Overnight Electroencephalogram to Forecast Epilepsy Development in Children with Autism Spectrum Disorders.

OBJECTIVE: To establish the utility of long-term electroencephalogram (EEG) in forecasting epilepsy onset in children with autism spectrum disorder (ASD). STUDY DESIGN: A single-institution, retrospective analysis of children with ASD, examining long-term overnight EEG recordings collected over a period of 15 years, was conducted. Clinical EEG findings, patient demographics, medical histories, and additional Autism Diagnostic Observation Schedule data were examined. Predictors for the timing of epilepsy onset were evaluated using survival analysis and Cox regression. RESULTS: Among 151 patients, 17.2% (n = 26) developed unprovoked seizures (Sz group), while 82.8% (n = 125) did not (non-Sz group). The Sz group displayed a higher percentage of interictal epileptiform discharges (IEDs) in their initial EEGs compared with the non-Sz group (46.2% vs 20.0%, P = .01). The Sz group also exhibited a greater frequency of slowing (42.3% vs 13.6%, P < .01). The presence of IEDs or slowing predicted an earlier seizure onset, based on survival analysis. Multivariate Cox proportional hazards regression revealed that the presence of any IEDs (HR 3.83, 95% CI 1.38-10.65, P = .01) or any slowing (HR 2.78, 95% CI 1.02-7.58, P = .046 significantly increased the risk of developing unprovoked seizures. CONCLUSION: Long-term EEGs are valuable for predicting future epilepsy in children with ASD. These findings can guide clinicians in early education and potential interventions for epilepsy prevention.

Different Numbers of Conjunctive Stimuli Induce LTP or LTD in Mouse Cerebellar Purkinje Cell.

Long-term depression (LTD) of synaptic transmission at parallel fiber (PF)-Purkinje cell (PC) synapses plays an important role in cerebellum-related motor coordination and learning. LTD is induced by the conjunction of PF stimulation and climbing fiber (CF) stimulation or somatic PC depolarization, while long-term potentiation (LTP) is induced by PF stimulation alone. Therefore, it is considered that different types of stimulation induce different types of synaptic plasticity. However, we found that a small number of conjunctive stimulations (PF + somatic depolarization of PC) induced LTP, but did not induce LTD of a small size. This LTP was not associated with changes in paired-pulse ratio, suggesting postsynaptic origin. Additionally this LTP was dependent on nitric oxide. This LTP was also induced by a smaller number of physiological conjunctive PF and CF stimuli. These results suggested that a larger number or longer period of conjunctive stimulation is required to induce LTD by overcoming LTP. Ca2+ transients at the PC dendritic region was measured by calcium imaging during LTD-inducing conjunctive stimulation. Peak amplitude of Ca2+ transients increased gradually during repetitive conjunctive stimulation. Instantaneous peak amplitude was not different between the early phase and late phase, but the average amplitude was larger in the later phase than in the early phase. These results show that LTD overcomes LTP, and increased Ca2+ integration or a number of stimulations is required for LTD induction.

Uncovering spatiotemporal dynamics of the corticothalamic network at ictal onset.

OBJECTIVE: Although the clinical efficacy of deep brain stimulation targeting the anterior nucleus (AN) and centromedian nucleus (CM) of the thalamus has been actively investigated for the treatment of medication-resistant epilepsy, few studies have investigated dynamic ictal changes in corticothalamic connectivity in human electroencephalographic (EEG) recording. This study aims to establish the complex spatiotemporal dynamics of the ictal corticothalamic network associated with various seizure foci. METHODS: We analyzed 10 patients (aged 2.7-28.1 years) with medication-resistant focal epilepsy who underwent stereotactic EEG evaluation with thalamic sampling. We examined both undirected and directed connectivity, incorporating coherence and spectral Granger causality analysis (GCA) between the diverse seizure foci and thalamic nuclei (AN and CM) at ictal onset. RESULTS: In our analysis of 36 seizures, coherence between seizure onset and thalamic nuclei increased across all frequencies, especially in slower bands (delta, theta, alpha). GCA showed increased information flow from seizure onset to the thalamus across all frequency bands, but outflows from the thalamus were mainly in slower frequencies, particularly delta. In the subgroup analysis based on various seizure foci, the delta coherence showed a more pronounced increase at CM than at AN during frontal lobe seizures. Conversely, in limbic seizures, the delta coherence increase was greater at AN compared to CM. SIGNIFICANCE: It appears that the delta frequency plays a pivotal role in modulating the corticothalamic network during seizures. Our results underscore the significance of comprehending the spatiotemporal dynamics of the corticothalamic network at ictal onset, and this knowledge could guide personalized responsive neuromodulation treatment strategies.

