Modulation index predicts the effect of ethosuximide on developmental and epileptic encephalopathy with spike-and-wave activation in sleep.

PURPOSE: In developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS), the thalamocortical network is suggested to play an important role in the pathophysiology of the progression from focal epilepsy to DEE-SWAS. Ethosuximide (ESM) exerts effects by blocking T-type calcium channels in thalamic neurons. With the thalamocortical network in mind, we studied the prediction of ESM effectiveness in DEE-SWAS treatment using phase-amplitude coupling (PAC) analysis. METHODS: We retrospectively enrolled children with DEE-SWAS who had an electroencephalogram (EEG) recorded between January 2009 and September 2022 and were prescribed ESM at Okayama University Hospital. Only patients whose EEG showed continuous spike-and-wave during sleep were included. We extracted 5-min non-rapid eye movement sleep stage N2 segments from EEG recorded before starting ESM. We calculated the modulation index (MI) as the measure of PAC in pair combination comprising one of two fast oscillation types (gamma, 40-80 Hz; ripples, 80-150 Hz) and one of five slow-wave bands (delta, 0.5-1, 1-2, 2-3, and 3-4 Hz; theta, 4-8 Hz), and compared it between ESM responders and non-responders. RESULTS: We identified 20 children with a diagnosis of DEE-SWAS who took ESM. Fifteen were ESM responders. Regarding gamma oscillations, significant differences were seen only in MI with 0.5-1 Hz slow waves in the frontal pole and occipital regions. Regarding ripples, ESM responders had significantly higher MI in coupling with all slow waves in the frontal pole region, 0.5-1, 3-4, and 4-8 Hz slow waves in the frontal region, 3-4 Hz slow waves in the parietal region, 0.5-1, 2-3, 3-4, and 4-8 Hz slow waves in the occipital region, and 3-4 Hz slow waves in the anterior-temporal region. SIGNIFICANCE: High MI in a wider area of the brain may represent the epileptic network mediated by the thalamus in DEE-SWAS and may be a predictor of ESM effectiveness.

A case report of odonto-hypophosphatasia with a novel variant in the ALPL gene.

OBJECTIVES: Hypophosphatasia (HPP) is a rare skeletal dysplasia caused by variants in the alkaline phosphatase (ALPL) gene. More than 400 pathogenic variants of the ALPL gene have been registered in the ALPL gene variant database. Here, we describe the case of a Japanese child with odonto-hypophsphatasia (odonto-HPP) and a novel ALPL variant. CASE PRESENTATION: At the age of 2 years and 1 month, he prematurely lost one deciduous tooth, with the root intact, when he fell and hit his face lightly. Three months later, he lost another adjacent deciduous tooth without incentive. His serum alkaline phosphatase (ALP) level was 72 U/L. His urine phosphoethanolamine (PEA) level was extremely high at 938 µmol/mg·Cre. The serum pyridoxal 5'-phosphaye (PLP) level was 255.9 nmol/L. Based on the clinical symptoms and laboratory findings, the patient was clinically diagnosed with odonto-HPP. Genetic analysis of the ALPL gene revealed a heterozygous variant (NM_000478.6:c.1151C>A, p.Thr384Lys). CONCLUSIONS: We report a case of odonto-HPP with a novel variant in the ALPL gene. HPP is a rare disease, and the heterozygous mutation in the ALPL gene highlights the novelty of this case.

Exploration of urine metabolic biomarkers for new-onset, untreated pediatric epilepsy: A gas and liquid chromatography mass spectrometry-based metabolomics study.

