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QUESTION: Several parents have recently asked me if oxytocin would be helpful for treating their children with autism spectrum disorder (ASD). What do we currently know about the use of oxytocin for the treatment of children with ASD? ANSWER: Autism spectrum disorder is prevalent among children in Canada, with most affected children experiencing difficulties with social function. Behavioural and educational interventions are the first-line treatments for children with ASD. Multiple studies of oxytocin in children with ASD from the past 2 decades provide equivocal results related to social functioning, and a recent large study did not show benefit from treatment with oxytocin. Small sample sizes and differences in participant age, oxytocin formulation and dose, treatment duration, outcome measures, and analytic methods may help explain some of these disparities. The fact that ASD has a range of clinical presentations may also contribute to mixed results. The use of oxytocin has limited benefit in changing social function in children with ASD and there is no support for its current use in the treatment of this population.

QUESTION: Plusieurs parents m’ont récemment demandé si l’ocytocine serait utile pour traiter leur enfant atteint du trouble du spectre de l’autisme (TSA). Que savons-nous sur l’ocytocine pour le traitement des enfants atteints du TSA? RÉPONSE: Le trouble du spectre de l’autisme est fréquent chez les enfants canadiens, et la plupart des enfants atteints éprouvent des difficultés à fonctionner socialement. Les interventions comportementales et éducatives sont les traitements de première intention pour les enfants atteints du TSA. De nombreuses études menées depuis 20 ans sur l’ocytocine chez les enfants atteints du TSA ont donné des résultats équivoques en matière de fonctionnement social, et une récente étude d’envergure n’a pas montré que le traitement par l’ocytocine était bénéfique. Certaines de ces disparités pourraient s’expliquer par la taille réduite des échantillons et les différences d’âge entre les participants, la préparation et la dose d’ocytocine, la durée du traitement, les paramètres d’évaluation et les méthodes analytiques. Le fait que le tableau clinique du TSA soit si vaste contribue également aux résultats mitigés. L’utilisation de l’ocytocine a des bienfaits limités sur la modification du fonctionnement social chez les enfants atteints de TSA, et rien n’appuie son emploi courant pour le traitement de cette population.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes permanent motor deficit "cerebral palsy (CP)," and may result in significant disability and death. Therapeutic hypothermia (TH) had been established as the first effective therapy for neonates with HIE; however, TH must be initiated within the first 6 hours after birth, and the number needed to treat is from 9 to 11 to prevent brain damage from HIE. Therefore, additional therapies for HIE are highly needed. In this review, we provide an introduction on the mechanisms of HIE cascade and how TH and cell therapies such as umbilical cord blood cells and mesenchymal stromal cells (MSCs), especially umbilical cord-derived MSCs (UC-MSCs), may protect the brain in newborns, and discuss recent progress in regenerative therapies using UC-MSCs for neurological disorders.The brain damage process "HIE cascade" was divided into six stages: (1) energy depletion, (2) impairment of microglia, (3) inflammation, (4) excitotoxity, (5) oxidative stress, and (6) apoptosis in capillary, glia, synapse and/or neuron. The authors showed recent 13 clinical trials using UC-MSCs for neurological disorders.The authors suggest that the next step will include reaching a consensus on cell therapies for HIE and establishment of effective protocols for cell therapy for HIE. KEY POINTS: · This study includes new insights about cell therapy for neonatal HIE and CP in schema.. · This study shows precise mechanism of neonatal HIE cascade.. · The mechanism of cell therapy by comparing umbilical cord blood stem cell with MSC is shown.. · The review of recent clinical trials of UC-MSC is shown..

Glucose metabolism has been the focus of research in order to understand pathological conditions associated with diseases such as neonatal hypoxic-ischemic-encephalopathy (HIE), cerebral palsy (CP) and cerebral infarction.[Objective] To evaluate the use of molecular imaging (SPECT and PET) for children with HIE and CP before and after cell therapy, and to propose future perspectives on the use of those modalities for assessment of brain function in children with these conditions.[Methods] PubMed search for studies using PET or SPECT scans for HIE and CP in children.[Results] We identified 18 PET and 17 SPECT studies that have been performed in cases under age of 19 over the past three decades (1991–2021). Six papers on PET use consisted of one with human umbilical cord derived mesenchymal stromal cells, one mobilized peripheral blood mononuclear cells, three autologous bone marrow mononuclear cells and one allogeneic umbilical cord blood. 4/6 papers reported that PET-CT scan revealed increased glucose metabolism and 1/6 showed no significant change in glucose metabolism after cell therapy. One article on SPECT reported that 2/5 cases had improvement of cerebral perfusion in the thalamus after treatment.[Discussion] SPECT in the first few weeks of life is useful and more sensitive than MRI in predicting major neurological disability. SPECT is not appropriate for neonates because of the risk of radiation, improvement of other clinical test equipment. PET studies reported high glucose metabolism in the early neonatal periods in children with mild to moderate HIE, but not in the most severe cases, including those neonates that died.We suggested that PET could be more useful tool to estimate effectiveness of stem cell therapy than SPECT.[Conclusion] PET might be a good clinical modalities to clarify mechanism of stem cell therapy for CP. We need further clinical studies to clarify more precisely.

