Improved Seizure Control Research Articles

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. To evaluate the clinical features of epileptic seizures in WHS and the therapeutic efficacy of oral antiseizure medications (ASMs) Methods: 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 to the pre-medication 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 ten 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.

Perspective: Vagal nerve stimulation in the treatment of new-onset refractory status epilepticus.

Resistance to drug therapy is a major hurdle in new-onset refractory status epilepticus (NORSE) treatment and there is urgent need to develop new treatment approaches. Non-drug approaches such as neuromodulation offer significant benefits and should be investigated as new adjunct treatment modalities. An important unanswered question is whether desynchronizing networks by vagal nerve stimulation (VNS) may improve seizure control in NORSE patients. We present a summary of published NORSE cases treated with VNS and our own data, discuss possible mechanisms of action, review VNS implantation timing, stimulation setting titration protocols and outcomes. Further, we propose avenues for future research. We advocate for consideration of VNS for NORSE both in early and late stages of the presentation and hypothesize a possible additional benefit from implantation in the acute phase of the disease. This should be pursued in the context of a clinical trial, harmonizing inclusion criteria, accuracy of documentation and treatment protocols. A study planned within our UK-wide NORSE-UK network will answer the question if VNS may confer benefits in aborting unremitting status epilepticus, modulate ictogenesis and reduce long-term chronic seizure burden.

Survival, Functional, and Seizure Control Outcomes After Resection of Perirolandic World Health Organization Grade II and III Gliomas: A Single-Center Retrospective Review.

We aimed to assess, in patients with perirolandic gliomas and gliomas originating from other regions, survival, functional outcomes, and seizure control and, in addition, to identify any clinical characteristics predictive of progression-free survival, overall survival, and seizure control. We retrospectively analyzed 87 patients who underwent resection of World Health Organization grade II or III gliomas at a single institution between 2009 and 2021. Tumors were classified by topographic involvement. One-year postoperative functional status was quantified with Karnofsky Performance Status. One-year seizure control was defined by Engel seizure classification. Dichotomous and categorical variables were reported as counts and percentages and compared using Fisher exact test. A Cox regression model was used to identify covariates that affect progression-free survival and overall survival. Patients with perirolandic gliomas had similar survival and functional outcomes to patients with gliomas from other regions and a low rate of lasting neurologic deficits. Patients with perirolandic gliomas had comparatively worse long-term seizure outcomes (approached statistical significance). Perirolandic involvement (hazard ratio [HR], 0.10; 95% confidence interval [CI], 0.02-0.46; P= 0.005) and preoperative seizures (HR, 0.14; 95% CI, 0.02-0.62; P= 0.017) conferred a lower likelihood of durable seizure control, whereas increased extent of resection (HR, 1.07; 95% CI, 1.03-1.12; P= 0.003) enhanced the likelihood of seizure freedom. Despite proximity to or presence in eloquent structures, perirolandic gliomas can largely be resected without incurring worse functional outcomes. Patients with perirolandic gliomas should be considered for maximal safe resection to optimize survival outcomes and improve seizure control.

Surgical Treatment for Epilepsy: An Updated Summary of Treatment Modalities and Clinical Evidence

The efficacy of surgical treatment for drug-resistant epilepsy has been proven based on accumulated evidence, such as several randomized controlled trials. There are emerging treatment modalities, including less invasive surgical techniques and neuromodulation devices, which have also been proven to benefit patients by improving seizure control. A recent methodological shift from subdural electrocorticography recordings to stereo-encephalography recordings for intracranialelectroencephalography (iEEG) monitoring has also positively impacted clinical decision-making. Although some of these newer modalities are yet to be implemented in Japan, this article provides updated evidence and a summary of the currently available options for surgical treatment of patients with drug-resistant epilepsy. We hope that this summary will widen the treatment opportunities for patients with this highly impactful disease.

Adjunctive cenobamate in highly active and ultra-refractory focal epilepsy: A "real-world" retrospective study.

