Effect of erythropoietin combined with hypothermia on serum tau protein levels and neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy

Although hypothermia therapy is effective to treat neonatal hypoxic-ischemic encephalopathy,many neonatal patients die or suffer from severe neurological dysfunction.Erythropoietin is considered one of the most promising neuroprotective agents.We hypothesized that erythropoietin combined with hypothermia will improve efficacy of neonatal hypoxic-ischemic encephalopathy treatment.In this study,41 neonates with moderate/severe hypoxic-ischemic encephalopathy were randomly divided into a control group（hypothermia alone for 72 hours,n = 20） and erythropoietin group（hypothermia ＋ erythropoietin 200 IU/kg for 10 days,n = 21）.Our results show that compared with the control group,serum tau protein levels were lower and neonatal behavioral neurological assessment scores higher in the erythropoietin group at 8 and 12 days.However,neurodevelopmental outcome was similar between the two groups at 9 months of age.These findings suggest that erythropoietin combined with hypothermia reduces serum tau protein levels and improves neonatal behavioral neurology outcome but does not affect long-term neurodevelopmental outcome.

Magnetic resonance imaging scanning susceptibility weighted imaging sequences in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy

BACKGROUND Magnetic resonance imaging(MRI)scanning with susceptibility weighted imaging(SWI)sequences plays a significant role in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy(HIE).AIM To observe the role of MRI multi-parameter quantitative indexes in the diagnosis of neonatal HIE.METHODS The imaging data from 23 cases of neonatal HIE admitted to the Imaging Department of Ganyu District People's Hospital of Lianyungang City and 23 neonates without HIE admitted during the same period were analyzed retrospectively from August,2021 to December,2023.The results of clinical judgment were compared with the results of computed tomography(CT)and MRI examinations.RESULTS The degree of cerebral edema(more than moderate),the number of damaged brain regions(>2),the number of cerebral hemorrhages(>2),and the percentage of small venous dilatation detected were higher in MRI than in CT examination,and the differences were statistically significant(P<0.05).The total area of the largest region of cerebral damage and of cerebral hemorrhage observed by MRI examination were significantly larger than those of CT examination(P<0.01).Multiparametric quantitative MRI combined with diffusion weighted imaging and SWI had higher sensitivity and accuracy than CT diagnosis,and the difference was statistically significant(P<0.05).The difference in the specificity of the two modes of diagnosis was not significant(P>0.05).CONCLUSION The use of MRI multi-parameter quantitative indexes can accurately diagnose and evaluate neonatal HIE.

Transplantation of human placental chorionic plate-derived mesenchymal stem cells for repair of neurological damage in neonatal hypoxic-ischemic encephalopathy

Neonatal hypoxic-ischemic encephalopathy is often associated with permanent cerebral palsy,neurosensory impairments,and cognitive deficits,and there is no effective treatment for complications related to hypoxic-ischemic encephalopathy.The therapeutic potential of human placental chorionic plate-derived mesenchymal stem cells for various diseases has been explored.However,the potential use of human placental chorionic plate-derived mesenchymal stem cells for the treatment of neonatal hypoxic-ischemic encephalopathy has not yet been investigated.In this study,we injected human placental chorionic plate-derived mesenchymal stem cells into the lateral ventricle of a neonatal hypoxic-ischemic encephalopathy rat model and observed significant improvements in both cognitive and motor function.Protein chip analysis showed that interleukin-3 expression was significantly elevated in neonatal hypoxic-ischemic encephalopathy model rats.Following transplantation of human placental chorionic plate-derived mesenchymal stem cells,interleukin-3 expression was downregulated.To further investigate the role of interleukin-3 in neonatal hypoxic-ischemic encephalopathy,we established an in vitro SH-SY5Y cell model of hypoxic-ischemic injury through oxygen-glucose deprivation and silenced interleukin-3 expression using small interfering RNA.We found that the activity and proliferation of SH-SY5Y cells subjected to oxygen-glucose deprivation were further suppressed by interleukin-3 knockdown.Furthermore,interleukin-3 knockout exacerbated neuronal damage and cognitive and motor function impairment in rat models of hypoxic-ischemic encephalopathy.The findings suggest that transplantation of hpcMSCs ameliorated behavioral impairments in a rat model of hypoxic-ischemic encephalopathy,and this effect was mediated by interleukin-3-dependent neurological function.