Background Neonates with hypoxic ischemic encephalopathy (HIE) on therapeutic hypothermia (TH) therapy may show persistent pulmonary hypertension of the newborn (PPHN). In Japan, reported mortality rate is lower than in the U.S., possibly due to treatment differences of newborns with moderate to severe HIE and PPHN. The objective of this study was to determine the feasibility and long term outcomes of Inhaled nitric oxide (iNO) and TH therapy in newborns with moderate to severe HIE with PPHN. Methods This was a retrospective review of neonates with moderate to severe HIE that were treated with TH from 2008 to 2017 at a large medical center in Japan. We documented their long term neurological prognosis measuring developmental quotient (DQ) and gross motor function classification system (GMFCS) at 18 months old. Results A total of 37 neonates with moderate to severe HIE underwent TH therapy and six of them were started with iNO therapy for PPHN. iNO with TH was safely started for all six newborns with moderate to severe HIE with PPHN. In two neonates TH was discontinued because of an intraventricular hemorrhage (IVH) and severe hypotension. Neurological outcomes were similar in newborns who were treated with iNO and TH and those who were treated with TH alone. Conclusion These initial findings suggest that monitoring hematologic and cardiovascular status is important with iNO for severe asphyxia infants with PPHN. We have to develop safer and more feasible protocols when we undergo iNO and TH therapy.

To explore the predictive value of the Thompson score during the first 4 days of life for estimating short-term adverse outcomes in neonatal encephalopathy.This observational study evaluated infants with neonatal encephalopathy (≥36 weeks of gestation) registered in a multicenter cohort of cooled infants in Japan. The Thompson score was evaluated at 0-24, 24-48, 48-72, and 72-90 h of age. Adverse outcomes included death, survival with respiratory impairment (requiring tracheostomy), or survival with feeding impairment (requiring gavage feeding) at discharge.Of the 632 infants, 21 (3.3%) died, 59 (9.3%) survived with respiratory impairment, and 113 (17.9%) survived with feeding impairment. The Thompson score throughout the first 4 days accurately predicted death, respiratory impairment, or feeding impairment. The 72-90 h score showed the highest accuracy. A cutoff of ≥15 had a sensitivity of 0.85 and specificity of 0.92 for death or respiratory impairment, while a cutoff of ≥14 had a sensitivity of 0.71 and a specificity of 0.92 for death, respiratory or feeding impairment.A high Thompson score during the first 4 days of life, especially at 72-90 h could thus be useful for estimating the need for prolonged life support.The Thompson score on days 1-4 of age was useful in predicting death and respiratory or feeding impairments. The 72-90 h Thompson score showed the highest predictive capability. Owing to the rarity of withdrawal of life-sustaining treatment in Japan, 43% of infants with persistent severe encephalopathy with a Thompson score of ≥15 at 72-90 h of age could regain spontaneous breathing, be extubated, and survive without tracheostomy. Meanwhile, approximately 50% of infants who survived without tracheostomy required gavage feeding. Our results could provide useful information for clinical decision making regarding infants with persistent severe encephalopathy.

This study investigated the 3-year clinical outcomes in relation to the severity of encephalopathy in high-survival infants who underwent therapeutic hypothermia. This retrospective observational study was conducted in level II/III neonatal intensive care units in Japan. The nationwide cohort included 474 infants registered in the Baby Cooling Registry of Japan between January 2012 and December 2016. Clinical characteristics, mortality rate and severe neurological impairment at age 3 years were evaluated. Of the infants, 48 (10.4%), 291 (63.1%) and 122 (26.5%) had mild, moderate and severe encephalopathy, respectively, upon admission. By age 3, 53 (11.2%) infants died, whereas 110 (26.1%) developed major disabilities. The mild group survived up to age 3. In the moderate group, 13 (4.5%) died and 44 (15.8%) developed major disabilities. In the severe group, 39 (32.0%) died by age 3. Adverse outcomes were observed in 100 (82.0%) infants. Mortality was relatively low in all subgroups, but the incidence of major disabilities was relatively high in the severe group. The relatively low mortality and high morbidity may be due to Japanese social and ethical norms, which rarely encourage the withdrawal of intensive life support. Cultural and ethical backgrounds may need to be considered when assessing the effect of therapeutic interventions.

Neonates with hypoxic-ischemic encephalopathy (HIE) on therapeutic hypothermia (TH) therapy may show persistent pulmonary hypertension of the newborn (PPHN). In Japan, the reported mortality rate is lower than in the US, possibly due to treatment differences of newborns with moderate to severe HIE and PPHN. This study aimed to determine the feasibility and long-term outcomes of inhaled nitric oxide (iNO) and TH therapy in newborns with moderate to severe HIE and PPHN.This was a retrospective review of neonates with moderate to severe HIE that were treated with TH from 2008 to 2017 at a large medical center in Japan. We documented their long-term neurological prognosis, measuring their developmental and Gross Motor Function Classification System level at 18 months old.A total of 37 neonates with moderate to severe HIE underwent TH therapy and six of them were started with iNO therapy for PPHN. iNO with TH was safely administered to all six newborns with moderate to severe HIE with PPHN. In two neonates TH was discontinued because of intraventricular hemorrhage (IVH) and severe hypotension. Neurological outcomes were similar in newborns who were treated with iNO and TH and those who were treated with TH alone.These initial findings suggest that monitoring hematological and cardiovascular status is important with iNO for severe asphyxia in infants with PPHN. Safer and more feasible protocols are needed for when iNO and TH therapy are administered together.