Recent clinical trials have shown that cenobamate substantially improves seizure control in focal-onset drug-resistant epilepsy (DRE). However, little is known about cenobamate's performance in highly active (≥20 seizures/month) and ultra-refractory focal epilepsy (≥6 failed epilepsy treatments, including antiseizure medications [ASMs], epilepsy surgery, and vagus nerve stimulation). Here, we studied cenobamate's efficacy and tolerability in a "real-world" severe DRE cohort. We conducted a single-center retrospective analysis of consecutive adults treated with cenobamate between October 2020 and September 2022. All patients received cenobamate through an Early Access Program. Cenobamate retention, seizure outcomes, treatment-emergent adverse events, and adjustments to concomitant ASMs were analyzed. Fifty-seven patients received cenobamate for at least 3 months (median duration, 11 months). The median cenobamate dose was 250 mg/day (range 75-350 mg). Baseline demographics were consistent with highly active (median seizure frequency, 60/month) and ultra-refractory epilepsy (median previously failed ASMs, nine). Most (87.8%) had prior epilepsy surgery and/or vagus nerve stimulation. Six patients stopped cenobamate due to lack of efficacy and/or adverse events. One patient died from factors unrelated to cenobamate. Among patients who continued cenobamate, three achieved seizure freedom (5.3% of cohort), 24 had a 75%-99% reduction in seizures (42.1% of cohort), and 16 had a 50%-74% reduction (28.1% of cohort). Cenobamate led to abolition of focal to bilateral tonic-clonic seizures in 55.6% (20/36) of patients. Among treatment responders, 67.4% (29/43) were treated with cenobamate doses of ≥250 mg/day. Three-fourths of patients reported at least one side-effect, most commonly fatigue and somnolence. Adverse events most commonly emerged at cenobamate doses of ≥250 mg/day. Side-effects were partially manageable by reducing the overall ASM burden, most often clobazam, eslicarbazepine, and perampanel. Patients with highly active and ultra-refractory focal epilepsy experienced meaningful seizure outcomes on cenobamate. Emergence of adverse events at doses above 250 mg/day may limit the potential for further improvements in seizure control at higher cenobamate doses.

Mortality, and life expectancy in Epilepsy and Status epilepticus-current trends and future aspects.

Patients with epilepsy carry a risk of premature death which is on average two to three times higher than in the general population. The risk of death is not homogenously distributed over all ages, etiologies, and epilepsy syndromes. People with drug resistant seizures carry the highest risk of death compared to those who are seizure free, whose risk is similar as in the general population. Most of the increased risk is directly related to the cause of epilepsy itself. Sudden unexplained death in epilepsy patients (SUDEP) is the most important cause of epilepsy-related deaths especially in the young and middle-aged groups. Population based studies with long-term follow up demonstrated that the first years after diagnosis carry the highest risk of death, while in the later years the mortality decreases. Improved seizure control and being exposed to a specialized comprehensive care centre may help to reduce the risk of death in patients with epilepsy. The mortality of status epilepticus is substantially increased with case fatality rates between 4.6% and 39%, depending on its cause and duration, and the age of the population studied. The epidemiological data on overall and cause specific mortality as well as their determinants and risk factors are critically reviewed and methodological issues pertinent to the studies on mortality of epilepsy and Status epilepticus are discussed.

In silico studies, X-ray diffraction analysis and biological investigation of fluorinated pyrrolylated-chalcones in zebrafish epilepsy models

Epilepsy is the third most common known brain disease worldwide. Several antiepileptic drugs (AEDs) are available to improve seizure control. However, the associated side effects limit their practical use and highlight the ongoing search for safer and effective AEDs. Eighteen newly designed fluorine-containing pyrrolylated chalcones were extensively studied in silico, synthesized, structurally analyzed by X-ray diffraction (XRD), and biologically and toxicologically tested as potential new AEDs in zebrafish epilepsy in vivo models. The results predicted that 3-(3,5-difluorophenyl)-1-(1H-pyrrol-2-yl)prop-2-en-1-one (compound 8) had a good drug-like profile with binding affinity to γ-aminobutyric acid receptor type-A (GABAA, −8.0 kcal/mol). This predicted active compound 8 was effective in reducing convulsive behaviour in pentylenetetrazol (PTZ)-induced larvae and hyperactive movements in zc4h2 knockout (KO) zebrafish, experimentally. Moreover, no cardiotoxic effect of compound 8 was observed in zebrafish. Overall, pyrrolylated chalcones could serve as alternative AEDs and warrant further in-depth pharmacological studies to uncover their mechanism of action.