OBJECTIVE: The discovery of objective indicators for recent epileptic seizures will help confirm the diagnosis of epilepsy and evaluate therapeutic effects. Past studies had shortcomings such as the inclusion of patients under treatment and those with various etiologies that could confound the analysis results significantly. We aimed to minimize such confounding effects and to explore the small molecule biomarkers associated with the recent occurrence of epileptic seizures using urine metabolomics. METHODS: This is a multicenter prospective study. Subjects included pediatric patients aged 2 to 12 years old with new-onset, untreated epilepsy, who had had the last seizure within 1 month before urine collection. Controls included healthy children aged 2 to 12 years old. Those with underlying or chronic diseases, acute illnesses, or recent administration of medications or supplements were excluded. Targeted metabolome analysis of spot urine samples was conducted using gas chromatography (GC)- and liquid chromatography (LC)-tandem mass spectrometry (MS/MS). RESULTS: We enrolled 17 patients and 21 controls. Among 172 metabolites measured by GC/MS/MS and 41 metabolites measured by LC/MS/MS, only taurine was consistently reduced in the epilepsy group. This finding was subsequently confirmed by the absolute quantification of amino acids. No other metabolites were consistently altered between the two groups. CONCLUSIONS: Urine metabolome analysis, which covers a larger number of metabolites than conventional biochemistry analyses, found no consistently altered small molecule metabolites except for reduced taurine in epilepsy patients compared to healthy controls. Further studies with larger samples, subjects with different ages, expanded target metabolites, and the investigation of plasma samples are required.

Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma.

West syndrome, an infantile developmental and epileptic encephalopathy with a deleterious impact on long-term development, requires early treatment to minimize developmental abnormality; in such cases, epilepsy surgery should be considered a powerful therapeutic option. We describe a 10-month-old female admitted with West syndrome associated with a hemispheric lesion following abusive head trauma. Her seizures were suppressed by hemispherotomy at 12 months of age, leading to developmental improvement. Surgical treatment of West syndrome following traumatic brain injury has not been reported previously but is worth considering as a treatment option, depending on patient age and brain plasticity.

Epilepsy in Children With Congenital Heart Disease: Risk Factors and Characteristic Presentations.

BACKGROUND: Children with a congenital heart disease (CHD) are at a higher risk of developing epilepsy than the general population, but detailed characteristics of CHD-associated epilepsy have not been clarified. The purposes of this study were to determine the risk factors for developing epilepsy associated with CHD and to elucidate the characteristics of such epilepsy. METHODS: We performed a retrospective cohort study based on medical records of pediatric patients with CHD who were born between January 2006 and December 2016, underwent cardiac surgery at Okayama University Hospital, and were followed up until at least age three years. Multivariate logistic regression analysis was used to determine factors particularly associated with epilepsy occurrence. In patients who developed epilepsy, clinical data on seizure characteristics were further investigated. RESULTS: We collected data from 1024 patients, and 41 (4.0%) developed epilepsy. The presence of underlying disease (odds ratio [OR]: 2.413; 95% confidence interval [CI]: 1.150 to 4.883) and the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score category 2 (OR: 4.373; 95% CI: 1.090 to 29.150) and category 5 (OR: 10.385; 95% CI: 1.717 to 89.016) were significantly related to epilepsy occurrence. Of the 41 patients with epilepsy, 15 (including nine with hypoplastic left heart syndrome) had focal impaired awareness seizures specified as autonomic seizures with vomiting, which tends to escape detection. CONCLUSIONS: We clarified the risk factors for developing epilepsy in children with CHD. We also found that autonomic seizure with vomiting is an important symptom in these children.

A female patient with adolescent-onset progressive myoclonus epilepsy carrying a truncating MECP2 mutation.