Therapeutic hypothermia following neonatal encephalopathy is neuroprotective. However, approximately one in two cooled infants still die or develop permanent neurological impairments. Further understanding of variables associated with the effectiveness of cooling is important to improve the therapeutic regimen. To identify clinical factors associated with short-term outcomes of cooled infants, clinical data of 509 cooled infants registered to the Baby Cooling Registry of Japan between 2012 and 2014 were evaluated. Independent variables of death during the initial hospitalization and survival discharge from the cooling hospital at ≤28 days of life were assessed. Death was associated with higher Thompson scores at admission (p

Therapeutic hypothermia is a standard of care for neonatal encephalopathy; however, approximately one in two newborn infants fails to respond to this treatment. Recent studies have suggested potential relationships between body temperature, heart rate and the outcome of cooled infants.The clinical data of 756 infants registered to the Baby Cooling Registry of Japan between January 2012 and December 2016 were analysed to assess the relationship between body temperature, heart rate and adverse outcomes (death or severe impairment at 18 months corrected age).A lower body temperature at admission was associated with adverse outcomes in the univariate analysis (P 0.001), the significance of which was lost when adjusted for the severity of encephalopathy and other covariates. A higher body temperature during cooling and higher heart rate before and during cooling were associated with adverse outcomes in both univariate (all P 0.001) and multivariate (P = 0.012, P 0.001 and P 0.001, respectively) analyses.Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling, whereas causal relationships between slightly higher temperatures during cooling and adverse outcomes need to be elucidated in future studies.In a large cohort of encephalopathic newborn infants, dual roles of body temperature to the outcome were shown; adverse outcomes were associated with a lower body temperature at admission and higher body temperature during cooling. A higher heart rate before and during cooling were associated with adverse outcomes. Severe hypoxia-ischaemia might be a common causative of faster heart rates before and during cooling and low body temperature before cooling. The exact mechanism underlying the relationship between slightly higher body temperature during cooling and adverse outcomes remains unknown, which needs to be elucidated in future studies.

Neonatal hypoxic-ischaemic encephalopathy (HIE) is a serious condition; many survivors develop neurological impairments, including cerebral palsy and intellectual disability. Preclinical studies show that the systemic administration of umbilical cord blood cells (UCBCs) is beneficial for neonatal HIE. We conducted a single-arm clinical study to examine the feasibility and safety of intravenous infusion of autologous UCBCs for newborns with HIE. When a neonate was born with severe asphyxia, the UCB was collected, volume-reduced, and divided into three doses. The processed UCB was infused at 12–24, 36–48, and 60–72 hours after the birth. The designed enrolment was six newborns. All six newborns received UCBC therapy strictly adhering to the study protocol together with therapeutic hypothermia. The physiological parameters and peripheral blood parameters did not change much between pre- and postinfusion. There were no serious adverse events that might be related to cell therapy. At 30 days of age, the six infants survived without circulatory or respiratory support. At 18 months of age, neurofunctional development was normal without any impairment in four infants and delayed with cerebral palsy in two infants. This pilot study shows that autologous UCBC therapy is feasible and safe.

Neonatal ischemic brain injury causes permanent motor-deficit cerebral palsy. Hypoxic-ischemic encephalopathy (HIE) is a very serious condition that can result in death and disability. In 1997, we reported that irreversible neuronal cell damage is induced by the elevation of intracellular Ca ion concentration that has occurred in sequence after excess accumulation of the excitatory neurotransmitter glutamate during ischemia. We also reported that hypothermia was effective in treating ischemic brain damage in rats by suppressing energy loss and raising intracellular Ca ion concentration. Following the 2010 revised International Liaison Committee on Resuscitation guideline, our group developed the Guideline for the treatment of Hypothermia in Japan, and we started online case registry in January 2012. However, therapeutic hypothermia must be initiated within the first 6 h after birth. By contrast, cell therapy may have a much longer therapeutic time window because it might reduce apoptosis/oxidative stress and enhance the regenerative process. In 2014, we administered autologous umbilical cord blood stem cell (UCBC) therapy for neonatal HIE, for the first time in Japan. We enrolled five full-term newborns with moderate-to-severe HIE. Our autologous UCBC therapy is leading to new protocols for the prevention of ischemic brain damage.

