TERM INFANTS WITH HYPOXIC-ISCHEMIC ENCEPHALOPATHY: OUTCOME AT 3.5 YEARS

A total of 167 term neonates with a diagnosis of hypoxic-ischemic encephalopathy (HIE) had detailed neurodevelopmental follow-up at 3.5 years of age. All 66 children with mild HIE were free from handicap; all seven with severe HIE were severely handicapped; and of the 94 with moderate HIE at birth, 21.3 per cent were handicapped. Mean IQ was significantly related to the category of HIE. Within the moderate HIE category, the neurological examination at discharge from the Neonatal Intensive Care Unit was more useful than the presence of neonatal convulsions in identifying children with subsequent developmental delay. Abnormalities on this examination related significantly to an increased number of handicapped children, decreased motor and language skills, and lower IQs. Although neonatal convulsions were associated with an increased number of handicapped children, they did not significantly affect most other developmental outcome measures. In term infants with documented HIE at birth, major neurodevelopmental dysfunction at 3.5 years depended more on prospectively established category of HIE than on other perinatal or social factors.     

Relation between visual perceptual impairment and neonatal ultrasound diagnosis of haemorrhagic-ischaemic brain lesions in 5-year-old children

Visual-perceptual abilities were assessed in 5-year-old children with the following neonatal neurological conditions: born preterm with normal ultrasound scan (NL, n=17); born preterm with ultrasound diagnosis of intraventricular haemorrhage (IVH, n=17); born preterm with ultrasound diagnosis of periventricular leukomalacia (PVL, n=12); born term with hypoxic-ischaemic encephalopathy (HIE, n=11). Visual-perceptual ability was evaluated with the L94: eight visual-perceptual tasks designed to evaluate different aspects of visual perception at the preschool level in children with multiple disabilities. Impairment was established in comparison to the performance age obtained on non-verbal intelligence subtests, instead of chronological age. Frequency of L94 impairment was highest in children with PVL, while children with IVH did not differ from the NL control group. Impairment rates were increased also in children with transient periventricular echodensities, and in children with HIE. Impairments were only moderately related to the delay of visual acuity maturation in infancy.     

Changes of brain edema after initiation of mild hypothermia therapy in children

To determine the effects of mild hypothermia therapy (34 degrees C) for brain edema caused by hypoxic ischemic encephalopathy (HIE) or acute encephalitis/encephalopathy, we reviewed the charts and serial brain CT images in six children (males 3, average age 1.6 years) treated with mild hypothermia therapy between November 2006 and April 2009. Both of the two children with HIE after cardiopulmonary arrest did not show any deterioration of brain edema after the initiation of hypothermia therapy. However, two of four non-HIE patients (acute encephalitis/encephalopathy 3 cases and metabolic encephalopathy plus HIE 1 case) showed progressive brain edema during the cooling phase and re-warming phase, respectively. There were no differences between patients with and those without progressive brain edema with regard to the interval until initiation of mild hypothermia therapy, duration of cooling phase, duration of re-warming phase, or peak serum NSE (neuron-specific enolase) levels. However, two children with progressive brain edema showed a delayed NSE peak time (15 and 13 days after onset, respectively), compared with those without progressive brain edema (2-6 days after onset). Our study suggests that serial measurement of serum NSE might be useful marker for adjusting the methods of hypothermia therapy according to neuropathology. Further study is necessary to establish optimal hypothermia therapy especially in children with acute encephalitis/ encephalopathy.     

What's in a Name? AIDS Dementia Complex, HIV-associated Dementia, HIV-associated neurocognitive disorder or HIV Encephalopathy

The current paper reviews currently used and proposed nomenclature for neurocognitive disorders associated with HIV, and proposes a unitary system as well as recommends an operational approach to screening/diagnosing severe forms of HIV associated neurocognitive disorder (HAND) in order to identify individuals who might benefit from antiretrovirals (ARVs). The terms HIV dementia complex, HIV-associated dementia (HAD) and HIV encephalopathy (HIE) are being replaced by more refined definitions for the spectrum HIV associated neurocognitive disorder (HANDs). The Diagnostic and Statistical Manual (DSM) will introduce a further term- major neurocognitive disorder. The nosology can become very confusing as the terms are not exactly equivalent. Clinicians need guidance on how to interpret new terms to implement current legislation and treatment guidelines that use the old term HIE. As a WHO stage 4 disease, patients with HIE are eligible for ARVs irrespective of their CD4 count. However, there are no locally available operational criteria how to diagnose HIV encephalopathy (HIE). The updated terminology is preferred because it requires assessing cognition objectively with neuropsychological tests. It is recommended that the International HIV Dementia Scale be used to screen patients and to thereafter confirm diagnosis with further neuropsychological tests e.g. the trail making and digit span tests.     

