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To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II.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.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.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.

This tutorial reviews history of silicon photonics from early-stage proof of concept to recent diverging applications based on large-scale integration, covering breakthrough technologies and key future prospects.

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.

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.

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six-month-old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure-free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and balloon cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34-positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of balloon cell and/or balloon-like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule-like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.

Background The initial presentation of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is indistinguishable from that of complex febrile seizures (FS), which poses a great diagnostic challenge for clinicians. Excitotoxicity is speculated to be the pathogenesis of AESD. Vitamin B6 (VB6) is essential for the biosynthesis of gamma-aminobutyric acid, an inhibitory neurotransmitter. The aim of this study is to investigate our hypothesis that VB6 deficiency in the brain may play a role in AESD. Methods We obtained cerebrospinal fluid (CSF) samples from pediatric patients with AESD after early seizures and those with FS. We measured pyridoxal 5′-phosphate (PLP) and pyridoxal (PL) concentrations in the CSF samples using high-performance liquid chromatography with fluorescence detection. Results The subjects were 5 patients with AESD and 17 patients with FS. Age did not differ significantly between AESD and FS. In AESD, CSF PLP concentration was marginally lower (p = 0.0999) and the PLP-to-PL ratio was significantly (p = 0.0417) reduced compared to those in FS. Conclusions Although it is impossible to conclude that low PLP concentration and PLP-to-PL ratio are causative of AESD, this may be a risk factor for developing AESD. When combined with other markers, this finding may be useful in distinguishing AESD from FS upon initial presentation.

Objectives To evaluate the performance of commercially available seizure detection algorithms in critically ill children. Design Diagnostic accuracy comparison between commercially available seizure detection algorithms referenced to electroencephalography experts using quantitative electroencephalography trends. Setting Multispecialty quaternary children's hospital in Canada. Subjects Critically ill children undergoing electroencephalography monitoring. Interventions Continuous raw electroencephalography recordings (n = 19) were analyzed by a neurophysiologist to identify seizures. Those recordings were then converted to quantitative electroencephalography displays (amplitude-integrated electroencephalography and color density spectral array) and evaluated by six independent electroencephalography experts to determine the sensitivity and specificity of the amplitude-integrated electroencephalography and color density spectral array displays for seizure identification in comparison to expert interpretation of raw electroencephalography data. Those evaluations were then compared with four commercial seizure detection algorithms: ICTA-S (Stellate Harmonie Version 7; Natus Medical, San Carlos, CA), NB (Stellate Harmonie Version 7; Natus Medical), Persyst 11 (Persyst Development, Prescott, AZ), and Persyst 13 (Persyst Development) to determine sensitivity and specificity in comparison to amplitude-integrated electroencephalography and color density spectral array. Measurements and main results Of the 379 seizures identified on raw electroencephalography, ICTA-S detected 36.9%, NB detected 92.3%, Persyst 11 detected 75.9%, and Persyst 13 detected 74.4%, whereas electroencephalography experts identified 76.5% of seizures using color density spectral array and 73.7% using amplitude-integrated electroencephalography. Daily false-positive rates averaged across all recordings were 4.7 with ICTA-S, 126.3 with NB, 5.1 with Persyst 11, 15.5 with Persyst 13, 1.7 with color density spectral array, and 1.5 with amplitude-integrated electroencephalography. Both Persyst 11 and Persyst 13 had sensitivity comparable to that of electroencephalography experts using amplitude-integrated electroencephalography and color density spectral array. Although Persyst 13 displayed the highest sensitivity for seizure count and seizure burden detected, Persyst 11 exhibited the best trade-off between sensitivity and false-positive rate among all seizure detection algorithms. Conclusions Some commercially available seizure detection algorithms demonstrate performance for seizure detection that is comparable to that of electroencephalography experts using quantitative electroencephalography displays. These algorithms may have utility as early warning systems that prompt review of quantitative electroencephalography or raw electroencephalography tracings, potentially leading to more timely seizure identification in critically ill patients.

