Eczema, sleep and daytime functioning in children

Eczema, sleep and daytime functioning in children by Danny Camfferman BA, Grad Dip Psych. A thesis submitted for the Degree of Doctor of Philosophy Department of Paediatrics Faculty of Health Sciences The University of Adelaide Submitted December 2010 Table of Contents Table of Contents………………………………………………...................................………ii List of Tables……….................................................................................................................ix List of Figures…..…................................................................................................................xii Abstract…………………………………………………………….......................................xvi Declaration…………………………………………………………......................................xix Publications in support of thesis…………………………………..........................................xx Acknowledgements………………………………………………....................................….xxi List of Abbreviations…………………………………………….........................................xxii Chapter 1: Introduction and literature review............................................................................1 1.1 Introduction……………………………………….....................................................1 1.2 Literature review……………………...….......................................................………2 1.2.1 The demographic profile of eczematous children with sleep disturbance......3 1.2.2 Notable questionnaire studies which focus on the sleep characteristics of children with eczema................................................................................................4 1.2.3 Sleep disturbance in parents of children affected with eczema......................5 1.2.4 Mechanism assumed to cause sleep disturbance in children with eczema.....5 1.2.5 Actigraphic studies on children with eczema and sleep..................................6 1.2.6 Biological markers of childhood eczema and sleep........................................7 1.2.7 Polysomnography data on children with eczema............................................8 1.3 Summary of current data on the sleep of children with eczema..................................9 ii 1.4 Body temperature and sleep in humans.....................................................................10 1.4.1 Eczematous skin and body temperature.................................................................11 1.5 Rhinitis and asthma disturbing sleep in children with eczema..................................12 1.6 Treatment of childhood eczema and sleep.................................................................14 1.7 Sleep disturbance and quality of life.........................................................................16 1.8 Childhood eczema, sleep, daytime behaviour and cognition....................................17 1.8.1 Eczema, sleep and behaviour in children with eczema.................................18 1.8.2 Eczema, sleep and ADHD in children with eczema.....................................19 1.8.3 Sleep and neurocognitive development in children......................................19 1.9 Summary of current literature on eczema, sleep and daytime functioning in children............................................................................................................................21 Chapter 2: Eczema, asthma, rhinitis, sleep and behaviour in children......................................40 2.1 The contribution of eczema, asthma and rhinitis to sleep disturbance and behaviour in children........................................................................................................................40 2.2 Method.......................................................................................................................41 2.2.1 Participants and Procedure............................................................................41 2.2.2 Apparatus......................................................................................................41 2.2.3 The Child Health Questionnaire-Parent Form...............................................43 2.2.4 The Children's Dermatology Life Quality Index...........................................43 2.2.5 The Sleep Disturbance Scale for Children....................................................44 2.2.6 The Conner's Parent Rating Scale - Revised (S)...........................................44 iii 2.3 Statistics.....................................................................................................................45 2.4 Results........................................................................................................................46 2.4.1 Correlations between atopic disorders and demographic/behavioural variables.................................................................................................................46 2.4.2 Correlations between eczema, sleep disorder and behaviour........................47 2.4.3 Structural Equation Modelling Analysis.......................................................47 2.4.4 Evaluation of the Models generated through Structural Equation Analysis..................................................................................................................49 2.4.5 Results of Structural Equation Analysis on children with eczema's sleep and behaviour................................................................................................................50 2.5 Discussion..................................................................................................................61 Chapter 3: Polysomnography data on the sleep of eczematous children..................................67 3.1 Rationale for conducting polysomnographic studies on children with eczema.........67 3.2 Potential measures of eczema severity......................................................................67 3.2.1 Current methods of measuring eczema severity............................................68 3.2.2 Biological markers of eczema severity.........................................................69 3.2.3 Urinary Leukotriene E4.................................................................................69 