Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-Up

We wanted to identify in children with epilepsy the factors associated with seizure control and recurrence after a 2-year remission. Methods: We did a 5-year follow-up of epileptic children whose antiepileptic medication had been stopped. Bivariate and multivariate analyses were used to compare features of electroencephalograms (EEGs) and clinical findings. In this study, 43 patients with and 64 without a seizure recurrence (SR) were enrolled. Results: Clinical features strongly associated with SR in the univariate analysis included a symptomatic etiology for seizures, a history of status epilepticus, treatment duration before stopping antiepileptic drugs, and abnormal EEG findings at the time of stopping antiepileptic drugs. Conclusion: We found that a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG when the medication was stopped are important predictors of SR. The risk factors of SR after discontinuing antiepileptic drugs have been investigated in several studies. However, a history of status epilepticus as a predictive factor is rarely mentioned

A Wide Spectrum of Genetic Disorders Causing Severe Childhood Epilepsy in Taiwan: A Case Series of Ultrarare Genetic Cause and Novel Mutation Analysis in a Pilot Study

Background: Pediatric epileptic encephalopathy and severe neurological disorders comprise a group of heterogenous diseases. We used whole-exome sequencing (WES) to identify genetic defects in pediatric patients. Methods: Patients with refractory seizures using ≥2 antiepileptic drugs (AEDs) receiving one AED and having neurodevelopmental regression or having severe neurological or neuromuscular disorders with unidentified causes were enrolled, of which 54 patients fulfilled the inclusion criteria, were enrolled, and underwent WES. Results: Genetic diagnoses were confirmed in 24 patients. In the seizure group, KCNQ2, SCN1A, TBCID 24, GRIN1, IRF2BPL, MECP2, OSGEP, PACS1, PIGA, PPP1CB, SMARCA4, SUOX, SZT2, UBE3A, 16p13.11 microdeletion, [4p16.3p16.1(68,345–7,739,782)X1, 17q25.1q25.3(73,608,322–81,041,938)X3], and LAMA2 were identified. In the nonseizure group, SCN2A, SPTBN2, DMD, and FBN1 were identified. Ten novel mutations were identified. The recurrent genes included SCN1A, KCNQ2, and TBCID24. Male pediatric patients had a significantly higher (57% vs. 29%; p < 0.05, odds ratio = 3.18) yield than their female counterparts. Seventeen genes were identified from the seizure groups, of which 82% were rare genetic etiologies for childhood seizure and did not appear recurrently in the case series. Conclusions: Wide genetic variation was identified for severe childhood seizures by WES. WES had a high yield, particularly in male infantile patients

Lenticulostriate Vasculopathy in Brain Ultrasonography is Associated with Cytomegalovirus Infection in Newborns

Lenticulostriate vasculopathy is associated with various disorders, in particular cytomegalovirus infection, which can cause neurological consequences. We wanted to evaluate the association of lenticulostriate vasculopathy and cytomegalovirus infection. We retrospectively collected data on lenticulostriate vasculopathy from 858 neonatal ultrasonography scans. Methods: Fifty-five patients with lenticulostriate vasculopathy were diagnosed. Lenticulostriate vasculopathy was classified as severe and mild according to the ultrasonographic findings. We analyzed gender, unilateral and bilateral lenticulostriate vasculopathy, mild and severe lenticulostriate vasculopathy, intrauterine growth retardation, and lenticulostriate vasculopathy associated with other brain malformations to determine whether they were correlated with cytomegalovirus infection. Results: Neonatal cytomegalovirus infections correlated primarily with lenticulostriate vasculopathy that was associated with brain structure anomalies p < 0.0001, followed by severe lenticulostriate vasculopathy (p = 0.029). Cytomegalovirus urine polymerase chain reaction ratios were 69% for severe and 23% for mild lenticulostriate vasculopathy (p = 0.002; odds ratio = 7.33). Of 72 newborns with intrauterine growth retardation without lenticulostriate vasculopathy, 33 were analyzed for cytomegalovirus, of whom only one was positive, which was significantly different from the newborns with lenticulostriate vasculopathy (p = 0.003; odds ratio = 11.64). Conclusion: Lenticulostriate vasculopathy on neonatal ultrasonography is useful for predicting cytomegalovirus infection, particularly in severe lenticulostriate vasculopathy. When severe lenticulostriate vasculopathy is associated with a brain structure anomaly, cytomegalovirus infection should be considered. The outcomes for the cases in which cytomegalovirus infection was associated with other brain structure anomalies were significantly worse than the outcomes in cases associated with lenticulostriate vasculopathy only

Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes

Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were “rescued” after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes

Polymorphisms of the RET Gene in Hirschsprung Disease, Anorectal Malformation and Intestinal Pseudo-obstruction in Taiwan

Mutations in the receptor tyrosine kinase RET gene are associated with Hirschsprung disease (HD), which is also known as congenital intestinal aganglionosis. We found an association with specific alleles in five single nucleotide polymorphism (SNP) sites of the RET gene in our HD patients. Methods: We compared the association of specific RET SNP alleles in patients with severe GI disorders such as anorectal malformation (ARM) or pediatric intestinal pseudo-obstruction (IPO) to that in HD patients. Sixty-four HD, 23 ARM and 35 IPO patients were included. Genomic DNA extracted from blood samples was analyzed by polymerase chain reaction and DNA sequencing analysis. Results: The allele distributions of all five RET SNPs in the HD patients deviated from those in the normal population (p < 0.05), whereas those of the ARM patients did not. The allele distributions of these RET SNPs in the IPO patients were all significantly different from those in the HD patients. Allele distributions of exon 2 and 13 in the IPO patients were also significantly different from those of the normal population. The frequencies of all the HD-predominant alleles were lower in the HD patients than the normal population, and were even lower in the IPO patients. Conclusion: This study strengthens the association of specific RET SNP alleles with typical HD in Taiwan