Magnitude of uncontrolled seizures and associated factors among people with epilepsy. Data from a major teaching hospital in Southwest Ethiopia

BackgroundEpilepsy is a major public health problem affecting 70 million people worldwide. 90% of global people with epilepsy were living in developing regions like Ethiopia. Due to the lack of clear guidelines for treatment selection and the difficulty of individualizing care in resource-poor settings, achieving seizure control can be challenging. Seizure control status among epileptic patients is affected by different factors. Accordingly, this study aimed to assess the magnitude of uncontrolled seizures and associated factors among people with epilepsy attending the outpatient clinic of Jimma Medical Center, Southwest Ethiopia. MethodsA hospital-based retrospective chart review and a respective patient interview conducted among people with epilepsy from October 2020 to June 2021. Sociodemographic, behavioral-related factors, medication adherence, and medication belief were obtained through patient interviews. Seizure control status in the last two years before the study period was retrospectively evaluated and recorded from the charts. Data were entered into Epi Data manager version 4.6 and then exported to SPSS version 23.0 for analysis. A backward logistic regression analysis was done to identify factors associated with uncontrolled seizures. ResultsFrom a total of 314 medical charts reviewed, 149(47.5 %) of patients were with uncontrolled seizures. 28.7 %,12.8 %, and 6 % of the patients experienced 1–5,6–10, and >10 seizure episodes during the last two years respectively. Comorbidity [adjusted odds ratio [(AOR): 2.13, 95 % confidence interval (CI):1.26–3.58], nonadherence [AOR: 2.41, 95 %CI: 1.46–3.9], possible adverse drug reaction (ADR) [AOR:1.79, 95 %CI: 1.107–3.01], and drug interaction [AOR: 3.06, 95 %CI: 1.24–7.57] were associated with an uncontrolled seizure. Conclusion and recommendationOur study showed that a substantial proportion of the patients were with uncontrolled seizures. Epileptic patients with comorbidities, nonadherence, adverse drug reactions, and drug interactions were more prone to have uncontrolled seizures. Hence, to overcome these problems, strategies like community-based education, treatment intensification, and routine assessment of adverse drug reactions and drug interaction may help to improve seizure control status.

Minimally Invasive Destructive, Ablative, and Disconnective Epilepsy Surgery

AbstractConventional epilepsy surgery performed by microsurgical dissection typically requires large cranial working windows created with high-speed drills and lengthy incisions. In the past few decades, minimally invasive techniques have been developed with smaller incisions, comparable efficacy, shorter hospitalizations, and better safety profiles. These minimally invasive alternatives utilize stereotactic, ultrasonic, radiotherapeutic, and endoscopic techniques. Although not able to completely replace conventional surgery for all etiologies of epilepsy, these minimally invasive techniques have revolutionized modern epilepsy surgery and have been an invaluable asset to the neurosurgeon's repertoire. The endoscope has allowed for surgeons to have adequate visualization during resective and disconnective epilepsy surgeries using keyhole or miniature craniotomies. Modern stereotactic techniques such as laser interstitial thermal therapy and radiofrequency ablation can be used as viable alternatives for mesial temporal lobe epilepsy and can destroy lesional tissue deep areas without the approach-related morbidity of microsurgery such as with hypothalamic hamartomas. These stereotactic techniques do not preclude future surgery in the settings of treatment failure and have been used successfully after failed conventional surgery. Multiple ablation corridors can be performed in a single procedure that can be used for lesioning of large targets or to simplify treating multifocal epilepsies. These stereotactic techniques have even been used successfully to perform disconnective procedures such as hemispherotomies and corpus callosotomies. In patients unable to tolerate surgery, stereotactic radiosurgery is a minimally invasive option that can result in improved seizure control with minimal procedural risks. Advances in minimally invasive neurosurgery provide viable treatment options for drug-resistant epilepsy with quicker recovery, less injury to functional brain, and for patients that may otherwise not choose conventional surgery.