Efficacy of Antiseizure Medications in Wolf-Hirschhorn Syndrome.

Wolf-Hirschhorn syndrome (WHS) is caused by deletion of the terminal region of chromosome 4 short arm and is frequently associated with intractable epilepsy. This article evaluates the clinical features of epileptic seizures in WHS and the therapeutic efficacy of oral antiseizure medications (ASMs). Patients with WHS who were treated for epilepsy at the Saitama Children's Medical Center under 5 years of age were included. WHS was diagnosed based on genetic tests and clinical symptoms. Medical records regarding the age of onset of epilepsy, seizure type, treatment of status epilepticus (SE), and effectiveness of ASMs were retrospectively reviewed. Oral ASMs were considered effective when seizures were reduced by at least 50% compared with the premedication level. Eleven patients were included in the study. The median age at the onset of epilepsy was 9 months (range: 5-32 months). Unknown-onset bilateral tonic-clonic seizure was the most common type of seizure, occurring in 10 patients. Focal clonic seizures occurred in four patients. Ten patients exhibited recurrent episodes of SE, and its frequency during infancy was monthly in eight patients and yearly in two. SE occurrence peaked at 1 year of age and decreased after 3 years of age. The most effective ASM was levetiracetam. Although WHS-associated epilepsy is intractable with frequent SE occurrence during infancy, improvement in seizure control is expected with age. Levetiracetam may be a novel ASM for WHS.

Adjunctive perampanel therapy for patients with epileptic spasms.

BACKGROUND: Perampanel is an antiepileptic drug. Some studies have documented the efficacy of perampanel in epileptic spasms. We aimed to evaluate the efficacy and safety of adjunctive perampanel therapy (PT) in patients with epileptic spasms. METHODS: We retrospectively surveyed the efficacy and safety of adjunctive PT in 14 patients with epileptic spasms at the Saitama Children's Medical Center between June 2016 and September 2021. Seizure outcomes and safety were evaluated 12 months after commencing PT. Response to perampanel was defined as complete remission of epileptic spasms for more than 3 months. RESULTS: The median age at onset of epileptic spasms was 0.4 years (range, 0.1-1.3 years). The etiology was structural in 11 patients, genetic in two, and unknown in one. The median age at the commencement of PT was 3.2 years (1.5-10.3 years). The initial and maintenance doses of perampanel were administered at 0.04 (range, 0.02-0.05) mg/kg/day and 0.12 (range, 0.03-0.24) mg/kg/day, respectively. Five of the 14 patients (35.7%) showed remission of epileptic spasms for more than 3 months at 12 months after PT; these patients had a structural etiology. The median duration between commencement of perampanel and spasm remission was 2 months (range, 1-6 months). No serious adverse effects occurred. CONCLUSIONS: This is the first case series evaluating adjunctive PT for epileptic spasms. PT is worth investigating to treat epileptic spasms in patients with structural etiologies. As our study population primarily comprised children aged 2 years and older, PT may be useful for epileptic spasms beyond infancy.

Efficient detection of copy-number variations using exome data: Batch- and sex-based analyses.

