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Preterm baby in neonatal unit being monitored

NIHR Signal Brain scan may predict long-term disabilities in babies with brain injury

Published on 12 March 2019

doi: 10.3310/signal-000745

Magnetic resonance spectroscopy, a type of scan which shows brain biochemistry, could help predict whether there will be long-term effects of brain injury (encephalopathy) in new-born babies. It is usually done alongside an MRI.

Researchers scanned 82 babies being treated for brain injury, using MRI and also magnetic resonance spectroscopy. One biomarker tested at seven days after birth, thalamic N-acetylaspartate, correctly identified all babies who went on to have adverse developmental outcomes at 23 months. It was also very good at distinguishing babies who did not have adverse outcomes.  

Neonatal brain injury can happen for many reasons, including oxygen deprivation. Babies with signs of brain injury, such as seizures, are usually treated by cooling, which may reduce brain damage. Researchers are usually hampered when looking at ways to improve outcomes by the need to wait years to find out their effect on child development. Therefore, the apparent accuracy of magnetic resonance spectroscopy scans will make this approach a welcome tool.

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Why was this study needed?

Each year, around 5 in 1,000 babies who are born in the UK do show signs of brain injury. Treatment with cooling is known to prevent the risk of long-term adverse outcomes. However, there is room for improvement and research is underway to find other effective strategies.

A difficulty of treatment trials is the need to wait 18 months or more to assess developmental outcomes. A biomarker that accurately predicted likely outcomes would speed up research. Importantly, it would also give families and carers time to make longer-term healthcare plans.

While individual hospital units have had some success with magnetic resonance spectroscopy (MRS), the variations between different scanners and lack of agreed standard measurements have hampered use of this technique. This trial was intended to test the predictive accuracy of biomarkers measured by different MRS machines, to try to find a marker that would be of use in clinical trials.

What did this study do?

Researchers followed up 190 babies in a prospective cohort study (MARBLE) involving eight neonatal units in the UK and US. All were full term or near full term infants being treated by cooling for brain injury.

Researchers excluded those with life-threatening malformations, syndromic disorders or neurometabolic diseases. Magnetic resonance imaging (MRI) and MRS scans were performed 4 to 14 days after birth. Eighteen months to two years later, children were given standard neurodevelopmental tests (Bayley Scales of Infant and Toddler Development) and a detailed neurological examination. Researchers compared MRI and MRS biomarker features with rates of adverse outcomes, defined as death, or severe or moderate brain damage. 

As this was multi-centre and included different MRS scanners, the results should be widely applicable, though need to be validated in a larger sample.

What did it find?

  • Thirty-one (16%) of the 190 babies who had developmental follow-up tests had an adverse outcome, a lower rate than expected. There was one death.
  • Eighty-two of the babies had proton MRS measurement of N-acetylaspartate (NAA) in the thalamus section of the brain. This accurately predicted an adverse outcome in 12 of the 82 infants. It correctly identified all infants with adverse outcomes (100% sensitivity, 95% confidence interval [CI] 74 to 100) and nearly all those without an adverse outcome (97% specificity, 95% CI 90 to 100). Only babies from five of the eight study sites had NAA concentrations assessed.
  • No other MRS biomarkers were as accurate as NAA concentration.
  • For comparison, conventional MRI scanning of basal ganglia or thalamic injury had a sensitivity of 71% (95% CI 52 to 86) and specificity of 88% (95% CI 82 to 93).
  • Clinical examination at birth and discharge was not effective in predicting long-term adverse outcomes.

What does current guidance say on this issue?

There are no relevant UK guidelines on the use of imaging to predict outcomes for babies with neonatal brain injury.

What are the implications?

This study could speed up the pace of research into treatments for neonatal encephalopathy. Most UK hospitals with neonatal intensive care units have MRS technology available.

Other studies show that cooling reduces absolute risk of an adverse outcome by around 15% (from 61% to 46%). This means that almost half of babies with encephalopathy treated with cooling still die or have long-term developmental problems.

