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Nocturnal eczema: Review of sleep and circadian rhythms in children with atopic dermatitis and future research directions

      Children with atopic dermatitis (AD) experience significant sleep disruption, and clinically, the disease is noted to worsen in a circadian manner at night. Epidemiologic findings highlight many negative consequences of AD, such as impaired linear growth, which is uniquely related to disturbed sleep. Clinical guidelines currently recommend assessing sleep in patients with AD as a crucial parameter of disease control with appropriate treatment. In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema). We present a schematic to explain the mechanism of nocturnal eczema. Treatment options for sleep disturbance and future directions for research are discussed in the context of AD.

      Key words

      Abbreviations used:

      AD (Atopic dermatitis), BMAL (Brain and muscle ARNT-like), CLOCK (Circadian locomotor output cycles kaput), NREM (Nonrapid eye movement), REM (Rapid eye movement), TEWL (Transepidermal water loss), WASO (Wake After Sleep Onset)
      Discuss this article on the JACI Journal Club blog: www.jaci-online.blogspot.com.
      Sleep plays an important role in promoting physical and mental health. Sleep deprivation has been shown to alter immune function.
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      Atopic dermatitis (AD; also called eczema) is a chronic inflammatory skin disorder affecting 10% to 20% of US children.
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      AD is characterized by intense nocturnal pruritus,
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      which can severely affect sleep continuity, sleep quality, and quality of life. Sixty percent of children with AD experience sleep disturbance caused by their disease, with 83% reporting sleep disturbance during exacerbations.
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      In fact, short stature has been described in children with AD only when associated with insufficient sleep.
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      Given the nocturnal pattern of eczema flares, abnormalities in circadian rhythms (24-hour cycles) or rhythmic secretion of biological factors (eg, cortisol secretion) might underlie the diurnal pattern of itch and flares. Diurnal variation in skin physiology is complex
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      and includes both peripheral circadian rhythms (skin and leukocyte-derived oscillations) and central circadian rhythms (directed by pineal gland–derived melatonin and cortisol).
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      such as IL-2 and the pruritus-specific TH2 cytokine IL-31,
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      Sleep-dependent activity of T cells and regulatory T cells.
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      IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis.
      might drive nocturnal AD flares. Nighttime factors, such as cortisol nadir, increased skin temperature and poor barrier function (leading to increased transepidermal water loss [TEWL]),
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      susceptibility to infections,
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      Sleep and circadian rhythm regulate circulating complement factors and immunoregulatory properties of C5a.
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      The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity.
      and itch exacerbation by bacterial products, such as staphylococcal superantigens, irritants, and allergens, can all promote the hallmark of inflammatory TH1, TH2, and TH22 cellular infiltrate
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      in patients with AD, homing to skin secondary to diurnally mediated chemokine gradients.
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      In this review we describe our current understanding of the roles of sleep cycles and circadian rhythms in the nighttime exacerbation of AD (nocturnal eczema, Fig 1). Treatment options for sleep disturbances and future directions for research are discussed in the context of AD.
      Figure thumbnail gr1
      Fig 1Schematic of the mechanism in nocturnal eczema exacerbations. A, Central circadian rhythms are directed by the suprachiasmatic nucleus, which stimulates cortisol release by the adrenal glands and melatonin release by the pituitary gland. In patients with eczema, melatonin levels can be increased and cortisol rhythms shifted from normal timing of production, resulting in increased systemic inflammation. Other nocturnal stimuli (local and systemic) that upregulate inflammation are drawn with arrows, including the vicious itch/scratch cycle that results from inflammation and leads to further barrier impairment. B, Poor barrier function is made worse at night by increased TEWL, increased aquaporin-3 [AQP3] expression, increased T-cell activation, and upregulated Toll-like receptor (TLR) expression. These feed back to increase systemic and skin-directed TH1, TH2, and TH22 cytokines. Published literature suggests that these cytokines and chemokines (thymus and activation-regulated chemokine [TARC], macrophage-derived chemokine [MDC], cutaneous T cell–attracting chemokine [cTACK], and CCL18 [also known as pulmonary and activation-regulated chemokine]) are upregulated at night in patients with eczema, stimulate T-cell homing, and increase further production of inflammatory cytokines, some of which directly disrupt sleep (IL-6) or exacerbate pruritus (IL-31), resulting in eczema flare.