KBG syndrome (KBGS) is an autosomal dominant multiple congenital anomaly-intellectual disability syndrome, characterized by developmental delay with neurological involvements, macrodontia of the upper central incisors, characteristic facial dysmorphism and skeletal anomalies. Variants in ANKRD11 cause KBGS. We present five individuals from four families with ANKRD11 variants identified by whole-exome sequencing. Four of the five were clinically affected, and their diagnoses were varied. One was typical KBGS, two were Coffin–Siris syndrome-like (CSS), and one was intellectual disability with infantile spasms. One individual showed extremely mild phenotype. All individuals fulfilled the proposed diagnostic criteria for KBGS. Phenotypic features overlap between KBGS and CSS to some extent, and characteristic dental and fifth finger/toe findings can indicate differential diagnosis. These findings indicate that patients with ANKRD11 variants occupy a wide spectrum of intellectual disability, including clinically normal individuals. This is the first report highlighting the clinical overlap between KBGS and CSS and supporting the recently proposed clinical concept, in which transcriptional machineries are disrupted.

ObjectiveApgar scores of zero at 10 min strongly predict mortality and morbidity in infants. However, recent data reported improved outcomes among infants with Apgar scores of zero at 10 min. We aimed to review the mortality rate and neurodevelopmental outcomes of infants with Apgar scores of zero at 10 min in Japan.DesignObservational study.PatientsTwenty-eight of 768 infants registered in the Baby Cooling Registry of Japan between 2012 and 2016, at >34 weeks’ gestation, with Apgar scores of zero at 10 min who were treated with therapeutic hypothermia.InterventionsWe investigated the time of first heartbeat detection in infants with favourable outcomes and who had neurodevelopmental impairments or died.Main outcome measuresClinical characteristics, mortality rate and neurodevelopmental outcomes at 18–22 months of age were evaluated.ResultsNine (32%) of the 28 infants died before 18 months of age; 16 (57%) survived, but with severe disabilities and 3 (11%) survived without moderate-to-severe disabilities. At 20 min after birth, 14 of 27 infants (52%) did not have a first heartbeat, 13 of them died or had severe disabilities and one infant, who had the first heartbeat at 20 min, survived without disability.ConclusionOur study adds to the recent evidence that neurodevelopmental outcomes among infants with Apgar scores of zero at 10 min may not be uniformly poor. However, in our study, all infants with their first heartbeat after 20 min of age died or had severe disabilities.

Objective To describe the current status of withholding or withdrawal of life-sustaining interventions (LSI) for neonates in Japan and to identify physician- and institutional-related factors that may affect advance care planning (ACP) practices with parents. Study design A self-reported questionnaire was administered to assess frequency of withholding and withdrawing intensive care at the respondent's facility, the physician's degree of affirming various beliefs about end-of-life care that was compared to 7 European countries, their self-reported ACP practices and perceived barriers to ACP. Three neonatologists at all 298 facilities accredited by the Japan Society for Neonatal Health and Development were surveyed, with 572 neonatologists at 217 facilities responding. Results At 76% of facilities, withdrawing intensive care treatments was “never” done, while withholding intensive care had been done “sometimes” or more frequently at 82% of facilities. Japanese neonatologists differed from European neonatologists regarding their degree of affirmation of 3 out of 7 queried beliefs about end-of-life care. In hospitals that were more likely to “sometimes” (or more often) withdraw treatments, respondents were less likely to affirm beliefs about doing “everything possible” or providing the “maximum of intensive care”. Self-reported ACP practices did not vary between neonatologists based on their hospital's overall pattern of withholding or withdrawing treatments. Conclusion Among NICU facilities in Japan, 21% had been sometimes withdrawing LSI and 82% had been “sometimes” withholding LSI. Institutional treatment practices may have a strong association with physicians' beliefs that then affect end-of-life discussions, but not with self-reported ACP practices.

Firstly, I mention on pathology of ischemic brain injury, including experimental history of hypothermia. Next, I explain about how clinical trial study starts and proceed to Consensus 2010 in which hypothermia therapy should be recommended for newborns with moderate to severe hypoxic-ischemic encephalopathy (HIE). Next I talk about how hypothermia therapy spreads and could be standardized on the guideline and nationwide online registry system in Japan since Consensus 2010. I explain about some research works about efficacy and criteria of hypothermia therapy. I also introduce unique research about how to control core temperature during transportation in Japan. Finally, I talk about the possibility to start new neuroprotective therapy for newborns with perinatal ischemic brain injury.

In Japan, we started autologous cord blood therapy for newborns with HIE in 2014 (described in Chap. 1). Another research group started autologous cord blood therapy for patients with cerebral palsy in 2017. However, cerebral palsy is induced in nearly twice as many premature babies with IVH and PVL as that by term newborns with HIE (Touyama et al. Brain Dev 38:792–799, 2016; Koterazawa et al. No to Hattatsu 48:14–19, 2016; Glinianaia et al. Dev Med Child Neurol 59:864–870, 2017). Therefore, we are now promoting a new clinical study protocol of cell therapy for premature newborns with PVL or IVH.

