Norwegian Studies – NorCAPITAL Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial

NorCAPITAL is the name for «The Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial» by MD PhD Vegard Bruun Wyller, Unit for Chronic Fatigue Syndrome, Dept. of Paediatrics, Oslo University Hospital Rikshospitalet, Norway.

In this post we will give a indruduction of the studyprotocol and some subjecive comments to the trial.

Information on the institution

Since 2003, children and adolescent with CFS/ME has been a field of high priority at the Division of Paediatrics, Rikshospitalet University Hospital, Oslo, Norway. The Unit for Chronic Fatigue Syndrome (UCFS) was formally established in 2007, and has been assigned a national responsibility for scientific and clinical development among children and adolescents with CFS. The unit serves as a national referral center, receiving two CFS patients < 18 years for outpatient evaluation each week.

Image: Employers at Rikshospitalet, Oslo. Dr. Wyller to the left.

There is a close scientific collaboration with highly reputed international institutions: Medical University of South Carolina, Charleston, USA (Prof. J. Philip Saul); Johns Hopkins University School of Medicine, Baltimore, USA (Prof. Peter C. Rowe); Massachusetts General Hospital/Harvard Medical School, Boston, USA (Dr. Riccardo Barbieri). Nationally, the unit has a central role in the research network “Chronic fatigue syndrome in theory and practice” (headed by Dr. Kirsti Malterud, Bergen). UCSF hosted a national conference on CFS/ME in 2008, and was a major contributor to the HTA-report from the Norwegian Health Knowledge Centre in 2006.

Dept. of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA, is a leading international institution for pediatric CFS/ME research, and particular concerned with the field of autonomic assessment. Dept. of Pediatrics, Medical University of South Carolina, Charleston, USA, is highly reputed for their competence in experimental studies of autonomic cardiovascular control and related data analyses.

The Cognitive Developmental Research Unit, Dept. of Psychology, University of Oslo is especially established to study cognitive function such as memory, emotion, executive function, and social-cognitive functions.

The methods and the laboratory facilities are particularly suited to the study of the possible problems that might be predicted in adolescents with CFS/ME. Dept. of Medical Biochemistry, Rikshospitalet University Hospital, Oslo, has as special focus on mitochondrial function and a close collaboration with Center of Molecular Biology and Neuroscience (a national centre of excellence).

The Pediatric Research Institute, Dept. of Microbiology, and Dept. of Endocrinology, Rikshospitalet University Hospital, are leading scientific institutions, regularly publishing in high-impact medical journal. The National Institute of Occupational Health has years of experience with similar research projects among adult patients.

Summary and introduction of NorCAPITALs Study protocol:

Epidemiology and clinical presentation

Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a long-lasting, disabling condition, existing in all cultures. The prevalence is uncertain; however, international studies suggest a point prevalence of 9 000 to 18 000 in Norway, including about 600 children and adolescents (< 18 years of age). The male: female relation is 1:3. CFS/ME is rare in children younger than 10 years. The clinical presentation is characterized by mental and physical fatigue, which is aggravated by minimal exercise and not relieved by rest. Additional symptoms include headache, pain in the muscles and skeleton, attenuated concentration and memory, insomnia and orthostatic intolerance. The level of disability varies; however, a majority has long-lasting absence from school and work, and is unable to participate in normal social activities. The most disabled is permanently bedridden.

Etiology and pathophysiology

The underlying causes of CFS/ME remain unknown, but it is generally assumed that the condition is multifactorial, and many advocate a bio-psycho-social perspective. Regarding predisposing factors, increased risk seem to be related to genetic factors as well as certain personality traits. Regarding precipitating factors, there is evidence for the importance of long-lasting infections and critical life events. Important perpetuating factors possibly include altered immune response such as Th2 vs Th1 predominance and ongoing inflammation, as well as endocrine alterations and alterations of autonomic nervous activity.