      Stages of sleep in children

      By around 3 months of age, 24-hour sleep architecture begins to become structurally more predictable and reproducible. Sleep is defined polysomnographically by 4 stages.
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      A typical night of sleep involves multiple cycles through stages N1-N3 (nonrapid eye movement [NREM]) and rapid eye movement (REM) sleep. During the first year of life, NREM and REM sleep are equally distributed across the nocturnal sleep period. After the first year, NREM sleep is most prominent during the first third to first half of the sleep period and REM sleep during the last third to last half of the sleep period. N1 sleep is considered transitional, and arousal from this state is easiest. Arousal thresholds during N2 and REM sleep are similar. N3 sleep is the deepest stage of sleep, with characteristic slow waves on a polysomnogram, and has the highest arousal threshold. Dreaming occurs during REM sleep. Muscle tone is at its nadir during REM sleep. Sixty-minute NREM/REM cycles are seen in infants and toddlers, extending to a mature 90-minute NREM/REM cycling between 2 and 5 years of age.
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      After each state change, brief (<1 minute) waking is normal, and most healthy children quickly fall back asleep.

      Sleep patterns in patients with AD

      Multiple studies using actigraphy and polysomnography have documented that children with severe AD have decreased sleep efficiency (defined as actual sleep time divided by the total polysomnogram recording time).
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      Resting energy expenditure, oxygen consumption and carbon dioxide production during sleep in children with atopic dermatitis.
      Children with AD also have frequent nighttime awakenings, greater difficulty falling asleep, and greater difficulty awakening for school.
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      • Lupo M.
      Sleep disturbances in children with atopic dermatitis.
      Because currently available tools to assess parental and patient reports of sleep disruption and itching correlate poorly with objective measures, objective studies are critical for the assessment of sleep disturbances in children with AD.
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      Sleep-wake disorders and dermatology.

       Polysomnography

      AD scratching is generally highest in transitional sleep (N1 and N2) compared with N3 sleep (N1: 0.46 ± 0.4 scratches/min)
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      ; however, the length of scratching episodes is the same throughout the sleep stage.
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      Although one earlier study contradicts the increased frequency of movements during stage 1 and 2 sleep,
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      Sleep, scratching and dreams in eczema. A new approach to alexithymia.
      children with AD generally have greater sleep disturbance during the first half of the night, resulting in decreased NREM but not REM sleep compared with control subjects.
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      Atopic dermatitis, melatonin, and sleep disturbance.
      The significantly higher arousals and awakenings in patients with AD might only be related to scratching in part because only 15% of patients with AD had arousals related to objective scratching.
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      Awakenings as a result of scratching can be brief or long,
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      and many children with AD have a comorbid diagnosis of restless leg syndrome apparently secondary to itch-induced movements.
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      Increased frequency of restless legs syndrome in atopic dermatitis.
      Restless leg syndrome is diagnosed clinically as an unrelenting urge at night and before sleep onset to move the legs.
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      Principles and practices of pediatric sleep medicine.
      Children with AD are also often given a diagnosis of periodic leg movement disorder,
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      Eczema: a diagnostic consideration for persistent nocturnal arousals.
      which is defined by the presence of repetitive limb movements that, in contrast to restless leg syndrome, only occur during sleep and not before sleep onset.

       Actigraphy

      Several studies have demonstrated that actigraphy is the preferred method of assessing sleep in children with AD because it reflects the home environment, is easy to use, is cost effective, and assesses the most common parameters of sleep affected in patients with AD (ie, sleep disruption secondary to nocturnal awakenings and scratching).
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      Measure of atopic dermatitis disease severity using actigraphy.
      Although parameters on actigraphy are not scored in a standard manner between research studies, in general, AD disease severity positively correlates with sleep disturbances by using the Wake After Sleep Onset (WASO) score,
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      Measure of atopic dermatitis disease severity using actigraphy.
      sleep onset latency, sleep fragmentation, time in bed, and sleep efficiency.
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      Atopic dermatitis, melatonin, and sleep disturbance.
      Actigraphy results correlate with itch and quality of life, and actigraphy is able to discriminate movement during sleep, number of awakenings, minutes asleep, and minutes awake.
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      Actigraphy assessment of sleep disturbance in patients with atopic dermatitis: an objective life quality measure.
      Actigraphy presents more accurate information about sleep fragmentation than self-reporting and strongly correlates with nocturnal scratch behavior when assessed with an infrared video camera. Patients with severe AD demonstrate a mean total scratch time of approximately 15% of the night.
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      Furthermore, nocturnal scratch behavior assessed by actigraphy correlates with pruritus and AD severity.
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      Mechanisms of sleep disturbance in patients with AD

      More information on mechanisms of sleep disturbance in patients with AD can be found in Fig 1. Despite the widespread prevalence of sleep disruption in children with AD, the mechanism of this disruption is poorly understood. Given the robust literature on sleep deprivation inducing T cell–derived inflammation,
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      Inflammatory pathways in children with insufficient or disordered sleep.
      the relative contributions of the natural circadian rhythm of immune cells, AD-induced inflammation, and further T cell–mediated inflammation from AD-induced sleep deprivation all need to be considered in understanding sleep disturbance in patients with AD.