Investigating the role of mobile health in epilepsy management: A systematic review.

Epilepsy is the most common chronic neurologic disease which is characterized by recurrent attacks of headache after seizure. Researches show that self-management is an important factor in improving the quality of life and quality of care of people affected by epilepsy. Mobile phone technologies play a potential role in patient care assistance and treatment of epilepsy. This systematic review was conducted with an aim to study the role of mobile health in the management of epilepsy. This study was conducted by searching databases such as PubMed, Scopus, Web of Science, and Google scholar search engines using the following keywords: "m-health," "mobile health," "Telemedicine," "Mobile Application," "Smartphone," "epilepsy," and "epilepsy management." Articles published from January 1, 1990 to September 1, 2021 were searched. Inclusion criteria included all articles published in English with a focus on the role of mHealth in the management of epilepsy. Review articles and studies that were not about patients were omitted. In this study, of a total of 4225 retrieved articles, 10 studies met the full-text inclusion criteria. Three types of researches (30%) were done in the USA, five studies (50%) were conducted as randomized controlled trials, and eight articles (80%) had the highest quality. Among the considered articles, three articles (30%) were engaged in training users in epilepsy management. Five articles (50%) reported improvement in seizure control in patients with epilepsy and two articles (20%) did not report any significant improvement. Mobile technologies have a promising role in providing health assessment, education, and other services for patients, and they also help in controlling seizures attack and improvement of epilepsy management. These technologies enjoy great attractiveness, and utilizing them will lead to patient satisfaction.

Avoidance of Pitfalls and Complications During Surgery for Temporal Lobe Epilepsy.

Anterior temporal lobectomy with amygdalohippocampectomy is the most common epilepsy surgery, which, in cases of mesial temporal lobe epilepsy caused by mesial temporal sclerosis, usually leads to improvements in seizure control, cognitive function, and quality of life. Nevertheless, while the primary goal of intervention is achieved in a large majority of patients, a small number of them, unfortunately, encounter complications. Some morbidity is nonspecific and may be noted after any craniotomy (e.g., surgical site infections, meningitis, bone flap osteomyelitis, and operative site or craniotomy-related hematomas). On the other hand, certain complications are specifically associated with surgery for temporal lobe epilepsy and can be discussed from the etiological standpoint: mechanical injuries of the brain; injury of eloquent neuronal structures; arterial and venous injuries; cerebral venous thrombosis; remote cerebellar hemorrhage; and postoperative hydrocephalus, seizures, and psychiatric disorders. In many cases, these complications are manifested in the early postoperative period by alterations of consciousness and a focal neurological deficit, and it may require immediate decisions on their appropriate management.

Neonatal Cholestasis as a Side Effect of Ketogenic Diet

The ketogenic diet has emerged as a therapeutic intervention for refractory seizures in infants, but its efficacy and safety in neonates are not well established. We present the case of a small for gestational age newborn who was admitted to the neonatal department at 8 hours of age for hypoglycemia. On admission, he began to have seizures, and despite escalation of antiepileptic drug treatment, they still persisted. As a consecuence, the ketogenic diet was started at 14 days of age. While this treatment improved seizure control, the patient developed significant jaundice and cholestasis 15 days after starting the ketogenic diet. Despite treatment, cholestasis persisted, and the ketogenic diet was discontinued at 46 days of age. This case highlights the importance of vigilant monitoring for potential adverse effects of the ketogenic diet in neonates, underlines the infrequency of cholestasis as a significant complication, and emphasises the need for close monitoring of liver function in neonates undergoing ketogenic therapy.

