TGI Friday! Our weekly round-up of recently published research abstracts and other items | 24 January 2014

January 24, 2014

From Journal of Neurology, Neurosurgery and Psychiatry< (JNNP), February 2014 (first published online 17 November 2012)
Full text available.


Unity of opposites? Chronic fatigue syndrome and the challenge of divergent perspectives in guideline development
Charlotte Smith, Simon Wessely
Department of Psychological Medicine, Institute of Psychiatry, Weston Education Centre, London, UK
Correspondence to Dr Charlotte Smith, Department of Psychological Medicine, Institute of Psychiatry, Weston Education Centre, Cutcombe Road, London SE5 9RJ, UK;


Guideline development by its nature is a process and method of integration and synthesis of information, be it originating from research, evidence-based medicine, clinical findings, patient experience and/or individual narratives of an illness or disease. In the majority of cases, it can be assumed that this information and these ideas are travelling in the same direction; however, it is possible that the objective and subjective cannot be synthesised, and appear mutually contradictory.

In this commentary, an example of where this might be the case has been analysed: a report published by the Scottish Public Health Network, a Health Care Needs Assessment of Services for people living with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS).

It appears from reflection and analysis of this document that this process may indeed have gone awry. We propose that, if followed, this document would lead to the adoption of dangerous diagnostic criteria for ME/CFS, as well as preventing patients from making informed decisions about treatment options, and discouraging clinicians from following evidence-based medicine and recommending proven treatments for ME/CFS, because of potential implications for future commissioning.

This commentary seeks to highlight some of the problems, contradictions and unintended consequences of a divergence between patient perspectives and evidence-based medicine despite probably sharing the same aim, that of improving patient care and striving for better understanding and better treatments for disease.

ALSO FROM JNNP, first published online 13 January 2014

Editorial commentary

Chronic fatigue syndrome/myalgic encephalomyelitis: more heat, some light — directions for research and clinical practice

Richard Morriss
Correspondence to Professor Richard Morriss, B Floor, Institute of Mental Health, University of Nottingham Innovation Park, Triumph Road, Nottingham NG7 2DU, UK;

Under proper supervision first-line treatments for chronic fatigue syndrome are effective and safe but research into second-line treatment is required.

In the paper by Smith and Wessely,1 problems are outlined in commissioning services in Scotland2 that accommodate the acrimonious debate between the views of those who consider myalgic encephalomyelitis (ME) to be a neurological condition versus an evidence-based medicine view that chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a condition of uncertain aetiology improved by graded exercise treatment (GET) and cognitive behaviour therapy (CBT).3 The debate threatens to hinder the development of safe, cost-effective and clinically effective services for patients with CFS/ME, and to stifle further research building on important discoveries on diagnosis, the limited effectiveness of current treatments and the validity of ‘objective’ outcome measures.

From Physiological Reports, 13 November 2013.

The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome

Akifumi Kishi(1,2,*), Fumiharu Togo(3), Dane B. Cook(4), Marc Klapholz(5), Yoshiharu Yamamoto(3), David M. Rapoport(1), Benjamin H. Natelson(6,†)
1) Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York City, New York
2) Japan Society for the Promotion of Science, Tokyo, Japan
3) Educational Physiology Laboratory, Graduate School of Education, The University of Tokyo, Tokyo, Japan
4) William S. Middleton Memorial Veterans Hospital and Department of Kinesiology, University of Wisconsin School of Education, Madison, Wisconsin
5) Department of Medicine, Rutgers-New Jersey Medical School, Newark, New Jersey
6) Pain & Fatigue Study Center, Department of Neurology, Rutgers-New Jersey Medical School, Newark, New Jersey
† Department of Pain Medicine and Palliative Care, Beth Israel Medical Center and Department of Neurology, Albert Einstein College of Medicine, New York City, New York
* Correspondence
Akifumi Kishi, NYU Sleep Disorders Center, New York University School of Medicine, 462 First Avenue, NBV7N3, New York, NY 10016.


Effects of exercise on dynamic aspects of sleep have not been studied.

We hypothesized exercise altered dynamic sleep morphology differently for healthy controls relative to chronic fatigue syndrome (CFS) patients.

