Edited by: Michael Noll-Hussong, Universitätsklinikum des Saarlandes, Germany
Reviewed by: Francisco José Eiroa-Orosa, University of Barcelona, Spain; Rosa Magallon, Universidad de Zaragoza, Spain; Andreas Dinkel, Technische Universität München, Germany
This article was submitted to Psychosomatic Medicine, a section of the journal Frontiers in Psychiatry
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Assessments were done by self-reports prior to the first consultation, 1 week before and 1 week after the intervention program, and at 3 months and 1 year after the intervention. SPSS 23 and R 3.3 were used for statistical analyses. The associations between case definitions and the outcome measures (Chalder Fatigue Scale (FS), Short Form 36 (SF-36) physical functioning scale) were assessed by a linear mixed effects model (LME).
A subgroup fulfilling the inclusion criteria from the PACE study (Chalder Fatigue Scale >6/11, SF-36 Physical functioning <65/100) showed clinically significant improvement through 1 year, changes in outcome measures were statistically significant (
Chronic Fatigue Syndrome (CFS), also named Myalgic Encephalopathy (ME), is an incapacitating illness characterized by severe and excessive fatigue, accompanied by a wide variety of health complaints involving several physiological organ systems including sleep problems, pain and cognitive dysfunctions, and with a general and often severe functional impairment (
Despite substantial research effort, no intervention has yet been proven universally effective (
It has been suggested that the variability in treatment response might be related to differentiated needs from subgroups of CFS/ME patients (
Based on our earlier study (
The aims of the study were (1) to study the clinical longitudinal course in chronic fatigue syndrome with two different case definitions, through changes from pre- to post-intervention including a 4-day concentrated treatment program, and (2) to study the patients' satisfaction with and acceptance of the content, format and effect of the intervention program.
Three hundred five patients (84% women) with a mean age of 39 years (
The therapy groups also included patients with non-CFS diagnoses, where the clinician found it relevant to offer this concentrated treatment approach.
The clinical study included patients who fulfilled inclusion criteria of CFS and who did not have any other medical illness giving reason for exclusion.
All patients who fulfilled inclusion criteria of the study and who were willing to participate in a group therapy program were offered participation in the study. All of these accepted. Twenty patients were not interested in participation because of the group format and, thus, were not offered participation in the program.
All participants fulfilled the Oxford criteria for chronic fatigue syndrome (
A semi-structured psychiatric interview, M.I.N.I. (
All patients were also examined according to the CDC (1994) case definition of chronic fatigue syndrome (
After referral, the patients received self-report questionnaires, which they returned at the first consultation (baseline).
Chalder Fatigue Scale (FS) (
Short Form Health Survey-36 (SF-36) is a validated self-rating questionnaire which measures health-related quality of life (HRQoL) (
The Client Satisfaction Questionnaire-8 (CSQ-8) is an 8-item widely used self-report questionnaire which covers the patients' satisfaction with quality, content, amount as well as effects of the treatment. The scale has known and acceptable psychometric qualities (
The Beck Depression Inventory (BDI-II) assessed level of depressive symptoms. This is a 21-item self-report questionnaire which measures depressive symptoms during the 2 weeks prior to assessment (
The Beck Anxiety Inventory (BAI) is a 21 item self-report questionnaire measuring the subjective, somatic, or panic-related symptoms of anxiety (
Internal consistency measured with Cronbach's alpha for the Chalder Fatigue Scale was 0.865, for SF-36 Physical Function 0.897, for BDI (depression score) 0.843 and for BAI (anxiety score) 0.878.
Aims of the initial consultation were to assess the clinical condition, confirm the diagnosis of CFS/ME and to establish a positive therapeutic alliance. Patients were offered a medical explanation of their illness, based on a model of predisposing, precipitating, and perpetuating factors. Explanation of excessive fatigue and exertion intolerance was based on models of physiological activation, dysregulation and sensitization processes. Illness behavior was addressed and cautiously challenged, presenting a simple program trying to establish alternative strategies concerning sleep, physical activity and nutrition. Patients were also given a brief introduction to mindfulness exercises to practice daily (
The time lap between the initial consultation and the intervention program was 6 weeks (mean), but varied according to availability of the next program, as well as private matters concerning family, work or intercurrent illness.
Prior to the groups, the patients were provided with an explanation of relevant maintaining factors, as well as basic principles for how to regulate the symptoms. Based on this information, they made a decision to allocate four consecutive days to the treatment.