538: KETAMINE OR TRADITIONAL CONTINUOUS ANESTHETICS IN REFRACTORY OR SUPER-REFRACTORY STATUS EPILEPTICUS

Introduction: Refractory (RSE) and super-refractory status epilepticus (SRSE) are challenging to manage due to the failure of traditional therapies to abort seizures. Agents that target the gamma-aminobutyric acid (GABA) receptor may be less effective in these scenarios secondary to receptor down regulation. However, antagonism of the upregulated N-methyl-D-aspartic acid [NMDA] receptor in RSE and SRSE with ketamine may result in improved seizure control. Few investigations of ketamine in RSE and SRSE exist, and no studies have compared the efficacy and safety of ketamine versus other traditional anesthetics (TA) for the resolution of status epilepticus (SE). Therefore, we aim to determine if the use of ketamine as compared to TA alone is associated with increased seizure resolution at 24 hours following last anesthetic initiation in patients with RSE and SRSE. Methods: We conducted a single-center, retrospective cohort study of patients admitted with RSE or SRSE from January 2012 through May 2022 and stratified by receipt of at least four hours of ketamine infusion or continuous TA such as midazolam, pentobarbital, or propofol. The primary outcome was seizure resolution within 24 hours of last anesthetic infusion initiation. Secondary outcomes included time to seizure resolution and SE relapse. Results: Of the 21 patients included, 5 received ketamine and 16 received TA. Baseline characteristics did not differ significantly between groups, including median age (59.1 vs 51.7 years), nonconvulsive SE (80.0% vs 56.3%), and history of epilepsy (60.0% vs 31.3%), in the ketamine and TA groups, respectively. Following last anesthetic initiation, ketamine was associated with a significant increase in seizure resolution within 24 hours (100% vs 44%; P=0.045) and reduced time to seizure resolution (median 2.1 [IQR 0.3-3.0] hours vs 27.9 [IQR 12.9-31.6] hours; P=0.001) compared to TA alone. There was no difference in SE relapse between groups (ketamine – 60.0% vs TA – 31.3%; P=0.325). Conclusions: The use of ketamine infusion in the setting of RSE and SRSE was associated with a significant increase in SE resolution at 24 hours of last anesthetic initiation compared to TA alone without an increase in relapse. Further evaluation of ketamine in the setting of RSE and SRSE is needed.

The Relationship Between Epilepsy, Obstructive Sleep Apnea, and Treatment Outcome.

Both epilepsy and obstructive sleep apnea are common conditions and hence frequently coexist in a given patient. A complex bidirectional relationship exists between the 2 conditions where the presence of one affects the other. Treatment of obstructive sleep apnea with continuous positive airway pressure may improve seizure control in medically refractory epilepsy patients, leading to improved quality of life. Understanding of this complex relationship between epilepsy, sleep, and sleep disorders such as obstructive sleep apnea continues to evolve.

Deep Brain Stimulation and Responsive Neurostimulation Implantation for Medically Refractory Epilepsy: A Case Report Study of a Single-Center's Experience

BACKGROUND AND IMPORTANCE: Nearly 25% of all epilepsy is drug-resistant epilepsy. Responsive neurostimulation (RNS) and deep brain stimulation (DBS) offer viable options when resection or ablation is not feasible. Neuromodulation leads to improved seizure control. However, in patients with highly complex epileptogenic networks, a multimodality approach using simultaneous RNS and DBS may provide a summative benefit. CLINICAL PRESENTATION: We present 2 cases of drug-resistant epilepsy who received simultaneous anterior nucleus of the thalamus DBS and RNS neuromodulation. To our knowledge, this is the first report of simultaneous DBS and RNS neurostimulation for the treatment of epilepsy. Given the complexity of their seizure networks, a combined neuromodulatory approach was deemed best to achieve seizure control. Both experienced multiple seizure semiology patterns consistent with multifocal onsets which were confirmed on phase I monitoring, nuclear medicine, and magnetoencephalography studies. Case 1 had a seizure reduction of 75% to 89% at 12 months which has remained stable at last follow-up (26 months) and case 2 achieved near seizure freedom and remained seizure-free at last follow-up (16 months). CONCLUSION: Neuromodulation has proven efficacious and safe in randomized controlled trials for the treatment of epilepsy. This is particularly important in multifocal epilepsy or if resective surgery is not an option. The optimal stimulation pathways and multimodal neuromodulation technique remains under investigation. We are the first to report that RNS and DBS implantation in the same patient is feasible, without major adverse effects and potentially effective.

