Neuropathologic documentation of prenatal brain damage

Neuropathologic evidence of prenatal brain damage, chiefly in cerebral white matter, was found in 25% of infants who died at 7 days of age or less, with a total of ten preterm (16%) and 12 term (48%) infants among the 89 subjects studied. Few clinical features distinguished infants with prenatal injury from those without such injuries. Apgar scores were low, seizures were rare, and acute intracranial hemorrhage occurred equally often in both groups. Few pregnancies were entirely normal, but hydramnios was the only factor that occurred more often in prenatally injured infants, a statistically significant difference only among term infants. Oligohydramnios was not associated with prenatal brain injury. Unless fetal/maternal abnormalities in late gestation are identified and corrected, improved neonatal care will increase survival for prenatally damaged infants and the incidence of cerebral palsy may rise.     

Transport,monitoring, and successful brain MR imaging in unsedated neonates

Neonatal cerebral MR imaging is a sensitive technique for evaluating brain injury in the term and preterm infant. In term encephalopathic infants, MR imaging reliably detects not only the pattern of brain injury but might also provide clues about the timing of injury. In premature infants, MR imaging has surpassed US in the detection of white matter injury, a common lesion in this population. Concerns remain about the safety and transport of sedated neonates for MR examination to radiology suites, which are usually located at a distance from neonatal intensive care units. We present our own institutional experience and guidelines used to optimize the performance of cerebral MR examinations in neonates without sedation or anesthesia.     

弥散张量成像在早产儿脑白质损伤神经发育评价中的应用

脑白质损伤是早产儿最常见的脑损伤形式,是造成神经和智力损伤以及后期脑性瘫痪的主要原因.影像学检查在脑白质损伤的早期诊断及后期随访中发挥着重要的作用.其中核磁共振因为其安全准确的特点已成为目前应用最普遍的影像学检查.有别于传统的核磁共振技术,弥散张量成像可以在活体内观察和定量分析脑白质纤维束,现已成为评价脑白质损伤的有力工具.该文对弥散张量成像在早产儿脑白质损伤神经发育评价中的应用进行综述.     

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。     

Is periventricular leucomalacia a result of hypoxic-ischaemic injury? Hypocapnia and the preterm brain

Decrease in the arterial partial pressure of carbon dioxide (PaCO(2)) causes a reduction in cerebral blood flow in humans and in most animal species; in adults as well as in newborns and even in fetal life. Severely decreased PaCO(2) increases cerebral lactate production, modifies spontaneous electric brain activity, and may decrease the metabolic rate of oxygen. A relation between very low PaCO(2) and brain injury, however, has not been shown in adult humans or full-term newborn infants, nor in perinatal animals. In contrast, an association between low PaCO(2) and cerebral palsy and white matter injury in preterm infants has been reported repeatedly. A cause-and-effect relation is suggested by data from the immature rat: brain damage induced by ligation of a carotid artery can be reduced by adding CO(2) to the inspired gas and hence avoiding the consequences of spontaneous hyperventilation. This may be relevant for the clinical care of preterm infants, since PaCO(2) to a large extent is a function of respiratory management. The questions to be addressed are whether hypocapnia sensitizes the brain to hypoxaemia, and also whether the escape mechanisms are less effective in the preterm human brain.     

The sequelae of neonatal brain injury

The neonatal brain is very vulnerable to injury due to its relatively large size, rapid rate of development and immature immunological systems. Injury at this time often results in lifelong neuro-developmental sequelae such as cerebral palsy, learning difficulties and sensory deficits. In the term brain injury is most commonly due to hypoxia–ischaemia during labour, but hyperbilirubinaemia, trauma, thrombosis and infections remain important causes.In the preterm infant, because of immaturity, the pattern of injury is different with forms of white matter damage predominating. Germinal matrix haemorrhage, parenchymal infarction and forms of periventricular leucomalacia predominate. Preterm white matter damage often leads to altered or reduced development of cortical grey matter subsequently. All forms of cerebral palsy are seen in preterm children, but spastic cerebral diplegia is the commonest. Minor motor impairments in childhood are also very common as are behavioural disorders.Exact prognoses for infants with neonatal brain lesions are difficult to make owing to the fact that more than one lesion may co-exist in the same infant.     