Observation on the Effect of Parental Participation in Nursing Under the IMCHB Model in Neonatal Hypoxic-Ischemic Encephalopathy

Objective:To investigate the clinical effects of parental participation in nursing under the Interaction Model of Client Health Behavior(IMCHB)model in neonatal hypoxic-ischemic encephalopathy(HIE).Methods:The First Affiliated Hospital of Gannan Medical University included 46 newborns with HIE admitted from October 2021 to October 2023 into the study population.They were divided into a control group and an observation group according to the random number table method,with the control group adopting routine nursing,and the observation group implementing parental participation in nursing under the IMCHB model.The indicators of physical,intellectual,and psychomotor development of the two groups were compared before and after nursing.Results:The physical,intellectual,and psychomotor development of the observation group was higher than that of the control group after 3 months of nursing,and the difference was statistically significant(P<0.05).Conclusion:The implementation of the IMCHB model of parental participation in the clinical care of HIE neonates can further promote their physical,intellectual,and psychomotor development.

Chlorogenic acid alleviates hypoxic-ischemic brain injury in neonatal mice

Recent studies have shown that chlorogenic acid(CGA),which is present in coffee,has protective effects on the nervous system.However,its role in neonatal hypoxic-ischemic brain injury remains unclear.In this study,we established a newborn mouse model of hypoxic-ischemic brain injury using a modified Rice-Vannucci method and performed intraperitoneal injection of CGA.We found that CGA intervention effectively reduced the volume of cerebral infarct,alleviated cerebral edema,restored brain tissue structure after injury,and promoted axon growth in injured brain tissue.Moreover,CGA pretreatment alleviated oxygen-glucose deprivation damage of primary neurons and promoted neuron survival.In addition,changes in ferroptosis-related proteins caused by hypoxic-ischemic brain injury were partially reversed by CGA.Furthermore,CGA intervention upregulated the expression of the key ferroptosis factor glutathione peroxidase 4 and its upstream glutamate/cystine antiporter related factors SLC7A11 and SLC3A2.In summary,our findings reveal that CGA alleviates hypoxic-ischemic brain injury in neonatal mice by reducing ferroptosis,providing new ideas for the treatment of neonatal hypoxic-ischemic brain injury.

Epileptic Seizures in Neonates Treated with Hypothermia for Hypoxo-Ischemic Encephalopathy in Brazzaville, Congo: Types and Evolution

Background: Moderate to severe hypoxic-ischemic encephalopathy (HIE) in neonates is often treated with hypothermia. However, some neonates may experience epileptic seizures during therapeutic hypothermia (TH). Data on the electrophysiologic and evolutionary aspects of these seizures are scarce in African countries. Objectives: To determine the types of epileptic seizures caused by HIE in neonates in Brazzaville;to describe the evolution of background EEG activities during TH and rewarming;to report the evolution of epileptic seizures. Methods: This was a cross-sectional, descriptive study conducted from January 2020 to July 2022. It took place in Brazzaville in the Neonatology Department of the Blanche Gomez Mother and Child Hospital. It focused on term neonates suffering from moderate or severe HIE. They were treated with hypothermia combined with phenobarbital for 72 hours. Results: Among 36 neonates meeting inclusion criteria, there were 18 boys and 18 girls. Thirty-one (86.1%) neonates had grade 2 and 5 (13.9%) grade 3 HIE. In our neonates, HIE had induced isolated electrographic seizures (n = 11;30.6%), electroclinical seizures (n = 25;69.4%), and 6 types of background EEG activity. During TH and rewarming, there were 52.8% of patients with improved background EEG activity, 41.7% of patients with unchanged background EEG activity, and 5.5% of patients with worsened background EEG activity. At the end of rewarming, only 9 (25%) patients still had seizures. Conclusion: Isolated electrographic and electroclinical seizures are the only pathological entities found in our studied population. In neonates with moderate HIE, the applied therapeutic strategy positively influences the evolution of both seizures and background EEG activity. On the other hand, in neonates with severe HIE, the same therapeutic strategy is ineffective. .

