Fatigue after pediatric acquired brain injury. Evaluation of methods of cognitive rehabilitation and impact on fatigue and related constructs.
Doctoral thesis by Ruth Elizabeth Hypher
Oslo University Hospital; Rikshospitalet
Department of Pediatric Medicine, Department of Pediatric Neurology
Department of Psychology Faculty of Social Sciences
University of Oslo 2022
© Ruth Elizabeth Hypher, 2023
Series of dissertations submitted to the Faculty of Social Sciences, University of Oslo No. 938
ISSN 1504-3991
All rights reserved. No part of this publication may be
reproduced or transmitted, in any form or by any means, without permission.
Cover: UiO.
Print production: Graphics Center, University of Oslo.
TABLE OF CONTENTS
ACKNOWLEDGEMENTS ………. 4
ABBREVIATIONS ………. 6
LIST OF PAPERS ……….8
GENERAL SUMMARY………9
1. INTRODUCTION………....12
1.1 Pediatric acquired brain injury ………. 13
1.1.1 Medical characteristics and treatments ……….. 13
1.1.2 Epidemiology ………...……..19
1.2 Effects of pediatric brain injuries on neurocognition, mental health, quality of life and school function………..………. 21
1.2.1 The biopsychosocial framework………. 21
1.2.2 Neurocognition and executive function………...22
1.2.3 Mental health and quality of life ………... 27
1.2.4 School outcomes………. 28
1.3 Fatigue………... 29
1.3.1 Conceptualization, prevalence and associated factors……… 29
1.3.2 Models of fatigue……… 31
1.3.3 Challenges in the assessment of fatigue………. 33
1.4 Cognitive rehabilitation of pediatric acquired brain injury………... 35
1.4.1 Cognitive rehabilitation of fatigue ………. 38
2. AIMS ……….. 40
2.1 Paper I……… 40
2.2 Paper II ………. 40
2.3 Paper III………. 40
2.4 Paper IV………. 40
3. METHODS ………..41
3.1 Study design………...41
3.2 Participants and healthy controls………... 41
3.3 Recruitment and procedures……….. 42
3.4 Interventions……….. 44
3.5 Assessments and outcome measures………. 47
3.6 Statistical analysis………. 50
3.7 Ethical considerations……… 52
4. RESULTS / SUMMARY OF PAPERS ………. 53
4.1 Paper I ………53
4.2 Paper II ………. 53
4.3 Paper III………. 53
4.4 Paper IV………. 54
5. DISCUSSION ……… 55
5.1 Discussion of main findings……….. 55
5.1.1 Fatigue in children and adolescence with ped. acq. brain injuries ……… 55
5.1.2 Associations of fatigue and related constructs………... 56
5.1.3 Treatment of fatigue in pediatric brain injury……… 60
5.1.4 Predictors of functional school outcomes……….. 63
5.2 Methodological issues, strengths and limitations and future research .……… 66
5.2.1 The use of self-and parent reports ………. 66
5.2.2 Specific challenges in pediatric studies ………. 68
5.2.3 Sample selection, sample size and representativity……… 71
5.2.4 Other confounding factors………...72
5.3 Clinical implications……….. 72
6. CONCLUSIONS……… 75
REFERENCES……… 76
4 ACKNOWLEDGEMENTS
After working many years in clinic, embarking on a doctoral thesis has been an exciting, demanding, sometimes frustrating, but most of all, valuable and enriching process. This thesis is truly a product of the collective efforts and help from a several people. First of all, I would like to thank the children, adolescents and their families for participating in this intervention study. Thanks to their participation and sharing of experiences, we are now one step closer to understanding how pediatric acquired brain injuries impact on function, as well as gaining insights into effective methods for improving executive function and fatigue.
A very special thanks to my main supervisor, Jan Stubberud. Jan has been generous, helpful and quick to respond throughout the process of planning and conducting the
intervention, analyzing the data and writing manuscripts. He has contributed to the original study idea and all parts of the study. His calm style, inspiring and encouraging comments and knowledge of neuropsychology in general, and cognitive rehabilitation in particular, have been invaluable for my completion of this thesis.
Kari Risnes, Torstein Baade Rø and Stein Anderson have served as central members of the study research group and my co-supervisors, Kari and Torstein have in addition alternated the roles of principal investigators. Thank you for your insightful and constructive advice, both in the planning and conductance of the study and reviewing manuscripts. Torun Gangaune Finnanger has served as my co-supervisor. In addition to participating in the development of the original study idea, she has been central in all parts of the study. Thank you for your encouraging supervision and optimism throughout the process. My colleague Anne E. Brandt is also a PhD candidate in the study, and has participated in the
development of the original study idea and been central in all parts of the study. Thank you for your help, essential contribution to the study and interesting discussions.
Thank you to the scientific advisory board, Brian Levine, Mathilde Chevignard and Cathy Cattroppa. I would like to express my gratitude to the Norwegian Research Council for funding this project. Thank you to the Head of the Children’s clinic Elisabeth Selvaag and St. Olavs hospital (SOH), in addition to the former Head of Clinic Terje Rootwelt, and Kjersti Ramstad at the Department of Clinical Neurosciences for Children, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Rikshospitalet (OUS-RH), for the collaboration in conducting the study.
5 I would like to give a special thanks to study nurse Synne Johannesen at OUS-RH. She has been essential for the practical organization and implementation of the study at OUS-RH, contributing to a positive atmosphere for both participants and colleagues. Furthermore, my colleague Anne-Britt Skarbø has served as co-therapist in the intervention groups at OUS-RH, and contributed with invaluable professional experience and integrity. Thank you for your support (and laughs!) throughout the study. Eva Skovlund set up and/or gave advice concerning statistical analyses, and Kristof Hoorelbeke was responsible for network analysis in this thesis. I am truly grateful for your patience, educational presentation of the results and constructive discussions.
Also, thanks to patient advisors and the staff at SOH and OUS-RH, in particular study coordinator Nina Bäcklund and study nurses at SOH, Marith Risan and Line R. Simonsen, occupational therapists Lene Bobakk and Gøril O. Johansen, neuropsychologists Helene Eidsmo Barder and Tobias Renzenbrink, paediatricians Selma M. Larsen and Espen Lien, and the test technicians Ingrid Lerø and Sara Høyås. Also, thanks to Anne Caroline Wiik responsible and economic advisor Mona Vehn Antonsen. Thank you to co-author Hanne C.
Lie for interesting and constructive discussions about fatigue. For their contribution to recruiting participants, thanks to Anine Pernille Strand-Saugnes from Statped and Bård Forsdahl from the University Hospital of North Norway. Also, thanks to user
representative Halvard Kjelås, and the Children’s Cancer Society for their interest and feedback throughout the study.
I also want to thank my lovely former colleagues at Neuropsychiatric Unit, OUS, for always cheering me on though these years, especially Anne Falsen, for granting me leave of absence from clinical work.
Finally, a thank you to my kind husband, Jørund, for encouraging me to go ahead with this doctoral thesis, for your love, patience and support over these years. And to my wonderful children Mats, Ida and little Iver, for your love and for keeping me focused on the essential (and silly) things in life. I would also like to thank my loving parents, Ragnhild and Peter, my brother Olav and sister Mari, for your interest and support in the project, as well as my extended family. Not to forget, thank you to my wonderful friends, for your
encouragement, interest and belief in a life after a doctoral thesis.
