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.

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.

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.

Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome.

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 ballooned 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 ballooned 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.

Seizure Detection Algorithms in Critically Ill Children: A Comparative Evaluation.

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.

Identification of new biomarkers of pyridoxine-dependent epilepsy by GC/MS-based urine metabolomics.

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.

Laboratory changes during adrenocorticotropic hormone therapy associated with renal calcified lesions.

BACKGROUND: Renal calcified lesions are known as one of the complications during adrenocorticotropic hormone (ACTH) therapy for intractable epilepsy. However, laboratory changes during the therapy or laboratory features of high-risk cases with renal calcified lesions are yet to be clarified. METHODS: In this study, 43 patients with West syndrome aged ≤2 years were included. We retrospectively reviewed age and body mass index at the beginning of ACTH therapy, as well as the amount of fluid intake, daily urinary volume, and laboratory data during therapy. In addition, we studied the urinary sediment of the cases with renal calcified lesions diagnosed by computed tomography. RESULTS: After initiating ACTH treatment, urinary calcium (Ca)/creatinine ratio and urinary pH increased within 2 weeks. Urinary crystals and renal tubular epithelial cells (RTECs) in urinary sediment were frequently found in most cases. Urinary Ca levels, proteinuria or frequency of urinary crystals, and number of RTECs in the urinary sediment were significantly higher in patients with epithelial casts (ECs) or hematuria than in patients without these findings. Among the seven patients who underwent abdominal CT, ECs or hematuria were found only in those with renal calcified lesions. These findings suggested that patients with ECs or hematuria were more likely to have calcified lesions. CONCLUSIONS: The risk of renal calcified lesions increased after 2 weeks of ACTH treatment. Abnormal findings in urinary sediments might be an early sign of renal calcification during ACTH therapy.

Metabolic Profiling of the Cerebrospinal Fluid in Pediatric Epilepsy.

To characterize metabolic profiles within the central nervous system in epilepsy, we performed gas chromatography-tandem mass spectrometry (GC-MS/MS)-based metabolome analysis of the cerebrospinal fluid (CSF) in pediatric patients with and without epilepsy. The CSF samples obtained from 64 patients were analyzed by GC-MS/MS. Multivariate analyses were performed for two age groups, 0-5 years of age and 6-17 years of age, to elucidate the effects of epilepsy and antiepileptic drugs on the metabolites. In patients aged 0-5 years (22 patients with epilepsy, 13 without epilepsy), epilepsy patients had reduced 2-ketoglutaric acid and elevated pyridoxamine and tyrosine. In patients aged 6-17 years (12 with epilepsy, 17 without epilepsy), epilepsy patients had reduced 1,5-anhydroglucitol. Valproic acid was associated with elevated 2-aminobutyric acid, 2-ketoisocaproic acid, 4-hydroxyproline, acetylglycine, methionine, N-acetylserine, and serine. Reduced energy metabolism and alteration of vitamin B6 metabolism may play a role in epilepsy in young children. The roles of 1,5-anhydroglucitol in epilepsy in older children and in levetiracetam and zonisamide treatment remain to be explained. Valproic acid influenced the levels of amino acids and related metabolites involved in the metabolism of serine, methionine, and leucine.

Pyridoxal 5'-phosphate and related metabolites in hypophosphatasia: Effects of enzyme replacement therapy.

OBJECTIVE: To investigate the utility of serum pyridoxal 5'-phosphate (PLP), pyridoxal (PL), and 4-pyridoxic acid (PA) as a diagnostic marker of hypophosphatasia (HPP) and an indicator of the effect of, and patient compliance with, enzyme replacement therapy (ERT), we measured PLP, PL, and PA concentrations in serum samples from HPP patients with and without ERT. METHODS: Blood samples were collected from HPP patients and serum was frozen as soon as possible (mostly within one hour). PLP, PL, and PA concentrations were analyzed using high-performance liquid chromatography with fluorescence detection after pre-column derivatization by semicarbazide. We investigated which metabolites are associated with clinical phenotypes and how these metabolites change with ERT. RESULTS: Serum samples from 20 HPP patients were analyzed. The PLP-to-PL ratio and PLP concentration were elevated in all HPP patients. They correlated negatively with serum alkaline phosphatase (ALP) activity and showed higher values in more severe phenotypes (perinatal severe and infantile HPP) compared with other phenotypes. PL concentration was reduced only in perinatal severe HPP. ERT reduced the PLP-to-PL ratio to mildly reduced or low-normal levels and the PLP concentration was reduced to normal or mildly elevated levels. Urine phosphoethanolamine (PEA) concentration did not return to normal levels with ERT in most patients. CONCLUSIONS: The serum PLP-to-PL ratio is a better indicator of the effect of ERT for HPP than serum PLP and urine PEA concentrations, and a PLP-to-PL ratio of <4.0 is a good indicator of the effect of, and patient compliance with, ERT.

Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate.

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.

Significance of High-frequency Electrical Brain Activity.

　Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (< 0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High-frequency oscillations (HFOs) including ripple and fast ripple oscillations (80-200 Hz and>200 / 250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological / epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long-term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs /FOs is rapidly expanding.

Importance of the multisystem follow-up in patients with tuberous sclerosis complex.

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.

A storm of fast (40-150Hz) oscillations during hypsarrhythmia in West syndrome.

