Seizure Freedom Research Articles

Refractory Epilepsy in Adult Patient With COQ8A Variant Improves With CoQ10 Supplementation: A Case for Exome Sequencing in the ICU.

Describe a case of stroke-like episodes and refractory status epilepticus diagnosed with primary CoQ10 deficiency-4 (COQ10D4) using whole-exome sequencing in the intensive care unit (ICU), with treatment implications. A patient presented to the emergency department with 1 month of progressively worsening focal motor status epilepticus and stroke-like imaging abnormalities. Multiple seizure medications, ketogenic diet, and elective intubation for anesthetic drips failed to achieve sustained seizure freedom. Genetic testing was pursued for prognostic information and identified potential treatment. Whole-exome sequencing revealed compound heterozygous variants of COQ8A, including 1 allele not previously described as pathogenic. The patient's history, imaging, and genetic testing supported a diagnosis of COQ10D4. High-dose coenzyme Q10 supplementation was started with gradual clinical improvement. Whole-exome sequencing is a fast and cost-effective means to diagnose rare neurologic disease in critically ill patients and can uncover treatment options. While primarily used in the neonatal ICU, appropriately selected adult patients may also benefit.

MRI-quality and morphometric MRI analysis to identify focal cortical dysplasia: An exploratory study

BackgroundIn the pre-surgical evaluation of people with focal epilepsy and a normal MRI, Morphometric Analysis Program v2018 (MAP18) aids in detecting visually inconspicuous focal cortical dysplasia (FCD). We investigated the impact of MRI scans with reduced signal-to-noise ratio (SNR) and spatial resolution (SR) on FCD detection by MAP18, aiming to improve the chances of achieving seizure freedom through epilepsy surgery. MethodsThirty MRI scans with the identified lesion using MAP18 radiologically confirmed as FCD by a neuroradiologist, were retrospective analysed. SNR and SR were artificially reduced in ten steps, and their impact on MAP18 outcomes was assessed using multilevel analysis. ResultsThere was a significant effect after reducing SR and SNR for z-score and volume of the FCD cluster, the total number of detected clusters, and volume of these clusters. After SNR reduction, there was also a significant effect for z-score of the total number of detected clusters. FCD became undetectable by MAP18 after six steps of SR reduction (voxel size 2.8 × 2.8 × 2.8 mm³) and after two steps of SNR reduction. ConclusionsThis exploratory study suggests that reduced SR and SNR negatively affect FCD detection with MRI post-processing (MAP18). The MAP18 evaluator should screen MRI quality before post-processing, particularly for scans with significant visual noise or voxel sizes of 2.8 × 2.8 × 2.8 mm³ and upwards, as repeating a low-quality MRI scan is less burdensome than the adverse effects of continued seizures due to failure to detect FCD.

Brain Stiffness Correlates With Pathological Tissue in Patients With Drug-Resistant Epilepsy Due to Rasmussen Encephalitis and Focal Cortical Dysplasia.

Complete resection of epileptogenic zone is the single most important determinant of favorable seizure outcomes in resective surgery. However, identifying and resecting this zone is challenging in patients harboring diffuse; MRI-occult malformations of cortical development, such as focal cortical dysplasia; or acquired pathology, such as Rasmussen encephalitis. Intraoperative adjuncts that can aid in identifying the lesion and/or epileptogenic zone can optimize the extent of resection and seizure outcome. We sought to study a novel intraoperative tool, brain tonometer, to measure brain stiffness and correlate with histopathological and radiological findings. Brain stiffness was measured at various presumed normal and abnormal areas of the cortex during surgery in 2 patients with drug-resistant epilepsy. These results were correlated with preoperative and intraoperative neuroimaging and histopathology. We found brain stiffness correlated well with the degree of inflammation and cortical disorganization. Brain tonometry may help to intraoperatively identify inflammatory brain tissue along with structural and histopathological abnormalities. In select cases, this could potentially allow more tailored resections of the underlying lesion, to ensure complete removal of the epileptogenic lesion and improve the probability of achieving seizure freedom, while sparing normal brain leading to better functional outcomes.

MEG in MRI-Negative Patients with Focal Epilepsy.

