54 Chapter 2 DISCUSSION Overall, evidence regarding risk factors for steroid-induced APRs and sleep problems in children with ALL is low, studies are scarce and the quality of summated evidence is low to very low. Therefore, the current summary should be interpreted with caution. Nevertheless, acquired data suggest that sex, type of steroid and (cumulative) steroid dose are no clear risk factors for steroid-induced APRs. A younger age (0-6 years old) seems to be a risk factor for behavioral problems. Older age seems more a risk factor for sleep problems. Sex does not seem a risk factor for overall sleep disturbance, but might be for specific sleep parameters. Steroid dose and type appear the be a risk factor for steroidinduced sleep problems, although these findings are only based on one patient cohort. We did not find any studies which analyzed parental stress/coping or medical or sleep history as risk factor for APRs/sleep problems. Genetic susceptibility associations are weak and not replicated, therefore no conclusions can be drawn. Overall, more high quality evidence and replication studies are needed to confirm our identified findings. In this review, APRs and sleep were evaluated as two independent phenomena. Indeed, both are usually described separately in literature. However, sleep problems can also be either an effect of or a trigger for APRs.14 The exact mechanism of how behavior and sleep are impacted by steroids is unknown but is thought to be caused by their effect on the glucocorticoid receptor and by their disruptive nature on the diurnal rhythm of the hypothalamic-pituitary-adrenal (HPA-) axis, and to suppression of endogenous cortisol production.59 Cortisol has a high affinity for the mineralocorticoid receptor (MR) in the brain, whereas exogenous steroids such as dexamethasone have a higher affinity for the glucocorticoid receptor (GR).60 In patients treated with steroids, the hypothesis is that the GR in the brain is stimulated, whereas the MR is not activated. This disturbance of GR:MR balance is thought to deregulate the stress-system and enhance vulnerability to stressrelated disorders.60 Furthermore, disruption of the diurnal rhythm at any level of the HPAaxis can disturb the regulation of the sleep-wake rhythm. Cortisol is secreted in a circadian rhythm which has its nadir in the night, important for falling asleep, and a peak when waking up.61 Glucocorticoid replacement therapy has been shown to be permissive for rapid eye movement sleep and sleep consolidation in patients with adrenal insufficiency who experience disturbed sleep phases.62 The heterogeneity of studied APRs and sleep problems makes it difficult to generalize conclusions regarding risk factors. For example, young children seem to be at risk for behavioral problems,25,41,52 whereas older children seem to experience more steroidinduced psychosis.42 These are two different outcomes within the spectrum of APRs, and it is possible that for each APR different risk factors exist. Another explanation is that
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