BACKGROUND: MECP2 is a well-known causative gene for Rett syndrome but other phenotypes have also been reported. Here, we report a case of a female patient with adolescent-onset progressive myoclonus epilepsy (PME) carrying a novel truncating mutation in the MECP2 gene. CASE REPORT: The patient was a 29-year-old woman with infantile-onset intellectual disability of unspecified cause. She had demonstrated slow but steady development with moderate intellectual disability until the age of 16, when she started having epileptic seizures. Her epilepsy progressed intractably with multiple seizure types accompanied by myoclonus, tremor, and gradual regression. She is currently apathetic and requires extensive assistance in all aspects of life. After an extensive work-up for underlying diseases for PME turned out negative, whole-exome sequencing revealed a de novo 113-bp deletion and 3-bp insertion in MECP2, a variant of NM_004992.4:c.1099_1211delinsGGG, p.(His367Glyfs*32). CONCLUSIONS: The clinical presentation of this case was inconsistent with Rett syndrome, and the rapid regression in the patient's twenties was considered characteristic. Mutations of MECP2 may result in variable neurodevelopmental phenotypes and may also be considered a causative gene for adolescent-onset PME.

Comprehensive study of metabolic changes induced by a ketogenic diet therapy using GC/MS- and LC/MS-based metabolomics.

OBJECTIVE: The ketogenic diet (KD), a high-fat and low-carbohydrate diet, is effective for a subset of patients with drug-resistant epilepsy, although the mechanisms of the KD have not been fully elucidated. The aims of this observational study were to investigate comprehensive short-term metabolic changes induced by the KD and to explore candidate metabolites or pathways for potential new therapeutic targets. METHODS: Subjects included patients with intractable epilepsy who had undergone the KD therapy (the medium-chain triglyceride [MCT] KD or the modified Atkins diet using MCT oil). Plasma and urine samples were obtained before and at 2-4 weeks after initiation of the KD. Targeted metabolome analyses of these samples were performed using gas chromatography-tandem mass spectrometry (GC/MS/MS) and liquid chromatography-tandem mass spectrometry (LC/MS/MS). RESULTS: Samples from 10 and 11 patients were analysed using GC/MS/MS and LC/MS/MS, respectively. The KD increased ketone bodies, various fatty acids, lipids, and their conjugates. In addition, levels of metabolites located upstream of acetyl-CoA and propionyl-CoA, including catabolites of branched-chain amino acids and structural analogues of γ-aminobutyric acid and lactic acid, were elevated. CONCLUSIONS: The metabolites that were significantly changed after the initiation of the KD and related metabolites may be candidates for further studies for neuronal actions to develop new anti-seizure medications.

Artificial Intelligence-based Detection of Epileptic Discharges from Pediatric Scalp Electroencephalograms: A Pilot Study.

We developed an artificial intelligence (AI) technique to identify epileptic discharges (spikes) in pediatric scalp electroencephalograms (EEGs). We built a convolutional neural network (CNN) model to automatically classify steep potential images into spikes and background activity. For the CNN model' training and validation, we examined 100 children with spikes in EEGs and another 100 without spikes. A different group of 20 children with spikes and 20 without spikes were the actual test subjects. All subjects were ≥ 3 to < 18 years old. The accuracy, sensitivity, and specificity of the analysis were >0.97 when referential and combination EEG montages were used, and < 0.97 with a bipolar montage. The correct classification of background activity in individual patients was significantly better with a referential montage than with a bipolar montage (p=0.0107). Receiver operating characteristic curves yielded an area under the curve > 0.99, indicating high performance of the classification method. EEG patterns that interfered with correct classification included vertex sharp transients, sleep spindles, alpha rhythm, and low-amplitude ill-formed spikes in a run. Our results demonstrate that AI is a promising tool for automatically interpreting pediatric EEGs. Some avenues for improving the technique were also indicated by our findings.

Folic acid inhibits 5-methyltetrahydrofolate transport across the blood-cerebrospinal fluid barrier: Clinical biochemical data from two cases.

