Evaluation of pediatric patients in new-onset seizure clinic (NOSc).

AIM: We evaluated the clinical and demographic features of children presenting with unprovoked seizures at a regional new-onset seizure clinic (NOSc). METHODS: We retrospectively reviewed charts of 492 consecutive patients evaluated in the NOSc at the Childrne's Healthcare of Atlanta RESULTS: Nonepileptic events (NEE) were diagnosed in 102 (24%) and epileptic seizures in the remaining 326 (76%). Patients with NEE were younger than patients with epileptic seizure (5.0 vs. 7.4 years). Except for headache which occurred more frequently in NEE (14% vs. 6%), frequencies of comorbidities were similar in groups with NEE and epileptic seizure. Electroencephalogram (EEG) was performed in 98%, and finding was abnormal in 51%. Brain magnetic resonance imaging (MRI) was performed in 55%, and finding was abnormal in 15%. An electroclinical epilepsy syndrome was diagnosed in 42%. Antiseizure medication was started in 25% with first seizure and in 77% with recurrent seizures. INTERPRETATION: For children with newly-presenting seizures, a regional NOSc provided efficient, timely diagnosis and appropriate evaluations and treatment. Timely recognition of NEE resulted in fewer unnecessary evaluations and treatment for a quarter of referred patients whereas identification of the specific types of seizures and epilepsy allowed appropriate use, including deferral, of neuroimaging and guided treatment selection.

Occurrence and prenatal exposure to persistent organic pollutants using meconium in Korea: Feasibility of meconium as a non-invasive human matrix.

Prenatal exposure to persistent organic pollutants (POPs) is of great concern due to the vulnerability of fetus. Nineteen Polychlorinated biphenyls (PCBs), 18 organochlorine pesticides (OCPs) including DDTs, HCHs, chlordanes, and hexachlorobenzene, and 22 polybrominated diphenyl ethers (PBDEs) were measured in meconium samples from 72 newborn infants using high resolution gas chromatography/mass spectrometry. The median concentrations (on wet weight basis) of PCBs, OCPs, and PBDEs were 26.8pg/g, 66.7pg/g, and 2.32pg/g, respectively. Highly significant correlations were observed among the compounds of PCBs and OCPs, suggesting their similar sources and kinetic behaviors. BDE 47 had significant correlations with PCBs and OCPs, whereas BDE 209 was not correlated with any of the contaminants due to different exposure sources. The concentrations of p,p'-DDE, ß-HCH, and trans-nonaCHL between paired maternal blood-meconium and cord blood-meconium showed significant correlations, while PCBs and PBDEs were not significantly correlated in the paired samples. Maternal age and gestational age were demographic parameters affecting POP levels in meconium. Multiple regression analysis showed that the levels of several OCPs in cord and maternal serum were contributing factors governing the levels of these contaminants in meconium. Our results indicate that meconium can be utilized as a human matrix for prenatal exposure to several OCPs.

Infant exposure to polybrominated diphenyl ethers (PBDEs) via consumption of homemade baby food in Korea.

Limited data are available on the residue levels of polybrominated diphenyl ethers (PBDEs) in baby food. In this study, 24 PBDE congeners were determined in 147 homemade baby food samples collected from 97 households for 6-, 9-, 12-, 15-, and from 24 to 27-month-old infant groups during the period of 2012-2013. The concentrations of total PBDEs (ΣPBDE) ranged from 24.5 to 6000 (mean: 263) pg/g fresh weight, higher than those found in commercial formulae from the United States. The predominant congeners were BDEs 209 and 47, accounting for 92% of the ΣPBDE concentrations, reflected by high deca-BDE consumption in Korea. The residue levels and detection rates of BDE 47 in the baby food samples showed a gradual increasing trend with an increase in infant ages, due to changes in the food ingredients from hypoallergenic to greasy. The daily intakes of BDEs 47 and 209 via baby food consumption ranged from 0.04 to 0.58, 0.80 to 20.3, and 1.06 to 22.3 ng/kg body weight/day for 6-, 9-, 12-, 15-, and 24-27-month-old infant groups, respectively; these intakes were lower than the oral reference doses proposed by the US EPA. Together with three exposure sources, baby food, breast milk and dust ingestion for 6-month-old infants, the daily intake of ΣPBDE was 25.5 ng/kg body weight/day, which was similar to the intake via baby food consumption only for over 24-month-old infants in our study. This indicates that baby food is an important exposure pathway of PBDEs for over 24-month-old infants. This is the first study regarding the occurrence and exposure assessment of PBDEs via homemade baby food.