Sixteen controls (38 ± 9 years) and 17 CFS patients (41 ± 8 years) underwent polysomnography on baseline nights and nights after maximal exercise testing.

We calculated transition probabilities and rates (as a measure of relative and temporal transition frequency, respectively) between sleep stages and cumulative duration distributions (as a measure of continuity) of each sleep stage and sleep as a whole. After exercise, controls showed a significantly greater probability of transition from N1 to N2 and a lower rate of transition from N1 to wake than at baseline; CFS showed a significantly greater probability of transition from N2 to N3 and a lower rate of transition from N2 to N1.

These findings suggest improved quality of sleep after exercise. After exercise, controls had improved sleep continuity, whereas CFS had less continuous N1 and more continuous rapid eye movement (REM) sleep. However, CFS had a significantly greater probability and rate of transition from REM to wake than controls.

Probability of transition from REM to wake correlated significantly with increases in subjective fatigue, pain, and sleepiness overnight in CFS – suggesting these transitions may relate to patient complaints of unrefreshing sleep. Thus, exercise promoted transitions to deeper sleep stages and inhibited transitions to lighter sleep stages for controls and CFS, but CFS also reported increased fatigue and continued to have REM sleep disruption. This dissociation suggests possible mechanistic pathways for the underlying pathology of CFS.

From the European Journal of Clinical Microbiology and Infectious Diseases, 16 January 2014 [Epub ahead of print]

Serology in chronic Q fever is still surrounded by question marks.

Wegdam-Blans MC, Tjhie HT, Korbeeck JM, Nabuurs-Franssen MN, Kampschreur LM, Sprong T, Teijink JA, Koopmans MP.
Department of Medical Microbiology, Laboratory for Pathology and Medical Microbiology (PAMM), de Run 6250, 5504 DL, Veldhoven, The Netherlands,


Detection of antibodies using immunofluoresence tests (IFAT) is recommended for diagnosis of chronic Q fever, but other commercial antibody assays are also available.

We compared an enzyme-linked immunosorbent assay (ELISA) (Virion/Serion) and a complement fixation test (CFT) (Virion/Serion) for the detection of Coxiella burnetii IgG phase I and IgA phase I in early- and follow-up serum samples from patients with chronic Q fever, diagnosed according to an algorithm that involves IFAT. For this, we tested sera of 49 patients, including 30 proven, 14 probable and five possible chronic Q fever cases.

Sensitivity of CFT for diagnosis of chronic Q fever was suboptimal (85 %), as eight patients, including five with chronic Q fever, tested negative at time of diagnosis, whereas IgG phase I antibodies were detected in these five patients by ELISA. Sensitivity of ELISA was higher, although three probable patients were missed.

No differences in ELISA IgA phase I detection between proven chronic Q fever and probable were observed; instead possible patients were in majority IgA negative (60 %). Serological examination using ELISA and CFT in follow-up sera from 26 patients on treatment was unsatisfactory.

Like IFAT, all kinetic options were possible: decreasing, remaining stable or even increase during time. This study demonstrated that the sensitivity of CFT-based phase I antibody detection is low and
therefore not recommended for diagnosis of chronic Q fever. Based on our results, serological follow-up to guide treatment decisions was of limited value.

From Advances in Mind-Body Medicine, Winter 2014.

Valacyclovir treatment of chronic fatigue in adolescents.

Henderson TA.


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

In a retrospective case series, 15 adolescents and preteens referred to the author for treatment-resistant depression or mood disorder were evaluated and found to have met the Fukuda diagnostic criteria for CFS.

While a subset (4/15) had been diagnosed in the past with CFS, the majority had a current diagnosis of depression or a mood disorder. The Diagnostic and Statistical Manual-IV Text Revision (DSM-IV TR) criteria for depression were not met in all patients, although 3 cases of mood disorder not otherwise
specified (MD-NOS) and 1 case of Tourette syndrome (TS) plus MD-NOS were diagnosed.

Baseline scores on the Children's Depression Inventory (CDI) were below the cutoff for depression in all but 1 patient. Baseline self-assessment scales for CFS or fatigue were obtained and sleep was evaluated with sleep logs.