Therapeutic hypothermia was first recommended as a standard of care by international guidelines in 2010. However, at that time, the number of centers capable of providing standard cooling was limited even in Japan. The aim of this project was to implement a nationwide network of evidence-based cooling within 3 years. A taskforce was formed in June 2010 to undergo the primary nationwide practice survey, design of action plans, and the appraisal of interventions by involving all registered level-II/III neonatal intensive care units in Japan. Based on findings from the primary survey, aggressive action plans were introduced that focused on the formulation of clinical recommendations, facilitation of educational events, and opening of an online case registry. Findings from the follow-up survey (January 2013) were compared with the results from the primary survey (June 2010). Four workshops and three consensus meetings were held to formulate clinical recommendations, which were followed by the publication of practical textbooks, large-scale education seminars, and implementation of a case registry. A follow-up survey covering 253 units (response rate: 89.1%) showed that cooling centers increased from 89 to 135. Twelve prefectures had no cooling centers in 2010, whereas all 47 prefectures had at least one in 2013. In cooling centers, adherence to the standard cooling protocols and the use of servo-controlled cooling devices improved from 20.7% to 94.7% and from 79.8% to 98.5%, respectively. A rapid improvement in the national provision of evidence-based cooling was achieved. International consensus guidelines coupled with domestic interventions might be effective in changing empirical approaches to evidence-based practice.

Objective Pediatric hospice has been the adoption of several service provision models in highly developed countries such as UK, Germany, Australia or Canada for a few decades, yet it has seldom been the case in the Asian Continent. This study aimed to evaluate the newest challenge for the children with Life-threatening illness (LTI) and described the characteristic of pediatric palliative care at the first pediatric hospice in Japan. Methods A retrospective review of all patients at our pediatric hospice in these three years was conducted. Of the 294 cases reviewed, 269 cases were eligible for analysis. Results We reviewed 269 patients admitted during the first three years. Most patients required intensive medical intervention. Patients were hospitalized in our pediatric hospice not only for end-of-life care (EOL), but also for respite care. Only 7% of the patients were with cancer. To support children and family to make the most of their time together, we provided a range of medical and recreational care. It is expected that the pediatric hospice will extend and establish cooperation with other hospitals or community services. Conclusion Three years’ experience of pediatric palliative care at the first pediatric hospice in the Asian Continent is encouraging. Further experience and improved communication with other pediatric service providers as well as their education in palliative care will enhance the recognition of the capacity of our hospice and support the needs of more children. Furthermore, we would like to introduce the idea of pediatric hospice and spread it throughout the Asian Continent in the future.

Therapeutic hypothermia is recommended for moderate and severe neonatal encephalopathy, but is being applied to a wider range of neonates than originally envisaged. To examine the clinical use of therapeutic hypothermia, data collected during the first 3 years (2012–2014) of the Baby Cooling Registry of Japan were analysed. Of 485 cooled neonates, 96.5% were ≥36 weeks gestation and 99.4% weighed ≥1,800 g. Severe acidosis (pH 10 min. Stage II/III encephalopathy was evident in 88.3%; hypotonia, seizures and abnormal amplitude-integrated electroencephalogram were observed in the majority of the remainder. In-hospital mortality was 2.7%; 90.7% were discharged home. Apgar scores and severity of acidosis/encephalopathy did not change over time. The time to reach the target temperature was shorter in 2014 than in 2012. The proportion undergoing whole-body cooling rose from 45.4% to 81.6%, while selective head cooling fell over time. Mortality, duration of mechanical ventilation and requirement for tube feeding at discharge remained unchanged. Adherence to standard cooling protocols was high throughout, with a consistent trend towards cooling being achieved more promptly. The mortality rate of cooled neonates was considerably lower than that reported in previous studies.

Neonatal encephalopathy (NE) secondary to intrapartum asphyxia remains a major cause of post-natal death and permanent neurological deficits worldwide. Supportive therapy has been the mainstay of the treatment until recent series of large clinical trials demonstrating benefit of therapeutic hypothermia (TH) in this high risk population. Now the International Liaison Committee on Resuscitation (ILCOR) recommends TH as a standard of care with the protocols used in the large clinical trials as tentative standard protocols. Our goal is to develop a nationwide consensus practice guideline not only consistent with the international standard protocols but also practical and compatible with the current medical system in Japan. In summary, TH should be offered to newborn infants born ≥36 weeks gestational age and birth weight ≥1800 g exhibiting clinical signs of moderate to severe NE as well as evidence of hypoxia-ischemia, i.e. 10 min Apgar score ≤5, a need for resuscitation at 10 min, blood pH

Background: Therapeutic hypothermia is now recommended as a standard of care for neonatal encephalopathy. Although adherence to standard cooling protocols used in the phase-III trials is essential, empiric approaches have prevailed in Japan. Aim: To elucidate the gap between the standard cooling methods and the current practice in Japan. Method: In July 2010, a questionnaire regarding the practice of neonatal encephalopathy was mailed to clinical leads of registered neonatal intensive care units. Result: 56.2% of the units were incapable of offering therapeutic hypothermia because of the reasons such as the shortage of human/medical resources (85.1%) and limited number of cases (21.1%). Eighty-nine centres provided therapeutic hypothermia using either selective-head cooling (88.8%) or whole-body cooling (11.2%). Various target temperatures and cooling durations were used; 20.2% of the units cooled infants without using purpose-built equipments, whereas 14.6% did not continuously monitor the body temperature. Discussion: Only 43.8% of the units provided therapeutic hypothermia. Even in centres where hypothermia was offered, adherence to the standard protocols was extremely poor. To secure the safety and efficacy, further promotion of the standard cooling protocols is required; an efficient cooling centre network has to be established by optimizing the work forth distribution and transportation system.