Many algorithms to detect copy number variations (CNVs) using exome sequencing (ES) data have been reported and evaluated on their sensitivity and specificity, reproducibility, and precision. However, operational optimization of such algorithms for a better performance has not been fully addressed. ES of 1199 samples including 763 patients with different disease profiles was performed. ES data were analyzed to detect CNVs by both the eXome Hidden Markov Model (XHMM) and modified Nord's method. To efficiently detect rare CNVs, we aimed to decrease sequencing biases by analyzing, at the same time, the data of all unrelated samples sequenced in the same flow cell as a batch, and to eliminate sex effects of X-linked CNVs by analyzing female and male sequences separately. We also applied several filtering steps for more efficient CNV selection. The average number of CNVs detected in one sample was <5. This optimization together with targeted CNV analysis by Nord's method identified pathogenic/likely pathogenic CNVs in 34 patients (4.5%, 34/763). In particular, among 142 patients with epilepsy, the current protocol detected clinically relevant CNVs in 19 (13.4%) patients, whereas the previous protocol identified them in only 14 (9.9%) patients. Thus, this batch-based XHMM analysis efficiently selected rare pathogenic CNVs in genetic diseases.

Use of Perampanel and a Ketogenic Diet in Nonketotic Hyperglycinemia: A Case Report.

BACKGROUND: Nonketotic hyperglycinemia is a severe form of early onset epileptic encephalopathy caused by disturbances in the glycine cleavage system; the neurological damage is mainly attributed to overstimulation of the N-methyl-D-aspartate receptor. CASE: The patient presented with a severe form of nonketotic hyperglycinemia and experienced frequent epileptic spasms and focal seizures, which were resistant to vigabatrin, adrenocorticotropic hormone therapy, and combined dextromethorphan and sodium benzoate treatments. By 9 months of age, perampanel reduced epileptic spasms by >50%. At 14 months of age, the ketogenic diet markedly reduced focal seizures and glycine levels in the cerebrospinal fluid. CONCLUSION: Perampanel reduced fast excitatory neuronal activity, which was induced by an α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor, followed by prolonged electrical depolarizations due to an N-methyl-D-aspartate receptor. Furthermore, the ketogenic diet may have modulated the excessive neurotoxic cascade through the N-methyl-D-aspartate receptor. Perampanel and ketogenic diet were effective for seizure control in our patient.

Relationship between Sedative Antihistamines and the Duration of Febrile Seizures.

Some studies have shown that sedative antihistamines prolong febrile seizure duration. Although the collective evidence is still mixed, the Japanese Society of Child Neurology released guidelines in 2015 that contraindicated the use of sedative antihistamines in patients with febrile seizure. Focused on addressing limitations of previous studies, we conducted a cross-sectional study to evaluate the relationship between febrile seizure duration and the use of sedative antihistamines. Data were collected from patients who visited St. Luke's International Hospital due to febrile seizure between August 2013 and February 2016. Patients were divided into groups based on their prescribed medications: sedative antihistamine, nonsedative antihistamine, and no antihistamine. Seizure duration was the primary outcome and was examined using multivariate analyses. Of the 426 patients included, sedative antihistamines were administered to 24 patients. The median seizure duration was approximately 3 minutes in all three groups. There was no statistical difference in the bivariate (p = 0.422) or multivariate analyses (p = 0.544). Our results do not support the relationship between sedative antihistamine use and prolonged duration of febrile seizure. These results suggest that the use of antihistamines may be considered for patients with past history of febrile seizure, when appropriate.

[Transplantation-associated thrombotic microangiopathy confirmed by renal biopsy].

An eight-year-old girl with myelodysplastic syndrome (refractory cytopenia) received a bone marrow transplant (BMT) from an unrelated donor because of immunosuppressive therapy failure. Following administration of foscarnet for cytomegalovirus reactivation at day40 post-BMT, serum creatinine increased, and proteinuria, hematuria, and hypertension gradually exacerbated and became prolonged. However, neither schistocytosis nor other organ damage was evident. At six months post-BMT, renal biopsy revealed diffuse glomerular damage with glomerular lobulation, a double contour of the glomerular basement membrane, erythrocyte congestion and thrombi in the glomerular endocapillaries, and mesangiolysis, confirming the diagnosis of transplantation-associated thrombotic microangiopathy (TA-TMA). We initiated strict controls regarding fluid balance, salt intake, and blood pressure. The patient's renal function improved 10 months post-BMT. TA-TMA often presents as non-specific symptoms, making diagnosis difficult. In cases of post-transplant renal damage, TA-TMA should be differentiated regardless of whether specific symptoms such as hemolytic anemia and other organ failure are evident, and a renal biopsy should, therefore, be considered.

