu, I., Falkenberg, VR., Narasimhan, S., Heim, C., Vernon, SD and Rajeevan, MS. Genetic evaluation of the serotonergic system in chronic fatigue syndrome. Psychoneuroendocrinology, 2008, 33, 188-197.

CFS is a debilitating disorder of unknown etiology with no known lesions, diagnostic markers or therapeutic intervention. The pathophysiology of CFS remains elusive, although abnormalities in the central nervous system (CNS) have been implicated, particularly hyperactivity of the serotonergic (5-hydroxytryptamine; 5-HT) system and hypoactivity of the HPA axis. Since alterations in 5-HT signaling can lead to physiologic and behavioral changes, a genetic evaluation of the 5-HT system was undertaken to identify serotonergic markers associated with CFS and potential mechanisms for CNS abnormality.

A total of 77 polymorphisms in genes related to serotonin synthesis (TPH2), signaling (HTR1A, HTR1E, HTR2A, HTR2B, HTR2C, HTR3A, HTR3B, HTR4, HTR5A, HTR6, and HTR7), transport (SLC6A4), and catabolism (MAOA) were examined in 137 clinically evaluated subjects (40 CFS, 55 with insufficient fatigue, and 42 non-fatigued, NF, controls) derived from a population-based CFS surveillance study in Wichita, Kansas (using CDC criteria ’94, operationalised).

Of the polymorphisms examined, three markers (-1438G/A, C102T, and rs1923884) all located in the 5-HT receptor subtype HTR2A were associated with CFS when compared to NF controls. Additionally, consistent associations were observed between HTR2A variants and quantitative measures of disability and fatigue in all subjects. The most compelling of these associations was with the A allele of -1438G/A (rs6311) which is suggested to have increased promoter activity in functional studies. In silico analysis revealed that the -1438 A allele creates a consensus binding site for Th1/E47, a transcription factor implicated in the development of the nervous system. Electrophoretic mobility shift assay supports allele-specific binding of E47 to the A allele but not the G allele at this locus. These data indicate that sequence variation in HTR2A, potentially resulting in its enhanced activity, may be involved in the pathophysiology of CFS.

Jason, LA., Torres-Harding, S., Friedberg, F., Corradi, K., Njoku, MG., Donalek, J., Reynolds, N., Brown, M. Weitner, BB., Rademaker, A and Papernik, M. Non-pharmacologic interventions for CFS: a randomized trial. Journal of Clinical Psychology in Medical Settings, 2007, 14, 4, 275-296.

Non-pharmacological behavioral treatments for CFS have been suggested as promising. These trials have tested protocols composed of behavioral, cognitive and cognitive-behavioral interventions but there have been few efforts to differentially evaluate their outcomes. The primary purpose of the current study was to evaluate the effectiveness of nurse delivered non-pharmacologic interventions. In the present study, 114 participants diagnosed with CFS were randomly assigned to four 6-month interventions. The interventions were: cognitive behavior therapy (CBT, n=29), cognitive therapy (COG*, n=28), anaerobic activity (ACT, n=29), and a relaxation control group (n=28).

The study found that these interventions led to increases in several areas of functioning, with more consistent changes occurring among those participants in the cognitive condition. For the 25 variables in this study, significant change occurred for 28%, 20%, 16%, and 12% of the variables for the cognitive therapy, CBT, anaerobic activity, and relaxation conditions, respectively. However, the majority of participants continued to be diagnosed with CFS following the treatment trial. Implications of these findings are discussed.

[Ed. Note: *Cognitive therapy covered a number of topics including coping skills training to reduce stress, anxiety, depression and anger, as well as pacing and ‘pleasant mood induction’. The activity programme focused on exercises to increase flexibility and strength. The CBT programme was based on the views of the CBT school and was focused on increasing activity according to a schedule (i.e. activity was not symptom-driven, as in pacing).

Extracts:

“For the 25 variables examined in this study, when one treatment condition evidenced significant positive change over at least one other condition, seven of these occurrences were for the COG condition, five for the CBT condition, four for the ACT condition, and three for the RELAX condition.... When examining clinical significance on the Physical Functioning subscale, somewhat similar findings occurred, with 30.4%, 18.2%, 11.1%, and 21.7% of individuals for the COG, CBT, ACT, and RELAX improving. It should be mentioned that the changes in the present trial were relatively modest and few participants experienced remission of illness. At the follow-up, there were no significant changes across conditions in the number of participants who were no longer classified as having CFS. These results are consistent with conclusions from other investigators, particularly those that have collected longer term follow-up data....

