KCNQ2 mutations cause unique neonatal behavior arrests without motor seizures: Functional characterization.

OBJECTIVE: KCNQ2 gene mutation usually manifests as neonatal seizures in the first week of life. Nonsense mutations cause a unique self-limited familial neonatal epilepsy (SLFNE), which is radically different from developmental epileptic encephalopathy (DEE). However, the exact underlying mechanisms remain unclear. METHODS: The proband, along with their mother and grandmother, carried the c.1342C > T (p.Arg448Ter) mutation in the KCNQ2 gene. The clinical phenotypes, electroencephalography (EEG) findings, and neurodevelopmental outcomes were comprehensively surveyed. The mutant variants were transfected into HEK293 cells to investigate functional changes. RESULTS: The proband exhibited behavior arrests, autonomic and non-motor neonatal seizures with changes in heart rate and respiration. EEG exhibited focal sharp waves. Seizures were remitted after three months of age. The neurodevelopmental outcomes at three years of age were unremarkable. A functional study demonstrated that the currents of p.Arg448Ter were non-functional in homomeric p.Arg448Ter compared with that of the KCNQ2 wild type. However, the current density and V1/2 exhibited significant improvement and close to that of the wild-type after transfection with heteromeric KCNQ2 + p.Arg448Ter and KCNQ2 + KCNQ3 + p.Arg448Ter respectively. Channel expression on the cell membrane was not visible after homomeric transfection, but not after heteromeric transfection. Retigabine did not affect homomeric p.Arg448Ter but improved heteromeric p. Arg448Ter + KCNQ2 and heteromeric KCNQ2 + Arg448Ter + KCNQ3. CONCLUSIONS: The newborn carrying the p. Arg448Ter mutation presented frequent behavioral arrests, autonomic, and non-motor neonatal seizures. This unique pattern differs from KCNQ2 seizures, which typically manifest as motor seizures. Although p.Arg448Ter is a non-sense decay, the functional study demonstrated an almost-full compensation mechanism after transfection of heteromeric KCNQ2 and KCNQ3.

Neurological manifestations of SARS-CoV-2 infection in children in Taiwan: A cross-section, multicenter study.

BACKGROUND: The SARS-CoV-2 virus has been a global public health threat since December 2019. This study aims to investigate the neurological characteristics and risk factors of coronavirus disease 2019 (COVID-19) in Taiwanese children, using data from a collaborative registry. METHODS: A retrospective, cross-sectional, multi-center study was done using an online network of pediatric neurological COVID-19 cohort collaborative registry. RESULTS: A total of 11160 COVID-19-associated emergency department (ED) visits and 1079 hospitalizations were analyzed. Seizures were the most common specific neurological symptom, while encephalitis and acute disseminated encephalomyelitis (ADEM) was the most prevalent severe involvement. In ED patients with neurological manifestations, severe neurological diagnosis was associated with visual hallucination, seizure with/without fever, behavior change, decreased GCS, myoclonic jerk, decreased activity/fatigue, and lethargy. In hospitalized patients with neurological manifestations, severe neurological diagnosis was associated with behavior change, visual hallucination, decreased GCS, seizure with/without fever, myoclonic jerk, fatigue, and hypoglycemia at admission. Encephalitis/ADEM was the only risk factor for poor neurological outcomes at discharge in hospitalized patients. CONCLUSION: Neurological complications are common in pediatric COVID-19. Visual hallucination, seizure, behavior change, myoclonic jerk, decreased GCS, and hypoglycemia at admission are the most important warning signs of severe neurological involvement such as encephalitis/ADEM.

Kawasaki Disease May Increase the Risk of Subsequent Cerebrovascular Disease.

