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Summary: Sleep disturbances in children with epilepsy are prevalent, and are associated with substantial adverse medical and psychosocial consequences. This study is a 5‐year follow‐up of a clinic‐based sleep intervention study that randomized 100 toddlers and preschool‐age children with epilepsy to a usual care group or a sleep intervention group. The intervention group received standard paediatric neurology care plus three education sessions during the child's routine clinic visit. The outcomes measured were: (1) child sleep by actigraphy and parental report; and (2) maternal sleep and depression. We aimed to evaluate the long‐term benefits of a clinic‐based sleep intervention for paediatric epilepsy. In total, 42 families (42.0%) participated. The average child's age at follow‐up was 9.55 years. Thirty‐eight (90.5%) children were not obtaining sufficient sleep at baseline, and 40 (95.2%) at the 5‐year follow‐up. The numbers of children with clinically significant sleep disturbances were 40 (95.2%) at baseline and 36 (85.7%) at the 5‐year follow‐up. Fourteen mothers (33.3%) had poor sleep quality and high depressive symptoms at both assessment time points. There were no differences (P > 0.05) in the child and maternal outcomes between the two trial arms. Overall, there was no evidence that a clinic‐based sleep intervention that effectively improved multiple aspects of sleep in toddlers and preschool‐age children with epilepsy had long‐lasting beneficial effects. Our findings suggest that sleep interventions for families of children with epilepsy require ongoing reinforcement and monitoring during routine paediatric neurology care to prevent sleep problems from persisting or recurring. [ABSTRACT FROM AUTHOR]

Management of pediatric epilepsies poses unique challenges around diagnosis, treatment options, comorbidities, and the potential for these factors to interact with processes in the developing brain. In pediatric patients, broad-spectrum antiseizure medications (ASMs) with minimal potential for adverse events (AEs) and limited impact on cognition and behavior are preferred. Perampanel is a first-in-class ASM with broad-spectrum efficacy, a tolerable safety profile, minimal negative impact on cognitive function, and other features that make it a viable treatment option in this patient population. However, evidence and experience of its use in pediatric patients are less extensive than in adult patients. Experts in pediatric epilepsy across the region convened at a series of meetings to discuss the use of perampanel in pediatric patients, including dose optimization, AE prevention and management, and considerations in particular groups. This article summarizes key evidence for perampanel in the pediatric population and consolidates the experts' recommendations for using the ASM in managing pediatric epilepsies. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association between daily screen time exposure and both sleep patterns (sleep onset, sleep offset, and nighttime, and daily sleep durations) and sleep disturbances among a clinical sample of children with epilepsy. Design: A cross‐sectional actigraphic sleep study. Methods: A convenience sample of 141 children with epilepsy (1.5–6 years of age) was recruited from an outpatient pediatric neurology clinic of a university‐affiliated children's hospital in northern Taiwan. Participating families completed questionnaires and reported children's screen time use, with children wearing an actigraphy monitor for 7 days to assess sleep patterns. Multivariable linear regression analyses were conducted to examine the association of screen time exposure with the child's sleep patterns and sleep disturbance scores. Findings: Mean minutes per day of screen time exposure was 89.79 ± 83.94 min, with 62 parents (44.0%) reporting their child having >1 hr of screen time daily. Mean daily sleep duration was 9.26 ± 1.01 hr, with 106 children (93.0%) sleeping <10 hr in a 24‐hr period. In multivariate regression models, daily screen time exposure of >1 hour was associated with 23.4‐min later sleep onset (b = 0.39, p =.02), 20.4‐min later sleep offset (b = 0.34, p =.04), and more severe sleep disturbances (b = 2.42, p =.04). Conclusions: In toddlers and preschool‐age children with epilepsy, daily screen time exposure is greater and sleep duration is shorter than the recommended amount, with increased screen time exposure associated with disturbed sleep. Clinical Relevance: Parents need to be informed about the possible adverse impact of screen time exposure on children's sleep and health as well as the importance of limiting screen time exposure to <1 hr per day for their toddlers and preschool‐age children with epilepsy. [ABSTRACT FROM AUTHOR]

• Primary Coenzyme Q10 deficiency is a treatable disease. • Patients have early pharmacoresistant epilepsy with global developmental delay and multisystemic involvement. • Early disease diagnosis and early treatment is very important. • COQ4 c.370G > A variant is a founder variant in Asia. Coenzyme Q10 (CoQ10) is one of the essential substances for mitochondrial energy synthesis and extra-mitochondrial vital function. Primary CoQ10 deficiency is a rare disease resulting from interruption of CoQ10 biosynthetic pathway and biallelic COQ4 variants are one of the genetic etiologies recognized in this hereditary disorder. The clinical heterogenicity is broad with wide onset age from prenatal period to adulthood. The typical manifestations include early pharmacoresistant seizure, severe cognition and/or developmental delay, dystonia, ataxia, and spasticity. Patients may also have multisystemic involvements such as cardiomyopathy, lactic acidosis or gastro-esophageal regurgitation disease. Oral CoQ10 supplement is the major therapeutic medication currently. Among those patients, c.370G > A variant is the most common pathogenic variant detected, especially in Asian population. This phenomenon also suggests that this specific allele may be the founder variants in Asia. In this article, we report two siblings with infantile onset seizures, developmental delay, cardiomyopathy, and diffuse brain atrophy. Genetic analysis of both two cases revealed homozygous COQ4 c.370G > A (p.Gly124Ser) variants. We also review the clinical manifestations of primary CoQ10 deficiency patients and possible treatment categories, which are still under survey. As oral CoQ10 supplement may improve or stabilize disease severity, early precise diagnosis of primary CoQ10 deficiency and early treatment are the most important issues. This review article helps to further understand clinical spectrum and treatment categories of primary CoQ10 deficiency with COQ4 variant. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To describe sleep patterns in young children with epilepsy and to examine levels of agreement between measurements derived from actigraphy and diary recordings. Design: Cross‐sectional study. Methods: Eighty‐nine toddlers and preschool‐aged children with epilepsy wore an actigraph on their wrists for 7 consecutive days. Parents and caregivers maintained a concurrent sleep diary while the child was wearing the monitor. Levels of agreement between actigraphy and diary recordings were examined using the Bland and Altman method separately for all recording days, weekdays, and weekends. Findings: Discrepancies between actigraphy‐derived and diary‐documented sleep onset, sleep offset, actual sleep at night, wake after sleep onset, and daytime sleep were ±35, ±15, ±82, ±70, and ±29 min, respectively. Differences between actigraphy and diary‐derived sleep variables were consistently greater for weekends than for weekdays. Discrepancies between actigraphy and diary‐derived actual sleep at night were significantly greater for children who slept alone than for those who co‐slept with a parent. Conclusions: Our study demonstrates an acceptable agreement between actigraphy and diary recordings for sleep onset, sleep offset, and daytime sleep, but insufficient agreement for actual sleep at night and wake after sleep onset, with parents of children sleeping alone more likely to misestimate child sleep behaviors. Deviation of weekend sleep from weekdays further decreased the accuracy of parental sleep estimates and increased the discrepancies between actigraphy and diary. Clinical Relevance: Sleep in children with epilepsy assessed using diary recordings alone could be misleading, and actigraphy should be preferred over diaries when resources are available. [ABSTRACT FROM AUTHOR]