While all of the treatments were found to be of modest benefit for individuals with CFS, the COG condition exhibited the most beneficial changes for depression and pain in joints, when compared to the other three treatment conditions... In addition, this condition had more favorable change when compared to at least one other condition for the following outcomes: physical functioning, pain severity, sore throats, muscle pain, pain in joints, impaired memory, and post-exertional malaise (although for pain severity and impaired memory, these findings were due to comparing the COG to the RELAX condition which evidenced worsening over time).

There were several important differences between the CBT and COG therapies in that the COG intervention placed more emphasis on pacing of activities when compared to the CBT treatment. Indeed in the COG therapy, individuals were not instructed to engage in regular amounts of activity, and were not encouraged to engage in regular or sustained physical activity. It is possible that pacing of activity, which puts a strong emphasis on becoming aware of total available energy, managing energy, and not going beyond one’s energy limits, may lead to the higher improvements seen in the post-exertional malaise and, ultimately, to better overall physical functioning... It is also of interest that the largest gains in self-efficacy occurred for the RELAX condition, particularly when compared to the ACT condition. The RELAX group also had the greatest reductions in muscle pain than any of the other conditions. Regarding headaches, both the RELAX group and the ACT group had more significant overall positive change in headache severity compared to the CBT condition... It is a bit unclear why RELAX would have been effective for the muscle pain and headache symptoms but not in other areas where pain is felt... Data from employment status and satisfaction were generally similar to the findings above. There were few significant differences for employment or the participant and clinician ratings among the four conditions at the 12-month follow-up. In general, participants in all four conditions were generally satisfied with the non-pharmacologic treatments and found them to be useful (with ratings in the 70–90%). While participants seemed to have been satisfied with the treatments and found them to be useful, individuals were less likely to indicate that these treatments made them feel better; and clinician ratings of improvements were also generally lower than the treatment satisfaction ratings... the results suggest that these different treatment techniques may have modest, differential effects on the symptoms of CFS and individualizing a person’s treatment might make sense.”

The drop-out rates were similar to those found for CBT trials (av.25%) but higher than those for multi-dimensional trials e.g. Goudsmit and Ho-Yen. The mean physical functioning scores indicate severe disability (39.17-46.36).]

Lerner, AM., Beqaj, SH., Deeter, RG and Fitzgerald, JT. Valacyclovir treatment in Epstein-Barr virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo, 2007, 21, 5, 707-713.

We hypothesized that subset classification of Epstein-Barr virus (EBV) in CFS is required. At first, a blinded-random placebo-controlled trial of valacyclovir in EBV CFS subset was performed (Group 1), and this EBV subset was followed for thirty-six months (Group 2). Patients were given valacyclovir at 14.3 mg/kg every 6 hours. The validated Energy Index (EI) point score assessing physical functional capacity, Holter monitor, multigated (radionuclide) MUGA rest/stress ventriculographic examination, EBV serum IgM viral capsid antibodies (VCA), and EBV early antigen diffuse (EA) were followed.

After six-months, Group 1 CFS patients receiving valacyclovir experienced an increased mean least square EI point score +1.12 units (122 kcal/day), while the placebo cohort increased +0.42 EI units (65 kcal/day). EI point scores at Group 2 increased progressively. Sinus tachycardias decreased and abnormal cardiac wall motion improved. Serum antibody titers to EBV VCA IgM decreased. Patients resumed normal activities

Malouff, JM., Thorsteinsson, EB., Rooke, SE., Bhullar, N and Schutte, NS. Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: a meta-analysis. Clinical Psychology Review, 2007 Nov 1 [Epub ahead of print]. doi:10.1016/j.cpr.2007.10.004.

A meta-analysis of the efficacy of CBT in treating chronic fatigue included 15 effect sizes for between-group outcome comparisons. Across analyses, which included a total of 1371 participants, there was a significant difference, d=0.48, in post-treatment fatigue between participants receiving CBT and those in control conditions. Results indicate that CBT for CFS tends to be moderately efficacious. Dropout rates in CBT varied from 0-42%, with a mean of 16%. In the five studies that reported the number of CBT clients who were no longer in the clinical range with regard to fatigue at the latest follow-up, the percentage varied from 33% to 73% of those assigned to CBT, with a mean of 50%. Moderator results suggest directions for future investigations.

[Ed. Note: The paper gives mean d values calculated for all outcome measures, which varied per study. The results show that the programmes of Deale et al 1997 and Powell et al 2001 (including three hours telephone encouragement and information: d = 1.67) were the most effective of those included in the analysis. Of interest is that d for Prins et al was .44. Treatments focusing on increasing activity had a somewhat higher effect size than treatment that also included CBT. Studies using the Oxford criteria also showed higher effect sizes. The study of pacing (Wallman et al 2004) had the lowest drop-out rate (0). The effect sizes for mental fatigue were lower than those for physical fatigue (d = .20 versus .81).]