6 ABBREVIATIONS
ADHD – Attention deficit/hyperactivity disorder AIS - Acute Ischemic Stroke
ASEBA – Achenbach System of Empirically Based Assessment
BADS-C - Behaviour Assessment of Dysexecutive Syndrome in Children BHW – Brain Health Workshop
BRIEF – Behavior Rating Inventory of Executive Function
CAVLT-2 – Children’s Auditory Verbal Learning Test- Second edition CBCL – Child Behavior Checklist (ASEBA)
CCT – Children’s Cooking Task CNS - Central Nervous System
CORE pABI - COgnitive REhabilitation in pediatric Acquired Brain Injury CPT 3 – Connors Continuous Performance Test – 3rd edition
CRT – Cranial/craniospinal Radiation Therapy CT – Computer Tomography
CWIT – Color-Word Interference Test DAI - Diffuse Axonal Injury
D-KEFS – Delis-Kaplan Executive Function System
DSM-5 - Diagnostic and Statistical Manual of Mental Disorders, 5th edition.
EEG - Electroencephalogram EF – Executive Function
EPS - Educational and Psychological Services GCS – Glasgow Coma Scale
GMT – Goal Management Training
GOS-E Peds - The Glasgow Outcome Scale Extended Pediatric Revision HCs- Healthy Controls
HRQoL – Health-related quality of life
ICCC-3 – International Classification of Childhood Cancer – 3rd edition ICD-10 – International Classification of Disease – 10th edition
7 ICF – International Classification of Functioning, Disability and Health
IQ – Intelligence Quotient
MRI – Magnetic Resonance Imaging MRV – Magnetic Resonance Venography MRA - Magnetic Resonance Arteriography
OUS-RH – Oslo University Hospital- Rikshospitalet
PedsQL GCS – Pediatric Quality of Life Inventory, Generic Core Scale
PedsQL MFS - Pediatric Quality of Life Inventory, Multidimensional Fatigue Scale PTA – Posttraumatic Amnesia
pABI - pediatric acquired brain injury pBHW – pediatric Brain Health Workshop pGMT – pediatric Goal Management Training pTBI – pediatric Traumatic Brain Injury RCI – Reliable Change Index
RCT – Randomized Controlled Trial SES – Socio-economic status
SOH – St. Olavs Hospital
TRF - Teacher’s Report Form (ASEBA) TBI – Traumatic brain injury
YSR – Youth self-report (ASEBA)
WISC-V- Wechsler Intelligence Scale for Children- 5th edition
WISC-WMI - Wechsler Intelligence Scale for Children – Working memory Index WISC-PSI - Wechsler Intelligence Scale for Children – Processing Speed Index
8 LIST OF PAPERS
This thesis is based on the following papers, which are referred to in the text by their Roman numbers I – IV.
Paper I
Hypher, R. E.*, Brandt, A. E.*, Risnes, K., Rø, T. B., Skovlund, E., Andersson, S., Finnanger, T. G., & Stubberud, J. (2019). Paediatric goal management training in patients with acquired brain injury: study protocol for a randomised controlled trial. BMJ
open, 9(8), e029273.
Paper II
Hypher, R., Andersson, S., Finnanger, T. G., Brandt, A. E., Hoorelbeke, K., Lie, H. C., Barder, H. E., Larsen, S. M., Risnes, K., Rø, T. B., & Stubberud, J. (2021). Fatigue
following pediatric acquired brain injury: Interplay with associated factors in a clinical trial population compared to healthy controls. Neuropsychology, 35(6), 609.
Paper III
Hypher, R., Brandt, A.E., Skovlund, E., Skarbø, A.B., Barder, H.E., Andersson, S., Rø, T.B., Risnes K., Finnanger, T.G., & Stubberud, J. (2022). Metacognitive strategy training versus psychoeducation for improving fatigue in children and adolescents with acquired brain injuries: A randomized controlled trial. Manuscript accepted for publication in Neuropsychology 6th of June, 2022.
Paper IV
Stubberud, J., Hypher, R., Brandt, A. E., Finnanger, T. G., Skovlund, E., Andersson, S., Risnes, K., & Rø, T. B. (2022). Predictors of functional school outcome in children with pediatric acquired brain injury. Frontiers in neurology, 727.
9 GENERAL SUMMARY
Pediatric acquired brain injury (pABI), resulting from either traumatic brain injury or non- traumatic injuries such as brain tumour, stroke, hypoxia, or infections/inflammation to the brain, is one of the leading causes of death and disability for children and adolescents.
Although survival rates from pABI are increasing with advances in medical treatment, the possibility of poor outcome remains. Previous assumptions that injuries early in life resulted in less adverse outcomes have been challenged by more recent research, suggesting that the young brain in fact may be vulnerable to more severe, diffuse and enduring deficits. Indeed, pABI constitutes a major disruption to child development and may affect cognitive, behavioural, emotional, and social function.
Fatigue is one of the most pervasive symptoms after pABI, with 58% to 74.6% reporting fatigue across multiple pABI etiologies. It is described as the experience of exhaustion and decreased capacity for physical or mental activity because of an imbalance in the
availability, use or restoration of resources needed to perform activity. While studies of fatigue following pABI are scarce, the literature suggests that for a significant proportion of survivors, fatigue continues to be a considerable problem, even years after injury or treatment. Fatigue after pABI seems to be relatively independent of etiology, injury
severity or age at injury. Despite the high prevalence and its detrimental effects on function after pABI, few treatment options are available.
Cognitive rehabilitation after pABI is essential for optimal outcome on several functional areas. However, effect studies of cognitive rehabilitation programs for children and
adolescents are confounded with a multitude of challenges, including poor research design, methodological inadequacies, lack of psychometrically sound and ecologically valid instruments for cognitive and behavioural assessments, and inconsistency of outcome measures. Few intervention studies have investigated the effects of cognitive rehabilitation programs on fatigue. Several studies point to identifying and treating risk factors that are associated with fatigue, such as psychological distress and cognitive deficits (the so-called biopsychosocial approach), as a mean to reduce fatigue symptomatology.
The purpose of this thesis was to investigate the efficacy of two evidence-based, group treatments, a pediatric version of Goal management Training (pGMT) and a
psychoeducational approach (pediatric Brain Health Workshop, pBHW), for reducing
10 fatigue in children and adolescents in the chronic phase of pABI (Paper I and III). The study also explored the interplay between fatigue and associated factors (Paper II), and predictors of functional school outcome (Paper IV).
Paper I describes the study protocol. The purpose of the study is to determine the efficacy of pGMT for children and adolescents with acquired brain injury and reported executive dysfunction, compared to a psychoeducational approach (pBHW). It is a parallel-
randomized controlled trial (RCT) including allocation concealment and assessor blinding.
The aim was to recruit 80 survivors after pABI, aged 10–17 years, and randomly allocate them to either pGMT (n=40) or pBHW (n=40). Both interventions consisted of seven group sessions for participants and parents, followed by external cueing and telephone counselling. The study also included involvement of teachers. Assessments were
performed at baseline, immediately post-intervention and at 6 months follow-up. Primary outcome was changes in daily life executive function (EF) as reported by parents (The Behavior Rating Inventory of Executive Function). Secondary aims were to assess
generalizing effects on other, related domains, such as fatigue and health-related quality of life (HRQoL).