Aromatic L-amino acid decarboxylase (AADC) deficiency is an uncommon inherited neurometabolic disease. The clinical presentations and MR findings in children with AADC deficiency were investigated. Total 12 children (6 boys, 6 girls), aged from 9 to 50 months (mean, 23 ±13 months), with AADC deficiency, were enrolled for analysis. Of 12 patients enrolled, clinical presentations included global developmental delay with generalized hypotonia in 12 (100%), dystonia in 12 (100%), oculogyric crisis in 12 (100%), and excessive sweating in 8 (67%). Sleep problem was also found in 4 (33%). Of 15 MR examinations, the major changes included 6 (40%) with diffusely prominent bilateral frontal sulci, 10 (67%) with prominent frontal horns, and 12 (80%) with hypomyelination. In AADC patients, the frontal horn was significantly widened ( P < 0.01), and the volume of caudate nucleus was also significantly smaller than that of controls ( P = 0.02). The ratios of thickness of the splenium to that of the genu of corpus callosum were also significantly increased ( P < 0.01). There was also significant decrease of fiber density indices in major white matter fiber tracts. Using Tract-Based Spatial Statistics approach, we also revealed significant change in major fiber tracts related to language function and motor function. In conclusion, the present study indicated that AADC deficiency may have significant impact on brain development, especially the frontal lobe and fiber tracts related to language function and motor function. Long-term follow-up of brain MRI in patients with AADC deficiency may clarify the possible effect of AADC deficiency on brain development. Hum Brain Mapp 38:1532-1540, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Seizures are a common presenting manifestation in children with disorders of amino acid metabolism. However, seizures may be very common in some specific diseases, but are rare in other diseases. In patients with classical maple syrup urine disease (MSUD), seizures commonly occur in the neonatal stage. But in intermittent or intermediate MSUD, seizures may develop in a later stage, or are uncommon. Patients with nonketotic hyperglycinemia often present with early myoclonic encephalopathy in the first weeks of life. However, in patients with atypical variants, seizures may be rare. In addition, patients with sulfite oxidase deficiency, serine deficiency, or GABA-related disorders may also present with different types of seizures. In monoamine biosynthesis disorders, seizures are rare, but paroxysmal dystonia is frequently misdiagnosed as seizures. Therefore, the incidence of seizures in disorders of amino acid metabolism is variable. Timely diagnosis and early treatment may improve the prognosis of these disorders. [Copyright &y& Elsevier]

Background: In tuberous sclerosis (TS), tubers usually involve the white matter. Diffusion tensor (DT) images are used to demonstrate white-matter tracts.Objective: To determine the changes in DT indices in supratentorial tubers and associated changes in the white-matter tracts adjacent to tubers in patients with TS.Materials and Methods: The DT imaging indices, including first, second and third eigenvalues (EVs), apparent diffusion coefficients (ADCs), and fractional anisotropy (FA) in the white-matter lesions of tubers, were assessed in seven patients with TS exhibiting developmental delay and compared with controls.Results: EV1, EV2, EV3, ADC and FA of the white-matter lesions of tubers were significantly different from contralateral unremarkable regions of the brain and from controls (P<0.05). The number of frontal and parietal tubers was significantly negatively correlated with EV1 of the superior longitudinal fasciculi of TS patients (r=-0.60, P =0.04). In addition, TS patients had significantly larger ADCs in the corona radiata and sagittal stratum than the control subjects. EV3s of the inferior longitudinal fasciculus and sagittal stratum were significantly more increased in the TS patients than in the control subjects.Conclusions: EV1, EV2, EV3, ADC and FA maps are potential tools for demonstrating cerebral white-matter changes owing to TS. [ABSTRACT FROM AUTHOR]

Huntington’s disease (HD) is an inherited neurodegenerative disease, in which there is progressive motor and cognitive deterioration, and for which the pathogenesis of neuronal death remains controversial. Mitochondrial toxins like 3-nitropropionic acid (3-NP) and malonate, functioning as the inhibitors of the complex II of mitochondrial respiratory chain, have been found to effectively induce specific behavioral changes and selective striatal lesions in rats and non-human primates mimicking those in HD. Furthermore, several kinds of transgenic mouse models of HD have been recently developed, and used in the development and assessment of novel treatments for HD.In the past, most studies evaluating the animal models for HD were based on histological changes or in vitro neuronal cultures. With the emergence of advanced magnetic resonance technologies, non-invasive magnetic resonance imaging (MRI) and spectroscopy provide more detail of cerebral alterations, including the changes of cerebral structure, function and metabolites. These studies support the hypothesis that mitochondrial dysfunction with increased excitation of N-methyl-d-aspartate (NMDA) receptors can replicate the neurobehavioral changes, selective brain injury and neurochemical alterations in HD.The present review focuses on our work as well as that of others regarding 3-NP-induced neurotoxicity and other animal models of HD. Using both conventional and advanced MRI and spectroscopy, we summarize the pathogenesis and possible therapeutic strategies in chemical and transgenic models of HD. The results show magnetic resonance techniques to be powerful techniques in the evaluation of pathogenesis and therapeutic intervention for both chemical and transgenic models of HD. [Copyright &y& Elsevier]

The authors present three patients with de novo absence epilepsy after administration of carbamazepine and vigabatrin. Despite the underlying diseases, the prognosis for drug-induced de novo absence seizure is good because it subsides rapidly after discontinuing the use of the offending drugs. The γ-aminobutyric acid-transmitted thalamocortical circuitry accounts for a major part of the underlying neurophysiology of the absence epilepsy. Because drug-induced de novo absence seizure is rare, pro-absence drugs can only be considered a promoting factor. The underlying epileptogenecity of the patients or the synergistic effects of the accompanying drugs is required to trigger the de novo absence seizure. The possibility of drug-induced aggravation should be considered whenever an unexpected increase in seizure frequency and/or new seizure types appear following a change in drug treatment. By understanding the underlying mechanism of absence epilepsy, we can avoid the inappropriate use of anticonvulsants in children with epilepsy and prevent drug-induced absence seizures. [Copyright &y& Elsevier]

Agyria-pachygyria complex is a disorder of neuronal migration and organization. Patients suffer either motor or intellectual retardation. We report our experiences of 10 patients with agyria-pachygyria complex and evaluate their clinical features, electroencephalography, and evoked potentials. Of nine electroencephalography examinations, five patients demonstrated characteristically high-amplitude fast activity. One of nine patients had an abnormal brainstem auditory-evoked potential. Three of seven patients had abnormal goggled visual-evoked potential. Six patients received somatosensory-evoked potential examinations, and five of these were abnormal, including four with prolonged central conduction times. Of the 10 patients, eight survived with variable intellectual and motor retardation; two died of sepsis. Patients with grades 1-4 agyria-pachygyria had high incidences of somatosensory-evoked potential abnormalities and also suffered worse neurologic outcomes. Normal brainstem auditory-evoked potential but abnormal cortical somatosensory-evoked potential components and prolonged central conduction time in these patients indicate that agyria-pachygyria is a supratentorial disease. We conclude that somatosensory-evoked potential examination is supplemental to neuroimaging in predicting the neurologic prognosis of patients with agyria-pachygyria. [Copyright &y& Elsevier]

Objective Background Methods Results Conclusions To evaluate factors associated with new‐onset migraine (NOM) after transcatheter atrial septal defect (ASD) closure and predictors of unremitting NOM. The pathogenic role of migraine biomarkers such as calcitonin gene‐related peptide (CGRP) and neuropeptide Y (NPY) were also assessed.New‐onset migraine has been observed after transcatheter ASD closure. Neuropeptides like CGRP and NPY stored both in the brain and heart are implicated in migraine pathophysiology. The potential role of those migraine biomarkers in NOM, as well as the risk factors and long‐term outcomes of NOM, remain largely unknown.We enrolled patients without previous migraine who underwent successful transcatheter ASD closure between 2001 and 2013. The parameters of transthoracic echocardiography, and plasma CGRP and NPY levels measured by enzyme‐linked immunosorbent assay, were collected prospectively before and after ASD closure, and compared between patients with NOM and those without. Predictors of NOM were assessed. Telephone interviews were performed in 2022 to assess migraine status. Clinical and procedural characteristics were compared between patients with unremitting migraine and those with transient migraine that remitted within 1 year.Of the 212 patients (median age, 21 years; 75.9% female), 43 (20.3%) had NOM. Potential predictors of NOM included a young age (adjusted odds ratio [aOR] 0.98, 95% confidence interval [CI] 0.96–0.99; p = 0.040), large ASD size (aOR 1.07, 95% CI 1.01–1.14; p = 0.022), and transient residual shunting after closure (aOR 2.78, 95% CI 1.05–7.36; p = 0.039). Post‐closure plasma CGRP levels, but not NPY levels, were significantly higher than pre‐closure levels (47.9 vs. 38.0 pg/mL, p = 0.023) among patients with NOM. Of the 27 patients with migraine who reported their migraine status at a median 14‐year follow‐up, 13 (48.1%) had unremitting migraine. Patients with unremitting migraine were more likely to have a smaller device‐to‐ASD size ratio (1.21 vs. 1.33, p = 0.039) and a larger pulmonary flow‐to‐systemic flow ratio (2.9 vs. 2.3, p = 0.012) than those with transient migraine.Calcitonin gene‐related peptide may play a pathogenic role in NOM after transcatheter ASD closure. A young age, large ASD size, and transient residual shunting potentially predict migraine occurrence after ASD closure. NOM not reaching remission for years may result from a significant shunt before closure. [ABSTRACT FROM AUTHOR]