Cytokine response in cerebrospinal fluid from preterm infants with posthaemorrhagic ventricular dilatation

Aim: Posthaemorrhagic ventricular dilatation (PHVD) is closely associated with white matter damage and neurological disability in the preterm infant. Proinflammatory cytokines have been implicated in the pathogenesis of white matter injury and subsequent cerebral palsy. The aim of this study was to determine the levels of proinflammatory cytokines in cerebrospinal fluid (CSF) from preterm infants with PHVD and to correlate the levels to white matter damage and neurodevelopmental outcome. Methods: CSF samples were obtained from 24 preterm infants with expanding PHVD and 19 preterm infants with normal ultrasound. Tumour necrosis factor-3 (TNF-3), interleukin-13 (IL-13), interleukin-8 (IL-8) and interferon-3 (IFN-3) in CSF were measured by enzyme-linked immunosorbent assay, and IL-6 was measured by bioassay. Results: The concentrations of TNF-3, IL-13, IL-6 and IL-8 were significantly elevated in CSF from infants with PHVD. TNF-3 was detected in 43% of PHVD infants and 11% of controls ( p = 0.04). IL-13 was detected in 67% of PHVD infants and 0% of controls (p 3 0.0001). The concentrations of IL-6 were 368 (145-460) pg ml 31 in the PHVD group and 30 (25-41) pg ml 31 in the control group (p 3 0.0001), and those of IL-8 were 3000 (1620-3400) pg ml 31 in the PHVD group and 35 (0-230) pg ml 31 in the control group (p 3 0.0001). Cytokine concentrations did not correlate with white matter lesions on ultrasound, shunt dependence or neurological outcome within the PHVD group. Conclusion: There was an intense and prolonged inflammatory reaction in CSF from preterm infants with PHVD and a high risk for subsequent white matter injury and permanent neurological impairment.     

早产儿暂时性低甲状腺素血症与脑损伤及神经行为学相关性研究

目的 通过对早产儿甲状腺素水平测定及脑、神经行为发育测评,分析甲状腺素水平与脑损伤、神经行为学的相关性.方法 选取2009年11月至2010年4月,上海交通大学附属上海市儿童医院新生儿科收治的早产儿52例,生后6 h内留取血清样本,放射免疫法测定T3、T4、TSH值.所有患儿出生后3 d行头颅B超检查,每周复查1次,出院前行头颅MRI检查.根据头颅MRI结果将患儿分为3组:无脑损伤组(33例)、脑室内出血组(10例)、脑白质损伤组(9例).所有患儿于纠正胎龄40±2周时行新生儿20项行为神经测定.结果 3组患儿TSH均正常,排除先天性甲状腺功能减低症;共8例早产儿甲状腺功能正常,占15.4%(8/52);另44例早产儿甲状腺功能均低下,占84.6%(44/52).无脑损伤组T3、T4水平高于脑室内出血组及脑白质损伤组,并以脑白质损伤组T3、T4水平最为低下,3组间比较差异有统计学意义(P＜0.05).无脑损伤组患儿行为能力、被动肌张力、主动肌张力及总分4项得分显著高于有脑损伤的两组患儿,且脑室内出血组患儿得分又高于脑白质损伤组患儿,3组间比较差异有统计学意义(P＜0.05).结论 早产儿脑损伤越严重,甲状腺素水平越低.有脑损伤的早产儿神经行为学评分较无脑损伤的早产儿低.     

