White matter damage in the preterm neonate

The most common form of brain injury in preterm infants is periventricular leukomalacia (PVL). PVL is also the most common cause of cerebral palsy in the smallest and most vulnerable preterm infant. The core theme in its pathogenesis is the effect of hypoxia, ischaemia, and inflammation on the vulnerable white matter of the developing brain. Over the last decade, with improved laboratory and imaging techniques, the complex relationships between the known associated factors involved in causation of PVL is becoming increasingly known. A better understanding of its pathogenesis provides the basis for future protective strategies against PVL.     

MRI和DTI评价早产儿脑白质髓鞘发育

目的 应用磁共振(MRI)、磁共振弥散张量成像(DTI)研究早产儿脑白质髓鞘发育的特点。方法 胎龄≤32周、出生体重<1 500 g的31例早产儿根据头部MRI检查分为早产脑损伤组(12例)和早产无脑损伤组(19例)。选取24例足月儿作为对照组。均于胎龄或纠正胎龄37~40周之间完成头部MRI及DTI检查。测定3组相同感兴趣区的部分各向异性参数(FA)和表观扩散系数(ADC)。结果 早产脑损伤组内囊后肢FA值小于早产无脑损伤组和足月对照组 (P < 0.05);早产脑损伤组和早产无脑损伤组的额叶白质和豆状核的FA值小于足月对照组 (P < 0.05);3组间枕叶白质的FA值差异无显著性 (P > 0.05)。早产脑损伤组和早产无脑损伤组内囊后肢、豆状核、枕叶白质、额叶白质的ADC值高于足月对照组 (P < 0.05)。结论 早产儿脑损伤容易出现内囊后肢深部脑白质髓鞘化障碍或延迟。早产儿至纠正胎龄足月时,无论有无脑损伤,脑周围白质及灰质成熟度均低于足月儿。     

Diffusion tensor imaging of brain development

Understanding early human brain development is of great clinical importance, as many neurological and neurobehavioral disorders have their origin in early structural and functional cerebral organization and maturation. Diffusion tensor imaging (DTI), a recent magnetic resonance (MR) modality which assesses water diffusion in biological tissues at a microstructural level, has revealed a powerful technique to explore the structural basis of normal brain development. In fact, the tissue organization can be probed non-invasively, and the age-related changes of diffusion parameters (mean diffusivity, anisotropy) reveal crucial maturational processes, such as white matter myelination. Nevertheless, the developing human brain presents several challenges for DTI applications compared with the adult brain. DTI may further be used to detect brain injury well before conventional MRI, as water diffusion changes are an early indicator of cellular injury. This is particularly critical in infants in the context of administration of neuroprotective therapies. Changes in diffusion characteristics further provide early evidence of both focal and diffuse white matter injury in association with periventricular leukomalacia in the preterm infant. Finally, with the development of 3D fiber tractography, the maturation of white matter connectivity can be followed throughout infant development into adulthood with the potential to study correlations between abnormalities on DTI and ultimate neurologic/cognitive outcome.     

Electroencephalography and brain damage in preterm infants

Electroencephalography (EEG) is a sensitive method for detection of brain injury in preterm infants. Although the acute and chronic EEG changes are mainly non-specific regarding type of damage, they correlate with later neurological and cognitive function. In infants developing brain white matter damage, acute EEG findings include depression of background activity and presence of epileptic seizure activity. The chronic EEG changes associated with white matter injury and abnormal neurological development include delayed maturation, and presence of abundant Rolandic sharp waves. Cognitive limitations in preterm infants have been associated with changes in various sleep measures in EEG's recorded at full term. Continuous EEG-monitoring during neonatal intensive care shows that cerebral electrical activity during this vulnerable period can be affected by several extracerebral factors, e.g. cerebral blood flow, acidosis and some commonly used medications. For diagnosis of brain damage in preterm infants with neurophysiological methods, a combination of early continuous EEG monitoring during the initial intensive care period and full EEG, performed at later stages, is probably optimal.     