SURG-18. VARIOUS APPLICATIONS OF INTRAOPERATIVE ELECTROCORTICOGRAPHY FOR EPILEPTOGENIC TISSUE MAPPING IN AWAKE GLIOMA SURGERY

Abstract New-onset epilepsy is a symptomatic expression of diffuse glioma and lowers the quality of life. Surgical resection could extend beyond the traditional lesionectomy and include the epileptic focus when permitted by neurological function. Intraoperative electrocorticography (ioECoG) is used during epilepsy surgery to estimate the epileptogenic tissue by mapping the irritative zone. We aimed to determine the added value of ioECoG for postoperative seizure control in patients with non-refractory, glioma-related seizures. We retrospectively included patients who underwent ioECoG-assisted (awake) tumor resection. The ioECoG tailoring strategy was based on electrographic seizures and interictal discharges (sporadic spikes, continuous spiking patterns, and sharp waves). The extent of resection (EOR) and the residual tumor volume (cm3) were quantified from pre- and postoperative magnetic resonance imaging. We used the Weibull regression model for multivariate time to event (seizure recurrence) analyses. Fifty patients underwent ioECoG-assisted surgery. IoECoG recorded eight (16%) spontaneous electrographic seizures. Seventeen patients had residual interictal discharges after tumor resection. Residual interictal discharges were significantly associated with shorter seizure-free period after surgery (HR = 3.1 [1.3 – 7.2], p-value = 0,01). This effect was especially prominent in primary high-grade glioma resections. Residual tumor volume and EOR did not associate with seizure outcome. We sampled 14 interictal spike-positive brain tissues (three inside and 11 outside the MRI abnormalities) for additional histopathological analyses. Tumor cells were found in all specimens. The overall sensitivity of interictal spikes for tumor infiltration was 78% (95%CI [56 – 93]) and the specificity was 100%. IoECoG could serve multiple purposes in brain tumor surgery. It can assist in intraoperative seizure detection. Complete resection of epileptic discharges may improve seizure outcome independently of rest tumor volume or EOR. IoECoG could help guide supramaximal resection to improve seizure control and assist patient counseling. Furthermore, interictal spikes might serve as markers for intraoperative tumor identification.

Implantation of Intracranial Electrodes Predicts Worse Outcome in Mesial Temporal Lobe Epilepsy

Anteromesial resection is an effective method for treating seizures arising from the medial temporal lobe, as these cases are often the most straightforward and have the best outcomes. Nevertheless, some patients who go on to have a mesial resection are recommended to have an implantation of electrodes before surgery. Whether the need for such an implant alters the rate of seizure freedom is not well-studied in this particular subgroup of epilepsy patients. We performed a retrospective review of consecutive anteromesial surgeries for medial temporal lobe epilepsy performed between 2005 and 2020. Of a total of 39 patients, 19 required electrode implantation (electrode group) and 20 did not (no-electrode group). The primary outcomes assessed were reduction in seizure frequency and Engel score. Complication rates were also compared. Postresection seizure frequency reduction was nonsignificantly higher in the no-electrode group (97.0±10.3%) than in the electrode group (88.5±23.7%, P= 0.15). The rate of Engel I outcome was nonsignificantly higher in the no-electrode group (84.2%) than in the electrode group (65.0%, P= 0.17). Major complication rates were nonsignificantly higher in the no-electrode group (15.8±1.9%) than in the electrode group (5.0±1.1%, P= 0.26). Power analysis revealed that 74 patients would need to be included in each group to reach statistical significance. Although not statistically significant, our study showed a trend for improved seizure control if a decision was made not to implant electrodes prior to potentially curative anteromesial resection. Engel I outcome in this group reached approximately 85%. A larger multi-instiutional study may be required to reach statistical significance.

Does long-term phenytoin have a place in Dravet syndrome?

Anti-seizure medications that block sodium channels are generally considered contraindicated in Dravet syndrome. There is, however, considerable debate about the sodium-channel blocker phenytoin, which is often used for status epilepticus, a frequent feature of Dravet syndrome. We describe four patients with Dravet syndrome in whom long-term phenytoin therapy reduced seizure frequency and duration. In two patients, phenytoin produced prolonged periods without status epilepticus for the first time. Attempting to wean phenytoin in all patients after 1 to 20 years of use resulted in seizure exacerbation. Reintroducing phenytoin improved seizure control, suggesting phenytoin is beneficial in some patients with Dravet syndrome.

