Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE): a prospective multicountry study

Abstract

IntroductionDespite cooling, adverse outcomes are seen in up to half of the surviving infants after neonatal encephalopathy. A number of novel adjunct drug therapies with cooling have been shown to be highly neuroprotective in animal studies, and are currently awaiting clinical translation. Rigorous evaluation of these therapies in phase II trials using surrogate MR biomarkers may speed up their bench to bedside translation. A recent systematic review of single-centre studies has suggested that MR spectroscopy biomarkers offer the best promise; however, the prognostic accuracy of these biomarkers in cooled encephalopathic babies in a multicentre setting using different MR scan makers is not known.Methods and analysisThe MR scanners (3 T; Philips, Siemens, GE) in all the participating sites will be harmonised using phantom experiments and healthy adult volunteers before the start of the study. We will then recruit 180 encephalopathic infants treated with whole body cooling from the participating centres. MRI and spectroscopy will be performed within 2 weeks of birth. Neurodevelopmental outcomes will be assessed at 18–24 months of age. Agreement between MR cerebral biomarkers and neurodevelopmental outcome will be reported. The sample size is calculated using the ‘rule of 10’, generally used to calculate the sample size requirements for developing prognostic models. Considering 9 parameters, we require 9×10 adverse events, which suggest that a total sample size of 180 is required.Ethics and disseminationHuman Research Ethics Committee approvals have been received from Brent Research Ethics Committee (London), and from Imperial College London (Sponsor). We will submit the results of the study to relevant journals and offer national and international presentations.Trial registration numberClinical Trials.gov Number: NCT01309711.

Does Magnetic Resonance Brain Scanning at 3.0 Tesla Pose a Hyperthermic Challenge to Term Neonates?

“…[6] All had previously received therapeutic hypothermia for 72 hours for suspected hypoxic-ischemic encephalopathy.…”

“…[6] In brief, the sequences comprised T1-weighted brain volume imaging, T2-weighted fast spin echo, diffusion-weighted imaging, T2 susceptibility-weighted imaging, T1 and T2 fluid-attenuated inversion recovery, and single-voxel point-resolved spectroscopy of the left thalamus. Table 1 (online) provides full technical details of sequence parameters.…”

Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy

“…We retrospectively identified all babies with mild encephalopathy who were cooled as part of clinical care and who had premature cessation of cooling due to clinical improvement,2 from the study database of the Magnetic Resonance Biomarkers in Neonatal Encephalopathy (MARBLE) study. All recruited babies had: (A) their encephalopathy grade assessed before 6 hours of age using a previously validated neurological examination3; (B) MRI and single voxel thalamic proton spectroscopy (3 Tesla) between 4 and 14 days after birth; and (A) a detailed neurological examination at 2 years of age using Bayley-III2or British Association of Perinatal Medicine (BAPM)/Royal College of Paediatrics and Child Health (RCPCH) working group classification, if Bayley-III was not available 4…”

“…All recruited babies had: (A) their encephalopathy grade assessed before 6 hours of age using a previously validated neurological examination3; (B) MRI and single voxel thalamic proton spectroscopy (3 Tesla) between 4 and 14 days after birth; and (A) a detailed neurological examination at 2 years of age using Bayley-III2or British Association of Perinatal Medicine (BAPM)/Royal College of Paediatrics and Child Health (RCPCH) working group classification, if Bayley-III was not available 4…”

Hydro-Mechanical Neonatal Encephalopathy (HNE): An Alternative Hypothesis

“…The terms Perinatal Asphyxia, Neonatal Asphyxia, Birth Asphyxia, Neonatal Encephalopathy, Hypoxic-ischemic Encephalopathy, all relate to the clinical observation [1] that fetuses that have apparently progressed normally may develop profound hypoxic injury during and following the birth process. This causes death or disability in 2-3 per 1000 cases and accounts for about 20% of all cases of cerebral palsy.…”