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.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.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).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.

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.

Enabled by a fully integrated autonomous calibration mechanism, crosstalk-free 32-ch WDM demultiplexer on standard Si PIC platform is demonstrated for the first time. Compatible with the vast component libraries of standard Si PIC platform, this device provides a path to ultrahigh-capacity integrated DWDM transceivers.

The recent development of various new antiepileptic drugs (AEDs) has provided a wide range of therapeutic strategies for epilepsy. Information regarding the mechanisms of the action of AEDs is valuable when selecting drugs for individual epilepsy patients. AEDs can be categorized as those acting at the excitatory synapse, at the inhibitory synapse, on the extrasynaptic neuronal membrane, or with multiple or miscellaneous mechanisms of action. We herein briefly summarize and illustrate the action of AEDs on neurons and related findings that are pertinent to the clinical aspect of epileptology.

Objective We studied ripple-band (80–200 Hz) high-frequency oscillations in scalp electroencephalogram (EEG) in various pediatric epilepsies featuring sleep-activated spikes, such as epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) and investigated their characteristics. Methods The subjects were 94 children with epileptic disorders including idiopathic and non-idiopathic CSWS, benign epilepsy with centrotemporal spikes (BECTS), Panayiotopoulos syndrome, other types of focal epilepsies (oFE), and focal spikes without clinical seizures (Latent). We detected ripple oscillations using a semi-automatic detection tool based on localized power increase. Results In the idiopathic CSWS Group, the median ratio of ripples per spike in the initial EEG was 5.73, which was significantly higher than those in the BECTS, Panayiotopoulos syndrome, oFE, and Latent Groups (0.39, 0.02, 0.35, 0, respectively, all with p Conclusions This paper is the first to confirm a high ratio of ripples per spike in CSWS in the largest number of patients to date. Significance The dense generation of ripples, which occurs through a combination of heavy loading of individual spikes with ripples and large numbers of spikes during sleep, characterizes CSWS and might be closely related to the pathophysiology of this epileptic encephalopathy.

Background Recently, many genes related to neurodevelopmental disorders have been identified by high-throughput genomic analysis; however, a comprehensive understanding of the mechanism underlying neurodevelopmental disorders remains to be established. To further understand these underlying mechanisms, we performed a comprehensive genomic analysis of patients with undiagnosed neurodevelopmental disorders. Methods Genomic analysis using next-generation sequencing with a targeted panel was performed for a total of 133 Japanese patients (male/female, 81/52) with previously undiagnosed neurodevelopmental disorders, including developmental delay (DD), intellectual disability (ID), autism spectrum disorder (ASD), and epilepsy. Genomic copy numbers were also analyzed using the eXome Hidden Markov Model (XHMM). Results Thirty-nine patients (29.3%) exhibited pathogenic or likely pathogenic findings with single-gene variants or chromosomal aberrations. Among them, 20 patients were presented here. Pathogenic or likely pathogenic variants were identified in 18 genes, including ACTG1, CACNA1A, CHD2, CDKL5, DNMT3A, EHMT1, GABRB3, GABRG2, GRIN2B, KCNQ3, KDM5C, MED13L, SCN2A, SHANK3, SMARCA2, STXBP1, SYNGAP1, and TBL1XR1. Conclusion A diagnostic yield of 29.3% in this study was nearly the same as that previously reported from other countries. Thus, we suggest that there is no difference in genomic backgrounds in Japanese patients with undiagnosed neurodevelopmental disabilities. Although most of the patients possessed de novo variants, one of the patients showed an X-linked inheritance pattern. As X-linked recessive disorders exhibit the possibility of recurrent occurrence in the family, comprehensive molecular diagnosis is important for genetic counseling.