In Paper II, investigating baseline fatigue and associated factors, the findings showed that parents of the pABI survivors reported significantly more fatigue (75% of scores in clinical range; <70) compared to the healthy control group (12% of scores in clinical range). No strong associations were found between fatigue and injury characteristics, but the results indicated more fatigue in the older than younger age-group for pABI participants. Network modeling revealed a central role for HRQoL, behavioral problems and EF in relation to fatigue.
In Paper III, we demonstrated a significant reduction in parent-reported fatigue in children and adolescents with pABI, from baseline to 6 months, for both pGMT and pBHW. There were no significant differences between the intervention groups. However, when
considering the proportion of participants that had a reliable change (RCI) in fatigue from baseline to 6 months, 40% of the total sample had a reliable change, with 26% in the pGMT-group and 54% in the pBHW-group. Fatigue scores at 6 months post intervention were significantly associated with age at injury, global outcome, sleep problems, headache, internalizing problems and executive attention at baseline, but not with primary injury,
11 time since injury and sex. Only higher global outcome scores and better executive attention predicted improvement in fatigue from baseline to 6 months follow-up.
The findings in Paper IV showed that demographic, medical, and psychological factors independently predicted functional school outcomes (e.g., aid from the Educational Psychological Service, quality of life (QoL) in the school setting and academic
performance), except school absence, in children and adolescents with pABI. Secondly, fatigue made the strongest unique contribution in explaining self- and parent reported QoL in the school setting.
In summary, the studies confirm that fatigue continues to be a significant problem for the majority of children and adolescents in the chronic phase of pABI, and is associated with a number of demographic, medical, cognitive and psychological factors, as well as
functional school outcomes. Group-based cognitive rehabilitation programs, with inclusion of parents and teachers, show promise in reducing fatigue following pABI.
12 1. INTRODUCTION
Studies of how insults to the brain during childhood may affect development and functions have a long history, and can roughly be divided into three eras (Yeates & Taylor, 2001). In the medical era, lasting up until the end of the 1930s, the dominating view was that there are predetermined cortical regions critical for the development and representation of cognitive functions. For example, early insults to the left hemisphere would result in lasting language problems, due to the lateralization of language functions. This era was hampered by the anecdotal nature of clinical reports. Around the time of World War II, experimental techniques were increasingly being applied to study the effects of brain injuries in children and adults (Strauss & Lehtinen, 1947) and marked the beginning of the second era of child neuropsychology. An interest in the unique consequences of early brain injury gained ground (Kennard, 1942; Hebb, 1949), as did the debate around brain
plasticity versus vulnerability. For example, the influential work of Hubel and Weisel (1970) demonstrated the plasticity of the visual system and its susceptibility to
environmental input. Gradually, both animal- and child-based research began to
accumulate, and comprehensive scientific reviews emerged (e.g. Isaacson, 1975; St James- Roberts, 1975; Finger & Stein, 1982). In these reviews, early insults were regarded as less detrimental than those acquired in adulthood, with reports of seemingly normal cognitive development in children with various lesions and injuries (Smith & Sugar, 1975; Bates et al., 2001). The assumption was that early in child development, spared brain regions could take on functions normally subsumed by damaged areas (Taylor, 1984). On the other hand, studies of less favorable outcomes for children with more generalized cerebral insults pointed to a more nuanced picture (Dennis, 1989; Anderson & Moore, 1995).
The advancement of modern neuroimaging technology and other gains in cognitive neuroscience (such as functional MRI) signaled the beginning of the third and current era of child neuropsychology. As child and adult survival rates increased significantly due to more effective emergency care and specialized treatment facilities, long-term
consequences of ABI from mild to severe injuries have become more evident (Anderson et al., 2000). In the last 20 years, an increasing number of pediatric studies have emerged, pointing to several short- and long-term consequences of pediatric acquired brain injuries (pABI). While early studies focused primarily on brain-specific functions, later
publications reflect a broadened scope of focus on environmental factors (such as social factors, access to medical help) and pre-morbid characteristics (gender, age at insult,
13 coping styles) as potential mediators for recovery after pABI (Yeates et al., 1997; Catroppa
& Anderson, 2009). Furthermore, an interest in how pABI may affect other, associated domains has gained ground in later years. In particular, fatigue has been demonstrated to be one of the most common and detrimental sequelae following pABI (Wilkinson et al., 2018).
The enhanced survival rates following pABI stimulated further development of effective cognitive rehabilitation programs, primarily for improving cognitive deficits, but also related domains pertaining to behavioral and psychological functions and family needs (Braga et al., 2005; Butler et al., 2008; Limond et al., 2014). While the evidence for effective cognitive rehabilitation following adult ABI has increased considerably the last decades, studies of rehabilitation programs for pABI are still scarce, in particular
randomized controlled trials (RCTs) (Robinson et al., 2014). To date, there is evidence for the effectiveness of programs targeting attention, memory, EF, and emotional/behavioral functioning after pABI, especially programs with family/caregiver involvement (Laatsch et al., 2020). However, despite the high prevalence and negative effects of fatigue on daily activity, school performance and HRQoL in survivors of pABI, studies of rehabilitative treatment options for fatigue following pABI are lacking (Robinson et al 2018).
The studies presented in this thesis investigate the prevalence of fatigue and associations to other domains in pABI, predictors of functional school outcomes after pABI with an emphasis on the impact of fatigue, as well as the effects of two different cognitive rehabilitations programs on reducing fatigue symptoms.
1.1 Pediatric acquired brain injury
1.1.1 Medical characteristics and treatments
Pediatric acquired brain injury (pABI) is the umbrella term for any injury to the brain that occurs during childhood, but after birth and the immediate neonatal period. Thus, pABI excludes injuries sustained as a result of genetic or congenital disorder, or birth traumas (Greenwald et al., 2003). The injuries cause changes to the brain’s neuronal activity, affecting the physical integrity, metabolic activity, or functional ability of nerve cells in the brain. There are two main types of acquired brain injuries: traumatic and non-traumatic. In this section, information about the major subgroups of pABI (traumatic brain injury, brain tumor, stroke and encephalitis) will be presented.
14 Traumatic Brain Injury
A traumatic brain injury (TBI) is defined as an alteration in brain function, or other
evidence of brain pathology, caused by an external force. Traumatic impact injuries can be defined as closed (or non-penetrating) or open (penetrating). Examples of TBI include falls, assaults, motor vehicle accidents and sports injuries. In young children (<4y), pediatric TBI (pTBI) is commonly caused by falls, whereas motor-vehicle accidents are more prevalent in older children (Li & Liu, 2013). Severity of TBI is categorized as mild, moderate or severe, based on the extent and nature of injury, duration of loss of
consciousness, posttraumatic amnesia (PTA; loss of memory for events immediately following injury), and severity of confusion at initial assessment during the acute phase of injury (Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5); American Psychiatric Association, 2013).
Mild TBI - loss of consciousness for less than 30 minutes, an initial Glasgow Coma Scale (GCS) or Pediatric GCS of 13–15 after 30 minutes of injury onset, and PTA not surpassing 24 hours. Mild TBI can be divided into uncomplicated (no overt neuroimaging findings) and complicated (positive findings of intracranial
abnormalities by neuroimaging techniques, e.g., bruising or a collection of blood in the brain).
Moderate TBI - loss of consciousness and/or PTA for 1–24 hours and a GCS of 9–
12.
Severe TBI - loss of consciousness for more than 24 hours and PTA for more than 7 days with a GCS of 3–8.