To review the evidence on the clinical value of magnetic source imaging (MSI) in patients with refractory focal epilepsy without evidence for an epileptogenic lesion on magnetic resonance imaging ("MRI-negative" or "non-lesional MRI"). We conducted a systematic literature search on PUBMED, which was extended by researchrabbit.ai using predefined criteria to identify studies that applied MSI in MRI-negative patients with epilepsy. We extracted data on patient characteristics, MSI methods, localization results, surgical outcomes, and correlation with other modalities. We included 23 studies with a total of 512 non-lesional epilepsy patients who underwent MSI. Most studies used equivalent current dipole (ECD) models to estimate the sources of interictal epileptic discharges (IEDs). MEG detected IEDs in 32-100% of patients. MSI results were concordant with other modalities, such as EEG, PET, and SPECT, in 3892% of cases. If MSI concordant surgery was performed, 52-89% of patients achieved seizure freedom. MSI contributed to the decision-making process in 28-75% of cases and altered the surgical plan in 5-33% of cases. MSI is a valuable diagnostic tool for MRI-negative patients with epilepsy, as it can detect and localize IEDs with high accuracy and sensitivity, and provides useful information for surgical planning and predicts outcomes. MSI can also complement and refine the results of other modalities, such as EEG and PET, and optimize the use of invasive recordings. MSI should be considered as part of the presurgical evaluation, especially in patients with non-lesional refractory epilepsy.

Augmented Reality in Extratemporal Lobe Epilepsy Surgery.

Background: Epilepsy surgery for extratemporal lobe epilepsy (ETLE) is challenging, particularly when MRI findings are non-lesional and seizure patterns are complex. Invasive diagnostic techniques are crucial for accurately identifying the epileptogenic zone and its relationship with surrounding functional tissue. Microscope-based augmented reality (AR) support, combined with navigation, may enhance intraoperative orientation, particularly in cases involving subtle or indistinct lesions, thereby improving patient outcomes and safety (e.g., seizure freedom and preservation of neuronal integrity). Therefore, this study was conducted to prove the clinical advantages of microscope-based AR support in ETLE surgery. Methods: We retrospectively analyzed data from ten patients with pharmacoresistant ETLE who underwent invasive diagnostics with depth and/or subdural grid electrodes, followed by resective surgery. AR support was provided via the head-up displays of the operative microscope, with navigation based on automatic intraoperative computed tomography (iCT)-based registration. The surgical plan included the suspected epileptogenic lesion, electrode positions, and relevant surrounding functional structures, all of which were visualized intraoperatively. Results: Six patients reported complete seizure freedom following surgery (ILAE 1), one patient was seizure-free at the 2-year follow-up, and one patient experienced only auras (ILAE 2). Two patients developed transient neurological deficits that resolved shortly after surgery. Conclusions: Microscope-based AR support enhanced intraoperative orientation in all cases, contributing to improved patient outcomes and safety. It was highly valued by experienced surgeons and as a training tool for less experienced practitioners.

Hippocampal sclerosis in women with temporal lobe epilepsy: seizure and pregnancy outcomes

BackgroundTemporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is typically resistant to pharmacological interventions; however, achieving seizure freedom is possible through surgery. Our objective was to focus on the pregnancy and seizure outcomes during pregnancy of women with TLE-HS, and aim to identify predictors of seizure control.MethodsThe West China Registry of Pregnancy of Women with Epilepsy (WCPR_EPi) was a monocentric prospective cohort study of women with epilepsy (WWE). We screened women with TLE-HS in this database. Their clinical profile, anti-seizure medication (ASM) use, and pregnancy outcomes were extracted from the records of the registry (2010–2023).ResultsOut of 2320 WWE followed up, 47 pregnancies in women with TLE-HS were identified and analyzed. Seizure exacerbation occurred in 40.4% of pregnancies, and seizure freedom was present in 34.0% of these during pregnancy. Factors associated with seizure exacerbation during pregnancy was ASM non-adherence (odds ratio [OR] =7.00, 95% confidence interval [CI] 1.43–34.07, P=0.016). The surgery group showed a significantly higher seizure freedom rate (OR = 6.87, 95% CI 1.02–46.23, P=0.016) and lower rate of induced labor (0.0% vs 26.5%, P=0.047) compared to the medically-treated group alone. Caesarean section was chosen in 77.1% of cases due to seizure concerns, with comparable in epilepsy-related (n=20) and obstetric causes (n=24). No major congenital malformations were reported.ConclusionsSurgical treatment before pregnancy appears to offer a higher chance of seizure freedom compared to medication alone. Most of women with TLE-HS can deliver healthy offspring regardless of suboptimal seizure control and unwarranted concerns.