Vascular endothelial growth factor in neonates with perinatal asphyxia

Background: Vascular endothelial growth factor (VEGF) is a polypeptide growth factor that is activated by tissue hypoxia. The role of VEGF in perinatal asphyxia in human neonates is yet to be clarified. In infants who develop moderate to severe acute hypoxic ischemic encephalopathy (HIE) it is crucial to clearly understand physiologic and biochemical changes that accompany HIE before a novel treatment can be developed. Objectives: To assess VEGF in cord blood of infants suffering from perinatal asphyxia, and to determine whether an association exists between increased concentrations of VEGF and the risk for development of encephalopathy. Study design: We prospectively studied 40 full term infants; of them 20 infants suffered from perinatal asphyxia, and 20 control infants of comparable age and sex. We obtained cord blood samples from all subjects immediately after delivery. Neurological examination and grading of HIE were performed during the first day of life. Results: Birth weight, gestational age and gender did not differ between the control (n = 20) and asphyxia (n = 20) groups. Within the asphyxia group four infants developed HIE; one with severe encephalopathy who died shortly after birth, while the other three infants had moderate HIE. Concentrations of VEGF were increased in infants with asphyxia when compared to controls (P  0.001). Within the asphyxia group, infants with HIE had significantly increased concentrations of VEGF when compared to non-HIE asphyxiated infants (P = 0.008). In the logistic regression model, VEGF inversely correlated with pH and PO₂ in cord blood, and Apgar scores at 1 min, while it did not associate with gestational age and birth weight. Conclusions: This study indicates that VEGF is increased in cord blood of neonates following birth asphyxia, and that VEGF is specifically most increased in infants who later developed encephalopathy. Further studies are required to determine the role of VEGF in brain insult. Such studies will help determine whether a therapeutic role for VEGF or VEGF inhibitors can exist for HIE infants.     

常规MRI正常的新生儿缺氧缺血性脑病弥散张量成像初探

目的研究弥散张量MRI(diffusion-tensor MR imaging,DTI)对于临床诊断为新生儿缺氧缺血性脑病(hypoxic-ischemic encephalopathy,HIE)而常规MRI所见为正常病例的评估能力。方法选择20例常规MRI所见为正常的足月HIE患儿,以10例正常新生儿为对照,分组进行常规MRI、DTI扫描,测定两组新生儿相同感兴趣区(region of interest,ROI)的平均弥散度(mean diffusivity,Da)、分数各向异性(fractional anisotropy,FA)和相对各向异性值(relative anisotropy,RA)。用Student t—test法检验两组患儿各项指标,并观察比较两组新生儿的彩色FA图和彩色编码张量图。结果两组新生儿的Da在侧脑室前角前外侧白质、内囊后肢,放射冠各个感兴趣区均无显著性差异,而FA和RA值各感兴趣区则有明显差异,表现为HIE患儿FA值和RA值的下降,并且Da的高低与孕龄的长短有一定相关性。结论FA和RA是HIE患儿白质损伤或功能障碍的敏感指标,结合彩色FA图和彩色编码张量图可对患儿白质髓鞘的损伤作出较为准确、客观的评价,并可能在今后评估患儿的预后转归方面起重要作用。     

Effect of asphyxia on non-protein-bound iron and lipid peroxidation in newborn infants

The effect of asphyxia on iron metabolism and lipid peroxidation in newborn infants with hypoxic-ischemic encephalopathy (HIE) was investigated. Non-protein-bound iron (NPBI) and lipid peroxidation (thiobarbituric-acid-reactive species; TBARS) in plasma and hematological iron indices were measured in 15 healthy newborn infants (mean gestational age 39 04 weeks, SD 1); 15 asphyxiated infants without neurological abnormalities (AS-HIE; mean gestational age 38.8 weeks, SD 0.9); and 15 asphyxiated infants with neurological abnormalities (AS+HIE; mean gestational age 39.75 weeks, SD 1.4). Follow-up was performed at the age of 5 months. It was found that the detectable rates of NPBI in 10 of 15 of the AS-HIE group and 13 of 15 of the AS+HIE group were significantly higher than that of the control group (5 of 15; both p < 0.01). Plasma levels of TBARS in the control (9.20 micromol/L, SD 1.9) and AS-HIE infants (10.13 micromol/L, SD 2.7) were significantly lower than those of the AS+HIE group (13.42 micromol/L, SD 2.8). Serum iron, total iron binding capacity, and transferrin saturation in the AS+HIE group was higher than the corresponding values of the control and AS-HIE groups, although no statistical difference was found among them. At 5 months of age, all control and AS-HIE infants were neurologically normal, whether or not their NPBI was detectable. Of the 12 AS+HIE infants, four (all of whom had detectable NPBI) were neurologically impaired. The average Gross Development Quotient of AS+HIE infants was significantly lower than that of the control or AS-HIE groups (p < 0.01). Results showed that asphyxia could affect iron metabolism and lead to a significant increase in NPBI and lipid peroxidation in newborn infants with HIE, indicating that iron delocalization induced by asphyxia plays a role in the brain injury of asphyxiated infants.     