One of the main features of this 4-day program is to deliver a composite of treatments that previously have been documented effective (
During the 4-day group program, the participants received two sessions of lecture /education (1st and 3rd day), each lasting 2 h. These sessions covered introduction to stress medicine with focus on physiological and psychological stress, sustained activation, dysautonomia, immune activation, and physiological dysregulation. The concept of sensitization (
The main illness model of CFS/ME in this program comprises both physiological and cognitive activation, sustained arousal and sensitization mechanisms, the effect of sleep disturbances and dysfunctional activity level, as well as focus on the illness behavior in CFS/ME and the frequent fear of exertion and further impairment.
In the educational sessions, patients were encouraged to ask questions for clarification, and alternative symptom explanations (e.g. energy loss vs. fatigue representing immune activation) were discussed and challenged or brought to the therapy groups.
A coping model with focus on stress expectation, positive outcome expectancy and active regulation of health complaints and symptoms was introduced (
The participants were introduced to guided mindfulness ad modum Kabat-Zinn (
The patients participated in group sessions 1–2 times daily, each lasting 30–60 min. In the very first session, each patient gave a brief outline of their illness history (5–10 min), without feedback from each other or from the therapist. After this, they were encouraged not to talk about illness and symptoms during breaks or leisure time, but to share experiences of success as well as plans for specific, observable changes they were going to make after the 4-day intervention, related to patterns of activity and rest.
During group therapy sessions the patients presented their concerns and typical coping strategies related to regulation of fatigue symptoms, e.g. sleep and physical activity. If not presented by the patients, topics like perfectionism and expectations from others, overachievement and fear of failure were introduced by the therapist. Acceptance and tolerance of subjective distress was included in the discussion, along with motivation for change and commitment by making decisions of change. Sessions were semi-structured, allowing for individual and group-specific dynamics, also allowing for topics introduced in educational sessions. Experiences from the mindfulness practices were frequently presented, aiming at strengthening the experience of self-efficacy and self-regulation.
During 3 days of the group program, the patients were instructed to write for 15 min about positive experiences and emotions (
The intervention program included daily walking sessions of 60–90 min, in low to moderate pace (aiming at HR <125). This activity included frequent stops and mindfulness sessions 5–15 min, focusing on being mindful of observing all senses at the present moment, encouraging the acceptance of disturbing thoughts and distressing physical sensations.
After the initial consultation and interview, lasting 2 h, all patients received written information regarding the group intervention program. The interval between the first consultation and the program was 1–46 weeks; the median time interval was 6 weeks, interquartile range (IQR) 7 weeks.
The group intervention program lasted for 4 days with 8 to 10 participants in each group. The participants stayed at a hotel nearby the clinic, in a rural area with an average travel distance of 2–3 h from home. The daily program lasted from 9 a.m. to 3–5 p.m. (A detailed description of the daily schedule is presented in Supplement Table
All patients had a 60 min individual consultation with a therapist during the program, discussing individual issues of concern.
After the program, patients were encouraged to report by email or phone about their condition after approximately 1 month, but no obligations were made. One week, 3 months and 12 months after the intervention program the patients completed the self-report questionnaires again. The “Client satisfaction questionnaire” (CSQ) evaluating the program was reported 1 week after completion of the program.
All patients fulfilling Oxford criteria for Chronic Fatigue Syndrome comprised the main sample (
This sub-sample used to compare results with PACE was divided into two groups; patients only meeting the Oxford criteria (
Descriptive methods were used to characterize the sample. The association between diagnoses (case definitions, Oxford and CFS-CDC) and the outcomes (fatigue scale (FS), SF-36 Physical Functioning) was assessed by a linear mixed effects model (LME) using case definitions, time and their interaction as predictors. We estimated the model adjusted for age, sex and the time between baseline (T0) and T1 one factor at the time as well as all together in a second model. For the final interpretation, we used the best of the models based on Akaike's Information Criterion (AIC) and the likelihood ratio test. Additionally we repeated the same procedure for the use of melatonin or anti-depressive medications as predictors instead of diagnosis (univariate models) as well as for all the predictors in the same model (multivariate model).
The Wilcoxon signed rank test was used to analyze change in Fatigue Scale, SF36 Physical functioning, BDI (depression) and BAI (anxiety) from baseline assessment to 1 year follow up (variables were not normally distributed). Effect sizes (
We compared the mean values of SF-36 Physical Functioning in this study sample to the population norm from Norway (
The significance level was set to 0.05. A Bonferroni adjustment for multiple testing was done in the main analysis (LME), setting the α level to.0083 (6 different models).
A goodness of fit evaluation for the linear mixed effects model was done, showing the model has acceptable fit for the data. The statistics for the goodness of fit evaluation are presented in Supplement Table
The computation was done using SPSS 23 (IBM Corp. Armonk, NY) and R 3.3(
All participants provided written informed consent prior to assessment. The study was approved by the Regional Committees for Medical and Health Research Ethics Committees (REC Western Norway) and the Norwegian Social Science Data Services (NSD). The study was performed in accordance with The Helsinki Declaration of the World Medical Association Assembly.