Electromagnetic Source Imaging in Presurgical Evaluation of Children with Drug-Resistant Epilepsy.

For children with drug-resistant epilepsy (DRE), seizure freedom relies on the delineation and resection (or ablation/disconnection) of the epileptogenic zone (EZ) while preserving the eloquent brain areas. The development of a reliable and noninvasive localization method that provides clinically useful information for the localization of the EZ is, therefore, crucial to achieving successful surgical outcomes. Electric and magnetic source imaging (ESI and MSI) have been increasingly utilized in the presurgical evaluation of these patients showing promising findings in the delineation of epileptogenic as well as eloquent brain areas. Moreover, the combination of ESI and MSI into a single solution, namely electromagnetic source imaging (EMSI), performed on simultaneous high-density electroencephalography (HD-EEG) and magnetoencephalography (MEG) recordings has shown higher source localization accuracy than either modality alone. Despite these encouraging findings, such techniques are performed in only a few tertiary epilepsy centers, are rarely recorded simultaneously, and are underutilized in pediatric cohorts. This study illustrates the experimental setup for recording simultaneous MEG and HD-EEG data as well as the methodological framework for analyzing these data aiming to localize the irritative zone, the seizure onset zone, and eloquent brain areas in children with DRE. More specifically, the experimental setups are presented for (i) recording and localizing interictal and ictal epileptiform activity during sleep and (ii) recording visual-, motor-, auditory-, and somatosensory-evoked responses and mapping relevant eloquent brain areas (i.e., visual, motor, auditory, and somatosensory) during visuomotor task, as well as auditory and somatosensory stimulations. Detailed steps of the data analysis pipeline are further presented for performing EMSI as well as individual ESI and MSI using equivalent current dipole (ECD) and dynamic statistical parametric mapping (dSPM).

Laser Ablation of Periventricular Nodular Heterotopia for Medically Refractory Epilepsy

ObjectivePeriventricular nodular heterotopia (PVNH) is the most common neuronal heterotopia, frequently resulting in pharmaco‐resistant epilepsy. Here, we characterize variables that predict good epilepsy outcomes following surgical intervention using stereo‐electroencephalography (SEEG) ‐informed magnetic resonance‐guided laser interstitial thermal therapy (MRgLITT).MethodsA retrospective review of consecutive cases from a single high‐volume epilepsy referral center identified patients who underwent SEEG evaluation for PVNH to characterize the intervention and outcomes.ResultsThirty‐nine patients underwent SEEG‐guided MRgLITT of the seizure onset zone (SoZ) in PVNH and associated epileptic tissue. PVNH and polymicrogyria (PMG) were densely sampled with a mean of 16.5 (SD = 2)/209.4 (SD = 36.9) SEEG probes/recording contacts per patient. Ablation principally targeted just the PVNH and cortex that was abnormal on imaging was ablated (5 patients) only if implicated in the SoZ. Volumetric analyses revealed a high percentage of PVNH SoZ ablation (96.6%, SD = 5.3%) in unilateral and bilateral (92.9%, SD = 7.2%) cases. Mean follow‐up duration was 31.4 months (SD = 20.9). Seizure freedom (ILAE 1) was excellent: unilateral PVNH without other imaging abnormalities, 80%; PVNH with mesial temporal sclerosis (MTS) or PMG, 63%; bilateral PVNH, 50%. SoZ ablation percentage significantly impacted surgical outcomes (p < 0.001).InterpretationPVNH plays a central role in seizure genesis as revealed by dense recordings and selective targeting by LITT. MRgLITT represents a transformative technological advance in PVNH‐associated epilepsy with seizure control outcomes consistent with those seen in focal lesional epilepsies. In localized unilateral cases and otherwise normal imaging, PVNH ablation without invasive recordings may be considered, and this approach deserves to be explored further. ANN NEUROL 2024

Clinical efficacy and safety of perampanel monotherapy as primary anti-seizure medication in the treatment of pediatric epilepsy: A single-center, prospective, observational study.