Diffuse axonal injury (DAI) is a brain injury characterized mainly as an axonal injury of the white matter. It often follows brain trauma involving shearing force, and mainly manifests in the form of focal axonal changes and axonal breakage (Ma et al., 2016). DAI is most commonly associated with moderate to severe TBI, and the mortality rate of DAI is 42%–62% (Staal et al., 2007). DAI has been as an independent category of disease
accepted by neurosurgery academic. However, due to the complicated pathological
mechanisms underlying DAI, there is no uniform standard for its clinical diagnosis, and the clinical utility of DAI for prognostic purposes is still unclear (Janas et al., 2022). Studies of pTBI have found that deeper DAI lesions are associated with worse functional outcome (Babikian et al., 2005).Currently, most of the commonly used diagnostic standards are
15 noninvasive methods, such as neuropsychological assessment, magnetic resonance imaging (MRI), in particular diffusion MRI, and biochemical markers (Ma et al, 2016).
Long-term recovery after pTBI is complex and dependent on a number of factors, including time since injury and injury severity, as well as pre-injury ability, family functioning and socio-economic status (SES) (Anderson et al., 2012; 2011; Taylor et al., 2002). Interestingly, in a 12-year longitudinal study of multiple outcomes after pTBI (Petranovich et al., 2020), the family and social environment were associated with recovery in nearly every domain of functioning. Moreover, evidence of the effects of genes on functional outcome after pTBI is emerging, demonstrating a possible link to, among others, genes associated with the neurotransmitter dopamine (Kurowski et al., 2017). However, the relationship between genes and functional recovery after pTBI is complex, mediated by environmental factors, such as parenting style (Smith-Paine et al., 2018).
Non-Traumatic Brain Injury
Non-traumatic brain injuries cause damage to the brain by internal factors, such as a lack of oxygen, exposure to toxins, or occlusion of cerebral arteries or veins. Examples include stroke, aneurysms, tumors, infectious diseases that affect the brain, or reduced oxygen supply to the brain (i.e., near-drowning, cardiac arrest).
Brain tumors
Pediatric brain tumors and spinal cord tumors are the second most common cancers in children, after leukemia, accounting for about one of four childhood cancers (Nasjonalt kvalitetsregister for barnekreft, Årsrapport 2020). Childhood cancers are classified in a standard system, i.e., the third edition of the International Classification of Childhood Cancer (ICC-3; Steliarova-Foucher et al., 2005), according to tumor morphology
(histological classification) and primary site of origin, with an emphasis on morphology.
Diagnostic group III in the ICC-3 corresponds to central nervous system (CNS) and diverse intracranial and intraspinal neoplasms. Astrocytomas (malignant and benign) are the most common of the pediatric brain tumors, followed by intracranial and intraspinal embryonal tumors (Nasjonalt kvalitetsregister for barnekreft, Årsrapport 2020). There are four severity grading of CNS tumors, according to the World Health Organization: grade I and II for non-cancerous, slow growing (benign) tumors, and grade III and IV for
16 cancerous, faster growing (malignant) tumors. These latter grades are more challenging to treat (Louis et al., 2016). The classification is primarily based on histological
characteristics, albeit in later years, molecular markers are also applied.
Brain tumors that occur during childhood differ in several ways from those acquired in adulthood. Children are more prone to developing astrocytomas, medullablastomas and ependymomas, whereas adults are more likely to develop brain metastase, glioblastomas and meningiomas (Gjerstad et al., 2010). Furthermore, pediatric brain tumors are more commonly localized infratentorially (brain stem and cerebellum), while adults tumors are more often found supratentorially (the cerebrum). Brain tumors in childhood are more often benign and have better prognosis than adults with similar conditions. The etiology of pediatric brain tumors is poorly understood, even though a few genetic conditions (e. g., tuberous sclerosis, neurofibromatosis type 1 and 2) are linked to tumor development. The only documented environmental risk factor is ionizing radiation (Wilne et al., 2013).
Symptoms of brain tumors may include diffuse signs such as headache, irritability, nausea, vomiting and drowsiness, possibly due to an increase in intracranial pressure caused by the tumor (Ullrich, 2009). Focal symptoms depend on the localization of the tumor, and may include uncoordinated muscle movements, seizures, endocrine problems (diabetes and/or hormone regulation), visual changes, hearing loss, and facial paralysis, among others (Gjerstad et al., 2010). The diagnostic process may include a number of procedures, such as neurological examination, brain imaging, cerebrospinal fluid analysis, tumor biopsy, and analysis of genetic mutations and the molecular basis of the tumor.
Considerable advances have been made in brain tumor treatment (e.g., neurosurgery, cranial/craniospinal radiation therapy (CRT) and chemotherapy) over the past decades.
Selection of treatment regimen depends largely on the type, size, location of the tumor, as well as the age and overall health of the child. While neurosurgical resection of the tumor is considered the first treatment option, chemotherapy and/or CRT is often necessary in cases where the tumor is either totally or partly inoperable (e.g., due to location in vital regions) or not curative (i.e., malign) (Ullrich et al., 2015). As chemotherapy has less severe long-term side effects on neurocognition, brain development and endocrine function than CRT, it may be used to postpone or replace CRT in the youngest patient group
(Karajannis et al., 2008). Advancements in studies in molecular markers have led to a more
17 personalized chemotherapy, which is showing promising results (Nasjonalt
kvalitetsregister for barnekreft, Årsrapport 2020).
Improved medical treatment has resulted in considerably higher 5-year survival rates for pediatric intracranial tumors (i.e., 65-75%; Gatta et al, 2014). In Norway, the 5-year
survival rate is about 78% for all CNS tumors, but with considerable subgroup variation, as treatments and prognosis vary based on age, tumor location, size histology, and staging (Nasjonalt kvalitetsregister for barnekreft, 2020). Several risk factors for developing long term neurocognitive sequelae have been identified, involving individual factors (such as premorbid function, age at diagnosis or treatment), tumor- and treatment variables, neurological comorbidities, and environmental factors (SES and family function) (Bull &
Kennedy, 2013; Stavinoha et al., 2018; Stensvold et al., 2020). One of the most well- documented treatment-risk factors is CRT, due to its severe neurotoxic effects on the immature brain (e.g., comprised white matter integrity and impaired growth of new
neurons post-treatment) (De Ruiter et al., 2013; Stavinoha et al., 2018). Thus, patients with younger age at treatment, higher radiation doses, larger radiation fields, and CRT
combined with chemotherapy, are at greater risk for poorer neurocognitive outcomes (Kahalley et al., 2016; Duffner, 2010). However, the increasing use of proton therapy shows promising results in terms of reducing sequelae after CRT treatment.
Stroke
Stroke is a type of cerebrovascular disorder and can be categorized as ischemic (caused by insufficient blood flow, due to occlusion of cerebral arteries or veins) and hemorrhagic (caused by bleeding into the brain). Hemorrhagic stroke is the result of bleeding from a ruptured cerebral artery or from bleeding into the site of an acute ischemic stroke (AIS) (Bjørnstad & Skjeldal, 2001). AIS accounts for about half of all strokes in children, in contrast to adults in whom 80–85% of all strokes are ischemic (Tsze & Valente, 2011).
The risk factors for acquiring a stroke in childhood (among others, congenital heart disease, sickle cell disease, and leukemia) are more diverse and differ significantly from adults. Furthermore, stroke is a rarer event in children than in adults. Roughly, 10–25% of children who sustain a stroke do not survive, and up to 25% of the children will have a recurrence (Tsze & Valente, 2011).