Lesch-Nyhan disease (LND) is an X-linked recessive disorder caused by a deficiency in hypoxanthine-guanine phosphoribosyl transferase. Patients with LND experience involuntary movements, including dystonia, choreoathetosis, opisthotonos, ballismus, and self-injury. Alleviating these involuntary movements is important to improve the quality of life in patients with LND. Many clinicians have difficulty controlling these involuntary movements in their patients, and there are no established and effective treatments. A 6-month-old boy with LND presented with generalized dystonia and self-injury behavior that was alleviated after receiving S-adenosylmethionine (SAMe). His self-injury behavior completely resolved after he received SAMe and risperidone. Although he had often experienced inspiratory stridor because of laryngeal dystonia and frequently developed aspiration pneumonitis and bronchitis, no inspiratory stridor was noted after SAMe treatment. The patient is continuing to receive SAMe and risperidone. SAMe treatment alleviates dystonic movements and improves quality of life in pediatric patients with LND. Additional research is needed to determine the long-term safety and efficacy of SAMe and its appropriate dosage.

Hypophosphatasia (HPP) is a rare disorder caused by low serum tissue non-specific alkaline phosphatase (ALP) activity due to hypomorphic mutations in the ALPL gene. HPP is characterized by defective bone mineralization. It frequently accompanies pyridoxine-responsive seizures. Because alkaline phosphatase change pyridoxal 5′ phosphate (PLP) into pyridoxal (PL), which can cross the blood brain barrier and regulates inhibitory neurotransmitter gamma-aminobutyric acid. The female patient was born at a gestational age of 37 weeks 2 days. She presented severe respiratory disorder due to extreme thoracic hypoplasia. With the extremely low serum ALP value (14 IU/L), she was clinically diagnosed as HPP. The diagnosis was confirmed with genetic testing. On day1, the subclinical seizures were detected by aEEG. Together with enzyme replacement therapy by asfotase alfa, pyridoxine hydrochloride was administered, then the seizures were rapidly controlled. While confirming that there was no seizure by aEEG monitoring, pyridoxine hydrochloride was gradually discontinued after 1 month. Before administration of pyridoxine hydrochloride, PL was extremely low (4.7 nM) and PLP was increased (1083 nM). After the withdrawal, PL was increased to 84.9 nM only by enzyme replacement. Monitoring with aEEG enabled early intervention for pyridoxine responsive seizures. Confirming increased serum PL concentration is a prudent step in determining when to reduce or discontinue pyridoxine hydrochloride during enzyme replacement therapy.

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.

Dihydropyrimidinase deficiency is a rare autosomal recessive disease affecting the second step of pyrimidine degradation. It is caused by mutations in the DPYS gene. Only approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. We report a case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry. Genetic testing of the DPYS gene revealed two mutations: a novel mutation (c.175G > T) and a previously reported mutation (c.1469G > A). Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000. As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment.

BackgroundHypophosphatasia (HPP) is a rare inherited metabolic disorder caused by mutations in the ALPL gene, which encodes tissue nonspecific alkaline phosphatase. The phenotype of HPP is widely diverse from the perinatal severe form to the adult mild form. The former represents the most severe form and was earlier associated with high mortality due to impaired development of the lungs and severe hypomineralization of the bones. Enzyme replacement therapy (ERT) using asfotase alfa 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 ERT experience in ten cases of childhood-onset HPP in nine families from January 2015 to November 2019 (median [interquartile range] age 11.0 years [7.6–12.5] years; 60% male). This is the largest study of a single-center cohort describing the clinical course of HPP patients treated with ERT in Asia. ResultsOne case of perinatal lethal form of HPP, two cases of perinatal benign form, six cases of childhood form, and one case of odontohypophophatasia were observed. The most common symptom at onset was bone abnormalities. All patients had low serum ALP levels as compared to the age-matched reference range before the commencement of ERT. All HPP patients responded to ERT without serious adverse effects. Genetic analysis showed that eight out of ten patients had compound heterozygosity; two patients had only one heterozygous variant. In this study, two patients had a heterozygous variant of ALPL and responded to ERT, although the variants did not have the dominant-negative effect. ConclusionsERT may be effective in patients with symptoms of HPP even with only one pathogenic variant of ALPL without dominant-negative effect. Early diagnosis based on symptoms such as bone abnormalities or low serum alkaline phosphatase levels might be essential for early treatment and can contribute to better prognosis.