To assess the efficacy and safety of perampanel (PER) as primary monotherapy in patients aged 4-18 years old with epilepsy. A single-center, prospective, observational study was conducted from October 2021 to October 2023, to evaluate PER monotherapy's efficacy and safety as initial therapy for pediatric epilepsy. Changes in seizure frequency, safety, and retention rate were observed at 3, 6, 9, and 12 months after initiating PER primary monotherapy. A total of 124 children aged 4-15 years (mean age = 8.25 ± 2.50 years) were included in the Analysis Sets. The retention rates at 3, 6, 9, and 12 months were 88.71% (110/124), 84.68% (105/124), 78.26% (90/115), and 71.58% (68/95), respectively. Seizure freedom rates at 3, 6, 9, and 12 months were 85.45%, 79.09%, 76.24%, and 75.31%, respectively. The responder rates (≥50% but <100%) at the same endpoints were 9.09%, 14.55%, 12.87%, and 7.41%, respectively. Seizure freedom rate of PER was independent of age at PER initiation, seizure onset age, gender, baseline frequency, seizure types, and family history of epilepsy (p > 0.05) but associated with duration of treatment (p = 0.001) and maintenance dose (p = 0.022). Additionally, 124 patients were included in the safety analysis set. The overall adverse event rate was 38.71% (48/124), with irritability (19 cases, 15.32%) and dizziness (18 cases, 14.52%) being the most common adverse effects. One patient discontinued PER monotherapy within 1 month due to unbearable itching of the skin. PER monotherapy as the primary anti-seizure medication (ASM) for pediatric epilepsy demonstrates high efficacy and safety in real-world clinical treatment. Patients who respond well to this drug and adhere to long-term treatment can achieve favorable seizure control. Furthermore, patients achieving seizure freedom with a relatively lower dose can opt for the same dose as the maintenance dose. This study provided the efficacy and safety of PER monotherapy as the primary ASM for Chinese pediatric epilepsy. In total, 124 patients took part. The seizure freedom rates were over 70% at different observation points (OPs), along with a retention rate of 71.58% at the 12-month OP. Most of adverse effects observed were mild to moderate.

Machine learning algorithm for predicting seizure control after temporal lobe resection using peri-ictal electroencephalography

Brain resection is curative for a subset of patients with drug resistant epilepsy but up to half will fail to achieve sustained seizure freedom in the long term. There is a critical need for accurate prediction tools to identify patients likely to have recurrent postoperative seizures. Results from preclinical models and intracranial EEG in humans suggest that the window of time immediately before and after a seizure (“peri-ictal”) represents a unique brain state with implications for clinical outcome prediction. Using a dataset of 294 patients who underwent temporal lobe resection for seizures, we show that machine learning classifiers can make accurate predictions of postoperative seizure outcome using 5 min of peri-ictal scalp EEG data that is part of universal presurgical evaluation (AUC 0.98, out-of-group testing accuracy > 90%). This is the first approach to seizure outcome prediction that employs a routine non-invasive preoperative study (scalp EEG) with accuracy range likely to translate into a clinical tool. Decision curve analysis (DCA) shows that compared to the prevalent clinical-variable based nomogram, use of the EEG-augmented approach could decrease the rate of unsuccessful brain resections by 20%.

Selective Amygdalohippocampectomy versus Anterior Temporal Lobectomy in Mesial Temporal Lobe Epilepsy: A Meta-Analysis of Seizure Control and Cognitive Outcomes