Worldwide national intervention of developmental screening programs in infant and early childhood.

The prevalence of developmental disabilities is increasing worldwide over time. Developmental issues in infancy or early childhood may cause learning difficulties or behavioral problem in school age, further adversely affecting adolescent quality of life, which finally lead to low socioeconomic status in family, increase in medical expenses, and other relevant issues in various ways. Early childhood has brain plasticity, which means there is a high chance of recovering from developmental issues by early detection and timely intervention. Pediatricians are placed an ideal position to meet with young children till 6 years of age, of which age range is the time applicable to early intervention. Determining child's developmental status can be made by 2 pathways such as developmental surveillance and developmental screening tests. For better results, pediatricians should update their knowledge about developmental issues, risk factors, and screening techniques through varying educational program or other relevant educating materials. This paper will update reports on the prevalence of developmental disabilities and review the recent results of the Korean developmental screening test and discuss relevant issues. Finally, it will be addressed the pediatrician's role in early detecting developmental issues and timely intervention.

Staring Spells: How to Distinguish Epileptic Seizures from Nonepileptic Staring.

OBJECTIVE: To determine the nature of staring spells and factors distinguishing epileptic from nonepileptic staring spells, we studied the clinical and demographic features of children with staring spells referred to a regional new-onset seizure clinic. STUDY DESIGN: Our retrospective chart review encompassed 2818 consecutive patients evaluated in the new-onset seizure clinic between September 22, 2015, and March 19, 2018. We identified 121 patients with newly presenting staring spells. RESULTS: Sixty-two of 121 (51%) children were diagnosed with nonepileptic staring spells and 59 (49%) with epileptic seizures (24 with absence epilepsy, 35 with focal epilepsy). Patients with nonepileptic staring spells were younger (4.8 vs 7.1 years, P = .001) and more likely to have developmental delay (P = .005) than the seizure group. There was an 8.9-month delay on average from the onset of staring spells to the new-onset seizure clinic visit. The emergency department was a referral source for 80% (28/35) of focal seizures. In children with focal seizures, the staring spells typically lasted >1minute (29/35, 83%), whereas only 19 of 62 (31%) of children with nonepileptic staring spells had events lasting this long (P = .04). All children had a routine electroencephalography (EEG) on the day of new-onset seizure clinic visit. EEG was diagnostic in 100% (24/24) of absence seizures and 51% (18/35) of focal seizures. CONCLUSIONS: In children presenting with staring spells, the differential diagnosis of epileptic staring spells vs nonepileptic staring spells can be made by history and routine EEG. Staring was as likely to be epileptic as nonepileptic spells. Younger children with developmental delay were more likely to have nonepileptic events. Our simple approach based on event duration, postictal symptoms, and EEG allowed identification of epileptic staring on first visit to new-onset seizure clinic but requires validation in future prospective studies including long-term video EEG monitoring and follow-up.

Development of the Parental Questionnaire for Cerebral Visual Impairment in Children Younger than 72 Months.

