Brain injury in the premature infant – from pathogenesis to prevention

Brain injury in the premature infant is an extremely important problem, in part because of the large absolute number of infants affected yearly. The two principal brain lesions that underlie the neurological manifestations subsequently observed in premature infants are periventricular hemorrhagic infarction and periventricular leukomalacia. The emphases of this article are the neurology, neuropathology and pathogenesis of these two lesions. Recent work suggests that the ultimate goal, prevention of the lesions, is potentially achievable. Periventricular hemorrhagic infarction may be preventable by prevention of germinal matrix-intraventricular hemorrhage, and periventricular leukomalacia, by detection of impaired cerebrovascular autoregulation, prevention of impaired cerebral blood flow and interruption of the cascade to oligodendroglial cell death by such agents as free radical scavengers.     

The clinically available NMDA receptor antagonist, memantine, exhibits relative safety in the developing rat brain

The N-methyl-d-aspartate glutamate receptor (NMDAR) has been implicated in preterm brain injury (periventricular leukomalacia (PVL)) and represents a potential therapeutic target. However, the antagonist dizocilpine (MK-801) has been reported to increase constitutive neuronal apoptosis in the developing rat brain, limiting its clinical use in the developing brain. Memantine is another use-dependent NMDAR antagonist with shorter binding kinetics and has been demonstrated to be protective in a rat model of PVL, without effects on normal myelination or cortical growth. To further evaluate the safety of memantine in the developing brain, we demonstrate here that, in contrast to MK-801, memantine at neuroprotective doses does not increase neuronal constitutive apoptosis. In addition, there are no long-term alterations in the expression of NMDAR subunits, AMPAR subunits, and two markers of synaptogenesis, Synapsin-1 and PSD95. Evaluating clinically approved drugs in preclinical neonatal animal models of early brain development is an important prerequisite to considering them for clinical trial in preterm infants and early childhood.     

Plasticity and injury in the developing brain

The child's brain is more malleable or plastic than that of adults and this accounts for the ability of children to learn new skills quickly or recovery from brain injuries. Several mechanisms contribute to this ability including overproduction and deletion of neurons and synapses, and activity-dependent stabilization of synapses. The molecular mechanisms for activity-dependent synaptic plasticity are being discovered and this is leading to a better understanding of the pathogenesis of several disorders including neurofibromatosis, tuberous sclerosis, Fragile X syndrome and Rett syndrome. Many of the same pathways involved in synaptic plasticity, such as glutamate-mediated excitation, can also mediate brain injury when the brain is exposed to stress or energy failure such as hypoxia-ischemia. Recent evidence indicates that cell death pathways activated by injury differ between males and females. This new information about the molecular pathways involved in brain plasticity and injury are leading to insights that will provide better therapies for pediatric neurological disorders.     

Cerebrospinal fluid concentrations of glutamate and GABA during perinatal cerebral hypoxia-ischemia and seizures

Cerebrospinal fluid (CSF) concentrations of glutamate and γ-aminobutyric acid (GABA), as estimates of levels in the extracellular compartment of brain, were determined in 7-day postnatal rats at the terminus of hypoxia-ischemia and during status epilepticus, induced with bicuculline, at 2 and 24 h of recovery. Hypoxia-ischemia was associated with increased CSF glutamate, which was not increased further during status epilepticus. In contrast, CSF GABA was increased by hypoxia-ischemia as well as by status epilepticus during recovery. CSF glutamate/GABA ratios in rat pups subjected to status epilepticus with or without prior hypoxia-ischemia were lower than control animals during recovery. The lack of any significant increase in glutamate or in the glutamate/GABA ratio during status epilepticus would preclude any neuronal injury from occurring in those immature rats sustaining seizures alone or any accentuation of brain damage in those animals subjected to prior cerebral hypoxia-ischemia.     

Chronic ischemia preferentially causes white matter injury in the neonatal rat brain

Chronic ischemic brain injuries were studied in 7- and 14-day-old rat pups, which were subjected to bilateral carotid artery occlusion (BCAO) on postnatal day 1. BCAO preferentially injured white matter in the corpus callosum, subcortex and internal capsule areas while largely spared cortical neurons. White matter rarefaction in the corpus callosum was observed in 12 out of the 17 BCAO rat brains and significantly enlarged lateral ventricles were found in five out of seven P14 BCAO rat brains. These white matter changes were similar to injuries found in newborn infants with periventricular leukomalacia (PVL). White matter injuries in the 7-day-old BCAO rat brain were accompanied with increased activation of microglia/macrophages, as indicated by ED1 and OX42 positive immunostaining. Immature oligodendrocytes in the 7-day-old BCAO rat brain, as indicated by O4+/O1+ staining, were much fewer than in the sham-operated rat brain. Immunostaining for myelin basic protein (MBP) at the fimbria hippocampus and the internal capsule areas in the 7-day-old BACO rat brain was also much less than in the control rat brain. Consistent with the immunostaining data, MBP mRNA expression in the 7-day-old, but not in the 14-day-old, BCAO rat brain was significantly less than in the control rat brain. The overall results suggest that pre-oligodendrocytes and immature oligodendrocytes might be major targets for chronic ischemic insults and activated microglia/macrophages are possibly involved in the process of white matter injury.     

