Prospective MRI Assessment of Early Myelination Over the First Month of Life in Neonates With Neonatal Hypoxic-Ischemic Encephalopathy Treated With Therapeutic Hypothermia With or Without Sildenafil.

BACKGROUND AND PURPOSE: Neonatal hypoxic-ischemic encephalopathy (HIE) remains a leading cause of mortality and long-term morbidities, and therapeutic hypothermia (TH), while the standard of care, is not universally effective. The objective of the study was to use T2* values as a surrogate marker of myelination to characterize early myelination after HIE and explore whether sildenafil, used as an adjunct to TH, is associated with improved myelination.

MATERIAL AND METHODS: This prospective neuroimaging study included neonates with HIE treated with TH; a subset of neonates with MRI-confirmed brain injury received sildenafil in addition to TH. Myelination was assessed using a T2* mapping. T2* values were measured in eight brain regions at three time-points (days 2, 10, and 30). T2* values were compared among neonates without brain injury treated with TH alone (NoBI+TH), neonates with brain injury treated with TH alone (BI+TH), and neonates with brain injury treated with TH plus sildenafil (BI+TH/S).

RESULTS: A total of 167 MRI scans were obtained from 77 neonates: 32 NoBI+TH neonates, 25 BI+TH neonates, and 20 BI+TH/S neonates. On day 2, neonates with brain injury exhibited significantly higher T2* values in the thalamus, posterior limb of the internal capsule [PLIC], anterior white matter [AWM], and anterior corpus callosum [ACC] than the NoBI+TH group. By day 10, elevated T2* values persisted in AWM and ACC in both brain injury groups, and also in PLIC in the BI+TH group. At day 30, T2* values in the BI+TH group remained persistently elevated across these regions, with additional increases in the thalamus, optic radiations [OR], and posterior corpus callosum [PCC]. In contrast, the BI+TH/S group demonstrated significantly lower T2* values in thalamus, PLIC, AWM, OR, ACC, and PCC compared to BI+TH; in several regions (thalamus, PLIC, AWM), T2* values in the BI+TH/S group were no longer different from NoBI+TH.

CONCLUSIONS: T2* values were increased after HIE despite TH, consistent with a possible disruption of early myelination. Sildenafil as an adjunct to TH was associated with lower T2* values over the first month of life, suggesting a potential neurorestorative effect on myelination.