Epilepsy surgery in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) present significant treatment challenges due to frequent, drug-resistant seizures and comorbidities that impact quality of life. DEEs include both developmental encephalopathy from underlying pathology and epileptic encephalopathy where seizures exacerbate cognitive and behavioral impairments. Classification by syndrome and etiology is essential for therapy and prognosis, with common syndromes like infantile epileptic spasms syndrome and Dravet syndrome having specific first-line treatments. Etiologies are predominantly genetic, structural, or combined, with targeted therapies increasingly available. Surgery aims to improve seizure control but also may improve development, if the epileptic encephalopathy can be ameliorated. Timely intervention can reduce seizures and epileptiform discharges, maximizing developmental potential and allowing reduction in antiseizure medication. In cases requiring extensive resections, new deficits may be offset by developmental gains. Studies indicate that parents are generally willing to accept some deficits for significant seizure reduction.

Practical considerations for the use of fenfluramine to manage patients with Dravet syndrome or Lennox-Gastaut syndrome in clinical practice.

Fenfluramine (FFA), an antiseizure medication (ASM) with serotonergic and sigma-1 receptor activity, is used to manage patients with developmental and epileptic encephalopathies (DEEs). It is approved in the US for treating seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) in patients ≥2 years old and as add-on therapy for seizures associated with DS and LGS in the EU, UK, and Japan in similarly aged patients. Consensus guidelines for treatment of DS have recommended FFA to be an early-line ASM, and it has also shown efficacy in managing seizures associated with LGS. DS and LGS are DEEs associated with a range of seizure types, developmental impairments, and multiple comorbidities. Here we provide case vignettes describing 4 patients (3 DS and 1 LGS) aged 4-29 years old in whom up to 14 ASMs had previously failed, to illustrate real-world practice issues encountered by neurologists. This review provides guidance on the use of FFA in the context of ASM polytherapy and drug-drug interactions (DDIs), behavioral issues, dose titration, and adverse events. Along with data from the clinical trial program, these case vignettes emphasize the low risk of DDIs, a generally well-tolerated safety profile, and other seizure and nonseizure benefits (eg, improved cognition and sleep) associated with the use of FFA in DS or LGS. PLAIN LANGUAGE SUMMARY: Fenfluramine is used to treat seizures in individuals with Dravet syndrome and Lennox-Gastaut syndrome, but there are a range of issues that clinicians may face when treating patients. This review highlights four patients from the authors' everyday clinical work and offers guidance and practical considerations by neurologists with expertise in managing these complex conditions related to drug interactions, dosing, and side effects associated with fenfluramine.

Overview of clinical and physiologic aspects of status epilepticus in the developmental and epileptic encephalopathies.

The Developmental and Epileptic Encephalopathies are a group of severe epilepsies which onset in early life and are characterized by recurrent, drug-resistant seizures and multiple comorbidities including intellectual disability, behavior and sleep problems, gait concerns, amongst others. Both convulsive and nonconvulsive status epilepticus are frequently seen, however the exact risk and type of status epilepticus depends on the underlying syndrome or etiology. The baseline degree of developmental impairment and EEG features characterized by background slowing and persistent, and at times, near-continuous high-amplitude epileptiform discharges can make a clearcut diagnosis of nonconvulsive status epilepticus, in a timely manner, very challenging. Furthermore, there is limited guidance on best management of nonconvulsive status epilepticus, and success of therapy is often suboptimal.

Global modified-Delphi consensus on comorbidities and prognosis of SCN8A-related epilepsy and/or neurodevelopmental disorders.