All patients were treated subsequently with valacyclovir, with 93% having a positive response. At the end of treatment, scores on fatigue self-assessment scales improved significantly (P < .001). Vigor subscale scores also improved significantly (P < .001). Some patients experienced complete resolution of symptoms.Although not every patient was tested, available laboratory testing revealed increased counts of natural killer (NK) cells and decreased human herpesvirus 6 (HHV-6) antibody titers in all patients who responded to valacyclovir.This article discusses the significance of infectious agents in the pathogenesis of psychiatric symptoms. The study's data support an intriguing hypothesis that a portion of treatment-resistant depression in fact may be undiagnosed CFS or other chronic viral infection.

From Disability and Rehabilitation, 27 December 2013 [Epub ahead of print]

Experiences of daily activity in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and their implications for rehabilitation programmes.

Sue Pemberton(1) and Diane L. Cox(2)
1) Yorkshire Fatigue Clinic, Forsyth Business Centre, York, North Yorkshire, UK and
2) Occupational Therapy Research Office & Graduate School, University of Cumbria, Lancaster, Lancashire, UK
Address for correspondence: Sue Pemberton, Therapy Director, Yorkshire Fatigue Clinic, Forsyth Business Centre, Tower Court, York, North Yorkshire YO30 4XL, UK. Tel: +44 1904 557 148. E-mail:



Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME), has a significant impact upon daily functioning. Most recommended treatments aim to alter activity patterns based upon assumptions of activity avoidance. However, as there is limited research on the experience of activity and occupational beliefs in people with CFS/ME, this study took a qualitative approach to understand the meaning of activity in people with this disabling condition.


This study applied a social constructivist grounded theory methodology. Semi-structured interviews took place with 14 participants attending a Specialist CFS/ME Service in England.


The emergent themes described a premorbid state of constant action with difficulty stopping an activity once it had commenced. When this pattern was interrupted by illness, participants attempted to maintain their previous level of occupational engagement. Negative associations and emotions were described in response to the concept of doing nothing or limited activity. A recurring cycle was reported of increasing activity levels when symptoms improved, followed by post exertional symptoms.


Consequently, participants' beliefs about concepts of both activity and inactivity need to be considered within the application of rehabilitation programmes for CFS/ME that aim to modify activity related behaviours. Implications for Rehabilitation Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is commonly treated in the UK using activity modification.

In this small qualitative study, patients expressed negative feelings and beliefs towards the concept of doing nothing and therefore sought to push their activity levels when this was available, leading to recurring cycles of symptoms and activity. Rehabilitation programmes need to consider how people with CFS/ME engaged with activity and inactivity before the condition and how this may impact upon engagement with activity-based rehabilitation programmes.

From Autoimmune Reviews, 12 August 2013. 2013 Epub 2013 Mar 26.

Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies – novel tool for diagnostics and patient follow-up.

Osnes LT, Nakken B, Bodolay E, Szodoray P.
Institute of Immunology, Rikshospitalet, Oslo University Hospital, Norway.


Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes.

The intricate interplay and fine balance of pro- and anti-inflammatory processes drive, whether inflammation and eventually organ damage will occur, or the inflammatory cascade quenches.

In the early and late, as well as inactive and active stages of autoimmune diseases, different cellular and molecular patterns can dominate in these patients. However, the simultaneous assessment of pro- and anti-inflammatory biomarkers aids to define the immunological state of a patient.

A group of the most useful inflammatory biomarkers are cytokines, and with increasing knowledge during the last decade their role have been well-defined in patients with autoimmune diseases and immunodeficiencies.

Multiple pathological processes drive the development of autoimmunity and immunodeficiencies, most of which involve quantitative and qualitative disturbances in regulatory cells, cytokine synthesis and signalling pathways.

The assessment of these biomarkers does not aid only in the mechanistic description of autoimmune diseases and immunodeficiencies, but further helps to subcategorize diseases and to evaluate therapy responses.

Here, we provide an overview, how monitoring of cytokines and regulatory cells aid in the diagnosis and follow-up of patients with autoimmune diseases and immunodeficiencies furthermore, we pinpoint novel cellular and molecular diagnostic possibilities in these diseases.

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