       Inflammatory cytokines and T cells

      Inflammatory cytokines, such as IL-6, have long been associated with sleep disturbance in multiple disease conditions
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      and might have the potential to drive sleep disturbance in patients with AD. Nocturnal itching might also correlate with mobilized T cells, as stimulated by nocturnal peaks in IL-2.
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      Circadian secretions of IL-2, IL-12, IL-6 and IL-10 in relation to the light/dark rhythm of the pineal hormone melatonin in healthy humans.
      A pilot study in patients with AD performed by Bender et al
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      Disease severity, scratching, and sleep quality in patients with atopic dermatitis.
      measured plasma IL-6, IL-10, and TNF-α levels and noted that higher daytime and nighttime values of IL-6 were correlated with poor sleep efficiency.
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      Disease severity, scratching, and sleep quality in patients with atopic dermatitis.
      In general, IL-1–mediated inflammation is increased at night, with less diurnal variation to IL-10.
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      The chronobiology of human cytokine production.
      In addition, T cells consistently were upregulated at night, including natural regulatory T cells, which have optimal suppressive function at 2 am. However, sleep deprivation abrogates the diurnal rhythm of regulatory T-cell activity.
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      Sleep-dependent activity of T cells and regulatory T cells.
      Chang et al argue that increased TH2 versus TH1 inflammation is associated with sleep disturbance based on the correlation of elevated morning levels of total IgE, dust mite–specific IgE, and staphylococcal toxin (staphylococcal enterotoxin B or A)–specific IgE with pruritus and increased WASO scores in patients with AD.
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      Atopic dermatitis, melatonin, and sleep disturbance.
      Morning blood plasma levels of IL-31 (but not IL-4, IL-10, IL-6, or IL-1β) correlated with sleep disturbance, specifically in N1 sleep. Other studies have found that circulating levels of IL-31 and CCL18/pulmonary and activation-regulated chemokine correlate with sleep loss but not pruritus.
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      IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis.
      • Hon K.L.
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      • Ng P.C.
      • Leung T.F.
      Exploring CCL18, eczema severity and atopy.
      Although actigraphic studies correlate nocturnal eczema with increased plasma levels of AD-associated chemokines (cutaneous T cell–attracting chemokine, macrophage-derived chemokine, and thymus and activation-regulated chemokine), self-reports of pruritus/sleep loss do not correlate with increases in levels of these chemokines.
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      Nocturnal wrist movements are correlated with objective clinical scores and plasma chemokine levels in children with atopic dermatitis.
      This discrepancy likely reflects the poor screening tools available to assess self-reported pediatric pruritus and sleep loss.

       Sensitivity to sensory stimulation

      Heightened sensitivity to sensory stimulation is not uncommon in patients with AD,
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      Sensory processing patterns of adults with atopic dermatitis.
      possibly reflecting nerve fiber dysfunction,
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      Innovative neurophysiological methods in itch research: long-latency evoked potentials after electrical and thermal stimulation in patients with atopic dermatitis.
      and might influence nocturnal arousals and disrupted sleep. However, the mechanism underlying this heightened sensitivity is not clear; theories include eosinophilic inflammation increasing the number of sensory neuron receptors, as measured by in vitro neurite branching and upregulation of eosinophil chemotactic factors on neurons,
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      Eosinophils increase neuron branching in human and murine skin and in vitro.
      with mixed data on diurnal signaling of nerve growth factor (neurotrophin) as a contributor to scratching in patients with AD.
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      The role of neurotrophins in inflammation and allergy.
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      • et al.
      A study of serum concentrations and dermal levels of NGF in atopic dermatitis and healthy subjects.
      Key questions remain about the role of different T-cell subsets, monocytes, eosinophils, and other inflammatory mediators in AD-related sleep disturbance.