3.3 Method.......................................................................................................................70 3.3.1 Subjects and Procedure.................................................................................70 3.3.2 Apparatus......................................................................................................71 3.3.3 Eczema Assessment......................................................................................71 iv 3.3.4 Asthma and Allergic Rhinitis........................................................................72 3.3.5 Leukotriene E4..............................................................................................72 3.3.6 Sleep Disturbance Scale for Children...........................................................73 3.3.7 Polysomnography..........................................................................................74 3.4 Statistics.....................................................................................................................75 3.5 Results........................................................................................................................76 3.5.1 Comparison of demographics, atopic disorders and sleep variables between children with eczema and controls.........................................................................76 3.5.2 Relationship between atopic disease and polysomnographic sleep data among children with eczema..................................................................................77 3.6 Discussion..................................................................................................................85 Chapter 4: An examination of the contribution of scratch disturbing sleep in children with eczema ……………………………………………..............................................................…92 4.1 Itch.............................................................................................................................92 4.2 Scratch.......................................................................................................................92 4.2.1 Measuring nocturnal scratch using polysomnography..................................93 4.3 Nocturnal scratching in children with eczema...........................................................94 4.3.1 Nocturnal scratching in adults with eczema..................................................96 4.4 Method.......................................................................................................................98 4.4.1 Actigraphy.....................................................................................................99 4.4.2 Scratching......................................................................................................99 v 4.5 Results......................................................................................................................100 4.5.1 Actigraphy data of children with eczema compared to controls.................100 4.5.3 Relationship between atopic disease and actigraphy data among children with eczema..........................................................................................................100 4.5.4 Relationship between actigraphy and polysomnography data among children with eczema controlling for frequency that asthma disturbs sleep in the last 12 months and the frequency that rhinitis controls sleep in the last 12 months........101 4.5.5 Relationship between the SCORAD, scratching, arousals and sleep stage in children with eczema...........................................................................................102 4.6 Discussion................................................................................................................109 Chapter 5: Eczema, sleep and body temperature in children..........………………………....116 5.1 Body temperature regulation in humans..................................................................116 5.2 Circadian rhythms and body temperature in humans..............................................117 5.3 Sleep disorders associated with temperature dysfunction.......................................119 5.4 The impact of eczema on heat transference in the human body..............................121 5.5 Co-sleeping and thermoregulation in children with eczema...................................122 5.6 Research on the skin of eczema patients and its impact on thermoregulation........122 5.7 Rationale for studying skin temperature in children with eczema...........................124 5.8 Method.....................................................................................................................125 5.8.1 Subjects and Apparatus...............................................................................125 5.8.2 Temperature.................................................................................................125 5.9 Results......................................................................................................................126 vi 5.9.1 ANOVA results of nocturnal temperature differences between children with eczema and controls ............................................................................................126 5.8.2 Correlation between sleep and nocturnal mean temperature values...........126 5.10 Discussion..............................................................................................................136 Chapter 6: Sleep and daytime functioning in eczematous children: Polysomnography and neurocognitive testing.............................................................................................................141 6.1 Sleep and Neurocognition........................................................................................141 6.2 Neurocognitive deficits, co-morbid disorders and sleep disturbance in eczematous children..........................................................................................................................143 6.3 Rationale for examining the neurocognitive profile of children with eczema and possible associations with their sleep quality................................................................143 