围产期不良事件致新生儿急性缺氧缺血性脑损伤的类型分析

目的 探讨围产期不良事件致新生儿急性缺氧缺血性脑损伤（HIBI）的临床及影像学特征。方法 选取2004~2013 年46 例HIBI 患儿,对其临床及脑损伤类型进行分析。结果 足月儿组脑白质损伤为95%、皮层损伤90%、基底节- 丘脑损伤75% 和脑干损伤65%。早产儿组脑白质损伤73%、皮层损伤23%、基底节- 丘脑损伤19%、脑干损伤15%。早产儿灰质损伤发生率均低于足月儿组（P<0.05）;46% 的急性HIBI患儿伴有多器官功能受累,足月儿组临床表现较典型,95% 符合中、重度脑病,影像学改变多为混合型损伤,且以中、重度基底节- 丘脑损伤为主（68%）。多器官受累及动脉血pH 值小于7.1 与中、重度脑损伤的发生密切相关。结论 白质损伤是最常见的HIBI 类型,早产儿组也可见灰质损伤,但发生率低。中、重度脑病患儿的影像学损伤程度较重,且以基底节- 丘脑损伤为主。多器官受累、异常神经系统表现及早期血气分析对新生儿HIBI 诊断尤为重要。     

早产儿脑室旁白质损伤发病机制的研究进展

脑室旁白质损伤是早产儿特征性脑损伤,也是早产儿最重要的脑病类型之一。其病理变化主要包括脑白质的凝固性坏死、少突胶质细胞损伤、髓鞘损害、轴突损伤以及坏死部位出现反应性胶质化和小胶质细胞浸润等,这些病变与新生儿期后的神经系统后遗症密切相关。早产儿脑室旁白质软化的发病机制主要是与脑血管发育未成熟和少突胶质细胞前体细胞损伤易感性有关。本文通过文献复习对早产儿脑室旁白质损伤发病机制的研究进展进行概述,为临床预防和诊治提供理论依据。     

Fetal and neonatal origins of altered brain development

Abnormal development of the brain during fetal life is now thought to contribute to the aetiology of many neurological disorders that manifest throughout life. Many factors are likely to underlie such abnormal development including genetic makeup and an adverse intrauterine environment. This review will focus on prenatal hypoxic/ischaemic injury, inflammatory/infective insults and preterm birth. A range of experimental models have been used to characterize lesions formed in response to these insults and to determine mechanisms of damage resulting from such events. Relatively brief periods of fetal hypoxia result in neuronal death (cerebellum, hippocampus, and cerebral cortex), white matter damage and reduced growth of neural processes. These effects are more profound at mid than late gestation. Chronic mild placental insufficiency can result in fetal growth restriction and deficits in neural connectivity and myelination. Exposure of the preterm fetus to inflammatory agents causes brain damage particularly in the white matter and this is exacerbated by hypoxia. Premature birth without potentiating factors can result in subtle neuropathologies including cerebral white matter gliosis, hippocampal sclerosis and subarachnoid haemorrhage; the extent of the damage appears to be related to the regimen of ventilatory support. These studies show that the timing, severity and nature of specific insults are critical in determining the pattern of injury and thus the extent to which neurological function will be affected postnatally. Defining the causes, patterns and mechanisms of brain injury is crucial if we are to develop rational neuroprotective strategies to reduce the burden of altered brain growth and poor functional and behavioural outcomes.     