Demographic and clinical characteristics for total population and subsamples are reported in Table
Sociodemographic characteristics in total population and diagnostic subgroups.
305 (100) | 171 (56) | 134 (44) | |
Age (mean, SD, years) | 39.3(11.4) | 36.9 (11.8) | 42.4 (10.2) |
Gender female (n, %) | 257 (84.3) | 143 (84.6) | 112 (83.6) |
Education (n, %) |
28/129/140 |
18/62/72 |
10/51/68 |
Married/living in |
147/52/69 |
77/32/43 |
70/20/26 |
Income in NOK (n, %) |
119/82/15 |
72/45/5 |
47/37/10 |
Work status (%) |
35% |
||
Beck depression inventory (mean, SD) | 13.8 (7.4) | 13.1 (6.8) | 14.6(8.1) |
13.8 (7.4) | 13.1 (6.8) | 14.6(8.1) | |
Melatonin | 10.3 (7.9) | 10.0(8.2) | 10.7(7.6) |
Anti-depressive medication | 19 (6.3) | 5 (2.9) | 14 (10.5) |
Two-hundred and 19 patients (72%) completed all assessments at pre-treatment, 1 week and 1 year follow-up. Patients completing all assessments had higher mean age than patients who did not complete all assessments [40.4 (
The patient population showed statistically significant improvements on FS, SF-36 Physical functioning subscale, BDI and BAI from pre- treatment to 1-year follow up (all
For the fatigue scale (FS) there was a statistically significant effect of time from baseline to all time points with a statistically significant drop in scores, see Figure
Changes in outcome measures by timeline and case definitions CFS.
Improvements in symptoms from baseline to 1-year follow up (
Fatigue scale | 24.8 | 4.8 | 16.0 | 6.6 | <0.001 |
Fatigue scale, mental fatigue | 8.1 | 2.2 | 5.4 | 2.9 | <0.001 |
Fatigue scale, physical fatigue | 16.9 | 3.3 | 10.5 | 4.6 | <0.001 |
SF36, physical function | 60.9 | 21.8 | 77.4 | 20.0 | <0.001 |
A clinically useful difference (
Based on the clinical case inclusion criteria in the PACE study (
Subsample of patients ≥18 years, bimodal FQ≥6, and SF 36 physical function ≤ 65 (PACE criteria),
Age | 39.3 (11.3) | ||
Fatigue scale | 26.7 (4.0) | 17.0 (6.9) | < 0.001, |
SF-36, Physical function | 44.1 (14.5) | 70.3 (22.7) | < 0.001, |
BDI | 14.8 (7.9) | 8.2 (6.5) | < 0.001, |
BAI | 11.0 (8.3) | 6.4 (5.9) | < 0.001, |
Comparison of change in Fatigue scale and SF-36 Physical functioning from pretreatment to 1 year after treatment in the two diagnostic subgroups.
Pretreatment(t0) | 25.7(4.4) |
27.3(3.7) |
46.7(14.0) |
42.6(14.5) |
||
One year follow-up(t2) | 18.4(6.1) |
16.0(7.3) |
67.7(21.1) |
72.1(23.6) |
||
Change(t0-t2) | 7.1(6.7) | 10.8(7.4) | 0.005 | 20.4(19.1) | 29.2(23.4) | 0.109 |
Number improved |
84.8% |
91.2% |
0.371 | 78.3% |
86.8% |
0.306 |
None of the patients included (
Acceptance and satisfaction with treatment program (CSQ-8). How would you rate the quality of service you have received?: 3.5 (SD = 0.6). Did you get the kind of service you wanted?: 3.4 (SD = 0.5). To what extent has our program met your needs?: 3.2 (SD = 0.7). If a friend were in need of similar help, would you recommend our program to him or her? 3.8 (SD = 0.4). How satisfied are you with the amount of help you have received?:3.5 (SD = 0.5). Have the services you received helped you to deal more effectively with your problems?: 3.5 (SD = 0.6). In an overall, general sense, how satisfied are you with the service you have received?:3.6 (SD = 0.5). If you were to seek help again, would you come back to our program? 3.7 (SD = 0.5).
The results from this open study indicate that a brief, concentrated treatment program for CFS/ME might be highly beneficial. Patients reported improvement in outcome measures representing both clinical and statistical significance. This is interesting, as most studies on effectiveness in CFS/ME interventions generally have shown low or modest effect. Most participants in this study had been impaired by fatigue and ill health for a long time without improvement, indicating that time in itself is insufficient.