Background: Mesial temporal lobe epilepsy (MTLE) is a common form of drug-resistant epilepsy often necessitating surgical intervention. The choice between selective amygdalohippocampectomy (SelAH) and anterior temporal lobectomy (ATL) remains a subject of debate, with each procedure offering potential advantages and disadvantages in terms of seizure control and cognitive outcomes. Methods: A comprehensive literature search was conducted across PubMed, Scopus, and Springer databases to identify studies published between 2013 and September 2024 that compared SELAH and ATL in patients with MTLE. The primary outcomes of interest were seizure freedom rates and changes in cognitive function, particularly IQ scores. A meta-analysis was performed using a random-effects model to pool the results of included studies. Results: The meta-analysis encompassed 5 studies involving 218 patients with MTLE (105 underwent SelAH, 113 underwent ATL). The pooled results demonstrated a statistically significant reduction in the odds of achieving seizure freedom following ATL compared to SelAH (odds ratio [OR] 0.38, 95% confidence interval [CI] 0.24-0.81, p = 0.008). Regarding cognitive outcomes, no significant difference was observed in Performance IQ (PIQ) between the two groups. However, a trend towards improved Verbal IQ (VIQ) was noted in the SelAH group, although this did not reach statistical significance. Conclusion: The findings suggest that SelAH may offer superior seizure control compared to ATL in patients with MTLE. While both procedures appear to have comparable effects on PIQ, SelAH may be associated with a trend towards better preservation or even improvement in VIQ. The choice between SelAH and ATL should be individualized based on patient-specific factors, including preoperative cognitive profile and the relative importance of seizure control versus cognitive preservation.

A novel AAV9-dual microRNA-vector targeting GRIK2 in the hippocampus as a treatment for mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy (mTLE) is the most prevalent type of epilepsy in adults. First and subsequent generations of anti-epileptic therapy regimens fail to decrease seizures in a large number of patients suffering from mTLE, leaving surgical ablation of part of the hippocampus as the only therapeutic option to potentially reach seizure freedom. GluK2 has recently been identified as a promising target for the treatment of mTLE using gene therapy. Here, we engineered an adeno-associated virus serotype 9 vector expressing a cluster of two synthetic microRNAs (miRNAs), expressed from the human synapsin promoter, that target GRIK2 mRNA. Intra-hippocampal delivery of this vector in a mouse model of mTLE significantly reduced GRIK2 expression and daily seizure frequency. This treatment also improved the animals' health, reduced their anxiety, and restored working memory. Focal administration of the vector to the hippocampus of cynomolgus monkeys in GLP toxicology studies led to the selective transduction of hippocampal neurons with little exposure elsewhere in the brain and no transduction outside the central nervous system. Expression of miRNAs in hippocampal neurons resulted in substantially decreased GRIK2 mRNA expression. These data suggest that the intra-hippocampal delivery of a GMP-grade AAV9 coding for a synthetic miRNAs targeting GRIK2 is a promising treatment strategy for mTLE.

Pediatric peri-insular hemispherotomy and functional hemispherectomy for severe medically refractory epilepsy: comparison of two techniques

PurposeSince it was first described in the 1970s, functional hemispherotomy has been an essential tool in treating disabling, medically refractory epilepsy resulting from diffuse unilateral hemispheric disease. We report our experience with 23 patients who underwent hemispherotomy, both using the functional hemispherotomy (FH) as well as a modified peri-insular hemispherotomy (PIH) technique. We present the surgical technique for the latter, review outcomes following disconnection surgery and discuss the differences between the techniques when it comes to complications and postoperative results. MethodsA retrospective study of 23 patients with refractory seizures who underwent cerebral hemispherectomy. A thorough analysis of the clinical, imaging, surgical features and postoperative results was performed. We also present the surgical technique for a modified PIH technique. ResultsBetween 2000 and 2020, 23 pediatric patients with refractory seizures underwent hemispherotomy (12 FHs, 11 modified PIHs). 91.3% of patients were seizure free at 6 months, 87% at 1 year, and 78.3% at last follow-up. None of the 23 patients presented Engel IV outcome. FH was found to have statistically longer surgical duration (5 ± 1.5 vs. 3.83 ± 0.5 h; p = <0.001). Neurocognition was improved in two thirds of the patients (66.9%). Our study also shows improvement of motor activity in the majority of the patients, regardless of the pathology and surgical technique. In the present report we modified the Cook et al. technique by implementing an amygdalohippocampectomy with resection of the tail of the hippocampus posteriorly and medially, to achieve temporo-occipital disconnection, instead of a complete temporal lobectomy. ConclusionWhen patients are wisely selected, the hemispherectomy procedure should be considered as a most attractive and curative treatment for children with refractory seizures, not only giving the patient a high chance of seizure freedom but also providing an improvement in motor and cognitive skills. In our particular case and based on the present study, the modified PIH proves to be a highly effective technique. It not only has a shorter surgical time but also a very low complication rate.

