Achieved Seizure Freedom Research Articles

Treatment response in newly diagnosed epilepsy: a syndromic approach

ABSTRACT Objective To investigate the seizure outcome and factors associated with that in patients with newly diagnosed epilepsy, based on a syndromic approach [i.e. idiopathic generalized epilepsies (IGEs) vs. symptomatic generalized epilepsies (SGEs) vs. focal epilepsies vs. unclassified epilepsy]. Methods This was a retrospective longitudinal study of a prospectively developed database. All newly-diagnoses patients with a diagnosis of IGE, focal epilepsy, SGE, or unclassified epilepsy, who received treatment from 2008 until 2018, were recruited at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran. All patients had to be followed at our center for at least 14 months. Results Four hundred and ten patients were studied [208 people with focal epilepsy (50.7%), 130 with IGE (31.7%), 49 with SGE (12%), and 23 patients with unclassified epilepsy (5.6%)]. Overall, 216 (52.7%) individuals became seizure-free for at least one year after their first therapeutic plan. The second therapeutic attempt in patients, who did not achieve seizure freedom with the first treatment plan, yielded seizure-free outcome in 52 patients (28.7%). The odds ratio of drug-resistance in patients with focal epilepsy compared with that in those with IGE was 1.816 (95% CI: 1.039–3.171; p = 0.036). The odds ratio of drug-resistance in patients with SGE compared with that in those with IGE was 8.543 (95% CI: 3.993–18.274; p = 0.0001). Conclusion Implementation of appropriate personalized treatment plans in PWE is of paramount significance and the primary step towards such a strategy is to making a syndromic diagnosis of the condition.

Social Media Analytics for Pharmacovigilance of Antiepileptic Drugs.

Epilepsy is a common neurological disorder worldwide and antiepileptic drug (AED) therapy is the cornerstone of its treatment. It has a laudable aim of achieving seizure freedom with minimal, if any, adverse drug reactions (ADRs). Too often, AED treatment is a long-lasting journey, in which ADRs have a crucial role in its administration. Therefore, from a pharmacovigilance perspective, detecting the ADRs of AEDs is a task of utmost importance. Typically, this task is accomplished by analyzing relevant data from spontaneous reporting systems. Despite their wide adoption for pharmacovigilance activities, the passiveness and high underreporting ratio associated with spontaneous reporting systems have encouraged the consideration of other data sources such as electronic health databases and pharmaceutical databases. Social media is the most recent alternative data source with many promising potentials to overcome the shortcomings of traditional data sources. Although in the literature some attempts have investigated the validity and utility of social media for ADR detection of different groups of drugs, none of them was dedicated to the ADRs of AEDs. Hence, this paper presents a novel investigation of the validity and utility of social media as an alternative data source for the detection of AED ADRs. To this end, a dataset of consumer reviews from two online health communities has been collected. The dataset is preprocessed; the unigram, bigram, and trigram are generated; and the ADRs of each AED are extracted with the aid of consumer health vocabulary and ADR lexicon. Three widely used measures, namely, proportional reporting ratio, reporting odds ratio, and information component, are used to measure the association between each ADR and AED. The resulting list of signaled ADRs for each AED is validated against a widely used ADR database, called Side Effect Resource, in terms of the precision of ADR detection. The validation results indicate the validity of online health community data for the detection of AED ADRs. Furthermore, the lists of signaled AED ADRs are analyzed to answer questions related to the common ADRs of AEDs and the similarities between AEDs in terms of their signaled ADRs. The consistency of the drawn answers with the existing pharmaceutical knowledge suggests the utility of the data from online health communities for AED-related knowledge discovery tasks.

Treatment and care of women with epilepsy before, during, and after pregnancy: a practical guide.