磁共振弥散加权成像在早产儿脑室周围白质软化早期的预测价值

目的 探讨磁共振弥散加权成像(DWI)早期评价和预测早产儿脑室周围白质软化(PVL)的作用及意义.方法 回顾分析2005年8月至2007年4月,在我院新生儿科住院,且经头部MRI确诊的12例PVL早产儿生后7 d内、2 w和4 w的DWI及常规MRI资料.结果 初次检查(平均生后4.5 d)全部病例DWI均显示双侧脑室周围脑白质对称性、弥漫性高信号,常规MRI基本正常;出生后2周DWI示脑白质内不规则高、低混杂信号,而常规MRI则显示相应部位小片状或点状T1WI高信号,T2WI稍低信号;出生后4W DWI示侧脑室后角、枕部三角区大小不等的囊性低信号,常规MRI显示相应病灶的T1WI低信号,T2WI高信号(即囊性PVL改变);出生后4个月常规MRI示囊腔逐渐变小、消失,脑白质减少、脑室扩大.结论 DWI显示的双侧脑室周围白质对称性弥漫性高信号是PVL的最早期表现;所提供的影像学异常变化与晚期常规MRl所证实PVL发生的高度相关性,表明了DWI可能是早期评价脑白质损伤及预测早产儿PVL发生的重要检测手段.     

早产儿脑白质损伤程度与早期脑电生理变化关系的研究

目的通过振幅整合脑电图(amplitude-integrated EEG,aEEG)及原始脑电抑制性电活动持续时间的研究,探讨早产儿脑白质损伤程度与早期脑功能变化的关系。方法 38例小于32周的脑白质损伤早产儿(轻度脑白质损伤20例,重度脑白质损伤18例)及42例无脑白质损伤的早产儿纳入研究。自生后开始每周进行一次aEEG监测和颅脑超声检查,直至生后4周或矫正胎龄32周。比较各组aEEG图形及振幅变化趋势及原始脑电爆发抑制比的变化。结果脑白质损伤组和对照组aEEG均呈高度不连续图形,无成熟的睡眠周期。重度脑白质损伤组下边界振幅明显低于轻度脑白质损伤组和对照组。脑白质损伤组和对照组的原始脑电图形均为爆发性电活动-抑制性电活动交替出现,重度脑白质损伤组抑制段时间及爆发抑制比明显大于轻度脑白质损伤组及对照组。结论脑白质损伤早产儿早期动态进行脑功能监测有助于早期发现严重脑白质损伤。     

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。     

高危晚期早产儿脑损伤病因学及其磁共振发现

目的 探讨以弥散加权成像(DWI)结合常规磁共振成像(T1WI-T2WI)诊断的高危晚期早产儿脑损伤的相关危险因素及临床特点,并分析不同时间MRI序列的信号特点及DWI的早期诊断价值。方法 首先对符合纳入标准的649例晚期早产儿的MRI片重新阅片,按照脑损伤评估标准得出诊断,其次收集相关的临床资料,分析不同类型脑损伤的危险因素和临床特点,并对其中271例确诊脑白质损伤（CWMD）的MRI序列进行分析,探讨不同类型CWMD的信号特点、损伤部位及结局。结果 ①晚期早产儿发生脑损伤332例（51.2%）,其中CWMD 271例（41.8%）,以局灶性CWMD为主（62.7％,170例）;颅内出血112例（17.3%）,主要为蛛网膜下腔出血55.4%（62/112）。②非出血性脑损伤的危险因素是男性（OR=1.510,95％CI：1.067～2.136,P=0.020）、阴道分娩（OR=2.367,95％CI：0.251～22.294 ,P=0.000）、早发型败血症（OR=2.194,95％CI：1.159～4.155,P=0.016）及抢救复苏史（OR=3.784,95％CI：1.908～7.506,P=0.000）。出血性脑损伤的危险因素是阴道分娩（OR=7.195,95％CI：4.249～12.184 ,P=0.000）和早发型败血症（OR=2.692,95％CI：1.185～6.117,P=0.018）。低钙血症（OR=2.593,95％CI：1.343～5.005,P=0.005）、晚发型败血症（OR=1.533,95％CI：1.012～2.323,P=0.044）和抽搐（OR=4.006,95％CI：1.790～8.970,P=0.001）是非出血性脑损伤组的主要临床特点。出血性脑损伤组主要表现为高血糖和抽搐。③局灶性CWMD 65.3％仅累及一处损伤,主要集中在侧脑室后脚（53.5%）,有97.1%病灶消失或病灶范围减少;广泛性CWMD 79.2%累及胼胝体和内囊;弥漫性CWMD 50％合并灰质损伤,全部发生软化。④生后2周内,DWI具有较高的敏感性,98.0%表现为高信号,T1WI信号无变化或稍高信号,伴或不伴T2WI低信号。局灶性CWMD DWI高信号持续时间长达3周以上,弥漫性CWMD DWI高信号持续时间2周以内。结论 晚期早产儿仍然容易受产前产时因素影响而发生不同类型的脑损伤。对有高危因素,或早期出现临床表现或电解质紊乱的患儿应选择生后2周内（1周内最佳）进行DWI和常规MRI检查,以早期发现病变。局灶性CWMD预后较好,合并有灰质损伤或弥漫性CWMD预后极差,需要动态随访,并进行早期康复训练。     