18 All though there are substantial differences in how strokes present in children, dependent on the child’s age, some generalizations can be made (Amlie-Lefond et al., 2008). AIS most often presents as a focal neurologic deficit with hemiplegia being the most common manifestation, occurring in up to 94% of cases. Hemorrhagic strokes most commonly present as headaches or altered level of consciousness, and are more likely to cause vomiting than in AIS. Seizures are common in both ischemic and hemorrhagic strokes.
They occur in up to 50% of children with strokes, and are not restricted to any specific age group or seizure type.
Management of stroke is less studied in children than in adults, but some generalizations and recommendations can still be made, based on available adult studies and consensus statements (Tsze & Valente, 2011). In the acute phase, some of these measures include fever control, relieving intracranial pressure, treatment of dehydration and correction for anemia. The diagnostic process involves the use of various imaging modalities, such as noncontrast computer tomography (CT), magnetic resonance imaging (MRI), venography (MRV) and arteriography (MRA). Other investigations may also be considered, such as ultrasound and lumbar puncture. Once the type of stroke is identified, treatment depends on the etiology. Hemorrhagic strokes may require medical management beyond supportive measures. Prevention of rebleeding includes correction of coagulation defects and
hematologic disorders. Several surgical options can be considered, however, the evidence is mixed regarding the potential for surgical interventions to improve chances of optimal recovery beyond best medical management. Finally, pharmacological options to prevent subsequent cerebrovascular events may include anticoagulation drugs and thrombolytic treatments (Amlie-Lefond et al., 2008).
Encephalitis
Encephalitis is an inflammation affecting the parenchyma of the brain. Most cases are caused by viruses, but bacteria, fungi, parasites and post-infectious and/or autoimmune forms also exist. The frequency and distribution of viruses and other agents causing encephalitis vary according to the geographical region with large differences between Europe, Asia and the USA (Fowler et al., 2008; de Blauw et al., 2020). This etiological diversity is in part due to variation in climate, presence of epidemics, arthropod-borne infections and variations in immunization programs. The highest frequency and the more severe cases of acute encephalitis are often seen in younger children.
19 Clinically, acute encephalitis can range from being a self-limiting condition with no
sequelae to being an illness with life-long morbidity or even mortality (Fowler et al., 2008). The classical presentation of encephalitis consists of fever, headache and an altered mental state, together with seizures and focal neurological findings in some cases. The diagnosis is based on the medical history and clinical picture, in addition to results of specific investigations such as electroencephalogram (EEG), neuroimaging and lumbar puncture. However, in up to 65% of all patients with encephalitis, the definite cause of the illness cannot be determined (Fowler et al., 2008).
Several factors have been suggested as indicative of a negative prognosis after pediatric encephalitis, such as young age, deteriorating EEG pattern, degree of blood-brain barrier damage, presence of focal neurological signs, abnormal neuroimaging and a low score on the initial GCS (Fowler et al., 2008; de Blauw et al., 2020; Koskiniemi et al., 1997).
1.1.2 Epidemiology
pABI is one of the leading causes of death and disability for children and adolescents globally (World Health Organization, 2009; Thurman, 2016). Incidence (number of new cases identified in a specified time period) and prevalence (number of children who are living with the condition in a given time period) rates of pABI vary across clinical and epidemiological studies. These variations are often due to differences in participant characteristics (e.g., ages included), diagnostic classification criteria within and across subtypes (for example, mild TBI versus severe TBI), and sources of data (e.g., hospital admissions, emergency room visits, general practitioner visits) (Dewan et al., 2016).
Moreover, current statistics do not take into account children and adolescents who do not seek medical care. Therefore, these estimates may significantly underestimate the
incidence and prevalence of pABI. For example, the prevalence of pABI amongst school- aged children the United Kingdom was estimated to be in the region of 1 in 30 (Wicks &
Walker, 2005), based on admissions to acute care. The prevalence may be higher, as other, more urgent injuries may override concerns of pABI at the time of admission.
A review examining worldwide annual incidence rates of pediatric pTBI revealed
variations by country ranging from 47 to 280 per 100,000 children (Dewan et al., 2016). A Norwegian study found the incidence rate of hospital-treated children to be 29 in 100,000 (0-15 years) (Dahl et al., 2021), similar to Scandinavian studies (Wilson et al., 2017). The
20 Scandinavian focus on road safety and the use of safety equipment may partly explain the lower incidences compared to other parts of the world.
For brain tumors, the annual incidence rate in Norway is 3,9 per 100 000 (Nasjonalt kvalitetsregister for barnekreft, Årsrapport 2018). In fact, the incidence of brain tumors in the Nordic countries is the highest in the world (Johannesen et al., 2004). This may be due to the completeness of the Nordic registries, as well as international variations in
classification.
International data suggest the incidence of childhood stroke range from 2 to 13 per 100 000 children (Amlie-Lefond et al., 2008), similar to Norwegian incidence rates (Bjørnstad &
Skjeldal, 2001). However, pediatric strokes are frequently undiagnosed or misdiagnosed, due to a variety of factors including a low level of suspicion by the clinician and patients who present with subtle symptoms that mimic other diseases (Tsze & Valente, 2011).
Data on incidence rates of pediatric encephalitis are limited, as pediatric cases have not been specified in broad population studies, in addition to the many unknown causes of encephalitis possibly leading to underestimations (de Blauw et al., 2020). Estimates ranging from 4 to 8 in 100 000 was found in a British study (Granerod et al., 2013), not specifying the pediatric population. A study in Finland (Koskiniemi et al., 1997) estimated the pediatric incidence rate to be 10,5 in 100 000, with most cases occurring within the first year after birth.
Sex differences
There is a tendency across several pABI etiologies for a male predominance. After the age of three, male children are up to three times more likely to sustain pTBI than female children (Dewan et al., 2016). This difference may be explained in part by the higher participation rate by males in physical, organized sport, or perhaps by the more physical nature of childhood play among boys relative to girls. Furthermore, there is a worldwide male predominance in childhood stroke (Golomb et al., 2009), and similar differences have been found for brain tumors (Louis et al., 2016; Sun et al, 2012), for reasons yet unknown.
The severity of most infectious diseases, such as those causing encephalitis, is also higher in boys than girls, with the impact of specific hormones and immune responses possibly explaining this discrepancy (Muenchhoff & Goulder, 2014; Granerod et al., 2013). On the other hand, higher levels of proinflammatory immunity also predispose females to
increased immunopathology in some infections.
21 1.2 Effects of pediatric brain injuries on neurocognition, mental health, quality of life
and school function
1.2.1 The biopsychosocial framework
The World Health Organization’s International Classification of Functioning, Disability and Health (ICF) model provides an integrative, bio-psycho-social framework for describing the complexities of pABI. ICF conceptualizes disability as a ‘dynamic interaction between a person’s health condition, environmental factors, and personal factors’ (World Health Organization, 2001), and may be useful for understanding the total symptom burden after pABI. In this framework, functional changes may occur at any three levels. Body functions and structures refer broadly to impairments at the level of the body, while activities reflect functioning at the level of the individual. Participation describes the involvement of the individual in all areas of life. Furthermore, the ICF model includes the impact of contextual factors on disability. Environmental factors encompass the ‘physical, social and attitudinal environment in which people live and conduct their lives’, while personal factors include internal psychological states and characteristics of the individual such as age, coping style and past experiences. In the context of pABI, a child who has sustained a brain damage (such as EF impairments due to a frontal lobe insult) may experience limitations to the types of activities she can perform independently (e.g.
homework, hygiene) and her ability to participate in valued life activities (e.g. school attendance, sports). Thus, the ICF provides a clear, holistic and universal structure for conceptualizing impairment and disability after pABI (Ditchman et al., 2016; Bilbao et al., 2003; World Health Organization, 2007), as well as inform rehabilitation efforts (Ylvisaker et al., 2005; Wade, 2020).