OBJECTIVES: We aimed to develop consensus on comorbidities (frequency, severity, and prognosis) and overall outcomes in epilepsy, development, and cognition for the five phenotypes of SCN8A-related disorders. METHODS: A core panel consisting of 13 clinicians, 1 researcher, and 6 caregivers was formed and split into three workgroups. One group focused on comorbidities and prognosis. All groups performed a literature review and developed questions for use in a modified-Delphi process. Twenty-eight clinicians, one researcher, and 13 caregivers from 16 countries participated in three rounds of the modified-Delphi process. Consensus was defined as follows: strong consensus ≥80% fully agree; moderate consensus ≥80% fully or partially agree, <10% disagree; and modest consensus 67%-79% fully or partially agree, <10% disagree. RESULTS: Consensus was reached on the presence of 14 comorbidities in patients with Severe Developmental and Epileptic Encephalopathy (Severe DEE) spanning non-seizure neurological disorders and other organ systems; impacts were mostly severe and unlikely to improve or resolve. Across Mild/Moderate Developmental and Epileptic Encephalopathy (Mild/Moderate DEE), Neurodevelopmental Delay with Generalized Epilepsy (NDDwGE), and NDD without Epilepsy (NDDwoE) phenotypes, cognitive and sleep-related comorbidities as well as fine and gross motor delays may be present but are less severe and more likely to improve compared to Severe DEE. There was no consensus on comorbidities in the SeL(F)IE phenotype but strong conesensus that seizures would largely resolve. Seizure freedom is rare in patients with Severe DEE but may occur in some with Mild/Moderate DEE and NDDwGE. SIGNIFICANCE: Significant comorbidities are present in most phenotypes of SCN8A-related disorders but are most severe and pervasive in the Severe DEE phenotype. We hope that this work will improve recognition, early intervention, and long-term management for patients with these comorbidities and provide the basis for future evidence-based studies on optimal treatments of SCN8A-related disorders. Identifying the prognosis of patients with SCN8A-related disorders will also improve care and quality-of-life for patients and their caregivers.

Global modified Delphi consensus on diagnosis, phenotypes, and treatment of SCN8A-related epilepsy and/or neurodevelopmental disorders.

OBJECTIVE: We aimed to develop consensus for diagnosis/management of SCN8A-related disorders. Utilizing a modified Delphi process, a global cohort of experienced clinicians and caregivers provided input on diagnosis, phenotypes, treatment, and management of SCN8A-related disorders. METHODS: A Core Panel (13 clinicians, one researcher, six caregivers), divided into three subgroups (diagnosis/phenotypes, treatment, comorbidities/prognosis), performed a literature review and developed questions for the modified Delphi process. Twenty-eight expert clinicians, one researcher, and 13 caregivers from 16 countries participated in the subsequent three survey rounds. We defined consensus as follows: strong consensus, ≥80% fully agree; moderate consensus, ≥80% fully/partially agree, <10% disagree; and modest consensus, 67%-79% fully/partially agree, <10% disagree. RESULTS: Early diagnosis is important for long-term clinical outcomes in SCN8A-related disorders. There are five phenotypes: three with early seizure onset (severe developmental and epileptic encephalopathy [DEE], mild/moderate DEE, self-limited (familial) infantile epilepsy [SeL(F)IE]) and two with later/no seizure onset (neurodevelopmental delay with generalized epilepsy [NDDwGE], NDD without epilepsy [NDDwoE]). Caregivers represented six patients with severe DEE, five mild/moderate DEE, one NDDwGE, and one NDDwoE. Phenotypes vary by age at seizures/developmental delay onset, seizure type, electroencephalographic/magnetic resonance imaging findings, and first-line treatment. Gain of function (GOF) versus loss of function (LOF) is valuable for informing treatment. Sodium channel blockers are optimal first-line treatment for GOF, severe DEE, mild/moderate DEE, and SeL(F)IE; levetiracetam is relatively contraindicated in GOF patients. First-line treatment for NDDwGE is valproate, ethosuximide, or lamotrigine; sodium channel blockers are relatively contraindicated in LOF patients. SIGNIFICANCE: This is the first-ever global consensus for the diagnosis and treatment of SCN8A-related disorders. This consensus will reduce knowledge gaps in disease recognition and inform preferred treatment across this heterogeneous disorder. Consensus of this type allows more clinicians to provide evidence-based care and empowers SCN8A families to advocate for their children.

