MRI assessment of brain tissue injury after hypothermia in neonates with hypoxic–ischaemic encephalopathy

Hypoxic–ischaemic encephalopathy after perinatal asphyxia is an important cause of mortality and morbidity. It accounts for about 20% of occurrences of cerebral palsy in childhood and is associated to other important neurodevelopmental sequelae.
In the Total Body Hypothermia for Neonatal Encephalopathy (TOBY) trial, infants receiving prolonged moderate hypothermia experienced no significant difference in the primary outcome of death or disability at 18 months, but had a reduced rate of cerebral palsy and improved mental and psychomotor outcomes compared with those allocated to standard care. However, since neurological assessment at 18 months of age is difficult, other signs of the therapeutic efficacy of cooling would further strengthen the evidence base for the treatment of hypoxic–ischaemic encephalopathy. MRI could be the optimum technique to detect perinatally acquired cerebral lesions, and the pattern and severity of the lesions provide a reliable guide to prognosis. To test this hypothesis, the TOBY investigators reviewed the MRI scans obtained during the neonatal period in a nested substudy of the TOBY trial. In particular, they evaluated the association between whole-body cooling and reduction in cerebral lesions seen on MRI that are characteristic of hypoxic–ischaemic encephalopathy and/or later neurodevelopmental impairments. Moreover, they assessed whether cooling would not alter the accuracy of neonatal MRI for predicting neurological outcome at 18 months of age.
In total, 325 infants were recruited in the TOBY trial between 2002 and 2006; images were available for analysis for 131 of them. Therapeutic hypothermia was associated with a reduction in lesions in the basal ganglia or thalamus (OR=0.36, 95%CI 0.15–0.84; p=0.02), white matter (0.30, 0.12–0.77; p=0.01), and abnormal posterior limb of the internal capsule (OR=0.38, 95%CI 0.17–0.85; p=0.02). Moreover, cooled infants had fewer scans that were predictive of later neuromotor abnormalities (OR=0.41, 95%CI 0.18–0.91; p=0.03) and were more likely to have normal scans (OR=2.81, 95%CI 1.13–6.93; p=0.03) than non-cooled babies. The accuracy of prediction by MRI of death or disability to 18 months of age was 0.84 (95%CI 0.74–0.94) in the cooled group and 0.81 (0.71–0.91) in the non-cooled group.
Overall, these findings show that therapeutic hypothermia is associated with less grey and white matter abnormalities, and more cooled than non-cooled infants had normal MRI scans. Of note, the clinical characteristics of the study infants were not different from the general population included in the TOBY trial. This fact further strengthens the validity of the results and the efficacy of therapeutic hypothermia in the therapy of hypoxic–ischaemic encephalopathy. Moreover, the accuracy of MRI done during the neonatal period for the prediction of neurological outcomes up to 18 months of age was unaltered by therapeutic hypothermia. Therefore, MRI in the neonatal period is a qualified biomarker of hypoxic–ischaemic encephalopathy and treatment response; this technique might be of use in other neuroprotective studies.

Top