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Exploring Chronic Fatigue Syndrome in Adolescents (PhD Thesis, September 19, 2006)

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By Elisabeth Machteld van de Putte • www.ProHealth.com • October 16, 2006


Note: This 190-page PhD thesis examines the results of three sequential studies of CFS in adolescents, undertaken by researchers at the University of Utrecht Medical Center in The Netherlands, as written up in a series of seven articles published - or submitted for publication - in scientific journals between 2002 and 2006. Included below is the overall abstract of the thesis, plus abstracts of the five articles published or in press to date, and of the final three articles submitted for journal publication as they appear in the thesis.

Overall, the thesis examines CFS in adolescents in terms of the “biopshychosocial model” - which is, EM van de Putte writes, a model that “offers the possibility for medicine to be a discipline that focuses on human beings as opposed to the discipline that focuses on bodies. A human being is both a biological organism and a person who lives in the context of family and community. In this respect the biopsychosocial model provides an integrative focus and relational context for understanding a range of problems associated with health, illness, and disease.”

The entire text of the 190-page thesis is offered online in pdf format by the University of Utrecht Publishing & Archiving Services at http://igitur-archive.library.uu.nl/dissertations/2006-0921-200054/index.htm

ISBN-10 90-393-4301-2
ISBN-13 978-90-393-4301-2

Correspondence to: EM van de Putte, KE04.133.1, University Medical Center Utrecht, PO Box 85090,3508 AB Utrecht, The Netherlands. Telephone: +31-30-2504001, Fax: +31-30-2505349 [E-mail: e.vandeputte@umcutrecht.nl ]

Reprint requests to the University Medical Center Utrecht, KE04.133.1, PO Box 85090, 3508 AB Utrecht, The Netherlands (EM van de Putte)

Overall Thesis Abstract

The research for this thesis has been conducted in three consecutive studies:
n Fatigue in Teenagers-I (FIT-I) in 2002; 2)
n Fatigue in Teenagers-II (FIT-II) in 2004
n FIT-III (FIT-III) in 2006.

In each FIT study different research questions were formulated on the basis of the biopsychosocial model. The three FIT studies resulted in the chapters of this thesis. These chapters appear in the chronological order of the FIT-studies. FIT-I and FIT-II both have a cross-sectional study design in which adolescents with CFS are compared with healthy adolescents. FIT-III is a follow-up of the patients who participated in FIT-I and FIT-II.

Chapter 2 focuses on a constitutional biological factor, which may partly explain the symptoms of fatigue and pain in the CFS. The main question is whether constitutional laxity of the connective tissues is more frequently present in adolescents with CFS than in healthy controls.

Chapter 3 investigates health beliefs, one of the psychological factors that determine health behaviour both in the adolescents and in their parents. Although health behaviour is often the focus of treatment, very little is known about the beliefs in families with an adolescent with CFS, neither as a predisposing nor as a maintaining factor.

Chapter 4 reports the findings of research in the relation between fatigue and other somatic symptoms, both in adolescents with CFS and healthy adolescents.

Chapter 5 is the first article of the FIT-II study. In this chapter the association of symptoms in children and in their parents is explored within the biopsychosocial model, with possible genetic contributions on the one hand, and possible psychosocial contributions on the other hand. The second goal of the study was to establish the relation between fatigue and psychological distress in the adolescents with CFS.

Chapter 6 explores a set of symptoms in the CFS adolescents, namely neurocognitive symptoms, which are frequently present without a clear substrate. We applied a neurocognitive measurement tool for interference control. The tool measures the ability to protect a response from interruption by competing responses or events. The goal of the study was to investigate whether adolescents with CFS show a lesser degree of interference control than healthy adolescents. The second goal was to explore the importance of familial factors by examining the interference control in the parents of both groups.