6.4 Method.....................................................................................................................144 6.4.1 Neurocognitive assessment.........................................................................144 6.4.2 Attention assessment...................................................................................145 6.4.3 Reading age.................................................................................................146 6.4.4 Snoring........................................................................................................146 6.5 Results......................................................................................................................146 6.5.1 Group Comparisons between eczema children and controls on snoring, atopic disorders and sleep variables...........................................................................................146 6.5.2 Comparison of neurocognition variables between eczema and control groups..................................................................................................................146 vii 6.5.3 Relationship between eczema, behaviour and neurocognition among children with eczema...........................................................................................147 6.5.4 Correlations between eczema, behaviour and neurocognitive variables among children controlling for snoring and co morbid atopic disease disturbing sleep.....................................................................................................................148 6.5.5 Correlations between polysomnography variables and behavioural ratings of eczematous children, controlling for the frequency of snoring and the frequency that co morbid atopic disease disturbed sleep.....................................................148 6.5.6 Correlations between polysomnography and neurocognitive variables of eczematous children, controlling for frequency of snoring and the frequency that co morbid atopic disease disturbed sleep............................................................148 6.6 Discussion...............................................................................................................156 Chapter 7: Eczema, sleep and daytime behaviour in children................................................164 7.1 Eczematous children's sleep findings......................................................................164 7.2 Neurocognition, behaviour and sleep in eczematous children................................164 7.3 Co-morbid disorders of Asthma and Rhinitis.........................................................165 7.4 Case study of female eczema patient (aged 7yrs) pre and post treatment..............165 7.5 Method....................................................................................................................166 7.6 Results.....................................................................................................................166 7.7 Discussion................................................................................................................170 7.8 Future directions for study......................................................................................170 7.9 Conclusion..............................................................................................................171 viii List of Tables Table 1.1: Eczema questionnaire studies reporting sleep information.……………….......….23 Table 1.2: Eczema treatment studies reporting sleep data.......................................................26 Table 1.3: Questionnaire studies which report the sleep of parents of children with eczema......................................................................................................................................27 Table 1.4: Studies using actigraphy to measure sleep in children with eczema......................29 Table 1.5: Studies using polysomnography to measure sleep in children with eczema..........30 Table 2.1: Atopic questionnaire items used to estimate severity and impact on sleep............42 Table 2.2: Correlation matrix of eczema, asthma and rhinitis variables..................................51 Table 2.3: Mean (SD) demographic, quality-of-life, sleep and behaviour questionnaire scores for children with eczema and controls together with F-test/Chi-square (χ) results.................52 Table 2.4: Correlation matrix: atopy variables versus demographic, quality-of-life, sleep and behaviour questionnaire variables in children with eczema..................................................................53 Table 2.5: Correlation matrix of sleep and behavioural scales and their subscales in children with eczema..............................................................................................................................54 Table 2.6: Results of Structural Equation Modelling (Maximum Likelihood Estimates) in the relationship between Asthma, Eczema, & Rhinitis on Sleep Problems and Behaviour Problems...................................................................................................................................55 Table 3.1: Mean (SD) demographic and sleep scores for children with eczema and controls together with F-test/Chi-square results ...................................................................................78 ix Table3.2: Correlation matrix: Atopic Disease with Polysomnography variables of children with eczema..............................................................................................................................79 Table 4.1: Mean (SD) demographic, atopic disease and actigraphy variables for children with eczema compared to controls together with F-test/Chi-square results...................................103 Table 4.2: Correlation matrix: Atopic disease severity and their relationship with actigraphic variables.................................................................................................................................104 Table 4.3: Correlation matrix of actigraphy and polysomnography sleep variables of children with eczema controlling