BACKGROUND: Previous epidemiological investigations examining the association between Kawasaki disease (KD) and cerebrovascular disease have had conflicting results. We analyzed the association between KD and cerebrovascular disease by conducting a population-based retrospective cohort study designed to investigate the hypothesis that KD could be a risk factor for subsequent cerebrovascular disease. METHODS: From the National Health Insurance Research Database of Taiwan, the data of children (aged 0-18 years old) with KD (n=8467) were collected. Starting with the first year of study observation (referred to as the baseline year), data was collected for each child with KD, and 4 non-KD patients matched for sex, urbanization level of residence, and parental occupation were randomly selected to form the non-KD cohort (n=33 868) for our analysis. For the period from January 1, 2000, to December 31, 2012, we calculated the follow-up person-years for each patient, which is the time from the index date to the diagnosis of cerebrovascular disease, death, or the end of 2012. Furthermore, we compared the incidence, the incidence rate ratio, and the 95% CI of cerebrovascular disease between the KD and non-KD cohorts. RESULTS: The overall cerebrovascular disease incidence rate was found to be 3.19-fold higher, which is significantly higher, in the KD cohort than in the non-KD cohort (14.73 versus 4.62 per 100 000 person-years), and the overall risk of cerebrovascular disease remained higher in the KD cohort (adjusted hazard ratio, 3.16 [95% CI, 1.46-6.85]). Furthermore, children aged <5 years showed a significantly higher risk of subsequent cerebrovascular disease in the KD cohort (adjusted hazard ratio, 3.14 [95% CI, 1.43-6.92]). CONCLUSIONS: This nationwide retrospective cohort study shows that KD may increase the risk of subsequent cerebrovascular disease, especially in those with KD aged <5 years old.

Effects of aldo-keto reductase family 1 member A on osteoblast differentiation associated with lactate production in MC3T3-E1 preosteoblastic cells.

Aldo-keto reductase family 1 member A (AKR1A) is an NADPH-dependent aldehyde reductase widely expressed in mammalian tissues. In this study, induced differentiation of MC3T3-E1 preosteoblasts was found to increase AKR1A gene expression concomitantly increased NOx- (nitrite + nitrate), increased glucose uptake, increased [NAD(P)+]/[NAD(P)H] and lactate production but decreased reactive oxygen species (ROS) without changes in endothelial nitric oxide synthase (eNOS) expression in differentiated osteoblasts (OBs). A study using gain- and loss-of-function MC3T3-E1 cells indicated that AKR1A is essential for modulating OB differentiation and gene expression of collagen 1 A1, receptor activator of nuclear factor kappa-B ligand, and osteoprotegerin in OBs. Immunofluorescence microscopy also revealed that changes in AKR1A expression altered extracellular collagen formation in differentiated OBs. Consistently, analyses of alkaline phosphatase activity and calcium deposits of matrix mineralization by Alizarin Red S staining verified that AKR1A is involved in the regulation of OB differentiation and bone matrix formation. In addition, AKR1A gene alterations affected the levels of NOx-, eNOS expression, glucose uptake, [NAD(P)+]/[NAD(P)H] dinucleotide redox couples, lactate production, and ROS in differentiated OBs. Herein, we report that AKR1A-mediated denitrosylation may play a role in the regulation of lactate metabolism as well as redox homeostasis in cells, providing an efficient way to quickly gain energy and to significantly reduce oxidative stress for OB differentiation.

Ictal and interictal electroencephalographic findings can contribute to early diagnosis and prompt treatment in KCNQ2-associated epileptic encephalopathy.

BACKGROUND: KCNQ2-associated epilepsy is most common in neonatal genetic epilepsy. A prompt diagnosis to initialize early treatment is important. METHODS: We studied the electroencephalographic (EEG) changes including automated EEGs and conventional EEGs monitoring of 10 nonconsanguineous cases with KCNQ2 mutations, identified among 162 (6%) childhood epilepsy. We compared 11 (25%) non-KCNQ2 seizures videoed from 44 automated EEG and EEG monitoring. RESULTS: Patients with KCNQ2 seizures had received more antiepileptic treatments than patients in non-KCNQ2 group. Seizures were detected in all patients with KCNQ2 epileptic encephalopathy (EE); the detection rate in KCNQ2 group was more than in patients with non-KCNQ2. The ictal recordings showed 3 newborns presented with initial lower amplitudes (<15 µV) and fast activity (>20 Hz), evolving into higher-amplitude theta-delta waves. Two patient's ictal seizures showed recurrent focal tonic movements of the unilateral limbs associated with slowly continuous spikes in the contralateral hemisphere. The interictal EEGs in 5 KCNQ2 EE were burst-suppression. In 5 patients with familial KCNQ2 mutations, the interictal EEGs showed focal paroxysmal activity. Compared with 11 non-KCNQ2 EEG of ictal seizures, the differences are ictal EEGs initially appeared manifesting theta-delta waves without fast activities. In KCNQ2 seizures, patients with mutations locating in the selectivity filter controlling K+ permeability had severe EEG patterns and poor neurodevelopmental outcomes. CONCLUSION: Ictal EEGs in KCNQ2 seizures are unique and different from the EEGs of seizures with other etiologies. An EEG monitoring can be a valuable tool for early diagnosing KCNQ2-associated seizures and for supporting prompt treatments.

Heterogeneous neurodevelopmental disorders in children with Kawasaki disease: what is new today?

BACKGROUND: Kawasaki disease (KD) is a common vasculitis of childhood in East Asia. The complications of KD ascribed to long-term cardiovascular sequelae are considerably diverse. Although studies have investigated neurodevelopmental problems following KD in the past few decades, they have reported inconsistent conclusions. This study investigated potential epilepsy and associated neurodevelopmental disorders (NDDs) following KD in Taiwanese children. METHODS: We retrospectively analyzed the data of children aged < 18 years with clinically diagnosed KD from January 1, 2005, to December 31, 2015. These patients were followed up to estimate the prevalence of epilepsy and associated NDDs in comparison with the prevalence in general pediatric population in Taiwan and worldwide. RESULTS: A total of 612 patients with an average age of 1.6 years were included. The prevalence of associated NDDs was 16.8% (n = 103/612) in the study group, which consisted of epilepsy, intellectual disability (ID), autism spectrum disorders, Tourette syndrome (TS), attention deficit hyperactivity disorder, (ADHD), and others. Moreover, children with KD had a higher prevalence of epilepsy and TS in both Taiwan and worldwide (epilepsy: 2.61% in the KD group vs 0.33% in Taiwan and 0.05-0.8% in worldwide, p < 0.05; TS: 2.77% in the KD group vs 0.56% in Taiwan and 0.3-1% in worldwide, p < 0.05). The prevalence of ID, ADHD, and developmental language disorders was not significantly different between our study patients and those in Taiwan or worldwide. CONCLUSIONS: Results revealed a higher prevalence rate of NDDs, especially epilepsy and TS, in Taiwanese children with KD than in the general pediatric population in Taiwan. However, these NDDs could be heterogeneous. Children diagnosed with KD were followed up because they had a higher risk of heterogeneous NDDs.

Epileptic spasms in PPP1CB-associated Noonan-like syndrome: a case report with clinical and therapeutic implications.

BACKGROUND: Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is an extremely rare disease caused by a heterozygous mutation in the PPP1CB gene on chromosome 2p23. The syndrome causes not only numerous dysmorphic features but also hypotonia, developmental delay, and even intellectual disability. We report the first case of NSLH2 in Asia and the 16th in the world. Moreover, the first case of PPP1CB-related infantile spasms. The clinical and therapeutic significance is outlined in this paper. CASE PRESENTATION: We found a male infant presented with severe intractable epileptic spasms. Although certain clinical features of somatic dysmorphism were noted, numerous laboratory and neuroimaging studies failed to identify the cause. To determine the underlying etiology, whole-exome sequencing was conducted. We identified a de novo heterozygous mutation, NM_206876.1: c.548A > C (p.Glu183Ala), in the PPP1CB gene. His seizures were almost refractory to conventional antiepileptic drugs but relative seizure control was eventually achieved with a ketogenic diet. CONCLUSION: This result expands the clinical spectrum of NSLH2 and strengthens the association between the PPP1CB gene and epileptic seizures. Furthermore, we suggest that the ketogenic diet can offer seizure reduction in particular drug-resistant epilepsy syndromes. Additional studies are warranted to clarify the pathogenic mechanisms underlying this PPP1CB mutation in epileptic seizures.

A KCNQ2 E515D mutation associated with benign familial neonatal seizures and continuous spike and waves during slow-wave sleep syndrome in Taiwan.