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。     

Impact of cerebral palsy in patients discharged from neonatal intensive care units

AIM: The aim of this study was to assess the impact and the peculiarities of cerebral palsy (CP) in children discharged from our neonatal intensive care unit (NICU) from January 1998 to April 2004. METHODS: A total of 2 303 children were discharged from our NICU during this period and 1 912 were followed up for 1 year through neurological examination (traditional, Brazelton, general movements) and cranial ultrasound (US); high-risk newborns were evaluated with brain magnetic resonance imaging (MRI) too. RESULTS: In 65 children (3.4% of the follow-up group) were diagnosed CP, and classified as follows: 21 (32%) diplegia, 19 (29%) quadriplegia, 20 (31%) hemiplegia, 4 (6%) double hemiplegia, 1 (2%) dyskinetic form. In diplegia and quadriplegia prevailed low birth weight infants (less than or equal to 2,500 g) and preterm infants, while in hemiplegia prevailed normal birthweight infants (greater than 2,500 g) and infants at term. The main MRI findings were: in diplegia 82% periventricular white matter lesions; in quadriplegia 94% periventricular and/or subcortical white matter lesions; in hemiplegia 95% bilateral periventricular or subcortical white matter lesions, predominating on contralateral cerebral hemisphere; in double hemiplegia 100% periventricular and/or subcortical white matter lesions, 100% enlargement of subarachnoid spaces; in dyskinetic form 100% basal ganglia lesions. CONCLUSIONS: The impact of CP in children discharged from our NICU, in agreement with the literature, is higher than in the total population of newborns, thus it is very important to evaluate carefully high-risk newborns during hospitalization and follow-up, through neurological examination and radiologic imaging (US, MRI), for an accurate and early treatment.     

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.     

Dynamic cerebral autoregulation in sick newborn infants

The sick newborn infant is vulnerable to brain injury and impaired cerebral autoregulation is thought to contribute to this. Coherent averaging is a method of measuring the dynamic cerebral autoregulatory response that is particularly suitable for neonates. We used this method in combination with a measure of the gradient of the cerebral blood flow velocity (CBFV) response following transient blood pressure (BP) peaks to study dynamic autoregulation in infants undergoing intensive care. Term and preterm infants at high risk of neurologic injury were compared with a control group of infants, also undergoing intensive care. Simultaneous video-EEG, CBFV (using transcranial Doppler), and arterial blood pressure measurements were obtained intermittently during a study period of at least 2 h. Cerebral autoregulatory response curves were constructed for high risk and control groups. Intact cerebral autoregulation produces a characteristic response consisting of a brief period when CBFV follows arterial blood pressure but quickly returns to baseline value. An impaired autoregulatory response shows CBFV mirroring the arterial blood pressure curve closely. Thirteen high-risk infants, who also had seizures (10 term and 3 preterm) and 12 control infants (6 term and 6 preterm) were studied. Autoregulation was absent in high-risk term and preterm infants. It was also absent in preterm control infants. Term, neurologically healthy infants undergoing intensive care have an intact autoregulatory response. The constant passive response seen in high-risk infants may reflect the severity of the underlying neurologic disease.