Metabotropic glutamate receptor antagonists and agonists: Potential neuroprotectors in diffuse brain injury

Our previous study has suggested that metabotropic glutamate receptors (mGluRs) were significantly involved in the secondary processes after diffuse brain injury (DBI) and that mGluRs antagonists or agonists may be used for the treatment of DBI. In the present study, the neuroprotective effects of antagonists or agonists of mGluRs on DBI were further investigated. Sprague-Dawly rats were randomized into the following six groups: (i) normal control; (ii) sham-operated control; (iii) DBI; (iv) DBI treated with normal saline (NS); (v) DBI treated with alpha-methyl-4-carboxy-phenylglycine (MCPG); and (vi) DBI treated with (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV). Animals were injected intracerebroventricularly (icv) with 10 microL MCPG (100mmol/L), DCG-IV (10nmol/L) or the equivalent volume of normal saline 1 h after injury. The neurological severity score (NSS), brain water content and the number of damaged neurons were determined 6, 12, 24, 72 and 168 h after injury. In rats with DBI, it was found that the NSS was improved and the water content in the frontal cortex and the number of damaged neurons in the parietal cortex were significantly reduced following icv injection of either MCPG or DCG-IV. This suggests that icv injection of the mGluR group I antagonist MCPG or the mGluR group II agonist DCG-IV may exert neuroprotective effects in the early stage after DBI.     

Relationship between characteristics on magnetic resonance imaging and motor outcomes in children with cerebral palsy and white matter injury

In a population cohort of children with white matter injury (WMI) and cerebral palsy (CP), we aimed to describe the magnetic resonance imaging (MRI) characteristics, identify key structure–function relationships, and classify the severity of WMI in a clinically relevant way. Stratified on MRI laterality/symmetry, variables indicating the extent and location of cerebral abnormalities for 272 children with CP and WMI on chronic-phase MRI were related to gross motor function and motor topography using univariable and multivariable approaches. We found that symmetrical involvement, severe WM loss in the hemispheres and corpus callosum, and cerebellar involvement were the strongest predictors of poor gross motor function, but the final model explained only a small proportion of the variability. Bilateral, extensive WM loss was more likely to result in quadriplegia, whereas volume loss in the posterior-mid WM more frequently resulted in diplegia. The extent and location of MRI abnormalities differed according to laterality/symmetry; asymmetry was associated with less extensive hemispheric involvement than symmetrical WMI, and unilateral lesions were more focal and located more anteriorly. In summary, laterality/symmetry of WMI, possibly reflecting different pathogenic mechanisms, together with extent of WM loss and cerebellar abnormality predicted gross motor function in CP, but to a limited extent.     

脑损伤修复与血管-神经新生

脑损伤是一个广义的概念,它包括外伤性、出血性、缺血性等各种原因引起的腩损伤.对于脑损伤的基础和临床研究目前主要集中在脑保护技术和脑神经修复再生两个方面.     

依达拉奉对颅脑损伤病人脑水肿及预后的影响

目的探讨依达拉奉对颅脑损伤病人脑水肿及预后的影响。方法采用随机双盲平行对照试验,98例急性颅脑损伤的病人随机分成治疗组50例和对照组48例,对照组按照急性脑损伤常规治疗,治疗组在常规治疗的基础上给予依达拉奉注射液30mg加入生理盐水注射液100ml中静滴,bid,共14d。2组在治疗后3、7、14、28d做头部CT检查,根据脑CT显示脑水肿最大层面的长×宽测算脑水肿面积表示脑水肿的程度,观察脑水肿的变化。于治疗前和治疗后28d分别进行格拉斯哥昏迷评分(GCS)。结果2组病人伤后脑水肿均逐渐加重而至第7d达高峰期,在第7d前2组脑水肿变化比较无统计学意义(P>0.05)。从第14～28d2组病人均明显减轻,但治疗组脑水肿减轻程度明显优于对照组(P<0.01);2组在第28dGCS评分均有提高,但治疗组GCS评分明显高于对照组(P<0.05)。依达拉奉治疗期间未发现明显不良反应。结论依达拉奉可以减轻颅脑损伤病人脑水肿,并能改善预后,无明显不良反应。     