Women with epilepsy (WWE) wishing for a child represent a highly relevant subgroup of epilepsy patients. The treating epileptologist needs to delineate the epilepsy syndrome and choose the appropriate anti-seizure medication (ASM) considering the main goal of seizure freedom, teratogenic risks, changes in drug metabolism during pregnancy and postpartum, demanding for up-titration during and down-titration after pregnancy. Folic acid or vitamin K supplements and breastfeeding are also discussed in this review. Lamotrigine and levetiracetam have the lowest teratogenic potential. Data on teratogenic risks are also favorable for oxcarbazepine, whereas topiramate tends to have an unfavorable profile. Valproate needs special emphasis. It is most effective in generalized seizures but should be avoided whenever possible due to its teratogenic effects and the negative impact on neuropsychological development of in utero-exposed children. Valproate still has its justification in patients not achieving seizure freedom with other ASMs or if a woman decides to or cannot become pregnant for any reason. When valproate is the most appropriate treatment option, the patient and caregiver must be fully informed of the risks associated with its use during pregnancies. Folate supplementation is recommended to reduce the risk of major congenital malformations. However, there is insufficient information to address the optimal dose and it is unclear whether higher doses offer greater protection. There is currently no general recommendation for a peripartum vitamin K prophylaxis. During pregnancy most ASMs (e.g. lamotrigine, oxcarbazepine, and levetiracetam) need to be increased to compensate for the decline in serum levels; exceptions are valproate and carbamazepine. Postpartum, baseline levels are reached relatively fast, and down-titration is performed empirically. Many ASMs in monotherapy are (moderately) safe for breastfeeding and women should be encouraged to do so. This review provides a practically oriented overview of the complex management of WWE before, during, and after pregnancy.

Early epilepsy surgery for non drug-resistant patients.

The aim of epilepsy treatment is to achieve seizure freedom. Surgery is often still considered a late option when pharmacological treatments have failed and epilepsy has become drug-resistant. We analyse the clinical features and surgical outcome in patients who underwent surgery without experiencing drug-resistance comparing with those observed in patients who became drug-resistant. Two-hundred and fifty patients with symptomatic focal epilepsy (12.1% of patients who underwent surgery at the "Claudio Munari" Epilepsy Surgery Center) were selected on the basis of initial period of seizure freedom and followed-up for at least 12months. Patients were divided into two groups: those who underwent surgery during the initial period of seizure freedom (n=74), and those who underwent surgery after an initial seizure-free period followed by drug-resistance (n=176). Outcomes were significantly better in non-drug-resistant patients (p<0.001), all of whom had Engel class Ia or Ic. In the drug-resistant group, 136 patients (77.3%) had class Ia or Ic. The median post-operative follow-up was respectively 75.0 and 84.0months. Epilepsy surgery is a successful treatment, especially for non-drug-resistant patients with focal epilepsy with structural etiology. The timing of surgery affects the outcomes, and "early" surgery should be preferred to prevent likely drug-resistance and to improve prognosis.

Effectiveness of vagus nerve stimulation therapy in refractory hypoxic-ischemic encephalopathy-induced epilepsy.

Epilepsy is one of the important long-term sequelae of neonatal hypoxic-ischemic encephalopathy (HIE) and is typically characterized by drug resistance and poor surgical outcomes. Vagus nerve stimulation (VNS) is a promising neuromodulation therapy for refractory epilepsy. The present study aimed to first evaluate the effectiveness of VNS in patients with refractory HIE-induced epilepsy and scrutinize potential clinical predictors. We retrospectively collected the outcomes of VNS in all patients with refractory HIE-induced epilepsy and at least 2 years of follow-up. Subgroups were classified as responders and nonresponders according to the effectiveness of VNS (⩾50% or <50% reduction in seizure frequency). Preoperative data were analyzed to screen for potential predictors of VNS effectiveness. A total of 55 patients with refractory HIE-induced epilepsy who underwent VNS therapy were enrolled. Responders represented 56.4% of patients, and 12.7% of patients achieved seizure freedom at the last follow-up. In addition, the responder rate increased over time with rates of 23.6%, 38.2%, 50.9%, and 56.4% at the 3-, 6-, 12- and 24-month follow-ups, respectively. After multivariate analysis, neonatal seizure was identified as a negative predictor (OR: 4.640, 95% CI: 1.129-19.066), and a predominant seizure type of generalized onset was identified as a positive predictor (OR: 0.261, 95% CI: 0.078-0.873) of VNS effectiveness. VNS therapy was effective in patients with refractory HIE-induced epilepsy and was well tolerated over a 2-year follow-up period. VNS therapy demonstrated better effectiveness in patients without neonatal seizures or with a predominant seizure type of generalized onset.