for frequency that asthma disturbs sleep in the last 12 months and frequency that rhinitis disturbs sleep in the last 12 months...................................................105 Table 4.4: Mean (SD) and F-test results of the nocturnal distribution of scratch-related activity in children with eczema.............................................................................................106 Table 4.5: Correlation matrix of eczema severity, polysomnography scratching events in children with eczema..............................................................................................................107 Table 4.6: Studies of actigraphy and scratch in children with eczema.................................112 Table 4.7: Studies of polysomnography and scratch in children and adults with eczema....113 Table 5.1: ANOVA results of nocturnal temperature differences between children with eczema and controls...............................................................................................................127 Table 5.2: Correlation between sleep and nocturnal mean temperature values.....................127 Table 6.1: Mean (SD) of frequency of snoring, atopic disease and sleep scores for children with eczema and controls together with F-test/Chi-square results.........................................149 x Table 6.2: Correlation matrix: Eczema, Behaviour, IQ, Attention and Reading Age variables of children with eczema co-varied for frequency of snoring, frequency that asthma disturbed sleep in the last 12 months and frequency that rhinitis disturbed sleep in the last 12 months....................................................................................................................................150 Table 6.3: Correlation matrix of the sleep and behavioural variables of children with eczema co-varied for frequency of snoring, frequency that asthma disturbs sleep in the last 12 months and frequency that rhinitis disturbs sleep in the last 12 months.............................................151 Table 6.4: Correlation matrix of the sleep and neurocognitive variables of children with eczema co-varied for frequency of snoring, frequency that asthma disturbed sleep in the last 12 months and frequency that rhinitis disturbed sleep in the last 12 months. Attention Total Score and Reading ability are also controlled for age............................................................155 Table 7.1: Pre and post treatment data of BMI, snoring, atopic disease severity, sleep questionnaire, actigraphy and polysomnography variables of a 7 year old female with eczema....................................................................................................................................168 Table 7.2: Pre and post treatment data of behavioural and neurocognitive variables of a 7 year old female with eczema..........................................................................................................169 xi List of Figures Figure 2.1: SEM Model for Hypothesised Relationships Between Conditions Sleep and Behaviour.................................................................................................................................56 Figure 2.2: Partial Mediation of Cognition by Asthma, Eczema and Rhinitis Effect on Sleep.........................................................................................................................................57 Figure 2.3: Partial Mediation of Hyperactivity by Asthma, Eczema and Rhinitis Effect on Sleep.........................................................................................................................................58 Figure 2.4: Partial Mediation of ADHD by Asthma, Eczema and Rhinitis Effect on Sleep.........................................................................................................................................59 Figure 2.5: Partial Mediation of Oppositional (Behaviour) by Asthma, Eczema and Rhinitis Effect on Sleep.........................................................................................................................60 Figure 3.1: Minutes of Stage 1 sleep per 30 minute epoch......................................................80 Figure 3.2: Minutes of Stage 2 sleep per 30 minute epoch......................................................80 Figure 3.3: Minutes of Stage 3 sleep per 30 minute epoch......................................................81 Figure 3.4: Minutes of Stage 4 sleep per 30 minute epoch......................................................81 Figure 3.5: Minutes of REM sleep per 30 minute epoch.........................................................82 Figure 3.6: Minutes of Wake After Sleep Onset per 30 minute epoch....................................82 Figure 3.7: Scatterplot of VAS scores of itch severity and Desaturation Nadir in Total Sleep Time in children with eczema..................................................................................................83 xii Figure 3.8: Scatterplot of VAS scores of itch severity and REM % in children with eczema......................................................................................................................................83 Figure 3.9: Screenshot of sub cortical respiratory event recorded during polysomnography..84 Figure 4.1: Nocturnal frequency per hour of scratching when awake and scratching when asleep in children with eczema...............................................................................................106 Figure 4.2: Screenshot of scratch event recorded during polysomnography (Brown and Kalucy, 1979).........................................................................................................................108 Figure 4.3: Screenshot of scratch event recorded during polysomnography (Aoki et al., 1991).......................................................................................................................................108 Figure 5a: Core body temperature of older adults (black) and children (white) over a 24 hour period......................................................................................................................................118 