      Circadian rhythms in skin

      Skin (eg, keratinocytes, fibroblasts, and hair follicle cells) and resident skin immune cells have an active circadian clock, which is also under the influence of the central circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus.
      • Geyfman M.
      • Andersen B.
      How the skin can tell time.
      The circadian clock refers to molecular machinery (eg, the core clock genes circadian locomotor output cycles kaput [CLOCK], brain and muscle ARNT-like [BMAL], period [PER], rev-erb/nuclear receptor subfamily 1, group D [NRlD], and cryptochrome [CRY]) that maintains a self-sustaining rhythm through autoregulatory feedback loops in which oscillating gene products regulate their own expression.
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      • Zee P.C.
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      Circadian clocks: tips from the tip of the iceberg.
      This clock machinery operates in almost all skin cells and influences the regulation of several phenomena, including cell-cycle regulation and proliferation.
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      • Andersen B.
      How the skin can tell time.
      Studies in keratinocyte cultures demonstrate the 24 rhythms of oscillating gene products that direct epidermal physiology, such as Krüppel-like factor.
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      • et al.
      Kruppel-like factor 9 is a circadian transcription factor in human epidermis that controls proliferation of keratinocytes.
      These products are influenced by stimuli, such as dexamethasone and temperature change, that induce a molecular response by clock genes.
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      A circadian clock in HaCaT keratinocytes.
      With regard to skin hydration, mice deficient in the core CLOCK gene were found to have decreased stratum corneum hydration because of dysfunction of aquaporins, particularly aquaporin-3, a membrane transporter of water and glycerol
      • Hara-Chikuma M.
      • Verkman A.S.
      Roles of aquaporin-3 in the epidermis.
      ; CLOCK/BMAL-1 in human keratinocytes similarly directs the function of aquaporin-3.
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      24-hour rhythm of aquaporin-3 function in the epidermis is regulated by molecular clocks.
      Beyond molecular changes, basic skin physiology with regard to skin temperature, pH, and TEWL varies in a circadian manner,
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      • Tschachler E.
      Analysis of circadian and ultradian rhythms of skin surface properties of face and forearm of healthy women.
      with the worst barrier function and greatest TEWL at night. Circadian timing mechanisms are sensitive to day length and temperature, and skin diseases, such as AD, can change with seasonal changes in day length.
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      Skin mast cell responses also have circadian rhythm and might contribute to timing of AD flares.
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      Circadian regulation of allergic reactions by the mast cell clock in mice.
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      Circadian rhythm in patients with AD

      Few studies have explored circadian rhythm in human patients with AD. Most studies evaluate biomarkers of central circadian rhythm (melatonin or cortisol), but none has assessed peripheral circadian function. With regard to central circadian rhythm, total melatonin levels are increased,
      • Chang Y.S.
      • Chou Y.T.
      • Lee J.H.
      • Lee P.t.
      • Dai Y.S.
      • Sun C.
      • et al.
      Atopic dermatitis, melatonin, and sleep disturbance.
      with suppressed cortisol and adrenocorticotropic hormone in some patients with AD,
      • Rupprecht M.
      • Hornstein O.P.
      • Schluter D.
      • Schafers H.J.
      • Koch H.U.
      • Beck G.
      • et al.
      Cortisol, corticotropin, and beta-endorphin responses to corticotropin-releasing hormone in patients with atopic eczema.
      and natural rhythmic secretion of melatonin might be diminished.
      • Schwarz W.
      • Birau N.
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      • Meyer C.
      • et al.
      Alterations of melatonin secretion in atopic eczema.
      Heubeck et al
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      • Hornstein O.P.
      [Are shifts in circadian cortisol rhythm an endocrine symptom of atopic eczema?].
      noted shifts in cortisol peaks/troughs in patients with AD compared with those in control subjects in addition to altered levels and rhythmicity, suggesting circadian misalignment.
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      • Schonberger A.
      • Hornstein O.P.
      [Are shifts in circadian cortisol rhythm an endocrine symptom of atopic eczema?].
      The effect of AD treatment on this circadian disruption has not been well studied, but resolution of cortisol suppression was noted in one small treatment study.
      • Fukuda H.
      • Suzuki T.
      • Saotome A.
      • Sode E.
      • Mukai H.
      Efficacy of inpatient treatment for atopic dermatitis evaluated by changes in serum cortisol levels.
      Further work is needed to clarify how peripheral circadian rhythms contribute to AD and how treatment of AD might influence central and peripheral rhythms.