Lesion Segmentation in Paediatric Epilepsy Utilizing Deep Learning Approaches

Focal cortical dysplasia (FCD) is one of the most common lesions responsible for drug-resistant epilepsy, and is frequently missed by visual inspection. FCD may be amenable to surgical resection to achieve seizure freedom. By improving lesion detection the surgical outcome of these patients can be improved. Image processing techniques are a potential tool to improve the detection of FCD prior to epilepsy surgery. In this research, we propose and compare the performance of two type of models, Fully Convolutional Network (FCN) and a multi-sequence FCN to classify and segment FCD in children with drug-resistant epilepsy. This experiment utilized the volumetric T1-weighted, T2 weighted and FLAIR sequences. The whole slice FCN models were applied to each sequence separately while the multi-sequence model leverages combined information of all three sequences simultaneously. A leave-one-subject-out technique was utilized to train and evaluate the models. We evaluated subjectwise sensitivity and specificity, which corresponds to the ability of the model to classify those with or without a lesion. We also evaluated lesional sensitivity and specificity, which expresses the ability of the model to segment the lesion and the dice coefficient to evaluate lesion coverage. Our data consisted of 80 FCD subjects (56 MR-positive and 24 MR-negative) and 15 healthy controls. Performance of whole slice FCN was best on T1-weighted, followed by T2-weighted and lowest with FLAIR sequences. Multi-sequence model performed better than the T1 whole slice FCN, and detected 98% vs. 93% respectively MR-positive cases, and 92% vs. 88% respectively MR-negative cases, as well as achieved lesion coverage of 74% vs. 67% respectively for MR-positive cases and 68% vs. 64% for MR negative cases. The dice coefficient for the multi-sequence model was 57% and for whole slice FCN was 56% for MR-positive cases. In the test cohort of six new cases, the multi-sequence model detected 4 out of 6 cases where the predicted lesion had 56% overlap with the actual lesion. This work showed that deep learning methods in particular fully convolutional networks are a promising tool for classification and segmentation of FCD. Additional work is required to further improve lesion classification and segmentation, particularly for small lesions, as well as to train and test optimal algorithms on a larger multi-center dataset.

Long-term epilepsy-associated tumors

The goal of this review is to summarize data concerning radiological and histological diagnosis of epileptogenic tumors, as well as to discuss their surgical treatment. PubMed literature database was searched for relevant articles, we also used our own clinical experience. Benign glioneuronal tumors are the second most common cause of drug resistant epilepsy in adults after hippocampal sclerosis. Exceptionally slow growth (more than 2 years), localization in the brain cortex, presence of differentiated neuronal tissue in tumoral body and long history of epilepsy are the key features of these tumors called LEAT (long-term epilepsy-associated tumors). Management of LEAT requires epileptological as well as neurooncological approach. The epileptogenic zone commonly spreads beyond the tumor borders and simple lesionectomy alone may not be sufficient for achieving seizure freedom. LEAT typically exhibit low proliferative activity, however they should be thoroughly differentiated from more aggressive glial tumors; while this task is sometimes quite challenging, it's achievable by means of histological and immunohistochemical examination.

Efficacy of levetiracetam in STXBP1 encephalopathy with different phenotypic and genetic spectra

ObjectiveSyntaxin binding protein 1 (STXBP1) plays an important role in the release of synaptic vesicles. STXBP1-related encephalopathy is a brain dysfunction caused by STXBP1 variation. Levetiracetam (LEV) exerts antiepileptic effects by binding to synaptic vesicle protein 2A (SV2A). This study aimed to analyze the prognosis of LEV treatment of STXBP1 encephalopathy (STXBP1-E) and the correlation among genotype, phenotype, and LEV efficacy. MethodsPatients with pathogenic STXBP1 variants were collected from multiple centers, and their clinical history, video electroencephalogram (vEEG) characteristics, imaging examination data, and anti-seizure medication (ASM) history were systematically analyzed. The ASMs related to the prognosis were explored. ResultsForty patients with STXBP1-E were enrolled in this study. The detailed ASM usage of 37 patients was recorded without intervening in ASM selection. At the endpoint of six months treatment, the results of Fisher's exact test showed that in all ASMs, LEV affected the prognosis of patients with STXBP1-E. LEV was effective in improving the partial remission rate but did not achieve seizure freedom. However, LEV monotherapy could achieve seizure freedom in patients with other early-onset epileptic and encephalopathy. For refractory West syndrome (WS) or Ohtahara syndrome (OS), LEV combined with other ASMs could improve the seizure remission rate. ConclusionLEV increased the seizure reduction rate and improved the vEEG characteristics in patients with STXBP1-E, but not seizure freedom. LEV combined with other ASMs could increase the seizure reduction rate, especially for refractory WS or OS. Thus, LEV could be considered after identifying the pathogenicity of STXBP1 variants.