BACKGROUND AND PURPOSE: Cerebral visual impairment (CVI) is an underdiagnosed condition in children, and its assessment tools have focused on older children. We aimed to develop a parental questionnaire for cerebral visual impairment (PQCVI) for screening CVI in young children. METHODS: The PQCVI comprised 23 questions based on a modified version of Houliston and Dutton's questionnaire for older children. The PQCVI with neurocognitive function tests was applied to 201 child-parent pairs with typically developing children younger than 72 months (age 32.4±20.1 months, mean±standard deviation). The children were classified into six age groups. The normative data, cutoff scores, and internal reliability were assessed and item analysis was performed. We referred to the total score for all questions as the cerebral visual function (CVF) score. RESULTS: The normative data showed that the CVF score and the scores corresponding to ventral-stream and dorsal-stream visual functions plausibly increased with age. The scores rapidly reached 90% of their maximum values up to the age of 36 months, after which they increased slowly. Cronbach's alpha for all questions across all age groups was 0.97, showing excellent consistency. The item difficulty and item discrimination coefficients showed that the questions were generally adequate for this age stage. CONCLUSIONS: The PQCVI items produced reliable responses in children younger than 72 months. The rapid increase in scores before the age of 3 years supports the importance of early identification of CVI. Following additional clinical verification, the PQCVI may be useful for CVI screening.

Bisphenol A in infant urine and baby-food samples among 9- to 15-month-olds.

Diet is the predominant source of bisphenol A (BPA) intake, but limited data are available on BPA levels in the diet of younger infants. This study investigated BPA levels in baby-food and urine samples collected from young infants (under 2 years old). Samples of homemade baby food (n = 210) and urine (n = 187) were collected at 9, 12, and 15 months after birth from a panel of Korean infants (n = 173). BPA levels in urine and food were measured using HPLC-MS/MS and GC-MS, respectively. BPA was above the limit of detection (LOD) in 85.5-85.7% of the urine samples and 32.5-76.3% of the baby-food samples. The median levels of BPA were 0.45 ng/g wet weight (IQR: not detectable to 5.16 ng/g wet weight) in homemade baby food, 0.93 µg/L (IQR:

Bisphenol A distribution in serum, urine, placenta, breast milk, and umbilical cord serum in a birth panel of mother-neonate pairs.

Bisphenol A (BPA) exposure during the perinatal and postnatal periods increases the susceptibility to disease over the life cycle. However, information on the BPA delivered to fetuses or infants via the placenta and breastfeeding is limited. We determined the BPA exposure levels in various bodily fluids and tissues of pregnant women and described fetus and infant exposures to BPA based on associations and BPA ratios in mother-neonate paired samples. Maternal serum, urine, placenta, breast milk, cord serum, and neonatal urine samples were collected from 318 mother-neonate pairs at six university hospitals in Korea. BPA levels were detected using liquid chromatography tandem mass spectrometry. The ratios of the BPA levels in the other sample types to the levels in maternal serum were calculated. BPA was detected in 79.5-100% of the maternal and fetal samples. The median BPA concentration in the samples decreased in the order of neonatal urine (4.75ng/mL), maternal urine (2.86ng/mL), cord serum (1.71ng/mL), maternal serum (1.56ng/mL), breast milk (0.74ng/mL), and the placenta (0.53ng/g). We estimated the ratios of BPA levels in the other sample types to those in maternal serum. The median (95th percentile) cord serum-to-maternal serum ratio was 1.12 (15.2) for 160 mother-fetal pairs, in which BPA was detected in both samples. The placenta-, maternal urine-, neonatal urine-, and breast milk-to-maternal serum ratios were 0.28 (5.31), 1.79 (29.9), 1.98 (28.2), and 0.51 (10.5), respectively. In addition, the median (95th percentile) cord serum-to-placenta ratio was 4.03 (45.8), and the neonatal urine-to-cord serum ratio was 1.95 (25.6). The 95th percentile values were 14-20-fold greater than the medians. Urine contained the highest BPA concentrations, followed by serum, breast milk, and the placenta. The variations of BPA ratio show individual differences in the amounts of BPA delivered from mother to fetus.