BACKGROUND/PURPOSE: Pediatric epilepsy caused by a KCNQ2 gene mutation usually manifests as benign familial neonatal seizures (BFNS) during the 1st week of life. However, the exact mechanism, phenotype, and genotype of the KCNQ2 mutation are unclear. METHODS: We studied the KCNQ2 genotype from 75 nonconsanguineous patients with childhood epilepsy without an identified cause (age range: from 2 days to 18 years) and from 55 healthy adult controls without epilepsy. KCNQ2 mutation variants were transfected into HEK293 cells to investigate what functional changes they induced. RESULTS: Four (5%) of the patients had the E515D KCNQ2 mutation, which the computer-based PolyPhen algorithm predicted to be deleterious. Their seizure outcomes were favorable, but three had an intellectual disability. Two patients with E515D presented with continuous spikes and waves during slow-wave sleep (CSWS), and the other two presented with BFNS. We also analyzed 10 affected family members with the same KCNQ2 mutation: all had epilepsy (8 had BFNS and 2 had CSWS). A functional analysis showed that the recordings of the E515D currents were significantly different (p<0.05), which suggested that channels with KCNQ2 E515D variants are less sensitive to voltage and require stronger depolarization to reach opening probabilities than those with the wild type or N780T (a benign polymorphism). CONCLUSION: KCNQ2 mutations can cause various phenotypes in children: they lead to BFNS and CSWS. We hypothesize that patients with the KCNQ2 E515D mutation are susceptible to seizures.

Electroencephalography and transcranial Doppler ultrasonography in neonatal citrullinemia.

The authors present a case of citrullinemia with a genotype of argininosuccinate synthetase (ASS1), c.380 G>A (p.R127Q)/c.380 G>A (p.R127Q), in two alleles. A 3-day-old female infant presented with status epilepticus and coma. Laboratory data showed hyperammonemia and marked lactic acidosis in the blood and cerebrospinal fluid; electroencephalography showed severely suppressed cerebral activity and focal paroxysmal volleys of slow and sharp waves (< 1Hz) over the left hemisphere. Real-time transcranial Doppler ultrasonography showed a brain edema and high peaked systolic and low diastolic flows in basal, anterior, and middle cerebral arteries; however, immediately after a blood exchange transfusion, systolic flows were lower and diastolic flows were higher. The resistance indices were significantly different (means: 0.58 vs. 0.37; p=0.01). The patient was placed on diet therapy. After six blood exchange transfusions and peritoneal dialysis, her neurologic examination results and serum ammonia and lactate values were normal. The authors found that electroencephalography and transcranial Doppler ultrasonography were useful for the diagnosis and follow-up treatment of neonatal citrullinemia.

Unconjugated bilirubin is correlated with the severeness and neurodevelopmental outcomes in neonatal hypoxic-ischemic encephalopathy.

Unconjugated bilirubin (UB) levels during the first week after birth are related to outcomes in neonatal hypoxic-ischemic encephalopathy (HIE). Clinical Sarnat staging of HIE, brain magnetic resonance imaging (MRI), hearing outcomes, and neurodevelopmental outcomes ≥ 1 year were used to correlate UB in 82 HIE patients. The initial UB level was significantly correlated with lactic acid levels. The peak UB was higher (p < 0.001) in stage I (10.13 ± 4.03 mg/dL, n = 34) than in stages II and III (6.11 ± 2.88 mg/dL, n = 48). Among the 48 patients receiving hypothermia treatment, a higher peak UB was significantly (p < 0.001) correlated with unremarkable brain MRI scans and unremarkable neurodevelopmental outcomes at age ≥ 1 year. The peak UB were higher (P = 0.015) in patients free of seizures until 1 year of age (6.63 ± 2.91 mg/dL) than in patients with seizures (4.17 ± 1.77 mg/dL). Regarding hearing outcomes, there were no significant differences between patients with and without hearing loss. The UB level in the first week after birth is an important biomarker for clinical staging, MRI findings, seizures after discharge before 1 year of age, and neurodevelopmental outcomes at ≥ 1 year of age.

SURF1-associated Leigh syndrome: a case series and novel mutations.