Chapter 7 is another reflection on a possible neurobiological basis for CFS. Sensory gating is the ability to be protected from the load of sensory information by filtering sensory stimuli, and is a critical function of all sensory systems. We hypothesized that adolescents with CFS and possibly one of their parents would show deficient sensory gating. A deficient sensory gating might be one of the biological factors predisposing or maintaining CFS-like symptoms.

Chapter 8 is based on the hypothesis that children’s early object relations may possibly have an etiologic relationship to CFS. It may be one of the psychological factors involved. Alexithymia, defined as an inability to recognize and describe emotions, has its origin in an insecure and disorganized development of attachment in childhood. It is hypothesized that adolescents with CFS exhibit more alexithymia than healthy adolescents. The second hypothesis is that alexithymia unfavourably affects the outcome of CFS. To answer this last question we used the data of the FIT-III study.

Chapter 9, finally, is the general discussion in which the findings from the three FIT-studies are discussed within the biopsychosocial model. A Dutch summary of the studies follows.

Keywords: Chronic Fatigue Syndrome, cardiovascular factors, locus of control, illness beliefs, illness behaviour, family interactions, somatic complaints, adolescence, genetic, Eriksen Flanker Task

* * * *

Abstract of Chapter 2
Is Chronic Fatigue Syndrome a Connective Tissue Disorder? A Cross-Sectional Study in Adolescents
By EM van de Putte, et al.

Journal: Pediatrics. Vol. 115 No. 4 April 2005, pp. e415-e422 [electronic article]

Authors and affiliation: Putte EM van de, Uiterwaal CSPM, Bots ML, Kuis W, Kimpen JLL, Engelbert RHH. Departments of Pediatrics, Pediatric Physical Therapy, and Pediatric Exercise Physiology, Wilhelmina Children’s Hospital, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.

DOI:10.1542/peds.2004-1515

Objectives:To investigate whether constitutional laxity of the connective tissues is more frequently present in adolescents with chronic fatigue syndrome (CFS) than in healthy controls. Increased joint hypermobility in patients with CFS has been described previously, as has lower blood pressure in fatigued individuals. This raises the question whether constitutional laxity is a possible biological predisposing factor for CFS.

Design: Cross-sectional study.

Participants: Included were 32 adolescents with CFS (according to the criteria of the Centers for Disease Control and Prevention) referred to a tertiary hospital and 167 healthy controls.

Methods: The 32 adolescents with CFS were extensively examined regarding collagen-related parameters: joint mobility, blood pressure, arterial stiffness and arterial wall thickness, skin extensibility, and degradation products of collagen metabolism. Possible confounding factors - age, gender, height, weight, physical activity, muscle strength, diet, alcohol consumption, and cigarette smoking - were also measured. The results were compared with findings in 167 healthy adolescents who underwent the same examinations.

Results: Joint mobility, Beighton score, and collagen biochemistry, all indicators of connective tissue abnormality, were equal for both groups. Systolic blood pressure, however, was remarkably lower in CFS patients (117.3 mmHg vs. 129.7 mmHg, adjusted difference -13.5 mmHg, 95% CI: -19.1; -7.0). Skin extensibility was higher in CFS adolescents (mean z-score 0.5 sd versus 0.1 sd; adjusted difference 0.3 sd; 95% CI 0.1; 0.5). Arterial stiffness, expressed as common carotid distension, was lower in CFS adolescents, indicating stiffer arteries (670 µm versus 820 µm, adjusted difference -110 µm, 95% CI: -220; -10). All analyses were adjusted for age, gender, body mass index, and physical activity. Arterial stiffness was additionally adjusted for lumen diameter and pulse pressure.

Conclusions: These findings do not consistently point in the same direction of an abnormality in connective tissue. CFS patients did have lower blood pressure and more extensible skin, but lacked the most important parameter indicating constitutional laxity, i.e., joint hypermobility. Moreover, the collagen metabolism measured by crosslinks and hydroxyproline in urine, mainly reflecting bone resorption, was not different. The unexpected finding of stiffer arteries in CFS patients warrants further investigation.