Scheeres, K., Wensing, M., Knoop, H and Bleijenberg, G. Implementing cognitive behavioral therapy for chronic fatigue syndrome in a mental health center: a benchmarking evaluation. Journal of Consulting and Clinical Psychology, 2008, 76, 1, 163-171.

This study evaluated the success of implementing CBT for CFS in a representative clinical practice setting and compared the patient outcomes with those of previously published randomized controlled trials (RCTs) of CBT for CFS (CDC criteria ’94, operationalised).

The implementation interventions were the following: spreading information about the new treatment setting to general practitioners and CFS patients; training mental health center (MHC) therapists in CBT for CFS; and organizing changes in the MHC patient workflow. Patient outcomes were documented with validated self-report measures of fatigue and physical functioning (MOS) before and after treatment. The comparison of the treatment results with RCT results was done following the benchmark strategy.

One-hundred forty-three CFS patients were referred to the MHC, of whom 112 started treatment. Patients applying for benefits were excluded. 30% had a co-morbid depressive disorder. The implementation was largely successful, but a weak point was the fact that 32% of all referred patients dropped out shortly after or even before starting treatment. Treatment effect sizes were in the range of those found in the benchmark studies. Post-treatment MOS-PF scores remained below normal (69.1).

“CBT for CFS can successfully be implemented in an MHC. Treatment results were acceptable, but the relatively large early dropout of patients needs attention.”

Van Houdenhove, B., Verheyen, L., Pardaens, K., Luyten, P and Van Wambeke P. Rehabilitation of decreased motor performance in patients with chronic fatigue syndrome: should we treat low effort capacity or reduced effort tolerance? Clinical Rehabilitation, 2007, 21, 12, 1121-1142.

The aetiology, pathophysiology, diagnostic delineation and treatment of CFS remain a matter of debate. Here some aspects of the debate are elucidated, with a particular focus on the patients' decreased motor performance. Hypothesis: The pathophysiological basis of decreased motor performance in CFS may, theoretically, involve three components: (1) a peripheral energetic deficit (impaired oxidative metabolism and/or physical deconditioning); (2) a central perceptual disturbance (higher effort sense or increased 'interoception'); and (3) a fundamental failure of the neurobiological stress system, leading to an abnormal 'sickness response'. It is proposed that the first two components may lead to low effort capacity, while the third component may lead to reduced effort tolerance. Although there is evidence for low effort capacity influencing symptoms and functional limitations in CFS, it is assumed that reduced effort tolerance might be the primary disturbance in CFS.

Diagnostic implications: Distinguishing low effort capacity and reduced effort tolerance may contribute to a refinement of current diagnostic criteria of CFS and the identification of subgroups. Therapeutic implications: The above-mentioned distinction may make it possible to formulate a rationale for an effective implementation and adequate outcome evaluation of rehabilitation strategies in CFS. Research implications: This new heuristic framework may inform future research aimed at disentangling the complex determination of impaired motor performance in CFS, as well as studies aimed at customizing treatment to different subtypes of patients

[Ed. Note: This paper refers to the Goudsmit version of pacing. “... an individually tailored exercise protocol should be implemented, modulated by a pacing strategy... This means that, if symptoms become worse during or after exercising, the next session is shortened or cancelled and subsequent sessions are reduced to a length that the patient feels is manageable.”]

Andersen, MM., Permin, H and Albrecht F. Nine-year follow-up of Danish chronic fatigue syndrome (CFS) patients: impact on health, social, vocational, and personal lives. Journal of Chronic Fatigue Syndrome, 2007, 14, 2, 7-23.

To determine quality of life (QOL) and health in Danish patients with CFS (CDC criteria ’88 and ’94), 9 years after diagnosis, 34 adults with CFS responded to questions regarding QOL at diagnosis, and again 5 and 9 years later. Standard medical care was provided (e.g. for pain, allergies). At 9-year follow-up, patients also responded to questions regarding health, fatigue, use of Health Care system, alcohol and exercise.

Two patients (6%) had recovered and 3 patients (10%) had received secondary diagnoses. Overall, there was no improvement, except with depression/anxiety. The order of severity among disabilities remained the same. Work had the highest disability score, followed by post-exertional malaise. Patients slept and rested 13.6 hours a day (mean). Self-reported physical health correlated with hours sleeping and resting. Rheumatic symptoms dominated the health symptoms. Alcohol consumption was low, and the use of the Health Care system was modest. After 9 years QOL was the same as at diagnosis, only mental health had improved.