Diagnose, treatment and prognosis

CFS/ME is diagnosed according to two main principles: 1) Identification of a typical history and symptom’s description, and 2) Exclusion of differential diagnosis, preferably according to a standardized set of investigations. There is no established diagnostic test. Diagnostic criteria are developed for scientific purposes; the most commonly used originate from the US Center for Disease Control and Prevention (CDC-criteria).

Several treatment regimens have been subjected to research. However, cognitive behavioral therapy (CBT) and graded exercise therapy (GET) remain the only ones with a documented beneficial effect in randomized controlled trials. The patients included in these studies are generally restricted to the least disabled ones. One trial only (studying CBT) has focused specifically on adolescent CFS/ME patients. Intervention trials of glucocorticoids, mineralcorticoids, antidepressants, anticholinergic agents, growth hormone, immunoglobulins and nutritional regimens have not shown any beneficial effect. However, supportive patient care is recognized to play an important, independent role.

CFS/ME is long-lasting, and the long-term prognosis is uncertain; in a recent review of adult patients, total recovery/improvement was estimated to 5 % and 40 %, respectively. Adolescents seem to have a better prognosis, which may improve further if the patient receives professional care from an early stage .

Ethical considerations and supervised by Norwegian National Committee for Ethics in Medical Research

Approval to conduct the project is granted from the Norwegian National Committee for Ethics in Medical Research, the Norwegian Data Inspectorate, the Norwegian Health Directorate, and the Norwegian Medicines Agency. The project will be carried out in accordance with Norwegian laws and precepts (FOR 2009-30-10), as well as the consolidated guidelines of Good Clinical Practice

Publication policy All results from this project will be published in international, peer-reviewed medical journal. We will also report negative results. Co-authorship will be granted according to the Vancouver guidelines.

Project administration and collaborators

Principal investigator Vegard Bruun Wyller, MD, PhD. Consultant and Associate Professor, Unit for Chronic Fatigue Syndrome, Dept. of Paediatrics, Oslo University Hospital Rikshospitalet, Norway.

For Research and Scientific and other collaborators, see protocol

Pilot study – 5 pilot patients: A pilot study specifically related to the intervention trial will be carried out, designed in accordance with analogous previous pilot studies of CFS/ME. The aim of the pilot study is twofold: to ascertain the dosage plan of clonidine for the main trial, and to assess our routines for activity measurement, questionnaire distribution, tilt-test protocol etc. The prestudy will be published in 2011.


Background and aims for the main trial:

The main study is ongoing and ends in 2013.

‘Sustained arousal’ – a model for disease mechanisms in CFS/ME

Since 2003, our research in this area has primarily focused upon autonomic circulatory regulation and thermoregulation in adolescents with CFS/ME. The patients reported symptoms indicative of alteration of these regulatory mechanisms, and experiments revealed higher resting heart rate, blood pressure, total peripheral resistance, core body temperature and plasma concentration of catecholamines as compared to healthy controls. Orthostatic challenge resulted in a more pronounced increase in heart rate, blood pressure and total peripheral resistance among patients, whereas cooling precipitated a stronger decrease in body temperature and a smaller reduction in acral skin blood flow.

Taken together, these results indicate that CFS/ME patients have enhanced sympathetic nervous activity at rest and altered sympathetic nervous responses to moderate somatic stressors, in accordance with recent reports from other research groups.

The character of the responses suggests an alteration in central nervous modeling of homeostatic control circuits. More specifically, the patients seem to possess a permanent stress response – commonly labeled ‘sustained arousal’ within stress theory.

We suggest that a state of sustained arousal might constitute a fundamental part of the underlying pathophysiology in CFS/ME, and we have developed a sustained arousal-model in an attempt of integrating research findings from different fields and traditions. It should be noted that this model is disputed and not “proven” in any scientific meaning. It enables, however, the deduction of hypothesis within different fields which might in turn be subjected to systematic testing. In this way, empirical evidence will accumulate that either supports or falsifies the underlying theory.