Speeding up research could improve these outcomes if new treatments can be tested or discarded without the need to wait years for the results.  

Citation and Funding

P Lally, P Montaldo, V Oliveira et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019;18:35-45.

This study was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London.

Bibliography

Alistair J Gunn, Malcolm Battin. Towards faster studies of neonatal encephalopathy. Lancet Neurol. 2019;18:21-22.

Why was this study needed?

Each year, around 5 in 1,000 babies who are born in the UK do show signs of brain injury. Treatment with cooling is known to prevent the risk of long-term adverse outcomes. However, there is room for improvement and research is underway to find other effective strategies.

A difficulty of treatment trials is the need to wait 18 months or more to assess developmental outcomes. A biomarker that accurately predicted likely outcomes would speed up research. Importantly, it would also give families and carers time to make longer-term healthcare plans.

While individual hospital units have had some success with magnetic resonance spectroscopy (MRS), the variations between different scanners and lack of agreed standard measurements have hampered use of this technique. This trial was intended to test the predictive accuracy of biomarkers measured by different MRS machines, to try to find a marker that would be of use in clinical trials.

What did this study do?

Researchers followed up 190 babies in a prospective cohort study (MARBLE) involving eight neonatal units in the UK and US. All were full term or near full term infants being treated by cooling for brain injury.

Researchers excluded those with life-threatening malformations, syndromic disorders or neurometabolic diseases. Magnetic resonance imaging (MRI) and MRS scans were performed 4 to 14 days after birth. Eighteen months to two years later, children were given standard neurodevelopmental tests (Bayley Scales of Infant and Toddler Development) and a detailed neurological examination. Researchers compared MRI and MRS biomarker features with rates of adverse outcomes, defined as death, or severe or moderate brain damage. 

As this was multi-centre and included different MRS scanners, the results should be widely applicable, though need to be validated in a larger sample.

What did it find?

  • Thirty-one (16%) of the 190 babies who had developmental follow-up tests had an adverse outcome, a lower rate than expected. There was one death.
  • Eighty-two of the babies had proton MRS measurement of N-acetylaspartate (NAA) in the thalamus section of the brain. This accurately predicted an adverse outcome in 12 of the 82 infants. It correctly identified all infants with adverse outcomes (100% sensitivity, 95% confidence interval [CI] 74 to 100) and nearly all those without an adverse outcome (97% specificity, 95% CI 90 to 100). Only babies from five of the eight study sites had NAA concentrations assessed.
  • No other MRS biomarkers were as accurate as NAA concentration.
  • For comparison, conventional MRI scanning of basal ganglia or thalamic injury had a sensitivity of 71% (95% CI 52 to 86) and specificity of 88% (95% CI 82 to 93).
  • Clinical examination at birth and discharge was not effective in predicting long-term adverse outcomes.

What does current guidance say on this issue?

There are no relevant UK guidelines on the use of imaging to predict outcomes for babies with neonatal brain injury.

What are the implications?

This study could speed up the pace of research into treatments for neonatal encephalopathy. Most UK hospitals with neonatal intensive care units have MRS technology available.

Other studies show that cooling reduces absolute risk of an adverse outcome by around 15% (from 61% to 46%). This means that almost half of babies with encephalopathy treated with cooling still die or have long-term developmental problems.

Speeding up research could improve these outcomes if new treatments can be tested or discarded without the need to wait years for the results.  

Citation and Funding

P Lally, P Montaldo, V Oliveira et al. Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study. Lancet Neurol. 2019;18:35-45.

This study was funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at Imperial College London.

Bibliography

Alistair J Gunn, Malcolm Battin. Towards faster studies of neonatal encephalopathy. Lancet Neurol. 2019;18:21-22.