高危晚期早产儿脑病临床特点及磁共振影像学评估

目的了解高危晚期早产儿(LPI)脑病的危险因素、临床特点及磁共振(MRI)影像学变化。方法对2009年1月至2014年12月住院且存在脑损伤高危因素的LPI,进行头颅MRI检查,分析LPI脑病危险因素、临床特点及头颅MRI特征。结果完成MRI检查的LPI共1 007例,影像学符合早产儿脑病患儿313例(31.1%)。LPI脑病中白质损伤占76.7%。LPI脑病的发生与胎龄无相关性,但随着出生体重增加,脑病检出率逐渐增高(P0.05)。Logistic回归分析结果显示:复苏史是早产儿脑病发生的独立危险因素(P0.01)。结论早产儿脑病在高危LPI中亦较常见,特别是脑白质损伤。复苏病史是LPI脑病的独立危险因素,需引起重视。     

MRI changes and deficits of higher brain functions in preterm diplegia

Goto M, Ota R, Iai M, Sugita K, Tanabe Y. MRI changes and deficits of higher brain functions in preterm diplegia. Acta Pædiatr 1994;83:506–11. Stockholm. ISSN 0803–5253
Forty-one preterm children (29 with spastic diplegia and 12 without motor deficits) who had a normal verbal IQ were studied to clarify the clinical significance of neuroanatomical abnormalities disclosed by TI-weighted and T2–weighted magnetic resonance imaging (MRI). Both types of images clearly showed abnormalities in the frontal corona radiata of the children with spastic diplegia, while there were no abnormalities in the children without motor deficits. We compared the T1–weighted imaging findings with deficits of higher brain functions, evaluated by the performance subtests of the Wechsler Intelligence Scale. Thinning of the parietal and/or occipital white matter was noted in children with visuospatial cognitive deficits. Thus, MRI may be helpful in confirming early clinical suspicions of visuospatial cognitive deficits as well as motor deficits in preterm children, especially those with spastic diplegia.     

晚期早产儿脑白质损伤临床特点及磁共振影像学发现

目的：探讨晚期早产儿脑白质损伤的临床特点及常规磁共振成像（MRI）和弥散加权成像（DWI）影像学特征。方法：总结2005年1月至2008年5月中国医科大学盛京医院收治的519例早产儿资料（277例晚期早产儿,242例早期早产儿）,对其头部常规MRI和DWI特征进行分析。结果：晚期早产儿中,脑白质损伤118例,占脑损伤的71.9%（118/164）,占全部晚期早产儿的42.6%（118/277）。早期早产儿脑白质损伤占脑损伤的69.2%（92/133）,占全部早期早产儿的38.0%（92/242）,晚期早产儿脑白质损伤发生率与早期早产儿相比无明显差异。晚期早产儿脑白质损伤中无明显临床症状者占61.9%（73/118）,重症脑损伤（广泛性及弥漫性脑损伤）早期有明显临床症状者占75%（15/20）。损伤1周内,DWI表现为高信号,T1WI信号正常或稍高信号,伴或不伴T2WI高信号;弥漫性损伤者呈DWI高信号,常规MRI无明显信号改变。结论：脑白质损伤在晚期早产儿亦较常见。重症脑白质损伤患儿早期多有明显的临床表现。DWI在损伤早期的敏感度高于常规MRI。［中国当代儿科杂志,2010,12（5）：321-326］     

Diffusion MRI of the neonate brain: acquisition, processing and analysis techniques

Diffusion MRI (dMRI) is a popular noninvasive imaging modality for the investigation of the neonate brain. It enables the assessment of white matter integrity, and is particularly suited for studying white matter maturation in the preterm and term neonate brain. Diffusion tractography allows the delineation of white matter pathways and assessment of connectivity in vivo. In this review, we address the challenges of performing and analysing neonate dMRI. Of particular importance in dMRI analysis is adequate data preprocessing to reduce image distortions inherent to the acquisition technique, as well as artefacts caused by head movement. We present a summary of techniques that should be used in the preprocessing of neonate dMRI data, and demonstrate the effect of these important correction steps. Furthermore, we give an overview of available analysis techniques, ranging from voxel-based analysis of anisotropy metrics including tract-based spatial statistics (TBSS) to recently developed methods of statistical analysis addressing issues of resolving complex white matter architecture. We highlight the importance of resolving crossing fibres for tractography and outline several tractography-based techniques, including connectivity-based segmentation, the connectome and tractography mapping. These techniques provide powerful tools for the investigation of brain development and maturation.     

