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Efficacy of Cognitive Behavioral Therapy for Adolescents With Chronic Fatigue Syndrome: Long-term Follow-up of a Randomized, Controlled Trial

^a Expert Centre Chronic Fatigue
^b Department of Medical Psychology
^c Department of Pediatrics, Radboud University, Nijmegen Medical Centre, Nijmegen, Netherlands

	ABSTRACT

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. The purpose of this work was to assess the long-term outcome of adolescents with chronic fatigue syndrome who received cognitive behavioral therapy and to determine the predictive value of fatigue severity and physical impairments of the adolescent and the fatigue severity of the mother at baseline for the outcome of the treatment at follow-up.

PATIENTS AND METHODS. Sixty-six adolescent patients with chronic fatigue syndrome who previously participated in a randomized, controlled trial that showed that cognitive behavioral therapy was more effective than a waiting-list condition in reducing fatigue and improving physical functioning were contacted for a follow-up assessment. Fifty participants of the follow-up study had received cognitive behavioral therapy for chronic fatigue syndrome (32 formed the cognitive behavioral therapy group in the original trial, and 18 patients received cognitive behavioral therapy after the waiting period). The remaining 16 patients had refused cognitive behavioral therapy after the waiting period. The main outcome measures were fatigue severity (Checklist Individual Strength), physical functioning (Short-Form General Health Survey), and school attendance.

RESULTS. Data were complete for 61 patients at follow-up (cognitive behavioral therapy group: 47 patients; no-treatment group: 14 patients). The mean follow-up time was 2.1 years. There was no significant change in fatigue severity between posttreatment and follow-up in the cognitive behavioral therapy group. There was a significant further increase in physical functioning and school attendance (10% increase). The adolescents in the cognitive behavioral therapy group were significantly less fatigued and significantly less functionally impaired and had higher school attendance at follow-up than those in the no-treatment group. Fatigue severity of the mother was a significant predictor of treatment outcome.

CONCLUSIONS. The positive effects of cognitive behavioral therapy in adolescents with chronic fatigue syndrome are sustained after cognitive behavioral therapy. Higher fatigue severity of the mother predicts lower treatment outcome in adolescent patients.

Key Words: chronic fatigue syndrome • cognitive behavioral therapy • follow-up study

Abbreviations: CFS—chronic fatigue syndrome • CBT—cognitive behavioral therapy • CIS—Checklist Individual Strength • SF-36—Short-Form General Health Survey • df—degrees of freedom • CI—confidence interval

Chronic fatigue syndrome (CFS) is characterized by severe fatigue lasting >6 months and leading to functional impairments. CFS is not the result of an organic disease or ongoing exertion and is not alleviated by rest.¹ Several controlled trials have shown that cognitive behavioral therapy (CBT) leads to a reduction of fatigue and disabilities in adults with CFS.² CBT is aimed at changing fatigue related cognitions and a gradual resumption of activities. We published the first and until now only randomized, controlled trial that tested the effectiveness of CBT for adolescent patients with CFS.³ The effects of CBT (10 sessions over a period of 5 months) were compared with a waiting-list condition. The adolescent patients who received CBT reported a greater reduction in fatigue and a larger improvement in physical functioning directly after treatment than patients from the waiting list. The school attendance of the CBT group also increased more than in the waiting list. The main objective of the present study was to determine whether the positive effects of CBT of the previous study were sustained over a longer period. Secondly, using an explorative analysis, we determined the predictive value of fatigue severity and physical functioning of the adolescent at baseline for the outcome of the treatment at the time of follow-up. In addition, we also looked at the predictive value of the fatigue severity of the mother of the adolescent patient with CFS for treatment outcome at follow-up. The parents of the adolescent patient with CFS are involved in the treatment.³ This is most often the mother, because she is generally more involved in the daily care of the child. During the treatment, she acts as a coach for younger adolescents. The parent supports older adolescent patients with CFS as they try to increase activity and change fatigue-related cognitions. We presume on the basis of our clinical experience that the ability of the mother to be effectively involved in the treatment is, to some extent, dependent on her own fatigue-related cognitions and level of fatigue. A recent study⁴ showed that the level of fatigue of the mother and that of the adolescent with CFS are related. In the current study, we wanted to determine whether such a relationship also existed between the level of fatigue of the mother and the treatment outcome of the adolescent patient with CFS.

	PATIENTS AND METHODS

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Patients
Sixty-nine consecutively referred adolescent patients were included in the original trial. They were randomly assigned to the CBT condition (n = 35) or waiting-list condition (n = 34).³ All of the patients met the CFS criteria of the US Centers for Disease Control and Prevention¹ and were between 10.0 and 17.2 years of age.