Prolonged EEG depression in term and near-term infants with hypoxic ischemic encephalopathy and later development of West syndrome

Purpose: This study was performed to clarify the relationship between prolonged depression of electroencephalography (EEG) in term and near‐term infants with hypoxic ischemic encephalopathy (HIE) and the later development of West syndrome (WS). Methods: We investigated 17 term and near‐term infants with HIE. Inclusion criteria were as follows: ≥35 weeks of gestation, clinical signs of HIE, magnetic resonance imaging (MRI) lesions corresponding to HIE, assessment of outcome at >18 months of age, depression of EEG, and serial EEG examinations. The 17 infants were divided into the following two groups: Group A (n = 4) with prolonged EEG depression over 21 days of age, and group B (n = 13) with disappearance of EEG depression by 21 days of age. Results: WS developed in all four infants in group A, but in only one of 13 infants in group B. WS occurred significantly more frequently in group A than in group B. For the prediction of subsequent development of WS, prolonged EEG depression over 21 days of age showed sensitivity of 0.80 and specificity of 1.0. In both groups, abnormal irregular faster waves with or without EEG depression were seen in 11 infants between 2 and 28 days of age. They had no significant relationship with WS, but were significantly related to an adverse developmental outcome. Conclusions: Prolonged depression of EEG over 21 days of age in term or near‐term infants with HIE is a valuable predictor of the later development of WS.     

Neuroimaging of neonatal encephalopathies

Neonatal brain disorders consist of a wide chapter including brain malformations, hypoxic-ischemic encephalopathy (HIE), intracranial infections, perinatal trauma and metabolic encephalopathy. We will focus here on HIE, intracranial infections (especially materno-fetal infection with or without prolonged and/or premature rupture of membranes) and metabolic encephalopathy, those three conditions being the most frequent so far in our experience. Neonatal stroke is also analyzed. Moreover minor perinatal events might be superimposed on an already damaged (infective, edematous, metabolically abnormal or maldeveloped) brain, highlighting the main role and potential benefits of neuroimaging during the neonatal period. The different methods of brain imaging are thus reported with their advantages and disadvantages.     

新生儿缺氧缺血性脑病的疗效观察(186例回顾性分析)

目的总结分析我科3年来新生儿缺氧缺血性脑病(HIE)的系统治疗方法及相应近期疗效和远期预后,探讨改善预后的措施。方法对186例HIE患儿在各个阶段进行全面系统治疗,对临床资料和随访结果进行回顾性分析。结果186例HIE中足月儿149例(80.1％),早产儿37例(19.9％)。病死率7.5％(重度HIE20.5％,中度5.1％,轻度0)。随访109例,后遗症发生率16.5％(重度HIE60.7％,中度6.1％,轻度0)。早产儿HIE者中度预后不良占37.0％,重度60.7％。结论重度和早产儿HIE预后较差。针对不同阶段病情特点给予综合治疗,可显著改善患儿预后。     

早期干预对新生儿缺氧缺血性脑病预后的影响

目的探讨早期干预对新生儿中、重度缺氧缺血性脑病（HIE）预后的影响。方法将2009年5月至2010年5月在商丘市第一人民医院治疗的85例足月中重度HIE患儿分为早期干预组49例和非干预组36例，对干预组进行系统的早期干预，均于出生后3，6，9，12月龄对两组患儿进行智能发育随访和评估。结果干预组平均智能发育指数（MDI）高于非干预组（P〈0．05）；干预组平均运动发育指数（PDI）除3个月时差异无统计学意义外，其余各时点均高于非干预组（P〈0．05），非干预组后遗症发生率明显高于干预组（P〈0．05）。结论对HIE患儿早期给予持续的干预，能有效地促进智力发育，改善预后，降低后遗症的发生率，是提高其生活质量的有效方法。     