An Update on Stiripentol Mechanisms of Action: A Narrative Review.

Stiripentol (Diacomit®) (STP) is an orally active antiseizure medication (ASM) indicated as adjunctive therapy, for the treatment of seizures associated with Dravet syndrome (DS), a severe form of childhood epilepsy, in conjunction with clobazam and, in some regions valproic acid. Since the discovery of STP, several mechanisms of action (MoA) have been described that may explain its specific effect on seizures associated with DS. STP is mainly considered as a potentiator of gamma-aminobutyric acid (GABA) neurotransmission: (i) via uptake blockade, (ii) inhibition of degradation, but also (iii) as a positive allosteric modulator of GABAA receptors, especially those containing α3 and δ subunits. Blockade of voltage-gated sodium and T-type calcium channels, which is classically associated with anticonvulsant and neuroprotective properties, has also been demonstrated for STP. Finally, several studies indicate that STP could regulate glucose energy metabolism and inhibit lactate dehydrogenase. STP is also an inhibitor of several cytochrome P450 enzymes involved in the metabolism of other ASMs, contributing to boost their anticonvulsant efficacy as add-on therapy. These different MoAs involved in treatment of DS and recent data suggest a potential for STP to treat other neurological or non-neurological diseases.

Efficacy of felbamate in a cohort of patients with epilepsy with myoclonic atonic seizures (EMAtS).

Epilepsy with myoclonic atonic seizures (EMAtS) is a rare childhood onset developmental and epileptic encephalopathy which is frequently refractory to medical therapy. The optimal antiseizure medication remains unknown. This study reports the efficacy of felbamate in children with EMAtS. Six large pediatric epilepsy centers performed a retrospective chart review on patients diagnosed with EMAtS at their institutions and collected data on felbamate usage and efficacy. Responders were classified as patients who had a 50% or greater reduction in seizures with a given therapy. Out of 259 patients, 37 (14%) were treated with felbamate. The efficacy of felbamate was 62%, which was greater than that of either levetiracetam or valproic acid (15%, p < 0.001% and 32%, p = 0.001 respectively) and similar to that of the ketogenic diet (69%, p = 0.8). Felbamate appears to be an effective treatment for EMAtS and should be strongly considered in the treatment course of this disease.

Which terms should be used to describe medications used in the treatment of seizure disorders? An ILAE position paper.

A variety of terms, such as "antiepileptic," "anticonvulsant," and "antiseizure" have been historically applied to medications for the treatment of seizure disorders. Terminology is important because using terms that do not accurately reflect the action of specific treatments may result in a misunderstanding of their effects and inappropriate use. The present International League Against Epilepsy (ILAE) position paper used a Delphi approach to develop recommendations on English-language terminology applicable to pharmacological agents currently approved for treating seizure disorders. There was consensus that these medications should be collectively named "antiseizure medications". This term accurately reflects their primarily symptomatic effect against seizures and reduces the possibility of health care practitioners, patients, or caregivers having undue expectations or an incorrect understanding of the real action of these medications. The term "antiseizure" to describe these agents does not exclude the possibility of beneficial effects on the course of the disease and comorbidities that result from the downstream effects of seizures, whenever these beneficial effects can be explained solely by the suppression of seizure activity. It is acknowledged that other treatments, mostly under development, can exert direct favorable actions on the underlying disease or its progression, by having "antiepileptogenic" or "disease-modifying" effects. A more-refined terminology to describe precisely these actions needs to be developed.

Adaptive functioning and neurodevelopment in patients with Dravet syndrome: 12-month interim analysis of the BUTTERFLY observational study.