Ciccolella, M., Stevens, SR., Snell, CR and VanNess, M. Legal and scientific considerations of the exercise stress test. Journal of Chronic Fatigue Syndrome, 2007, 14, 2, 61-75.

doi:10.1136/adc.2007.126649.

The authors describe children who presented to the Bath paediatric CFS/ME service under the age of 12. Inventories measuring fatigue, pain, functional disability, anxiety, family history and symptoms were collected prospectively for all children presenting to the Bath CFS/ME service between September 2004 and April 2007. Data from children who presented to the service under the age of 12 were described and compared to those who presented at age 12 or older.

178 children (under the age of 18) were diagnosed as having CFS/ME using the RCPCH criteria out of 216 children assessed. The mean age at assessment for children with CFS/ME was 14.5 years old (SD 2.9). 32 (16%) children were under 12 years old at the time of assessment, four children were under 5 years old and the youngest child was 2 years old. Children under 12 were very disabled with mean school attendance of just over 40% (average 2 days a week), Chalder Fatigue score of 8.29 (CI 7.14 -9.43 maximum possible score=11) and pain visual analogue score of 39.7 (possible range 0-100). Comparison with the children aged 12 or older showed that both groups were remarkably similar at assessment. Moreover, 24/26 children with complete symptom lists, would have been diagnosed as having CFS/ME using the stricter adult CDC criteria.

Disability in the under 12 age group was high, with low levels of school attendance, high level of fatigue, anxiety, functional disability and pain. The clinical pattern seen is almost identical to that seen in older children and the majority of children would also be diagnosed as having CFS/ME using the stricter adult definition.

Faulkner, S and Smith, A. A longitudinal study of the relationship between psychological distress and recurrence of upper respiratory tract infections in chronic fatigue syndrome. British Journal of Health Psychology, 2008, 13, 177-186.

Previous research has found that CFS patients report increased susceptibility to upper respiratory tract illnesses (URTIs) when compared with healthy volunteers. This study aimed to replicate and extend this research by investigating the role of psychological distress (stress and negative mood) in the recurrence of URTIs in CFS patients as well as its role in the recurrence of CFS symptoms. This study used a 15-week diary, measures of psychological stress, negative mood, recurrence of URTIs and symptoms which were recorded each week for a 15-week period. CFS patients (n=21), who had been assessed and diagnosed according to the Oxford criteria, were recruited from the Cardiff Chronic Fatigue Clinic and compared with a matched group of healthy controls (n=18). Frequency of occurrence of infectious illness and the relationship between psychological stress/negative mood and occurrence of illness were assessed.

CFS patients reported more URTIs than the controls. Stress scores (and negative mood) were significantly higher in the week prior to the occurrence of URTIs than in weeks when no subsequent illness occurred. High levels of psychological stress also preceded the severity of reported symptoms of fatigue in the CFS group.

[Ed. Note: Among the participants, 68% reported that their fatigue was precipitated by stress. The relationship between chronic stress, fatigue and immunodeficiency has been reported before. More strictly defined CFS is commonly associated with immune activation and there are fewer reports of an increased susceptibility to URTIs. The journal has no correspondence section to challenge the possible confounding effect of pre-existing stress and the possibility that the relationship documented here may not be evident in those with an acute, post-viral onset, or evidence of ongoing infection. The lack of a chronically-ill comparison group makes it difficult to interpret the apparent relationship between stress and URTIs in CFS.]

Galland, BC., Jackson, PM., Sayers, RM and Taylor BJ. A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome. Pediatric Research, 2008, 63, 2, 196-202.

The objective of this study was to define cardiovascular and heart rate variability (HRV) changes following head-up tilt (HUT) in children/adolescents with CFS (CDC criteria ‘94) in comparison to age- and gender-matched controls. Twenty-six children/adolescents with CFS (11-19 yr) and controls underwent 70-degree HUT for a maximum of 30 min, but returned to horizontal earlier at the participant's request with symptoms of orthostatic intolerance (OI) that included light-headedness. Using electrocardiography and beat-beat finger blood pressure, a positive tilt was defined as OI with 1) neurally mediated hypotension (NMH); bradycardia (HR <75% of baseline), and hypotension [systolic pressure (SysP) drops >25 mm Hg)] or 2) postural orthostatic tachycardia syndrome (POTS); HR increase >30 bpm, or HR >120 bpm (with/without hypotension).