Residual Hippocampal Atrophy in Asphyxiated Term Neonates

BACKGROUND AND PURPOSE: Previous studies have shown the hippocampus and basal ganglia to be highly sensitive to hypoxic-ischemic insult. The authors' aim was to evaluate the long-term effects of perinatal asphyxia (PA) on the hippocampus and caudate nucleus in a group of participants born at term and who met the criteria for hypoxic-ischemic encephalopathy (HIE). Additionally, the authors looked for damage in other brain regions using voxel-based morphometry (VBM). METHODS: The sample consisted of 13 participants (8 boys and 5 girls) with a mean age at study of 16.23 years (+/- 2.89) with antecedents of perinatal asphyxia, diagnosed as moderate hypoxic-ischemic encephalopathy. A group of 13 healthy adolescents matched for age, sex, educational level, and social background were recruited as a comparison group. MR scans were acquired on a 1.5T Signa (General Electric, Milwaukee, WI) to evaluate hippocampal and caudate volumes and to perform VBM analysis. Finally, Rey's Auditory Verbal Learning Test was administered to evaluate verbal long-term memory. RESULTS: HIE participants were found to have bilateral hippocampal atrophy (P = .015) and gray matter damage in temporal and frontal lobes. The caudate nucleus showed no atrophic changes in PA participants, and VBM analysis did not reveal other consistent brain abnormalities. Verbal long-term memory was slightly worse in HIE participants. CONCLUSIONS: These findings indicate that PA produces hippocampal and other nonspecific long-term damage, which cannot be compensated for by plasticity mechanisms. However, this damage does not preclude normal development and scholarship.     

High incidence of fatal cytokine-related disease among children with sequelae of perinatal hypoxic-ischemic encephalopathy

Children with sequelae of perinatal hypoxic-ischemic encephalopathy (HIE) occasionally suffer from cytokine-related disease. We investigated 12 children with perinatal HIE sequelae, who died in childhood, concerning (1) the incidence of cytokine-related disease as the cause of death, and (2) the characteristics of the cytokine-related disease. Six (50%) of the 12 patients died from cytokine-related disease:two had virus-associated hemophagocytic syndrome (VAHS) ; one had acute encephalopathy;one had systemic inflammatory response syndrome (SIRS); and two had severe pneumonia/acute respiratory distress syndrome (ARDS). These six patients presented with increased liver transaminase, LDH, and CK, and decreased platelet count and albumin. This study shows the high incidence of cytokine-related disease as the cause of death in children with perinatal HIE sequelae. Further investigation is needed to clarify the pathogenesis of this disease.     

Flunarizine in therapy-resistant infantile epilepsies

An open add-on trial with flunarizine has been carried out in 27 cases of therapy resistant infantile epilepsies: 15 partial and 12 generalized epilepsies. Etiology was an hypoxic-ischemic encephalopathy (HIE) in 13 cases, cerebral malformations in 10 cases and 4 various prenatal and perinatal cases. After a 2 months baseline period, flunarizine was given in addition to the previous therapy in a 5 mg once daily dose. A single blind versus placebo study was carried out in another series of 16 cases. Better results were found in HIE cases than in malformative cases, and in cases with perinatal HIE than in cases with prenatal hypoxic encephalopathy. The improvement in symptomatic generalized epilepsies was more evident than in symptomatic partial epilepsies. Drowsiness was the only side effect reported.     

新生儿缺氧缺血性脑病MRI表现

目的探讨新生儿缺氧缺血性脑病（hypoxic ischemic encephalopathy,HIE）的MRI表现。方法回顾分析2009-05—2011-10经临床证实的25例新生儿急性缺氧缺血性脑病的临床及MRI表现。结果 25例患者MRI于侧脑室旁见多发异常信号影,其中7例累及额顶叶或半卵圆区,5例累及基底节区,4例累及胼胝体,2例患者病变区可见小出血灶。结论 MRI对新生儿急性缺氧缺血性脑病的早期诊断和治疗具有重要指导作用。     

Increased neurogenesis after hypoxic-ischemic encephalopathy in humans is age related