OBJECTIVE: The BUTTERFLY observational study aims to elucidate the natural trajectory of Dravet syndrome (DS) and associated comorbidities in order to establish a baseline for clinical therapies. We present the 12-month interim analysis of the study. MATERIALS AND METHODS: Patients with a genetically confirmed diagnosis of DS were enrolled in the study. Adaptive functioning and neurodevelopmental status were measured using the Vineland Adaptive Behavior Scale, Third Edition (Vineland-III), Bayley Scales of Infant Development, Third Edition (BSID-III), and Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition (WPPSI-IV). Executive function, ambulatory function and locomotor activities, and overall clinical status were measured using the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P) scale, Gillette Functional Assessment Questionnaire (Gillette FAQ), and Clinician or Caregiver Global Impression of Change scales (CGI-C or CaGI-C) respectively. RESULTS: Overall, 36 patients were enrolled across three age groups, with 35 patients completing at least part or all of one post-baseline visit through Month 12. Significant improvements in receptive communication, as assessed by Vineland-III and BSID-III raw scores, and in verbal comprehension subtests, as assessed by WPPSI-IV raw scores, were observed in BUTTERFLY patients for the all-patient group. Many patients performed on the impaired end of the BRIEF-P Global Executive Composite scale at baseline suggesting difficulties in executive function, and no significant change was observed in BRIEF-P scores for the all-patient group. Most patients performed in the dynamic range of the Gillette FAQ at baseline, and no significant change was observed in Gillette FAQ scores for the all-patient group. Lastly, there was significant improvement observed in the CaGI-C scores for the all-patient group. SIGNIFICANCE: This BUTTERFLY interim analysis shows small improvements in communication skills along with stability in other developmental abilities across patients with DS enrolled in the study from baseline to Month 12.

Long-term intellectual and developmental outcomes after pediatric epilepsy surgery: A systematic review and meta-analysis.

In addition to the primary aim of seizure freedom, a key secondary aim of pediatric epilepsy surgery is to stabilize and, potentially, optimize cognitive development. Although the efficacy of surgical treatment for seizure control has been established, the long-term intellectual and developmental trajectories are yet to be delineated. We conducted a systematic review and meta-analysis of studies reporting pre- and postsurgical intelligence or developmental quotients (IQ/DQ) of children with focal lesional epilepsy aged ≤18 years at epilepsy surgery and assessed at >2 years after surgery. We determined the IQ/DQ change and conducted a random-effects meta-analysis and meta-regression to assess its determinants. We included 15 studies reporting on 341 patients. The weighted mean age at surgery was 7.1 years (range = .3-13.8). The weighted mean postsurgical follow-up duration was 5.6 years (range = 2.7-12.8). The overall estimate of the mean presurgical IQ/DQ was 60 (95% confidence interval [CI] = 47-73), the postsurgical IQ/DQ was 61 (95% CI = 48-73), and the change was +.94 IQ/DQ (95% CI = -1.70 to 3.58, p = .486). Children with presurgical IQ/DQ ≥ 70 showed a tendency for higher gains than those with presurgical IQ/DQ < 70 (p = .059). Higher gains were determined by cessation of antiseizure medication (ASM; p = .041), not just seizure freedom. Our findings indicate, on average, stabilization of intellectual and developmental functioning at long-term follow-up after epilepsy surgery. Once seizure freedom has been achieved, ASM cessation enables the optimization of intellectual and developmental trajectories in affected children.

Severe communication delays are independent of seizure burden and persist despite contemporary treatments in SCN1A+ Dravet syndrome: Insights from the ENVISION natural history study.

