Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia

Mitra, S.; Kendall, G M; Bainbridge, Alan; Sokolska, Magdalena; Dinan, Mary; Uria-Avellanal, Cristina; Price, David L.; McKinnon, Karen; Gunny, Roxana; Huertas-Ceballos, Ángela; Golay, Xavier; Robertson, Nicola J.

doi:10.1136/archdischild-2018-315478

Cited by 44 publications

(70 citation statements)

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“…The MARBLE study reported that the NAA metabolite concentration in the thalamus was the optimal predictor following neonatal encephalopathy, but another recent study reported a similar predictive accuracy for the thalamic Lac/NAA ratio [11]. The predictive performance of the Lac/NAA ratio in our study was nearly identical to that reported in the MARBLE study when deaths are included in the adverse outcome group (AUC 0.94, 95% CI 0.866-1.000 in MARBLE and AUC 0.938, 95% CI 0.866-1.000 in this study).…”

Section: Discussionmentioning

confidence: 98%

“…The Lac/NAA ratio measured by proton spectroscopy is a bridging biomarker which detects the effect of neuroprotective therapy in animal studies. Tract based spatial statistics with diffusion tensor imaging allows statistically powerful assessment of white matter microstructure, and the separation of small groups of subjects, thus reducing the sample size significantly compared to using visual analysis [8][9][10][11][12][13][14]. The TOBY-Xe study found no evidence of an effect of xenon combined with hypothermia on the cerebral biomarkers and on other outcomes assessed in the neonatal period.…”

Section: Introductionmentioning

confidence: 99%

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Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

et al. 2019

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Background: The TOBY-Xe proof of concept randomised trial found no effect of xenon combined with hypothermia after birth asphyxia on the lactate to N-acetyl aspartate ratio (Lac/NAA) in the thalamus and fractional anisotropy (FA) in white matter tracts measured within 15 days of birth. To confirm that these biomarkers are qualified to predict long-term outcome after neural rescue therapy we assessed surviving participants at 2-3 years of age. Methods: Of the 92 infants in TOBY-Xe, one was omitted from the study, 69 survived and we assessed 62 participants, 32 in the hypothermia and xenon and 30 in the hypothermia only groups. We examined the relation between Lac/NAA and FA and the scores of the Bayley Scales of Infant and Toddler Development III and calculated their predictive accuracy for moderate or severe disability or death. Results: Fifteen of 62 participants (24%) developed moderate/severe disability, and 22/92 (24%) died. The Lac/NAA ratio (difference in medians 0.628, 95% CI-0.392 to 4.684) and FA (difference in means −0.055, 95% CI-0.033 to −0.077) differed significantly between participants with or without moderate or severe disability or death and were significantly related with development scores in both groups. Adverse outcomes were correctly identified in 95.65% of cases by Lac/NAA and 78.79% by FA, with adequate mean calibration of the model. Interpretation: The results confirm the qualification of the cerebral magnetic resonance biomarkers employed in the TOBY-Xe study as predictors of outcome after neuroprotective therapy. Fund: The Centre for the Developing Brain, King's College London, UK.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

et al. 2019

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“…MRS biomarkers predict 2-year neurodevelopmental outcome in NE infants 23,24 . Higher NTP and PCr on 31 P MRS is associated with better 2-year outcome in clinical studies 26 ; we saw higher ATP and PCr in HT+M versus HT at 48 h. 1 H MRS Lac/NAA is a validated translational biomarker; high levels of thalamic Lac/NAA on MRS in NE babies predict poor 2-year outcomes 23,24 . We saw lower Lac/NAA on WM MRS with HT+M at 24 and 48 h and in grey matter at 48 h versus HT.…”

Section: Scientific Reports |mentioning

confidence: 99%

“…Primary outcome measures were: (i) Cerebral MRS biomarkers (proton (1H) and phosphorus ( 31 P) MRS). Thalamic lactate/N-acetyl aspartate (Lac/NAA) is the most accurate outcome biomarker at 2-years 23,24 , used in clinical neuroprotection trials 25 , with clear superiority over other MR methods 24 . 31 P MRS is less accessible on MRI systems but has defined secondary energy failure in NE 26 and its relation with 1-year brain growth and outcome 27 ; (ii) aEEG recovery; aEEG is used in NE babies during cooling and recovery predicts outcome 28 ; (iii) Quantitative cell death in 8 brain regions (TUNEL-positive cells) at 48 h.…”

