==== Front Nat Sci SleepNat Sci SleepNature and Science of SleepNature and Science of Sleep1179-1608Dove Medical Press 10.2147/NSS.S174608nss-10-225EditorialSleep disturbance after pediatric traumatic brain injury: critical knowledge gaps remain for the critically injured Williams Cydni N 1Lim Miranda M 2345Shea Steven A 5 1 Department of Pediatrics, Division of Pediatric Critical Care 2 Department of Neurology 3 Department of Medicine 4 Department of Behavioral Neurosciences 5 Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR, USA, sheast@ohsu.eduCorrespondence: Steven A Shea, Oregon Institute of Occupational Health Sciences, 3181 SW Sam Jackson Park Road, Oregon Health & Science University, Portland, OR 97239, USA, Email sheast@ohsu.edu2018 08 8 2018 10 225 228 © 2018 Williams et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. ==== Body Traumatic brain injury (TBI), the alteration of brain function or brain pathology following external force, is common in children. TBI affects the sleep of victims, and poor sleep itself can impair recovery from TBI. Due to the developing brains of children, it is especially important to understand the complex interactions between sleep and TBI. Such understanding could lead toward optimizing recovery from TBI in children. Thus, here, we introduce the main issues in this field with a specific focus on the pediatric population and point out the important gaps in knowledge that need to be filled. TBI accounts for 60,000 pediatric hospitalizations in the USA annually.1 Half of these children require critical care admission for serious injuries such as skull fractures and intracranial hemorrhage (critical TBI).2 Injury and critical care hospitalization leave survivors with physical, cognitive, and psychosocial morbidities encompassed by the postintensive care syndrome.3 Few studies have assessed these important morbidities in survivors of pediatric critical TBI, and interventions to improve outcomes are limited. Sleep wake disturbances (SWD) are increasingly recognized as an important morbidity following TBI and as a barrier to recovery in adult TBI and in concussion (the mildest form of TBI without identified intracranial pathology). SWD in pediatric survivors of critical TBI have been under-appreciated by clinicians and under-evaluated by researchers but may be key to improving the important myriad of sequelae suffered by these children. Sleep is integral to many physiologic systems, and in children, it is critical for brain maturation and development.4,5 SWD during childhood brain development, through effects on synaptic plasticity and memory consolidation, may be particularly impactful on long-term pediatric health.6,7 SWD in otherwise healthy children are associated with physical, cognitive, and psychosocial impairments and may substantially compound the negative health consequences of pediatric diseases.8–10 SWD of any type are reported in over half of all TBI survivors, occur across all spectrums of severity and location of TBI, and persist for years after injury.7,11 SWD including insomnia, awakenings, daytime fatigue, and sleep disordered breathing are reported in adult TBI survivors though to date are poorly quantified in children.12,13 SWD after TBI are associated with impaired functional outcomes, decreased participation in activities, and reduced quality of life.14,15 Data from our Pediatric Neurocritical Care follow-up clinic show multiple types of SWD complicate recovery in more than half of survivors of pediatric critical TBI months after hospital discharge.16 However, most pediatric critical TBI survivors do not receive this type of specialized follow-up that includes systematic evaluation of sleep or postintensive care syndrome. Currently, clinicians have little data guiding methods to identify SWD or to support therapeutic interventions for SWD following pediatric critical TBI. While there has been a recent upswing in pediatric sleep literature, variable methodology is used in these studies and few focus on TBI.17 Polysomnography is the gold standard for the diagnosis of some SWD but is not always feasible in clinical and research populations and may fail to diagnose disorders such as insomnia and excessive daytime sleepiness.18 A recent review of available pediatric sleep questionnaires resulted in 183 tools reported, but only two fulfilled all appropriate psychometric criteria and only 11 fulfilled most criteria.19 Actigraphy is increasingly utilized in children for sleep research providing objective data that have been validated against polysomnography for some SWD and also lacks standard methodology or accepted normative data for many measures in children.20 It is likely that the combination of well-validated questionnaires and actigraphy is needed to evaluate the multidimensional aspects of SWD in pediatric critical TBI. SWD literature is dominated by concussion patients in pediatric TBI cohorts, and available reports are often secondary evaluations of data not designed to collect sleep outcomes.13 