Thirteen CFS and five controls exhibited OI generating a sensitivity and specificity for HUT of 50.0% and 80.8%, respectively. POTS without hypotension occurred in seven CFS subjects but no controls. POTS with hypotension and NMH occurred in both. Predominant sympathetic components to HRV on HUT were measured in CFS tilt-positive subjects. In conclusion, CFS subjects were more susceptible to OI than controls, the cardiovascular response predominantly manifest as POTS without hypotension, a response unique to CFS suggesting further investigation is warranted with respect to the pathophysiologic mechanisms involved.

Hoseini, SS and Gharibzadeh, S. Potential drugs for improving chronic fatigue syndrome. Neuropsychiatry and Clinical Neurosciences, 2007, 19, 472.

Letter. There are several hypotheses about the etiology of CFS, including postinfectious, immunological, neuroendocrine, neurological, and psychological ones. A CNS dysfunction brought about by abnormal cytokine release in response to antigenic challenge has been described. Substantial evidences show a pivotal role for proinflammatory cytokines (e.g., interleukin-1, interleukin-6, and tumor necrosis factor-) in induction of CNS mediated responses such as fever, somnolence, and sickness behavior in acute infections. A significant elevation in serum levels of interleukin-1, and tumor necrosis factor- in the patient with CFS have been reported. Recently, biological agents that bind and neutralize the tumor necrosis factor have become available:

1) Etanercept, a tumor necrosis factor type 2 receptor fused to IgG1, is assessed to be effective in psoriasis.

2) Infliximab, a chimeric mouse-human monoclonal antibody to the tumor necrosis factor, has shown successful trials for treating inflammatory bowel disease.

3) Adalimumab, a fully human antibody to the tumor necrosis factor, is used in cutaneous sarcoidosis.

4) Thalidomide has immunomodulatory and anti-inflammatory effects including inhibition of synthesis of the tumor necrosis factor –. It is effective for treating Behçets syndrome.

We suggest that these drugs, which are approved by FDA for some of the aforementioned diseases, can be useful in treating patients with CFS.

Jones, JF. An extended concept of altered self: chronic fatigue and post-infection syndromes. Psychoneuroendocrinology, 2008, 33, 2, 119-129.

Sickness behavior in active infectious diseases is defined here as the responses to cytokines and other mediators of inflammation as well as the adaptability of a pre-existing integrated immunological, psychological, neurological, and philosophical self. These complex behaviors are biologically advantageous to the afflicted individual, but they also impact surrounding individuals. If chronic conditions, such as CFS or post-infection fatigue, exhibiting these behaviors follow infection in the absence of ongoing changes in immunological self associated with an active infection or subsequent injury, they are currently considered illness states rather than true diseases. Self-referential recognition (interoception) of bodily processes by the brain and subsequent unconscious and conscious adaptive responses arising in the brain, i.e., in the endocrine system and immune systems, which are initiated during the infection and would normally lead to positive maintenance, may become maladaptive and lead to an "extended altered self state." Exploratory measurements of such alterations using a "top-down" approach such as monitoring responses to appropriate challenges can be obtained using functional brain imaging techniques. Once identified, processes remediable to biological/pharmacologic and/or psychological intervention can be targeted in directed trials.

[Ed. Note: The author assumes that CFS is a homogeneous condition and hence argues for a universal response, i.e. focusing on a reaction based partly on previous ones. The author downplays evidence of ongoing disease e.g. Chia and Chia 2007, Klimas and O’Brien Koneru 2007 etc. using the modus operandi of the CBT school, and he uses this selective view to posit that CBT may be helpful for any ‘learned’ or ‘conditioned responses’. He also suggests that CBT “remains an effective therapy for CFS”, thus ignoring the data on effect size (see above), studies conducted in clinical settings and the use of limited outcome measures.]

Klimas, NG and O’Brien Koneru, A. Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Current Rheumatology Reports, 2007, 9, 6, 482-487.

Review. Investigations into the underlying cause of CFS have advanced the field considerably in the past year. Gene microarray data have led to a better understanding of pathogenesis. Recent research has evaluated genetic signatures, described biologic subgroups, and suggested potential targeted treatments. Acute viral infection studies found that initial infection severity was the single best predictor of persistent fatigue. Genomic studies showed that persistent cases express Epstein Barr virus-specific genes and demonstrate abnormalities of mitochondrial function. Studies of immune dysfunction extended observations of natural killer cytotoxic cell dysfunction of the cytotoxic T cell through quantitative evaluation of intracellular perforins and granzymes. Other research has focused on a subgroup of patients with reactivated viral infection. These advances should result in targeted therapies that impact immune function, HPA regulation, and persistent viral reactivation.

Kuo, DZ., Cheng, TL and Rowe, PC. Successful use of a primary care practice specialty collaboration in the care of an adolescent with chronic fatigue syndrome. Pediatrics, 2007, 120, 6, e1536-1539.