22 Figure 1. Interaction between the elements of ICF.
From International Classification of Functioning, Disability and Health (p. 18), by World Health Organization, 2001, Geneva: World Health Organization. Copyright 2010 by the World Health Organization.
1.2.2 Neurocognition and executive function
On the impairment level, neurocognitive deficits after pABI are common, in particular in the domain of EF. As EF processes are central to the intervention study and related to the outcome of interest (fatigue) in this thesis, they will be presented in more detail in the following.
Executive function
EF is a blanket term that incorporates a number of inter-related processes responsible for purposeful, goal-directed behavior (Gioia, Isquith, & Guy, 2001). These executive processes are fundamental for the synthesis of external stimuli, formation of goals and strategies, preparation for action, and verification that plans and actions have been
implemented appropriately (Diamond, 2013). EF includes the ability to identify, plan and organize steps towards goal attainment; to be aware and adjust of one’s behavior in relation to situational demands; to initiate actions; to focus on task and avoid distractions; to
monitor and flexibly adjust or shift to more effective strategies when needed (Lezak et al., 2012). In general, EF enables a person to function independently and engage successfully with the environment (Kalbfleisch, 2017), especially, in novel contexts where there are no well learned behaviors to draw upon (Friedman & Miyake, 2017). A distinction has been suggested between “cold” and “hot” EF processes; the cool functions reflect the relatively
“mechanistic” or “logically” based skills (such as attentional control, working memory,
23 planning, organizing), whereas hot functions operate in contexts that evoke emotion, motivation and competition between instant gratification and long-term rewards (Peterson
& Welsh, 2014). These hot EF processes are essential components in empathy, moral understanding and affective decision-making (De Luca & Leventer, 2010).
Previously, EF was mainly linked to frontal lobe functioning, as executive dysfunction was mostly observed in patients with damage to this region (Lezak et al., 2012). In later years, studies of the underlying circuitry of these functions have increased considerably. It is now well established that a number of inter-connected cortical and subcortical networks are involved in EF, and that the (pre)frontal areas may serve as a relay station or “conductor”
of these skills (Gioia et al., 2001; Stuss & Alexander, 2000). Thus, EF is vulnerable not only to damages to the frontal lobe, but also to other regions of the brain involved in EF networks.
EF is a broad construct, and there is a lack of consensus on a definition of the various EF processes. One of the most influential models of EF is proposed by Miyake and colleagues (2000). The model focuses on three of the most central EF skills in the literature; (a) shifting between mental tasks or sets, (b) updating, monitoring and manipulation of working memory processes (i.e., maintaining information active in consciousness while performing mental operations to achieve goals), and (c) inhibitory control of dominant or automatic responses (e.g., stopping inappropriate responses or ignoring irrelevant
information). These processes are some of the most studied in the neuropsychological literature (Toplak et al., 2013). Studies confirm the existence of separable, but interrelated EF skills, a pattern that has been described as “unity and diversity” (Miyake et al., 2000;
Friedman & Miyake, 2017).
The “unity and diversity” pattern of EF skills is also reflected in developmental models, suggesting that EF may emerge hierarchically throughout childhood. That is, more fundamental skills such as sustained attention and inhibition develop early in childhood, and facilitate the emergence of more complex skills with more prolonged developmental curves, such as working memory and shifting (Tillman et al., 2015). In fact, trajectory studies show that, parallel to the maturation of brain structures, inhibitory control is in active development from late infancy to about the age of 11 (Brocki & Bohlin, 2004;
Tillman et al., 2015), while working memory and shifting seem to have a slower and more
24 prolonged trajectory from early preschool years into adolescence (Garon et al., 2008;
Luciana et al., 2005). The complex and protracted development of EF skills may in part explain the tendency found in studies of children with pABI to “grow into deficit” with time, with a delayed onset and increase of impairments (Narad et al., 2017; Anderson et al., 2018). Adding to the complexity; environmental factors, such as changes in social and academic settings, with increasing cognitive demands from childhood into young adulthood, may also contribute to this tendency (Anderson et al., 2010).
As EF is a complex construct with no common definition, assessments of EF is challenging (Chan et al., 2008). Furthermore, the “impurity problem” (i.e., most measures of EF also involve non-executive processes, such as color naming (language) in inhibition tasks) impedes the validity of the measures. Both performance-based and rating measures of EF have been used to clinically assess many of the EF skills. However, the extent to which these two types of measures actually reflect the same underlying mental construct is far from certain. It has been argued that performance-based tests to a larger extent reflect the efficiency of cognitive abilities (ICF: impairment level), whereas rating instruments assess rational control and goal pursuit in the real environment (ICF: activity and performance level; Toplak et al., 2013). There are important differences between the nature of these two modes of measures, that may explain the minimal correlation between them. While the role of EF may be rather limited in many laboratory tasks, since much of the organization or structure of the tasks is provided by the examiner (Salthouse et al., 2003), EF ratings provide an estimate of the frequency, or typicality, of EF skills in everyday life. Both modes of assessment may provide important information about an individual’s efficiency and success in achieving goals.
Neurocognitive effects in pediatric acquired brain injuries
In line with the ICF model, recovery after pABI is complex, varies over time, and involves the interplay of injury-related influences (such as severity levels and age at injury),
cognitive ability, genetics, and premorbid, caregiver and family functioning (Petranovich et al., 2020). Younger age at injury constitute a significant risk factor for developing neurocognitive impairments, as the development in the immature brain may be interrupted and derailed, and lead to cascading effects later in development (Anderson et al., 2011;
Babikian & Asarnow, 2009; Bull & Kennedy, 2013). However, where a child’s outcome falls along the “recovery continuum” depends on the combined effects of the above
25 mentioned factors (Anderson et al., 2011). Longitudinal studies of pABI show that less favorable cognitive outcomes may persist for years after injury or treatment (Puhr et al., 2019a; 2019b; Yeates et al., 2002; Anderson et al., 2011; Stadskleiv et al., 2020). Most recovery of cognitive skills occurs during the first year, and there is a tendency of a plateau thereafter.
As pTBI is the most common pABI etiology, impairments after pTBI have been
investigated more extensively, compared to the other etiologies. Severity levels moderate outcomes, in the sense that children with severe pTBI display more pronounced deficits, compared to children with moderate and mild injuries (Ryan et al., 2016; Babikian &
Asarnow, 2009), in particular for adaptive abilities and processing speed (Anderson et al., 2012). However, a study of 10-year outcome after pTBI (Anderson et al., 2012) showed that children in all severity levels had greater impairments on the domains of IQ, EF, behavioral problems and social skills, compared to population expectations. Some studies point to increased risk in pTBI for problems with EF skills reflecting hot aspects of EF (Peterson & Welsh, 2014), such as behavior regulation (Li & Liu, 2013; Catroppa et al., 2012; Anderson et al., 2002).