A systematic review in 2015 of SWD after pediatric TBI identified only eight studies exclusive of case reports that included children with critical TBI.13 Only one study of 15 patients with critical TBI included objective actigraphy data evaluating sleep,21 and only three studies used a validated sleep questionnaire.8,21,22 A 2017 study evaluating fatigue after pediatric critical TBI showed that it remained a significant problem 12 months after injury but was not evaluated in conjunction with sleep measures.23 Most prior reports do not delineate the specific type of SWD or the severity of SWD in the analysis. Additionally, prior reports stratifying injury severity by Glasgow Coma Scale did not find a significant association with SWD.13,24 Glasgow Coma Scale fails to incorporate other concurrent injuries, such as extremity fractures and abdominal trauma, that occur in the majority of pediatric critical TBI patients and have implications for sleep outcomes such as pain, medications, and casting. The pathophysiology of SWD after critical TBI is unclear but has been attributed to structural and functional disruptions of sleep circuitry, circadian rhythm disturbances, hormonal dysfunction, and comorbidities such as pain and psychological disorders.7 However, evaluation of disease mechanisms remains in its infancy, despite a rapidly growing body of literature.7 A variety of neural networks, neurotransmitters, and neuropeptides are linked to normal and disordered sleep. After a critical TBI, many of these sleep-related systems are affected either through the primary injury or through the secondary injury related to inflammation and physiologic derangements. Secondary injury related to inflammation has been under-evaluated in TBI with regard to sleep outcomes. TBI induces an acute systemic inflammatory response that increases neuroinflammation and directly injures the brain.25–28 Interleukins (ILs) and other proinflammatory cytokines, including IL-1β, IL-6, and tumor necrosis factor alpha (TNFα), are elevated in serum and cerebrospinal fluid after TBI, cross the blood–brain barrier freely after injury, and are evaluated as mediators of other TBI outcomes.25–28 Levels correlate with injury severity, increased intracranial pressure, increased mortality, and worsened Glasgow Outcome Score in TBI survivors.28 Chronic elevations of TNFα, IL-6, and IL-1β levels weeks to months after TBI correlate with significantly worse Disability Ranking Scale, Glasgow Outcome Score, and slowed trajectory of cognitive recovery.29–31 The same inflammatory cytokines elevated after TBI influence sleep through damaging neurons in the hypothalamus, modifying astrocyte and microglial function, altering levels of melatonin and orexin, and impairing circadian regulation.32–36 SWD also potentiate chronic inflammation, and this is a proposed mechanism leading to many of the negative health consequences linked to SWD.33,34 Despite overlap between inflammation after critical TBI and inflammation in SWD reported separately in the literature, prior studies have not assessed the link between inflammation and SWD following critical TBI. In sum, SWD after pediatric critical TBI are an important morbidity. There remain substantial gaps in available knowledge due to limited data. Research is needed to identify the incidence, risk factors, and pathophysiologic mechanisms underlying SWD. Untreated SWD delay recovery and compound other morbidities encompassed by postintensive care syndrome, including physical, neurocognitive, and psychosocial dysfunction after pediatric critical TBI (Figure 1). Understanding the burden of SWD in critical TBI survivors is the first step toward identifying effective interventions for SWD and evaluating sleep as a modifiable target for other important morbidities plaguing pediatric survivors of critical TBI. Disclosure The authors report no conflicts of interest in this work. Figure 1 Proposed relationship between traumatic brain injury, inflammation, sleep wake disorders, and postintensive care syndrome. ==== Refs References 1 Faul MXL Wald MM Coronado VG [webpage on the Internet] Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006 Atlanta (GA) Centers for Disease Control and Prevention, National Center for Injury Prevention and Control 2010 Available from: https://www.cdc.gov/traumaticbrain-injury Accessed May 10, 2017 2 Asemota AO George BP Bowman SM Haider AH Schneider EB Causes and trends in traumatic brain injury for United States adolescents J Neurotrauma 2013 30 2 67 75 22989254 3 Herrup EA Wieczorek B Kudchadkar SR Characteristics of postintensive care syndrome in survivors of pediatric critical illness: a systematic review World J Crit Care Med 2017 6 2 124 134 28529914 4 Volk C Huber R Sleep to grow smart? Arch Ital Biol 2015 153 2–3 99 109 26742664 5 Ringli M Huber R Developmental aspects of sleep slow waves: linking sleep, brain maturation and behavior Prog Brain Res 2011 193 63 82 21854956 6 Tononi G Cirelli C Sleep and the price of plasticity: from synaptic