We report on the successful collaborative care of an adolescent with CFS between a primary care pediatrician and an academic CFS specialist located in different cities. Regular telephone and e-mail communication and clearly defined patient-care roles allowed for timely management of symptoms and marked clinical improvement. We discuss ways to improve the collaboration of primary care and subspecialty physicians for patients with CFS and children with special health care needs.

Le Bon, O., Neu, D., Valente, F and Linkowski, P. Paradoxical NREMS distribution in "pure" chronic fatigue patients: a comparison with sleep apnea-hypopnea patients and healthy control subjects. Journal of Chronic Fatigue Syndrome, 2007, 14, 2, 45-59.

CFS is a debated clinical entity, not presently associated with specific sleep abnormalities. However, higher levels of deep sleep and/or lower levels of light sleep have been reported in several all-night polysomnography studies in CFS patients. This distribution of Non-Rapid Eye Movement Sleep (NREMS) contrasts with what would be expected if sleep was interrupted by microawakenings, such as in sleep apneas or periodic limb movements, where more light sleep and less deep sleep are commonly observed. This "paradoxical" distribution of NREMS could represent a characteristic feature of chronic fatigue and deserved to be investigated.

A retrospective comparison of the NREMS distribution was performed between 28 "pure" CFS patients (CDC criteria ’94, without primary sleep or psychiatric disorders), 27 apneic-hypopneic patients and 27 healthy controls. Data showed CFS patients to have a higher stage 4/stage 2 or stage 4/light sleep ratios than the other two conditions. This sleep pattern is closer to what is observed in cases of infections than to what is seen after sleep fragmentation by primary sleep or in psychiatric disorders. Such a particular sleep pattern could provide insights into the pathophysiology of fatigue

Lu, TV., Torres-Harding, SR and Jason, LA. The effectiveness of early educational intervention in improving future physicians' attitudes regarding CFS/FM. Journal of Chronic Fatigue Syndrome, 2007, 14, 2, 25-30.

The aim of this study was to assess the effects of an early educational intervention program's ability to alter the perceptions and attitudes of future physicians regarding CFS/FM, improve their understanding and acceptance of these diseases and make them feel more comfortable in diagnosing and treating patients. Third-year medical students were surveyed before and after an educational intervention program. The three questions posed to the students in the survey were:

(1) How comfortable do you feel you are in diagnosing and treating patients with CFS/FM?,
(2) Do you consider CFS/FM legitimate illnesses?, and
(3) Do you want to treat patients with CFS/FM?

The four important features of this educational intervention included providing accurate facts on CFS/FM; dispelling myths and misconceptions about patients with CFS/FM; presenting a live case to allow face-to-face interaction with a patient with CFS/FM; and increasing students’ awareness of multiple pharmacological and non-pharmacological treatment options.

The educational intervention program helped about half of the future physicians feel comfortable in diagnosing and treating patients with CFS/FM and improved by over 25% their willingness to treat patients with CFS. In conclusion, an educational intervention program appeared to improve future physicians' understanding and appreciation of CFS/FM, made them feel more comfortable diagnosing and treating these diseases, and increased their willingness to treat patients with CFS/FM.

Maes, M., Mihaylova, I and Leunis, JC. Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity. Neuroendocrinology Letters, 2007, 28, 6, 861-867.

Major depression and CFS are accompanied by signs of oxidative and nitrosative stress (O&NS) and an inflammatory response. Phosphatidyl inositol (Pi) is thought to play a role in depression. The aim of the present study is to examine whether depression and CFS are characterized by an IgM-mediated immune response directed against Pi. Toward this end, this study examines the serum IgM antibodies directed against Pi in 14 patients with major depression, 14 patients with CFS, 14 subjects with partial CFS, and in 11 normal controls.

We found that the prevalence and mean value for the serum IgM levels directed against Pi were significantly greater in patients with major depression and CFS than in normal controls and patients with partial CFS. There were significant and positive correlations between serum IgM levels directed against Pi and two symptoms of the FibroFatigue Scale, i.e. fatigue and depression.

The results show that an IgM-related immune response directed against Pi may occur in both depression and CFS and may play a role in the pathophysiology of the key symptom of CFS and major depression. It is suggested that the above disorders in Pi result from increased O&NS in both depression and CFS. Autoanti-Pi antibodies may have biological effects, for example, by changing inositol 1,4,5-triphosphate (IP3), phosphatidylinositol-4,5-bisphosphate (PIP2), diacylglycerol and phosphatidylinositol-3,4,5-triphosphate (PIP3) production, thus interfering with intracellular signalling processes. Future research in major depression and CFS should focus on the functional consequences of the immune responses directed against Pi.