OBJECTIVE: Dravet syndrome (DS) is a developmental and epileptic encephalopathy characterized by high seizure burden, treatment-resistant epilepsy, and developmental stagnation. Family members rate communication deficits among the most impactful disease manifestations. We evaluated seizure burden and language/communication development in children with DS. METHODS: ENVISION was a prospective, observational study evaluating children with DS associated with SCN1A pathogenic variants (SCN1A+ DS) enrolled at age ≤5 years. Seizure burden and antiseizure medications were assessed every 3 months and communication and language every 6 months with the Bayley Scales of Infant and Toddler Development 3rd edition and the parent-reported Vineland Adaptive Behavior Scales 3rd edition. We report data from the first year of observation, including analyses stratified by age at Baseline: 0:6-2:0 years:months (Y:M; youngest), 2:1-3:6 Y:M (middle), and 3:7-5:0 Y:M (oldest). RESULTS: Between December 2020 and March 2023, 58 children with DS enrolled at 16 sites internationally. Median follow-up was 17.5 months (range = .0-24.0), with 54 of 58 (93.1%) followed for at least 6 months and 51 of 58 (87.9%) for 12 months. Monthly countable seizure frequency (MCSF) increased with age (median [minimum-maximum] = 1.0 in the youngest [1.0-70.0] and middle [1.0-242.0] age groups and 4.5 [.0-2647.0] in the oldest age group), and remained high, despite use of currently approved antiseizure medications. Language/communication delays were observed early, and developmental stagnation occurred after age 2 years with both instruments. In predictive modeling, chronologic age was the only significant covariate of seizure frequency (effect size = .52, p = .024). MCSF, number of antiseizure medications, age at first seizure, and convulsive status epilepticus were not predictors of language/communication raw scores. SIGNIFICANCE: In infants and young children with SCN1A+ DS, language/communication delay and stagnation were independent of seizure burden. Our findings emphasize that the optimal therapeutic window to prevent language/communication delay is before 3 years of age.

Scoping review and expert-based consensus recommendations for assessment and management of psychogenic non-epileptic (functional) seizures (PNES) in children: A report from the Pediatric Psychiatric Issues Task Force of the International League Against Epilepsy.

Limited guidance exists regarding the assessment and management of psychogenic non-epileptic seizures (PNES) in children. Our aim was to develop consensus-based recommendations to fill this gap. The members of the International League Against Epilepsy (ILAE) Task Force on Pediatric Psychiatric Issues conducted a scoping review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SR) standards. This was supplemented with a Delphi process sent to pediatric PNES experts. Consensus was defined as ≥80% agreement. The systematic search identified 77 studies, the majority (55%) of which were retrospective (only one randomized clinical trial). The primary means of PNES identification was video electroencephalography (vEEG) in 84% of studies. Better outcome was associated with access to counseling/psychological intervention. Children with PNES have more frequent psychiatric disorders than controls. The Delphi resulted in 22 recommendations: Assessment-There was consensus on the importance of (1) taking a comprehensive developmental history; (2) obtaining a description of the events; (3) asking about potential stressors; (4) the need to use vEEG if available parent, self, and school reports and video recordings can contribute to a "probable" diagnosis; and (5) that invasive provocation techniques or deceit should not be employed. Management-There was consensus about the (1) need for a professional with expertise in epilepsy to remain involved for a period after PNES diagnosis; (2) provision of appropriate educational materials to the child and caregivers; and (3) that the decision on treatment modality for PNES in children should consider the child's age, cognitive ability, and family factors. Comorbidities-There was consensus that all children with PNES should be screened for mental health and neurodevelopmental difficulties. Recommendations to facilitate the assessment and management of PNES in children were developed. Future directions to fill knowledge gaps were proposed.

How have the recent updated epilepsy classifications impacted on diagnosis and treatment?

INTRODUCTION: Epilepsies are a diverse group of disorders which differ regarding prognosis for seizure control and associated comorbidities. Accurate classification is critical to choose the highest yield investigations and best therapeutic options and to provide the most accurate prognoses regarding the expected degree of seizure control, possible remission, and risk of associated comorbidities to patients and their families. This article reviews the recent updates in epilepsy classification to illustrate how accurate classification impacts care for persons with epilepsy. AREAS COVERED: The authors discuss the ILAE 2017 Classification of the Epilepsies along with the modification of the classification for neonatal seizures and epilepsies. They also discuss the ILAE position papers on Epilepsy syndromes in neonates and infants and children of variable age and the Idiopathic Generalized Epilepsies. EXPERT OPINION: Accurate epilepsy classification allows selection of the highest yield investigations, choice of optimal therapies, and accurate prognostication of seizures (likelihood of response to antiseizure treatments and likelihood of remission with age), as well as comorbidities (likelihood, type, and severity). As we move into the era of disease modifying therapy, early accurate identification of underlying causes with timely introduction of specific treatments will be crucial to lessen the severity of epilepsy, with improved seizure control and attenuation of associated comorbidities.