Keywords: chronic fatigue syndrome, connective tissue disease, cardiovascular factors, autonomic nervous system

 

* * * *

Abstract of Chapter 3
Chronic Fatigue Syndrome and Health Control in Adolescents and Parents
By EM van de Putte, et al.

Journal: Archives of Disease in Childhood. 2005 Oct;90(10):1020-4. [E-publication, July 27, 2005]

Authors and affiliations: Putte EM van de,1 Engelbert RHH, 1 Kuis W, Sinnema G, 1 Kimpen JLL, 1 Uiterwaal CSPM.2 1)Wilhelmina Children's Hospital, Netherlands; 2)Julius Center for Health Sciences and Primary Care, Netherlands. Address correspondence to EM van de Putte [E-mail: e.vandeputte@wkz.azu.nl ]

PMID: 16049059

Background: Health behaviour and beliefs about health control are known to influence the outcome of an illness. Locus of health control is defined as the source from which health related behaviour is initiated. An internal locus refers to the belief that health is determined by one's own behaviour or capacities. Locus of health control in children and adolescents with chronic fatigue syndrome (CFS) and their parents has not been previously investigated.

Objective: To explore the locus of health control in adolescents with CFS and their parents in comparison with healthy adolescents and their parents.

Method: In this cross-sectional study 32 adolescents with CFS were compared with 167 healthy controls and their respective parents. The Multidimensional Health Locus of Control (MHLC) questionnaire was applied to all participants.

Results: There was significantly less internal health control in adolescents with CFS than in healthy controls. An increase of internal health control of one standard deviation was associated with a 61% reduced risk for CFS (odds ratio (OR) = 0.39, 95% confidence interval (CI): 0.25; 0.61). Internal health control of the parents was protective as well (OR fathers: 0.57 (95% CI: 0.38; 0.87) and OR mothers: 0.74 (95% CI: 0.50; 1.09)). The external loci of health control were higher in adolescents with CFS and in their parents. Increased levels of fatigue (56%) were found in the mothers of the adolescents with CFS, in contrast with the fathers who reported a normal percentage of 13%.

Conclusions: In comparison with healthy adolescents, adolescents with CFS and their respective parents show a less internal locus of health control. They attribute their health more to external factors, such as chance and physicians. This outcome is of relevance for treatment strategies like cognitive behaviour therapy, for which health behaviour is the main focus.

Keywords: chronic fatigue syndrome, family interactions, illness behaviour, illness beliefs, locus of control

 

* * * *

Abstract of Chapter 4
How fatigue is related to other somatic symptoms
By EM van de Putte, et al.

Journal: Archives of Disease in Childhood. 2006 Oct;91(10):824-7. Published online first, 2006 June 5. [In Press as of October 18, 2006]

Authors and affiliation: Putte EM van de, Engelbert RHH, Kuis W, Kimpen JLL, Uiterwaal CSPM. Department of Paediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. [E-mail: e.vandeputte@umcutrecht.nl ]

PMID: 16754655 DOI: 10.1136/adc.2006.094623

Objective: In this study we assessed the relation between fatigue and somatic symptoms in healthy adolescents and adolescents with Chronic Fatigue Syndrome (CFS).

Methods: 72 adolescents with Chronic Fatigue Syndrome were compared within a cross-sectional study design with 167 healthy controls. Fatigue and somatic complaints were measured using self-report questionnaires, respectively the subscale subjective fatigue of the Checklist Individual Strength (CIS-20) and the Children’s Somatization Inventory.

Results: Healthy adolescents reported the same somatic symptoms as adolescents with CFS, but with a lower score of severity. The top 10 of somatic complaints were the same: low energy, headache, heaviness in arms/legs, dizziness, sore muscles, hot/cold spells, weakness in body parts, pain in joints, nausea/upset stomach, back pain. There was a clear positive relation between log somatic symptoms and fatigue (linear regression coefficient: 0.041 points log somatic complaints per score point fatigue (95% Confidence Interval 0.033; 0.049, p-value < 0.001) which did not depend on disease status (interaction between CFS and fatigue: p-value 0.847).