      Effect of sleep disturbances on daily function and health in patients with AD

      Disrupted sleep caused by AD has also been linked with behavioral and discipline problems,
      • Dahl R.E.
      • Bernhisel-Broadbent J.
      • Scanlon-Holdford S.
      • Sampson H.A.
      • Lupo M.
      Sleep disturbances in children with atopic dermatitis.
      as well as poor performance in daytime activities, specifically school performance.
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      • Doyle J.J.
      • Jackson A.
      Perceptions of physicians and pediatric patients about atopic dermatitis, its impact, and its treatment.
      Although AD has been associated with attention deficit hyperactivity disorder in children, the association only occurs in children with sleep problems (odds ratio, 2.67; 95% CI, 1.51-4.71; P = .001; n = 1112) and not in children with AD without sleeping issues (odds ratio, 1.24; 95% CI, 0.83-1.84; P = .30; n = 5796).
      • Romanos M.
      • Gerlach M.
      • Warnke A.
      • Schmitt J.
      Association of attention-deficit/hyperactivity disorder and atopic eczema modified by sleep disturbance in a large population-based sample.
      Children with AD, when compared with control subjects, had worse sleep on polysomnograms; demonstrated neurocognitive defects in verbal comprehension, perceptual reasoning, and working memory; and scored 16 points lower on the composite IQ exam.
      • Camfferman D.
      • Kennedy J.D.
      • Gold M.
      • Martin A.J.
      • Lushington K.
      Eczema and sleep and its relationship to daytime functioning in children.
      Recent studies have also linked sleep disturbance in patients with AD to obesity and hypertension in children
      • Silverberg J.I.
      • Becker L.
      • Kwasny M.
      • Menter A.
      • Cordoro K.M.
      • Paller A.S.
      Central obesity and high blood pressure in pediatric patients with atopic dermatitis.
      and in adults to impaired overall health.
      • Silverberg J.I.
      • Garg N.K.
      • Paller A.S.
      • Fishbein A.B.
      • Zee P.C.
      Sleep disturbances in adults with eczema are associated with impaired overall health: a US population-based study.
      Importantly, adults with AD who had fatigue/sleepiness were more likely to have fracture and bone or joint injuries compared with healthy adults with an equal level of fatigue/sleepiness.
      • Garg N.
      • Silverberg J.I.
      Association between eczema and increased fracture and bone or joint injury in adults: a US population-based study.

      Treatment of sleep disturbance in patients with AD

      As recommended in guidelines,
      • Eichenfield L.F.
      • Tom W.L.
      • Chamlin S.L.
      • Feldman S.R.
      • Hanifin J.M.
      • Simpson E.L.
      • et al.
      Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis.
      • Schneider L.
      • Tilles S.
      • Lio P.
      • Boguniewicz M
      • Beck L
      • LeBovidge J
      • et al.
      Atopic dermatitis: a practice parameter update 2012.
      treatment of AD should focus on disease control, with sleep disturbance as an important measure of control. Several studies demonstrate that topical steroids can improve sleep disturbance, likely related to overall disease control.
      • Sugarman J.L.
      • Parish L.C.
      Efficacy of a lipid-based barrier repair formulation in moderate-to-severe pediatric atopic dermatitis.
      • Doss N.
      • Kamoun M.R.
      • Dubertret L.
      • Cambazard F.
      • Remitz A.
      • Lahfa M.
      • et al.
      Efficacy of tacrolimus 0.03% ointment as second-line treatment for children with moderate-to-severe atopic dermatitis: evidence from a randomized, double-blind non-inferiority trial vs. fluticasone 0.005% ointment.
      • Blume-Peytavi U.
      • Metz M.
      Atopic dermatitis in children: management of pruritus.
      In children in whom sleep disturbance persists, despite adequate disease control and a trial of sedating oral antihistamines, other treatments should be considered. Evaluation of comorbid sleep-disordered breathing, such as pediatric obstructive sleep apnea, asthma, or allergic rhinitis, as well as the effects of medications used to manage these disorders, should be conducted. Assessment of other sleep disturbances commonly seen in patients with AD, such as restless leg syndrome/periodic limb movement disease or pediatric insomnia with difficulty in maintaining sleep or falling asleep should be performed. In addition, sleep hygiene should be evaluated, and a personalized treatment plan should be made. Referral to a pediatric sleep medicine specialist is indicated for in-depth assessment of persistent sleep disturbances in patients with AD and optimization of treatment.