Sleep problems are prevalent among individuals with Rett syndrome. We aimed to investigate sleep problems in individuals with Rett syndrome and their caregivers. A total of 29 participants diagnosed with Rett syndrome and their respective 29 caregivers were included. The Children Sleep Habits Questionnaire (CSHQ), the Pittsburgh Sleep Quality Index (PSQI), the Center for Epidemiologic Studies Depression Scale (CES-D), and the actigraphy data collected from Actiwatch 2 were used to investigate the change of sleep pattern. Based on the CSHQ questionnaire, 75.9% (22/29) of the patients reported sleep disturbances. The younger patients exhibited higher CSHQ scores. Actigraphy data revealed that both young and older patients had short total sleep duration, low sleep efficiency, long sleep-onset latency, long awaking duration, and fragmented sleep. The caregivers reported significantly higher PSQI scores, mildly declined sleep efficiency, and shorter total sleep duration in the actigraphy study. Associations were identified between smaller head circumference and shorter total sleep duration, more severe motor dysfunction and longer wake after sleep onset, worsen scoliosis and more awakenings per night. Sleep efficiency was inversely associated with epilepsy and positively associated with somatic growth. Sleep disturbances are common and should be investigated in individuals with Rett syndrome and their caregivers. Sleep problems are common and impactful among individuals with Rett syndrome (RTT) and their caregivers. We examined the sleep patterns of 29 RTT patients and their primary caregivers using various assessment tools. The study found that a majority of the patients experienced sleep disturbances, with younger patients showing more sleep difficulties. Caregivers also reported poor sleep quality. The findings emphasize the need to address sleep problems in RTT management, as improving sleep quality can positively impact the well-being of individuals with RTT and their caregivers. [ABSTRACT FROM AUTHOR]

We present a patient with postinfectious dysautonomia, which developed 2 weeks after a meningoencephalitic episode. The chief dysautonomic symptoms and signs included constipation, urinary dysfunction, anhydrosis, ptosis, and orthostatic hypotension. Neurophysiologic studies revealed no involvement of the somatic nervous system. The dysautonomia recovered gradually 3 months later with minimal supportive treatment. [Copyright &y& Elsevier]

This pilot study investigates the feasibility and assesses the impact of Lactobacillus plantarum PS128 probiotics on the neurological function in Rett syndrome. We conducted a randomized, double-blind, and placebo-controlled trial on Rett syndrome with MECP2 mutation aged between 1 and 50 years in Taiwan. In this pilot study, twice-daily L. plantarum PS128 or placebo was administered for 16 weeks. In addition to feasibility, we also assessed the changes utilizing the Mullen Scales of Early Learning. In total, 36 participants were finally randomized into L. plantarum PS128 (n = 18) or placebo (n = 18) groups. At the end of intervention, the retention rates were 100% for L. plantarum PS128 and 94.44% for placebo, with withdrawal rates of 5.56% for the placebo group. Both groups tolerated well, except for one L. plantarum PS128 participant who reported loose stool. The probiotic group showed a change of 2.19 ± 3.76, while the placebo group had −0.85 ± 5.09 (p = 0.051) in the total age-equivalent scores of Mullen Scales of Early Learning. There was a significant difference in the change of the total score on the Burke–Fahn–Marsden Movement Scale between probiotc group and placebo group (−12.19 ± 12.12 vs −4.59 ± 4.20, p = 0.020). In leg dystonia, the probiotic group exhibited a change of −4.11 ± 5.11 compared with −0.38 ± 1.50 in the placebo group (p = 0.008). Our findings affirm the feasibility of L. plantarum PS128 in Rett syndrome. Future clinical trials are mandatory to further explore its long-term impact on Rett syndrome. Rett syndrome often involves gastrointestinal symptoms and gut microbiota imbalances. We conducted a study to explore the feasibility of probiotic Lactobacillus plantarum PS128 and the impact on neurological functions in Rett syndrome. The results of our investigation demonstrated that the supplementation of probiotic L. plantarum PS128 was feasible and well tolerated, with 100% retention rate and 0% withdrawal rate. In addition, there was only one participant who had loose stool after taking L. plantarum PS128. Further, there was a tendency to enhance overall cognitive developmental level, as assessed using Mullen Scales of Early Learning. In addition, it significantly improved dystonia, as assessed using the Burke–Fahn–Marsden Movement Scale, in comparison with the placebo group. This study provides a strong foundation for future research and clinical trials exploring the potential of L. plantarum PS128 probiotics as a complementary therapy for individuals with Rett syndrome. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is caused by a defect in the survival motor neuron 1 (SMN1) gene. The Cooperative Study of the natural history of SMA Type I in Taiwan is a retrospective, longitudinal, observational study that helps in further understanding SMA disease progression in patients who have not received disease-modifying therapeutic interventions. Case report forms were used to collect demographics; genetic confirmation; SMN2 copy number; treatment patterns; and clinical outcomes including ventilator use, endotracheal tube intubation, tracheostomy, gastrostomy, complications, and survival. A total of 111 patients with SMA Type I were identified over the study period (1979–2015). Mean (median) age of onset and age at confirmed diagnosis were 1.3 (0.8) and 4.9 (4.4) months, respectively. SMN1 deletion/mutation was documented in 70 patients and SMN2 copy number in 32 (2 copies, n = 20; 3 copies, n = 12). At 240 months, survival probability for patients born during 1995–2015 versus 1979–1994 was significantly longer (p = 0.0057). Patients with 3 SMN2 copies showed substantially longer 240-month survival versus patients with 2 SMN2 copies. Over the 36-year period, mean (median) age at death was 31.9 (8.8) months. As of December 2015, 95 patients had died, 13 were alive, and 3 were lost to follow-up. The use of supportive measures (tracheostomy and gastrostomy) was associated with improved survival. These data describe the short survival of patients with SMA Type I in Taiwan in the pretreatment era, emphasizing the positive impact of supportive measures on survival. [ABSTRACT FROM AUTHOR]

We report a patient diagnosed with Aicardi-Goutières syndrome (AGS) with homozygous TREX1 gene mutation. Her magnetic resonance angiography (MRA) showed intracerebral large artery disease, which was rarely reported in the past in TREX1 AGS patients. Her younger sister also had homozygous TREX1 gene mutation and died of necrotizing enterocolitis. Intracerebral large artery involvement has been seen as a particular feature of SAMHD1-related disease. Our patient also had arthropathy, which is a finding more commonly mentioned in SAMHD1-related diseases. The observations in our case may contribute to our understanding of the pathogenetic mechanism of TREX1 AGS, involving the intracerebral large arteries, arthropathy, and possibly the gastrointestinal tract. [ABSTRACT FROM AUTHOR]