Conclusions: Our findings suggest a continuum with a gradual transition from fatigue with associated symptoms in healthy adolescents to the symptom complex of CFS.

 

* * * *

Abstract of Chapter 5
Mirrored Symptoms in Mother and Child with Chronic Fatigue Syndrome
By EM van de Putte, et al.

Journal: Pediatrics. 2006 Jun;117(6):2074-9.

Authors and affiliations: Putte EM van de, Doornen LJP van, Engelbert RHH, Kuis W, Kimpen JLL, Uiterwaal CSPM. Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. [E-mail e.vandeputte@wkz.azu.nl ]

PMID: 16740850

Objective: Our aim with this study was to assess the relation between chronic fatigue syndrome in adolescents and fatigue and associated symptoms in their fathers and mothers, more specifically the presence of chronic fatigue syndrome-like symptoms and psychologic distress.

Method: In this cross-sectional study, 40 adolescents with chronic fatigue syndrome according to the Centers for Disease Control and Prevention criteria were compared with 36 healthy control subjects and their respective parents. Questionnaires regarding fatigue (Checklist Individual Strength), fatigue-associated symptoms, and psychopathology (Symptom Checklist-90) were applied to the children and their parents.

Results: Psychologic distress in the mother corresponds with an adjusted odds ratio of 5.6 for the presence of CFS in the child. The presence of fatigue in the mother and dimensional assessment of fatigue with the Checklist Individual Strength revealed odds ratios of, respectively, 5.29 and 2.86 for the presence of chronic fatigue syndrome in the child. An increase of 1 SD of the hours spent by the working mother outside the home reduced the risk for chronic fatigue syndrome in their child with 61%. The fathers did not show any risk indicator for chronic fatigue syndrome in their child.

Conclusions: Mothers of adolescents with chronic fatigue syndrome exhibit fatigue and psychologic symptoms similar to their child in contrast with the fathers. The striking difference between the absent association in fathers and the evident association in mothers suggests that the shared symptom complex of mother and child is the result of an interplay between genetic vulnerability and environmental factors.

 

* * * *

Abstract of Chapter 6
Distinctive Neurocognitive Impairment in Adolescents with Chronic Fatigue Syndrome
By EM van de Putte, et al.

Journal: Submitted for journal publication as of this posting (October 18, 2006). Following abstract is as included in EM van de Putte’s thesis Exploring Chronic Fatigue Syndrome in Adolescents.

Authors and affiliation: Putte EM van de, Böcker K, Buitelaar J, Kenemans JL, Engelbert RHH, Kuis W, Kimpen JLL, Uiterwaal CSPM. Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. [E-mail e.vandeputte@wkz.azu.nl ]

Background: Adolescents with Chronic Fatigue Syndrome (CFS) experience neurocognitive problems, which were not previously investigated.

Aims:To investigate whether adolescents with CFS show impairments in the performance on a complex information processing task, irrespective of possible confounding factors like depression and anxiety. Secondly, familial aspects were explored by examining the parents.

Methods: 34 adolescents with CFS and their parents performed an Eriksen Flanker Task and filled-out questionnaires regarding fatigue, anxiety and depression. The results were compared with findings in 29 healthy adolescents and their parents.

Results: Taking all possible confounding factors (age, gender, anxiety, depression, educational level) into account, the adolescents with CFS scored significantly lower (-12.7% (95% CI: -21.9; -3.5), p-value = 0.007) on incongruent trials producing the highest level of interference. Corresponding results were found for the fathers.

Conclusions: Adolescents with CFS show a lesser degree of interference control than healthy adolescents.