One-year seizure freedom and quality of life in patients with drug-resistant epilepsy receiving adjunctive vagus nerve stimulation in Japan.

Amount of seizure-free days is a critical determinant of quality of life (QoL) in patients with drug-resistant epilepsy (DRE). The fractions of patients experiencing prolonged periods of seizure freedom with adjunctive vagus nerve stimulation (VNS) have yet to be assessed on a large scale. Retrospective analysis of patients in the Japanese VNS prospective observational registry who experienced at least 1 year of seizure freedom from all seizures, focal seizures, or tonic-clonic seizures (TCS), as well as patient-reported change in QoL in these groups. The study included 362 patients with DRE, 147 were female (40.6%), and the median age at VNS implant was 23.0 years (range: 1.0-73.0). A total of 225 patients reported focal seizures and 184 patients reported TCS. After 36 months of adjunctive VNS, the cumulative proportion of patients experiencing at least 1 year of complete seizure freedom was 11% (38/356) with an average duration of seizure freedom of 19.4 months. In patients with focal seizures, 25% (n = 57/225) experienced at least 1 year of freedom from focal seizures with an average duration of 24.8 months. Higher cumulative rates of freedom from TCS were observed: 55% (n = 101/184) experienced at least 1 year without TCS with an average duration of TCS-free periods of 28.9 months. 82.1% of patients with 12-month complete seizure freedom reported markedly improved or improved QoL compared with 51.9% of patients who were not seizure-free. QoL changes in patients with 12-month seizure freedom from TCS and focal seizures were similar: 61.8% and 63% of respective patients reported either markedly improved or improved QoL at 36 months. Complete seizure freedom is rare in patients treated with VNS; however, this analysis found approximately half of patients who experienced TCS prior to VNS experienced prolonged periods of freedom from TCS with adjunctive VNS. We studied patients in Japan with epilepsy that is difficult to treat. To understand if adding vagus nerve stimulation (VNS) helps such patients, we looked at which patients stopped having all seizures or stopped having a specific seizure type (such as tonic-clonic seizures or focal seizures), and how long these periods lasted. With VNS treatment, about 2 out of 4 patients with tonic-clonic seizures and 1 out of 4 patients with focal seizures had more time without these seizure types. Without seizures, patients felt better about their daily lives. Even patients who still had seizures felt better about their daily lives after 3 years of VNS treatment. The clinical trial registry number is UMIN000014728.

Epilepsy in Patients With Primary CNS Lymphoma: Prevalence, Risk Factors, and Prognostic Significance.

Epilepsy is a common comorbidity of brain tumors; however, little is known about the prevalence, onset time, semiology, and risk factors of seizures in primary CNS lymphoma (PCNSL). Our objectives were to determine the prevalence of epilepsy in PCNSL, to identify factors associated with epilepsy, and to investigate the prognostic significance of seizures in PCNSL. We performed an observational, retrospective single-center study at a tertiary neuro-oncology center (2011-2023) including immunocompetent patients with PCNSL and no history of seizures. We collected clinical, imaging, and treatment data; seizure status over the course of PCNSL; and oncological and seizure outcome. The primary outcome was to determine the prevalence of epilepsy. Furthermore, we aimed to identify clinical, radiologic, and treatment-related factors associated with epilepsy. Univariate analyses were conducted using the χ2 test for categorical variables and unpaired t test for continuous variables. Predictors identified in the unadjusted analysis were included in backward stepwise logistic regression models. We included 330 patients, 157 (47.6%) were male, median age at diagnosis was 68 years, and the median Karnofsky Performance Status score was 60. Eighty-three (25.2%) patients had at least 1 seizure from initial diagnosis to the last follow-up, 40 (12.1%) as the onset symptom, 16 (4.8%) during first line of treatment, 27 (8.2%) at tumor progression and 6 (1.8%) while in remission. Focal aware seizures were the most frequent seizure type, occurring in 43 (51.8%) patients. Seizure freedom under antiseizure medication was observed in 97.6% patients. Cortical contact (odds ratio [OR] 8.6, 95% CI 4.2-15.5, p < 0.001) and a higher proliferation index (OR 5.7, 95% CI 1.3-26.2, p = 0.02) were identified as independent risk factors of epilepsy. Patients with PCNSL and epilepsy had a significantly shorter progression-free survival (median progression-free survival 9.6 vs 14.1 months, adjusted hazard ratio 1.4, 95% CI 1.0-1.9, p = 0.03), but not a significantly shorter overall survival (17 vs 44.1 months, log-rank test, p = 0.09). Epilepsy affects a quarter of patients with PCNSL, with half experiencing it at the time of initial presentation and potentially serving as a marker of disease progression. Further research is necessary to assess the broader applicability of these findings because they are subject to the constraints of a retrospective design and tertiary center setting.