Figure 5.1: Right versus left finger temperature control children..........................................128 Figure 5.2: Right versus left clavicle temperature control children.......................................128 Figure 5.3: Right versus left finger temperature children with eczema.................................129 Figure 5.4: Right versus left clavicle temperature children with eczema..............................129 Figure 5.5: Control versus children with eczema right index temperature............................130 xiii Figure 5.6: Control versus children with eczema right clavicle temperature.........................130 Figure 5.7: Control versus children with eczema left index temperature..............................131 Figure 5.8: Control versus children with eczema left clavicle temperature...........................131 Figure 5.9: Control versus children with eczema right index finger minus right clavicle temperature difference............................................................................................................132 Figure 5.10: Control versus children with eczema left index finger minus left clavicle temperature difference............................................................................................................132 Figure 5.11: Right versus left distal-proximal gradient (finger minus clavicle) for control children...................................................................................................................................133 Figure 5.12: Right versus left distal-proximal gradient (finger minus clavicle) for children with eczema............................................................................................................................133 Figure 5.14: Average index finger (left versus right) temperature for children with eczema and control children................................................................................................................134 Figure 5.15: Average clavicle (left versus right) temperature for children with eczema and control children......................................................................................................................134 Figure 5.16: Average (left versus right) distal-proximal gradient (finger minus clavicle) for children with eczema and control children.............................................................................135 Figure 6.1: Scatterplot of Hyperactivity and Sleep Onset Latency (minutes) in children with eczema....................................................................................................................................152 Figure 6.2: Scatterplot of ADHD Index and Sleep Onset Latency (minutes) in children with eczema....................................................................................................................................153 xiv Figure 6.3: Scatterplot of Oppositional behaviour and Sleep Onset Latency (minutes) in children with eczema..............................................................................................................154 xv Abstract Eczema affects up to 20% of children in western industrialised countries. Chronic childhood eczema has significant morbidity characterised by physical discomfort, emotional distress, reduced child and family quality-of-life and, of particular note, disturbed sleep. Sleep disturbance, characterised by frequent and prolonged arousals, affects up to 60% of children with eczema, increasing to 83% during exacerbation. Even in clinical remission, children with eczema demonstrate more sleep disturbance than healthy children. Disturbed sleep in otherwise healthy children is associated with behavioural and neurocognitive deficits. Preliminary evidence suggests that disturbed sleep in children with eczema is also associated with behavioural deficits while the impact on neuropsychological functioning remains unexplored. Two major studies were undertaken to examine the sleep of children with eczema and possible secondary deficits due to poor sleep. Parents of children (6-16y) with eczema (n = 77) and healthy controls (n = 30) completed a validated omnibus questionnaire which included items which assessed sleep, behaviour, general health, quality-of-life and additional items assessing eczema, asthma, rhinitis and demographics. Structural Equation Analyses revealed that the effect of eczema on the behavioural variables of Hyperactivity, ADHD Index and Oppositional behaviours were mediated through sleep with no direct effect of eczema on behaviour. A similar relationship between sleep and behaviour was observed for the co morbid atopic disorders of rhinitis and asthma. In the second study, children (aged 6-16y) with eczema (n = 24) and controls (n = 19) were assessed through polysomnography to provide data on their sleep quality. Eczema severity was evaluated using SCORAD ratings scales and eczematous children provided a urine sample for analysis for Leukotriene E4, a biological marker of atopic inflammation. xvi Scratching was assessed using infra-red camera. Distal and Proximal body temperature was measured to ascertain potential deficits in homeostatic processes and actigraphy was employed to record nocturnal activity. To evaluate neurocognitive ability all children underwent IQ testing with eczematous children undergoing additional children attention and reading age measurements. Polysomnographic data on children with eczema showed that they had a longer REM onset latency, higher percentage stage 3 & 4 sleep, longer Wake After Sleep Onset and a lower Sub Cortical Arousal Index than controls. Higher Leukotriene E4 levels was strongly associated with longer Wake after Sleep Onset. In addition, Wake after Sleep Onset also exhibited a trend toward higher itch and sleep loss ratings of the SCORAD. Increased Leukotriene E4 levels also demonstrated associated trends in lower Sleep Efficiency, longer REM Onset Latency, a lower percentage of REM and fewer Stage Shifts. Using infra-red video contiguous with polysomnography, scratching was found to occur during sleep in all sleep stages. The SCORAD variable of Erythema, which is the redness or inflammation