Treatment of children with infantile spasms: A network meta-analysis.

AIM: We performed a systematic review and network meta-analysis (NMA) to obtain comparative effectiveness estimates and rankings of non-surgical interventions used to treat infantile spasms. METHOD: All randomized controlled trials (RCTs) including children 2 months to 3 years of age with infantile spasms (with hypsarrhythmia or hypsarrhythmia variants on electroencephalography) receiving appropriate first-line medical treatment were included. Electroclinical and clinical remissions within 1 month of starting treatment were analyzed. RESULTS: Twenty-two RCTs comparing first-line treatments for infantile spasms were reviewed; of these, 17 were included in the NMA. Both frequentist and Bayesian network rankings for electroclinical remission showed that high dose adrenocorticotropic hormone (ACTH), methylprednisolone, low dose ACTH and magnesium sulfate (MgSO4 ) combination, low dose ACTH, and high dose prednisolone were most likely to be the 'best' interventions, although these were not significantly different from each other. For clinical remission, low dose ACTH/MgSO4 combination, high dose ACTH (with/without vitamin B6 ), high dose prednisolone, and low dose ACTH were 'best'. INTERPRETATION: Treatments including ACTH and high dose prednisolone are more effective in achieving electroclinical and clinical remissions for infantile spasms. WHAT THIS PAPER ADDS: Adrenocorticotropic hormone and high dose prednisolone are more effective than other medications for infantile spasms. Symptomatic etiology decreases the likelihood of remission even after adjusting for treatment lag.

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

OBJECTIVE: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation). METHODS: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth. RESULTS: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections. CONCLUSIONS: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates.

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development.SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.