Magnetic resonance spectroscopy assessment of brain injury after moderate hypothermia in neonatal encephalopathy: a prospective multicentre cohort study

Published on 14 November 2018

P Lally, P Montaldo, V Oliveira, A Soe, R Swamy, P Bassett, MJMendoza,G Atreja, U Kariholu, S Pattnayak, P Sashikumar, H Harizaj, M Mitchell, V Ganesh, S Harigopal, J Dixon, P English, P Clarke, P Muthukumar, P Satodia, S Wayte, L Abernethy, K Yajamanyam, A Bainbridge, D Price, A Huertas, D Sharp, V Kalra, S Chawla, S Shankaran, S Thayyil

The Lancet Neurology , 2018

Background In neonatal encephalopathy, 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 (MR) spectroscopy (MRS) biomarkers as early predictors of the neurodevelopmental abnormalities observed years after neonatal encephalopathy. Methods We did a prospective multicentre cohort study across eight neonatal intensive care units in the UK and USA, recruiting term and near-term neonates who received therapeutic hypothermia for neonatal encephalopathy. We excluded infants with life-threatening congenital malformations, syndromic disorders, neurometabolic diseases, or any alternative diagnoses for encephalopathy that were apparent within 6 h of birth. We obtained T1-weighted, T2-weighted, and diffusion-weighted MRI and thalamic proton MRS 4–14 days after birth. Clinical neurodevelopmental tests were done 18–24 months later. The primary outcome was the association between MR biomarkers and an adverse neurodevelopmental outcome, defined as death or moderate or severe disability, measured using a multivariable prognostic model. We used receiver operating characteristic (ROC) curves to examine the prognostic accuracy of the individual biomarkers. This trial is registered with ClinicalTrials.gov, number NCT01309711. Findings Between Jan 29, 2013, and June 25, 2016, we recruited 223 infants who all underwent MRI and MRS at a median age of 7 days (IQR 5–10), with 190 (85%) followed up for neurological examination at a median age of 23 months (20–25). Of those followed up, 31 (16%) had moderate or severe disability, including one death. Multiple logistic regression analysis could not be done because thalamic N-acetylaspartate (NAA) concentration alone accurately predicted an adverse neurodevelopmental outcome (area under the curve [AUC] of 0·99 [95% CI 0·94–1·00]; sensitivity 100% [74–100]; specificity 97% [90–100]; n=82); the models would not converge when any additional variable was examined. The AUC (95% CI) of clinical examination at 6 h (n=190) and at discharge (n=167) were 0·72 (0·65–0·78) and 0·60 (0·53–0·68), respectively, and the AUC of abnormal amplitude integrated EEG at 6 h (n=169) was 0·73 (0·65–0·79). On conventional MRI (n=190), cortical injury had an AUC of 0·67 (0·60–0·73), basal ganglia or thalamic injury had an AUC of 0·81 (0·75–0·87), and abnormal signal in the posterior limb of internal capsule (PLIC) had an AUC of 0·82 (0·76–0·87). Fractional anisotropy of PLIC (n=65) had an AUC of 0·82 (0·76–0·87). MRS metabolite peak-area ratios (n=160) of NAA–creatine (<1·29) had an AUC of 0·79 (0·72–0·85), of NAA–choline had an AUC of 0·74 (0·66–0·80), and of lactate–NAA (>0·22) had an AUC of 0·94 (0·89–0·97). Interpretation Thalamic 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. Funding National Institute for Health Research UK.

Magnetic resonance spectroscopy is a type of MRI that can capture changes in brain biochemistry.

Expert commentary

In this group of 82 infants with brain injury at birth, only 12 had ‘poor outcome’ at two years, all 12 with severe cerebral palsy. The magnetic resonance spectroscopy (MRS) showed a difference at one week between those who went on to have poor and good outcomes.

Many infants with brain injury around birth later show serious cognitive impairment without cerebral palsy. This study does not apparently identify any such children. Many parents are more concerned about learning ability than movement difficulties.

These interesting findings need confirmation from a larger patient group with a full range of mild, moderate and severe developmental outcomes to validate MRS as a predictor.

Marianne Thoresen, Professor of Neonatal Neuroscience and Honorary Consultant Neonatologist, University of Bristol

The commentator declares no conflicting interests