Meta-analysis evaluation of the treatment of neonatal hypoxic-ischemic encephalopathy with ganglioside

The efficacy and safety of ganglioside in the treatment of neonates who suffer from hypoxic-ischemic encephalopathy(HIE)needs to be fully evaluated.We searched the following databases:PubMed,ScienceDirect,LISTA,CNKI,Chinese biomedical literature database and Wanfang digital journals of full-text database to determine the inclusion and exclusion criteria of papers and a total of 12 papers were included after quality evaluation.Then we conducted the meta-analysis with RevMan5.0 software.The results showed that compared with the control group,the abnormal rate declined in the ganglioside-treated group(relative risk(RR)=0.27,95%confidence interval(CI)=0.05-1.96).NBNA records of the 7,10-14d neonates were improved effectively:RR(95%CI)were 2.28(0.86-3.42)and 2.53(1.04-2.92)respectively.Neural system sequelae incidence was reduced significantly:RR(95%CI)=0.35:(0.15-0.79).Ganglioside treatment could effectively reduce the abnormality rate of head size,improve the neurological score,reduce the incidence of neurological sequelae,and significantly prompt clinical recovery for neonates with HIE.

Thioperamide treats neonatal hypoxic-ischemic encephalopathy by postsynaptic H1 receptors

Thioperamide, a selective histamine H3 receptor antagonist, can increase histamine content in the brain, improve brain edema, and exert a neuroprotective effect. This study aimed to examine the mechanism of action of thioperamide during brain edema in a rat model of neonatal hypoxic ischemic encephalopathy. Our results showed that thioperamide significantly decreased brain water content and malondialdehyde levels, while significantly increased histamine levels and superoxide dismutase activity in the hippocampus. This evidence demonstrates that thioperamide could pre vent oxidative damage and attenuate brain edema following neonatal hypoxicischemic encepha Iopathy. We further observed that changes in the above indexes occurred after combined treatment of thioperamide with the H1 receptor antagonist, pyrilamine, and the H2 receptor antagonist, ci metidine. Experimental findings indicated that pyrilamine reversed the effects of thioperamide; however, cimetidine had no significant influence on the effects of thioperamide. Our present findings suggest that thioperamide can increase brain histamine content and attenuate brain edema and oxidative damage by acting in combination with postsynaptic H1 receptors in a rat model of neo natal hypoxicischemic encephalopathy.

Neurodevelopmental Problems in Children at 9 Months of Age Associated with Neonatal Hypoxic-Ischemic Encephalopathy

Introduction: Neonatal asphyxia is a major cause of infant morbidity in Cameroon. The aim of this study was to describe the short-term neurological outcome of children following neonatal Hypoxic-ischemic encephalopathy (HIE). Methodology: We conducted a retrospective cohort study from May 2010 to September 2013. We included 39 exposed cases against 78 non-exposed cases followed-up for at least 9 months. The variables studied were: age, sex, head circumference, neurological sequelae, postural anomalies and motor skills and developmental age/quotient. The data collected were analyzed using Epi info software version 3.5.3. The Fisher Exact Test was used to compare the variables with a significance threshold defined for p Results: We recruited 39 cases for 78 controls. The majority (74.40%) of cases were classified as HIE Sarnat 3 and 25.60% Sarnat 2. Most of the children were aged 12 - 36 months with a mean age of 18 months. The male sex was predominant with a sex ratio of 1.2;and 61.50% of children with HIE had head circumference Conclusion: The frequency of neurological sequelae following HIE was high in our series. Efforts should be made to prevent perinatal asphyxia and to ensure the availability of material and staff trained to help babies’ breath in all the delivery rooms in our maternities.

Grading Method for Hypoxic-Ischemic Encephalopathy Based on Neonatal EEG

The grading of hypoxic-ischemic encephalopathy(HIE)contributes to the clinical decision making for neonates with HIE.In this paper,an automated grading method based on electroencephalogram(EEG)data is proposed to describe the severity of HIE infants,namely mild asphyxia,moderate asphyxia and severe asphyxia.The automated grading method is based on a multi-class support vector machine(SVM)classifier,and the input features of SVM classifier include long-term features which are extracted by decomposing the EEG data into different 64 s epoch data and short-term features which are extracted by segmenting the 64 s epoch data into 8 s epoch data with 4 s overlap.Of note,the correlation coefficient and asymmetry extracted in this paper have obvious discriminating capability in HIE infants classification.The experimental results show that the proposed method can achieve the classification accuracy of 78.3%,75.8%and 87.0%of the mild asphyxia group,moderate asphyxia group and severe asphyxia group,respectively.Moreover,the overall accuracy and kappa used to evaluate the performance of the proposed method can reach 79.5%and 0.69,respectively.

