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Front. Neurol. | doi: 10.3389/fneur.2018.00086

Raised plasma neurofilament light protein levels are associated with abnormal MRI outcomes in newborns undergoing therapeutic hypothermia.

 Divyen Shah1, 2*, Vennila Ponnusamy3, 4, Jane Evanson5, Olga Kapellou6, Georgia Ekitzidou6,  Neelam Gupta7,  Paul Clarke8,  Adina Micahel-Titus2 and  Ping Yip2
  • 1Neonatal Unit, Royal London Hospital, Barts Health NHS Trust, United Kingdom
  • 2Centre of Neuroscience, Queen Mary University of London, United Kingdom
  • 3Centre of Genomics and Child Health, Queen Mary University of London, United Kingdom
  • 4Ashford and St Peter's Hospitals NHS Foundation Trust, United Kingdom
  • 5Radiology, The Royal London Hospital, United Kingdom
  • 6Neonatalogy, Homerton University Hospital NHS Foundation Trust, United Kingdom
  • 7University Hospital Southampton NHS Foundation Trust, United Kingdom
  • 8Neonatology, Norfolk and Norwich University Hospital, United Kingdom

Aims and Hypothesis: Hypoxic-ischaemic encephalopathy (HIE) remains an important cause of death and disability in newborns. Mild therapeutic hypothermia (TH) is safe and effective, however there are no tissue biomarkers available at the bedside to select babies for treatment. Aims: To show that it is feasible to study plasma neurofilament light (NfL) levels from newborns and to evaluate their temporal course. Hypothesis: raised plasma NfL protein levels from newborns who undergo TH after HIE are associated with abnormal MRI outcomes.

Methods: Between February 2014 to January 2016, term newborns with HIE treated with TH for 72 hours had plasma samples taken at three time points: (i) after the infant had reached target temperature, (ii) prior to commencing rewarming and (iii) after completing rewarming. Infants with mild HIE who did not receive TH had a single specimen taken. NfL protein was analyzed using an enzyme-linked immunosorbent assay.

Results: Twenty-six newborns with moderate-severe HIE treated with TH were studied. Half of these had cerebral MRI predictive of an unfavorable outcome. Plasma NfL levels were significantly higher in the TH group with unfavorable outcome (median age 18 hours) compared to levels from both the mild HIE group and TH group with favorable outcome (F=25.83, p<0.0001). Newborns who had MRIs predictive of unfavorable outcome had significantly higher NfL levels compared to those with favourable outcomes, at all three time points (mixed models, F=27.63, p<0.001). A cut-off NfL level >29 pg/mL at 24 hours is predictive of an unfavorable outcome (sensitivity 77%, specificity 69%, PPV 67%, NPV 72%) with increasing predictive value until after rewarming (sensitivity 92%, specificity 92%, PPV 92%, NPV).

Interpretation of Research: Plasma NfL protein levels may be a useful biomarker of unfavorable MRI outcomes in newborns with moderate-severe HIE and may assist in selecting newborns for adjunctive neuroprotective interventions. Larger studies with NfL testing at earlier time points are required.

Keywords: Neurofilament Proteins, hypoxic-ischemic encephalopathy, Therapeutic hypothermia, MRI imaging, Neuroprotection., biomarkers

Received: 15 Sep 2017; Accepted: 06 Feb 2018.

Edited by:

Carl E. Stafstrom, Johns Hopkins Medicine, United States

Reviewed by:

David Hsu, University of Wisconsin-Madison, United States
Ryan J. Felling, School of Medicine, Johns Hopkins University, United States
Raul Chavez-Valdez, Johns Hopkins Medicine, United States  

Copyright: © 2018 Shah, Ponnusamy, Evanson, Kapellou, Ekitzidou, Gupta, Clarke, Micahel-Titus and Yip. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Divyen Shah, Barts Health NHS Trust, Neonatal Unit, Royal London Hospital, London, United Kingdom,