Background: Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized clini- cally by biphasic seizures and late magnetic resonance imaging abnormalities, such as reduced subcortical diffusion from day 3 onwards, often accompanied with some neurological sequelae. In the early stages of the disease, AESD closely resembles its far more prevalent and relatively benign counterpart, febrile seizure (FS). Methods: We measured and compared the serum or cerebrospinal fluid (CSF) levels of S100B, neuron-specific enolase (NSE), and total tau protein in 43 patients with FS and 18 patients withAESD, at any point during the disease. To assess early diagnostic validity, we compared these biomarkers in 43 FS and eight AESD patients, with whom the day 0-2 samples were available. We used the receiver-operator characteristic curve to evaluate the diagnostic values of these markers. Results: The levels of all biomarkers were significantly higher in AESD than FS patients. When only day 0-2 samples from AESD patients were used, the levels of all the measured biomarkers, except serum NSE, were still significantly higher in patients with AESD than in FS, suggesting that AESD could damage astrocytes, neurons, and axons, even in the early stages of the disease. According to the receiver-operator characteristic curve analyses, CSF S100B (cut-off value, 100 pg/mL) and CSF total tau protein (cut-off value, 100 pg/mL) were better predictors of AESD than other biomarkers. Conclusion: The combination of CSF S100B and CSF total tau protein resulted in a positive predictive value of AESD 83.3%, which could be helpful for early diagnosis, facilitating early therapeutic interventions.

Background Severe hypotension in infants, especially in preterm infants, is associated with poor neurological outcome and high mortality. In adults, low-dose vasopressin (arginine vasopressin: AVP) infusion therapy has been effective for treating hypotension that is refractory to vasopressors and inotropes. Methods The effects of AVP infusion therapy for refractory hypotension were retrospectively evaluated in extremely low-birthweight infants. Between January 2002 and November 2005, 22 infants with refractory hypotension treated with low-dose AVP infusion were reviewed. The average birthweight was 658 g (+/-142 g), and the average gestational age was 24.9 weeks (+/-1.4). The changes in blood pressure, urinary output, and other parameters in response to AVP therapy were analyzed in all the infants. Results After AVP infusion, systolic blood pressure increased from 30 mmHg to 43 mmHg (P Conclusions Low-dose AVP therapy should be considered as rescue therapy when high-dose catecholamine therapy and/or steroid administration do not produce sufficient increase in the blood pressure. Further investigations are required to prove the efficacy and safety of AVP infusion therapy in preterm infants.

We experienced six cases who could undergo therapeutic hypothermia (TH) therapy combined with inhaled nitric oxide (iNO) therapy and one persistent pulmonary hypertension (PPHN) case who could undergo and stop TH during 2002-2014. We experienced no complication in these six cases. We have compared perinatal factors, MRI findings around one-year-old, Gross Motor Function Classification System (GMFCS) and developmental quotient around one and a half year old between 6 cases who underwent TH therapy completely combined with iNO therapy (TH+iNO group) and 38 cases who underwent only TH therapy (TH group). There are no significant differences of perinatal factors, MRI findings, GMFCS, and developmental quotient between (TH+iNO group) and (TH group). These results showed TH could be performed safely for HIE cases with PPHN combined with iNO therapy maintaining the stable condition of respiration and circulation. We need to investigate more PPHN cases with iNO therapy to clarify criteria which cases could be performed TH therapy safely.

Objective: Recently, COL4A1 mutations have been reported in porencephaly and other cerebral vascular diseases, often associated with ocular, renal, and muscular features. In this study, we aimed to clarify the phenotypic spectrum and incidence of COL4A1 mutations. Methods: We screened for COL4A1 mutations in 61 patients with porencephaly and 10 patients with schizencephaly, which may be similarly caused by disturbed vascular supply leading to cerebral degeneration, but can be distinguished depending on time of insult. Results: COL4A1 mutations were identified in 15 patients (21%, 10 mutations in porencephaly and 5 mutations in schizencephaly), who showed a variety of associated findings, including intracranial calcification, focal cortical dysplasia, pontocerebellar atrophy, ocular abnormalities, myopathy, elevated serum creatine kinase levels, and hemolytic anemia. Mutations include 10 missense, a nonsense, a frameshift, and 3 splice site mutations. Five mutations were confirmed as de novo events. One mutation was cosegregated with familial porencephaly, and 2 mutations were inherited from asymptomatic parents. Aberrant splicing was demonstrated by reverse transcriptase polymerase chain reaction analyses in 2 patients with splice site mutations. Interpretation: Our study first confirmed that COL4A1 mutations are associated with schizencephaly and hemolytic anemia. Based on the finding that COL4A1 mutations were frequent in patients with porencephaly and schizencephaly, genetic testing for COL4A1 should be considered for children with these conditions. ANN NEUROL 2013.