Magnetic resonance imaging in perinatal brain injury: clinical presentation, lesions and outcome

Neonatal MR imaging is invaluable in assessing the term born neonate who presents with an encephalopathy. Successful imaging requires adaptations to both the hardware and the sequences used for adults. The perinatal and postnatal details often predict the pattern of lesions sustained and are essential for correct interpretation of the imaging findings, but additional or alternative diagnoses in infants with apparent hypoxic ischaemic encephalopathy should always be considered. Perinatally acquired lesions are usually at their most obvious between 1 and 2 weeks of age. Very early imaging (<3 days) may be useful to make management decisions in ventilated neonates, but abnormalities may be subtle at that stage. Diffusion-weighted imaging is clinically useful for the early identification of ischaemic white matter in the neonatal brain but is less reliable in detecting lesions within the basal ganglia and thalami. The pattern of lesions seen on MRI can predict neurodevelopmental outcome. Additional useful information may be obtained by advanced techniques such as MR angiography, venography and perfusion-weighted imaging. Serial imaging with quantification of both structure size and tissue damage provides invaluable insights into perinatal brain injury.     

早产儿脑病的研究进展

随着低出生体重儿存活率的提高,早产儿脑损伤成为热点问题,损伤部位不仅局限于脑白质,灰质区域也有受累,故提出了“早产儿脑病”的概念。早产儿脑病包括脑白质损伤和神经元轴突病变。在缺血缺氧、围生期感染等致病因素作用下,脑组织发生直接或间接的神经细胞死亡或者是成熟障碍,最终导致脑性瘫痪、认知、语言、行为等能力障碍。该文总结了早产儿脑病的病理、发病机制、治疗及预后等情况。     

Sex differences in cerebral volumes of 8-year-olds born preterm

We investigate sex-associated effects of preterm birth on cerebral gray matter (GM) and white matter (WM) volumes. Preterm children (n=65) and 31 healthy, term control children had usable magnetic resonance imaging (MRI) data acquired at 8 years of age. Both GM and WM volumes were significantly reduced in the preterm group compared with controls. However, only males with preterm birth had significantly reduced WM compared with term males (P=.021), whereas WM volumes were equivalent in the female groups. Lower birth weight was associated with reduced WM in both boys and girls with preterm birth, whereas intraventricular hemorrhage (IVH) was associated with reduced GM in girls only. Positive correlations between GM and cognitive outcome were observed in girls with preterm birth but not boys. We conclude that preterm birth has a significant impact on brain development with increased risk for smaller GM and WM cerebral volumes. Males appear particularly vulnerable to adverse effects of preterm birth on WM development. However, girls with preterm birth show stronger correlations between neuro-anatomical variables and both neonatal risk factors and cognitive outcome, compared with boys. These findings indicate that the sex of the very preterm newborn influences the mechanisms by which the developing brain is affected.     

