Towards faster studies of neonatal encephalopathy
Authors: Alistair J Gunn, Malcolm Battin
Journal: The Lancet Neurology (2018)

Cooling was first suggested for the treatment of brain injuries several millennia ago.1Celcus AC On medicine, volume 1. Books 1–4. Harvard University Press, Cambridge, MA1935Google Scholar There is now compelling evidence that therapeutic hypothermia for moderate to severe neonatal encephalopathy significantly improves survival and reduces disability in infancy.2Jacobs SE Berg M Hunt R Tarnow-Mordi WO Inder TE Davis PG Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2013; 1 (CD003311.)PubMed Google Scholar However, a meta-analysis suggested an absolute reduction in risk of approximately 15%, from 61% to 46%,2Jacobs SE Berg M Hunt R Tarnow-Mordi WO Inder TE Davis PG Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2013; 1 (CD003311.)PubMed Google Scholar meaning that nearly half of infants die or survive with disability despite treatment. A large trial3Shankaran S Laptook AR Pappas A et al.Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial.JAMA. 2017; 318: 57-67Crossref PubMed Scopus (143) Google Scholar has shown that existing protocols for therapeutic hypothermia are very close to optimal. Given that a range of interventions show encouraging neuroprotection in animal studies,4Davidson JO Dean JM Fraser M et al.Perinatal brain injury: mechanisms and therapeutic approaches.Front Biosci (Landmark Ed). 2018; 23: 2204-2226Crossref PubMed Scopus (32) Google Scholar progress is most likely to come from incremental trials of these candidate therapies. Neonatal trials largely use neurodevelopmental follow-up to 18–24 months of age as a measure of outcome. This is appropriate, but substantially prolongs the time needed to complete each study. Biomarkers of outcome could substantially speed up each trial. The best existing biomarker, conventional MRI, measures a biological change that is directly linked to both the injury process and patient outcome. Changes visible in the scans are associated with neurodevelopmental outcomes5Rutherford M Ramenghi LA Edwards AD et al.Assessment of brain tissue injury after moderate hypothermia in neonates with hypoxic-ischaemic encephalopathy: a nested substudy of a randomised controlled trial.Lancet Neurol. 2010; 9: 39-45Summary Full Text Full Text PDF PubMed Scopus (419) Google Scholar but MRI does not perform well enough as the primary outcome of a trial because it can overpredict adverse neurodevelopmental outcome and, conversely, miss some cases of adverse outcome. Magnetic resonance (MR) spectroscopy is also highly predictive in single-centre studies but has not been widely taken up in clinical practice because of differences in calibration between the various models of MR scanners. In The Lancet Neurology, Peter J Lally and colleagues report results of the magnetic resonance biomarkers in neonatal encephalopathy (MARBLE) study,6Lally PJ Montaldo P Oliveira V et al.Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre study.Lancet Neurol. 2018; (published online Nov 14.)http://dx.doi.org/10.1016/S1474-4422(18)30325-9Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar a prospective multicentre cohort study of 223 infants with neonatal encephalopathy who were all treated with hypothermia and then had MR imaging and proton spectroscopy within 14 days after birth; 190 (85%) had neurodevelopmental follow-up at a median age of 23 months. Spectroscopy was highly predictive of neurodevelopmental outcomes, with an area under the curve (AUC) for the peak-area ratio of lactate to N-acetylaspartate (NAA)—found in large amounts in neurons and oligodendrocytes—of 0·94 (95% CI 0·89–0·97). Remarkably, in the 82 infants for whom thalamic concentrations of NAA were available, the AUC was 0·99 (0·94–1·00), with a far higher prognostic accuracy than conventional MRI (98% [95% CI 91–100] vs 87% [81–91] for injury to the posterior limb of internal capsule assessed by MRI, which had the highest accuracy of all MRI assessments). The reason for this tight association is probably that the thalamus is highly susceptible to injury and, in turn, associated with disabilities that can be assessed at 2 years of age. A potential limitation would be that, in animal studies, very mild hypoxic-ischaemic injury has been shown to cause isolated hippocampal damage,7Gunn AJ Bennet L Fetal hypoxia insults and patterns of brain injury: insights from animal models.Clin Perinatol. 2009; 36: 579-593Summary Full Text Full Text PDF PubMed Scopus (127) Google Scholar which would be associated with academic problems in mid-childhood, without neuromotor disability. Furthermore, some of the infants classified as having mild neonatal encephalopathy might have had moderate but more slowly evolving encephalopathy,8Lodygensky GA Battin MR Gunn AJ Mild neonatal encephalopathy—how, when, and how much to treat?.JAMA Pediatrics. 