Cognitive and behavioral effects of the anti-epileptic drug cenobamate (YKP3089) and underlying synaptic and cellular mechanisms

Antiseizure medication is the mainstay of treatment for seizures, and adjunctive therapy is widely used to achieve adequate seizure control in patients with epilepsy who fail to respond to the first monotherapy. The newly developed antiepileptic drug cenobamate (YKP3089) as an adjunctive therapy improved seizure control in patients with uncontrolled focal seizures. Cenobamate is thought to reduce neuronal excitability through action on multiple targets, including GABA A receptors (GABAARs) and voltage-gated sodium channels. However, its effects on brain function and synaptic plasticity are unclear. Here, we explored the behavioral, synaptic, and cellular actions of cenobamate. Cenobamate influenced novel object recognition, object location memory, and Morris water maze performance in mice. Cenobamate enhanced inhibitory postsynaptic potentials by prolonging inhibitory postsynaptic current (IPSC) decay without affecting presynaptic GABA release or the peak amplitude of IPSCs. In addition, cenobamate suppressed hippocampal excitatory synaptic transmission by reducing the excitability of Schaffer collaterals and interfered with the induction of long-term potentiation. A reduction in neuronal excitability induced by cenobamate was associated with an elevation of action potential (AP) threshold, and which progressively increased in later APs during repetitive firing, indicating the activity-dependent modulation of neuronal sodium currents. Cenobamate suppressed neuronal excitability under the condition that GABAergic neurotransmission is excitatory, and administration of cenobamate rapidly enhanced the phosphorylation of eukaryotic elongation factor 2 in the hippocampus of adult and neonatal mice. Collectively, these results suggest that the combined action of cenobamate on sodium currents and GABAAR-mediated synapse responses results in reduced excitability in neurons.

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil.

Consumption of medium-chain triglycerides (MCT) has been shown to improve seizure control, reduce behavioural comorbidities and improve cognitive function in epileptic dogs. However, the exact metabolic pathways affected by dietary MCT remain poorly understood. In this study, we aimed to identify changes in the metabolome and neurotransmitters levels relevant to epilepsy and behavioural comorbidities associated with the consuming of an MCT supplement (MCT-DS) in dogs with idiopathic epilepsy (IE). Metabolic alterations induced by a commercial MCT-DS in a population of 28 dogs with IE were evaluated in a 6-month multi-centre, prospective, randomised, double-blinded, controlled cross-over trial design. A metabolic energy requirement-based amount of 9% MCT or control oil was supplemented to the dogs' stable base diet for 3 months, followed by the alternative oil for another 3 months. A validated, quantitative nuclear magnetic resonance (NMR) spectroscopy platform was applied to pre- and postprandially collected serum samples to compare the metabolic profile between both DS and baseline. Furthermore, alterations in urinary neurotransmitter levels were explored. Five dogs (30%) had an overall reduction in seizure frequency of ≥50%, and were classified as MCT-responders, while 23 dogs showed a ≤50% reduction, and were defined as MCT non-responders. Amino-acid metabolism was significantly influenced by MCT consumption compared to the control oil. While the serum concentrations of total fatty acids appeared similar during both supplements, the relative concentrations of individual fatty acids differed. During MCT supplementation, the concentrations of polyunsaturated fatty acids and arachidonic acid were significantly higher than under the control oil. β-Hydroxybutyric acid levels were significantly higher under MCT supplementation. In total, four out of nine neurotransmitters were significantly altered: a significantly increased γ-aminobutyric acid (GABA) concentration was detected during the MCT-phase accompanied by a significant shift of the GABA-glutamate balance. MCT-Responders had significantly lowered urinary concentrations of histamine, glutamate, and serotonin under MCT consumption. In conclusion, these novel data highlight metabolic changes in lipid, amino-acid and ketone metabolism due to MCT supplementation. Understanding the metabolic response to MCT provides new avenues to develop better nutritional management with improved anti-seizure and neuroprotective effects for dogs with epilepsy, and other behavioural disorders.