Objective: The use of folic acid (FA) has been discouraged in cerebral folate deficiency (CFD) because, theoretically, it could inhibit the transport of 5-methyltetrahydrofolic acid (5MTHF) across the blood-cerebrospinal fluid (CSF) barrier. We present the clinical biochemical data of two cases with CFD to support this hypothesis. Methods: We measured CSF and serum 5MTHF concentrations in a patient with Kearns-Sayre syndrome (KSS) and a patient homozygous for MTHFR C677T polymorphism before and during folate supplementation therapy. To evaluate these 5MTHF concentrations, we also analyzed CSF and serum samples in pediatric patients without folate supplementation. Results: Both patients had low CSF 5MTHF before treatment and high-dose FA therapy did not normalize CSF 5MTHF. There was a dissociation between serum total folate and 5MTHF concentrations during FA therapy, which was considered to be due to the appearance of unmetabolized FA. The addition of folinic acid did not improve low CSF 5MTHF in the KSS patient and the cessation of FA resulted in the normalization of CSF 5MTHF. In the patient homozygous for MTHFR C677T, minimization of the FA dosage resulted in the normalization of CSF 5MTHF and an increased CSF-to-serum 5MTHF ratio. Conclusions: Our data suggest that excess supplementation of FA impaired 5MTHF transport across the blood-CSF barrier. In the treatment of CFD, supplementation of folinic acid or 5MTHF (in cases of impaired 5MTHF synthesis) is preferred over the use of FA. The reference values of CSF 5MTHF concentration based on 600 pediatric cases were also provided.

Two Cases of Monozygotic Twins with Early-onset Isolated (DYT1) Dystonia Effectively Treated with Bilateral Globus Pallidus Internus Stimulation.

Early-onset isolated (DYT1) dystonia is one of the most common forms of primary dystonia in childhood, and deep brain stimulation of the globus pallidus internus (GPi-DBS) is a highly effective treatment for it. However, the effectiveness of GPi-DBS in monozygotic twins with DYT1 dystonia has never been reported globally. Here, we report the cases of monozygotic twins with DYT1 dystonia who were treated using GPi-DBS, and we include a literature review. The younger brother showed an abnormal gait, with external rotation of the right lower leg at 6 years old. The symptoms gradually became so severe that he had difficulty walking on his own at 9 years of age. Treatment with levodopa-carbidopa partially resolved his symptoms, but most of the symptoms remained. Meanwhile, the older brother developed dystonia in both upper limbs at 8 years of age, with gradual symptom progression. At 13 years of age, they were diagnosed with DYT1 dystonia. Bilateral GPi-DBS was performed in both patients at 16 years of age. Their symptoms remarkably improved after surgery. The Burke-Fahn-Marsden dystonia rating scale (BFMDRS) movement score was reduced from 52 to 2 points for the younger brother and from 35 to 1 point for the older brother. Even if monozygotic twins have the same genes, the onset and severity of symptoms might vary in accordance with differences in epigenomic profiles. However, GPi-DBS treatment was very effective for the two cases; thus, we should consider the surgical interventions for each patient.

Simultaneous assay of urine sepiapterin and creatinine in patients with sepiapterin reductase deficiency.

OBJECTIVES: Sepiapterin reductase deficiency (SRD) causes central nervous system symptoms due to dopamine and serotonin depletion because sepiapterin reductase plays an important role in tetrahydrobiopterin biosynthesis. SRD cannot be detected by newborn screening because of the absent hyperphenylalaninemia. To diagnose SRD biochemically, confirmation of reduced monoamine metabolites and elevated sepiapterin in the cerebrospinal fluid (CSF) has been considered necessary, because a past study showed no elevation of urine sepiapterin. Recently, however, the elevation of urine sepiapterin in SRD was reported. METHODS: We developed a fast method to measure sepiapterin and creatinine simultaneously using high-performance liquid chromatography with fluorescence and ultraviolet detection. Urine sepiapterin and creatinine were measured in three SRD patients, two SRD carriers, four SRD siblings, and 103 non-SRD patients. RESULTS: In the three SRD cases, concentrations of urine sepiapterin were 1086, 914, and 575 µmol/mol creatinine (upper limit: 101.7 µmol/mol creatinine), and were markedly higher than those in other groups. CSF sepiapterin concentration was also measured in one SRD case and it was 4.1 nmol/L (upper limit: 0.5 nmol/L). CONCLUSIONS: The simultaneous determination of urine sepiapterin and creatinine appears helpful for the diagnosis of SRD. This assay system can also be used to measure sepiapterin in the CSF.