The number of participants (305), the statistical significance of improvements and the persistent changes through the 1-year follow up also indicate an effect of the program, more than what is expected by time or usual medical care.
The study population probably represents a selection bias with a positive attitude of the treatment approach before intervention, and this might have influenced the reported outcome. This is, however, a situation in clinical real life, where the profile of a clinic and the reputation of the therapists are known or accessible for the patients, and may influence the acceptance of treatment as well as the active participation and outcome. It seems reasonable to assume that this also is an important factor for the unusually low dropout during the program. As we examined the motivation for participating prior to inclusion, not inviting the patients who explicitly refused the program, this probably contributed to a low dropout as well.
Many patients with CFS/ME tend to be critical to biopsychosocial interventions, and possibly most of these patients did not accept referral to the clinic, contributing to the possible selection bias. Then again, the patients included in the study did all fulfill criteria for Chronic Fatigue Syndrome, and considering the large number of participants, they clearly represent a CFS population, albeit not representing the total body of CFS/ME patients.
The intervention program was motivated by earlier clinical work and research studies (
By and large, this was recognized and accepted by the patients in this study. One week after the intervention the participants expressed high satisfaction with the 4-day program in terms of content, quality as well as the amount of help they received. More importantly, they regarded the program as helpful with respect to their problems. The patients' initial evaluation was supported by self-reported highly significant change. Furthermore, the self-reported improvement reported 1 year after the intervention was large, also compared to previous studies.
Examining a subgroup defined as functionally impaired, using the criteria for clinical improvement defined in the PACE study (
It is interesting to note that the clinical status and changes reported through 1-year follow-up course in the Oxford and the CFS-CDC case definition groups are quite identical, but that the most severely impaired group at baseline (CDC) reported the greatest improvement by 1 year. This result differs from our earlier RCT study (
At 1 year follow-up, half of the patients completing assessments (56%) still report levels of fatigue representing substantial fatigue (> 4/11 Fatigue Scale). Whether this reflects characteristics of the sample, such as heterogeneity and severity, or is related to inadequacies of the treatment interventions (
In this study, patients were offered additional medical treatment for comorbid conditions, especially for sleep disturbance and depression. When controlling for the possible effects of melatonin and antidepressants, the clinical changes from pre- to post intervention and through 1-year follow-up were not influenced by melatonin medication, while use of antidepressants from baseline to 1 week pre-treatment had a weak influence on changes within this period. Since antidepressants were prescribed based on clinical judgment of a comorbid depression, medication might have had an effect also on fatigue symptoms. Nevertheless, the impact of medication seems overall insignificant.
The feasibility of doing such a concentrated intervention program in regular clinical practice should be good, as the current program was actually carried out in a clinical practice, part of the national health care system. The low drop-out rate also indicate that such a program is feasible as well as acceptable for a clinical population.
The current study has obvious methodological limitations. The open study design does not allow for comparison with control groups, making conclusion of the actual effect of the treatment program and its impact on the clinical course through the follow-up period difficult.
Whether the reported improvement and symptom reduction represent the effect of the program or merely represent the time effect, return to homeostasis or regression to the mean, is not possible to determine due to the study design and available data. Possibly, a selection bias from a majority of patients having a positive attitude to the clinic and the treatment approach might also influence the outcome. The outcome measures based on self-report represent a methodological challenge, as self-reported improvement and objective functional improvement may differ (
Still, the results are promising, with respect to the acceptance, satisfaction as well as acute and long-term clinical improvements. The number of patients included is substantial, and even though the design does not allow for identification of specific factors that might have contributed to the results, the highly promising results might be a starting point for a controlled study.
A brief, concentrated intervention program is well tolerated by patients with CFS/ME, and clinical changes reported from pre-treatment to 1-year follow-up are substantial with high satisfaction reported by patients.
This study was carried out in accordance with the recommendations of ethical guidelines by REK Norway and with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the REK Vest (Regional Ethics committee), Norway.
BS designed the study, conducted the clinical work, and wrote the first draft of all parts of the manuscript. GK participated in the design of the study and in the writing of all parts of the manuscript. HL participated in all parts of the manuscript and participated in the statistical analyses. JA conducted the LME statistical analyses. AR added medications to the database and critically reviewed the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Helse Vest RHF Health Authority has supported the study by funding of a part-time clinical position. Thanks to research assistants Mien Parlati and Anna Sigrun Furdal in transferring data to statistical databases, and to all our patients who have contributed with clinical data by their response in numerous questionnaires throughout the study.
The Supplementary Material for this article can be found online at: