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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Early Biomarkers and Hearing Impairments in Patients with Neonatal Hypoxic-Ischemic Encephalopathy.

Identifying biomarkers for hearing impairments (HIs) in patients with neonatal hypoxic-ischemic encephalopathy (HIE), to initialize early hearing habilitation, is crucial. Seventy-eight neonates with HIE were divided into the following two groups: those with HIs and those without HIs. We compared those patients with 11,837 newborns without HIE, and analyzed the risk factors of HIs among neonatal HIE. Of the 78 patients, 11 were confirmed to have an HI, which is a substantially higher percentage than in the 11,837 newborns without HIE (14.1% vs. 0.87%; p < 0.001). More patients with moderate-to-severe HIE had confirmed HIs (p = 0.020; odds ratio, 8.61) than those with mild HIE. Clinical staging, and blood lactate and glucose levels could be predictive factors for HIs among patients with HIE. The patients who exhibited HIs had significantly higher lactate (104.8 ± 51.0 vs. 71.4 ± 48.4; U = 181, p = 0.032) and serum glucose (159.5 ± 86.1 vs. 112.1 ± 62.3; U = 166, p = 0.036) levels than those without HIs. A higher prevalence of HIs was noted in the patients with stage III HIE than those with stage II HIE (43.8% vs. 10%; p = 0.008). The degree of HI correlated with brain anomalies and neurodevelopmental outcomes at 1 year of age. Clinical staging, and blood lactate and glucose levels could be predictive factors for HIs among patients with HIE.

Clinical spectrum and the comorbidities of Dravet syndrome in Taiwan and the possible molecular mechanisms.

Dravet syndrome (DS) is an uncommon epilepsy syndrome that may negatively affect the patients and their caregivers. However, reliable and valid measures of its impact on caregivers and the characteristics of patients with DS in Taiwan are lacking. This study aimed to describe the characteristics of patients with DS and concerns of their caregivers and establish a baseline frequency of disease characteristics using a cross-sectional survey in Taiwan. We assessed the caregivers of patients with DS using an online anonymous questionnaire. The seizure frequency decreased with age, although lacking statistical significance. Vaccines show no influence on the condition of patients with DS. Our findings revealed the highest impact on the domains affecting the caregivers' daily life, including additional household tasks, symptom observation, further medical plan, and financial issues. Caregivers also expressed concerns regarding the lack of independence/constant care, seizure control, speech/communication, and impacts on siblings because of long-term care of the patients in parents' absence. Our findings highlight the significant effects of caring for a child with DS on the lives of their caregivers in Taiwan; these findings will help raise awareness regarding the needs of these families. Furthermore, we discussed the possible pathophysiological mechanisms of associated comorbidities.

Troponin I Levels in Neonatal Hypoxic-Ischemic Encephalopathy Are Related to Cardiopulmonary Comorbidity and Neurodevelopmental Outcomes.

Troponin I is a biomarker for cardiac injury in children. The role of troponin I in neonatal Hypoxic-Ischemic encephalopathy (HIE) may have valuable clinical implications. Troponin I levels were measured within 6 h of birth to determine their relationship to HIE stage, short-term cardiac functional outcomes, and neurodevelopmental outcomes at 1 year. Seventy-three patients were divided into two groups: mild HIE and moderate to severe HIE. Troponin I levels within 6 h of birth were obtained in 61 patients, and were significantly higher in patients with moderate to severe HIE than in patients with mild HIE (Mann-Whitney U test, U = 146, p = 0.001). A troponin I cut-off level of ≥60 pg/mL predicted moderate to severe HIE with a specificity of 81.1% and a negative prediction rate of 76.9%. A troponin I cut-off level of ≥180 pg/mL was significantly (χ2 (1, n = 61) = 33.1, p = 0.001, odds ratio 96.8) related with hypotension during first admission and significantly (χ2 (1, n = 61) = 5.3, p = 0.021, odds ratio 4.53) related with abnormal neurodevelopmental outcomes at 1 year. Early troponin I level may be a useful biomarker for predicting moderate to severe HIE, and initialization of hypothermia therapy.

Amplitude Integrated Electroencephalography and Continuous Electroencephalography Monitoring Is Crucial in High-Risk Infants and Their Findings Correlate With Neurodevelopmental Outcomes.