Leigh syndrome (LS) is a mitochondrial disease that typically presents in infancy with subacute neurodegenerative encephalopathy. It is genetically heterogeneous, but mutations in the complex IV assembly genes, particularly SURF1, are an important cause. In this study, SURF1 gene was sequenced in 590 patients with clinical suspicion of LS, complex IV deficiency, or clinical features of mitochondrial disorders. We identified 21 patients with clinical features of LS who are either homozygous or compound heterozygous for SURF1 mutations. Twenty-two different mutations were identified, including 13 novel mutations. Of the 42 mutant alleles, 36 (86%) are null mutations (frameshift, splicing, or nonsense) and 6 (14%) are missense. We have also reviewed the previously reported SURF1 mutations and observed a clustering of mutation in exon 8 of SURF1, suggesting a vital function for this region. Although mutations in SURF1 have been mainly associated with typical LS, five of the patients in this report had an atypical course of LS. There is no definite genotype-phenotype correlation; however, frameshift mutations resulting in protein truncation closer to the C-terminus may carry a better prognosis.

Nine genes that may contribute to partial trisomy (6)(p22→pter) and unique presentation of persistent hyperplastic primary vitreous with retinal detachment.

We report on a newborn girl with facial anomalies, a congenital heart defect, severe pre- and postnatal growth retardation, feeding problems, and persistent hyperplastic primary vitreous. Cytogenetic analysis by high resolution GTG banding showed extra chromosomal material on the short arm of one chromosome 1 of the patient, but neither parent. SKY and CGH analysis demonstrated that the patient had a de novo 46,XX, der(1)t(1;6)(p36.3; p22). Compared with previously reported cases of partial trisomy 6p22 syndrome, this patient exhibited a unique condition for this syndrome: persistent hyperplastic primary vitreous (PHPV) with retinal detachment. The human genome database was searched for candidate genes and we propose the following nine genes located in the 6p22→6pter region for their potential contribution to the phenotype of partial trisomy 6p22→pter and persistent hyperplastic primary vitreous (PHPV) with retinal detachment: Forkhead box Q1 (FOXQ1), FOXF2, FOXC1, NRN1, EDN1, ATXN1, DEK oncogene, E2F3, and NRNS1.

Syndromic and non-syndromic etiologies causing neonatal hypocalcemic seizures.

Background: The diagnosis of neonatal hypocalcemic seizures (HS) in newborns is made based on clinical signs and serum calcium level. Their etiology is broad and diverse, and timely detection and initiation of treatment is essential. Methods: We retrospectively reviewed 1029 patients admitted to the neonatal intensive care unit. Neonatal HS were diagnosed in 16 patients, and we compared etiologies and clinical outcomes, including clinical seizures and neurodevelopment at least over 1 year old. Results: The etiologies can be broadly categorized into 5 syndromic and 11 non-syndromic neonatal HS. Syndromic neonatal HS included 3 Digeorge syndrome, 1 Kleefstra syndrome and 1 Alström syndrome. Non-syndromic neonatal HS included 8 vitamin D deficiency, 1 hypoparathyroidism, and 2 hypoxic-ischemic encephalopathy. Patients with syndromic neonatal HS were found to have worse clinical outcomes than those with nonsyndromic HS. In eight patients with vitamin D deficiency, neurodevelopment was normal. Five of five patients (100%) with syndromic HS used two or more antiseizure drugs. However, among patients with non-syndromic neonatal HS, only one of 11 (9.1%) used more than one drug (p = 0.001). Conclusion: This finding highlighted that syndromic hypocalcemic seizures in newborns have worse neurodevelopmental outcomes and are more often difficult to manage, and would benefit from a genetic diagnostic approach.

KCNQ2 Selectivity Filter Mutations Cause Kv7.2 M-Current Dysfunction and Configuration Changes Manifesting as Epileptic Encephalopathies and Autistic Spectrum Disorders.