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.

We demonstrate fully automatic suppression of crosstalk, inevitable in WDM demultiplexers on Si nanowire PIC. This is realized with a low-cost CMOS ASIC dedicatedly designed for low-power control of our proposed CAT demultiplexer. It is shown to have zero OSNR penalty even under continuous control required to cancel dynamic environmental change.

Introduction Epilepsy associated with tuberous sclerosis complex (TSC) has very complex clinical characteristics. Scalp electroencephalogram (EEG) fast (40–200 Hz) oscillations (FOs) were recently suggested to indicate epilepsy severity. Epileptic FOs may undergo age-dependent longitudinal change in individual patients, however, and the typical pattern of such change is not yet fully clarified. We therefore investigated the age-related correspondence between clinical courses and FOs in pediatric patients with TSC-associated epilepsy. Subjects and methods FOs were semi-automatically detected from scalp sleep EEG data recorded from 23 children (15 boys, 8 girls; initial data obtained at Results The number of FOs per patient that were associated with spikes was significantly greater than that of FOs unassociated with spikes (median 145 and 5, respectively; p = 0.0001 by the Wilcoxon signed-rank test). In the eight patients who had West syndrome (WS) in infancy, FOs associated with spikes were abundant during the WS period prior to adrenocorticotropic hormone therapy, with significantly greater numbers of FOs compared to the post-WS period (median 242 and 0, respectively; p = 0.0078). As there was no such time-dependent difference regarding FOs unassociated with spikes, FOs associated with spikes were identified as epileptic. The detected FOs included both gamma and ripple oscillations with no consistent age-dependent shifts in dominant frequency. There were no apparent age-related changes in FO duration. Conclusions Epileptic scalp FOs are confirmed to correspond to severity of epileptic encephalopathy, particularly in WS, even during the long-term evolutional courses of TSC-associated epilepsy.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in ALDH7A1 that included NM_001182.4:[c.1196G > T] and [c.1200 + 1G > A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.

Background Nonepileptic twilight state with convulsive manifestations (NETC) is a nonepileptic state following a febrile seizure (FS), which may be misdiagnosed as a prolonged seizure and result in overtreatment. We aimed to describe clinical manifestations of NETC and to determine characteristics that are helpful to distinguish NETC from other pathological conditions. Methods We conducted a retrospective chart review from January 2010 to December 2016 and selected the patients who presented with symptoms resembling status epilepticus with fever and a confirmed diagnosis using an electroencephalogram (EEG). We compared the NETC clinical features and venous blood gas analysis results with those of other conditions that mimic NETC. We also compared the characteristics of NETC with past reports. Results Our NETC patients presented with short durations of the preceding generalized convulsions followed by tonic posturing, closed eyes, no cyanosis, responsiveness to painful stimulation, and no accumulation of CO2 in the venous blood gas. Most of these characteristics were consistent with past reports. Prolonged FS or acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) showed several of these features, but all the characteristics were not consistent with our study. Conclusions Prolonged FS and AESD need to be differentiated from NETC, and close clinical observation makes it possible to partially distinguish NETC from the other conditions. EEG is recommended for patients with symptoms that are inconsistent with these features.