Background: To evaluate seizure diagnosis in sick infants in the neonatal intensive care unit (NICU) based on electroencephalography (EEG) monitoring combined with amplitude integrated electroencephalography (aEEG). Methods: We retrospectively reviewed EEG and aEEG findings and determined their correlations with neurodevelopmental outcomes at the age of >1 year in 65 patients with diagnosed seizures, encephalopathy, or both. Results: Seizure identification rate was 43.1%. The rate in nonstructural groups (hypocalcemic, hypoglycemic, and genetic seizures) was 71.4%, which was higher (p < 0.05) than the rate of 35.3% of structural brain lesion group [hypoxic-ischemic encephalopathy (HIE) and congenital brain structural malformation]. The aEEG background correlating with neurodevelopmental outcomes had 70.0% positive prediction value (PPV), 65.5%% negative prediction value (NPV), 67.7% specificity, and 67.9% sensitivity (p < 0.005). The aEEG background strongly (PPV, 93.8%; p < 0.005) correlated with the outcomes in HIE. For genetic seizures, the detected rate was high. The ictal recordings for the nonstructural seizures revealed downflected on the aEEG background initially, which differed from the structural lesion. Conclusions: EEG monitoring combined with aEEG can detect seizures, facilitating early treatment. EEG changes during seizures could exhibit delta-theta waves with or without clinical seizures in patients with brain lesions. In non-structural etiologies (hypocalcemic and KCNQ2 seizures), aEEG initially exhibited lower background during seizures that could aid in differentiating these EEG changes from those of other etiologies. The aEEG background was correlated with neurodevelopmental outcome and exhibited high PPV but not NPV in neonatal HIE.

Is Preterm Birth a Risk Factor for Subsequent Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorder in Children with Febrile Seizure?-A Retrospective Study.

Febrile seizure (FS) is the most prevalent childhood seizure; it is significantly related to subsequent epilepsy and has possible links to childhood neurodevelopmental disorders. Separately, premature births are believed to increase the risk of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Therefore, this study investigated whether preterm birth is a risk factor for subsequent epilepsy, ASD, and ADHD in children with FS. We retrospectively collected data for children aged < 5 years with FS from 1 January 2005, to 31 December 2013. We divided these children into two groups-the premature birth group and the full-term group-and compared their incidence rates of epilepsy, ASD and ADHD. The data of 426 patients with history of febrile convulsion were retrospectively collected. The premature birth group (FS+/preterm+) had 108 patients and the full-term group (FS+/preterm-) had 318 patients. The overall epilepsy risk in the FS+/preterm+ group was higher than in the FS+/preterm- group (odds ratio [OR], 2.52; 95% confidence interval [CI], 1.14-5.58; p = 0.02). The overall risk of ADHD in the FS+/preterm+ group was higher than that in the FS+/preterm- group (OR, 6.41; 95% CI, 3.39-12.09; p = 0.0001). In addition, children with FS+/preterm+ had 16.9 times (95% CI, 4.79-59.7; p = 0.0001) higher odds of having ASD compared with those with FS+/preterm-. Preterm birth may be a risk factor for subsequent epilepsy, ASD and ADHD in children with FS.

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.

Association Between Kawasaki Disease and Childhood Epilepsy: A Nationwide Cohort Study in Taiwan.

Background: Kawasaki disease is a common vasculitis of childhood in East Asia. The complications following Kawasaki disease mostly included cardiovascular sequelae; non-cardiac complications have been reported but less studied. This study investigated potential epilepsy following Kawasaki disease in Taiwanese children. Objectives: Through National Health Insurance Research Database, we retrospectively analyzed the data of children aged <18 years with clinically diagnosed Kawasaki disease from January 1, 2000 to December 31, 2012 in Taiwan. These patients were followed up to estimate the incidence of epilepsy in the Kawasaki cohort in comparison with that in the non-Kawasaki cohort in Taiwan. Results: A total of 8,463 and 33,872 patients in the Kawasaki and non-Kawasaki cohorts were included in the study, respectively. Of the total eligible study subjects, 61.1% were boys and 38.9% were girls; most patients with newly diagnosed Kawasaki disease were aged <5 years [88.1%]. Patients with Kawasaki disease showed a higher incidence rate [47.98 vs. 27.45 every 100,000 person years] and significantly higher risk [adjusted hazard ratio = 1.66, 95% confidence interval = 1.13-2.44] of epilepsy than those without the disease. Additionally, female sex [adjusted hazard ratio = 2.30, 95% confidence interval = 1.31-4.04] and age <5 years [adjusted hazard ratio = 1.82, 95% confidence interval = 1.22-2.72] showed a significantly higher risk of epilepsy in the Kawasaki cohort. Conclusion: Results revealed a higher incidence rate and significant risk of epilepsy in Taiwanese children with Kawasaki disease than in those without the disease. Therefore, children diagnosed with Kawasaki disease are recommended follow-up as they have a high risk of epilepsy and seizure disorders.

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.

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.