Maes, M., Coucke, F and Leunis, JC. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuroendocrinology Letters, 2007, 28, 6, 739-744.

There is now evidence that CFS is accompanied by an increased translocation of endotoxins from gram-negative enterobacteria through the gut wall, as demonstrated by increased prevalences and median values for serum IgM and IgA against the endotoxins of gram-negative enterobacteria. This condition can also be described as increased gut permeability or leaky gut and indicates intestinal mucosal dysfunction (IMD). Here we report a case of a 13 year old girl with CFS who showed very high values for serum IgM against the LPS of some enterobacteria and signs of oxidative and nitrosative stress, activation of the inflammatory response system, and IgG3 subclass deficiency. Upon treatment with specific antioxidants and a "leaky gut diet", which both aim to treat increased gut permeability, and immunoglobins intravenously, the increased translocation of the LPS of gram negative enterobacteria normalized and this normalization was accompanied by a complete remission of the CFS symptoms.

Majer, M., Jones, JF., Unger, ER., Solomon Youngblood, L., Decker, MJ., Gurbaxani, B., Heim, C and Reeves, WC. Perception versus polysomnographic assessment of sleep in CFS and non-fatigued control subjects: results from a population-based study. BMC Neurolology, 2007, 7:40.

Complaints of unrefreshing sleep are a prominent component of CFS; yet, polysomnographic studies have not consistently documented sleep abnormalities in CFS patients. We conducted this study to determine whether alterations in objective sleep characteristics are associated with subjective measures of poor sleep quality in persons with CFS.

We examined the relationship between perceived sleep quality and polysomnographic measures of night-time and daytime sleep in 35 people with CFS (CDC criteria ’94) and 40 non-fatigued control subjects, identified from the general population of Wichita, Kansas and defined by empiric criteria. Perceived sleep quality and daytime sleepiness were assessed using clinical sleep questionnaires. Objective sleep characteristics were assessed by nocturnal polysomnography and daytime multiple sleep latency testing.

Participants with CFS reported unrefreshing sleep and problems sleeping during the preceding month significantly more often than did non-fatigued controls. Participants with CFS also rated their quality of sleep during the overnight sleep study as significantly worse than did control subjects. Control subjects reported significantly longer sleep onset latency than latency to fall asleep as measured by PSG and MSLT. There were no significant differences in sleep pathology or architecture between subjects with CFS and control subjects.

In conclusion, people with CFS reported sleep problems significantly more often than control subjects. Yet, when measured these parameters and sleep architecture did not differ between the two subject groups. A unique finding requiring further study is that control, but not CFS subjects, significantly over reported sleep latency suggesting CFS subjects may have an increased appreciation of sleep behaviour that may contribute to their perceived sleep problems.

http://www.biomedcentral.com/content/pdf/1471-2377-7-40.pdf

Ohinata, J., Suzuki, N., Araki, A., Takahashi, S., Fujieda, K and Tanaka, H. Actigraphic assessment of sleep disorders in children with chronic fatigue syndrome. Brain & Development, 2007, Nov 26; [Epub ahead of print]. doi.org/10.1016/j.braindev.2007.10.004.

Children with CFS often suffer from sleep disorders, which cause many physiological and psychological problems. Understanding sleep characteristics in children with CFS is important for establishing a therapeutic strategy. We conducted an actigraphic study to clarify the problems in sleep/wake rhythm and physical activity in children with CFS.

Actigraphic recordings were performed for 1-2 weeks in 12 CFS children. The obtained data were compared with those of healthy age-matched children used as the control. Sleep patterns were divided into two groups based on subjects' sleep logs: irregular sleep type and delayed sleep phase type. Compared to the control group, total sleep time was longer and physical activity was lower in both groups of CFS. Continuous sleep for more than 10h was not uncommon in CFS. In the irregular sleep type, impaired daily sleep/wake rhythms and disrupted sleep were observed. Using actigraphy, we could identify several characteristics of the sleep patterns in CFS children. Actigraphic analysis proved to be useful in detecting sleep/wake problems in children with CFS.

Rosenhagen, MC., Schmidt, U., Ebinger, M., Nickel, T and Uhr, M. Successful treatment of chronic fatigue syndrome with duloxetine and trijodthyronine - a case study. Journal of Clinical Psychopharmacology, 2008, 28, 1, 105-107.

Letter.

Spence, VA., Kennedy, G., Belch, JJF., Hill, A and Khan, F. Low grade inflammation and arterial wave reflection in patients with chronic fatigue syndrome. Clinical Science, 2007, November 21st, Online First. doi:10.1042/CS20070274.