Background: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. Objective: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. Methods: Patients with biallelic NDUFAF5 mutations were recruited from multi‐centers in Taiwan. Clinical, laboratory, radiological, and follow‐up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. Results: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early‐onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late‐onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late‐onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early‐onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early—versus late‐onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early‐onset case than a late‐onset patient. Conclusions: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background Both refractory convulsive status epilepticus (SE) and super-refractory SE are medical emergencies. However, there are limited data on super-refractory SE in children. Thus, this study focuses on characterizing the demographics, outcomes, and prognostic factors for super-refractory SE in children. Methods This study was a retrospective analysis of super-refractory SE treated in a tertiary referral center in Taiwan. The functional outcome was evaluated by modified Rankin scale (mRS). Significant functional decline was defined as an mRS difference (before hospital admission and at discharge) of more than 2. The variates and the follow-up mRS values were then analyzed statistically. Results We enrolled 134 patients with 191 episodes of convulsive SE and identified 30 patients with 38 episodes of convulsive super-refractory SE. The incidence of convulsive super-refractory SE in the group with SE was 19.9%, and the age ranged from 2.5 months to 17 years. In-hospital mortality was 13.3%, which was much lower than that of adult cohorts. Newly acquired epilepsy and cognitive deficit occurred in 100% and 88.5%, respectively. Newly acquired epilepsy, as a sequel of super-refractory SE, was observed in all 18 patients (100%) who survived and had no history of epilepsy. Significant functional decline (mRS difference of more than 2) at discharge occurred in 76.7%. Poor functional outcome was associated with acute symptomatic etiology (P < 0.001) and the number of anesthetic agents (P = 0.002). The functional outcome improved after 1 year of follow-up in our population. Conclusions Super-refractory SE is associated with significant morbidity and mortality in children. However, the in-hospital mortality rate is much lower compared with adults. The functional outcome in children is associated with acute symptomatic etiology and the number of anesthetic agents and may improve after long-term follow-up. [ABSTRACT FROM AUTHOR]

Neuronal ceroid lipofuscinoses type 2 disease (CLN2) is a very rare, autosomal recessive neurodegerative disease caused by deficient activity of the enzyme tripeptidyl peptidase 1 (TPP1). The seizures in CLN2 are polymorphic and resistant to antiepileptic drugs. In particular, myoclonus (epileptic and non-epileptic) predominant as the disease progresses. Herein, we present a child of CLN2 disease, who had near-continuous myoclonus, and was subsequently attenuated by administration of Perampanel. This girl had initially presented with language delay and generalized tonic clonic seizure at 3 years of age. The diagnosis of CLN2 was made via genetic study, which showed compound heterozygous mutation on TPP1 gene (c.622 C > T and partial gene deletion including at least exons 1–3). Currently, at the age of 8 years, there was near-continuous myoclonus (epileptic and non-epileptic), which worsen during acute illness. Eventually, she was given Perampanel with starting dose of 1 mg/day and slowly titrated upto 6 mg/day in 4 weeks. There was significant attenuation of myoclonus (>50% seizure reduction). To our knowledge, this is the first case in the literature describing the efficacy of perampanel in treating myoclonus in CLN2 disease. [ABSTRACT FROM AUTHOR]

• Children had a lower COVID-19 vaccination rate and a higher transmission rate. • Children with COVID-19 had more fever and higher peak fever than adults. • The home rapid antigen test had a suboptimal negative predictive rate in children. • The cycle threshold value of those with false-negative antigen tests was lower in children. The SARS-CoV-2 Omicron variant pandemic struck Taiwan in April 2022. Rapid antigen tests (RATs) play an important role in providing rapid results during a pandemic. However, self-collected samples by the children's caregivers without the supervision of medical personnel raise some concerns. This study was performed to investigate household transmission, clinical characteristics, and antigen performance in a special COVID-19 family clinic in a children's hospital. The performance of at-home RATs was evaluated based on reverse transcription-polymerase chain reaction. We included 627 patients in our study between May 11 and June 10, 2022. The COVID-19 full vaccination rate was significantly higher in adults (98.5%) than in children (5.9%, P <0.001). The transmission rate was significantly higher in children (91.3%) than in adults (76.6%, P <0.001). Infected children had more incidents of fever (82.4% vs 22.4%, P <0.001) and a higher peak fever than adults. Based on the reverse transcription-polymerase chain reaction, the negative predictive rate of the home RAT was only 38.7% (95% confidence interval: 31.9-46.0%) in children. The cycle threshold value of those with false-negative antigen tests was significantly lower in children. Children had a higher transmission rate, more fever, and higher peak fever than adults. Home RAT has a suboptimal negative predictive rate in children. [Display omitted] [ABSTRACT FROM AUTHOR]

Compound heterozygous variants of SHQ1 , an assembly factor of H/ACA ribonucleoproteins (RNPs) involved in critical biological pathways, have been identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. We investigated the role of SHQ1 in brain development and movement disorders. SHQ1 expression was knocked down using short-hairpin RNA (shRNA) to investigate its effects on neurons. Shq1 shRNA and cDNA of WT and mutant SHQ1 were also introduced into neural progenitors in the embryonic mouse cortex through in utero electroporation. Co-immunoprecipitation was performed to investigate the interaction between SHQ1 and DKC1, a core protein of H/ACA RNPs. We found that SHQ1 was highly expressed in the developing mouse cortex. SHQ1 knockdown impaired the migration and neurite morphology of cortical neurons during brain development. Additionally, SHQ1 knockdown impaired neurite growth and sensitivity to glutamate toxicity in vitro. There was also increased dopaminergic function upon SHQ1 knockdown, which may underlie the increased glutamate toxicity of the cells. Most SHQ1 variants attenuated their binding ability toward DKC1, implying SHQ1 variants may influence brain development by disrupting the assembly and biogenesis of H/ACA RNPs. SHQ1 plays an essential role in brain development and dopaminergic function by upregulating dopaminergic pathways and regulating the behaviors of neural progenitors and their neuronal progeny, potentially leading to dystonia and developmental delay in patients. Our study provides insights into the functions of SHQ1 in neuronal development and dopaminergic function, providing a possible pathogenic mechanism for H/ACA RNPs-related disorders. • Compound heterozygous variants of SHQ1 were identified in patients with developmental delay, dystonia, epilepsy, and microcephaly. • SHQ1 knockdown impaired the migration and neurite morphology of cortical neurons during brain development. • There was increased dopaminergic function upon SHQ1 knockdown, which may underlie the increased glutamate toxicity. [ABSTRACT FROM AUTHOR]

Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive metabolic disorder affecting γ-aminobutyric acid degradation. We described a boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency and novel mutations of ALDH5A1 gene. He was referred because of developmental delay, focal seizures, and choreoathetosis at 6 months of age. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by increased level of γ-hydroxybutyric acid in urine and novel compound heterozygous mutations in the ALDH5A1 gene. His seizures were successfully controlled. However, the patient showed a slowly progressive clinical course with severe neurologic deficits. A magnetic resonance imaging (MRI) revealed abnormal high intensities in the putamen and globus pallidi on T2-weighted images when he was 6 months old, and more diffuse abnormal signal intensities over bilateral hemispheres were noted when he was 3 years old. [ABSTRACT FROM AUTHOR]

Among dystonia patients receiving globus pallidus internus (GPi) deep brain stimulation (DBS), long-term outcomes remain to be established. To report the long-term outcomes of GPi DBS in a patient cohort with idiopathic and acquired dystonia. In this long-term follow-up cohort, there were 4 patients with idiopathic dystonia and 2 patients with acquired dystonia. The Burke-Fahn-Marsden Dystonia Rating Scale was used to evaluate 6 consecutive patients preoperatively and at 6 months, 12 months, and the last follow-up. The relationship between etiology and clinical improvement was analyzed. Stimulation parameters were evaluated for similarities and differences among these patients. The mean follow-up of our cohort was 65.3 months (median 40.5 months). The average improvement in the Burke-Fahn-Marsden Dystonia Rating Scale (mean ± SEM) were 56% ± 7.6, 67% ± 6.8 and 66% ± 9.7 at 6 months, 12 months, and the last follow-up, respectively. There was greater improvement during the long-term follow-up in the 4 patients with idiopathic dystonia than in the 2 patients with acquired dystonia. The 2 most ventral electrodes (contact 0 and 1) were activated in all 11 leads in this cohort. The average stimulation intensity, pulse width and frequency were 2.0 ± 0.24 mA, 252 ± 43 μs, and 99 ± 6.0 Hz, respectively. Isolated dystonia, either monogenic or idiopathic, usually responds better to GPi DBS than to acquired dystonia. Selection of patients by dystonia etiology, accurate placement of DBS leads in GPi targets, and proper stimulation programming are crucial to achieve better long-term outcomes. [ABSTRACT FROM AUTHOR]