Following the guidelines of the human ethics committee of the Radboud University Nijmegen Medical Centre evaluating the original research protocol, patients who were assigned to the waiting list were offered CBT directly after the postwaiting-list assessment. Of the 34 patients, 16 did not want CBT and 18 were treated according to the same protocol as in the original study.³

At the start of the study, patients were informed that they could be contacted for a follow-up assessment. In total, 66 patients were contacted for the follow-up. Fifty of them had received CBT (32 patients from the original CBT condition and 18 patients who received CBT after the waiting-list period). Because the main objective of the present study was to determine whether the positive effects of CBT are sustained over time, the 3 patients from the original CBT condition who never started with therapy were not contacted for the follow-up.

Design and Procedures
The 18 patients who received CBT after the waiting period were assessed 5 months later, immediately after CBT, for a posttreatment assessment. Most patients were contacted by mail for the follow-up assessment. Some were contacted by telephone, and if they agreed to cooperate, a set of questionnaires was sent to them. If patients did not send the questionnaires back within 2 weeks, a reminder was sent to them by mail. This was repeated if the patient did not respond to the reminder within 3 weeks. The time interval between follow-up and the posttreatment or post–waiting-list assessment varied. This was because patients entered the study and started treatment at different times, whereas the follow-up moments were fixed because of the limited availability of the participating researchers.

Outcome Variables
Fatigue was measured in the same way as in the original trial, with the subscale "fatigue severity" of the Checklist Individual Strength (CIS). It consists of 8 items on a 7-point scale, with scores ranging from 8 (no fatigue) to 56 (severely fatigued). The CIS is a reliable and valid instrument.^3,5 Functional impairment was measured with the subscale "physical functioning" of the Short-Form General Health Survey (SF-36).⁶ Scores range between 0 (maximal physical limitation) to 100 (ability to do vigorous activity). The SF-36 is reliable and valid⁶ and was also used in the previous study.³ Patients had to score 40 on the fatigue severity scale of the CIS and 65 on the SF-36 physical functioning subscale to participate in the original trial. School attendance was established as the percentage of regular school hours attended in the previous week.³ If a patient worked at the time of follow-up, the percentage of work attendance was calculated in the same way.

Predictors of Treatment Outcome
We determined the predictive value of fatigue severity and physical functioning at baseline for treatment outcome at follow-up. The mother of the adolescent patient completed the fatigue severity subscale of the CIS at baseline.

Analysis
Statistical analysis was performed using SPSS 12.01 (SPSS Inc, Chicago, IL). Significance was assumed at a P value of <.05. The effect of CBT for the patients from the waiting list was determined with a pairwise t test comparing pretreatment with the posttreatment assessment. In case of missing observations, the last value was carried forward. With a t test for independent groups, it was tested if the posttreatment scores of the patients treated after the waiting period were different from the scores of the CBT group from the original study. If data at follow-up were missing, they were replaced with estimates derived from single imputation (missing variable analysis, regression with baseline value as predictor). The relationship between time to follow-up (varied) and change in the outcome measures was determined with a Pearson correlation. Comparing the scores at follow-up with those at posttreatment with pairwise t tests helped to determine whether the effects of CBT were sustained. This was also done for the no-treatment group to get an indication of the course of CFS without CBT. We defined patients as showing clinical significant improvement³ at follow-up if they had a reliable change index of >1.96 and a score of <35.7 (1 SD above the mean for 420 healthy adolescents) on the fatigue severity subscale, had an increase of >50 or an end score of 75 for on the physical functioning subscale of the SF-36,⁷ and were fully attending work and/or school at follow-up. A ² test was used to assess the difference between the percentage of clinical significant improvement between the last assessment and follow-up. Furthermore, the scores on the outcome measures and the percentages of clinical significant change at follow-up of the CBT group were compared, using t tests and ² tests with the group who did not receive treatment. The predictive value of the selected variables on treatment outcome (fatigue) was determined with the use of multiple regression.

	RESULTS

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Effect of CBT After the Waiting-List Condition
Of the patients who received CBT after the waiting-list condition, 15 completed the treatment and the posttreatment assessment, and 3 patients (16%) withdrew from therapy. Their posttreatment data were missing. In those cases, the last observation was carried forward. Patients showed a significant decrease in fatigue severity and an increase in physical functioning (Table 1). School attendance was already high at the start of the treatment and was not significantly different at posttreatment assessment. The posttreatment scores of the patients who received CBT after the waiting-list condition were compared with the posttreatment scores of the 32 patients from the treatment condition in the original study. The posttreatment fatigue score of the treated patients from the original study was 28.2 (SD: 16.1) and was not significantly different from the posttreatment score of the patients who received CBT after the waiting list (mean: 29.6 [SD: 15.0]; t = –0.3; degrees of freedom [df]: 48; P = .765). The level of physical functioning (72.0 [SD: 28.9]) and the school attendance (75% [SD: 38.9%]) of the patients treated with CBT in the original study were also not significantly different from those of the patients treated after the waiting list (mean physical functioning: 72.2 [SD: 20.5]; t = –0.03; df: 48; P = .979; mean school attendance: 81.0% [SD: 28.7%]; t = 0.6; df: 48; P = .581).