Resective, Ablative and Radiosurgical Interventions for Drug Resistant Mesial Temporal Lobe Epilepsy: A Systematic Review and Meta-Analysis of Outcomes

Objectives: One-third of individuals with focal epilepsy do not achieve seizure freedom despite best medical therapy. Mesial temporal lobe epilepsy (MTLE) is the most common form of drug resistant focal epilepsy. Surgery may lead to long-term seizure remission if the epileptogenic zone can be defined and safely removed or disconnected. We compare published outcomes following open surgical techniques, radiosurgery (SRS), laser interstitial thermal therapy (LITT) and radiofrequency ablation (RF-TC).Methods: PRISMA systematic review was performed through structured searches of PubMed, Embase and Cochrane databases. Inclusion criteria encompassed studies of MTLE reporting seizure-free outcomes in ≥10 patients with ≥12 months follow-up. Due to variability in open surgical approaches, only comparative studies were included to minimize the risk of bias. Random effects meta-analysis was performed to calculate effects sizes and a pooled estimate of the probability of seizure freedom per person-year. A mixed effects linear regression model was performed to compare effect sizes between interventions.Results: From 1,801 screened articles, 41 articles were included in the quantitative analysis. Open surgery included anterior temporal lobe resection as well as transcortical and trans-sylvian selective amygdalohippocampectomy. The pooled seizure-free rate per person-year was 0.72 (95% CI 0.66–0.79) with trans-sylvian selective amygdalohippocampectomy, 0.59 (95% CI 0.53–0.65) with LITT, 0.70 (95% CI 0.64–0.77) with anterior temporal lobe resection, 0.60 (95% CI 0.49–0.73) with transcortical selective amygdalohippocampectomy, 0.38 (95% CI 0.14–1.00) with RF-TC and 0.50 (95% CI 0.34–0.73) with SRS. Follow up duration and study sizes were limited with LITT and RF-TC. A mixed-effects linear regression model suggests significant differences between interventions, with LITT, ATLR and SAH demonstrating the largest effects estimates and RF-TC the lowest.Conclusions: Overall, novel “minimally invasive” approaches are still comparatively less efficacious than open surgery. LITT shows promising seizure effectiveness, however follow-up durations are shorter for minimally invasive approaches so the durability of the outcomes cannot yet be assessed. Secondary outcome measures such as Neurological complications, neuropsychological outcome and interventional morbidity are poorly reported but are important considerations when deciding on first-line treatments.

Predictors of Seizure Outcome after Repeat Pediatric Epilepsy Surgery: Reasons for Failure, Sex, Electrophysiology, and Temporal Lobe Surgery.

Considering that seizure freedom is one of the most important goals in the treatment of epilepsy, repeat epilepsy surgery could be considered for patients who continue to experience drug-resistant seizures after epilepsy surgery. However, the chance of seizure freedom is reported to be below 50% after reoperation for failed epilepsy surgery. This study aimed to elucidate the predictive factors for seizure outcomes after repeat pediatric epilepsy surgery. In all, 39 pediatric patients who underwent repeat curative epilepsy surgery between 2008 and 2020 at our institution were retrospectively studied. The relationship between preoperative clinical factors and postoperative seizure freedom at the last follow-up was statistically evaluated. The mean age at the first surgery was 5.5 years (0–16). The etiology of epilepsy was malformation of cortical development in 33 patients. The average time to seizure recurrence after the first surgery was 6.4 months (range, 0–26 months). In all, 16 patients (41.0%) achieved seizure freedom after the second surgery. Seven patients underwent a third surgery, and three (42.9%) achieved seizure freedom. Overall, 19 patients achieved seizure freedom after repeat epilepsy surgery (48.7%). Female sex, surgical failure due to technical limitations, congruent electroencephalography (EEG) findings, lesional magnetic resonance imaging (MRI) and Rt-sided surgery were predictive of seizure freedom, and surgery limited to the temporal lobe was predictive of residual seizures, as determined in the multivariate analysis. The reoperation of failed epilepsy surgery is challenging. Consideration of the above predictive factors can be helpful in deciding whether to reoperate on pediatric patients whose initial surgical intervention failed.

Abnormal functional connectivity profiles predict drug responsiveness in patients with temporal lobe epilepsy.