Summary: Objective: To investigate the attentional processes and symptoms of attention-deficit hyperactivity disorder (ADHD) in pediatric patients with epilepsy and IQ greater than 70 in Taiwan. Methods: We assessed 61 children (male, 62.3%; full-scale IQ >70) with epilepsy, ages 6–16 years, and 61 sex-, age-, and parental education-matched typically developing children (controls). All participants completed the intelligence (WISC-III) and attention assessments (Conners’ Continuous Performance Test, CPT). The parents reported on the ADHD symptoms of their children. Results: Children with epilepsy had more omission errors and deviant response style (β) and scored lower in the Hit Reaction Time (RT) Block Change, reflecting inattention and slowness. Epileptic children with ADHD symptoms had longer and more variable Hit RT than those without ADHD and controls. Higher full-scale IQ was significantly associated with less change in Hit RT, Hit RT block, standard error, and inter-stimulus intervals. There were no effects from age of onset, duration of having epilepsy, etiology of epilepsy, and brain anomaly on the CPT profiles. Conclusion: The findings suggest that children with epilepsy, despite not mentally retarded, may have attention deficits. Hence, screening for attention problems among patients with epilepsy regardless of intelligence level and ADHD symptoms is recommended to offset possible learning adversities of this population. [Copyright &y& Elsevier]

We studied the sensory evoked potentials in pediatric Wilson disease to verify their subclinical neurologic involvement and to elucidate the role of cirrhosis in abnormal evoked potentials in non-neurologic Wilson disease. Thirty children (17 male, 13 female), diagnosed with Wilson disease before 18 years, were enrolled. The mean age during studies was 15.8 ± 6.3 years, and disease duration since diagnosis was 3.0 ± 3.3 years. In 12 neurologic Wilson disease cases, there were prolonged interpeak latencies of brainstem auditory evoked potentials III-V, I-V, somatosensory evoked potentials N13-N20 (P < 0.01 vs controls and non-neurologic cases), and P100 latency (P < 0.01 vs controls). All 12 patients had at least one abnormal evoked potential, including 91.7% brainstem auditory, 58.3% somatosensory, and 25% visual evoked potentials. In 18 non-neurologic Wilson disease cases, there were still prolonged interpeak latencies for brainstem auditory evoked potentials I-V and somatosensory evoked potentials N13-N20 (P < 0.05 vs controls), with 27.8% of them having at least one abnormal evoked potential, including 16.6% brainstem auditory, 5.6% somatosensory, and 11.1% visual evoked potentials. In those with non-neurologic Wilson disease, there were no significant differences in all the evoked potential parameters between the cirrhotic and non-cirrhotic patients. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Chronic tic disorder and Tourette syndrome are common childhood-onset neurological diseases. However, the pathophysiology underlying these disorders is unclear, and most studies have focused on the disinhibition of the corticostriatal–thalamocortical circuit. An autoimmune dysfunction has been proposed in the pathogenetic mechanism of Tourette syndrome and related neuropsychiatric disorders such as obsessive–compulsive disorder, autism, and attention-deficit/hyperactivity disorder. This is based on evidence from animal model studies and clinical findings. Herein, we review and give an update on the clinical characteristics, clinical evidence, and genetic studies in vitro as well as animal studies regarding immune dysfunction in Tourette syndrome. [ABSTRACT FROM AUTHOR]

• The total EEG complexity is a potential biomarker of infantile spasms. • Higher total EEG complexity before AED and 6 months after ACTH is associated with spasm-freedom. • The total EEG complexity is not associated with the presence of hypsarrhythmia. To investigate the potential of EEG multiscale entropy and complexity as biomarkers in infantile spasms. We collected EEG data retrospectively from 16 newly diagnosed patients, 16 age- and gender-matched healthy controls, and 15 drug-resistant patients. The multiscale entropy (MSE) and total EEG complexity before anti-epileptic drug (AED) treatment, before adrenocorticotropic hormone (ACTH) treatment, 14 days after ACTH therapy, and after 6 months of follow-up were calculated. The total EEG complexity of 16 newly diagnosed infantile spasms patients was lower than the 16 healthy controls (median [IQR]: 351.5 [323.1–388.1] vs 461.6 [407.7–583.4]). The total EEG complexity before treatment was higher in the six patients with good response to AED than the 10 patients without response (median [IQR]: 410.0 [388.1–475.0] vs 344.5 [319.6–352.0]). The total EEG complexity before and after 14-days of ACTH therapy was not different between 13 ACTH therapy responders and nine non-responders. After 6-months follow-up, the total EEG complexity of ACTH therapy responders were higher than non-responders (median [IQR]: 598.5 [517.4–623.3] vs 448.6 [347.1–536.3]). The total EEG complexity before AED and 6 months after ACTH are associated with spasm-freedom. The total EEG complexity is a potential biomarker to predict and monitor the treatment effect in infantile spasms. [ABSTRACT FROM AUTHOR]

Individuals with Rett syndrome (RTT) commonly demonstrate Parkinsonian features and dystonia at teen age; however, the pathological reason remains unclear. Abnormal iron accumulation in deep gray matter were reported in some Parkinsonian-related disorders. In this study, we investigated the iron accumulation in deep gray matter of RTT and its correlation with dystonia severity. We recruited 18 RTT-diagnosed participants with MECP2 mutations, from age 4 to 28, and 28 age-gender matched controls and investigated the iron accumulation by susceptibility weighted image (SWI) in substantia nigra (SN), globus pallidus (GP), putamen, caudate nucleus, and thalamus. Pearson's correlation was applied for the relation between iron accumulation and dystonia severity. In RTT, the severity of dystonia scales showed significant increase in subjects older than 10 years, and the contrast ratios of SWI also showed significant differences in putamen, caudate nucleus and the average values of SN, putamen, and GP between RTT and controls. The age demonstrated moderate to high negative correlations with contrast ratios. The dystonia scales were correlated with the average contrast ratio of SN, putamen and GP, indicating iron accumulation in dopaminergic system and related grey matter. As the first SWI study for RTT individuals, we found increased iron deposition in dopaminergic system and related grey matter, which may partly explain the gradually increased dystonia. [ABSTRACT FROM AUTHOR]

Background and objective: The epidemiology of pediatric acquired demyelinating disorders remains to be clarified in many parts of Asia. We carry out this study to depict the epidemiology of pediatric multiple sclerosis (MS), neuromyelitis optica (NMO), and optic neuritis (ON) in Taiwan. Methods: We conducted a retrospective nationwide population-based study using data from Taiwan's National Health Insurance Research Database. Prevalent cases of pediatric MS and NMO during 2001–2015, and incident cases of pediatric MS, NMO, and ON during 2003–2015 were identified. The demographic features and comorbidities were investigated. Results: We identified 403 MS, 42 NMO, and 1496 ON incident cases under the age of 20 during 2003–2015. The majority of pediatric MS (86.1%) and NMO (90.5%) patients were 10 years old or above. The incidence of MS and ON was relatively steady, while that of NMO increased prominently later during the study period. The average incidence of pediatric MS and NMO during 2011–2015 was 0.52 and 0.11 per 100,000 person-years, respectively. The female preponderance was evident for pediatric MS and NMO, and less so for pediatric ON. The most common autoimmune comorbidities for pediatric MS were thyrotoxicosis (1.0%) and systemic lupus erythematosus (0.7%). Conclusion: The epidemiology of pediatric MS was largely stationary in Taiwan during 2001–2015, while the prevalence of pediatric NMO rose steeply during this period, probably reflecting better recognition of this clinical entity. Autoimmune comorbidities were uncommon for pediatric MS and NMO in Taiwan. [ABSTRACT FROM AUTHOR]