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confidence: 99%

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Robertson

Lingam

Meehan

et al. 2020

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With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (Ht+V; n = 7); (iii) HT + Melatonin (Ht+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after Hi. comparing Ht+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/ exchangeable phosphate were higher at 48 h in HT+M versus Ht (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in Ht+M (47.1 cells/mm 2 ) compared to HT (123.8 cells/mm 2 ) (p = 0.0003) and HT+V (97.5 cells/mm 2 ) compared to Ht (p = 0.012). Localized protection was seen in white matter for HT+M versus Ht (p = 0.036) and internal capsule for HT+M compared to Ht (p = 0.001) and HT+V versus Ht (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.Intrapartum-related neonatal encephalopathy (NE) is a major healthcare problem. Worldwide in 2010, NE accounted for 287,000 deaths and 400,000 survivors with impairment 1 . NE cannot be prevented in most cases and therapies are limited. The incidence of NE in Western Europe is 1-3/1000 term births and in low-and mid-resource settings the incidence is ~10 times higher 1,2 . Over the last 2 decades, in settings with neonatal intensive care facilities, therapeutic hypothermia (HT) is routinely used for moderate-to-severe NE, improving survival and reducing disability 3 . However, although the severity of cerebral palsy has reduced with HT 4 , survivors have significantly lower cognitive scores which are on average 14 IQ points lower than matched peers even in the absence of cerebral palsy at school-age 5 . Further adjustments to HT protocols do not improve outcome 6,7 , therefore adjunct therapies to augment HT protection are urgently needed.Pre-clinical studies suggest that melatonin (N-acetyl-5-methoxytryptamine) in pharmacologic levels is safe and neuroprotective for hypoxic-ischemic injury in the adult 8 and neonatal 9 brain, mediated by anti-oxidant, anti-apoptotic and anti-inflammatory properties 10,11 . Ex...

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“…There is an evolution of a delayed cascade of molecular events triggered by the initial insult (Fatemi et al., 2009). Phosphorus ( 31 P) and proton ( 1 H) MRS studies have confirmed a significant and prolonged changes in brain metabolism following HIE (Azzopardi et al., 1989; Mitra et al., 2018a). A biphasic pattern of cerebral energy failure following HIE was demonstrated using on 31 P and 1 H MRS studies; the first phase occurs during the insult (primary energy failure), which is followed by re‐perfusion and a period of cerebral recovery.…”

Section: Introductionmentioning

confidence: 94%

Metabolic brain measurements in the newborn: Advances in optical technologies

2020

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Neonatal monitoring in neonatal intensive care is pushing the technological boundaries of newborn brain monitoring in order to improve patient outcome. There is an urgent need of a cot side, real time monitoring for assessment of brain injury severity and neurodevelopmental outcome, in particular for term newborn infants with hypoxic‐ischemic brain injury. This topical review discusses why brain tissue metabolic monitoring is important in this group of infants and introduces the currently used neuromonitoring techniques for metabolic monitoring in the neonatal intensive care unit (NICU). New optical techniques that can monitor changes in brain metabolism together with brain hemodynamics at the cot side are presented. Early studies from these emerging technologies have demonstrated their potential to deliver continuous information regarding cerebral physiological changes in sick newborn infants in real time. The promises of these new tools as well as their potential limitations are discussed.

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Proton magnetic resonance spectroscopy lactate/N-acetylaspartate within 2 weeks of birth accurately predicts 2-year motor, cognitive and language outcomes in neonatal encephalopathy after therapeutic hypothermia

Cited by 44 publications

References 35 publications

Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

Prospective qualification of early cerebral biomarkers in a randomised trial of treatment with xenon combined with moderate hypothermia after birth asphyxia

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model

Metabolic brain measurements in the newborn: Advances in optical technologies

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