A Japanese single-center experience of the efficacy and safety of asfotase alfa in pediatric-onset hypophosphatasia.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The severity of HPP is widely diverse from the perinatal form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to pneumonia which was caused by severe hypomineralization of the bones-such as chest deformity and fractured ribs-and muscle weakness. Enzyme replacement therapy using asfotase alfa (AA) was approved in 2015 in Japan for treating patients with HPP and has improved their pulmonary function and life prognosis. There are several practical and ethical challenges related to using orphan drugs for a rare disorder in a publicly funded healthcare system. Sharing experiences about their application is essential towards formulating guidelines to assist clinicians with decisions about their initiation and withdrawal. We report the details of AA experience in ten cases of pediatric-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 [7.6-12.5] years; 60% male). This is a study of a single-center cohort describing the clinical course of patients with HPP, mainly consisting of the mild childhood form of HPP, treated with AA in Japan. RESULTS: One case of perinatal form of HPP, two cases of benign prenatal form, and seven cases of childhood form were observed. The most common symptom at onset was pain. All patients had low serum alkaline phosphatase levels as compared to the age-matched reference range before the commencement of AA. All HPP patients seem to have responded to AA treatment, as evidenced by pain alleviation, increased height standard deviation, improvement in respiratory condition and 6-min walk test result improvement, disappearance of kidney calcification, alleviation of fatigue, and/or increases in bone mineralization. There were no serious adverse events, but all patients had an injection site reaction and skin changes at the injection sites. Genetic analysis showed that eight out of ten patients had compound heterozygosity. CONCLUSIONS: AA may be effective in patients with mild to severe pediatric-onset forms of HPP.

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

OBJECTIVE: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II. METHODS: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES-FCD) in which 60 patients with FCD type II were included as an external control group. RESULTS: The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1-4-, 5-8-, and 9-12-week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus-treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL-6 level was elevated over time. INTERPRETATION: The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations.

A Time-Series Scale Mixture Model of EEG with a Hidden Markov Structure for Epileptic Seizure Detection.

In this paper, we propose a time-series stochastic model based on a scale mixture distribution with Markov transitions to detect epileptic seizures in electroencephalography (EEG). In the proposed model, an EEG signal at each time point is assumed to be a random variable following a Gaussian distribution. The covariance matrix of the Gaussian distribution is weighted with a latent scale parameter, which is also a random variable, resulting in the stochastic fluctuations of covariances. By introducing a latent state variable with a Markov chain in the background of this stochastic relationship, time-series changes in the distribution of latent scale parameters can be represented according to the state of epileptic seizures. In an experiment, we evaluated the performance of the proposed model for seizure detection using EEGs with multiple frequency bands decomposed from a clinical dataset. The results demonstrated that the proposed model can detect seizures with high sensitivity and outperformed several baselines.

Case Report: High-Gamma Oscillations on an Ictal Electroencephalogram in a Newborn Patient With Hypoxic-Ischemic Encephalopathy.

Fast oscillations (FOs) >40 Hz in electroencephalograms (EEGs) are associated with ictogenesis and epileptogenesis in adults and children with epilepsy. However, only a few previous studies showed FOs in neonates. Reported frequencies of such neonatal FOs were in the low-gamma (<60 Hz) band and, therefore, they were not high compared to those in pediatric patients. We herein report a newborn patient with severe hypoxic-ischemic encephalopathy (HIE), who showed pathological FOs with a frequency in the high-gamma band. She was born at a gestational age of 39 weeks 4 days by emergency cesarean section because of non-reassuring fetal status. She had focal motor seizures involving unilateral upper and lower limbs lasting for tens of seconds on days 0, 1, 4, 5, 8, and 9 and subclinical seizures on days 4-11. Phenobarbital (PB) was intravenously administered on days 0, 2, 4, 5, and 6. We found FOs that were superimposed on the ictal delta activities using visual inspection and time-frequency analysis on 8-11 days of age. Among them, we detected high-gamma (71.4-100 Hz) oscillations that appeared to be temporally independent of low-gamma activities in the ictal EEG on 11 days of age. To the best of our knowledge, this is one of the earliest reports showing pathological FOs with a frequency of >60 Hz in the high-gamma band in human neonatal seizures, which were previously observed in animal studies. Further studies are needed to elucidate the pathophysiology of ictal FOs in neonatal seizures.