The leading cause of morbidity and mortality after successful resuscitation is hypoxic-ischemic encephalopathy (HIE), which results in neuronal loss within the neocortex and the hippocampal formation. This study focuses on the impact of HIE on adult neurogenesis in the human hippocampal dentate gyrus as a potential intrinsic regenerative mechanism in response to neuronal damage. Brain sections of 22 autopsy cases with HIE and of 19 age-matched controls without neuropathological abnormalities were investigated by means of immunohistochemistry. The densities of immature granule cells during axon guidance and outgrowth (assessed by TUC-4 immunohistochemistry) and of young calretinin-expressing postmitotic neurons were increased in the granule cell layer of cases who had suffered from HIE (P = 0.0002 and P = 0.0001, respectively). Similarly, the density of apoptotic granule cells, as detected by in situ tailing and morphological criteria, was increased in HIE (P = 0.014). In cases with HIE, the increase in the density of TUC-4-labeled cells inversely correlated with age (P = 0.027). In contrast, neither the density of proliferating nor that of apoptotic cells was substantially influenced by age within the control group. Taken together, both an increase in adult neurogenesis and in neuronal apoptosis was observed in the human dentate gyrus in response to HIE. The data suggest a decrease of adult neurogenesis in older-aged cases. Whether neurogenesis can contribute to recovery after HIE remains to be determined. The stimulation of adult neurogenesis may be less efficient in older victims of HIE. W.-R. C. Mattiesen and S. C. Tauber have equally contributed to this work.     

自由基与新生儿缺氧缺血性脑病

本文检测了３９例新生儿缺氧缺血性脑病（ＨＩＥ）及３０例足月健康新生儿血中超氧化物歧化酶（ＳＯＤ）、过氧化氢酶（ＣＡＴ）及脂质过氧化物（ＬＰＯ），结果ＨＩＥ患儿血中ＬＰＯ增高，ＳＯＤ、ＣＡＴ下降，而且比较了中度与重度、急性期与恢复期检测结果，表明ＨＩＥ时，自由基参与了该病的发生与发展。     

肾上腺髓质素与新生儿缺氧缺血性脑病的关系

目的探讨肾上腺髓质素与新生儿缺氧缺血性脑病的关系。方法以80例足月缺氧缺血性脑病患儿为对象，30例足月正常新生儿为对照，于生后1d内，（10～14）d取外周静脉血，用放射免疫法测定血浆肾上腺髓质素水平。结果（1）缺氧缺血性脑病轻、中、重度组血浆肾上腺髓质素水平较对照组明显升高（P〈O．01）；缺氧缺血性脑病轻度组血浆肾上腺髓质素水平显著低于中、重度组（P〈0．01）；缺氧缺血性脑病中度组血浆肾上腺髓质素水平较重度组明显降低（P〈0．01）；血浆肾上腺髓质素水平随缺氧缺血性脑病患儿病情程度的加重而有增高的趋势；（2）缺氧缺血性脑病中、重度组恢复期血浆肾上腺髓质素水平较急性期下降，差异有显著性（P〈O．05，P〈0．01），而轻度组差异无显著性（P〉0．05）。结论肾上腺髓质素可能对新生儿缺氧缺血性脑病有保护作用；肾上腺髓质素可作为新生儿缺氧缺血性脑病严重程度的标志物。     

单唾液酸四己糖神经节苷酯治疗新生儿缺氧缺血性脑病90例

目的研究单唾液酸四己糖神经节苷酯(GM1)静滴治疗新生儿缺氧缺血性脑病(HIE)疗效。方法将90例HIE患儿随机分为观察组和对照组,每组45例,均予常规治疗,观察组加用GM1。观察和记录2组临床症状、体征恢复情况和新生儿行为神经测定(NBNA)评分。结果应用GM1治疗新生儿HIE对改善HIE所致的远期神经系统发育障碍有较好的疗效。结论在常规治疗基础上加用GM1是目前治疗中重度HIE较理想的方法。     

CT 对新生儿缺氧缺血性脑病的诊断价值分析

目的：对C T在诊断新生儿缺氧缺血性脑病中的应用价值进行探讨。方法选取2009-06-2012-12就诊于我院的确诊为缺氧缺血性脑病的40例新生儿作为研究对象，对其一般资料及C T结果进行统计分析。结果对 H IE临床诊断分度与CT诊断分度进行Spearman秩相关分析，结果显示两者呈正相关（r＝0.76，P＜0.05）。对Apgar评分与CT分度的关系进行Spearman秩相关分析，结果显示两者呈负相关（r＝-0.66，P＜0.05）。结论 CT 分度与临床分度一致，神经系统损伤越严重，CT分度越高。CT检查是诊断HIE的可靠手段，对临床诊断和治疗具有重要作用。