of the skin that is the result of dilation of superficial capillaries was found to be strongly associated with nocturnal scratching. Actigraphic data demonstrated that children with severe eczema had more nocturnal activity and for longer periods of time than either mild to moderate eczema patients or controls. Actigraphy variables were also associated with the frequency that asthma and rhinitis disturbed sleep as well as eczema severity and Leukotriene E4 levels in children with eczema. The actigraphic variables of Sleep Efficiency and Awakenings were moderately associated with the polysomnographic variables of Total Sleep Time, Sleep Efficiency and Sleep Onset Latency. xvii Sleep Onset temperatures were similar between eczema and control groups, however the skin temperature profile of children with eczema differed markedly from control subjects thereafter. Distal skin temperature in eczematous children was found to be significantly lower than controls for approximately a third of the night. Overnight trends in eczema subject's Distal temperature indicated that the heat loss usually associated with nocturnal sleep was markedly greater than controls. Eczema children scored significantly lower on Full Scale IQ, Verbal Comprehension and Perceptual Reasoning scores than controls. On the WISC-IV subtests, scores of similarities, comprehension, picture concepts and letter-number sequencing were also significantly lower in children with eczema than controls. After controlling for the impact of snoring, asthma and rhinitis disturbing sleep, our findings suggest that lower neurocognitive performance in children with eczema is related to their sleep quality. In conclusion, eczema was found to affect the sleep of children with longer periods of awake during the night and with more nocturnal movement than controls. The sleep architecture of children with eczema was also found to be associated with behavioural and neurocognitive deficits. Nocturnal scratching was found to occur during sleep and further, produce arousal from sleep, however the lack of associations between itch and sleep variables indicate that itch is also not a primary cause of sleep disturbance in children with eczema. The role of skin temperature in nocturnal thermoregulation appears to be disturbed in this patient group with eczema children showing evidence of a greater and more rapid heat loss than controls. It is also suggested that these rapid changes in temperature are associated with sleep disturbance. While the findings of a case study indicating that treatment improving sleep quality is also associated with neurocognitive and behavioural improvements, further study is required to determine the mechanism associating sleep fragmentation with daytime functioning. xviii Declaration Name: Danny Camfferman Program: PhD in Medicine This work contains no material which has been accepted for the award of any other degree or diploma in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by another person, except where due reference is made in the text. I give consent to this copy of my thesis, when deposited in the University Library, being made available for loan and photocopying, subject to the provisions of the Copyright Act 1968. I also give permission for the digital version of my thesis to be made available on the web, via the University's digital research repository, the Library catalogue, the Australasian Digital Theses Program (ADTP and also through web search engines, unless permission has been granted by the University to restrict access for a period of time. Signed:……………………… Date:………………………… xix Publications in support of thesis Publications Camfferman D, Kennedy JD, Gold M, Martin AJ, Lushington K. (2010) Eczema and sleep and its relationship to daytime functioning in children. Sleep Medicine Reviews, 14 (6), 359369. Camfferman D, Kennedy D, Gold M, Winwood P, Martin AJ, Lushington K. (2010), Eczema and sleep and behaviour in children. Journal of Clinical Sleep Medicine, 6 (6), 581-588. xx Acknowledgements First, I would like to thank all the parents and children who participated in the study for their time, interest and compliance, as without their support, this work could not have been possible. To Yvonne Pamula and staff of the Sleep Disorders Unit at the Women’s and Children’s Hospital for their help and accommodating me in the use of their facilities. To Fiona Futo and Margaret Heddle working as research assistants in the Sleep Disorder Unit, for their assistance with recruitment of subjects for this project. To Kathy Carmen from the Immunology Department for her help in the collection and analyses of the Leukotriene E4 samples. To fellow PhD. students Mark Kohler, Andrew Valkulin and Scott Coussens for their help and advice throughout the study. The final acknowledgement is to my supervisors Assoc. Prof. Kurt Lushington, Dr. Declan Kennedy and Dr. Mike Gold for teaching me research skills that I will endeavour to expand upon in the future. xxi List of Abbreviations Acetylcholine (Ach) Arteriovenous-anastomoses (AVAs) Attention Deficit Hyperactivity Disorder (ADHD). Brain-Derived Neurotrophic Factor (BDNF) Childhood Atopic Dermatitis Impact Scale (CADIS) Child Health Questionnaire-Parent Form (CHQ-PF-28) Children’s Dermatology Life Quality Index (CDLQI) Circulatory Temperature Index (CTI) Dermatitis Family Impact questionnaire (DFI) Eczema Area Severity Index (EASI) Immunoglobulin E (IgE) Infants’ Dermatology Quality of Life Index (IDQoLI) International Study of Asthma and Allergies in Childhood (ISSAC) Leukotriene E4 (LTE4) Macrophage-Derived Chemokine (MDC) Nottingham Eczema Severity Score (NESS) Polysomnography (PSG) Rapid Eye Movement (REM) SCORing Atopic Dermatitis (SCORAD) Socio-Economic Indexes For Areas (SEIFA) Sleep Disordered Breathing (SDB) Sleep Disturbance Scale for Children (SDSC) Suprachiasmatic nucleus (SNC) T-cell attracting cytokine (CTACK) Temperature environment (Te) Temperature rectal (Tr) Temperature skin (Ts) The German Health Interview and Examination Survey for Children and Adolescents (KiGGS) Thymus and Activation Regulated Chemokine (TARC) Visual Analogue Scale (VAS) Wechsler Intelligence Scale for Children (WISC-IV) xxii