and cellular homeostasis to memory consolidation and integration Neuron 2014 81 1 12 34 24411729 7 Sandsmark DK Elliott JE Lim MM Sleep-wake disturbances after traumatic brain injury: synthesis of human and animal studies Sleep 2017 40 5 8 Shay N Yeates KO Walz NC Sleep problems and their relationship to cognitive and behavioral outcomes in young children with traumatic brain injury J Neurotrauma 2014 31 14 1305 1312 24665961 9 Owens JA Neurocognitive and behavioral impact of sleep disordered breathing in children Pediatr Pulmonol 2009 44 5 417 422 19382210 10 Gozal D Kheirandish-Gozal L Neurocognitive and behavioral morbidity in children with sleep disorders Curr Opin Pulm Med 2007 13 6 505 509 17901756 11 Beebe DW Krivitzky L Wells CT Wade SL Taylor HG Yeates KO Brief report: parental report of sleep behaviors following moderate or severe pediatric traumatic brain injury J Pediatr Psychol 2007 32 7 845 850 17442693 12 Singh K Morse AM Tkachenko N Kothare SV Sleep disorders associated with traumatic brain injury-a review Pediatr Neurol 2016 60 30 36 27161048 13 Gagner C Landry-Roy C Laine F Beauchamp MH Sleep-wake disturbances and fatigue after pediatric traumatic brain injury: a systematic review of the literature J Neurotrauma 2015 32 20 1539 1552 25891946 14 Aaro Jonsson CC Emanuelson IM Charlotte Smedler A Variability in quality of life 13 years after traumatic brain injury in childhood Int J Rehabil Res 2014 37 4 317 322 25153788 15 Tham SW Palermo TM Vavilala MS The longitudinal course, risk factors, and impact of sleep disturbances in children with traumatic brain injury J Neurotrauma 2012 29 1 154 161 22029569 16 Williams CN Kirby A Piantino J If you build it, they will come: initial experience with a multi-disciplinary pediatric neurocritical care followup clinic Children (Basel) 2017 4 9 83 17 Lam DJ Shea SA A growth spurt in pediatric sleep research Nat Sci Sleep 2016 8 133 135 27199573 18 Mouthon AL Huber R Methods in pediatric sleep research and sleep medicine Neuropediatrics 2015 46 3 159 170 25961599 19 Spruyt K Gozal D Pediatric sleep questionnaires as diagnostic or epidemiological tools: a review of currently available instruments Sleep Med Rev 2011 15 1 19 32 20934896 20 Meltzer LJ Montgomery-Downs HE Insana SP Walsh CM Use of actigraphy for assessment in pediatric sleep research Sleep Med Rev 2012 16 5 463 475 22424706 21 Sumpter RE Dorris L Kelly T McMillan TM Pediatric sleep difficulties after moderate-severe traumatic brain injury J Int Neuropsychol Soc 2013 19 7 829 834 23601180 22 Osorio MB Kurowski BG Beebe D Association of daytime somnolence with executive functioning in the first 6 months after adolescent traumatic brain injury PM R 2013 5 7 554 562 23375631 23 Crichton A Anderson V Oakley E Biomarker and Quality of Life in Children with Traumatic Brain Injury Group Fatigue following traumatic brain injury in children and adolescents: a longitudinal follow-up 6 to 12 months after injury J Head Trauma Rehabil 2017 33 3 200 209 24 Baumann CR Werth E Stocker R Ludwig S Bassetti CL Sleep-wake disturbances 6 months after traumatic brain injury: a prospective study Brain 2007 130 pt 7 1873 1883 17584779 25 Kelley BJ Lifshitz J Povlishock JT Neuroinflammatory responses after experimental diffuse traumatic brain injury J Neuropathol Exp Neurol 2007 66 11 989 1001 17984681 26 Das M Mohapatra S Mohapatra SS New perspectives on central and peripheral immune responses to acute traumatic brain injury J Neuroinflammation 2012 9 236 23061919 27 Hinson HE Rowell S Morris C Lin AL Schreiber MA Early fever after trauma: does it matter? J Trauma Acute Care Surg 2018 84 1 19 24 28640776 28 Hinson HE Rowell S Schreiber M Clinical evidence of inflammation driving secondary brain injury: a systematic review J Trauma Acute Care Surg 2015 78 1 184 191 25539220 29 Licastro F Hrelia S Porcellini E Peripheral inflammatory markers and antioxidant response during the post-acute and chronic phase after severe traumatic brain injury Front Neurol 2016 7 189 27853449 30 Kumar RG Diamond ML Boles JA Acute CSF interleukin-6 trajectories after TBI: associations with neuroinflammation, polytrauma, and outcome Brain Behav Immun 2015 45 253 262 25555531 31 Kumar RG Boles JA Wagner AK Chronic inflammation after severe traumatic brain injury: characterization and associations with outcome at 6 and 12 months postinjury J Head Trauma Rehabil 2015 30 6 369 381 24901329 32 Clark IA Vissel B Inflammation-sleep interface in brain disease: TNF, insulin, orexin J Neuroinflammation 2014 11 51 24655719 33 Kapsimalis F Basta M Varouchakis G Gourgoulianis K Vgontzas A Kryger M Cytokines and pathological sleep Sleep Med 2008 9 6 603 614 18024171 34 Weschenfelder J Sander C Kluge M Kirkby KC Himmerich H The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems Psychiatr Danub 2012 24 2 112 126 22706407 35 Opp MR Cytokines and sleep Sleep Med Rev 2005 9 5 355 364 16102986 36 Kapsimalis F Richardson G Opp MR Kryger M Cytokines and normal sleep Curr Opin Pulm Med 2005 11 6 481 484 16217172