This work was undertaken to study the functional connectivity differences between non-seizure-free and seizure-free patients with temporal lobe epilepsy (TLE) and to identify imaging predictors for drug responsiveness in TLE. In this prospective study, 52 patients with TLE who presented undetermined antiseizure medication responsiveness and 55 demographically matched healthy controls were sequentially recruited from Xiangya Hospital. Functional magneticresonanceimaging data were acquired during a Chinese version of the verbal fluency task. The patients were followed up until the outcome could be classified. The subject groups were compared in terms of activation profile, task-residual functional connectivity (trFC), and generalized psychophysiological interaction (gPPI) analyses. Moreover, we extracted imaging characteristics for logistic regression and receiver operating characteristic evaluation. With a mean follow-up of 1.1years, we identified 27 non-seizure-free patients and 19seizure-free patients in the final analyses. The Chinese character verbal fluency task successfully activated the language network and cognitive control network (CCN) and deactivated the default mode network (DMN). In the non-seizure-freedom group, the trFC between the hippocampus and bilateral brain networks was attenuated (p<.05, familywise error corrected). For the gPPI analysis, group differences were mainly located in the precuneus, middle frontal gyrus, and inferior parietal lobule (p<.001, uncorrected; k ≥ 10). The regression model presented high accuracy when predicting non-seizure-free patients (area under the curve = .879, 95% confidence interval = .761-.998). In patients with TLE who would not achieve seizure freedom with current antiseizure medications, the functional connectivity between the hippocampus and central nodes of the DMN, CCN, and language network was disrupted, leading to language decline. Independent of hippocampal sclerosis, abnormalities, especially the effective connectivity from the hippocampus to the DMN, were predictive biomarkers of drug responsiveness in patients with TLE.

Carisbamate add-on therapy for drug-resistant focal epilepsy.

Epilepsy is one of the most common neurological disorders. Many people with epilepsy are drug-resistant and require add-on therapy, meaning that they concomitantly take multiple antiepileptic drugs. Carisbamate is a drug which is taken orally and inhibits voltage-gated sodium channels. Carisbamate may be useful for drug-resistant focal epilepsy. To evaluate the efficacy and tolerability of carisbamate when used as an add-on therapy for drug-resistant focal epilepsy. We searched the following databases on 8 April 2021: Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) 1946 to April 07, 2021. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane review groups including Epilepsy. We also searched ongoing trials registers, checked reference lists, and contacted authors of the included trials. Double-blind randomised controlled trials (RCTs) comparing carisbamate versus placebo or another antiepileptic drug, as add-on therapy for drug-resistant focal epilepsy. Trials could have a parallel-group or cross-over design. Two review authors independently selected the trials for inclusion, assessed trial quality, and extracted data. The primary outcome was 50% or greater reduction in seizure frequency (responder rate). The secondary outcomes were: seizure freedom, treatment withdrawal (for any reason and due to adverse events); adverse events, and quality of life. We analysed data using the Mantel-Haenszel statistical method and according to the intention-to-treat population. We presented results as risk ratios (RRs) with 95% confidence intervals (CIs). We included four RCTs involving a total of 2211 participants. All four trials compared carisbamate with placebo for drug-resistant focal epilepsy. Participants in all trials were over 16 years of age and received at least one other antiepileptic drug concomitantly. We detected substantial risk of bias across the included trials. All four trials were at high risk of attrition bias due to the incomplete reporting of attrition and the high treatment withdrawal rates noted, especially with higher doses. All four trials also had unclear risk of detection bias, as they did not specify whether outcome assessors were blinded. Meta-analysis suggested that carisbamate produced a higher responder rate compared to placebo (RR 1.36, 95% CI 1.14 to 1.62; 4 studies; moderate-certainty evidence). More participants in the carsibamate group achieved seizure freedom (RR 2.43, 95% CI 0.84 to 7.03; 1 study); withdrew from treatment for any reason (RR 1.32, 95% CI 0.82 to 2.12; 4 studies); and withdrew from treatment due to adverse events (RR 1.80, 95% CI 0.78 to 4.17; 4 studies) than in the placebo group. However, the evidence for the three outcomes was very low-certainty. There was no difference between treatment groups for the proportion of participants experiencing at least one adverse event (RR 1.10, 95% CI 0.93 to 1.30; 2 studies; low-certainty evidence). More participants in the carisbamate group than in the placebo group developed dizziness (RR 2.06, 95% CI 1.23 to 3.44; 4 studies; very low-certainty evidence) and somnolence (RR 1.82, 95% CI 1.28 to 2.58; 4 studies; low-certainty evidence), but not fatigue (RR 1.11, 95% CI 0.73 to 1.68; 3 studies); headache (RR 1.13, 95% CI 0.92 to 1.38; 4 studies); or nausea (RR 1.19, 95% CI 0.81 to 1.75; 3 studies). None of the included trials reported quality of life. The results suggest that carisbamate may demonstrate efficacy and tolerability as an add-on therapy for drug-resistant focal epilepsy. Importantly, the evidence for all outcomes except responder rate was of low to very low certainty, therefore we are uncertain of the accuracy of the reported effects. The certainty of the evidence is limited by the significant risk of bias associated with the included studies, as well as the statistical heterogeneity detected for some outcomes. Consequently, it is difficult for these findings to inform clinical practice. The studies were all of short duration and only included adult study populations. There is a need for further RCTs with more clear methodology, long-term follow-up, more clinical outcomes, more seizure types, and a broader range of participants.