• Serotonin receptor agonist DOI causes tic-like behaviors and gut dysbiosis in rat. • DOI triggers hyperactive signaling in mesocortical and nigrostriatal pathways. • PS128 alleviate. DOI-induced behavior and hyperactive signaling. • PS128 modulates enteric serotonergic system and stabilizes gut microbiota. • PS128 strengthens the microbiota–gut–brain axis function of the host. We previously reported a novel psychobiotic strain of Lactobacillus plantarum PS128 (PS128) which could ameliorate anxiety-like& depression-like behaviors and modulate cerebral dopamine (DA) and serotonin (5-HT) in mice. Here, we examine the possibility of using PS128 administration to improve tic-like behaviors by using a 5-HT 2A and 5-HT 2C receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI). PS128 was orally administered to male Wistar rat for 2 weeks before two daily DOI injections. We recorded the behaviors immediately after the second DOI injection and compared the results with control and haloperidol treatment groups. PS128 significantly reduced tic-like behaviors and pre-pulse inhibition deficit in a threshold-dose of 109 CFU per day. Brain tissue analysis showed that DOI induced abnormal DA efflux in the striatum and prefrontal cortex, while PS128 ingestion improved DA metabolism and increased norepinephrine (NE) levels in these two regions. In addition, PS128 ingestion increased DA transporter and β-arrestin expressions and decrease. DOI-induced phosphorylation of DA and cAMP regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at Thr34 and extracellular regulated protein kinases (ERK). PS128 ingestion also modulated peripheral 5-HT levels and shaped the cecal microbiota composition, which helps to alleviate DOI-induced dysbiosis. These results suggested that PS128 ameliorated DOI-induced tic-like hyper-active behaviors via stabilizing cerebral dopaminergic pathways through its modulation of host's microbiota–gut–brain axis. Thus, we believe there are potentials for utilizing psychobiotics to improve syndromes caused by DA dysregulation in DA-related neurological disorders and movement disorders such as Tourette syndrome. [ABSTRACT FROM AUTHOR]

Genetic mutations in TBC1D24 have been associated with multiple phenotypes, with epilepsy being the main clinical manifestation. The TBC1D24 protein consists of the unique association of a Tre2/Bub2/Cdc16 (TBC) domain and a TBC/lysin motif domain/catalytic (TLDc) domain. More than 50 missense and loss-of-function mutations have been described and are spread over the entire protein. Through whole genome/exome sequencing we identified compound heterozygous mutations, R360H and G501R, within the TLDc domain, in an index family with a Rolandic epilepsy exercise-induced dystonia phenotype (http://omim.org/entry/608105). A 20-year long clinical follow-up revealed that epilepsy was self-limited in all three affected patients, but exercise-induced dystonia persisted into adulthood in two. Furthermore, we identified three additional sporadic paediatric patients with a remarkably similar phenotype, two of whom had compound heterozygous mutations consisting of an in-frame deletion I81_K84 and an A500V mutation, and the third carried T182M and G511R missense mutations, overall revealing that all six patients harbour a missense mutation in the subdomain of TLDc between residues 500 and 511. We solved the crystal structure of the conserved Drosophila TLDc domain. This allowed us to predict destabilizing effects of the G501R and G511R mutations and, to a lesser degree, of R360H and potentially A500V. Next, we characterized the functional consequences of a strong and a weak TLDc mutation (TBC1D24G501R and TBC1D24R360H) using Drosophila, where TBC1D24/Skywalker regulates synaptic vesicle trafficking. In a Drosophila model neuronally expressing human TBC1D24, we demonstrated that the TBC1D24G501R TLDc mutation causes activity-induced locomotion and synaptic vesicle trafficking defects, while TBC1D24R360H is benign. The neuronal phenotypes of the TBC1D24G501R mutation are consistent with exacerbated oxidative stress sensitivity, which is rescued by treating TBC1D24G501R mutant animals with antioxidants N-acetylcysteine amide or α-tocopherol as indicated by restored synaptic vesicle trafficking levels and sustained behavioural activity. Our data thus show that mutations in the TLDc domain of TBC1D24 cause Rolandic-type focal motor epilepsy and exercise-induced dystonia. The humanized TBC1D24G501R fly model exhibits sustained activity and vesicle transport defects. We propose that the TBC1D24/Sky TLDc domain is a reactive oxygen species sensor mediating synaptic vesicle trafficking rates that, when dysfunctional, causes a movement disorder in patients and flies. The TLDc and TBC domain mutations' response to antioxidant treatment we observed in the animal model suggests a potential for combining antioxidant-based therapeutic approaches to TBC1D24-associated disorders with previously described lipid-altering strategies for TBC domain mutations. [ABSTRACT FROM AUTHOR]

The febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epileptic encephalopathy which developed the refractory status epilepticus following or during a nonspecific febrile illness. To analyze the short-term and long-term outcome of FIRES in the children, we retrospectively analyzed the related data. The motor outcome was evaluated by modified Rankin scale (mRS). Poor motor outcome was defined as a mRS score of 4 or higher at discharge. Significant motor decline was defined as the mRS difference more than 2 before hospital admission and at discharge. We totally enrolled 25 patients for analysis. Four patients were expired during hospitalization, and one patient was lost to follow-up after discharge. Therefore, a total 20 patients were finally analyzed. The age of disease onset ranged from 1.6 to 17.2 years (mean: 9.6 ± 4.4 years). Newly acquired epilepsy and cognitive deficit occurred in 100% and 61%, respectively. The duration of the anesthetic agents ranged from 7 to 149 days (mean: 34.2 ± 36.1 days). The duration of anesthetic agent usage (p = 0.011), refractory epilepsy (p = 0.003), and the use of ketogenic diet (p = 0.004) were significantly associated with the poor long-term motor outcome, and the number of anesthetic agents tended to be associated with the poor long-term motor outcome (p = 0.050). In-hospital mortality was 16%. Significant functional decline at discharge occurred in 100%. However, there was improvement in long-term follow-up. The outcome of FIRES is poor with significant mortality and morbidities. Refractory epilepsy with cognitive deficit in survived cases is common, but improvement is possible. • The FIRES is a epileptic encephalopathy which develops refractory status epilepticus following or during a febrile illness. • The duration of anesthetic agent usage and refractory epilepsy were associated with poor long-term motor outcome. • The outcome of FIRES is poor with significant mortality and morbidities. • Refractory epilepsy with cognitive deficit in survived cases is common, but improvement is possible. [ABSTRACT FROM AUTHOR]

Background: Microglia is responsible for neuroinflammation, which may aggravate brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) kinase is related to microglial activation with subsequent neuroinflammation. In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation.Methods: In vitro, we treated BV2 cells with KA and LPS. In vivo, KA was used to induce seizures on postnatal day 25 in B6.129P-Cx3cr1tm1Litt/J mice. Rapamycin and everolimus were evaluated in their modulation of neuroinflammation detected by real-time PCR, Western blotting, and immunostaining.Results: Everolimus was significantly more effective than rapamycin in inhibiting iNOS and mTOR signaling pathways in both models of neuroinflammation (LPS) and seizure (KA). Everolimus significantly attenuated the mRNA expression of iNOS by LPS and nitrite production by KA and LPS than that by rapamycin. Only everolimus attenuated the mRNA expression of mTOR by LPS and KA treatment. In the present study, we also found that the modulation of mTOR under LPS and KA treatment was not mediated by Akt pathway but was primarily mediated by ERK phosphorylation, which was more significantly attenuated by everolimus. This inhibition of ERK phosphorylation and microglial activation in the hippocampus by everolimus was also confirmed in KA-treated mice.Conclusions: Rapamycin and everolimus can block the activation of inflammation-related molecules and attenuated the microglial activation. Everolimus had better efficacy than rapamycin, possibly mediated by the inhibition of ERK phosphorylation. Taken together, mTOR inhibitor can be a potential pharmacological target of anti-inflammation and seizure treatment. [ABSTRACT FROM AUTHOR]

Aim To assess the clinical trial and real-world data for adjunctive perampanel in adolescents and develop consensus recommendations to guide the use of perampanel in this population in clinical practice. Methods In May 2015, 15 epilepsy experts attended a Consensus Development Meeting to assess the clinical trial data for perampanel, specific to the adolescent age group (12-17 years) and develop consensus treatment recommendations. Results and Discussion Analysis of the adolescent subgroup data of three pivotal placebo-controlled, double-blind, phase 3 trials investigating perampanel in patients with ongoing focal epileptic seizures despite receiving one to three antiepileptic drugs found that perampanel 4-12 mg was superior to placebo. The tolerability profile of perampanel was generally acceptable. Adolescent patients receiving long-term treatment with perampanel in an open-label extension study maintained improvements in seizure control compared with baseline, with a favorable risk-benefit profile. A phase 2 study showed that perampanel had no clinically important effects on cognitive function, growth, and development. Conclusion Perampanel is a welcome addition to the armamentarium of existing antiepileptic drugs as it represents a new approach in the management of epilepsy, with a novel mechanism of action, and the potential to have a considerable impact on the treatment of adolescents with epilepsy. [ABSTRACT FROM AUTHOR]