Association between maternal exposure to major phthalates, heavy metals, and persistent organic pollutants, and the neurodevelopmental performances of their children at 1 to 2years of age- CHECK cohort study.

Exposure of the developing fetus and infants to toxic substances can cause serious lifelong health consequences. Several chemicals have been associated with adverse neurodevelopmental disorders in the early life stages of humans. However, most epidemiological studies have focused on a limited number of chemicals, and hence may exclude important chemicals from consideration or result in conclusions built on associations by chance. In the present study, we investigated the chemical exposure profile of the women, and associated these with the early neurodevelopmental performance of their offspring at 13-24months of age. The chemicals assessed include four phthalates, bisphenol A, three heavy metals, 19 polychlorinated biphenyls (PCBs), 19 organochlorine pesticides, and 19 polybrominated diphenyl ethers, which were measured from urine, whole blood, serum, and/or breastmilk of the pregnant or lactating women. For neurodevelopmental performance, the Bayley Scales of Infant Development-II (BSID-II), Social Maturity Scale (SMS), and Child Behavior Checklist (CBCL) were measured from a total of 140 toddlers. Among the measured chemicals, monoethyl phthalate (MEP) in maternal urine was significantly associated with early mental, psychomotor, and social development. In addition, breast milk di-ethylhexyl phthalate (DEHP) metabolite and blood lead concentrations were inversely associated with mental and psychomotor development indices, respectively. Maternal blood PCB153, heavy metals, and urinary MEP levels were also higher among the children with behavioral problems, as indicated by the CBCL range. Taken together, maternal exposure to several EDCs such as PCBs and DEHP was associated with adverse neurodevelopmental performances among the children aged 1-2years. Confirmation of these association in larger populations, as well as longer-term consequences of such exposure warrant further investigation.

Exposure to lead and mercury through breastfeeding during the first month of life: A CHECK cohort study.

Mercury and lead are naturally occurring toxicants and are responsible for various health issues including neurobehavioral and developmental disorders. Because of crucial synchronized developmental processes occurring at the early stage of life, infancy and childhood are considered as among the most susceptible windows to the exposure to these metals. Breastmilk is often the only source of nutrition during the first months of life. As breastmilk can be contaminated with these metals, breastfeeding may serve as a significant route of heavy metal exposure among infants. In order to understand current levels of exposure to mercury and lead through breastfeeding, and their associated risks, a total of 157 lactating mothers were recruited from Children's Health and Environmental Chemicals of Korea (CHECK) cohort, and breastmilk samples were collected at 15 and 30days after delivery (n=207). Mercury was detected from 100% of breastmilk with a median concentration of 0.59µg/L, and lead was detected in 77% of the samples with a median at 4.71µg/L. Higher concentrations of lead were found in the 30- day breastmilk than in the 15-day. Up to 45% of the breastmilk samples exceeded the normal range of the breastmilk lead suggested by WHO. Based on Monte Carlo simulation, about 71% of 15days old infants and 56% of 30days old infants were estimated at risk due to lead exposure through breastfeeding. Considering vulnerability of infants and well-known neurological toxicity of these metals, further studies to identify major exposure sources that contribute the lead concentration in breastmilk and health implication of early life stage exposure to lead among the breastfed infants are warranted.

Urinary phthalate metabolites over the first 15months of life and risk assessment - CHECK cohort study.