Risk Factors for Hospital-acquired Clostridium difficile Infection Among Pediatric Patients With Cancer.

Hospital-acquired Clostridium difficile infection (CDI) may cause life-threatening colitis for children with cancer, making identification of risk factors important. We described characteristics of pediatric cancer patients with primary and recurring CDI, and evaluated potential risk factors. Among 189 cancer patients, 51 cases (27%) of CDI and 94 matched controls of cancer patients without CDI were analyzed. Multivariable logistic regression was used to evaluate the association between CDI and several potential risk factors. Median age of CDI cases was lower (3.3 y; 0.60 to 16.2) than controls (7.7 y; 0.4 to 20.5). Median duration of neutropenia before CDI was longer for CDI cases (10.0 d; 0.0 to 30.0) compared with duration calculated from reference date in controls (6.0 d; 0.0 to 29.0). Multivariable analysis showed that older age was associated with reduced risk (≥7 vs. 0 to 3 y, odds ratio=0.11; 95% confidence interval, 0.02-0.54), and prolonged neutropenia was associated with increased risk (odds ratio=1.11; 95% confidence interval, 1.01-1.22). CDI recurred in 26% of cases. Younger age and prolonged neutropenia were risk factors for CDI in children with cancer. Increasing awareness to these risk factors will help to identify opportunities for CDI prevention in cancer patients.

Computational EEG attributes predict response to therapy for epileptic spasms.

OBJECTIVE: We set out to evaluate whether response to treatment for epileptic spasms is associated with specific candidate computational EEG biomarkers, independent of clinical attributes. METHODS: We identified 50 children with epileptic spasms, with pre- and post-treatment overnight video-EEG. After EEG samples were preprocessed in an automated fashion to remove artifacts, we calculated amplitude, power spectrum, functional connectivity, entropy, and long-range temporal correlations (LRTCs). To evaluate the extent to which each feature is independently associated with response and relapse, we conducted logistic and proportional hazards regression, respectively. RESULTS: After statistical adjustment for the duration of epileptic spasms prior to treatment, we observed an association between response and stronger baseline and post-treatment LRTCs (P = 0.042 and P = 0.004, respectively), and higher post-treatment entropy (P = 0.003). On an exploratory basis, freedom from relapse was associated with stronger post-treatment LRTCs (P = 0.006) and higher post-treatment entropy (P = 0.044). CONCLUSION: This study suggests that multiple EEG features-especially LRTCs and entropy-may predict response and relapse. SIGNIFICANCE: This study represents a step toward a more precise approach to measure and predict response to treatment for epileptic spasms.

PyHFO: lightweight deep learning-powered end-to-end high-frequency oscillations analysis application.

Objective. This study aims to develop and validate an end-to-end software platform, PyHFO, that streamlines the application of deep learning (DL) methodologies in detecting neurophysiological biomarkers for epileptogenic zones from EEG recordings.Approach. We introduced PyHFO, which enables time-efficient high-frequency oscillation (HFO) detection algorithms like short-term energy and Montreal Neurological Institute and Hospital detectors. It incorporates DL models for artifact and HFO with spike classification, designed to operate efficiently on standard computer hardware.Main results. The validation of PyHFO was conducted on three separate datasets: the first comprised solely of grid/strip electrodes, the second a combination of grid/strip and depth electrodes, and the third derived from rodent studies, which sampled the neocortex and hippocampus using depth electrodes. PyHFO demonstrated an ability to handle datasets efficiently, with optimization techniques enabling it to achieve speeds up to 50 times faster than traditional HFO detection applications. Users have the flexibility to employ our pre-trained DL model or use their EEG data for custom model training.Significance. PyHFO successfully bridges the computational challenge faced in applying DL techniques to EEG data analysis in epilepsy studies, presenting a feasible solution for both clinical and research settings. By offering a user-friendly and computationally efficient platform, PyHFO paves the way for broader adoption of advanced EEG data analysis tools in clinical practice and fosters potential for large-scale research collaborations.

Discovering Neurophysiological Characteristics of Pathological High-Frequency Oscillations in Epilepsy with an Explainable Deep Generative Model.