       Nonpharmacologic approaches

      Nonpharmacologic approaches should target both improvement of disease overall (eg, with aggressive nocturnal moisturization, wet wrap therapy, and textile choices) and improved sleep hygiene. Specifically, wet wrap therapy can be performed with wet gauze or simply by wearing wet cotton pajamas and can improve sleep. This maintains skin hydration and can suppress inflammation, decrease pruritus, and provide a physical barrier to prevent further damage to the skin from scratching.
      • Boguniewicz M.
      • Nicol N.
      • Kelsay K.
      • Leung D.Y.
      A multidisciplinary approach to evaluation and treatment of atopic dermatitis.
      • Oranje A.P.
      • Devillers A.C.
      • Kunz B.
      • Jones S.L.
      • DeRaeve L.
      • Van Gysel D.
      • et al.
      Treatment of patients with atopic dermatitis using wet-wrap dressings with diluted steroids and/or emollients. An expert panel's opinion and review of the literature.
      • Paller A.S.
      • Simpson E.L.
      • Eichenfield L.F.
      • Ellis C.N.
      • Mancini A.J.
      Treatment strategies for atopic dermatitis: optimizing the available therapeutic options.
      Cosleeping with parents is common in children with AD
      • Chamlin S.L.
      • Mattson C.L.
      • Frieden I.J.
      • Williiams M.L.
      • Mancini A.J.
      • Cella D.
      • et al.
      The price of pruritus: sleep disturbance and cosleeping in atopic dermatitis.
      and is often reported as a reason for poor sleep. Counseling families to avoid cosleeping can improve parental and child sleep because parental presence (eg, lying down with a child) is a predictor of nighttime awakenings, even in healthy children.
      • Sadeh A.
      • Mindell J.A.
      • Luedtke K.
      • Wiegand B.
      Sleep and sleep ecology in the first 3 years: a web-based study.
      General sleep hygiene recommendations can focus on developing positive and consistent bedtime routines. Although limited to self-reported sleep outcomes, a recent Cochrane review suggested no improvement in sleep of children with AD after currently tested psychological and educational interventions.
      • Ersser S.J.
      • Cowdell F.
      • Latter S.
      • Gardiner E.
      • Flohr C.
      • Thompson A.R.
      • et al.
      Psychological and educational interventions for atopic eczema in children.
      However, sleep-directed behavioral therapies have not been assessed in improving AD, and further research is needed.

       Antihistamines

      Antihistamines are often first-line therapy in treating sleep disturbance in children with eczema. However, there are limited data to support this practice.
      • Kelsay K.
      Management of sleep disturbance associated with atopic dermatitis.
      At best, sedating antihistamines improve global sleep assessments in 26% of children with eczema.
      • Korossy S.
      • Doroszlay J.
      • Munkacsi A.
      • Domotor A.
      Evaluation of peritol in the management of allergic diseases of the skin.
      Another study, which evaluated a general population of 50 children, including 7 children with AD, suggested that sleep latency (time to fall asleep) and numbers of nocturnal awakenings were decreased with diphenhydramine compared with placebo.
      • Russo R.M.
      • Gururaj V.J.
      • Allen J.E.
      The effectiveness of diphenhydramine HCI in pediatric sleep disorders.
      However, a more recent study of healthy children found that nighttime awakenings were not decreased by administration of diphenhydramine.
      • Merenstein D.
      • Diener-West M.
      • Halbower A.C.
      • Krist A.
      • Rubin H.R.
      The trial of infant response to diphenhydramine: the TIRED study—a randomized, controlled, patient-oriented trial.
      It is important to recognize that children can develop tolerance to sedating properties of antihistamines, despite the persistence of antimuscarinic and anticholinergic side effects. Antihistamines have not been demonstrated to improve pruritus in randomized controlled trials,
      • Klein P.A.
      • Clark R.A.
      An evidence-based review of the efficacy of antihistamines in relieving pruritus in atopic dermatitis.
      suggesting improvement in nocturnal symptoms is most likely due to the sedative effect.
      • Darsow U.
      • Lubbe J.
      • Taieb A.
      • Seidenari S.
      • Wollenberg A.
      • Calza A.M.
      • et al.
      Position paper on diagnosis and treatment of atopic dermatitis.
      • Hanifin J.M.
      • Cooper K.D.
      • Ho V.C.
      • Kang S.
      • Krafchik B.R.
      • Margolis D.J.
      • et al.
      Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines.”.
      Although these data suggest a minimal effect of antihistamines on sleep architecture and daytime functioning, further research is needed.
      • Zisapel N.
      Drugs for insomnia.
      Doxepin, which has high histamine H1 receptor antagonist activity and sedative effects (as well as antidepressant effects at higher doses) might reduce pruritus.
      • Kelsay K.
      Management of sleep disturbance associated with atopic dermatitis.
      • Hanifin J.M.
      The role of antihistamines in atopic dermatitis.
      However, a small study in adults with AD (n = 12) found that tricyclic antidepressants decrease sleep latency and WASO scores but do not reduce pruritus.
      • Savin J.A.
      • Paterson W.D.
      • Adam K.
      • Oswald I.
      Effects of trimeprazine and trimipramine on nocturnal scratching in patients with atopic eczema.
      In children, the initial dose of 10 mg nightly can be titrated to reach the desired effect. As with oral antihistamines, the sedating effects of tricyclic antidepressants have not been clearly separated from the antipruritic effects.