妊娠期高血压疾病对新生儿脑损伤及大脑发育的影响

目的探讨妊娠期高血压疾病(HDCP)对新生儿脑损伤及大脑发育的影响。方法选取我院2014-12—2016-01收治的102例HDCP孕妇分娩新生儿为研究组,并选取非HDCP高危围生因素孕妇分娩胎儿180例为对照组,2组新生儿均接受颅脑超声检查,统计对比2组新生儿颅脑超声异常结果,并根据孕妇HDCP严重程度将其分为轻度HDCP组(n=57)与重度HDCP组(n=45),对比不同程度HDCP孕妇分娩新生儿颅脑超声异常表现。结果2组颅脑超声异常检出率相比,研究组70.58%(72/102)远高于对照组33.89%(61/180),差异有统计学意义(P0.05);与重度HDCP组相比,轻度HDCP组新生儿颅脑超声异常率较低,差异有统计学意义(P0.05)。结论 HDCP可导致新生儿出现脑损伤及大脑发育迟缓,加强孕期保健,有效防控HDCP可降低后遗症、改善新生儿预后,在临床治疗中具有重要意义。     

Hypoxic-ischemic brain injury in infants with congenital heart disease dying after cardiac surgery

Cardiac surgery for congenital heart disease is performed increasingly earlier in infancy, including in the neonatal period. With increased survival of infants, there is growing concern about the long-term neurological sequelae of hypoxic-ischemic injury due to congenital heart disease itself prior to surgery, corrective surgery with the use of low-flow cardiopulmonary bypass (CPB) and/or deep hypothermic circulatory arrest (DHCA), and/or unstable hemodynamic factors postoperatively. In analyzing the neuropathology of 38 infants dying after cardiac surgery, we tested a set of questions related to the severity and patterns of brain injury, CPB, DHCA, and age of the infants at the time of surgery. In all infants dying after cardiac surgery, irrespective of the modality, cerebral white matter damage [periventricular leukomalacia (PVL) or diffuse white matter gliosis] was the most significant lesion in terms of severity and incidence, followed by a spectrum of gray matter lesions. There was no significant association between the duration of deep hypothermic circulatory arrest and the degree of severity of overall brain injury, and the pattern of brain injury was similar irrespective of the modality of cardiac surgery. There was no significant association between the age at the time of surgery (neonatal versus postneonatal) and the severity of overall brain injury. The patterns of brain injury were not age-related in the limited time-frame analyzed, except that infants who developed acute PVL after both closed and DHCA/CPB surgery (14/38 infants, 34%) were significantly younger at death (median age 13.0 days) compared to unaffected infants (median age at death 42.5 days) (P=0.031). This observation suggests that neonatal (<30 postnatal days), but not postneonatal (>30 postnatal days), brains are at risk for acute PVL, and likely reflects the vulnerability of immature (pre-myelinating) white matter to hypoxia-ischemia.     

Differences between periventricular hemorrhagic infarction and periventricular leukomalacia

Purpose: To clarify the differences between infants with periventricular hemorrhagic infarction (PVHI) and those with periventricular leukomalacia (PVL). Methods: We retrospectively evaluated the clinical features, ultrasonography, and electroencephalogram (EEG) findings in 22 preterm infants with PVHI and 49 with PVL. EEG and cranial ultrasonography were serially performed in all participants starting immediately after birth. Acute and chronic stage EEG abnormalities were evaluated separately. Results: Gestational age and birth weight were significantly lower in infants with PVHI than those with PVL. EEGs were normal in the majority of infants with PVHI on days 1–2. However, EEG abnormalities appeared after ultrasonography abnormalities. The majority of infants with PVL showed acute-stage EEG abnormalities on days 1–2. The rate of infants with acute-stage EEG abnormalities decreased with age, whereas the rate of infants with chronic-stage EEG abnormalities increased with age. Normal EEG before ultrasonography abnormalities was more common in infants with PVHI than in those with PVL. However, deterioration of acute-stage EEG abnormalities was more frequent in infants with PVHI than in those with PVL. Conclusions: PVHI was presumed to cause mostly postnatal injury, whereas PVL was presumed to cause mostly pre-or perinatal injury.     

外伤性大面积脑梗死的临床研究

目的 探讨外伤性大面积脑梗死的发病机理、早期诊断与治疗要点.方法 回顾总结外伤性大面积脑梗死15例的临床资料.6例手术治疗,9例保守处理.结果 发病6个月后按GOS标准评价,本组病人死亡6例,重残4例,中残3例,良好2例.结论 外伤性大面积脑梗死的发病机理与血液流变学变化、血管内皮损伤、血管的解剖学特点等因素有关.对于颅脑外伤病人根据病情变化及时复查CT,对本病力求早期发现,早期治疗,以提高治疗成功率.     