 

* * * *

Abstract of Chapter 7
Sensory Gating in Adolescents with Chronic Fatigue Syndrome
By EM van de Putte, et al.

[Note: Sensory gating "helps prevent incoming irrelevant sensory information from entering into the higher cortex and ensures normal information processing,” according to the Virginia Tech Digital Library and Archives.]

Journal: Submitted for journal publication as of this posting (October 18, 2006). Following abstract is as included in EM van de Putte’s thesis Exploring Chronic Fatigue Syndrome in Adolescents.

Authors and affiliation: Putte EM van de, Gerritsen J, Uiterwaal CSPM, Engelbert RHH, Kuis W, Kimpen JLL, Böcker K. Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. [E-mail e.vandeputte@wkz.azu.nl ]

Background: In addition to fatigue, CFS patients exhibit symptoms of neuropsychological impairment and hypersensitivity to pain and other sensory input. The nature of this impairment has not been elucidated. We hypothesized that adolescents with CFS exhibit sensori(motor) gating deficits as an explanation, possibly as a familial trait.

Methods: Cross-sectional study in which 34 adolescents with CFS according to the CDC-criteria were compared with 29 healthy controls. Sensori(motor) gating measures were: P50 event-related potential suppression (P50 ERP) and Prepulse Inhibition (PPI). The same measurements were taken in parents. Confounding factors as anxiety and depression were determined by self-report questionnaires.

Results: The P50 ERP auditory gating was marginally diminished in CFS adolescents in the adjusted model. The P50 amplitude was decreased as well. The PPI, however, was similar in both groups. The results of the parents of both groups were not different.

Conclusion: The high sensitivity to somatic sensations with lowered pain threshold, and the neurocognitive symptoms of CFS in adolescents, may be explained by deficient sensory gating.

 

* * * *

Abstract of Chapter 8
Alexithymia in Adolescents with Chronic Fatigue Syndrome
By EM van de Putte, et al.

[Note: “Alexithymia” involves in part difficulties in identifying and describing emotions or feelings in a verbal manner.]

Journal: Submitted for journal publication as of this posting (October 18, 2006). Following abstract is as included in EM van de Putte’s thesis Exploring Chronic Fatigue Syndrome in Adolescents.

Authors and affiliation: Putte EM van de, Engelbert RHH, Kuis W, Kimpen JLL, Uiterwaal CSPM. Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center, Utrecht, The Netherlands. [E-mail e.vandeputte@wkz.azu.nl ]

Background: Alexithymia is postulated as an important factor in the development of medically unexplained physical symptoms. Chronic Fatigue Syndrome (CFS) is presently medically unexplained. The aim of this study was to investigate whether the prevalence of alexithymia was higher in adolescents with CFS compared with healthy adolescents. Comorbid anxiety and depression were analyzed as possible confounding factors. Secondly, alexithymia was investigated as a prognostic factor for the recovery of CFS.

Methods: A cross-sectional study was performed among 40 adolescent outpatients diagnosed with CFS and 36 healthy controls. All participants completed a number of questionnaires regarding fatigue (CIS-20), somatic complaints (Checklist Somatization Inventory, CSI-35), depression (CDI-27), trait anxiety (Spielberger State Trait Anxiety Questionnaire, STAIC-20). The Toronto Alexithymia Scale (TAS-20) was used to assess all participants for alexithymia. A follow-up study was performed among the CFS adolescents 11/2 year after the initial assessment.

Results: CFS adolescents scored higher on the TAS-20 (mean difference 9.8 (95% CI: 5.7; 13.9), in particular the subscales identifying feelings and expressing feelings. This difference attenuated after adjustment for anxiety and depression. Thirty percent of the CFS adolescents fulfilled criteria for alexithymia. At follow-up no differences in recovery were established between the alexithymic and non-alexithymic CFS adolescents.

Conclusions: Alexithymia is present in a subgroup of adolescents with CFS but does not appear to be a prognostic factor for recovery of the CFS illness.





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