Phthalates are important group of endocrine disruptors. Infants and young children are susceptible to phthalate exposure. However, information on the phthalate exposure during the early stages of life is very limited. This study was conducted to understand the temporal trend of exposure to major phthalates among infants of Korea during the first 15months after birth, and to estimate associated risks. A total of 286 urine samples were collected from 171 children at 3, 9, 12, or 15months of age, with 77 children sampled for two or more times. Four phthalates, i.e., di(2-ethylhexyl) phthalate (DEHP), di-isobutyl phthalate (DiBP), di-n-butyl phthalate (DnBP), and diethyl phthalate (DEP) were chosen, and their major metabolites were analyzed in the urine. The DEHP metabolites were detected in 100% of the urine samples at relatively higher levels compared to those reported in other countries. The levels of mono-ethyl phthalate (MEP) were generally lower. Urinary concentrations of most phthalate metabolites, especially DEHP metabolites, increased as children grew older. Intra-class correlation coefficients (ICCs) calculated for DEHP metabolites over time were high (0.7-0.8), suggesting persistence of consistent exposure sources during this sensitive period of life. Hazard quotient (HQ) and hazard index (HI) were calculated from daily intake estimates divided by recommended toxicity thresholds. Among the study population, 4, 16, and 26% of the children showed HI >1 at 9, 12, and 15months of age, respectively. DEHP exposure explained most of the risk estimates. Considering vulnerability of young children to endocrine disruption, efforts to identify sources of exposure and to develop appropriate mitigation options are warranted.

A Unique Mutational Spectrum of MLC1 in Korean Patients With Megalencephalic Leukoencephalopathy With Subcortical Cysts: p.Ala275Asp Founder Mutation and Maternal Uniparental Disomy of Chromosome 22.

BACKGROUND: Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited disorder characterized by infantile-onset macrocephaly, slow neurologic deterioration, and seizures. Mutations in the causative gene, MLC1, are found in approximately 75% of patients and are inherited in an autosomal recessive manner. We analyzed MLC1 mutations in five unrelated Korean patients with MLC. METHODS: Direct Sanger sequencing was used to identify MLC1 mutations. A founder effect of the p.Ala275Asp variant was demonstrated by haplotype analysis using single-nucleotide polymorphic (SNP) markers. Multiple ligation-dependent probe amplification (MLPA) and comparative genomic hybridization plus SNP array were used to detect exonic deletions or uniparental disomy (UPD). RESULTS: The most prevalent pathogenic variant was c.824C>A (p.Ala275Asp) found in 7/10 (70%) alleles. Two pathogenic frameshift variants were found: c.135delC (p.Cys46Alafs*12) and c.337_353delinsG (p.Ile113Glyfs*4). Haplotype analysis suggested that the Korean patients with MLC harbored a founder mutation in p.Ala275Asp. The p.(Ile113Glyfs*4) was identified in a homozygous state, and a family study revealed that only the mother was heterozygous for this variant. Further analysis of MLPA and SNP arrays for this patient demonstrated loss of heterozygosity of chromosome 22 without any deletion, indicating UPD. The maternal origin of both chromosomes 22 was demonstrated by haplotype analysis. CONCLUSIONS: This study is the first to describe the mutational spectrum of Korean patients with MLC, demonstrating a founder effect of the p.Ala275Asp variant. This study also broadens our understanding of the mutational spectrum of MLC1 by demonstrating a homozygous p.(Ile113Glyfs*4) variant resulting from UPD of chromosome 22.

Association of diethylhexyl phthalate with obesity-related markers and body mass change from birth to 3†months of age.

BACKGROUND: Several studies have suggested potential links of phthalates to obesity in children and adults. Limited evidence, however, has been available for the relations between diethylhexyl phthalate (DEHP) and obesity-related markers or body mass change in early life. METHODS: 128 healthy pregnant women were recruited and, after delivery, their newborns' first urine and umbilical cord blood samples were collected. We measured urinary levels of two DEHP metabolites, mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP). We also measured the levels of leptin, total cholesterol and triglyceride (TG) in cord serum, and used them along with weight, length, head circumference and ponderal index (PI, 100 g/cm(3)) at birth, as obesity-related markers, and estimated the relations between DEHP metabolites and obesity-related markers using generalised linear models. For the evaluation of body mass increase by early life DEHP exposure, body mass index (BMI) z-score change during 3 months after birth by DEHP metabolites in the first urine samples of the newborns were evaluated using logistic regression. RESULTS: DEHP exposure was associated with decrease of PI and increase of TG (PI, ß=-0.11, p=0.070 and TG, ß=0.14, p=0.027), especially for boys (PI, ß=-0.13, p=0.021; and TG, ß=0.19, p=0.025). Moreover, DEHP exposure was positively associated with body mass increase during 3 months after birth (change of BMI z-scores, OR=4.35, p=0.025). CONCLUSIONS: Our findings suggest that DEHP exposure may affect body mass change in early life through changes of obesity-related markers.

