Centre for Perinatal Neuroscience, Imperial College London, London, UK.
Oliver Fisher Neonatal Unit, Medway NHS Foundation Trust, Kent, UK.
Lancet Neurol. 2019 Jan;18(1):35-45. doi: 10.1016/S1474-4422(18)30325-9. Epub 2018 Nov 15.
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.
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 T-weighted, T-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.
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).
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.
National Institute for Health Research UK.
在新生儿脑病中，干预后数年才能可靠地评估损伤的临床表现，这使得早期预后变得复杂，并使有前景的神经保护剂的试验变得缓慢且昂贵。我们旨在确定丘脑质子磁共振波谱（MRS）生物标志物作为新生儿脑病数年后神经发育异常的早期预测因子的准确性。
我们在英国和美国的 8 个新生儿重症监护病房进行了一项前瞻性多中心队列研究，招募了接受新生儿脑病治疗性低温治疗的足月和近足月新生儿。我们排除了生命威胁性先天性畸形、综合征障碍、神经代谢疾病或出生后 6 小时内明显的任何其他脑病诊断的婴儿。我们在出生后 4-14 天获得 T1 加权、T2 加权和弥散加权 MRI 以及丘脑质子 MRS。18-24 个月后进行临床神经发育测试。主要结局是磁共振生物标志物与不良神经发育结局（定义为死亡或中度或重度残疾）之间的关联，使用多变量预后模型进行测量。我们使用接收器工作特征（ROC）曲线来检查单个生物标志物的预后准确性。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01309711。
2013 年 1 月 29 日至 2016 年 6 月 25 日期间，我们招募了 223 名婴儿，他们在中位数年龄为 7 天（IQR 5-10）时均接受了 MRI 和 MRS 检查，其中 190 名（85%）在中位数年龄为 23 个月（20-25）时接受了神经检查。在随访的婴儿中，31 名（16%）有中度或重度残疾，包括 1 名死亡。由于单独的丘脑 N-乙酰天冬氨酸（NAA）浓度可以准确预测不良神经发育结局，因此无法进行多变量逻辑回归分析（曲线下面积[AUC]为 0.99[95%CI 0.94-1.00]；灵敏度 100%[74-100%]；特异性 97%[90-100%]；n=82）；当检查任何其他变量时，模型都无法收敛。6 小时（n=190）和出院时（n=167）的临床检查的 AUC（95%CI）分别为 0.72（0.65-0.78）和 0.60（0.53-0.68），6 小时异常振幅整合脑电图的 AUC（n=169）为 0.73（0.65-0.79）。在常规 MRI 上（n=190），皮质损伤的 AUC 为 0.67（0.60-0.73），基底节或丘脑损伤的 AUC 为 0.81（0.75-0.87），后内囊后肢（PLIC）异常信号的 AUC 为 0.82（0.76-0.87）。PLIC 分数各向异性（n=65）的 AUC 为 0.82（0.76-0.87）。MRS 代谢物峰面积比（n=160）的 NAA-肌酸（<1.29）的 AUC 为 0.79（0.72-0.85），NAA-胆碱的 AUC 为 0.74（0.66-0.80），乳酸-NAA（>0.22）的 AUC 为 0.94（0.89-0.97）。
新生儿脑病出生后不久获得的丘脑质子 MRS 测量值具有预测 2 年后神经发育的最高准确性。这些方法可以应用于增加神经保护试验的效力，同时缩短其持续时间。
英国国家卫生研究院。