Therapeutic hypothermia is now recommended as a standard of care for neonatal encephalopathy. Although adherence to standard cooling protocols used in the phase-III trials is essential, empiric approaches have prevailed in Japan.To elucidate the gap between the standard cooling methods and the current practice in Japan.In July 2010, a questionnaire regarding the practice of neonatal encephalopathy was mailed to clinical leads of registered neonatal intensive care units.56.2% of the units were incapable of offering therapeutic hypothermia because of the reasons such as the shortage of human/medical resources (85.1%) and limited number of cases (21.1%). Eighty-nine centres provided therapeutic hypothermia using either selective-head cooling (88.8%) or whole-body cooling (11.2%). Various target temperatures and cooling durations were used; 20.2% of the units cooled infants without using purpose-built equipments, whereas 14.6% did not continuously monitor the body temperature.Only 43.8% of the units provided therapeutic hypothermia. Even in centres where hypothermia was offered, adherence to the standard protocols was extremely poor. To secure the safety and efficacy, further promotion of the standard cooling protocols is required; an efficient cooling centre network has to be established by optimizing the work forth distribution and transportation system.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is characterized clinically by biphasic seizures and late magnetic resonance imaging abnormalities, such as reduced subcortical diffusion from day 3 onwards, often accompanied with some neurological sequelae. In the early stages of the disease, AESD closely resembles its far more prevalent and relatively benign counterpart, febrile seizure (FS).We measured and compared the serum or cerebrospinal fluid (CSF) levels of S100B, neuron-specific enolase (NSE), and total tau protein in 43 patients with FS and 18 patients with AESD, at any point during the disease. To assess early diagnostic validity, we compared these biomarkers in 43 FS and eight AESD patients, with whom the day 0-2 samples were available. We used the receiver-operator characteristic curve to evaluate the diagnostic values of these markers.The levels of all biomarkers were significantly higher in AESD than FS patients. When only day 0-2 samples from AESD patients were used, the levels of all the measured biomarkers, except serum NSE, were still significantly higher in patients with AESD than in FS, suggesting that AESD could damage astrocytes, neurons, and axons, even in the early stages of the disease. According to the receiver-operator characteristic curve analyses, CSF S100B (cut-off value, 100 pg/mL) and CSF total tau protein (cut-off value, 100 pg/mL) were better predictors of AESD than other biomarkers.The combination of CSF S100B and CSF total tau protein resulted in a positive predictive value of AESD 83.3%, which could be helpful for early diagnosis, facilitating early therapeutic interventions.

Neonatal encephalopathy (NE) secondary to intrapartum asphyxia remains a major cause of post-natal death and permanent neurological deficits worldwide. Supportive therapy has been the mainstay of the treatment until recent series of large clinical trials demonstrating benefit of therapeutic hypothermia (TH) in this high risk population. Now the International Liaison Committee on Resuscitation (ILCOR) recommends TH as a standard of care with the protocols used in the large clinical trials as tentative standard protocols. Our goal is to develop a nationwide consensus practice guideline not only consistent with the international standard protocols but also practical and compatible with the current medical system in Japan. In summary, TH should be offered to newborn infants born ≥36 weeks gestational age and birth weight ≥1800 g exhibiting clinical signs of moderate to severe NE as well as evidence of hypoxia-ischemia, i.e. 10 min Apgar score ≤5, a need for resuscitation at 10 min, blood pH7.00, or base deficit ≥16 mmol/L. TH should be conducted in the NICUs capable of multidisciplinary care and under the standard protocols, i.e. utilization of cooling device, target (rectal or esophageal) temperatures at 33.5±0.5 and 34.5±0.5°C for whole body and selective head cooling respectively, duration of TH for 72 h, gradual rewarming not exceeding the rate of 0.5°C/h. Long term follow-up with multidisciplinary approach including standardized psychological assessment is warranted.

Severe hypotension in infants, especially in preterm infants, is associated with poor neurological outcome and high mortality. In adults, low-dose vasopressin (arginine vasopressin: AVP) infusion therapy has been effective for treating hypotension that is refractory to vasopressors and inotropes.The effects of AVP infusion therapy for refractory hypotension were retrospectively evaluated in extremely low-birthweight infants. Between January 2002 and November 2005, 22 infants with refractory hypotension treated with low-dose AVP infusion were reviewed. The average birthweight was 658 g (+/-142 g), and the average gestational age was 24.9 weeks (+/-1.4). The changes in blood pressure, urinary output, and other parameters in response to AVP therapy were analyzed in all the infants.After AVP infusion, systolic blood pressure increased from 30 mmHg to 43 mmHg (P0.0001), and the diastolic pressure increased from 15 mmHg to 24 mmHg (P0.0001). The urine output dramatically increased from 1.5 mL/kg per h to 4.0 mL/kg per h (P0.0001). AVP infusion, however, was not effective in four of the 22 patients (18%). The sodium concentration in the serum decreased mildly after administration. In six patients the serum sodium concentration decreased below 130 mEq/L. Severe mitral regurgitation was observed in two patients. Three infants showed a transient decrease in the platelet count during AVP infusion.Low-dose AVP therapy should be considered as rescue therapy when high-dose catecholamine therapy and/or steroid administration do not produce sufficient increase in the blood pressure. Further investigations are required to prove the efficacy and safety of AVP infusion therapy in preterm infants.