Concentrations of phthalate metabolites in breast milk in Korea: estimating exposure to phthalates and potential risks among breast-fed infants.

Phthalates have been associated with endocrine disruption and developmental effects in many experimental and epidemiological studies. Developing infants are among the most susceptible populations to endocrine disruption. However, limited information is available on phthalate exposure and its associated risks among breast-fed newborn infants. In the present study, breast milk samples were collected from 62 lactating mothers at 1 month post-partum from four cities of Korea in 2012 and were evaluated for six phthalate metabolites (mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono(2-ethyl-hexyl) phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) and monoethyl phthalate (MEP)). MEP was detected in all breast milk samples, with a median concentration of 0.37 µg/L, and MiBP, MnBP and MEHP were detected in 79-89% of samples, with median concentrations of 1.10, 1.70, and 2.08 µg/L, respectively. However, MEHHP and MEOHP, the oxidized forms of di-ethyl-hexyl phthalate (DEHP), were detected in only one sample. For exposure assessment, the levels of phthalate diesters were estimated based on the parent:metabolite ratios in the breast milk that are reported elsewhere. For risk assessment, the endocrine-related toxicity of the monoester was assumed to be the same as that of its diester form. Median daily intake estimates of phthalates, including both monoester and diester forms, through breast milk consumption ranged between 0.91 and 6.52 µg/kg body weight (bw) for DEHP and between 0.38 and 1.43 µg/kg bw for di-n-butyl phthalate (DnBP). Based on the estimated daily intake, up to 8% of infants exceeded the reference dose of anti-androgenicity (RfD AA) for DEHP, and 6% of infants exceeded the tolerable daily intake (TDI) for DnBP. Breast milk MiBP and MnBP concentrations showed significant positive associations with maternal consumption of whipped cream or purified water. Considering vulnerability of young infants, efforts to mitigate phthalate exposure among lactating women are warranted.

Occurrence and exposure assessment of polychlorinated biphenyls and organochlorine pesticides from homemade baby food in Korea.

Data on the residue levels of persistent organic pollutants (POPs) in baby food samples are scarce. This is the first study to explore current contamination status and exposure assessment of organochlorines (OCs), including polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs), in baby food from Korea. In this study, the concentrations of OCs were determined in homemade baby food samples (n=100) collected from 6-, 9-, 12- and 15-month-old infant groups. The average concentrations of PCBs, dichloro-diphenyl-trichloroethanes (DDTs), hexachlorocyclohexanes (HCHs) and chlordanes (CHLs) in baby food samples were 37.5, 96.6, 26.0, and 13.2 pg/g fresh weight, respectively. The major compounds were CBs 28, 153, 52, and 33 for PCBs and p,p'-DDE, p,p'-DDT and ß-HCH for OCPs. The contribution of DDTs to the total OC concentrations increased from 30% (6-month-old infants) to 67% (15-month-old infants) with increasing infant age, while the concentrations of PCBs, HCHs and CHLs gradually decreased with increasing infant age, suggesting that highest priority for risk reduction of DDTs. The estimated daily intakes (EDIs) of OCs in Korean infants from baby food consumption were lower than the thresholds proposed by the United States Environmental Protection Agency and Health Canada, implying limited potential health risks. However, considering simultaneous exposure from baby food and breast milk consumption, chlordanes and heptachlor epoxide posed potential health risks. Considering the importance of early development and the vulnerability of infants, it is essential to perform systematic monitoring and management programs of OCs in baby food for risk reduction in Korean infants.