The sustained arousal-model will constitute the framework for further research projects, including those described in the following: Part A – Basic disease mechanisms in adolescents with CFS/ME, and Part B – Treatment of CFS/ME in adolescents with clonidine.

Part A – Basic disease mechanisms in adolescents with CFS/ME

Genetic predisposition in CFS/ME

Catecholamines, corticotropin releasing hormone (CRH) and serotonin (5HT) act as neurotransmitters in various brain stem areas, influencing the stress response. These neurotransmitters have also been associated with the perception of fatigue. Based upon the sustained arousal-model of CFS/ME, an association to genetic variants (polymorphisms) influencing these transmitters is to be expected. Preliminary data suggest that this polymorphism is prevalent among our CFS/ME patients (unpublished results).

In this project, therefore, we will focus on possible relations between this and other well-defined polymorphisms and alterations of the stress response.

Infections and immunological alterations in CFS/ME

The possible relations between the immunological and microbiological findings remain largely unknown.

Based upon the sustained arousal-model, two alternative hypotheses might be deduced:

a) Infections are somatic stressors, promoting a state of sustained arousal in concert with other mental and physical stressors, which in turn results in immunological alterations through altered endocrine and autonomic mechanisms. In addition, long-lasting infections may cause immunological alterations directly.

b) Sustained arousal causes immunological alterations which in turn result in reactivation of latent infections In a), infections are regarded as a causal factor, in b) as an epi-phenomenon.

A third, competing hypothesis is direct microbiological damage of the central nervous system, explaining both autonomic, endocrine and immunological alterations.

Endocrine alterations in CFS/ME

Previous studies of CFS/ME in this field has mainly focused on the hypothalamus-pituitary-adrenal axis (HPA axis): The patients tend to have low levels of cortisol in plasma, urine and saliva, altered circadian rhythms and attenuated HPA responsiveness during stimuli that normally increase cortisol secretion.

Taken together, the documented endocrine alterations are in agreement with the sustained arousal-model. In particular, attenuated HPA axis responses are an expected finding during chronic stress, as opposed to acute stress. We plan to explore endocrine abnormalities further, with a particular emphasis on the HPA axis, catecholamines and regulation of osmolality.

Cognitive impairments, neurotransmitters and functional neuroradiologic assessment in CFS/ME

The cognitive impairments are in agreement with the sustained arousal-model. In adolescents, however, such impairments are not thoroughly explored, despite a potential strong negative impact upon daily living, school functioning in particular. In addition, cognitive behavioral therapy is the intervention with best evidence of beneficial effects.

The relation between specific cognitive functions, neurotransmitters and well-defined brain areas is rapidly evolving field of research. The documented impairments in CFS/ME patients may indicate alterations of noradrenergic transmission: Physical exercise promotes brain norepinephrine secretion, and is related to further decrease in cognitive function among CFS/ME patients.

Furthermore, pharmacological attenuation of noradrenergic transmission using clonidine, improved executive functions – such as planning abilities – in one study Furthermore, the indications of increased 5HT neurotransmission in CFS/ME are in agreement with the sustained arousal-model.

Sensory hypersensitivity and autonomic responses in CFS/ME

The sustained arousal-model implies that central sensitization does not only influence pain perception and responses; autonomic responses to other sensory signals might be altered as well. This, in turn, is in accordance with patients’ own description of being sensitive towards all kinds of sensory input (light, smell, sounds, touch).

The cognitive impairments in CFS/ME might be related to decreased ability to process thoughts and memories with emotional content, as discussed above. Distressing emotions are, in turn, associated with somatic stress responses. Thus, the finding of altered autonomic response during orthostatic challenges might in fact be caused by emotional distress in the experimental setting rather than a central sensitization phenomenon. If so, one would expect a similar autonomic response when patients just imagine themselves in an upright position.