Exclusion of the Possibility of "False Ripples" From Ripple Band High-Frequency Oscillations Recorded From Scalp Electroencephalogram in Children With Epilepsy.

AIM: Ripple-band epileptic high-frequency oscillations (HFOs) can be recorded by scalp electroencephalography (EEG), and tend to be associated with epileptic spikes. However, there is a concern that the filtration of steep waveforms such as spikes may cause spurious oscillations or "false ripples." We excluded such possibility from at least some ripples by EEG differentiation, which, in theory, enhances high-frequency signals and does not generate spurious oscillations or ringing. METHODS: The subjects were 50 pediatric patients, and ten consecutive spikes during sleep were selected for each patient. Five hundred spike data segments were initially reviewed by two experienced electroencephalographers using consensus to identify the presence or absence of ripples in the ordinary filtered EEG and an associated spectral blob in time-frequency analysis (Session A). These EEG data were subjected to numerical differentiation (the second derivative was denoted as EEG″). The EEG″ trace of each spike data segment was shown to two other electroencephalographers who judged independently whether there were clear ripple oscillations or uncertain ripple oscillations or an absence of oscillations (Session B). RESULTS: In Session A, ripples were identified in 57 spike data segments (Group A-R), but not in the other 443 data segments (Group A-N). In Session B, both reviewers identified clear ripples (strict criterion) in 11 spike data segments, all of which were in Group A-R (p < 0.0001 by Fisher's exact test). When the extended criterion that included clear and/or uncertain ripples was used in Session B, both reviewers identified 25 spike data segments that fulfilled the criterion: 24 of these were in Group A-R (p < 0.0001). DISCUSSION: We have demonstrated that real ripples over scalp spikes exist in a certain proportion of patients. Ripples that were visualized consistently using both ordinary filters and the EEG″ method should be true, but failure to clarify ripples using the EEG″ method does not mean that true ripples are absent. CONCLUSION: The numerical differentiation of EEG data provides convincing evidence that HFOs were detected in terms of the presence of such unusually fast oscillations over the scalp and the importance of this electrophysiological phenomenon.

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD. In 2015, Korean and Japanese groups independently reported that FCD is caused by somatic mosaic mutation of the MTOR gene in the brain tissue. Based on these results we decided to test a novel treatment using sirolimus, an mTOR inhibitor, for epileptic seizures in patients with FCD type II. A single arm open-label clinical trial for FCD type II patients is being conducted in order to evaluate the efficacy and safety of sirolimus. The dose of sirolimus is fixed for the first 4 weeks and dose adjustment is achieved to maintain a blood level of 5 to 15 ng/mL during 8 to 24 weeks after initiation of administration, and it is kept within this level during a maintenance therapy period of 12 weeks. Primary endpoint is a reduction in the rate of incidence of focal seizures (including focal to bilateral tonic-clonic seizures) per 28 days during the maintenance therapy period from the observation period. To evaluate the frequency of epileptic seizures, registry data will be used as an external control group. We hope that the results of this trial will lead to future innovative treatments for FCD type II patients.

A study on the relationship between non-epileptic fast (40 - 200 Hz) oscillations in scalp EEG and development in children.