Studies of long-term effects after pediatric brain tumors are hampered by confounding medical treatment effects, to a larger degree than other pABI etiologies, especially the disruption of cerebral white matter (Araujo et al., 2017). Medical effects may be divided into five categories: physical (such as changes to physical appearance, or reduced growth), endocrinological (such as growth hormone deficiency, diabetes or obesity), neurological and sensory late effects (as in seizures, cognitive dysfunction, or auditory and visual impairments), and secondary neoplasms (Turner et al., 2009). Of note, several late effects do not occur until years or even decades following completion of cancer treatments, thus, it has been argued that pediatric brain tumor survivors will need life-long follow-up and rehabilitation (Stensvold et al., 2020). Neurocognitive late effects are relatively common in pediatric brain tumor survivors (40-100%), with impairments of processing speed,
attention, working memory, IQ and general EF being the most affected cognitive functions (Bull & Kennedy, 2013; Palmer, 2008; Stadskleiv et al., 2020). Some studies indicate that the cool aspects of EF skills, such as inattention, slower processing speed and lack of initiation, are the most affected in brain tumor survivors (Puhr et al., 2019a), compared to other pABI etiologies (Araujo et al., 2017). The cerebellum is the most common site of
26 pediatric brain tumors, and both motor and cognitive functions are linked to this area (Stadskleiv et al., 2020).
Pediatric strokes may lead to significant impairments, and up to 66% will have persistent neurological deficits or develop subsequent seizure disorders, learning, or developmental problems (Tze & Valente, 2011). Neuropsychological vulnerabilities have been
highlighted in a number of studies, particularly in the areas of processing speed, working memory, higher-level language and EF (O’Keefe et al., 2017). Children with bilateral strokes may also be expected to have greater disruptions to white matter brain regions than those with unilateral strokes, and these disruptions are linked to, among others, poorer inhibitory control (Araujo et al., 2017).
Only a few studies have performed follow-up of children with encephalitis, but studies indicate a considerable variation in cognitive outcome (Fowler et al., 2008). Many children have significant symptoms (e.g. headache, tiredness and cognitive problems, in particular EF) at the time of discharge from hospital (Clarke et al., 2006). Furthermore, these
symptoms may persist for several months and even years (Aygün et al., 2001). Some long- term follow-up studies also show that many children suffer from severe sequelae such as epilepsy, paresis with motor function disability and moderate to severe learning difficulties (Ilias et al., 2006). A recent review of outcome after an autoimmune form of encephalitis (Tarantino et al., 2021), found EF and memory skills to be especially vulnerable.
Thus, the long-term neurocognitive outcomes after pABI vary as a function of both injury type, severity and other influential pre-morbid, psychological and environmental factors.
Rosenbaum and Lipton (2012) noted, in the context of mild TBI, that heterogeneity in patient profiles is a hallmark characteristic and therefore cannot be avoided or ignored.
Because brain injuries occur in unique and highly individualized circumstances, neither the impact of biomechanics nor the individual genetic and experiential background of any two injured individuals are ever identical (Saatman et al., 2008). Nevertheless, some causes of injury involve similar mechanisms, and some brain regions are more vulnerable than others to injury, and therefore more commonly damaged (Bigler et al., 2013). These observation are equally relevant to other ABI etiologies. Rosenbaum & Lipton proposed that
embracing the great variety of mechanistic, pathologic and clinical manifestations of brain injury, instead of regarding them as limitations, can improve research efficacy and clinical
27 care of patients. This notion is consistent with recent expert recommendations (Maas et al., 2017), stressing the need for a comprehensive, holistic approaches to cognitive
rehabilitation after ABI.
1.2.3 Mental health and quality of life
The impact of pABI is not limited to cognitive abilities, but may also influence other areas, such as mental health, health-related quality of life (HRQoL) and fatigue, mapping onto both impairment, activity and participation levels in the ICF model. Reduced HRQoL has been documented across both traumatic and non-traumatic brain injuries (Ilmer et al., 2016), with close associations to behavioral and emotional problems. The importance of social and environmental factors for long-term outcome, such as family function, parental health and SES, has increasingly come into focus in later years, showing associations with measures of psychological distress in children with pABI (Cousino et al., 2017; O’Keefe et al., 2012).
Mood disorders, such as depression and anxiety, and behavior problems are more common in children with pTBI than healthy controls (Li & Liu, 2013), as well as reduced HRQoL (Limond et al., 2009). In a follow-up study 7 years after pTBI, EF, behavior problems and fatigue were strongly linked to reduced HRQoL (Camara-Costa et al., 2020). Internalizing disorders are more likely to resolve than externalizing disorders after pTBI (Bloom et al., 2001). For survivors of pediatric brain tumors, studies find a higher risk of experiencing significantly more psychological distress, both internalizing and externalizing problems, compared to other childhood cancers and healthy controls (Brinkman et al., 2018), as well as other pABI populations (Zeltzer et al., 2009). This may be due to the added burden of a protracted treatment, uncertain prognosis and other treatment effects. As such, pediatric brain tumor survivors may be placed at increased risk of low self-esteem and self-identity issues due to social factors, and the sense of being “left behind” and disconnected from their peers (Vetsch et al, 2018). Furthermore, treatment-related and medical factors, such as functional or sensorimotor deficits, pain, cardiovascular, endocrine and/or pulmonary conditions following cancer treatment, are linked to enhanced risk for developing symptoms of anxiety and depression (Cousino et al., 2017). Finally, neurocognitive dysfunction, in particular EF problems, has been consistently associated with emotional and behavioral health outcomes (Stavinoha et al., 2018). HRQoL has been found to be significantly lower for children with stroke (AIS) compared to norms, across all domains
28 of social, emotional, physical, school and cognitive function (O’Keeffe et al., 2012).
Moreover, reduced HRQoL was related to lower IQ and attentional capacities after
pediatric stroke (Kornfeld et al., 2017). Survivors of childhood meningitis and encephalitis have also reported lower HRQoL, with strong connections to learning disabilities and SES (Sumpter et al., 2011), and fatigue (Tarantino et al., 2021), as well as neurological findings at discharge (Rao et al., 2017).
Furthermore, fatigue is a common sequela after pABI, with close associations to other functional domains, and will be discussed in further detail in a separate section below.
Taken together, the evidence underscores the need to systematically assess the children’s mental health, HRQoL and experience of fatigue following pABI, both in the acute and chronic phase of the condition.
1.2.4 School outcomes
In the ICF framework, the participation level describes the involvement of the individual in all areas of life (World Health Organization, 2007). School is one of the most central arenas for development of not only academic skills such as mastering the school curriculum, but also cognitive, social, and community-related skills during childhood.
Return to school life after pABI may represent an indicator of a return to normality.
However, functional school impairments often emerge over time, characterized by poor school performance, high rates of grade retention, and need of external educational services across several pABI etiologies (Ewing-Cobbs et al., 1998; Bruce et al., 2008;
Bonneau et al., 2011; O’Keeffe et al., 2017). Thus, many children in the chronic phase of pABI often have unmet needs in the educational setting. Kingery and colleagues (2017) followed children who had sustained a TBI early in childhood over 7 years, and found that children across all severities did not receive the educational support they were in need of, in particular children with milder injuries. One possible explanation for this may be that children and adolescents with less obvious sequelae from their injuries may be at greatest risk of not having their academic needs met.