Interictal high-frequency oscillation (HFO) is a promising biomarker of the epileptogenic zone (EZ). However, objective definitions to distinguish between pathological and physiological HFOs have remained elusive, impeding HFOs' clinical applications. We employed self-supervised deep generative variational autoencoders to learn such discriminative HFO features directly from their morphologies in a data-driven manner. We studied a large retrospective cohort of 185 patients who underwent intracranial monitoring and analyzed 686,410 candidate HFO events collected from 18,265 brain contacts across diverse brain regions. The model automatically clustered HFOs into distinct morphological groups in the latent space. One cluster consisted of putative morphologically defined pathological HFOs (mpHFOs): HFOs in that cluster were observed to be associated with spikes and exhibited high signal intensity both in the HFO band (>80 Hz) at detection and in the sub-HFO band (10-80 Hz) surrounding the detection and were primarily localized in the seizure onset zone (SOZ). Moreover, resection of brain regions based on a higher prevalence of interictal mpHFOs better predicted postoperative seizure outcomes than current clinical standards based on SOZ removal. Our self-supervised, explainable, deep generative model distills pathological HFOs and thus potentially helps delineate the EZ purely from interictal intracranial EEG data.

Characteristics of ictal thalamic EEG in pediatric-onset neocortical focal epilepsy.

OBJECTIVE: To characterize ictal EEG change in the centromedian (CM) and anterior nucleus (AN) of the thalamus, using stereoelectroencephalography (SEEG) recordings. METHODS: Forty habitual seizures were analyzed in nine patients with pediatric-onset neocortical drug-resistant epilepsy who underwent SEEG (age 2-25 y) with thalamic coverage. Both visual and quantitative analysis was used to evaluate ictal EEG signal in the cortex and thalamus. The amplitude and cortico-thalamic latencies of broadband frequencies at ictal onset were measured. RESULTS: Visual analysis demonstrated consistent detection of ictal EEG changes in both the CM nucleus and AN nucleus with latency to thalamic ictal EEG changes of less than 400 ms in 95% of seizures, with low-voltage fast activity being the most common ictal pattern. Quantitative broadband amplitude analysis showed consistent power changes across the frequency bands, corresponding to ictal EEG onset, while while ictal EEG latency was variable from -18.0 seconds to 13.2 seconds. There was no significant difference between detection of CM and AN ictal activity on visual or amplitude analysis. Four patients with subsequent thalamic responsive neurostimulation (RNS) demonstrated ictal EEG changes consistent with SEEG findings. CONCLUSIONS: Ictal EEG changes were consistently seen at the CM and AN of the thalamus during neocortical seizures. SIGNIFICANCE: It may be feasible to use a closed-loop system in the thalamus to detect and modulate seizure activity for neocortical epilepsy.

Uncovering Spatiotemporal Dynamics of the Corticothalamic Network during Seizures.

Objective: Although the clinical efficacy of deep brain stimulation targeting the anterior nucleus (AN) and centromedian nucleus (CM) of the thalamus has been actively investigated for the treatment of medication-resistant epilepsy, few studies have investigated dynamic ictal changes in corticothalamic connectivity in human EEG recording. This study aims to establish the complex spatiotemporal dynamics of the ictal corticothalamic network associated with various seizure foci. Methods: We analyzed ten patients (aged 2.7-28.1) with medication-resistant focal epilepsy who underwent stereotactic EEG evaluation with thalamic coverage. We examined both undirected and directed connectivity, incorporating coherence and spectral Granger causality analysis (GCA) between the diverse seizure foci and thalamic nuclei (AN and CM). Results: In our analysis of 36 seizures, coherence between seizure onset and thalamic nuclei increased across all frequencies, especially in slower bands (delta, theta, alpha). GCA showed increased information flow from seizure onset to the thalamus across all frequency bands, but outflows from the thalamus were mainly in slower frequencies, particularly delta. In the subgroup analysis based on various seizure foci, the delta coherence showed a more pronounced increase at CM than at AN during frontal lobe seizures. Conversely, in limbic seizures, the delta coherence increase was greater at AN compared to CM. Interpretation: It appears that the delta frequency plays a pivotal role in modulating the corticothalamic network during seizures. Our results underscore the significance of comprehending the spatiotemporal dynamics of the corticothalamic network during seizures, and this knowledge could guide personalized neuromodulation treatment strategies.