OBJECTIVE: Physiological gamma and ripple activities may be linked to neurocognitive functions. This study investigated the relationship between development and non-epileptic, probably physiological, fast (40-200 Hz) oscillations (FOs) including gamma (40 - 80 Hz) and ripple (80 - 200 Hz) oscillations in scalp EEG in children with neurodevelopmental disorders. METHODS: Participants were 124 children with autism spectrum disorder (ASD) and/or attention deficit/hyperactivity disorder (ADHD). Gamma and ripple oscillations were explored from 60-second-long sleep EEG data in each subject using a semi-automatic detection tool supplemented with visual confirmation and time-frequency analysis. RESULTS: Gamma and ripple oscillations were detected in 25 (20.2%) and 22 (17.7%) children, respectively. The observation of one or more occurrence(s) of ripple oscillations, but not gamma oscillations, was significantly related to lower age at EEG recording (odds ratio, OR: 0.727 [95% confidence interval, CI: 0.568-0.929]), higher intelligence/developmental quotient (OR: 1.041, 95% CI: 1.002-1.082), and lack of a diagnosis with ADHD (OR: 0.191, 95% CI: 0.039 - 0.937) according to a binominal logistic regression analysis that included diagnosis with ASD, sex, history of perinatal complications, history of febrile seizures, and use of a sedative agent for the EEG recording as the other non-significant parameters. Diagnostic group was not related to frequency or power of spectral peaks of FOs. CONCLUSION: The production of non-epileptic scalp ripples was confirmed to be associated with brain development and function/dysfunction in childhood. Further investigation is necessary to interpret all of the information on higher brain functions that may be embedded in scalp FOs.

Cascaded AMZ triplets: a class of demultiplexers having a monitor and control scheme enabling dense WDM on Si nano-waveguide PICs with ultralow crosstalk and high spectral efficiency.

We propose a class of wavelength-division multiplexing (WDM) demultiplexers having a novel monitor and control scheme enabling dense WDM on Si nano-waveguide (NW) photonic integrated circuits (PICs), which had been impossible due to the critically small fabrication tolerance of the extremely miniaturized waveguide structure. With a computer simulation, we show our proposed demultiplexers enable crosstalk in the range of -50 to -40 dB, flat-topped spectrum for high spectral efficiency, and channel counts as large as 64. We have experimentally evaluated the validity of this type of demultiplexers by using a 4-ch WDM demultiplexer, which has shown total crosstalk of < -49 dB as a result of fully automatic control of heaters. This technology is expected to drastically shrink the size of dense WDM transceivers, paving the way for future sustainable scalability in the capacity of optical transceiver systems.

Monozygotic twins with DYT-TOR1A showing jerking movements and levodopa responsiveness.

BACKGROUND: DYT-TOR1A is caused by a GAG deletion in the TOR1A gene. While it usually manifests as early-onset dystonia, its phenotype is extremely diverse, even within one family. Recent reports have revealed that some DYT-TOR1A cases have novel mutations in the TOR1A gene while others have mutations in both TOR1A and another DYT gene (THAP1 or SGCE). Our understanding of the correlation between genotype and phenotype is becoming increasingly complicated. CASE PRESENTATIONS: Here, we report on monozygotic twins who developed dystonia in childhood. The two children had different presentations in terms of onset age and dominant disturbances, but both exhibited marked diurnal fluctuation and jerking movements of the limbs as well as levodopa/levodopa-carbidopa responsiveness. These features are commonly associated with DYT/PARK-GCH1 and DYT-SGCE, yet these twins had no mutations in the GCH1 or SGCE genes. Whole exome sequencing eventually revealed a single GAG deletion in the TOR1A gene. CONCLUSION: Monozygotic twins whose only mutation was a GAG deletion in TOR1A exhibited DYT/PARK-GCH1-asssociated features and jerking movements reminiscent of myoclonus. This finding may expand the spectrum of phenotypes associated with DYT-TOR1A, and suggests that levodopa has potential as a treatment for DYT-TOR1A with DYT/PARK-GCH1-associated features.