早产儿血清S100B蛋白与脑损伤的关系

目的：探讨血清S100B蛋白在早产儿脑损伤中的变化及意义。方法：47名早产儿纳入本研究,根据影像学MRI和头颅B超检查结果分为无脑损伤组（20 例）、非脑白质损伤组（14例）和脑白质损伤组（13例）。留取生后＜24 h、72 h及7 d的血清样本,采用酶联免疫吸附测定法（ELISA）双抗体夹心法测定S100B蛋白水平。结果：脑白质损伤组和非脑白质损伤组出生后24 h、72 h及7 d血清S100B蛋白水平均明显高于无脑损伤组（P＜0.05）,且脑白质损伤组血清S100B蛋白水平在各监测时间点明显高于非脑白质损伤组（P＜0.05）。结论：脑损伤早产儿生后7 d内血清S100B蛋白水平增高,提示血清S100B蛋白可以作为一种脑损伤的早期敏感标志物,对于临床早产儿脑损伤特别是脑白质损伤的诊断更有意义。     

Periventricular low intensities on fluid attenuated inversion recovery imaging in the newborn infant: Relationships to chronic white matter lesions

BACKGROUND: Neurological disadvantages due to hypoxic ischemic encephalopathy (HIE) are still very serious problems. In order to support the infant with HIE, it is important to evaluate the severity of the brain injury early. The authors performed a magnetic resonance imaging (MRI) study of the neonatal brain in order to assess the clinical value of periventricular low intensities (PVLI) detected on fluid attenuated inversion recovery (FLAIR) imaging. METHODS: A total of 451 MRI from 167 preterm and 113 term infants were sorted into groups according to the corrected age at the time of scanning. Intensities in the white matter were then divided into five grades according to the severity of the finding on FLAIR imaging. Chronic abnormalities such as periventricular hyperintensities (PVHI) were also analyzed. RESULTS: In early MRI, which was obtained before 2 months corrected age, the incidence of PVLI was 63%, while it was only 3% and 0% in the middle (2-8 months) and the late (8-18 months) scans, respectively. Instead of PVLI, PVHI were commonly observed both on late FLAIR imaging (89%) and late T2-weighted imaging (72%). The severity of the white matter damage diagnosed on early FLAIR imaging had a significant correlation with that of late FLAIR imaging. CONCLUSIONS: F-PVLI on early FLAIR imaging would be a good predictor of chronic white matter damage. FLAIR imaging would be also useful in follow-up of infants because of its high sensitivity to the chronic white matter lesion.     

超早产儿脑病危险因素的病例对照研究

目的：了解超早产儿（胎龄＜28周）脑病的发生状况并探讨其发生的危险因素。方法：收集复旦大学附属儿科医院NICU 2009年1月1日至2015年12月31日期间住院的、出生胎龄＜28周的、于纠正胎龄足月时或出院前完成MRI检查的超早产儿,排除纠正胎龄或出院时MRI单纯脑出血的病例。根据头颅MRI影像学报告结果分为单纯EOP组、EOP+出血组和正常组,采集与发生EOP可能相关的母亲和新生儿影响因素,三组之间进行单因素比较。结果：115例超早产儿进入本文分析,单纯EOP 组20例,EOP+出血组15例,正常组80例。35例EOP患儿中,白质损伤31例（88.6%）,灰质损伤4例（11.4%）,小脑损伤3例（8.6%）,多发广泛损伤1例（2.9%）,白质合并小脑损伤2例（5.7%）。脑白质损伤中,脑室周围白质损伤17例,其中非囊性损伤16例,囊性PVL1例;皮层下白质损伤14例,其中额叶损伤7例。单因素分析显示,单纯EOP组、EOP+出血组、正常组3组比较,母亲因素和新生儿因素差异均无统计学意义（P均＞0.05）。结论：超早产儿EOP与早产儿脑病一样最多见于脑白质损伤,影响超早产儿脑病为非单一危险因素起作用。     

Microstructural development of human brain assessed in utero by diffusion tensor imaging