       Other pharmacotherapy

      Benzodiazepines are used in sleep therapy because they induce hypnotic effects with shortened sleep-onset latency and increased total sleep time. However, they can disrupt sleep architecture and be addictive.
      • Sheldon S.H.
      • Kryger M.
      • Ferber R.
      • Gozal D.
      Principles and practices of pediatric sleep medicine.
      In a small placebo-controlled study in adults with AD (n = 10), nitrazepam did not decrease nocturnal scratch time.
      • Ebata T.
      • Izumi H.
      • Aizawa H.
      • Kamide R.
      • Niimura M.
      Effects of nitrazepam on nocturnal scratching in adults with atopic dermatitis: a double-blind placebo-controlled crossover study.
      In children with comorbid attention deficit hyperactivity disorder, clonidine could be effective, but REM sleep suppression and tolerance to sedative effects can develop.
      • Genois A.
      • Haig M.
      • Des Roches A.
      • Sirard A.
      • Le May S.
      • McCuaig C.C.
      Case report of atopic dermatitis with refractory pruritus markedly improved with the novel use of clonidine and trimeprazine.
      Although previously suggested as a treatment for sleep disturbance in patients with AD,
      • Kelsay K.
      Management of sleep disturbance associated with atopic dermatitis.
      chloral hydrate has been discontinued in the United States. Given its risk for hepatotoxicity and respiratory depression, chloral hydrate use should be avoided.
      Leukotriene receptor antagonists are frequently used in patients with sleep-disordered breathing
      • Goldbart A.D.
      • Goldman J.L.
      • Veling M.C.
      • Gozal D.
      Leukotriene modifier therapy for mild sleep-disordered breathing in children.
      to treat increases in levels of airway cysteinyl leukotreines.
      • Goldbart A.D.
      • Krishna J.
      • Li R.C.
      • Serpero L.D.
      • Gozal D.
      Inflammatory mediators in exhaled breath condensate of children with obstructive sleep apnea syndrome.
      One study of montelukast in children with AD (n = 25) demonstrated decreased self-reported sleep disturbance
      • Ehlayel M.S.
      • Bener A.
      • Sabbah A.
      Montelukast treatment in children with moderately severe atopic dermatitis.
      ; however, further research is needed to clarify whether this benefit was related to improvement in sleep-disordered breathing.

       Melatonin

      Based on a 2002 study suggesting that melatonin might induce inflammation in a PBMC stimulation model of nocturnal asthma,
      • Sutherland E.R.
      • Martin R.J.
      • Ellison M.C.
      • Kraft M.
      Immunomodulatory effects of melatonin in asthma.
      melatonin has not been widely used in atopic children. However, recent analyses suggest that melatonin might benefit some children with AD and asthma.
      • Marseglia L.
      • D'Angelo G.
      • Manti S.
      • Salpietro C.
      • Arrigo T.
      • Barberi I.
      • et al.
      Melatonin and atopy: role in atopic dermatitis and asthma.
      The effect of melatonin on sleep promotion has been extensively studied, and melatonin is noted to have a small but statistically significant effect on sleep onset, duration, and efficiency.
      • Kelsay K.
      Management of sleep disturbance associated with atopic dermatitis.
      Dosing of melatonin can also change its effect, with 0.5 mg 3 to 4 hours before bedtime used to advance bedtime, and higher dosing (1 mg in infants, 2.5-3 mg in older children, and 5 mg in adolescence) 30 minutes before bed given for a sedating effect.
      • Sanchez-Barcelo E.J.
      • Mediavilla M.D.
      • Reiter R.J.
      Clinical uses of melatonin in pediatrics.

       Light therapy

      Bright-light therapy is a mainstay of delayed or advanced-phase sleep disorders but has not been evaluated in patients with AD. Bright-light therapy can be prescribed as natural (outdoor) light exposure or delivered as a light box (white or blue light) at approximately 10,000 lux 1 foot from a patient. It is used at specifically timed intervals to advance or delay bedtime. Further evaluation by a sleep specialist of the sleep patterns and circadian chronotypes of individual patients with AD might make this a feasible option. Although UV phototherapy has been effective in the treatment of AD, it has not been studied as a sleep therapy. Visible-range light therapy, such as blue-spectrum light therapy, in one study of 36 adults with AD was administered with a photonic irradiation system to the whole body for 24 minutes daily for 5 day cycles and repeated 2 or 3 times. It was shown to improve sleep quality by the end of 15 days and result in even further sleep improvement at 3 and 6 months after treatment.
      • Becker D.
      • Langer E.
      • Seemann M.
      • Seemann G.
      • Fell I.
      • Saloga J.
      • et al.
      Clinical efficacy of blue light full body irradiation as treatment option for severe atopic dermatitis.
      High cost and feasibility challenges make this a less desirable therapeutic option.