Some of the symptoms reported by people with CFS are associated with various cardio-vascular phenomena. Markers of cardiovascular risk, including inflammation and oxidative stress, have been demonstrated in some CFS patients but little is known about the relationship of these and prognostic indicators of cardiovascular risk in this patient group. We sought to investigate the relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness, in 41 well characterised CFS patients (CDC criteria ’94) and in 30 healthy subjects.

The augmentation index, normalised for a heart rate of 75 beats per minute (Alx@75), was significantly greater in CFS patients than in control subjects (22.5 ± 1.7 versus 13.3 ± 2.3%, p=0.002). CFS patients also had significantly increased levels of C-reactive protein (2.58 ± 2.91 versus 1.07 ± 2.16 g/mL, p<0.01) and 8-iso-prostaglandin F2α isoprostanes (470.7 ± 250.9 versus 331.1 ± 97.6 pg/mL, p<0.005). In CFS patients, Alx@75 significantly correlated with log C-reactive protein (r=0.507, p=0.001), isoprostanes (r=0.366, p=0.026), oxidised LDL (r=0.333, P=0.039) and systolic blood pressure (r=0.371, p=0.017). In a stepwise multiple regression model, (including systolic and diastolic blood pressure, body mass index, C-reactive protein, TNFα, IL-1, oxidised LDL, HDL cholesterol levels, isoprostanes, age and gender), Alx@75 was independently associated with log CRP (β=0.385, p=0.006), age (β=0.363, p=0.022), and female gender (β=0.302, p=0.03) in CFS patients.

The combination of increased arterial wave reflection, inflammation and oxidative stress may result in an increased risk of future cardiovascular events. Assessment of arterial wave reflection might be useful for determining cardiovascular risk in this patient group.

VanNess, JM., Snell, CR and Stevens, SR. Diminished cardiopulmonary capacity during post-exertional malaise. Journal of Chronic Fatigue Syndrome, 2007, 14, 2, 77-85.

Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of CFS. That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO2max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms. The aim of the study was to compare results from repeated exercise tests as indicators of post-exertional malaise in CFS. Peak oxygen consumption (VO2 peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients (CDC criteria ’94) and six control subjects for two maximal exercise tests separated by 24 hours.

Multivariate analysis showed no significant differences between control and CFS, res-pectively, for test 1: VO2 peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2 peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p=0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p=0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p=0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%.

Zwarts, MJ., Bleijenberg, G and van Engelen, BG. Clinical neurophysiology of fatigue. Clinical Neurophysiology, 2008, 119, 1, 2-10.

Fatigue is a multidimensional concept covering both physiological and psychological aspects. Chronic fatigue is a typical symptom of diseases such as cancer, multiple sclerosis (MS), Parkinson's disease (PD) and cerebrovascular disorders but is also presented by people in whom no defined somatic disease has been established. If certain criteria are met, CFS can be diagnosed. The 4-item Abbreviated Fatigue Questionnaire allows the extent of the experienced fatigue to be assessed with a high degree of reliability and validity. Physiological fatigue has been well defined and originates in both the peripheral and central nervous system. The condition can be assessed by combining force and surface-EMG measurements (including frequency analyses and muscle-fibre conduction estimations), twitch interpolation, magnetic stimulation of the motor cortex and analysis of changes in the readiness potential. Fatigue is a well-known phenomenon in both central and peripheral neurological disorders. Examples of the former conditions are multiple sclerosis, Parkinson's disease and stroke. Although it seems to be a universal symptom of many brain disorders, the unique characteristics of the concomitant fatigue also point to a specific relationship with several of these syndromes. As regards neuromuscular disorders, fatigue has been reported in patients with post-polio syndrome, myasthenia gravis, Guillain-Barré syndrome, facioscapulohumeral dystrophy, myotonic dystrophy and hereditary motor and sensory neuropathy type-I. More than 60% of all neuromuscular patients suffer from severe fatigue, a prevalence resembling that of patients with MS. Except for several rare myopathies with specific metabolic derangements leading to exercise-induced muscle fatigue, most studies have not identified a prominent peripheral cause for the fatigue in this population. In contrast, the central activation of the diseased neuromuscular system is generally found to be suboptimal. The reliability of the psychological and clinical neurophysiological assessment techniques available today allows a multidisciplinary approach to fatigue in neurological patients, which may contribute to the elucidation of the pathophysiological mechanisms of chronic fatigue, with the ultimate goal to develop tailored treatments for fatigue in neurological patients. The present report discusses the different manifestations of fatigue and the available tools to assess peripheral and central fatigue.