The role of stereo-electroencephalography to localize the epileptogenic zone in children with nonlesional brain magnetic resonance imaging

ObjectiveThis study aimed to assess the clinical outcome and outcome predictive factors in pediatric epilepsy patients evaluated with stereo-electroencephalography (SEEG). MethodsThirty-eight patients who underwent SEEG implantation at the Pediatric Epilepsy Center in New York Presbyterian Hospital between June 2014 and December 2019 were enrolled for retrospective chart review. Postoperative seizure outcomes were evaluated in patients with at least 12-months follow up. Meta-analysis was conducted via electronic literature search of data reported from 2000 to 2020 to evaluate significant surgical outcome predictors for SEEG evaluation in the pediatric population. ResultsIn the current case series of 25 postsurgical patients with long-term follow up, 16 patients (64.0%) were seizure free. An additional 7 patients (28.0%) showed significant seizure improvement and 2 patients (8.0%) showed no change in seizure activity. Patients with nonlesional magnetic resonance imaging (MRI) achieved seizure freedom in 50% (5/10) of cases. By comparison, 73% (11/15) of patients with lesional MRI achieved seizure freedom.Out of 12 studies, 158 pediatric patients were identified for inclusion in a meta-analysis of the effectiveness of SEEG. Seizure freedom was reported 54.4% (n = 86/158) of patients at last follow up. Among patients with nonlesional MRI, 45% (n = 24) achieved seizure freedom compared with patients with lesional MRI findings (61.2%, n:= 60) (p = 0.02). The risk for seizure recurrence was 2.15 times higher [95% confidence interval [CI] 1.06–4.37, p = 0.033] in patients diagnosed with nonlesional focal epilepsy compared to those with lesional epilepsy [ 1.49 (95% CI 1.06–2.114, p = 0.021]. ConclusionEvaluation by SEEG implantation in pediatric epilepsy is effective in localizing the epileptogenic zone with favorable outcome. Presence of a non-lesional brain MRI was associated with lower chances of seizure freedom. Further research is warranted to improve the efficacy of SEEG in localizing the epileptogenic zone in pediatric patients with non-lesional brain MRI.

Future of Neurology & Technology: Stereoelectroencephalography in Presurgical Epilepsy Evaluation.

Stereoelectroencephalography (SEEG) is not only a sophisticated and highly technological investigation but a new and better way to conceptualize the spatial and temporal dynamics of epileptic activity. The first intracranial investigations with SEEG were performed in France in the mid-twentieth century; however, its use in North America is much more recent. Given its significantly lower risk of complications and its ability to sample both superficial and deep structures and both hemispheres simultaneously, SEEG has become the preferred method to conduct intracranial EEG monitoring in most comprehensive epilepsy centers in North America. SEEG is an invasive neurophysiologic methodology used for advanced presurgical workup in the 20% of drug-resistant patients with more complex focal epilepsy in whom noninvasive investigations do not allow to decide on surgical candidacy. SEEG uses stereotactically implanted depth electrodes to map the origin and propagation of epileptic seizures by creating a 3-dimensional representation of the abnormal electrical activity in the brain. SEEG analysis takes into account the background, interictal, and ictal activity, as well as the results of cortical electrical stimulation procedures, to reliably delineate the epileptogenic network. By means of a clinical vignette, this article will walk general neurologists, but especially neurology trainees through the immense potential of this methodology. In summary, SEEG enables to accurately identify the epileptogenic zone in patients with drug-resistant focal epilepsy who otherwise would be not amenable to surgical treatment. In this patient population, SEEG is the best way to improve seizure control and achieve seizure freedom.