Optimizing detection and deep learning-based classification of pathological high-frequency oscillations in epilepsy.

OBJECTIVE: This study aimed to explore sensitive detection methods for pathological high-frequency oscillations (HFOs) to improve seizure outcomes in epilepsy surgery. METHODS: We analyzed interictal HFOs (80-500 Hz) in 15 children with medication-resistant focal epilepsy who underwent chronic intracranial electroencephalogram via subdural grids. The HFOs were assessed using the short-term energy (STE) and Montreal Neurological Institute (MNI) detectors and examined for spike association and time-frequency plot characteristics. A deep learning (DL)-based classification was applied to purify pathological HFOs. Postoperative seizure outcomes were correlated with HFO-resection ratios to determine the optimal HFO detection method. RESULTS: The MNI detector identified a higher percentage of pathological HFOs than the STE detector, but some pathological HFOs were detected only by the STE detector. HFOs detected by both detectors had the highest spike association rate. The Union detector, which detects HFOs identified by either the MNI or STE detector, outperformed other detectors in predicting postoperative seizure outcomes using HFO-resection ratios before and after DL-based purification. CONCLUSIONS: HFOs detected by standard automated detectors displayed different signal and morphological characteristics. DL-based classification effectively purified pathological HFOs. SIGNIFICANCE: Enhancing the detection and classification methods of HFOs will improve their utility in predicting postoperative seizure outcomes.

Characteristics of ictal thalamic EEG in pediatric-onset neocortical focal epilepsy.

Objective: To characterize ictal EEG change in the centromedian (CM) and anterior nucleus (AN) of the thalamus, using stereoelectroencephalography (SEEG) recordings. Methods: Forty habitual seizures were analyzed in nine patients with pediatric-onset neocortical drug-resistant epilepsy who underwent SEEG (age 2-25 y) with thalamic coverage. Both visual and quantitative analysis was used to evaluate ictal EEG signal in the cortex and thalamus. The amplitude and cortico-thalamic latencies of broadband frequencies at ictal onset were measured. Results: Visual analysis demonstrated consistent detection of ictal EEG changes in both the CM nucleus and AN nucleus with latency to thalamic ictal EEG changes of less than 400ms in 95% of seizures, with low-voltage fast activity being the most common ictal pattern. Quantitative broadband amplitude analysis showed consistent power changes across the frequency bands, corresponding to ictal EEG onset, while while ictal EEG latency was variable from -18.0 seconds to 13.2 seconds. There was no significant difference between detection of CM and AN ictal activity on visual or amplitude analysis. Four patients with subsequent thalamic responsive neurostimulation (RNS) demonstrated ictal EEG changes consistent with SEEG findings. Conclusions: Ictal EEG changes were consistently seen at the CM and AN of the thalamus during neocortical seizures. Significance: It may be feasible to use a closed-loop system in the thalamus to detect and modulate seizure activity for neocortical epilepsy.

Optimizing Detection and Deep Learning-based Classification of Pathological High-Frequency Oscillations in Epilepsy.

Objective: This study aimed to explore sensitive detection methods and deep learning (DL)-based classification for pathological high-frequency oscillations (HFOs). Methods: We analyzed interictal HFOs (80-500 Hz) in 15 children with medication-resistant focal epilepsy who underwent resection after chronic intracranial electroencephalogram via subdural grids. The HFOs were assessed using the short-term energy (STE) and Montreal Neurological Institute (MNI) detectors and examined for pathological features based on spike association and time-frequency plot characteristics. A DL-based classification was applied to purify pathological HFOs. Postoperative seizure outcomes were correlated with HFO-resection ratios to determine the optimal HFO detection method. Results: The MNI detector identified a higher percentage of pathological HFOs than the STE detector, but some pathological HFOs were detected only by the STE detector. HFOs detected by both detectors exhibited the most pathological features. The Union detector, which detects HFOs identified by either the MNI or STE detector, outperformed other detectors in predicting postoperative seizure outcomes using HFO-resection ratios before and after DL-based purification. Conclusions: HFOs detected by standard automated detectors displayed different signal and morphological characteristics. DL-based classification effectively purified pathological HFOs. Significance: Enhancing the detection and classification methods of HFOs will improve their utility in predicting postoperative seizure outcomes. HIGHLIGHTS: HFOs detected by the MNI detector showed different traits and higher pathological bias than those detected by the STE detectorHFOs detected by both MNI and STE detectors (the Intersection HFOs) were deemed the most pathologicalA deep learning-based classification was able to distill pathological HFOs, regard-less of the initial HFO detection methods.