Pediatric psychogenic non-epileptic seizures: A retrospective observational cohort study at a quaternary center.

BACKGROUND: Psychogenic non-epileptic seizures (PNES) represent a common functional disorder in the pediatric population. We aimed to characterize pediatric PNES by describing their clinical characteristics, PNES semiologies, and healthcare pathway towards and after diagnosis. MATERIAL AND METHODS: This was a retrospective, observational chart review of pediatric patients aged 6 to 18 years admitted between December 2020 and December 2021 for spell classification or suspected PNES. Psychogenic non-epileptic seizure diagnosis was made by the capture of a typical event on video electroencephalogram (vEEG). We used descriptive statistics to summarize demographic and clinical characteristics. RESULTS: We included 26 patients (18 females, 69.2%) with a mean age (SD) of 13.9 (2.5) years. Pre-morbid neurologic and psychiatric conditions included: epilepsy (23.1%), migraine (46.2%), mild traumatic brain injury (26.9%), anxiety (57.7%), ADHD (34.6%), and depression (30.8%). Six patients (23.1%) had a prior diagnosis of PNES. 14 patients (53.8%) presented with convulsive, and 6 (23.1%) each with non-convulsive and mixed PNES. Patients were seen by a range of providers prior to diagnosis including ED providers (50%), neurologists (53.8%), pediatricians (34.6%), and psychology/psychiatry (11.5%). Emergency department evaluation occurred for 13 patients (50%) on 15 occasions, and six (23.1%) were admitted to the hospital. The median (p25-p75) time from PNES onset to presentation and diagnosis at our institution was 3.5 (1.5-6.2) and 4.1 (3-7) months, respectively. A total of 33 events from the 26 patients were captured on vEEG. The most frequent semiologies in our cohort were rhythmic motor (27.3%) followed by equal frequency (18.2%) of complex motor and dialeptic. Eighteen patients (69.2%) were followed after the PNES diagnosis, for a median (p25-p75) of 17.3 months (6.3-21) with variable outcome. CONCLUSION: Pediatric PNES has female predominance and often presents with comorbid psychosocial stressors and psychiatric conditions. High clinical suspicion and early recognition are crucial to decrease healthcare utilization and establish timely diagnosis and treatment.

Clinical presentation and evaluation of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: The objective of this study was to determine areas of consensus among an international panel of experts for the clinical presentation and diagnosis of epilepsy with eyelid myoclonia (EEM; formerly known as Jeavons syndrome) to improve a timely diagnosis. METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This international expert panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the diagnosis of EEM. RESULTS: There was a strong consensus that EEM is a female predominant generalized epilepsy syndrome with onset between 3 and 12 years of age and that eyelid myoclonia must be present to make the diagnosis. There was a strong consensus that eyelid myoclonia may go unrecognized for years prior to an epilepsy diagnosis. There was consensus that generalized tonic-clonic and absence seizures are typically or occasionally seen in patients. There was a consensus that atonic or focal seizures should lead to the consideration of reclassification or alternate diagnoses. There was a strong consensus that electroencephalography is required, whereas magnetic resonance imaging is not required for diagnosis. There was a strong consensus to perform genetic testing (either epilepsy gene panel or whole exome sequencing) when one or a combination of factors was present: family history of epilepsy, intellectual disability, or drug-resistant epilepsy. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the presentation and evaluation of EEM. These areas of consensus may be used to inform clinical practice to shorten the time to the appropriate diagnosis.

Management of epilepsy with eyelid myoclonia: Results of an international expert consensus panel.