Real-World Preliminary Experience With Responsive Neurostimulation in Pediatric Epilepsy: A Multicenter Retrospective Observational Study.

Despite the well-documented utility of responsive neurostimulation (RNS, NeuroPace) in adult epilepsy patients, literature on the use of RNS in children is limited. To determine the real-world efficacy and safety of RNS in pediatric epilepsy patients. Patients with childhood-onset drug-resistant epilepsy treated with RNS were retrospectively identified at 5 pediatric centers. Reduction of disabling seizures and complications were evaluated for children (<18 yr) and young adults (>18 yr) and compared with prior literature pertaining to adult patients. Of 35 patients identified, 17 were <18yr at the time of RNS implantation, including a 3-yr-old patient. Four patients (11%) had concurrent resection. Three complications, requiring additional surgical interventions, were noted in young adults (2 infections [6%] and 1 lead fracture [3%]). No complications were noted in children. Among the 32 patients with continued therapy, 2 (6%) achieved seizure freedom, 4 (13%) achieved ≥90% seizure reduction, 13 (41%) had ≥50% reduction, 8 (25%) had <50%reduction, and 5 (16%) experienced no improvement. The average follow-up duration was 1.7 yr (median 1.8 yr, range 0.3-4.8 yr). There was no statistically significant difference for seizure reduction and complications between children and young adults in our cohort or between our cohort and the adult literature. These preliminary data suggest that RNS is well tolerated and an effective off-label surgical treatment of drug-resistant epilepsy in carefully selected pediatric patients as young as 3 yr of age. Data regarding long-term efficacy and safety in children will be critical to optimize patient selection.

Patient Characteristics Associated with Seizure Freedom after Vagus Nerve Stimulation in Pediatric Intractable Epilepsy: An Analysis of “Super-Responders”

AbstractClinical responses to vagus nerve stimulation (VNS) therapy for intractable epilepsy can be unpredictable, and factors that predict response to therapy are elusive. Minority of children undergoing VNS achieve seizure freedom. The current study aimed to characterize this exceptional patient population, defined as “super-responders” (SRs). Retrospective data were collected from 150 children who underwent VNS at a single pediatric institution. The patients' mean age at VNS device implantation was 12.0 years (range, 3.09–17.9 years). Ten SRs (6.7%) were identified who achieved and maintained seizure freedom for longer than 1 year following implantation. The interval between epilepsy onset and VNS device implantation was significantly shorter in SRs than in the other children (mean epilepsy duration 5.72 vs. 8.44 years, respectively; p = 0.032). SRs also had a significantly shorter proportion of life with epilepsy compared with the other children (mean ratio of epilepsy duration to age at implantation 0.52 vs. 0.71, respectively; p = 0.023). SRs reported their seizure freedom relatively early (six patients within 6 months and all patients within 12 months after implantation) at relatively low device settings (mean output current 0.81 mA at their last follow-up). Compared with conventional models, responsive VNS models with autostimulation features did not increase the ratio of SRs. No other clinical or imaging characteristic difference between SRs and the other children was found in this cohort. The current study showed a significant association between shorter epilepsy duration and shorter proportion of life with epilepsy and seizure freedom after VNS.

PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

A retrospective, real-world experience of perampanel monotherapy in patient with first new onset focal seizure: A Thailand experience.