颅脑损伤术后并发脑梗死的临床分析

目的探讨颅脑损伤术后脑梗死的发生机制及治疗方法。方法回顾分析24例颅脑损伤术后病人发生脑梗死的临床资料。结果保守治疗19例,开颅减压5例,死亡7例。结论颅脑损伤后如手术指征明确则须及时手术。术后注意病情变化采取综合治疗措施。应积极保持脑灌注压、维持血压及血氧,降低颅内压,改善脑血管痉挛,早期扩管改善微循环,有利于降低死残率,改善预后。     

血红素氧合酶-2基因缺失对氧化应激性脑损伤的保护作用

目的 探讨血红素氧合酶-2基因缺失对血红素诱导氧化应激性脑损伤的保护作用.方法 分别将6 μl (8 μmol/L)灭菌氯高铁血红素定向注入野生型小鼠和基因(HO-2)敲除小鼠的纹状体内,72 h后分别检测纹状体细胞生存率,蛋白和脂类的氧化作用.用蛋白质印迹法检测血红素氧合酶-1,2(HO-1)的表达.结果 与野生型相比,基因(HO-2)敲除小鼠纹状体内蛋白和脂类的氧化作用显著降低,而纹状体细胞的存活率显著增加;HO-1的表达在两种小鼠注射前后没有明显差异.结论 结果提示,血红素氧合酶-2基因缺失对血红素诱导的氧化应激性脑损伤具有保护作用;选择性抑制神经元血红素氧合酶-2基因的表达可减轻氧化应激性脑损伤.     

Pancreatitis associated with remote traumatic brain injury in children

Vomitting, abdominal distension, and feeding intolerance are common findings following brain injury in children, and are usually attributed to the brain injury or to delayed gastric emptying: a specific cause is usually not sought. We report six children who developed mild to moderate pancreatitis at least 7 days following apparently isolated brain injury, a previously unreported association. Five of the six patients received drugs that are known or suspected pancreatotoxins; all recovered without changes in the medications. When children develop feeding intolerance or upper gastrointestinal symptoms following traumatic brain injury, pancreatitis should be suspected.     

低温对实验型颅脑损伤大鼠免疫功能的影响

目的：研究不同低温状态下实验颅脑损伤大鼠免疫功能的动态变化,方法;采用^3H-TdR掺入法,LDH释放法及流式细胞术分别检测实验型液压颅脑损伤大鼠不同低温处后脾脏T,B淋巴细胞转化功能,NK细胞活性及外周血T细胞亚群的动态变化,结果,与颅脑损伤常温（37℃）组相比,损伤27℃组伤后1天B细胞转化率,NK细胞活性,伤后3天T细胞转化率降低,T细胞亚群CD3细胞伤后1天降低,损伤33℃组伤后1天B细胞转化率降低,伤后3天CD4／CD8升高,结论：（1）27℃低温对实验型颅脑伤大鼠免疫功能有抑制作用,（2）33℃低温不影响实验型颅服损伤大鼠细胞免疫,但对介导体液免疫的B细胞功能有一定的可逆性损害作用。     

Concentrations of glutamate released following spinal cord injury kill oligodendrocytes in the spinal cord

We investigated in vivo in rats whether sufficient glutamate is released following spinal cord injury (SCI) to kill oligodendrocytes. Microdialysis sampling was used to establish the level of glutamate released (550 +/- 80 microM) in the white matter during SCI. This glutamate concentration was administered into the spinal cords of other rats and the densities of oligodendrocytes remaining 24 and 72 h later determined by counting cells immunostained with the oligodendrocyte marker CC-1. Administration of ACSF, 4.0 mM glutamate (estimated resulting tissue exposure 500 microM) and 10.0 mM glutamate by microdialysis reduced oligodendrocyte density 22%, 57%, and 74%, respectively, relative to normal at 24 h post-exposure. Therefore, sufficient glutamate is released following SCI to damage white matter. Oligodendrocyte densities near the fiber track were not significantly different at 72 h from 24 h post-exposure, so most glutamate-induced oligodendrocyte death occurs within 24 h after exposure. Injecting the AMPA/kainate receptor blocker NBQX into the spinal cord during glutamate administration reduced the glutamate-induced decrease in oligodendrocyte density, evidence for AMPA/kainate receptor involvement in glutamate-induced oligodendrocyte death. This work directly demonstrates in vivo that following SCI glutamate reaches concentrations toxic to white matter and that AMPA/kainate receptors mediate this glutamate toxicity to oligodendrocytes.