Application of Simple Head Cooling Combined with Gangliosides in Neonatal Hypoxic-ischemic Encephalopathy

Objective To investigate the effect of simple head cooling combined with ganglioside therapy on neonatal hypoxic-ischemic encephalopathy(HIE)and its clinical efficacy.Methods A total of 100 children with HIE admitted in the neonatal ward of our hospital from August 2018 to October 2020 were selected as the research objects,and were divided into control group and observation group according to the random number table method,with 50 cases in each group.The control group was treated with gangliosides,and the observation group was treated with simple head cooling combined with gangliosides.Observe and compare the clinical performance improvement time,the level of relevant hematological examination indexes before and after treatment,and the neonatal behavioral neurological assessment(NBNA),clinical efficacy,and adverse reactions.Results The improvement time of convulsions,disturbance of consciousness,pupil changes,hypotonia,and gastrointestinal dysfunction in the observation group was significantly lower than that in the control group(all P<0.001).After treatment,the NSE,IL-6,CK,CK-MB of the two groups of children were significantly lower than before treatment,and the serum calcium and NBNA scores were significantly higher than before treatment,and the decrease or increase in the observation group was significantly higher than that of the control Group(all P<0.001).The total effective rate of treatment of children in the observation group(82.00%)was higher than that of the control group(62.00%)(P<0.05).There were no obvious adverse reactions in both groups.Conclusion The simple head cooling combined with gangliosides in the treatment of HIE can improve the clinical symptoms,blood test index levels,and NBNA scores.The clinical effect is clear and superior to the single use of gangliosides.

Hyperbaric oxygen treatment promotes neural stem cell proliferation in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage

Hyperbaric oxygen therapy for the treatment of neonatal hypoxic-ischemic brain damage has been used clinically for many years, but its effectiveness remains controversial. In addition, the mechanism of this potential neuroprotective effect remains unclear. This study aimed to investigate the influence of hyperbaric oxygen on the proliferation of neural stem cells in the subventricular zone of neonatal Sprague-Dawley rats （7 days old） subjected to hypoxic-ischemic brain damage. Six hours after modeling, rats were treated with hyperbaric oxygen once daily for 7 days. Immunohistochemistry revealed that the number of 5-bromo-2＇-deoxyuridine positive and nestin positive cells in the subventricular zone of neonatal rats increased at day 3 after hypoxic-ischemic brain damage and peaked at day 5. After hyperbaric oxygen treatment, the number of 5-bromo-2＇- deoxyuddine positive and nestin positive cells began to increase at day 1, and was significantly higher than that in normal rats and model rats until day 21. Hematoxylin-eosin staining showed that hyperbaric oxygen treatment could attenuate pathological changes to brain tissue in neonatal rats, and reduce the number of degenerating and necrotic nerve cells. Our experimental findings indicate that hyperbaric oxygen treatment enhances the proliferation of neural stem cells in the subventricular zone of neonatal rats with hypoxic-ischemic brain damage, and has therapeutic potential for promoting neurological recovery following brain injury.

Resatorvid protects against hypoxic-ischemic brain damage in neonatal rats

Secondary brain damage caused by hyperactivation of autophagy and inflammatory responses in neurons plays an important role in hypoxic-ischemic brain damage(HIBD).Although previous studies have implicated Toll-like receptor 4(TLR4)and nuclear factor kappa-B(NF-κB)in the neuroinflammatory response elicited by brain injury,the role and mechanisms of the TLR4-mediated autophagy signaling pathway in neonatal HIBD are still unclear.We hypothesized that this pathway can regulate brain damage by modulating neuron autophagy and neuroinflammation in neonatal rats with HIBD.Hence,we established a neonatal HIBD rat model using the Rice-Vannucci method,and injected 0.75,1.5,or 3 mg/kg of the TLR4 inhibitor resatorvid(TAK-242)30 minutes after hypoxic ischemia.Our results indicate that administering TAK-242 to neonatal rats after HIBD could significantly reduce the infarct volume and the extent of cerebral edema,alleviate neuronal damage and neurobehavioral impairment,and decrease the expression levels of TLR4,phospho-NF-κB p65,Beclin-1,microtubule-associated protein l light chain 3,tumor necrosis factor-α,and interleukin-1βin the hippocampus.Thus,TAK-242 appears to exert a neuroprotective effect after HIBD by inhibiting activation of autophagy and the release of inflammatory cytokines via inhibition of the TLR4/NF-κB signaling pathway.This study was approved by the Laboratory Animal Ethics Committee of Affiliated Hospital of Yangzhou University,China(approval No.20180114-15)on January 14,2018.

Can we further optimize therapeutic hypothermia for hypoxic-ischemic encephalopathy?