Follow-up of Patients Treated With CBT
After CBT there was no significant difference in fatigue between posttreatment assessment and follow-up. There was a significant further increase in physical functioning. At follow-up, 34 patients attended school and 8 worked. The school and/or work attendance was significantly higher at follow-up (see Table 2).

Significantly more patients had a clinically significant change in physical functioning at follow-up assessment when compared with the post–waiting-list assessment. There was no difference in the number of patients with a clinically significant improvement in fatigue and a full school and/or work attendance at the time of follow-up (Table 3).

Difference in Outcome at Follow-up Between CBT Group and the Group Who Did Not Receive CBT
Patients from the CBT group were significantly less fatigued (mean difference in fatigue severity: –11.3; 95% confidence interval [CI] of the difference: –2.9 to –19.7; t = –2.7; df: 64; P = .009), had a higher physical functioning score (mean difference physical functioning: 13.5; 95% CI: 0.8 to 26.2; t = 2.1; df: 64; P = .037), and a higher school and/or work attendance (mean difference attendance: 23.%; 95% CI: 9.1% to 37.8%; t = 3.3; df: 52; P = .002) at the time of the follow-up assessment than the patients who had not received treatment.

More patients from the CBT group showed a clinically significant change in fatigue severity (mean difference: 33%; 95% CI: 5% to 60%; ² = 5.3; df: 1; P = .02). The difference between the percentage of clinically significant improvement in physical functioning (mean difference: 24%: 95% CI: –6% to 54%; ² = 3.2; df: 1; P = .073) and school/work attendance (mean difference: 27%; 95% CI: –4% to 58%; ² = 3.0; df: 1: P = .083) between the patients from the CBT group and the patients who did not receive treatment failed to reach statistical significance.

Prediction of Treatment Outcome
Fatigue severity and the level of physical functioning of the adolescents at baseline did not predict fatigue severity at follow-up for the patients who received CBT (Table 4). The more fatigued the mother of the adolescent patient was, the more negative the treatment outcome of the adolescent. Twenty-eight percent of the mothers who filled the fatigue severity subscale of the CIS in at baseline (11 of 40) were extremely fatigued (score of >35⁸).

	DISCUSSION

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In the original trial, 2 treatment protocols were used: 1 for patients with a passive physical activity pattern and 1 for relatively active patients.³ The physical activity pattern of the adolescent patient with CFS was measured with an actometer, a motion-sensing device attached to the ankle. Directly after treatment, passive and active patients showed equal improvements on all of the primary outcome variables.³ We also compared the change scores between the postintervention assessment and follow-up for passive and relative active patients. The results of this analysis (data not shown) showed that there were no significant differences in the changes in fatigue severity, physical functioning, and school/work attendance between passive and active patients with CFS.

The level of fatigue of the mother was a significant predictor of the fatigue of the treated patient at follow-up. The finding that the level of symptoms of 1 of the parents and their children with CFS are related is not new.^4,11,12 What is new is that the fatigue of the mother was also related to the response to CBT. Of the fathers, a high proportion (8 of 36 [22%]) was also severely fatigued at baseline. However, there was no significant correlation between the fatigue of the father at baseline and the fatigue of the adolescent at follow-up (r = –0.05; P = .757). This is in correspondence with the study of van de Putte et al,⁴ who also found that the level of fatigue of the father was not related to that of the adolescent patient with CFS. The fact that the fatigue of the mother is related to treatment outcome of the adolescent patient with CFS could implicate that additional interventions aimed at the mother will facilitate the response of the adolescent to CBT, especially when the mother has a level of fatigue that is within the range of adult patients with CFS (28% in our sample⁸). Other research has shown that adults with CFS can also be effectively treated with CBT.² Future research has to determine whether the outcome of adolescent patients with CFS after CBT can be improved by individually treating the severely fatigued mother simultaneous with individual treatment of the child.