       Chronotherapy

      Despite the clear clinically noted diurnal variation in AD, chronotherapy, as defined by specifically timed pharmacologic treatment (eg, only at night), has not been well studied or systematically attempted. In patients with other atopic diseases, such as nocturnal asthma, chronotherapy is effective and regularly practiced.
      • Schleimer R.P.
      Interactions between the hypothalamic-pituitary-adrenal axis and allergic inflammation.
      • Kraft M.
      • Beam W.R.
      • Wenzel S.E.
      • Zamora M.R.
      • O'Brien R.F.
      • Martin R.J.
      Blood and bronchoalveolar lavage endothelin-1 levels in nocturnal asthma.
      Nocturnal inflammation is more effectively suppressed by evening administration of oral steroids and leukotriene receptor antagonists.
      • Durrington H.J.
      • Farrow S.N.
      • Loudon A.S.
      • Ray D.W.
      The circadian clock and asthma.
      • Kraft M.
      Corticosteroids and leukotrienes: chronobiology and chronotherapy.
      A better mechanistic understanding of circadian rhythms in patients with AD could help direct chronotherapy in patients with AD.

      Future directions

      Sleep disturbance occurs in the majority of children with AD, and the resultant neurocognitive effects are concerning.
      • Chamlin S.L.
      • Mattson C.L.
      • Frieden I.J.
      • Williiams M.L.
      • Mancini A.J.
      • Cella D.
      • et al.
      The price of pruritus: sleep disturbance and cosleeping in atopic dermatitis.
      Our understanding of the underlying mechanism of the nocturnal predominance of this disease is poor, and few treatments effectively improve sleep in these patients. As discussed in this review, the majority of patients with AD have overall poor sleep efficiency and frequent sleep disturbances, possibly caused by multiple factors, as outlined in Fig 1 (eg, peripheral and central circadian elements, increased inflammation, increased susceptibility and exposure to allergens, and bacteria). The detrimental effects of sleep disturbances in pediatric patients with AD emphasize the importance of early recognition and treatment of sleep disruption. However, consistent methods of evaluation, such as standardized actigraphic scoring, are necessary to compare outcomes between studies.
      Exploring epidemiology and characterizing sleep patterns is an important first step to understanding the relationship between sleep and AD. The existing epidemiologic understanding of sleep in patients with AD is limited because sleep outcomes in cohort studies have not included objective sleep measures and, at best, include 1 nonspecific question related to sleep in the Children's Dermatology Life Quality Index.
      • Lewis-Jones M.S.
      • Finlay A.Y.
      The Children's Dermatology Life Quality Index (CDLQI): initial validation and practical use.
      • Dertlioglu S.B.
      • Cicek D.
      • Balci D.D.
      • Halisdemir N.
      Dermatology life quality index scores in children with vitiligo: comparison with atopic dermatitis and healthy control subjects.
      A standardized patient-centered outcome tool that could provide an in-depth assessment of sleep and sleep-related impairment in children with AD correlated with objective sleep measures is necessary. This tool would allow us to understand the effect of nocturnal eczema on sleep and would inform diagnostic algorithms to better personalize treatment. In addition, improved characterization of sleep architecture in children with AD and their circadian rhythms could lead to novel treatment paradigms.
      Genetic studies of AD, as it relates to sleep and circadian rhythm, have not been performed. Mutations in the filaggrin gene have been linked to an increased risk of AD.
      • Carson C.G.
      Risk factors for developing atopic dermatitis.
      However, there are limited data on whether these mutations are associated with the presence and severity of sleep disruption in patients with AD. Other known risk factors for AD, such as genetics, common environmental triggers, and extreme temperatures, could be analyzed to see whether they predict sleep disruption or severity in patients with AD.
      Given that approximately 10% of genes are under circadian control,
      • Scheiermann C.
      • Kunisaki Y.
      • Frenette P.S.
      Circadian control of the immune system.
      • Storch K.F.
      • Lipan O.
      • Leykin I.
      • Viswanathan N.
      • Davis F.C.
      • Wong W.H.
      • et al.
      Extensive and divergent circadian gene expression in liver and heart.
      exploring central and peripheral circadian biomarkers can begin to provide clues into the complicated mechanism of nocturnal eczema. This could offer a novel treatment paradigm to this disease. Borrowing from models and studies in nocturnal asthma and circadian research on other skin diseases
      • Kumar V.
      • Andersen B.
      • Takahashi J.S.
      Epidermal stem cells ride the circadian wave.
      will be crucial to uncovering the influence of sleep and circadian rhythms on AD.

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