ObjectiveReal‐world data on efficacy and tolerability of perampanel (PER) monotherapy in treatment‐naïve patients with focal onset seizures (FOS) and/or focal‐to‐bilateral tonic‐clonic seizures (FBTCS) to assess efficacy effectiveness and tolerability.MethodsThis is a retrospective review of study patients with new FOS with or without FBTCS, aged ≥15 years, who had been prescribed PER as monotherapy. Treatment outcome included retention rate, responder, and seizure‐free rate at observational point 3, 6, and 12 months (OP3, OP6, and OP12). Treatment‐emergent adverse events (TEAEs) and adverse drug reactions were recorded.ResultsA total of 41 patients enrolled in the study (male:female; 17:22, mean age =46.1 ± 21.8 years), with new FOS and/or FBTCS. The proportions of individuals remaining on PER monotherapy at 3, 6, and 12 months were evaluated. The median PER dosage was 4 mg (range 2‐8 mg). The retention rates at OP3, OP6, and OP12 were 88%, 73%, and 61%, respectively. The seizure freedom rates at OP3, OP6, and OP12 were 78%, 80%, and 76%, respectively. About 14% had discontinued the PER monotherapy because of lack of efficacy. Sixteen individuals (41%) had TEAEs; common AEs were dizziness, somnolence, and ataxia; and only one case had depression. The AEs with somnolence and ataxia were found higher in elderly (15% and 30%) than adult patients (7% and 3%), respectively. Only 14% had intolerant adverse events, and it was found higher in elderly (23%).SignificanceReal‐world data of PER monotherapy in treatment‐naïve patients with focal onset seizures demonstrated good effectiveness and a good safety profile at relatively low doses. By starting with low dosage and slow titration of PER help to minimize the impact of adverse effects, maximize adherence, and increase patient retention. PER has a once‐daily dosing schedule that supports patient adherence contributes to achieving seizure freedom.

Mapping Functional Connectivity of Epileptogenic Networks through Virtual Implantation.

Children with medically refractory epilepsy (MRE) require resective neurosurgery to achieve seizure freedom, whose success depends on accurate delineation of the epileptogenic zone (EZ). Functional connectivity (FC) can assess the extent of epileptic brain networks since intracranial EEG (icEEG) studies have shown its link to the EZ and predictive value for surgical outcome in these patients. Here, we propose a new noninvasive method based on magnetoencephalography (MEG) and high-density (HD-EEG) data that estimates FC metrics at the source level through an "implantation" of virtual sensors (VSs). We analyzed MEG, HD-EEG, and icEEG data from eight children with MRE who underwent surgery having good outcome and performed source localization (beamformer) on noninvasive data to build VSs at the icEEG electrode locations. We analyzed data with and without Interictal Epileptiform Discharges (IEDs) in different frequency bands, and computed the following FC matrices: Amplitude Envelope Correlation (AEC), Correlation (CORR), and Phase Locking Value (PLV). Each matrix was used to generate a graph using Minimum Spanning Tree (MST), and for each node (i.e., each sensor) we computed four centrality measures: betweenness, closeness, degree, and eigenvector. We tested the reliability of VSs measures with respect to icEEG (regarded as benchmark) via linear correlation, and compared FC values inside vs. outside resection. We observed higher FC inside than outside resection (p<0.05) for AEC [alpha (8-12 Hz), beta (12-30 Hz), and broadband (1-50 Hz)] on data with IEDs and AEC theta (4-8 Hz) on data without IEDs for icEEG, AEC broadband (1-50 Hz) on data without IEDs for MEG-VSs, as well as for all centrality measures of icEEG and MEG/HD-EEG-VSs. Additionally, icEEG and VSs metrics presented high correlation (0.6-0.9, p<0.05). Our data support the notion that the proposed method can potentially replicate the icEEG ability to map the epileptogenic network in children with MRE.Clinical Relevance - The estimation of FC with noninvasive techniques, such as MEG and HD-EEG, via VSs is a promising tool that would help the presurgical evaluation by delineating the EZ without waiting for a seizure to occur, and potentially improve the surgical outcome of patients with MRE undergoing surgery.

Seizure Onset Zone Identification Based on Phase-Amplitude Coupling of Interictal Electrocorticogram.

Presurgical localization from interictal electrocorticogram (ECoG) and resection of seizure onset zone (SOZ) are difficult processes to achieve seizure freedom. Recently, high frequency oscillations (HFOs) have been recognized as reliable biomarkers for epilepsy surgery which has a relation with the phase of low frequency activities in ECoG. Considering the recent valid biomarker for epilepsy surgery, we hypothesize that the approach of coupling between HFOs and low frequency phases differs SOZ from non-seizure onset zone (NSOZ). This study proposes phase-amplitude coupling (PAC) method to identify SOZ by measuring whether the amplitude of HFOs is coupled with a phase at 2-34 Hz in ECoG. Besides, three machine learning models for PAC-based features are designed for SOZ detection. Four patients with focal cortical dysplasia (FCD) are examined to observe efficiency. Experimental results indicate that the mode of coupling is a potential feature to detect SOZ.Clinical relevance- This suggests the PAC feature between low frequency phase and HFO amplitude may be used as a candidate biomarker to detect SOZ.