OBJECTIVE: There are limited data about the treatment and management of epilepsy with eyelid myoclonia (EEM). The objective of this study was to determine areas of consensus among an international panel of experts for the management of EEM (formerly known as Jeavons syndrome). METHODS: An international steering committee was convened of physicians and patients/caregivers with expertise in EEM. This committee summarized the current literature and identified an international panel of experts (comprising 25 physicians and five patients/caregivers). This panel participated in a modified Delphi process, including three rounds of surveys to determine areas of consensus for the treatment, other areas of management, and prognosis for EEM. RESULTS: There was a strong consensus for valproic acid as the first-line treatment, with levetiracetam or lamotrigine as preferable alternatives for women of childbearing age. There was a moderate consensus that ethosuximide and clobazam are also efficacious. There was a strong consensus to avoid sodium channel-blocking medications, except for lamotrigine, as they may worsen seizure control. There was consensus that seizures typically persist into adulthood, with remission occurring in <50% of patients. There was less agreement about other areas of management, including dietary therapy, lens therapy, candidacy for driving, and outcome. SIGNIFICANCE: This international expert panel identified multiple areas of consensus regarding the optimal management of EEM. These areas of consensus may inform clinical practice to improve the management of EEM. In addition, multiple areas with less agreement were identified, which highlight topics for further research.

Drug resistance in epilepsy.

Drug resistance is estimated to affect about a third of individuals with epilepsy, but its prevalence differs in relation to the epilepsy syndrome, the cause of epilepsy, and other factors such as age of seizure onset and presence of associated neurological deficits. Although drug-resistant epilepsy is not synonymous with unresponsiveness to any drug treatment, the probability of achieving seizure freedom on a newly tried medication decreases with increasing number of previously failed treatments. After two appropriately used antiseizure medications have failed to control seizures, individuals should be referred whenever possible to a comprehensive epilepsy centre for diagnostic re-evaluation and targeted management. The feasibility of epilepsy surgery and other treatments, including those targeting the cause of epilepsy, should be considered early after diagnosis. Substantial evidence indicates that a delay in identifying an effective treatment can adversely affect ultimate outcome and carry an increased risk of cognitive disability, other comorbidities, and premature mortality. Research on mechanisms of drug resistance and novel therapeutics is progressing rapidly, and potentially improved treatments, including those targeting disease modification, are on the horizon.

Stereo-EEG localization of midline onset seizures on scalp EEG.

PURPOSE: The objective of this study was to describe the sEEG-defined seizure onset zone (SOZ), seizure semiology, presurgical evaluations, surgical intervention and outcome in patients with midline onset noninvasive phase I monitoring. METHODS: A single center sEEG database was reviewed to identify patients with seizures onset predominantly involving midline electrodes (FZ, CZ, PZ, OZ) on scalp EEG. Data abstracted included clinical factors, seizure semiology graded into lobar segmentation, imaging and electrographic findings, sEEG plan, interventions, and outcome. RESULTS: Twelve patients were identified (8 males, median age of sEEG 28 years) out of 100 cases of sEEG performed from January 2015-September 2019. "Frontal lobe" seizure semiology was the most common. sEEG-defined SOZ were frontal (5), diffuse (1), multifocal (1), frontal and insular (1), frontal and cingulate (1), insular (1), cingulate (1), and mesial temporal (1). CZ and/or FZ scalp EEG changes were present for all patients with SOZ involving the frontal, cingulate, and insular regions. PZ/OZ scalp involvement was present in one patient with mesial temporal SOZ. Four patients underwent a definitive resective or ablative surgery, and the remaining patients underwent a palliative intervention. Of those with follow-up information available, 8/11 had seizure reduction by ≥ 50%, including 4 with an Engel I outcome. No clinical factors were associated with outcome. CONCLUSIONS: SOZ for midline onset seizures from noninvasive phase I monitoring was most commonly in the frontal, cingulate, and insular regions. A complex cortical network between these regions may explain overlap in semiology and scalp EEG findings. While the number rendered seizure-free was limited, a significant proportion experienced a reasonably favorable outcome justifying use of sEEG to identify surgical options in these patients.