KCNQ2 mutations can cause benign familial neonatal convulsions (BFNCs), epileptic encephalopathy (EE), and mild-to-profound neurodevelopmental disabilities. Mutations in the KCNQ2 selectivity filter (SF) are critical to neurodevelopmental outcomes. Three patients with neonatal EE carry de novo heterozygous KCNQ2 p.Thr287Ile, p.Gly281Glu and p.Pro285Thr, and all are followed-up in our clinics. Whole-cell patch-clamp analysis with transfected mutations was performed. The Kv7.2 in three mutations demonstrated significant current changes in the homomeric-transfected cells. The conduction curves for V1/2, the K slope, and currents in 3 mutations were lower than those for the wild type (WT). The p.Gly281Glu had a worse conductance than the p.Thr287Ile and p.Pro285Thr, the patient compatible with p.Gly281Glu had a worse clinical outcome than patients with p.Thr287Ile and p.Pro285Thr. The p.Gly281Glu had more amino acid weight changes than the p.Gly281Glu and p.Pro285Thr. Among 5 BFNCs and 23 EE from mutations in the SF, the greater weight of the mutated protein compared with that of the WT was presumed to cause an obstacle to pore size, which is one of the most important factors in the phenotype and outcome. For the 35 mutations in the SF domain, using changes in amino acid weight between the WT and the KCNQ2 mutations to predict EE resulted in 80.0% sensitivity and 80% specificity, a positive prediction rate of 96.0%, and a negative prediction rate of 40.0% (p = 0.006, χ2 (1, n = 35) = 7.56; odds ratio 16.0, 95% confidence interval, 1.50 to 170.63). The findings suggest that p.Thr287Ile, p.Gly281Glu and p.Pro285Thr are pathogenic to KCNQ2 EE. In mutations in SF, a mutated protein heavier than the WT is a factor in the Kv7.2 current and outcome.

Perinatal Factors in Newborn Are Insidious Risk Factors for Childhood Autism Spectrum Disorders: A Population-based Study.

We analyzed claims data from the Taiwan National Health Insurance database, which contains data of 23.5 million Taiwan residents. We included children born after January 1, 2000 who had received a diagnosis of autism spectrum disorders (ASD). Patients who were not diagnosed with ASD were included in the control group. The ASD prevalence was 517 in 62,051 (0.83%) children. Neonatal jaundice, hypoglycemia, intrauterine growth retardation (IUGR), and craniofacial anomalies (CFA) differed significantly between the ASD and control groups. After logistic regressive analysis, the adjusted odds ratios of IUGR, CFA, neonatal hypoglycemia, and neonatal jaundice were 8.58, 7.37, 3.83, and 1.32, respectively. Those insidiously perinatal risk factors, namely CFA, IUGR, neonatal hypoglycemia, and neonatal jaundice, could increase the risk of ASD.

Approach to Neurological Channelopathies and Neurometabolic Disorders in Newborns.

Ion channel disorders (channelopathies) can affect any organ system in newborns before 2 months of life, including the skeletal muscle and central nervous system. Channelopathies in newborns can manifest as seizure disorders, which is a critical issue as early onset seizures can mimic the presentation of neurometabolic disorders. Seizures in channelopathies can either be focal or generalized, and range in severity from benign to epileptic encephalopathies that may lead to developmental regression and eventually premature death. The presenting symptoms of channelopathies are challenging for clinicians to decipher, such that an extensive diagnostic survey through a precise step-by-step process is vital. Early diagnosis of a newborn's disease, either as a channelopathy or neurometabolic disorder, is important for the long-term neurodevelopment of the child.

Clinical Diagnosis and Treatment of Leigh Syndrome Based on SURF1: Genotype and Phenotype.

SURF1 encodes the assembly factor for maintaining the antioxidant of cytochrome c oxidase (COX) stability in the human electron respiratory chain. Mutations in SURF1 can cause Leigh syndrome (LS), a subacute neurodegenerative encephalopathy, characterized by early onset (infancy), grave prognosis, and predominant symptoms presenting in the basal ganglia, thalamus, brainstem, cerebellum, and peripheral nerves. To date, more than sixty different SURF1 mutations have been found to cause SURF1-associated LS; however, the relationship between genotype and phenotype is still unclear. Most SURF1-associated LS courses present as typical LS and cause early mortality (before the age of ten years). However, 10% of the cases present with atypical courses with milder symptoms and increased life expectancy. One reason for this inconsistency may be due to specific duplications or mutations close to the C-terminus of the SURF1 protein appearing to cause less protein decay. Furthermore, the treatment for SURF1-associated LS is unsatisfactory. A ketogenic diet is most often prescribed and has proven to be effective. Supplementing with coenzyme Q and other cofactors is also a common treatment option; however, the results are inconsistent. Importantly, anti-epileptic drugs such as valproate-which cause mitochondrial dysfunction-should be avoided in patients with SURF1-associated LS presenting with seizures.

Early Blood Glucose Level Post-Admission Correlates with the Outcomes and Oxidative Stress in Neonatal Hypoxic-Ischemic Encephalopathy.