Pediatric Epilepsy Genetic Testing Results and Long-term Seizure Freedom.

Objective: To determine whether there is a correlation of genetic diagnosis/result with long-term seizure freedom in pediatric epilepsy patients. Methods: This was a prospective and retrospective cohort study of children with epilepsy referred for genetic testing at a single center. The primary outcomes were presence and type of genetic diagnosis (pathogenic, benign, or variant of uncertain significance) and patient epilepsy status (seizure free, treatment failure, uncertain). Epilepsy gene panels were the primary method of genetic testing. Results: The prospective cohort had 22 patients followed for >11 years and for whom genetic testing was then performed; the retrospective cohort had 78 patients with previous genetic testing followed for >8 years. In the prospective cohort, one patient each of the seizure free or treatment failure groups had a pathogenic genetic variant; mean Combined Annotation Dependent Depletion (CADD) scores 22 and 24, respectively (P = .62). In the retrospective cohort, there was no difference in the number of variants (P = .97), the variant interpretations (P = .29 ClinVar, P = .39 lab interpretation) or mean CADD scores (P = .29) between the seizure-free, treatment failure, and uncertain epilepsy patients. Whole exome and genome sequencing identified pathogenic variants in 70% of patients with treatment failure but were not performed in seizure-free patients. Significance: Our findings show no correlation of the presence or type of epilepsy gene panel result with long-term seizure freedom in pediatric patients. The yield and specificity of pathogenic variants may be higher using whole exome and whole genome sequencing in patients with treatment-resistant epilepsy. Whole exome and whole genome sequencing, or more targeted understanding of specific variants, may be needed to improve the utility of pediatric epilepsy genetic testing.

Bilateral Todd's paralysis in a patient with left fronto-opercular epilepsy.

Postictal paresis ("Todd's paralysis") is commonly observed as a unilateral, transient motor weakness, lasting minutes to hours, after focal or focal to bilateral tonic-clonic seizures, contralateral to the epileptogenic zone. Bilateral postictal paresis is exceedingly rare and could be misinterpreted, especially if the preceding convulsive phase was not witnessed. An 18-year-old right-handed male patient with refractory focal epilepsy with seizure onset at age 3 years, was admitted for presurgical video-EEG monitoring. His seizures were predominantly nocturnal, consisting of a laryngeal somatosensory aura, occasionally evolving to bilateral tonic or tonic-clonic seizures with occasional asymmetrical limb extension during the tonic phase (right arm extension). Postictally, consciousness recovery was fast, if ever lost. At that stage, we documented severe dysarthria and bilateral symmetrical arm paresis lasting several minutes. The ictal pattern and interictal epileptiform activity were projected on the fronto-central midline. Brain MRI was highly suggestive of a bottom-of-sulcus dysplasia with underlying transmantle sign on the left premotor, fronto-opercular region and an FDG-PET-CT showed a concordant left fronto-operculo-insular hypometabolism. A complete lesionectomy was performed, with the additional guidance of intraoperative electrocorticography, resulting in sustained seizure freedom. Anatomo-pathology confirmed a type 2b focal cortical dysplasia. We speculate that, in our patient, a left fronto-opercular ictal onset with an early spread to both primary motor cortices and relative sparing of consciousness networks allowed the emergence of a clinically detectable postictal bilateral paresis.