Perinatal hypoxic-ischemic encephalopathy is a leading cause of neonatal death and disability.Therapeutic hypothermia significantly reduces death and major disability associated with hypoxic-ischemic encephalopathy;however,many infants still experience lifelong disabilities to movement,sensation and cognition.Clinical guidelines,based on strong clinical and preclinical evidence,recommend therapeutic hypothermia should be started within 6 hours of birth and continued for a period of 72 hours,with a target brain temperature of 33.5 ±0.5℃ for infants with moderate to severe hypoxic-ischemic encephalopathy.The clinical guidelines also recommend that infants be re warmed at a rate of 0.5℃ per hour,but this is not based on strong evidence.There are no randomized controlled trials investigating the optimal rate of rewarming after therapeutic hypothermia for infants with hypoxic-ischemic encephalopathy.Preclinical studies of rewarming are conflicting and results were confounded by treatment with sub-optimal durations of hypothermia.In this review,we evaluate the evidence for the optimal start time,duration and depth of hypothermia,and whether the rate of rewarming after treatment affects brain injury and neurological outcomes.

Applications of advanced signal processing and machine learning in the neonatal hypoxic-ischemic electroencephalography

Perinatal hypoxic-ischemic-encephalopathy significantly contributes to neonatal death and life-long disability such as cerebral palsy. Advances in signal processing and machine learning have provided the research community with an opportunity to develop automated real-time identification techniques to detect the signs of hypoxic-ischemic-encephalopathy in larger electroencephalography/amplitude-integrated electroencephalography data sets more easily. This review details the recent achievements, performed by a number of prominent research groups across the world, in the automatic identification and classification of hypoxic-ischemic epileptiform neonatal seizures using advanced signal processing and machine learning techniques. This review also addresses the clinical challenges that current automated techniques face in order to be fully utilized by clinicians, and highlights the importance of upgrading the current clinical bedside sampling frequencies to higher sampling rates in order to provide better hypoxic-ischemic biomarker detection frameworks. Additionally, the article highlights that current clinical automated epileptiform detection strategies for human neonates have been only concerned with seizure detection after the therapeutic latent phase of injury. Whereas recent animal studies have demonstrated that the latent phase of opportunity is critically important for early diagnosis of hypoxic-ischemic-encephalopathy electroencephalography biomarkers and although difficult, detection strategies could utilize biomarkers in the latent phase to also predict the onset of future seizures.

Resting-state network complexity and magnitude changes in neonates with severe hypoxic ischemic encephalopathy

Resting-state functional magnetic resonance imaging has revealed disrupted brain network connectivity in adults and teenagers with cerebral palsy. However, the specific brain networks implicated in neonatal cases remain poorly understood. In this study, we recruited 14 termborn infants with mild hypoxic ischemic encephalopathy and 14 term-born infants with severe hypoxic ischemic encephalopathy from Changzhou Children's Hospital, China. Resting-state functional magnetic resonance imaging data showed efficient small-world organization in whole-brain networks in both the mild and severe hypoxic ischemic encephalopathy groups. However, compared with the mild hypoxic ischemic encephalopathy group, the severe hypoxic ischemic encephalopathy group exhibited decreased local efficiency and a low clustering coefficient. The distribution of hub regions in the functional networks had fewer nodes in the severe hypoxic ischemic encephalopathy group compared with the mild hypoxic ischemic encephalopathy group. Moreover, nodal efficiency was reduced in the left rolandic operculum, left supramarginal gyrus, bilateral superior temporal gyrus, and right middle temporal gyrus. These results suggest that the topological structure of the resting state functional network in children with severe hypoxic ischemic encephalopathy is clearly distinct from that in children with mild hypoxic ischemic encephalopathy, and may be associated with impaired language, motion, and cognition. These data indicate that it may be possible to make early predictions regarding brain development in children with severe hypoxic ischemic encephalopathy, enabling early interventions targeting brain function. This study was approved by the Regional Ethics Review Boards of the Changzhou Children's Hospital(approval No. 2013-001) on January 31, 2013. Informed consent was obtained from the family members of the children. The trial was registered with the Chinese Clinical Trial Registry(registration number: ChiCTR1800016409) and the protocol version is 1.0.

Mild hypothermia combined with neural stem cell transplantation for hypoxic-ischemic encephalopathy: neuroprotective effects of combined therapy

Neural stem cell transplantation is a useful treatment for ischemic stroke, but apoptosis often occurs in the hypoxic-ischemic environment of the brain after cell transplantation. In this study, we determined if mild hypothermia （27-28~C） can increase the survival rate of neural stem cells （1.0 x 105/~tL） transplanted into neonatal mice with hypoxic-ischemic encephalopathy. Long-term effects on neurological functioning of the mice were also examined. After mild hy- pothermia combined with neural stem cell transplantation, we observed decreased expression levels of inflammatory factor nuclear factor-kappa B and apoptotic factor caspase-3, reduced cerebral infarct volumes, increased survival rate of transplanted cells, and marked improvements in neurological function. Thus, the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation are superior to those of monotherapy. Moreover, our findings suggest that the neuroprotective effects of mild hypothermia combined with neural stem cell transplantation on hypoxic-ischemic encephalopathy are achieved by anti-inflammatory and an- ti-apoptotic mechanisms.

The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage

Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.

Brainstem tegmental lesions in neonates with hypoxicischemic encephalopathy: Magnetic resonance diagnosis and clinical outcome

Lesions of the brainstem have been reported in the clinical scenarios of hypoxic-ischemic encephalopathy(HIE), although the prevalence of these lesions is probably underestimated. Neuropathologic studies have demonstrated brainstem involvement in severely asphyxiated infants as an indicator of poor outcome. Among survivors to HIE, the most frequent clinical complaints that may be predicted by brainstem lesions include feeding problems, speech, language and communication problems and visual impairments. Clinical series, including vascular and metabolic etiologies, have found selective involvement of the brainstem with the demonstration of symmetric bilateral columnar lesions of the tegmentum. The role of brainstem lesions in HIE is currently a matter of debate, especially when tegmental lesions are present in the absence of supratentorial lesions. Differential diagnosis of tegmental lesions in neonates and infants include congenital metabolic syndromes and drug-related processes. Brainstem injury with the presence of supratentorial lesions is a predictor of poor outcome and high rates of mortality and morbidity. Further investigation will be conducted to identify specific sites of the brainstem that are vulnerable to hypoxic-ischemic and toxic-metabolic insults.

Feasibility of allogeneic mesenchymal stem cells in pediatric hypoxic-ischemic encephalopathy: Phase I study

BACKGROUND Hypoxic-ischemic encephalopathy(HIE)is one of the leading causes of death and long-term neurological impairment in the pediatric population.Despite a limited number of treatments to cure HIE,stem cell therapies appear to be a potential treatment option for brain injury resulting from HIE.AIM To investigate the efficacy and safety of stem cell-based therapies in pediatric patients with HIE.METHODS The study inclusion criteria were determined as the presence of substantial deficit and disability caused by HIE.Wharton’s jelly-derived mesenchymal stem cells(WJ-MSCs)were intrathecally(IT),intramuscularly(IM),and intravenously administered to participants at a dose of 1×10^(6)/kg for each administration route twice monthly for 2 mo.In different follow-up durations,the effect of WJ-MSCs administration on HIE,the quality of life,prognosis of patients,and side effects were investigated,and patients were evaluated for neurological,cognitive functions,and spasticity using the Wee Functional Independence Measure(Wee FIM)Scale and Modified Ashworth(MA)Scale.RESULTS For all participants(n=6),the mean duration of exposure to hypoxia was 39.17+18.82 min,the mean time interval after HIE was 21.83±26.60 mo,the mean baseline Wee FIM scale score was 13.5±0.55,and the mean baseline MA scale score was 35±9.08.Three patients developed only early complications such as low-grade fever,mild headache associated with IT injection,and muscle pain associated with IM injection,all of which were transient and disappeared within 24 h.The treatment was evaluated to be safe and effective as demonstrated by magnetic resonance imaging examinations,electroencephalographies,laboratory tests,and neurological and functional scores of patients.Patients exhibited significant improvements in all neurological functions through a 12-mo follow-up.The mean Wee FIM scale score of participants increased from 13.5±0.55 to 15.17±1.6 points(mean±SD)at 1 mo(z=-1.826,P=0.068)and to 23.5±3.39 points at 12 mo(z=-2.207,P=0.027)post-treatment.The percentage of patients who achieved an excellent functional improvement(Wee FIM scale total score=126)increased from 10.71%(at baseline)to 12.03%at 1 mo and to 18.65%at 12 mo posttreatment.CONCLUSION Both the triple-route and multiple WJ-MSC implantations were safe and effective in pediatric patients with HIE with significant neurological and functional improvements.The results of this study support conducting further randomized,placebo-controlled studies on this treatment in the pediatric population.