The effectiveness of intravenous benzodiazepine for status epilepticus in Dravet syndrome.

PURPOSE: We aimed to evaluate choice and efficacy of intravenous antiepileptic drugs (AEDs) for status epilepticus (SE) in Dravet syndrome and to find predictable clinical features demonstrating the effectiveness of benzodiazepine (BZD) for SE. METHODS: We retrospectively investigated the medical records in patients with Dravet syndrome and evaluated the effectiveness rate of intravenous AEDs and the rate of adverse effects. To find the clinical features of BZD-effective SE, we divided the SE episodes into the following two groups: BZD effective group and BZD non-effective group. The choice of treatment was dependent on physicians' discretion according to the protocol for SE in our institution. RESULTS: Sixty-eight SE episodes in 10 patients were assessed. The median age at SE was 31 months. Of 68 episodes, 42 episodes (61.8%) were in the BZD effective group and 26 (38.2%) in the BZD non-effective group. There were no significant differences in clinical features. In the BZD non-effective group, the effective rates of continuous midazolam, phenobarbital, phenytoin/fosphenytoin were 9/9 episodes (100%), 14/17 (82.4%), and 2/5 (40.0%), respectively. Adverse effects were identified in 19/68 episodes (27.9%), including 11/42 episodes in the BZD effective group and 8/26 in the BZD non-effective group, which was no statistical difference between the two groups. Respiratory suppression was found in all 19 episodes and the incidence of endotracheal intubation in the BZD non-effective group (15.4%) was higher than that in the BZD effective group (2.4%) (p = 0.046). CONCLUSION: BZD may be used as first choice, and phenobarbital prior to continuous midazolam as second choice for SE with Dravet syndrome. There might be no predictable clinical features showing that BZD will be effective.

Serum matrix metallopeptidase-9 and tissue inhibitor of metalloproteinase-1 levels may predict response to adrenocorticotropic hormone therapy in patients with infantile spasms.

OBJECTIVE: To evaluate whether serum matrix metallopeptidase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels predict response to adrenocorticotropic hormone (ACTH) therapy in patients with infantile spasms. METHODS: We prospectively evaluated patients with infantile spasms who were referred to Saitama Children's Medical Center from January 2011 to December 2020. We measured Q-albumin and serum MMP-9 and TIMP-1 levels before ACTH therapy. Patients were divided into three groups based on the etiology of their infantile spasms: those with an unknown etiology and normal development (unknown-normal group); those with a structural and acquired etiology (structural-acquired group); and those with a structural and congenital, genetic, metabolic, or unknown etiology with developmental delay (combined-congenital group). Responders were defined as those having complete cessation of spasms for more than 3 months with the resolution of hypsarrhythmia on electroencephalography during ACTH therapy. RESULTS: We collected serum from 36 patients with West syndrome and five patients with infantile spasms without hypsarrhythmia before ACTH therapy. Twenty-three of 41 patients (56.1%) were responders, including 8/8 (100%) in the unknown-normal group, 6/9 (66.7%) in the structural-acquired group, and 9/24 (37.5%) in the combined-congenital group. The serum MMP-9 level and MMP-9/TIMP-1 ratio were significantly higher in responders than in nonresponders (P = 0.001 for both). CONCLUSION: A therapeutic response to ACTH was associated with a higher serum MMP-9 level and higher MMP-9/TIMP-1 ratio in patients with infantile spasms. Therefore, these biomarkers may predict responses to ACTH therapy in this patient population.