Mammalian Target of Rapamycin Inhibitor Levels Decrease Under Cenobamate Treatment

BackgroundEverolimus therapy has been approved in Tuberous Sclerosis Complex (TSC), for drug-resistant epilepsy as adjunctive therapy. A novel anti-seizure medication is cenobamate, which was approved for adults as adjunctive treatment for focal-onset seizures in drug-resistant epilepsy and is now commonly used in patients with TSC. Drug-drug interactions between cenobamate and mammalian target of rapamycin (mTORi) have not been prospectively evaluated, even though these agents are frequently administered together. MethodsWe performed a retrospective analysis of patients with TSC and compared mTORi drug levels before and after treatment initiation with cenobamate. ResultsWe evaluated 20 patients with clinically diagnosed TSC (male: 55%, female: 45%) with a median current age at last visit of 17.0 years (range: 4-41 years, interquartile range [IQR]: 12.5 years). All patients received mTORi treatment of either everolimus (N = 12, 60%) or sirolimus (N = 8, 40%). Cenobamate treatment led to seizure freedom in 2 patients (10%), reduction of seizures in 9 patients (45%) and no change in seizure frequency in 9 patients (45%). Median maximal cenobamate dose was 200 mg (range: 100-500 mg, IQR: 262.5 mg), for example, 3.2 mg/kg/day (range: 0.8-9.5 mg/kg/day, IQR: 3.2 mg/kg/day). Median everolimus levels decreased significantly after cenobamate initiation from 5.1 ng/ml (range: 1.9-11.6 ng/ml, IQR: 3.8 ng/ml) to 3.4 ng/ml (range: 1-7.9 ng/ml, IQR: 1.7 ng/ml, P = 0.01221). The median sirolimus level did not decrease significantly (P = 0.3828). ConclusionEverolimus levels decreased following cenobamate initiation. This is likely due to CYP3A4 induction of cenobamate. We recommend monitoring of serum plasma levels of mTORi co-administered with cenobamate and adjustment of mTORi doses accordingly.

Epilepsy surgery for tuberous sclerosis complex in children: literature review and clinical case

Tuberous sclerosis complex (TSC) is a multisystem, autosomal-dominant, neurocutaneous syndrome that is characterized by the presence of hamartomas involving multiple organs, including the brain. Epilepsy is the most common neurological manifestation and the main cause of disability in children. Drug-resistant epilepsy is seen in 62.5 % of cases. The challenge of surgical treatment in these patients is the multifocal nature of epilepsy. Nonetheless, there is available data to suggest that surgical intervention is most likely to achieve long-term seizure freedom.The aim of the work – to analyze current data and aspects of surgical treatment of epilepsy associated with tuberous sclerosis in children.A literature search for was done on PubMed, Google Scholar, and eLIBRARY. RU for the period from 2000 to 2022. Search phrases included: TSC-associated epilepsy in children, epilepsy surgery in children with TSC, epilepsy surgery for TSC. The tubers are not the only source of epileptic activity; the perituberal brain tissue is also a proven focus. Currently, there is a tendency towards early pre-surgical evaluation and surgical treatment, which is recommended after the failure of two antiepileptic drugs. Considering the multiple brain lesions and multifocal epilepsy, the use of invasive electroencephalography is invaluable in the preoperative assessment of these patients. The effectiveness of resection surgery is 65–75 %. Over time, the proportion of patients in complete remission from seizures decreases. Lobectomy and tuberectomy plus procedures are favorable prognostic factors. Surgical treatmentsignificantly increasesthe chances of seizure freedom. Eliminating seizures in children has been shown to improve cognitive development.There is no algorithm for pre-surgical patient evaluation or selection criteria for surgical treatment. Some methods of presurgical evaluation are not included in the compulsory health insurance system, making early diagnosis and treatment very difficult. This leads to an increase in the number of patients with disabilities and a poor quality of life.

Candesartan restores blood-brain barrier dysfunction, mitigates aberrant gene expression, and extends lifespan in a knockin mouse model of epileptogenesis.

Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes play a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability. CND treatment also partially reversed or 'normalized' disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-β signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust effectiveness of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy.