Ethosuximide Research Articles

Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents.

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

PurposeIn 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. MethodsWe 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. ResultsWe 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. SignificanceHigh 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.

Alpha-2a adrenergic receptor activation in genetic absence epilepsy: An absence status model?

The objective of the study was to propose a candidate animal model of absence status epilepticus induced by specific alpha-2a adrenergic receptor (α2AR) activation. We also aim to investigate the responsiveness of this model to classical anti-status or anti-absence medications. An α2AR agonist, dexmedetomidine (DEX), was injected intracerebroventricularly into adult rats with genetic absence epilepsy, and their electroencephalography (EEG) was recorded. The total duration, number, and mean duration of each spike-and-wave discharges (SWDs) were evaluated. The blocks of absence status events were classified as the initial and second sets of absence statuses. Ethosuximide (ETX) was administered as a pretreatment to another group of rats and later injected with 2.5 μg DEX. In addition, ETX, valproic acid (VPA), diazepam (DIAZ), and atipamezole (ATI) were administered after induced status-like events following DEX administration. Power spectral characteristics and coherence analysis were performed on the EEG to assess the absence status events and sleep. The 2.5 μg dose of DEX increased the total SWD duration and induced continuous SWDs up to 26 min. Following the initial absence status event, sleep was induced; then, the second period of absence status-like activities were initiated. ETX pretreatment blocked the occurrence of absence status-like activities. Power spectral density analyses revealed that DEX-induced post-sleep activities had higher power in delta frequency band (1-4 Hz) and attenuated power of 7 Hz harmonics (14 and 21 Hz) than the pre-injection seizure. The mean duration of SWDs were decreased in all the groups, but occasional prolonged activities were seen in ETX or VPA-injected rats but not with DIAZ or ATI. This study presents an absence status epilepticus animal model that is activated by α2AR activation to investigate the pathophysiological role of absence status. Unlike other agents ATI switched off the second set of absence statuses to normal SWDs, without sedation or lethargy, can show it may preferentially block absence status-like activity. This study proposes a rat model for prolonged seizures, resembling absence status epilepticus. Activating the brain's alpha-2a adrenergic receptor with dexmedetomidine induced seizures lasting up to 26 minutes. Ethosuximide pretreatment and post-treatment with valproic acid, diazepam, and atipamezole decreased induced seizures. The findings suggest this model is valuable for studying absence status epilepticus. In addition, atipamezole normalized abnormal seizures without sedation, hinting at its potential for targeted treatment and further research.

A 5-Year Study of Antiseizure Medications (ASMs) Monitoring in Patients with Neuropsychiatric Disorders in an Italian Clinical Center.

Despite receiving appropriate antiseizure medications (ASMs), a relevant percentage of neuropsychiatric patients do not benefit from this approach, and one reason is subtherapeutic ASMs plasma concentration (C(p)) due to improper drug adherence, interindividual pharmacokinetic differences, or metabolic interactions among different drugs. For these reasons, therapeutic drug monitoring (TDM) by measuring ASMs C(p) is an effective tool that improves pharmacological therapies in clinical practice. Based on these premises, in the present real-world study, we analyzed the C(p) of the most used ASMs in diverse medical conditions, which were assayed during the years 2018-2022 at the University Hospital of Pisa, including about 24,000 samples. This population was largely heterogeneous, and our database did not contain clinical information about the patients. The most used ASMs were Valproate (VPA: 54.5%) and Levetiracetam (LEV: 18.6%), followed by Oxcarbazepine (OxCBZ: 8.3%) and Carbamazepine (CBZ: 7.2%), whereas the associations LEV/VPA, Ethosuximide (ESM)/VPA, and CBZ/VPA were the most frequently proposed. In about 2/3 of assays, ASMs C(p) was in range, except for VPA, which was underdosed in almost half of the samples. Importantly, toxic levels of ASMs C(p) were found very rarely. For VPA, there was a decrease of mean C(p) across ages, from adolescents to older patients, while the C(p) of LEV, CBZ, OxCBZ, and Topiramate (TPM) showed a slight tendency to increase. When we compared females and males, we found that for VPA, the average age was higher for females, whereas women taking Lamotrigine (LTG) and OxCBZ were younger than men. Then, comparing ASMs used in neurologic and psychiatric disorders, based on the request form, it emerged that the mean C(p) of CBZ, OxCBZ, and LTG on samples collected in the Psychiatric Unit was lower compared to the Neurology and Child Neuropsychiatry Units. Finally, the ASMs subjected to multiple dosing starting from an initial subtherapeutic C(p) increased their level at different time points within a year, reaching the reference range for some of them. In conclusion, the present study suggests that TDM is widely applied to monitor ASMs C(p), finding many of them within the reference range, as a demonstration of its utility in clinical practice.

Epilepsy in a mouse model of GNB1 encephalopathy arises from altered potassium (GIRK) channel signaling and is alleviated by a GIRK inhibitor.

De novo mutations in GNB1, encoding the Gβ1 subunit of G proteins, cause a neurodevelopmental disorder with global developmental delay and epilepsy, GNB1 encephalopathy. Here, we show that mice carrying a pathogenic mutation, K78R, recapitulate aspects of the disorder, including developmental delay and generalized seizures. Cultured mutant cortical neurons also display aberrant bursting activity on multi-electrode arrays. Strikingly, the antiepileptic drug ethosuximide (ETX) restores normal neuronal network behavior in vitro and suppresses spike-and-wave discharges (SWD) in vivo. ETX is a known blocker of T-type voltage-gated Ca2+ channels and G protein-coupled potassium (GIRK) channels. Accordingly, we present evidence that K78R results in a gain-of-function (GoF) effect by increasing the activation of GIRK channels in cultured neurons and a heterologous model (Xenopus oocytes)-an effect we show can be potently inhibited by ETX. This work implicates a GoF mechanism for GIRK channels in epilepsy, identifies a new mechanism of action for ETX in preventing seizures, and establishes this mouse model as a pre-clinical tool for translational research with predicative value for GNB1 encephalopathy.

カルバマゼピン投与によるミオクロニー発作増悪時にDoose症候群と診断しエトスクシミドが著効した3歳男児

A 3-year-old boy with a history of four febrile convulsions since the age of 1 year was admitted to the hospital after experiencing a cluster of tonic seizures. Treatment was started with valproic acid (VPA), which proved to be ineffective, so carbamazepine (CBZ) was administered instead. This was judged to be effective because the tonic seizures disappeared temporarily. The patient was discharged, but he then had a similar cluster of tonic seizures and was consequently readmitted. Zonisamide (ZNS) was administered, which resolved the tonic seizures. CBZ was discontinued because we thought it would exacerbate the myoclonic seizures he was experiencing. The myoclonic seizures disappeared, and the addition of ethosuximide (ESM) completely resolved his tonic seizures. In this patient, the onset of tonic seizures was characterized by clusters, but because myoclonic seizures were not prominent initially, we were unable to diagnose Doose syndrome early. However, ESM proved remarkably effective, and the patient has remained seizure free.

Ethosuximide is an allosteric blocker of girk channels with Gβγ and is subunit dependent.

Ethosuximide (ETX) is a common drug in the treatment of absence epilepsy. ETX is known to act via inhibition of T-type voltage gated Ca2+ channels. Later, it was shown that ETX blocks GIRK channels as well. Recently, ETX was shown to reduce absence-like epileptiform activity in mice carrying disease-causing mutations in GNB1 gene, which encodes for Gβ1 subunit. Gβγ subunits are the main gating factor of GIRK channels. Here, we study the mechanism by which ETX blocks GIRK channels. We confirmed that CaV3.2, as well as CaV1.2 channels are weakly blocked by ETX at therapeutic doses (0.25-0.75 mM), as was shown previously. Homotetrameric GIRK2 channels co-expressed with Gβγ subunits were almost completely inhibited at therapeutic doses of ETX, while heterotetrameric GIRK1/2 channels were mildly inhibited, and GIRK1/3 were non-sensitive. We found that the open channel mutant GIRK2N94H or ivermectin activated GIRK2WT channel were not sensitive to ETX, suggesting that it is not an open channel blocker. The affinity of ETX to GIRK2 homotetramers was increased with increasing doses of Gβγ, suggesting an allosteric inhibition. Exchange of the GIRK2 transmembrane domain (TM) with GIRK3's (GIRK2G3TM) turned the channel non-sensitive to ETX block, the opposite exchange made GIRK3G2TM more sensitive to ETX block. This data suggests that ETX blocks GIRK channels in subunit-dependent manner, it is an allosteric- rather than open channel blocker, and its binding site may be located within the TM or extracellular domain of the channel.

Electrical Status Epilepticus during Sleep: Risk Factors, Clinical Course, and Treatment Approaches

Abstract Background The efforts of clinicians are focused on determining the predictors for electrical status epilepticus in sleep (ESES) manifestation, due to the negative effect of ESES on cognition. Treatment approaches remain a leading problem because of therapeutic resistance. Objective We looked for potential risk factors for ESES manifestation and summarize the clinical course and therapeutic approaches in patients with idiopathic and symptomatic ESES. Patients and Methods We retrospectively reviewed the medical data of 51 children with idiopathic ESES and 20 children with symptomatic ESES. Results We observed an earlier age of seizure onset (p = 0.0002) and a higher percentage of cases with multiple seizures (p < 0.00001) and with postictal paralysis (p < 0.00001) in idiopathic ESES compared with childhood epilepsy with centrotemporal spikes. In the idiopathic ESES, the treatment consisted of corticosteroids in patients with permanent ESES remission and transient remission, levetiracetam (LEV) children with permanent ESES remission and transient, clonazepam (CZP) children with permanent ESES remission and transient, ethosuximide (ESM), and sulthiame. The patients with symptomatic ESES had more unfavorable evolution, as 19 children had persistent or relapsing ESES course. Conclusion We consider the earlier age of seizure onset (below 5 years) and the presence of multiple seizures and postictal paresis as risk factors for ESES manifestation. ESES is characterized by a significant therapeutic resistance, especially in the group of symptomatic cases. Good results are observed with LEV, ESM, CZP, and steroids.

Two cases of childhood absence epilepsy who showed seizure disappearance after ethosuximide drug eruption

BackgroundRecent studies suggest potential roles of immune response in the pathophysiology of epilepsy. Anti-seizure medications (ASMs) are known to have side effects of drug eruption caused by immune responses. A few reports in adults have demonstrated disappearance of seizures after an ASM drug eruption episode. In this paper, we described 2 cases of childhood absence epilepsy (CAE) who showed seizure disappearance after ethosuximide (ESM) drug eruption, suggesting the possibility that the epilepsy disappears due to immune responses to ASM.Case presentationCase 1 was an 8-year-old girl diagnosed with CAE. She was treated with valproate acid (VPA) initially, and then ESM was administered as an additional treatment. Her epileptic seizure disappeared 4 days after initiation of ESM. However, drug eruption appeared 1 week after the administration of ESM. Even after discontinuation of ESM administration, she maintains no seizure after the drug eruption. Case 2 was a 5-year-old boy diagnosed as CAE. He was treated with VPA initially, and ESM was administered additionally. Drug eruption appeared 1 month after the administration of ESM. Even after ESM was terminated, he maintained seizure freedom after the appearance of eruption.ConclusionsEpileptic seizures may have been suppressed due to the immune responses caused by ASM eruption. Further studies are needed to elucidate the pathophysiologic effects of drug eruption on epilepsy through immune responses.

A deep learning-based prediction model of college students' psychological problem categories for post-epidemic era-Taking college students in Jiangsu Province, China as an example.

For a long time, it takes a lot of time and energy for psychological workers to classify the psychological problems of college students. In order to quickly and efficiently understand the common psychological problems of college students in the region for real-time analysis in the post-epidemic era, 2,000 college students’ psychological problems were selected as research data in the community question section of the “Su Xin” application, a psychological self-help and mutual aid platform for college students in Jiangsu Province. First, word segmentation, removal of stop words, establishment of word vectors, etc. were used for the preprocessing of research data. Secondly, it was divided into 9 common psychological problems by LDA clustering analysis, which also combined with previous researches. Thirdly, the text information was processed into word vectors and transferred to the Attention-Based Bidirectional Long Short-Term Memory Networks (AB-LSTM). The experimental results showed that the proposed model has a higher test accuracy of 78% compared with other models.

Intrathecal application of ethosuximide is highly efficient in suppressing seizures in a genetic model of absence epilepsy

Systemic drug application is the main approach in epilepsy treatment. However, the central nervous system (CNS) is a challenging target for drug delivery as the blood-brain barrier (BBB) restricts the transfer of drugs into the brain. Accordingly, there is a general interest in developing new therapeutic strategies to improve CNS drug accessibility. Intrathecal administration of antiseizure drugs (ASDs) e.g. via pumps or advanced materials could be a possible approach to bypass the BBB and increase the availability of neuroactive compounds in the CNS. The aim of this study was the evaluation of intracerebroventricular (i.c.v.) compared to systemic drug application in generalized epilepsy. The i.c.v. administration of the established ASD ethosuximide (ETX) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) caused a robust and dose-dependent reduction of spike-wave discharges (SWDs) without causing obvious behavioral abnormalities. Additionally, we could show that i.c.v. treatment with ETX is significantly more effective in seizure suppression than systemic treatment with the same dose. The localized application resulted in reduced systemic drug exposure compared to standard systemic ETX therapy. The tracing of dye distribution throughout the CNS supported the view that i.c.v. applied drugs cross into brain tissue surrounding the ventricles but largely remain restricted to the site of injection. Our data suggest that intrathecal application represents a possible route for the treatment in generalized epilepsy through direct drug penetration from CSF into brain tissue.

Clemizole and trazodone are effective antiseizure treatments in a zebrafish model of STXBP1 disorder.

CRISPR‐Cas9–generated zebrafish carrying a 12 base‐pair deletion in stxbpb1b, a paralog sharing 79% amino acid sequence identity with human, exhibit spontaneous electrographic seizures during larval stages of development. Zebrafish stxbp1b mutants provide an efficient preclinical platform to test antiseizure therapeutics. The present study was designed to test antiseizure medications approved for clinical use and two recently identified repurposed drugs with antiseizure activity. Larval homozygous stxbp1b zebrafish (4 days postfertilization (dpf)) were agarose‐embedded and monitored for electrographic seizure activity using a local field recording electrode placed in midbrain. Frequency of ictal‐like events was evaluated at baseline and following 45 min of continuous drug exposure (1 mM, bath application). Analysis was performed on coded files by an experimenter blinded to drug treatment and genotype. Phenytoin (PHT), valproate (VPA), ethosuximide (ESX), levetiracetam (LEV), and diazepam (DZP) had no effect on the ictal‐like event frequency in stxbp1b mutant zebrafish. Clemizole and trazodone decreased ictal‐like event frequency in stxbp1b mutant zebrafish by 80% and 83%, respectively. These results suggest that repurposed drugs with serotonin receptor–binding affinities could be effective antiseizure treatments. Clemizole and trazodone were previously identified in a larval zebrafish model for Dravet syndrome. Based primarily on these preclinical zebrafish studies, compassionate‐use and double‐blind clinical trials with both drugs have progressed. The present study extends this approach to a preclinical zebrafish model representing STXBP1 (syntaxin‐binding protein 1)‐related disorders and suggests that future clinical studies may be warranted.

The effect of chronic treatment with sodium channel blocker lacosamide on early development of absence seizures in genetic absence epilepsy rats

ObjectiveLacosamide (LCM) is a new generation antiepileptic drug that affects the slow inactivation of voltage-gated sodium channels. We studied whether chronic LCM treatment prior to onset of absence seizures was able to prevent/reduce the development of absence seizures in GAERS rats, a well-validated animal model of absence epilepsy and epileptogenesis. Drug effects on the duration, mean duration, number and spectral characteristics of spike-wave discharges (SWDs) were measured both 1 and 2 months after treatment withdrawal and compared with the ethosuximide (ETX) that has anti-epileptogenic activity in GAERS. Furthermore, the acute effects of LCM on SWDs in adult GAERS were evaluated. MethodsGAERS rats were administered either with LCM (10 mg/kg/day or 30 mg/kg/day, i.p) or ETX (25 mg/kg/day, i.p) or saline (%0.9 NaCl) until PN60 for 40 consecutive days starting from PN20. Animals were stereotaxically implanted with cortical screw electrodes under ketamine/xylazine anesthesia at PN53. Following recovery period, EEG were recorded at PN60 (last day of drug administration)− 61–62, PN90–91–92 and PN120–121–122 time periods for 3 consecutive days. ResultsThe chronic treatment with both LCM and ETX led to an ∼50% reduction in the development of spontaneous absence seizures in GAERS at PN90 and PN120 after the treatment withdrawal at PN60. The spectral analysis of EEG data revealed significant slowing of the peak frequency of SWDs in LCM treated animals at PN62. ConclusionThese results confirm that chronic LCM treatment modifies the development of absence seizures in GAERS and suggest that LCM exerts beneficial effects on absence seizure epileptogenesis.

Absence seizures in children and teenagers: ethosuximide, valproate or lamotrigine? A systematic review from 1999 to 2021 / Apreensões de ausência em crianças e adolescentes: etosuximida, valproato ou lamotrigina? Uma revisão sistemática de 1999 a 2021

The onset of AS generally occurs during childhood or adolescence, and it is the most prevalent convulsion in 15 to 20% of epileptic children. Historically, first-line drugs in pediatric AS are Ethosuximide (ETX), Valproic Acid (VPA), and Lamotrigine (LTG). This review aims to determine the best pharmacological therapy for pediatric AS, considering that all three drugs have been established as superior to placebo.

Childhood absence epilepsy: Electro-clinical manifestations, treatment options, and outcome in a tertiary educational center.

Purpose and BackgroundTo evaluate the electro-clinical manifestations and outcomes of children with absence epilepsy at a tertiary center in Saudi Arabia.MethodsThis retrospective study reviewed the medical and EEG records of patients who were diagnosed to have CAE as per the International League Against Epilepsy (ILAE) definition for CAE. The study was conducted in the pediatric neurology clinic of King Khalid University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia, between January 2000 and December 2019. Patients who did not meet (ILAE) criteria, lost follow-up, and those who did not receive treatment at KKUH were excluded. Data regarding the patient's disease, electro-clinical manifestations, anti-seizure medication response, and outcomes were collected.ResultsA total of 35 patients, with an average age at diagnosis of 7 ± 2.1 y, were included in the study; among them, 51.4% were female and approximately 48.6% presented with a family history of epilepsy. Regarding clinical features, all patients experienced staring and altered awareness, 94.2% had less than 20 spells per day at the time of diagnosis, and 65.7% were provoked by the hyperventilation test. Regarding EEG findings, all patients had bilateral, symmetrical, and synchronous discharges in the form of regular 3 Hz spike-and-wave complexes, and 94.3% had a generalized initial ictal discharge. Also, 22.8% had eye fluttering with electrographic seizures. Ethosuximide (ESM) was used as the drug of choice in 45.7% of the patients. Regarding clinical outcomes, 94.3% had their disease clinically controlled, and 80% had a normalized EEG after few months of starting anti-seizure medication. Finally, 37.2% experienced complete remission of epilepsy after 3–5 y; however, one patient developed juvenile myoclonic epilepsy.ConclusionThis study described the electro-clinical manifestations of patients with childhood absence epilepsy and outcomes. Furthermore, early diagnosis and prompt treatment of childhood absence epilepsy improve treatment outcomes.

First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat.

A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

Contribution of rare genetic variants to drug response in absence epilepsy

ObjectiveWe investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. MethodsWe recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. ResultsSixty-two patients were included; 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43; 0.43–27.65; p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82; 1.68−8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups; these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. SignificanceWe conclude that if CACNA1H rare variants predict lack of response to ETX, a larger sample is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.

William L.Nyhan, Georg F.Hoffmann. Atlas of inherited metabolic diseases (Hardcover and e‐Book)4th ed. Boca Raton: CRC Press, Taylor & Francis Group, 2020, 855 p., $175; £120, €124. ISBN‐13: 9781138196599. (With contributions from Aida I. Al‐Aqeel and Bruce A. Barshop).

William L.Nyhan, Georg F.Hoffmann. Atlas of inherited metabolic diseases (Hardcover and e‐Book)4th ed. Boca Raton: <scp>CRC</scp> Press, Taylor &amp; Francis Group, 2020, 855 p., $175; £120, €124. <scp>ISBN</scp>‐13: 9781138196599. (With contributions from Aida I. Al‐Aqeel and Bruce A. Barshop).

Equilibrative Nucleoside Transporters-1 Inhibitors Act as Anti-epileptic Agents by Inhibiting Glutamatergic Transmission.

Background and Purpose: Adenosine dysregulation is associated with the occurrence of the epilepsy and equilibrative nucleoside transporters-1 (ENT-1) functions as an important regulator of extracellular adenosine in the brain. This study was aimed to prove the anti-epileptic effect of BBB permeable ENT-1 inhibitors, JMF1907 and J4, on animal models of various epilepsy, and the mechanisms that are involved.Experimental Approach: Maximal electroshock seizure (MES), pentylenetetrazol (PTZ)-induced seizure and kindling models were used as mouse models of generalized tonic-clonic epilepsy, generalized myoclonic epilepsy, and partial epilepsy, respectively. The epilepsy frequency, duration, and Racine score were evaluated. Whole-cell recordings were made from the hippocampal dentate granule cells by using a patch-clamp technique in the brain slice of the mice.Key Results: In MES, JMF1907 at a dose of 5 mg kg–1 was efficacious in decreasing hindlimb extension, while J4 did not decrease hindlimb extension until a higher dose (10 mg kg–1). Both JMF1907 and J4 were more potent in lengthening onset latency than ethosuximide (ETH) in PTZ-induced myoclonic epilepsy model, whereas ETH had better effects on the Racine score. In kindling model, JMF1907 and J4 at a dose of 1 mg kg–1 had effects on seizure frequency and duration, and the effects of JMF1907 were comparable with those of carbamazepine. Both JMF1907 and J4 can reduce the glutamatergic spontaneous excitatory post-synaptic currents (sEPSCs) frequency. The maximal inhibition was about 50% for JMF1907 at a concentration of 1 μg L–1, whereas J4 only inhibited 40% of sEPSCs frequency at a dose of 10 μg L–1.Conclusion and Implications: ENT-1 inhibitors, JMF1907 and J4, showed anti-epileptic effects in different epilepsy models and the effects involved pre-synaptic neuronal modulation.

Cardiovascular changes in genetic absence epileptic WAG/Rij rats: Effects of chronic ethosuximide treatment

Purpose: The aim of this study was to investigate the effects of chronic ethosuximide (ETX) treatment on absence seizures and cardiovascular parameters in WAG/Rij rats with genetic absence epilepsy.Materials and Methods: Eight-weeks old, male Wistar and WAG/Rij rats were divided into four groups (n=20): Wistar control, Wistar ETX, WAG/Rij control and WAG/Rij ETX. ETX groups received chronic ETX treatment (oral, 300 mg/kg/day) for 3 months. At the end of the 3-month-treatment period; the total and mean duration, also number of spike wave discharges (SWDs) were evaluated using EEG recordings. Mean arterial blood pressure (MAP) and heart rate (HR) measurements were performed. Results: ETX treatment significantly decreased the duration and frequency of SWDs in WAG/Rij rats. MAP in WAG/Rij control group was markedly higher than Wistar control group. In Wistar ETX group, HR was significantly slower than Wistar control group. KCl-induced contraction response enhanced in Wistar ETX group and diminished in WAG/Rij control group compared to Wistar control group. Conclusion: Increased MAP and vascular reactivity in WAG/Rij rats. ETX treatment did not alter cardiovascular parameters in WAG/Rij rats whereas the treatment decreased the HR and vascular reactivity without affecting MAP in Wistar rats. T-type Ca++ channels may play a role in these changes.