We retrospectively investigated the incidence, neuroimaging findings, and motor and intellectual disability of infants with cerebral palsy (CP) who were born between 1983 and 1997. The incidence of CP was found to have increased gradually and the major cause was periventricular leukomalacia. The prognosis of preterm infants was better than that of term infants. These findings suggest that the increase in the incidence of CP has been due mainly to changes in medical care for neonates.

We investigated the correlation between energy metabolism and neural activity during glucose deprivation and during replacement of glucose with lactate and beta-hydroxybutyrate (OHBA) in neural tissue from rats of different ages. Hippocampal slices were prepared from 4-, 7-, 10-, 13- and 16-day-old and adult rats. The population spikes (PS) were recorded in the pyramidal cell layer of the CA3 area as the index of neural activity. ATP and creatine-phosphate (CrP) levels in each slice were determined during glucose deprivation and during replacement of glucose with lactate or OHBA. After deprivation of glucose, the PS of the slices from 4-, 7- and 10-day-old and adult rats decayed and extinguished in 30 min and the decay time was shortened according to the age of the rat. The levels of ATP and CrP in the slices also decreased, but to a lesser extent than the amplitudes of PS. After substitution of lactate or beta-hydroxybutyrate (OHBA) for glucose, PS of the adult rat disappeared as was the case with glucose deprivation, although the levels of high energy phosphates were well maintained. In the case of the immature rat, however, PS decayed more slowly. Especially in the case of 4-day-old rat, ATP and CrP in the slices were maintained as high as those under the initial concentrations and PS amplitude showed no decay even after 60 min. These results indicate that the presence of glucose is essential for neural activity in the adult rat, and lactate or OHBA cannot replace it for the maintenance of neural activity. In the immature rat, glucose metabolites such as lactate and OHBA are available for both neural activity as well as maintaining the levels of high-energy phosphates in the tissue slice.

The protective effects of mild hypothermia (33 and 29 degrees C) on the neuronal activity, intracellular Ca2+ accumulation and ATP levels during deprivation of oxygen and/or glucose were investigated using guinea pig hippocampal slices. During oxygen and glucose deprivation and oxygen deprivation only, mild hypothermia had only minor effects on the maintenance of neuronal activity and ATP levels, but it suppressed Ca2+ accumulation and drastically improved the reversibility of neuronal activity. During glucose deprivation only, mild hypothermia could maintain the neuronal activity as well as ATP levels.

Subpopulations of interleukin-2 receptor (IL-2R)-positive CD4 and CD8 T cells and IL-2R+ CD20 B cells in the peripheral blood lymphocytes as well as serum concentrations of soluble IL-2R (sIL2R) were measured in children aged 1–7 years who suffered acute severe asthmatic attack. Subpopulations of CD4+ IL-2R+ cells, CD8+ IL-2R+ cells and CD20+ IL-2R+ cells in the peripheral blood lymphocytes at acute severe asthmatic attack phase were significantly higher than those at non-asthmatic attack phase (P < 0.02, P < 0.03 and P < 0.02, respectively). Subpopulations of CD20+ IL-2R+ cells in the peripheral blood lymphocytes significantly decreased 5–10 days after acute severe asthmatic attack (at recovery phase, P < 0.02) and were significantly correlated with clinical severity of asthmatic attack (P < 0.05). These results indicated that activation of both T cells and B cells was important in the pathogenesis of acute asthmatic attack in young children.

We investigated the effect of fructose, mannose and lactate on the preservation of synaptic transmission in the granule cell layer of guinea pig hippocampal slices during deprivation of glucose. After replacement of glucose with lactate (5 mM) or fructose (10 mM), population spikes (PS) extinguished transiently and thereafter recovered to 60–70% of the original amplitude. Replacement of glucose with mannose (10 mM) decreased the PS amplitude by 50–60% within 20 min. and was followed by recovery to 80% of the original amplitude. The levels of ATP and CrP (creatine phosphate) in fructose, mannose and lactate containing medium were maintained at 80–90% of the original levels. PS of the slices exposed to both glucose and lactate showed a similar pattern to that observed in lactate medium with deprivation of glucose. These results suggest that lactate, mannose and fructose could be metabolic substrates for energy production and are able to preserve the synaptic potentials, however, it takes 20–30 min for the functional replacement of glucose with these sugars or metabolites to occur

MRI-Based White Matter Volumes and Motor Impairment in Preterm Infants with Spastic Cerebral Palsy