We successfully developed a high-density broadband 16-channel × 25 Gb/s on-package silicon photonics optical transceiver. The flip chip bonded bridge structure realized high density of about 363 Gb/s/cm2 . We demonstrated simultaneously on all 16 channels error-free operations with low crosstalk penalties of Tx-to-Tx 1.4 dB, Rx-to-Rx 1.4 dB, and Tx-to-Rx

Objective Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES-), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations. In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES-. Methods We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz). Results In ES+ (n = 10), the OR(FRs) , the number of electrodes with high-rate FRs, and the MI(FRs & 3-4 Hz) in all electrodes were significantly higher than in ES- (n = 14). In both the ES+ and ES- groups, MI(ripples/FRs & 3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR(FRs) and the MI(FRs & 3-4 Hz) in the resected area in ES+ were significantly higher than in ES- (OR[FRs] , P = .04; MI[FRs & 3-4 Hz] , P = .04). Significance In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES-. High values of OR(FRs) and MI(FRs & 3-4 Hz) in ES+ compared to ES- are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.

Hypophosphatasia (HPP) is a metabolic bone disease characterized by failure of bone calcification and vitamin B6 dependent seizures. It is caused by loss-of-function mutations in the ALPL gene. A newborn girl required respiratory support by nasal-directional positive airway pressure at birth, and pyridoxine hydrochloride administration for vitamin B6-dependent seizures observed from day two. Umbilical cord blood showed low alkaline phosphatase (ALP) activity and high pyridoxal phosphate levels. Radiographs showed severe rickets-like appearance of the bones. Genetic analysis of the ALPL gene revealed compound heterozygous mutations, c.1559delT/p.Ser188Pro. We diagnosed her with perinatal severe HPP, and started the patient on asfotase alfa from day six. Following enzyme replacement therapy (ERT), skeletal mineralization and respiratory insufficiency improved with no remarkable side-effects. Crying vital capacity (CVC) was used to evaluate respiratory status, which continuously improved from 13.3 mL/kg (day 22) to 20.6 mL/kg (day 113). Since no seizures occurred, pyridoxine hydrochloride was tapered off at one year of age. Strategies to manage perinatal severe HPP cases following ERT have not been established till date. A review of the literature shows that CVC may be a good indicator for weaning from ventilatory support. In addition, ERT will most likely enable withdrawal of pyridoxine treatment.

We quantified pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) in paired serum and cerebrospinal fluid (CSF) samples from children and investigated the effect of age on the concentrations and CSF-to-serum ratios of these vitamers.Serum and CSF samples prospectively collected from 49 pediatric patients were analyzed. PLP, PL, and PA were measured using high-performance liquid chromatography with fluorescence detection, using pre-column derivatization by semicarbazide. Effects of age on these vitamers, the PLP-to-PL ratio, CSF-to-serum PLP ratio, and CSF-to-serum PL ratio were evaluated using correlation analysis.The PLP, PL, and PA concentrations in the serum and CSF were higher at younger ages, except for CSF PA concentrations that were mostly below the limit of detection (1.2nmol/l). The PLP-to-PL ratios in the serum and CSF correlated positively with age. The CSF-to-serum PLP ratio and CSF-to-serum PL ratio were independent of age.Age-related changes in PLP, PL, and PA in serum and in CSF from pediatric patients and CSF-to-serum ratios of PLP and PL demonstrated in this study will provide valuable information for evaluating PLP supply to the central nervous system from the peripheral blood.

A 40-year-old Japanese woman presented to our hospital with general fatigue and muscle weakness. She had a history of premature loss of deciduous teeth at 4 years old, her serum alkaline phosphatase (ALP) activity was as low as 91 U/L, and radiologic studies revealed thoracic deformity and sacroiliac calcification. Genetic sequencing revealed a heterozygous c.1559delT mutation in the tissue non-specific alkaline phosphatase gene (ALPL). Based on these findings, she was diagnosed with hypophosphatasia (HPP), and treatment with asfotase alfa, a recombinant human tissue-nonspecific alkaline phosphatase (TNSALP), was initiated. After six months of treatment with asfotase alfa, improvements were observed in the SF-36 score, six-minute walk distance, and grasping power. Although the overdiagnosis needs to be avoided, HPP should be considered in patients with undiagnosed musculoskeletal symptoms and a low serum ALP activity.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal-recessive disorder typically presenting with neonatal seizures and is sometimes difficult to diagnose, because the clinical features mimic those of birth asphyxia. A Japanese newborn boy presented with pulmonary haemorrhage and convulsions on the day of birth. Brain computed tomography showed diffuse, but mild, low-density cerebral white matter and a thin subdural hematoma in the posterior fossa. He did not have thrombocytopenia or coagulopathy. His respiratory status improved with conservative treatment, but his convulsions were persistent even after prescription of several antiepileptic drugs. His serum and cerebrospinal fluid showed decreased vitamin B6 vitamers and increased upstream metabolites of α-aminoadipic semialdehyde dehydrogenase, strongly suggesting a diagnosis of PDE; the epileptic spasms ceased after administration of intravenous pyridoxal phosphate hydrate. Gene analysis revealed novel compound heterozygous mutations in ALDH7A1 that included NM_001182.4:[c.1196G > T] and [c.1200 + 1G > A]. Atypical birth asphyxia with persistent neonatal seizure should prompt vitamin B6/metabolite screening.

Background: Hypophosphatasia (HPP) is a rare inborn error of metabolism that results from a dysfunctional tissue non-specific alkaline phosphatase enzyme (TNSALP). Although genotype-phenotype correlations have been described in HPP patients, only sparse information is currently available on the genetics of mild type HPP. Methods: We investigated 5 Japanese patients from 3 families with mild HPP (patients 1 and 2 are siblings; patient 4 is a daughter of patient 5) who were referred to Fujita Health University due to the premature loss of deciduous teeth. Physical and dental examinations, and blood, urine and bone density tests were conducted. Genetic analysis of the ALPL gene was performed in all patients with their informed consent. Results: After a detailed interview and examination, we found characteristic symptoms of HPP in some of the study cases. Mobile teeth or the loss of permanent teeth were observed in 2 patients, and 3 out of 5 patients had a history of asthma. The serum ALP levels of all patients were 30% below the lower limit of the age equivalent normal range. ALPL gene analysis revealed compound heterozygous mutations, including Ile395Val and Leu520Argfs in family 1, Val95Met and Gly491Arg in family 2, and a dominant missense mutation (Gly456Arg) in family 3. The 3D-modeling of human TNSALP revealed three mutations (Val95Met, Ile395Val and Gly456Arg) at the homodimer interface. Severe collisions between the side chains were predicted for the Gly456Arg variant. Discussion: One of the characteristic findings of this present study was a high prevalence of coexisting asthma and a high level serum IgE level. These characteristics may account for the fragility of tracheal tissues and a predisposition to asthma in patients with mild HPP. The genotypes of the five mild HPP patients in our present study series included 1) compound heterozygous for severe and hypomorphic mutations, and 2) dominant-negative mutations. All of these mutations were at the homodimer interface, but only the dominant-negative mutation was predicted to cause a severe collision effect between the side chains. This may account for varying mechanisms leading to different effects on TNSALP function. Keywords: Hypophosphatasia, ALPL, Premature loss of deciduous teeth, Dominant-negative mutations

We propose and theoretically validate a novel demultiplexer capable to automatically correct all fabrication-error-induced spectrum impairments. This technology, once realized, enables high-channel-count (> 64 ch) dense WDM systems on low-end Si PIC platforms.

Objective To describe an assay of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF) of children, to determine reference values, and to report the clinical significance of this assay in metabolic disorders affecting folate transport and metabolism. Methods CSF 5MTHF was determined by high-performance liquid chromatography with fluorescent detection in pediatric patients including one with FOLR1 gene mutation and one with methylenetetrahydrofolate reductase (MTHFR) deficiency. CSF total folate was measured using an automated analyzer. Results 5MTHF and total folate were determined in 188 and 93 CSF samples, respectively. CSF 5MTHF was high throughout the first six months of life and subsequently declined with age. Reference values of CSF 5MTHF and total folate were determined from 162 and 82 samples, respectively. The patient with FOLR1 gene mutation had extremely low CSF 5MTHF and total folate, though these values normalized after folinic acid supplementation. The patient with MTHFR deficiency had extremely low 5MTHF and moderately low total folate; these values were not associated and showed no significant change after folic acid supplementation. Conclusions This 5MTHF assay is simple, rapid, sensitive, reliable, and cost-effective. It will aid in the diagnosis and therapeutic monitoring of metabolic disorders affecting folate transport and metabolism.

α-Aminoadipic semialdehyde and its cyclic form (Δ1-piperideine-6-carboxylate) accumulate in patients with α-aminoadipic semialdehyde dehydrogenase (AASADH; antiquitin; ALDH7A1) deficiency. Δ1-Piperideine-6-carboxylate is known to react with pyridoxal 5'-phosphate (PLP) to form a Knoevenagel condensation product, resulting in pyridoxine-dependent epilepsy. Despite dramatic clinical improvement following pyridoxine supplementation, many patients still suffer some degree of intellectual disability due to delayed diagnosis. In order to expedite the diagnosis of patients with suspected AASADH deficiency and minimize the delay in treatment, we used gas chromatography-mass spectrometry-based metabolomics to search for potentially diagnostic biomarkers in urine from four patients with ALDH7A1 mutations, and identified Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as candidate biomarkers. In a patient at postnatal day six, but before pyridoxine treatment, Δ2-piperideine-6-carboxylate and pipecolate were present at very high concentrations, indicating that these compounds may be good biomarkers for untreated AASADH deficiency patients. On the other hand, following pyridoxine/PLP treatment, 6-oxopipecolate was shown to be greatly elevated. We suggest that noninvasive urine metabolomics screening for Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate will be useful for prompt and reliable diagnosis of AASADH deficiency in patients within any age group. The most appropriate combination among Δ2-piperideine-6-carboxylate, 6-oxopipecolate, and pipecolate as biomarkers for AASADH deficiency patients appears to depend on the age of the patient and whether pyridoxine/PLP supplementation has been implemented. We anticipate that the present bioanalytical information will also be useful to researchers studying glutamate, proline, lysine and ornithine metabolism in mammals and other organisms.

Objective: Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the formation of hamartoma in multiple organ systems of the body. However, without a well-established cooperative system involving related departments, some organ lesions might be overlooked until symptoms appear or even until the disorder progresses. Therefore, the purpose of this study is to investigate the current status of follow-ups in the TSC patients in the Department of Child Neurology at Okayama University Medical Hospital. Methods: We performed a retrospective chart review of 38 patients with TSC who visited our hospital at least twice between January 2005 and December 2014. Patients were between 3 years and 48 years of age at their latest visit. We divided the patients into a child group and an adult group, and investigated the patients’ follow-up data while focusing on the various multiorgan systems. Results: The follow-ups were well conducted in the child group in terms of every organ. In the adult group, neuroimaging tests were unsatisfactorily performed. The kidney has not been examined in seven patients more than five years even though these patients all had kidney lesions. The lung was not been examined in 7 out of 14 female patients over 18 years of age who are most at risk for lymphangioleiomyomatosis (LAM). In 12 out of 18 child patients, echocardiograms were performed every few years, while electrocardiograms to assess underlying conduction defects were rarely performed in either age group. Conclusions: In Europe, guidelines for the management of TSC have been well established. However, in our hospital, the multiorgan system follow-up is not satisfactorily performed especially in adult patients. We decided the establishment of a TSC board in our hospital for the management of this multiorgan disorder.