Mitochondrial function in CFS/ME

As for CFS/ME, there are different possibilities for a causal relation between a suggested mitochondrial dysfunction and the sustained arousal-model:

a) Mitochondrial dysfunction may cause sustained arousal through a direct effect on the central nervous system. The neurons’ dependency upon a normal energy metabolism is generally recognized; only small deviations in mitochondrial function might have negative consequences for the brain.

b) Sustained arousal may cause a mitochondrial dysfunction through alterations of endocrine and/or autonomic control systems. Indeed, both catecholamines and cortisol influences mitochondrial function in vivo.

Patients’ experiences in CFS/ME

Taken together, these issues might have negative impact upon quality of life and self confidence, and eventually disturb the normal cognitive, emotional and social development in childhood and adolescence. Furthermore, the sustained arousal-model infers a possible reinforcing process, as negative experiences of social interactions might enhance a stress response and thereby create a vicious circle. Finally, one would fear a negative influence upon treatment compliance; mutual trust between patient and health care worker is a prerequisite for cognitive behavioral therapy as well as graded exercise therapy.

Part B – Treatment of CFS/ME in adolescents with clonidine

Treatment of CFS/ME with the alfa-2 adrenergic agonist clonidine

The sustained arousal-model implies that treatment attenuating stress responses might have a beneficial effect in CFS/ME. This is in accordance with the documented effect of cognitive behavioral therapy, and is also in line with case reports of strong beneficial effect from the so-called “Lightning Process”, in which different mental techniques is pin-pointed towards reducing somatic stress (Phil Parker, founder of Lightning Process, London, UK. Personal communication).

Based upon these lines of evidence, we have tried low-dose clonidine for short periods of time to selected CFS/ME patients as part of our regular outpatient service, and some report a significant improvement of symptoms and functional level.

Design overview

A design overview is given in Figure 1. After a pilot study of 5 CFS/ME patients (not shown in the figure), 120 CFS/ME patients are consecutively included in part B, which is a randomized, placebo controlled, double-blinded intervention trial of clonidine. A randomly selected sample of 30 patients from part B is also enrolled in part A, which is an experimental study of pathophysiology. In addition, 30 volunteer healthy control subjects are included in part A.

Thus, a total of 150 individuals (+ 5 pilots) are subjected to baseline program at the point of inclusion (cf. below). 30 patients and 30 controls will also go through an extended program confined to part A, whereas all 120 patients are accomplishing a part B specific program. The patients are thoroughly assessed at UCFS during week 8 (day 56-63) and week 30 (day 203-210).

Read the Study Protocol here: NorCAPITAL final protocol 16 feb 2010


Comments to the trial:

In this this stydy Dr. Wyller is trying to prove his «sustained arousal-model» and he says:

The sustained arousal-model will constitute the framework for further research projects, including those described in the following: Part A – Basic disease mechanisms in adolescents with CFS/ME, and Part B – Treatment of CFS/ME in adolescents with clonidine.

There is something that we can not familiarize ourselves with in this triel, and that is this team is active users and strongly belivers of GET and CBT. Patiens in this trial can not have taken LP in forehand and are even excluded.  These attitudes have still a big impact for ME/CFS patiens in Norway and www, and we all know that GET/CBT/LP is not a clinical medical treatment for this disease.

Still the Study Protocol shows that it is scientifically well described in a good fundemental way, to try to prove the hypothesis in the study.

The academic description in this stydy is done in a positive and good way, and research is based on proving the hypotheses. There are actually what science is all about!!

BUT: If this triel conclude with that clonidin and GET/CBT is the best treatment – the ME/CFS community will still meet future problems. AND yes we mean Problems.

The ME/CFS community in Norway will and do pay a huge attention to the result and outcome of this trial!!!



En kommentar om “Norwegian Studies – NorCAPITAL Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial

  1. Tilbaketråkk: Norwegian research studies: Protocol for intervention «Mental training for chronic fatigue syndrome (CFS/ME) following EBV infection in adolescents: a randomised controlled trial» – ToTo NeuroImmunologisk Kurativ Behandling

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