Background Diffusion-weighted MR imaging (DWI) has been shown to be a great tool to assess white matter development in normal infants. Comparison of cerebral diffusion properties between preterm infants and fetuses of corresponding ages should assist in determining the impact of premature ex utero life on brain maturation. Objective To assess in utero maturation-dependent microstructural changes of fetal cerebral white matter using diffusion tensor MR imaging. Materials and methods An echoplanar sequence with diffusion gradient (b=700 s/mm²) applied in six non-colinear directions was performed between 31 and 37⁺³ weeks of gestation in 24 fetuses without cerebral abnormality on T1- and T2-weighted images. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in the white matter. Results Mean ADC values were 1.8 μm²/ms in the centrum semiovale, 1.2 μm²/ms in the splenium of the corpus callosum and 1.1 μm²/ms in the pyramidal tract. The paired Wilcoxon rank test showed significant differences in ADC between these three white matter regions. Mean FA values were 1.1%, 3.8% and 4.7%, respectively, in the centrum semiovale, corpus callosum and pyramidal tract. A significant age-related decrease in ADC and an increase in FA towards term were demonstrated in the pyramidal tract and corpus callosum. Conclusion Diffusion tensor imaging in utero can provide a quantitative assessment of the microstructural development of fetal white matter. Anisotropic parameters of the diffusion tensor should improve with technical advances.     

磁共振形态学半定量评分对新生儿细菌性脑膜炎出院结局的评估价值

目的 分析MRI形态学半定量评分对新生儿细菌性脑膜炎出院结局的评估价值。方法 收集复旦大学附属儿科医院2011年7月至2013年12月NICU收治的出院诊断为新生儿细菌性脑膜炎的病例,采用基于大脑损伤MRI形态学分析的半定量评分,对头颅MRI图像进行回顾性分析。MRI形态学评价包括脑室扩大、脑室旁白质容积丢失、脑白质囊性病灶、内囊后肢髓鞘化异常、皮质信号异常、颅内脑外间隙异常、基底节信号异常、脑白质非囊性信号异常、脑室内出血、脑室积脓、脑膜异常强化、室管膜异常强化和脑脓肿。将上述13项评分归纳为脑白质异常（WMA）、脑灰质异常（GMA）和非脑实质异常（NPA）。同时采集患儿出生孕周、发病时间、MRI检查时间、发病至MRI检查间隔时间和出院结局。按照出生孕周分为早产儿组和足月儿组,再按照出院结局分为预后良好和预后不良亚组,在各组内比较亚组之间时间因素、MRI单项评分和综合评分的差异。结果 63例新生儿细菌性脑膜炎病例进入分析（早产儿组18例,足月儿组45例）。MRI单项评分构成预后良好和预后不良亚组间差异有统计学意义的指标：早产儿组中有脑室扩大(P=0.012)和脑室旁白质容积丢失(P=0.004);足月儿组有脑室扩大(P=0.002)、脑室旁容积丢失(P=0.040)、颅内脑外间隙异常(P=0.005)和脑室内出血(P=0.038)。MRI综合评分中,早产儿组WMA评分(P=0.001)和NPA评分（P=0.039）、足月儿组NPA评分(P=0.018)在预后不良和预后良好亚组之间分布差异有统计学意义。足月儿组和早产儿组内不同预后亚组的各时间因素差异未发现统计学意义或临床意义。结论 新生儿细菌性脑膜炎MRI脑室扩大和脑室旁白质容积丢失预示早产儿出院不良结局;脑室扩大、脑室旁白质容积丢失、颅内脑外间隙异常和脑室内出血预示足月儿出院不良结局。WMA评分高预示早产儿出院不良结局,NPA评分高预示早产儿和足月儿出院不良结局。     

MRI brain imaging in neonates

MRI is now commonly used in the assessment of neonates for diagnosis and prognosis. The advantages over ultrasound are increased contrast resolution, complete coverage and multiplanar imaging. MRI is most commonly used for the assessment of neonatal encephalopathy to determine an underlying cause such as hypoglycaemia, neonatal infarction, or viral encephalitis, and may also be useful in determining complications of meningitis and planning surgical treatment. In hypoxic-ischaemic injury, where the diagnosis is typically made clinically, MRI has conventionally confirmed the diagnosis and provided prognostic information. However advanced techniques such as magnetic resonance spectroscopy and arterial spin labelling allow for earlier diagnosis and may guide treatment options. MRI may also detect less common patterns of brain injury in term infants such as punctuate white matter lesion. Imaging of preterm infants at term equivalent age can demonstrate complications such as periventricular leucomalacia or periventricular haemorrhagic infarction and provide information on neurological outcome.     