Early-onset epileptic encephalopathy (EOEE) is a devastating condition in early childhood that often results in severe and permanent cognitive and motor deficit. Advances in genetics have unveiled many genes involved in EOEE. STXBP1 and SPTAN1 genes, of interest, are mapped to the same chromosomal region 9q34.11. Microdeletions involving this 9q34.11 region can lead to variable clinical phenotypes depending on the range of, and the genes within, the deletion. In this region, STXBP1, SPTAN1, ENG, and TOR1A genes seem to be dosage-sensitive. LMX1B, which is mapped to 9q33.3 and is closely located to the above four genes, could be also involved in the deletion. Twenty cases with deletions involving 9q34.11, including our own case in this article, have been reported in the literature. STXBP1 seems to cause epilepsy, often EOEE, and intellectual disability. SPTAN1 appears to be linked with hypomyelination and hypoplasia of various brain regions, especially corpus callosum, intellectual disability, and abnormal muscle tones. ENG can present with vascular abnormalities including arteriovenous malformation of the lung, liver, and brain. TOR1A can lead to dystonia. LMX1B is responsible for nail and patella malformation. The other deleted genes may add other clinical features such as facial dysmorphism and anomalies of other multiple organs. Utilizing high-resolution microarray analysis to determine the exact range of deletion will help identify more patients in the future to understand various phenotype of 9q34.11 microdeletion.

Objective: Acute electroencephalogram (EEG) findings are important for diagnosing emergency patients with suspected neurological disorders, but they can be difficult for untrained medical staff to interpret. In this research, we will develop an emergency EEG trend figure that we hypothesize will be more easily understood by untrained staff compared with the raw original traces. Methods: For each of several EEG patterns (wakefulness, sleep, seizure activity, and encephalopathy), trend figures incorporating information on both amplitude and frequency were built. The accuracy of untrained reviewers’ interpretation was compared with that of the raw EEG trace interpretation. Results: The rate of correct answers was significantly higher in response to the EEG trend figures than to the raw traces showing wakefulness, sleep, and encephalopathy, but there was no difference when seizure activity patterns were viewed. The rates of misjudging normal or abnormal findings were significantly lower with the trend figures in the wakefulness pattern; in the other patterns, misjudgments were equally low for the trend figures and the raw traces. Conclusion: EEG trend figures improved the accuracy with which untrained medical staff interpreted emergency EEGs. Emergency EEG figures that can be understood intuitively with minimal training might improve the accuracy of emergency EEG interpretation. However, additional studies are required to confirm these results because there may be many types of clinical EEGs that are difficult to interpret.

We propose (de)multiplexers based on tunable cascaded asymmetric Mach-Zehnder interferometers to exclude necessity of highly-scaled expensive Si process by fully-automated fabrication error correction. Incorporating two sets of (de)multiplexers in a 12 × 12 mm transceiver assembly with modulators, photodiodes, drivers, and TIAs, we demonstrate an error-free 25 Gb/s × 4 ch loopback communication.

Objective We explored fast (40–150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures. Subjects and methods The participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis. Results We identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019). Conclusion FOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system.

We propose a novel transmitter with a microring modulator providing seed light to injection-lock a laser at ring resonance. As resonance tuning becomes negligible, power consumption of 0.93 mW/Gbps including laser, lowest among all Si PIC transmitters, has been achieved.

We successfully developed a high density broadband 16-channel × 25 Gb/s silicon photonics optical transceiver. The flip chip bonded structure realized the density of about 363 Gb/s/cm2. We demonstrated the simultaneous multichannel error free operations with low crosstalk penalties.

Objective Fast oscillations (FOs) were first explored from scalp electroencephalographic (EEG) data from hypsarrhythmia in West syndrome (infantile spasms) to investigate the meaning of FOs in this epileptic encephalopathy. Methods In 17 infants with West syndrome, we conservatively detected fast frequency peaks that stood out from the time-frequency spectral background with square root power > 1µV (spectral criterion) and corresponded to clear FOs with at least 4 oscillations in the filtered EEG traces (waveform criterion) in sleep EEGs. Results We found a total of 1,519 interictal FOs that fulfilled both the spectral and waveform criteria. The FOs with a median frequency of 56.6Hz (range = 41.0–140.6Hz) were dense, with a median rate of 66 (range = 24–171) per minute before adrenocorticotropic hormone (ACTH) treatment, which was significantly higher than that in control infants without seizures (median = 1, p