Both epilepsy and tic disorders may share common mechanisms with the involvement of abnormal cortical-basal ganglion circuit connection and dopaminergic dysfunction. However, the association between epilepsy and tic disorders has never been studied. This study investigated the risks of developing tic disorders among children with epilepsy using databases of a universal health insurance system in Taiwan. The data analyzed in this study were retrieved from the National Health Insurance Research Database in Taiwan. The study cohort included children with epilepsy between 2001 and 2007 (n=2629) and a three-fold age- and gender-matched controls (n=7887). All subjects were followed up for 3 years from the date of cohort entry to identify their admissions due to tic disorders (ICD-9-CM codes 307.2, 307.20-307.23). Cox hazard regression analysis was performed to estimate the effect of epilepsy on the occurrence of tics. The epilepsy cohort had a higher prevalence of tics (1.7% vs. 0.2%), and a 8.70-fold increased risk of developing a tic disorder compared with the controls (adjusted hazard ratio (AHR) 8.70, 95% confidence interval (CI) 4.26-16.37, p<0.001). Male patients were observed to have a higher risk of developing a tic disorder (AHR 1.90, 95% CI=1.04-3.46, p<0.001) compared to female individuals. Patients with multiple antiepileptic drugs treatment also exhibited higher crude OR for developing tic disorders. This nationwide population-based cohort study, for the first time, demonstrated that there is a significantly increased risk for tic disorders among children with epilepsy. We also found males, attention deficit disorder and the use of multiple AEDs to be independent risk factors of tic disorders. Closely evaluating possible tic disorders would be crucial for improving the outcome and life quality in children with epilepsy. [ABSTRACT FROM AUTHOR]

The association between epilepsy and Tourette syndrome has rarely been investigated. In this retrospective cohort study, we analyzed a dataset of 1,000,000 randomly sampled individuals from the Taiwan National Health Insurance Research Database to determine the risk of epilepsy in children with Tourette syndrome. The study cohort consisted of 1062 patients with Tourette syndrome aged ≤ 18 years, and the control group consisted of three times the number of age- and sex-matched patients without Tourette syndrome, who were insurants, from the same database during the same period. The Tourette syndrome group had an 18.38-fold increased risk of epilepsy than the control group [hazard ratio=18.38, 95% confidence interval (CI)=8.26-40.92; P<0.001]. Even after adjusting for the comorbidities, the risk of epilepsy in the Tourette syndrome group with comorbidities remained high (hazard ratio=16.27, 95% CI=6.26-18.46; P<0.001), indicating that the increased risk was not associated with comorbidities. This population-based retrospective cohort study provides the first and strong evidence that Tourette syndrome is associated with a higher risk of epilepsy. A close follow-up of children with Tourette syndrome for the development of epilepsy is warranted. [ABSTRACT FROM AUTHOR]

Preterm infants are at risk for emotional difficulties and behavioral problems. This study was aimed to investigate the effects of a clinic-based intervention program (CBIP) and a home-based intervention program (HBIP) compared with a usual care program (UCP) on emotion regulation to stress in preterm infants with very low birth weight (VLBW, birth weight <1500 g). A total of 178 VLBW preterm infants had been previously randomly assigned to receive one of three interventions (57 in CBIP, 63 in HBIP and 58 in UCP). The CBIP and HBIP contained identical child-, parent- and dyad-focused interventions that were provided to infants during hospitalization and were respectively delivered at clinics and at home at PMA 36-38 and 40 weeks, and 1, 2, 4, 6, 9, 12 months of corrected age. All infants were prospectively observed for behavioral reactivity and regulation in response to experimentally evoke stress evoked by a toy-behind-barrier procedure at 12, 18, and 24 months of corrected age. Their cognitive and language abilities, and mothers' responsiveness were also assessed at 12 months as potential covariates. Compared to the UCP-group infants, the HBIP-group infants exhibited shorter durations of visual orientation to a toy (adjusted difference [95% CI]=-1.60 [-3.07 to -0.13], p=0.03), and the CBIP-group infants exhibited shorter durations of avoidance (adjusted difference [95% CI]=-0.84 [-1.57 to -0.10], p=0.03) from 12 to 24 months of corrected age. The CBIP and HBIP showed no difference in the stress reactivity from the UCP, however. These results suggest that comprehensive interventions incorporating child-, parent- and dyad-focused services enhanced VLBW preterm infants' emotion regulation in response to stress at toddler age. [ABSTRACT FROM AUTHOR]

Peroxisomal proliferator-activated receptor gamma (PPARγ) is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA) receptor-mediated temporal lobe epilepsy (TLE). We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC) analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE. [ABSTRACT FROM AUTHOR]

Objective: Increasing animal studies supported the harmful effects of prolonged or frequent neonatal seizures in developing brain, including increased risk of later epilepsy. Various nonlinear analytic measures had been applied to investigate the change of brain complexity with age. This study focuses on clarifying the relationship between later epilepsy and the changes of electroencephalogram (EEG) complexity in neonatal seizures. Methods: EEG signals from 19 channels of the whole brain from 32 neonates below 2 months old were acquired. The neonates were classified into 3 groups: 9 were normal controls, 9 were neonatal seizures without later epilepsy, and 14 were neonatal seizures with later epilepsy. Sample entropy (SamEn), multiscale entropy (MSE) and complexity index (CI) were analyzed. Results: Although there was no significant change in SamEn, the CI values showed significantly decreased over Channels C3, C4, and Cz in patients with neonatal seizures and later epilepsy compared with control group. More multifocal epileptiform discharges in EEG, more abnormal neuroimaging findings, and higher incidence of future developmental delay were noted in the group with later epilepsy. Conclusions: Decreased MSE and CI values in patients with neonatal seizures and later epilepsy may reflect the mixed effects of acute insults, underlying brain immaturity, and prolonged seizures-related injuries. The analysis of MSE and CI can therefore provide a quantifiable and accurate way to decrypt the mystery of neonatal seizures, and could be a promising predictor. [ABSTRACT FROM AUTHOR]

Absence epilepsy is an important epileptic syndrome in children. Multiscale entropy (MSE), an entropy-based method to measure dynamic complexity at multiple temporal scales, is helpful to disclose the information of brain connectivity. This study investigated the complexity of electroencephalogram (EEG) signals using MSE in children with absence epilepsy. In this research, EEG signals from 19 channels of the entire brain in 21 children aged 5-12 years with absence epilepsy were analyzed. The EEG signals of pre-ictal (before seizure) and ictal states (during seizure) were analyzed by sample entropy (SamEn) and MSE methods. Variations of complexity index (CI), which was calculated from MSE, from the pre-ictal to the ictal states were also analyzed. The entropy values in the pre-ictal state were significantly higher than those in the ictal state. The MSE revealed more differences in analysis compared to the SamEn. The occurrence of absence seizures decreased the CI in all channels. Changes in CI were also significantly greater in the frontal and central parts of the brain, indicating fronto-central cortical involvement of “cortico-thalamo-cortical network” in the occurrence of generalized spike and wave discharges during absence seizures. Moreover, higher sampling frequency was more sensitive in detecting functional changes in the ictal state. There was significantly higher correlation in ictal states in the same patient in different seizures but there were great differences in CI among different patients, indicating that CI changes were consistent in different absence seizures in the same patient but not from patient to patient. This implies that the brain stays in a homogeneous activation state during the absence seizures. In conclusion, MSE analysis is better than SamEn analysis to analyze complexity of EEG, and CI can be used to investigate the functional brain changes during absence seizures. [ABSTRACT FROM AUTHOR]