新生鼠缺氧缺血脑损伤的组织学和MR影像变化

目的调查新生大鼠缺氧缺血脑白质和灰质损伤的组织学和磁共振（MR）影像的变化。方法7日龄Wistar鼠（n=24）随机分为假手术组和实验组（右颈动脉结扎＋吸入8％氧1．5h）。在缺氧前、缺氧最后5-10分钟、缺氧后1h和24h行头部MR扫描获得吧和表面弥散系数（ADC）。结果1．5h缺氧将结束时，在缺氧缺血半球皮质下白质和顶部灰质可见ADC明显降低和他增高；缺氧缺血后1h，皮质下白质和顶部灰质ADC部分恢复，他持续增高，而缺氧缺血后24h，T2进一步增高。与灰白质类似的MRI改变相反，组织学检查显示：缺血半球白质不可逆细胞损伤发生早于灰质。在缺氧缺血后1h，缺血半球皮质下白质可见神经纤维稀疏或紊乱，并可见TUNEL阳性细胞增加，而在缺血半球顶部灰质区未见明显细胞损伤或TUNEL阳性细胞增加，到缺氧缺血后24h，灰白质均可见明显的损伤。结论在目前的新生鼠脑缺氧缺血模型，吧和ADC均能发现急性缺氧缺血脑白质和灰质水肿或损伤，但它们不能区分白质和灰质不同的病理变化，组织学上新生鼠脑白质比灰质更易遭受缺氧缺血损害。     

White matter injury after repeated endotoxin exposure in the preterm ovine fetus

Intrauterine infection has been linked to neurologic injury in preterm infants. However, a reproducible model of white matter injury in the preterm fetus in a long gestation species that can be monitored in utero is currently unavailable. Thus, our objective was to determine the effects of bacterial endotoxin (lipopolysaccharide, LPS) on physiologic and inflammatory responses and brain structure in the preterm ovine fetus. At 0.7 of gestation, six catheterized fetuses received three to five intravenous injections of LPS (1 micro g/kg) over 5 d; seven fetuses served as controls. Fetal responses were monitored and brain tissue examined 10-11 d after the initial LPS injection. After LPS on d 1 and 2, fetuses became transiently hypoxemic and hypotensive and blood IL-6 levels were increased, but these responses were smaller or absent after subsequent LPS exposures. Neural injury was observed in all LPS-exposed fetuses, most prominently in the cerebral white matter. Injury ranged from diffuse subcortical damage to periventricular leukomalacia, and in the brainstem the cross-sectional area of the corticospinal tract was reduced by 30%. Thus, repeated exposure of the preterm ovine fetus to LPS causes neuropathology resembling that of cerebral palsy and provides a robust model for exploring the etiology, prevention, and treatment of white matter damage.     

Cerebral white matter damage in the preterm infant: pathophysiology and risk factors

Based on clinical, epidemiologic, and experimental studies, the aetiology of white matter damage, specifically periventricular leukomalacia (PVL), is multifactorial and involves pre- and perinatal factors possibly including genetic factors, hypoxic-ischaemic insults, infection, excess cytokines, free radical production, increased excitatory amino acid release, and trophic factor deficiencies. The article summarizes research findings about the aetiology of white matter damage and cerebral palsy in preterm infants. The information is organized according to specific antecedents, for which we present epidemiological and neurobiological data. The most important prenatal factor appears to be intrauterine infection. We discuss the evidence supporting the hypothesis that the foetal inflammatory response contributes to neonatal brain injury and later developmental disability. We recently established an animal model of excitotoxic lesions in the developing mouse brain. Brain damage was induced by intra-cortical injections of ibotenate, a glutamatergic agonist. When administered on post-natal day 5 ibotenate induced the formation of white matter cysts. Our animal model could be used to further explore the mechanisms involved in the formation of PVL. Potentially preventive strategies will be discussed.