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 < 0.001). The FOs were reduced by treatment. The mean gamma and ripple oscillation rates that were detected using the waveform criterion alone were 40.62/min and 15.75/min, respectively, per channel; these results were 112.8 and 98.4 times higher, respectively, than the previously reported corresponding rates in adult epilepsy patients. INTERPRETATION: The observed FOs corresponded to epileptogenicity because of their close relation to the severity of hypsarrhythmia during the course of ACTH treatment. The very high epileptic FO rates in hypsarrhythmia are thought to affect the process of neurodevelopment by interfering with physiological functions in West syndrome, taking into account that high frequencies are also important in physiological higher brain functions.

Total folate and 5-methyltetrahydrofolate in the cerebrospinal fluid of children: correlation and reference values.

BACKGROUND: Cerebral folate deficiency (CFD) may be underdiagnosed, as it manifests with various non-specific neurological symptoms. The diagnosis of CFD requires a determination of 5-methyltetrahydrofolate (5MTHF) in the cerebrospinal fluid (CSF), which is available in a limited number of specialized laboratories. In clinical biochemistry laboratories, total folate (TF) determination in serum or plasma is routinely performed by automated analyzers. The aim of this study is to determine whether the automated assay of CSF TF is a helpful screening tool for CFD. METHODS: We analyzed CSF samples collected from 73 pediatric patients. We measured CSF TF, serum TF, and CSF 5MTHF in 73, 70, and 48 patients, respectively. The assay of 5MTHF was conducted by a newly developed system utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS). We investigated the correlation between TF and 5MTHF in the CSF. RESULTS: There was a strong positive correlation between CSF TF and 5MTHF (ρ=0.930, p<0.0001, n=48). Age was negatively correlated with CSF TF (ρ=-0.557, p<0.0001, n=51), serum TF (ρ=-0.457, p=0.0008, n=51), and CSF 5MTHF (ρ=-0.387, p=0.0263, n=33), but not with the CSF/serum TF ratio. CONCLUSIONS: The automated assay of CSF TF is helpful to estimate CSF 5MTHF. The CSF TF assay may have a significant impact on the early diagnosis of CFD, because clinicians have better access to it than the 5MTHF assay.

Interictal high frequency oscillations correlating with seizure outcome in patients with widespread epileptic networks in tuberous sclerosis complex.

OBJECTIVE: Multiple tubers in patients with tuberous sclerosis complex (TSC) often are responsible for drug-resistant epilepsy. The complexity of the epileptic network formed by multiple tubers complicates localization of the epileptogenic zone that is needed to design a surgical treatment strategy. High frequency oscillations (HFOs) on intracranial video-electroencephalography (IVEEG) may be a valuable surrogate marker for the localization of the epileptogenic zone. The purpose of this study was to test the hypothesis that high occurrence rate (OR) of interictal HFOs can guide the localization of the epileptogenic zone. METHODS: We analyzed the OR of interictal HFOs at 80-200 Hz (ripples) and >200 Hz (fast ripples, FRs). We divided OR of interictal HFOs between high and low rates by thresholding. We analyzed the correlation between seizure outcomes using Engel classification and the resection ratio of the seizure onset zone (SOZ), and high-OR HFOs using ordinal logistic regression analysis. RESULTS: We collected 10 patients. The seizure outcomes resulted in Engel classification I in three patients, II in four, III in one, and IV in two. High-OR ripples (5-57 [mean 29] channels, 1-4 [2.8] lobes) and high-OR FRs (9-66 [mean 27] channels, 1-4 [2.6] lobes) were widely distributed. The resection ratio of SOZ did not show statistically significant correlation with the seizure outcome. The resection ratio of high-OR ripples showed statistically significant correlation with the seizure outcome (p = 0.038). The resection ratio of high-OR FRs showed statistically significant correlation with the seizure outcome (p = 0.048). SIGNIFICANCE: The multiple extensive zones with high-OR HFOs suggest a complex and widespread epileptic network in patients with TSC. In a subset of TSC patients with drug-resistant epilepsy, resection of cortex with both interictal high-OR FRs and ripples on IVEEG correlated with a good seizure outcome.

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.

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.

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.

Neocortical pathological high-frequency oscillations are associated with frequency-dependent alterations in functional network topology.

Synchronization of neural oscillations is thought to integrate distributed neural populations into functional cell assemblies. Epilepsy is widely regarded as a disorder of neural synchrony. Knowledge is scant, however, regarding whether ictal changes in synchrony involving epileptogenic cortex are expressed similarly across various frequency ranges. Cortical regions involved in epileptic networks also exhibit pathological high-frequency oscillations (pHFOs, >80 Hz), which are increasingly utilized as biomarkers of epileptogenic tissue. It is uncertain how pHFO amplitudes are related to epileptic network connectivity. By calculating phase-locking values among intracranial electrodes implanted in children with intractable epilepsy, we constructed ictal connectivity networks and performed graph theoretical analysis to characterize their network properties at distinct frequency bands. Ictal data from 17 children were analyzed with a hierarchical mixed-effects model adjusting for patient-level covariates. Epileptogenic cortex was defined in two ways: 1) a hypothesis-driven method using the visually defined seizure-onset zone and 2) a data-agnostic method using the high-frequency amplitude of each electrode. Epileptogenic cortex exhibited a logarithmic decrease in interregional functional connectivity at high frequencies (>30 Hz) during seizure initiation and propagation but not at termination. At slower frequencies, conversely, epileptogenic cortex expressed a relative increase in functional connectivity. Our findings suggest that pHFOs reflect epileptogenic network interactions, yielding theoretical support for their utility in the presurgical evaluation of intractable epilepsy. The view that abnormal network synchronization plays a critical role in ictogenesis and seizure dynamics is supported by the observation that functional isolation of epileptogenic cortex at high frequencies is absent at seizure termination.

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.