Non-ketotic hyperglycinaemia usually presents in neonates or infants with seizures, hypotonia, and developmental delays. Baker et al. describe a variant form with atypical features including leukodystrophy in patients without AMT, GLDC or GCSH mutations, and report defects in lipoic acid synthesis and related iron-sulphur cluster biogenesis genes including LIAS, BOLA3 and GLRX5.Patients with nonketotic hyperglycinemia and deficient glycine cleavage enzyme activity, but without mutations in AMT, GLDC or GCSH, the genes encoding its constituent proteins, constitute a clinical group which we call ‘variant nonketotic hyperglycinemia’. We hypothesize that in some patients the aetiology involves genetic mutations that result in a deficiency of the cofactor lipoate, and sequenced genes involved in lipoate synthesis and iron-sulphur cluster biogenesis. Of 11 individuals identified with variant nonketotic hyperglycinemia, we were able to determine the genetic aetiology in eight patients and delineate the clinical and biochemical phenotypes. Mutations were identified in the genes for lipoate synthase (LIAS), BolA type 3 (BOLA3), and a novel gene glutaredoxin 5 (GLRX5). Patients with GLRX5-associated variant nonketotic hyperglycinemia had normal development with childhood-onset spastic paraplegia, spinal lesion, and optic atrophy. Clinical features of BOLA3-associated variant nonketotic hyperglycinemia include severe neurodegeneration after a period of normal development. Additional features include leukodystrophy, cardiomyopathy and optic atrophy. Patients with lipoate synthase-deficient variant nonketotic hyperglycinemia varied in severity from mild static encephalopathy to Leigh disease and cortical involvement. All patients had high serum and borderline elevated cerebrospinal fluid glycine and cerebrospinal fluid:plasma glycine ratio, and deficient glycine cleavage enzyme activity. They had low pyruvate dehydrogenase enzyme activity but most did not have lactic acidosis. Patients were deficient in lipoylation of mitochondrial proteins. There were minimal and inconsistent changes in cellular iron handling, and respiratory chain activity was unaffected. Identified mutations were phylogenetically conserved, and transfection with native genes corrected the biochemical deficiency proving pathogenicity. Treatments of cells with lipoate and with mitochondrially-targeted lipoate were unsuccessful at correcting the deficiency. The recognition of variant nonketotic hyperglycinemia is important for physicians evaluating patients with abnormalities in glycine as this will affect the genetic causation and genetic counselling, and provide prognostic information on the expected phenotypic course. [ABSTRACT FROM AUTHOR]

Highlights: [•] The BSID-II and Bayley-III were concurrently administered in this study. [•] The Bayley-III was reliable and generally contained similar constructs as the BSID-II. [•] The Bayley-III overestimated the developmental performance of Taiwanese infants. [•] Upward adjustments of the Bayley-III scores for definition of developmental delay were suggested. [Copyright &y& Elsevier]

Abstract: Purpose: PRRT2 mutations were recently identified in benign familial infantile epilepsy (BFIE) and infantile convulsions with paroxysmal choreoathetosis (ICCA) but no abnormalities have so far been identified in their phenotypically similar seizure disorder of benign convulsions with mild gastroenteritis (CwG), while mutations in KCNQ2 and KCNQ3 have been recognized in benign familial neonatal epilepsy (BFNE). The aim of this study was to identify PRRT2 mutations in infantile convulsions in Asian families with BFIE and ICCA, CwG and BFNE. Methods: We recruited 26 unrelated Japanese affected with either BFIE or non-familial benign infantile seizures and their families, including three families with ICCA. A total of 17 Japanese and Taiwanese with CwG, 50 Japanese with BFNE and 96 healthy volunteers were also recruited. Mutations of PRRT2 were sought using direct sequencing. Results: Heterozygous truncation mutation (c.649dupC) was identified in 15 of 26 individuals with benign infantile epilepsy (52.1%). All three families of ICCA harbored the same mutation (100%). Another novel mutation (c.1012+2dupT) was found in the proband of a family with BFIE. However, no PRRT2 mutation was found in either CwG or BFNE. Conclusions: The results confirm that c.649dupC, a truncating mutation of PRRT2, is a hotspot mutation resulting in BFIE or ICCA regardless of the ethnic background. In contrast, PRRT2 mutations do not seem to be associated with CwG or BFNE. Screening for PRRT2 mutation might be useful in early-stage differentiation of BFIE from CwG. [Copyright &y& Elsevier]

Abstract: Introduction: Intervention studies of developmental care for preterm infants in Western societies have shown early but unsustainable effects on child outcomes, however only a limited of studies have examined if developmental care interventions produce similar effects in Eastern cultural contexts. Aims: To examine the effectiveness of in-hospital developmental care on neonatal morbidity, growth and development of preterm infants with very low birth weight (VLBW; birth weight<1500g) in Taiwan. Methods: One hundred and seventy-eight VLBW preterm infants were randomly assigned to the clinical trial during hospitalization at three hospitals in Taiwan; the control group received five sessions of standard child-focused developmental care and the intervention group received five sessions of child- and parent-focused developmental care. Sixty-two normal term infants were also included as a comparison group. Infants were examined for morbidity, growth and developmental outcomes at term age. Results: At study entry, more infants in the intervention group were twins or multiples than those in the control group (29% vs. 16%, p =0.05). After adjusting for birth set, the intervention group had lower incidences of stage II–III retinopathy (odds ratio [OR]=0.34 [95% confidence interval (CI): 0.15–0.79]; p =0.01) and feeding desaturation (OR=0.32 [95% CI: 0.10–1.00]; p =0.05) and had greater daily weight gains (difference=2.0g/day [95% CI: 0–4.0g/day]; p =0.05) as compared with the control group. However, the intervention and control groups did not differ in any of the neurodevelopmental measures. Conclusions: In-hospital developmental care has short-term benefits for Taiwanese VLBW preterm infants in reducing the risk of retinopathy and feeding desaturation as well as in enhancing weight gains at term age. [Copyright &y& Elsevier]

Abstract: The treatment of later-onset Pompe disease with enzyme replacement therapy may not lead to significant improvement in muscle function, probably because of the irreversible muscle destruction caused by glycogen storage. A prospective study was performed to understand early muscle pathology in patients and the response of these pathologic changes to treatment. Five newborns and one child with later-onset Pompe disease but no signs at time of diagnosis were prospectively followed, and treatment was initiated when signs appeared. Six pretreatment biopsies taken at ages 1.5 months to 7 years indicated glycogen storage, lipid storage, stage 4 myocytes, and autophagic debris. Four 6-month posttreatment biopsies revealed glycogen clearance, but stage 4 myocytes and autophagic debris were still evident in three. In conclusion, among patients with later-onset Pompe disease and very mild signs, advanced pathologic changes were evident in a small portion of their myocytes. Because these pathologic changes may not respond to treatment, early treatment is necessary to achieve the best outcomes. [Copyright &y& Elsevier]

We investigated the clinical characteristics of children with continuous spike waves during slow-wave sleep syndrome and their treatment response to levetiracetam. Five boys and one girl, diagnosed with epilepsy with continuous spike waves during slow-wave sleep syndrome, were enrolled. Their clinical characteristics, including neuroimaging findings, were reviewed. The signs related to continuous spike waves during slow-wave sleep included increased seizure frequency (6/6), impaired responsiveness (3/6), and psychomotor regression (2/6). Magnetic resonance imaging disclosed lissencephaly in one patient, and porencephaly of the left hemisphere in another. The number of antiepileptic drugs before the use of levetiracetam was 0-4 (mean ± SD, 2.3 ± 1.5). Five of 6 children demonstrated a good response to levetiracetam, whereas 2 (40%) underwent a relapse of electrical status epilepticus during sleep pattern on electroencephalograms 4 and 5 months after clinical improvement. Both were 5 years old. The most common presenting sign in children with continuous spike waves during slow-wave sleep syndrome is increasing seizure frequency. Levetiracetam is effective in treating children with continuous spike waves during slow-wave sleep syndrome. However, the relapse rate of continuous spike waves during slow-wave sleep syndrome remains high in young children. [Copyright &y& Elsevier]