Steroid-Related Neuropsychiatric Symptoms (SRNS) in Children with Acute Lymphoblastic Leukemia (ALL): A Systematic Review of Clinical Features, Risk Factors, and Management.
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BACKGROUND: Steroid-related neuropsychiatric symptoms (SRNS) constitute clinically significant, yet heterogeneous, adverse effects associated with dexamethasone and prednisolone regimens in the treatment of pediatric acute lymphoblastic leukemia (ALL). These manifestations, ranging from mild mood disturbances to severe psychotic episodes, typically emerge during the induction and intensification phases of chemotherapy. METHODS: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive systematic search was performed across four major databases: PubMed, Scopus, Cochrane Library, and Web of Science, covering records published up to February 25, 2026. The inclusion criteria focused on peer-reviewed clinical trials, cohort studies, and case-control studies examining pediatric ALL patients (aged 0-18 years) treated with glucocorticoids. Study selection and extraction were performed independently, and risk of bias was assessed with tools appropriate to completed randomized and observational studies. RESULTS: Seven studies, comprising a total cohort of 2,745 pediatric patients, were synthesized in this review, one being a trial protocol and six reported clinical outcomes. Heterogeneous definitions and measurements of neuropsychiatric outcomes precluded quantitative pooling. Mild neurobehavioral symptoms were reported in up to 40% of the study population. In one observational cohort, 94 of 1,813 children (5.2%) had clinically significant SRNS; estimates of milder behavioral symptoms varied by instrument and setting. In a 52-patient crossover trial, adjunctive hydrocortisone did not improve the primary neurobehavioral outcome over placebo. Steroid-comparison findings varied by outcome, and evidence for standardized SRNS-specific management remains limited. Severe neuropsychiatric events, affecting approximately 5% of patients, were significantly more frequent with dexamethasone compared to prednisone. The array of clinical neurotoxic symptoms included acute psychosis, agitation, aggression, emotional lability, and insomnia. These manifestations predominantly peaked during the induction (first month) and intensification (fifth and sixth months) phases of treatment, typically lasting between one week and one month. CONCLUSION: Pediatric patients with ALL experiencing SRNS represent a distinct clinical group requiring specialized, multidisciplinary management. Therapeutic interventions should be integrated with existing evidence-based protocols that aim to mitigate steroid-induced toxicities, such as AIEOP ALL BFM 2000, 2009, and 2017 as well as ICiCLe ALL 14. There is an urgent imperative to develop reproducible management pathways, which necessitates the implementation of prospective, multi-institutional data registries to establish robust clinical guidelines and refine risk stratification strategies specifically for steroid-induced neurotoxicity.