Existing literature indicates that the prognosis for CFS in adolescents (without and after treatment) is more favorable^12–16 than in adults.¹⁷ A recent community study showed that chronic fatigue and CFS in adolescents has a relatively good prognosis.¹² However, as the authors of this study point out, the prognosis of adolescent patients with CFS who are referred to tertiary care seems less favorable, and those adolescents remain disabled for long periods of time.¹³ Our results confirm this. The group of patients who did not receive treatment showed substantially less clinically significant change at follow-up (31%–50%) than patients who received CBT (64%–74%). A majority of the untreated adolescent patients with CFS remained severely fatigued and functionally impaired. The substantial differences between the untreated patients with CFS and the patients with CFS who did receive CBT suggest that the outcome of adolescents with CFS is more favorable after treatment with CBT. We recommend that future research pay close attention to the reasons of adolescent patients with CFS for declining the offered CBT. One could use this information to develop strategies to motivate patients for CBT. It is also important to investigate the possible determinants of the lack of a positive response to CBT in a subgroup of adolescent patients.

One could argue that nonspecific effects, like having had regular contact with health care staff rather than the specific intervention, could explain the difference in outcome between the adolescents who received CBT and the patients in the waiting-list condition. There are 2 studies with adult patients with CFS that compared the effect of CBT for CFS with a "placebo" or nonspecific condition. Both showed a superior effect of CBT on fatigue and the level of disabilities.^9,18 Furthermore, a recent review showed that the placebo response of patients with CFS to psychological interventions is lower than in other medical conditions.¹⁹

To assess the long-term effects of CBT, we sent questionnaires to the patients by mail. A patient can be more easily influenced by others when filling in the questionnaire at home than at the treatment center, as was done in the earlier assessments. We cannot rule out that patients might have been influenced by others during the assessment and that this might have had an effect on the results of the follow-up assessment.

The mean follow-up time was 2 years, with a wide variation between patients in the time period between the postintervention assessment and follow-up. One could argue that this introduced a bias in the study, because the long-term effect of the treatment could change over time. We think that this is unlikely, because the results showed no statistically significant relationship between time passed since the postintervention assessment and the change scores of the outcome measures.

Data on the type of activities of patients at the time of the follow-up assessment were not available for all of the patients. Some patients only indicated on the questionnaires that they did not study and did not work. We decided not to impute these missing values, because more detailed information about their activities were lacking. This could have introduced a bias when determining the long-term effects of CBT on work and/or school attendance. An example of such a bias would be that these patients are less active and function at a lower level than the patients who indicated that they worked or attended school, which, in turn, might have led to an overestimation of the effect of CBT.

In assessing the predictive value of the fatigue of the mother on treatment outcome, data on the fatigue severity of a substantial number of mothers were lacking. We can only conclude that the relationship between the fatigue of the mother and the treatment outcome of the adolescent patients existed in the subgroup of patients where the fatigue severity of the mother was assessed. Furthermore, an alternative explanation for the association between the fatigue of the mother and that of the adolescent could be the negative influence of a child being sick on the functioning of the mother. However, it is our clinical experience that if the mother of the adolescent patient with CFS is severely fatigued, her fatigue exists longer than (and, thus, precedes) that of the child.

In comparing the long-term outcome of patients treated with CFS and the patients who did not want CBT, it must be noted that it is possible that the patients with untreated CFS form a subgroup of the total group of patients with CFS who were referred for treatment. This subgroup could have some specific characteristics. These characteristics and not the fact that they did not receive CBT could have negatively influenced their level of fatigue and disabilities at follow-up. Lastly, it must be noted that the group of untreated patients in this study was small, which limits the scope of the conclusions that can be drawn from this sample. We suggest that the results of the current study can only be generalized to those adolescent patients with CFS who do want to be treated with CBT.

	CONCLUSIONS

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
The original trial showed that CBT significantly reduced the symptoms of CFS in adolescents in 10 sessions. The current study showed that these results were not only sustained over a time span of 2 years but that some aspects of CFS symptoms and disabilities had decreased even further after CBT. It is important that this effective treatment becomes available to more adolescent patients with CFS.

	ACKNOWLEDGMENTS

 
This work was supported by the Foundation for Children's Welfare Stamps Netherlands (Stichting Kinderpostzegels Nederland) and the ME Foundation (ME Stichting).

We thank all of the participants and their parents, and we thank Maaike van Kuijk and Ester Meijer for carrying out the therapy of the patients from the waiting list.

	FOOTNOTES

 
Accepted Aug 16, 2007.

Address correspondence to Hans Knoop, MSc, Expert Centre Chronic Fatigue, Radboud University, Nijmegen Medical Centre, Postbox 9011, 6525 EC Nijmegen, Netherlands. E-mail: j.knoop{at}nkcv.umcn.nl

The authors have indicated they have no financial relationships relevant to this article to disclose.

	REFERENCES

TOP ABSTRACT PATIENTS AND METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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This Article Abstract Full Text (PDF) P3Rs: Submit a response Alert me when this article is cited Alert me when P3Rs are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Knoop, H. Articles by Bleijenberg, G. Search for Related Content PubMed PubMed Citation Articles by Knoop, H. Articles by Bleijenberg, G. Related Collections Adolescent Medicine

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