2018; 172: 3-4Crossref PubMed Scopus (19) Google Scholar as suggested by the wide overlap in outcomes between the mild and moderate groups.6Lally PJ Montaldo P Oliveira V et al.Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre study.Lancet Neurol. 2018; (published online Nov 14.)http://dx.doi.org/10.1016/S1474-4422(18)30325-9Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar Intriguingly, the overall rate of adverse outcome was extremely low, with just 31 (16%) infants showing abnormal neurodevelopment at 2 years. It is not completely clear why the event rate was so much lower than in treated infants with moderate to severe neonatal encephalopathy in either the original trials of therapeutic hypothermia (about 46%)2Jacobs SE Berg M Hunt R Tarnow-Mordi WO Inder TE Davis PG Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2013; 1 (CD003311.)PubMed Google Scholar or a recent large trial (29%).3Shankaran S Laptook AR Pappas A et al.Effect of depth and duration of cooling on death or disability at age 18 months among neonates with hypoxic-ischemic encephalopathy: a randomized clinical trial.JAMA. 2017; 318: 57-67Crossref PubMed Scopus (143) Google Scholar In part, the low rate of adverse outcome might reflect the translation of therapeutic hypothermia to routine care, and changes such as wide use of passive cooling after resuscitation. Additionally, given that the rate of adverse outcome after severe neonatal encephalopathy (13 [57%] of 23 infants)6Lally PJ Montaldo P Oliveira V et al.Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre study.Lancet Neurol. 2018; (published online Nov 14.)http://dx.doi.org/10.1016/S1474-4422(18)30325-9Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar was essentially the same as in the randomised controlled TOBY trial2Jacobs SE Berg M Hunt R Tarnow-Mordi WO Inder TE Davis PG Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2013; 1 (CD003311.)PubMed Google Scholar (109 [56%] of 193 infants), the low overall rate in the MARBLE study probably reflects inclusion of infants with milder neonatal encephalopathy in the first 6 h of life who would have been excluded from previous studies. The recent PRIME study9Chalak LF Nguyen KA Prempunpong C et al.Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months.Pediatr Res. 2018; (published online Sept 13.)DOI:10.1038/s41390-018-0174-xCrossref Scopus (64) Google Scholar suggests that infants with mild neonatal encephalopathy in the first 6 h of life who are not treated with hypothermia have a 16% risk of disability9Chalak LF Nguyen KA Prempunpong C et al.Prospective research in infants with mild encephalopathy identified in the first six hours of life: neurodevelopmental outcomes at 18–22 months.Pediatr Res. 2018; (published online Sept 13.)DOI:10.1038/s41390-018-0174-xCrossref Scopus (64) Google Scholar compared with 3% in infants treated with therapeutic hypothermia in the MARBLE study.6Lally PJ Montaldo P Oliveira V et al.Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre study.Lancet Neurol. 2018; (published online Nov 14.)http://dx.doi.org/10.1016/S1474-4422(18)30325-9Summary Full Text Full Text PDF PubMed Scopus (102) Google Scholar Infants with mild neonatal encephalopathy were excluded from the original randomised controlled trials of therapeutic hypothermia.2Jacobs SE Berg M Hunt R Tarnow-Mordi WO Inder TE Davis PG Cooling for newborns with hypoxic ischaemic encephalopathy.Cochrane Database Syst Rev. 2013; 1 (CD003311.)PubMed Google Scholar Thus, this encouraging apparent benefit after treatment in the MARBLE study supports that it is urgent to undertake pragmatic trials of treatment for mild neonatal encephalopathy. Early MR spectroscopy would strengthen such trials. In conclusion, this demonstration of the extremely high prognostic accuracy for MR spectroscopic measurements of NAA concentration will enable much faster incremental studies of neonatal encephalopathy because it offers robust measurement of outcome within weeks. Moreover, the reference data from the MARBLE study will be made available, allowing MR sequences, and thus individual patient scans, to be done more rapidly within large pragmatic studies. Clinicians in this field can look forward to an era of clinical research in which it is no longer necessary to delay gratification for years! We are supported by the Health Research Council of New Zealand and the Neurological foundation of New Zealand. We declare no competing interests. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort studyThalamic proton MRS measures acquired soon after birth in neonatal encephalopathy had the highest accuracy to predict neurdevelopment 2 years later. These methods could be applied to increase the power of neuroprotection trials while reducing their duration. Full-Text PDF Open Access