The antioxidant defense system is involved in the pathogenesis of neonatal hypoxic-ischemic encephalopathy (HIE). To analyze the relationship between first serum blood glucose levels and outcomes in neonatal HIE, seventy-four patients were divided, based on the first glucose level, into group 1 (>0 mg/dL and <60 mg/dL, n =11), group 2 (≥60 mg/dL and <150 mg/dL, n = 49), and group 3 (≥150 mg/dL, n = 14). Abnormal glucose levels had poor outcomes among three groups in terms of the clinical stage (p = 0.001), brain parenchymal lesion (p = 0.004), and neurodevelopmental outcomes (p = 0.029). Hearing impairment was more common in group 3 than in group 1 (p = 0.062) and group 2 (p = 0.010). The MRI findings of group 3 exhibited more thalamus and basal ganglion lesions than those of group 1 (p = 0.012). The glucose level was significantly correlated with clinical staging (p< 0.001), parenchymal brain lesions (p = 0.044), hearing impairment (p = 0.003), and neurodevelopmental outcomes (p = 0.005) by Pearson's test. The first blood glucose level in neonatal HIE is an important biomarker for clinical staging, MRI findings, as well as hearing and neurodevelopment outcomes. Hyperglycemic patients had a higher odds ratio for thalamus, basal ganglia, and brain stem lesions than hypoglycemic patients with white matter and focal ischemic injury. Hyperglycemia can be due to prolonged or intermittent hypoxia and can be associated with poor outcomes.

Identifying Early Diagnostic Biomarkers Associated with Neonatal Hypoxic-Ischemic Encephalopathy.

BACKGROUND: Identifying an effective method for the early diagnosis of neonatal hypoxic-ischemic encephalopathy (HIE) would be beneficial for effective therapies. METHODS: We studied blood biomarkers before 6 h after birth to correlate the degree of neonatal HIE. A total of 80 patients were divided into group 1 (mild HIE) and group 2 (moderate or severe HIE). Then, 42 patients from group 2 received hypothermia therapy and were further divided into group 3 (unremarkable or mild MRI results) and group 4 (severe MRI results). RESULTS: Between groups 1 and 2, lactate, creatinine, white blood cells, and lactate dehydrogenase (LDH) were significantly different. Between groups 3 and 4, lactate, prothrombin time, and albumin were significantly different. Sarnat staging was based on our observation that more than 45 mg/dL of lactate combined with more than 1000 U/L of LDH yielded the highest positive predictive value (PPV) (95.7%; odds ratio, 22.00), but a low negative predictive value (NPV) for moderate or severe HIE. Using more than 45 mg/dL of lactate yielded the highest NPV (71.4%) correlated with moderate or severe HIE. CONCLUSIONS: Lactate combined with LDH before 6 h after birth yielded a high PPV. Using combined biomarkers to exclude mild HIE, include moderate or severe HIE, and initialize hypothermia therapy is feasible.

Cytomegalovirus Infection in Infancy May Increase the Risk of Subsequent Epilepsy and Autism Spectrum Disorder in Childhood.

Cytomegalovirus (CMV) is a ubiquitous virus, and CMV-associated diseases range from mild illness in immunologically normal hosts to life-threatening diseases in newborns and immunocompromised children. This study investigated the association between childhood CMV infection and subsequent epilepsy or neurodevelopmental disorders, attention deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD). A retrospective analysis was performed on data for 69 children with confirmed CMV infections (CMV infection group) and 292 patients with other infections (control group) between 1 January 2006 to 31 December 2012. The results indicated that the CMV infection group had a higher risk of epilepsy in comparison to the control (odds ratio (OR), 16.4; 95% CI (confidence interval), 3.32-80.7; p = 0.001). Epilepsy risk increased in younger children (age 0-2) with CMV infection when compared to the control group (OR, 32.6; 95% CI, 3.84-276; p = 0.001). The ASD risk was also determined to be higher in the CMV infection group (OR, 17.9; 95% CI, 1.96-162; p = 0.01). The ADHD risk between the groups was not significant. This study suggests that CMV infection in infancy may increase the risk of subsequent epilepsy and ASD, especially in infants younger than 2 years, but is not associated with ADHD.