Functional school outcomes may be influenced and explained by multiple variables and factors, which demonstrate the complex and interdependent relationship between demographic (e.g., age and sex; Navarro et al., 2015)), medical (e.g., injury-related variables such as age at injury, time since injury and functional outcome; Prasad et al.,
29 2017), psychological (Li & Liu, 2013), and cognitive variables (Babikian & Asarnow, 2009). Importantly, neurocognitive and behavioral impairments may have adverse effects on school outcomes (Li and Liu, 2013). In particular, associations between EF and functional school outcomes have been demonstrated, with EF also being longitudinally predictive of academic difficulties and school dropout (Kingery et al, 2017; Spiegel et al., 2021; Puhr et al., 2019b). Furthermore, fatigue is another potential predictor of functional school outcome that has been largely overlooked. Of note, there is preliminary evidence to suggest an association between fatigue and unfavorable functional school outcomes (i.e., schoolwork being negatively affected and worse academic performance; Borg et al., 2009;
Eisenberg et al., 2014). The extended literature shows evidence of an association between fatigue and worse cognitive and academic outcomes in pediatric multiple sclerosis (Goretti et al., 2012), as well as with unfavorable functional outcomes of young adult survivors of pediatric brain tumor and stroke (Puhr et al., 2019b, O’Keeffe et al., 2017). Berrin and colleagues (2007) observed that the relationship between diagnostic subtypes of cerebral palsy and school functioning was partially mediated by fatigue.
Thus, the evidence so far suggests that school outcomes may be affected in several ways after pABI. However, more studies are needed to understand the complex relationship between demographic, injury-related, psychological and cognitive factors and the various aspects of school outcomes in order to improve the educational support after pABI.
1.3 Fatigue
1.3.1 Conceptualization, prevalence and associated factors
Fatigue refers to a set of symptoms common in healthy individuals (Loge et al., 1998;
Pawlikowska et al., 1994), as well as in a range of medical conditions, such as cancer, multiple sclerosis, brain injuries, and other neurological conditions (Curt et al., 2000;
Englander et al., 2010; Kluger et al., 2013; Levine & Greenwald, 2009; Mulhern et al., 2004; Thomas, 2018; Maher et al., 2015). A common definition of fatigue is the subjective experience of exhaustion and decreased capacity for physical or mental activity because of an imbalance in the availability, use or restoration of resources needed to perform activity (Aaronson et al., 1999). While fatigue in the general population is normally transitory and alleviated by rest and sleep, fatigue in the medical sense refers to an enduring experience of weariness that interferes with daily functioning, does not recede after rest, and is not proportional to recent activity (Bower, 2014). The etiology of the symptom is complex,
30 influenced by several common factors in a variety of disorders, pertaining to changes in the central and peripheral nervous system and endocrine disturbances (Armstrong et al., 2010;
Crichton et al., 2015; Kluger et al., 2013). External factors such as social and academic demands, may exacerbate fatigue symptoms (Ezekiel et al., 2021). Furthermore, acts and processes that require cognitive effort, like revising for an exam, may in general incur a cost on limited cognitive resources, for instance EF, resulting in a subjective feeling of fatigue (e.g., Gailliot et al., 2007; Kool et al., 2010). These findings underpin the transdiagnostic nature of the construct (Menting et al., 2018).
Fatigue has been demonstrated to cluster with other symptoms, including physical, psychiatric, and cognitive problems, such as reduced activity, pain, sleep and mood disorders, as well as EF impairment (Armstrong et al., 2010; Manoli et al., 2020; van Markus-Doornbosch et al., 2020). The causal pathways between these domains are still poorly understood, but there is emerging evidence of cognitive and somatic risk factors for the experience of chronic fatigue in adult ABI, especially executive dysfunction, pain and sleep problems, as well as psychological distress, (Løke et al., 2022; Menting et al., 2018).
Studies find no consistent associations between the prevalence and severity of fatigue and etiology, disease duration and severity or treatment factors (Armstrong et al., 2010; Cantor et al., 2008; Levine & Greenwald, 2009; Struik et al., 2009). However, some treatments for brain tumor, that is, chemo- and radiation therapy, are considered to be significant risk factors (Bower, 2014; Brand et al., 2016; Meeske et al., 2004).
In children and adolescence with pABI, fatigue has been described as one of the most common sequelae (Crichton et al., 2015). In a review by Wilkinson and colleagues (2018), pABI survivors reported significantly higher levels of fatigue than healthy controls (Borg et al., 2009; Palmer et al., 2007), with 58%–74.6% reporting fatigue across multiple pABI etiologies (i.e., encephalitis, brain tumor, TBI, meningitis; Eisenberg et al., 2014;
Tarantino et al., 2021; Logar et al., 2000; Macartney et al., 2014; Sumpter et al., 2011).
Importantly, fatigue following pABI interferes with daily function, academic performance, and social/ school participation, and is linked to poorer HRQoL (Berrin et al., 2007;
Dornonville de la Cour et al., 2018; Goretti et al., 2012). Studies have observed a decrease in fatigue symptoms from six to twelve months post injury, and a plateau thereafter
(Bogdanov et al., 2021; Crichton et al., 2018), similar to neuropsychological outcomes after pABI (Yeates et al., 2002). Despite this, studies of fatigue in pABI are still scarce.
31 1.3.2 Models of fatigue
Fatigue constitutes a complex set of symptoms and can be conceptualized in many ways, from a unidimensional to multidimensional construct (Payne, 2004). Several subdivisions of fatigue exist, ranging from physical and cognitive (mental) fatigue, central and
peripheral fatigue, and emotional and stress fatigue (Wylie & Flashman, 2017). Cognitive fatigue has been found to be one of the most prevalent dimensions of fatigue in pABI (Riccardi & Ciccia, 2021; Crichton et al., 2015). It can be described as feelings of mild to extreme mental exhaustion, often felt as a rebound effect after cognitive effort, which can last anywhere from several hours to days (Wylie & Flashman, 2017). A classification system of primary (early) fatigue - caused by a specific disease/disorder - and secondary (late) fatigue - caused by exacerbating factors - has been proposed to assist clinicians and researchers in addressing the debilitating symptoms (DeLuca, 2005; Wu et al., 2015).
While the etiology of primary fatigue in individuals with brain injury is unclear, with possible associations to impaired excitability of the motor cortex (Chistayakov et al., 2001), impaired attentional networks (Nordin et al., 2016) and hypopituitarism (Bushnik et al., 2007), a greater number of potential causes for secondary fatigue in pABI have been studied; these include sleep disorders, pain, depression, cognitive deficits, parent health and family function (Nap-van der Vlist et al., 2021; Riccardi & Ciccia, 2021; Dornonville de la Cour et al., 2018; van Markus-Doornbsoch et al., 2020; Bogdanov et al., 2021;
Crichton et al., 2018). For survivors of pediatric brain tumor, there is additional evidence of treatment-related fatigue improving significantly after ended treatment (Greene- Schloesser et al., 2012), whereas, long-term fatigue may be linked to a white matter damage emerging after treatment (Wood & Verity, 2021).
Several models have been suggested to encompass the development and continuation of fatigue symptomatology across different etiologies, primarily in adult patient groups.
Wylie & Flashman (2017) reviewed studies of four approaches for understanding chronic fatigue in TBI, with a focus on cognitive fatigue; (1) fatigue as an indication of increased mental effort, (2) neuro-inflammation, (3) a result of psychological risk factors, and (4) as a function of sleep disturbances. They found most support for the models that attribute fatigue to increased mental effort and sleep problems. However, they argue that the linkage between psychological processes and fatigue is difficult to assess, as there is a considerable item-overlap between the available rating instruments, described as a “conflation of ideas”.
