Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multi-centre study
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Background
In neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.
Methods
We conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was an
abnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.
Findings
We recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independently
associated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).
Interpretation
Thalamic 1H MRS measures acquired soon after birth in NE accurately predict neurodevelopment two years later. These could be applied to increase the power of neuroprotection trials, while reducing their duration.
In neonatal encephalopathy (NE), the clinical manifestations of injury can only be reliably assessed several years after an intervention, complicating early prognostication and rendering trials of promising neuroprotectants slow and expensive. We aimed to determine the accuracy of thalamic proton magnetic resonance spectroscopy (1H MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after NE.
Methods
We conducted a prospective multi-centre cohort study across eight neonatal intensive care units, recruiting term neonates who received therapeutic hypothermia for NE. We obtained thalamic 1H MRS 4 to 14 days after birth, which were compared to clinical neurodevelopmental tests performed 18 to 24 months later. The primary endpoint was an
abnormal outcome, defined as death, or moderate or severe disability. Receiver operating characteristic (ROC) curves were used to examine the strength of the relationship between selected biomarkers and this outcome.
Findings
We recruited 223 infants who all underwent MR imaging and spectroscopy at a median (IQR) age of 7 (5 to 10) days, with 190 (85%) followed up for neurological examination at a median (IQR) age of 23 (20 to 25) months. Of those followed up, 31 (16%) had moderate or severe disability, including one death. The thalamic concentration of Nacetylasparate, [NAA], had an area under the ROC curve (AUC) of 0·99 (95% CI 0·94 to 1·00, n=82), and lactate/NAA peak area ratio had an AUC of 0·94 (95% CI 0·89 to 0·97, n=160). From conventional MRI, abnormal signal in the posterior limb of the internal capsule (PLIC) gave an AUC of 0·82 (95% CI 0·76 to 0·87, n=190). Thalamic [NAA] was independently
associated with neurodevelopmental outcome scores on multivariable analysis, and had higher prognostic accuracy than conventional MR imaging (98% versus 87%; p<0·001).
Interpretation
Thalamic 1H MRS measures acquired soon after birth in NE accurately predict neurodevelopment two years later. These could be applied to increase the power of neuroprotection trials, while reducing their duration.
Date Issued
2019-01-01
Date Acceptance
2018-08-26
Citation
Lancet Neurology, 2019, 18 (1), pp.35-45
ISSN
1474-4422
Publisher
Elsevier
Start Page
35
End Page
45
Journal / Book Title
Lancet Neurology
Volume
18
Issue
1
Copyright Statement
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/)
Sponsor
Medical Research Council
National Institute for Health Research
National Institute for Health Research
Health Education England (HEE)
Medical Research Council (MRC)
National Institute for Health Research
Grant Number
MR/R001375/1
NIHR/CS/010/022
n/a
ICA-CDRF-2016-02-071
MR/R001375/1
NIHR-RP-011-048
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences & Neurology
HYPOXIC-ISCHEMIC ENCEPHALOPATHY
PROTON MR SPECTROSCOPY
PROGNOSTIC VALUE
NEWBORNS
BIOMARKERS
DISABILITY
DURATION
ASPHYXIA
DEATH
DEPTH
Aspartic Acid
Brain
Female
Humans
Hypothermia, Induced
Hypoxia-Ischemia, Brain
Infant
Infant, Newborn
Magnetic Resonance Spectroscopy
Male
Prospective Studies
Thalamus
Treatment Outcome
MARBLE consortium
Brain
Thalamus
Humans
Hypoxia-Ischemia, Brain
Aspartic Acid
Treatment Outcome
Hypothermia, Induced
Magnetic Resonance Spectroscopy
Prospective Studies
Infant
Infant, Newborn
Female
Male
Neurology & Neurosurgery
1103 Clinical Sciences
1109 Neurosciences
Publication Status
Published
Date Publish Online
2018-11-14