Verbal memory network mapping in individual patients predicts postoperative functional impairments.

Verbal memory decline is a significant concern following temporal lobe surgeries in patients with epilepsy, emphasizing the need for precision presurgical verbal memory mapping to optimize functional outcomes. However, the inter-individual variability in functional networks and brain function-structural dissociations pose challenges when relying solely on group-level atlases or anatomical landmarks for surgical guidance. Here, we aimed to develop and validate a personalized functional mapping technique for verbal memory using precision resting-state functional MRI (rs-fMRI) and neurosurgery. A total of 38 patients with refractory epilepsy scheduled for surgical interventions were enrolled and 28 patients were analyzed in the study. Baseline 30-min rs-fMRI scanning, verbal memory and language assessments were collected for each patient before surgery. Personalized verbal memory networks (PVMN) were delineated based on preoperative rs-fMRI data for each patient. The accuracy of PVMN was assessed by comparing post-operative functional impairments and the overlapping extent between PVMN and surgical lesions. A total of 14 out of 28 patients experienced clinically meaningful declines in verbal memory after surgery. The personalized network and the group-level atlas exhibited 100% and 75.0% accuracy in predicting postoperative verbal memory declines, respectively. Moreover, six patients with extra-temporal lesions that overlapped with PVMN showed selective impairments in verbal memory. Furthermore, the lesioned ratio of the personalized network rather than the group-level atlas was significantly correlated with postoperative declines in verbal memory (personalized networks: r = -0.39, p = .038; group-level atlas: r = -0.19, p = .332). In conclusion, our personalized functional mapping technique, using precision rs-fMRI, offers valuable insights into individual variability in the verbal memory network and holds promise in precision verbal memory network mapping in individuals.

Drug-resistant epilepsy and ketogenic diet therapy - a qualitative study of families' experiences.

BACKGROUND: A diagnosis of drug-resistant epilepsy is life changing for a family. Ketogenic diet therapy (KDT) can offer hope when other treatments have failed. However, it often requires a significant change in daily routine and dietary habits. This qualitative descriptive study aimed to explore families' experiences of epilepsy and KDT. METHODS: Parents of a child aged ≤18 years with epilepsy, currently or recently treated with KDT, were recruited from the UK and internationally via UK Ketogenic Diet (KD) centres, charities, and social media. Semi-structured interviews were audio recorded, transcribed verbatim, anonymised, coded using Nvivo (V12), and inductive thematic analysis undertaken. RESULTS: Twenty-one parents participated. Four themes and 12 subthemes emerged: 1. 'Epilepsy is all consuming' explored the impact of epilepsy on the family. 2. 'KD provides a window to new opportunities' explores the motivators for KDT and positive outcomes. 3. 'The reality of KD' explores day to day life and how families adapt to KD. 4. 'Looking to the future' explores the factors that may make KD easier for families. All were glad their child trialled KD, even when less successful. The importance of a support network including family, friends, charity organisations and the KD team was evident across all themes. CONCLUSIONS: We conclude with five recommendations to help support families in their management of KDT; Improved access to KDT and transition to adult services, access to quality education and support, enhanced variety of KD foods, regular social education and finally consideration of peer mentoring.

High-precision stereotactic irradiation for focal drug-resistant epilepsy versus standard treatment: a randomized waitlist-controlled trial (the PRECISION trial).

INTRODUCTION: The standard treatment for patients with focal drug-resistant epilepsy (DRE) who are not eligible for open brain surgery is the continuation of anti-seizure medication (ASM) and neuromodulation. This treatment does not cure epilepsy but only decreases severity. The PRECISION trial offers a non-invasive, possibly curative intervention for these patients, which consist of a single stereotactic radiotherapy (SRT) treatment. Previous studies have shown promising results of SRT in this patient population. Nevertheless, this intervention is not yet available and reimbursed in the Netherlands. We hypothesize that: SRT is a superior treatment option compared to palliative standard of care, for patients with focal DRE, not eligible for open surgery, resulting in a higher reduction of seizure frequency (with 50% of the patients reaching a 75% seizure frequency reduction at 2 years follow-up). METHODS: In this waitlist-controlled phase 3 clinical trial, participants are randomly assigned in a 1:1 ratio to either receive SRT as the intervention, while the standard treatments consist of ASM continuation and neuromodulation. After 2-year follow-up, patients randomized for the standard treatment (waitlist-control group) are offered SRT. Patients aged ≥ 18 years with focal DRE and a pretreatment defined epileptogenic zone (EZ) not eligible for open surgery will be included. The intervention is a LINAC-based single fraction (24 Gy) SRT treatment. The target volume is defined as the epileptogenic zone (EZ) on all (non) invasive examinations. The seizure frequency will be monitored on a daily basis using an electronic diary and an automatic seizure detection system during the night. Potential side effects are evaluated using advanced MRI, cognitive evaluation, Common Toxicity Criteria, and patient-reported outcome questionnaires. In addition, the cost-effectiveness of the SRT treatment will be evaluated. DISCUSSION: This is the first randomized trial comparing SRT with standard of care in patients with DRE, non-eligible for open surgery. The primary objective is to determine whether SRT significantly reduces the seizure frequency 2 years after treatment. The results of this trial can influence the current clinical practice and medical cost reimbursement in the Netherlands for patients with focal DRE who are not eligible for open surgery, providing a non-invasive curative treatment option. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT05182437. Registered on September 27, 2021.

Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Stereoelectroencephalography-guided radiofrequency thermocoagulation of the epileptogenic zone: a potential treatment and prognostic indicator for subsequent excision surgery.

PURPOSE: To evaluate the safety and efficacy of stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) for drug-resistant focal epilepsy and investigate the relationship between post-RFTC remission duration and delayed excision surgery effectiveness. METHODS: We conducted a retrospective analysis of 43 patients with drug-resistant focal epilepsy who underwent RFTC via SEEG electrodes. After excluding three, the remaining 40 were classified into subgroups based on procedures and outcomes. Twenty-four patients (60%) underwent a secondary excision surgery. We determined the predictive value of RFTC outcome upon subsequent surgical outcome by categorizing the delayed secondary surgery outcome as success (Engel I/II) versus failure (Engel III/IV). Demographic information, epilepsy characteristics, and the duration of seizure freedom after RFTC were assessed. RESULTS: Among 40 patients, 20% achieved Engel class I with RFTC alone, while 24 underwent delayed secondary excision surgery. Overall, 41.7% attained Engel class I, with a 66.7% success rate combining RFTC with delayed surgery. Seizure freedom duration was significantly longer in the success group (mean 4.9 months, SD = 2.7) versus the failure group (mean 1.9 months, SD = 1.1; P = 0.007). A higher proportion of RFTC-only and delayed surgical success group patients had preoperative lesional findings (p = 0.01), correlating with a longer time to seizure recurrence (p < 0.05). Transient postoperative complications occurred in 10%, resolving within a year. CONCLUSION: This study demonstrates that SEEG-guided RFTC is a safe and potential treatment option for patients with drug-resistant focal epilepsy. A prolonged duration of seizure freedom following RFTC may serve as a predictive marker for the success of subsequent excision surgery.

Synaptic vesicle protein 2A mitigates parthanatos via apoptosis-inducing factor in a rat model of pharmacoresistant epilepsy.

AIMS: Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF. METHODS: An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF. RESULTS: Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction. SIGNIFICANCE: SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.

EEG Ictal Power Dynamics, Function-Structure Associations, and Epilepsy Surgical Outcomes.

BACKGROUND AND OBJECTIVES: Postoperative seizure control in drug-resistant temporal lobe epilepsy (TLE) remains variable, and the causes for this variability are not well understood. One contributing factor could be the extensive spread of synchronized ictal activity across networks. Our study used novel quantifiable assessments from intracranial EEG (iEEG) to test this hypothesis and investigated how the spread of seizures is determined by underlying structural network topological properties. METHODS: We evaluated iEEG data from 157 seizures in 27 patients with TLE: 100 seizures from 17 patients with postoperative seizure control (Engel score I) vs 57 seizures from 10 patients with unfavorable surgical outcomes (Engel score II-IV). We introduced a quantifiable method to measure seizure power dynamics within anatomical regions, refining existing seizure imaging frameworks and minimizing reliance on subjective human decision-making. Time-frequency power representations were obtained in 6 frequency bands ranging from theta to gamma. Ictal power spectrums were normalized against a baseline clip taken at least 6 hours away from ictal events. Electrodes' time-frequency power spectrums were then mapped onto individual T1-weighted MRIs and grouped based on a standard brain atlas. We compared spatiotemporal dynamics for seizures between groups with favorable and unfavorable surgical outcomes. This comparison included examining the range of activated brain regions and the spreading rate of ictal activities. We then evaluated whether regional iEEG power values were a function of fractional anisotropy (FA) from diffusion tensor imaging across regions over time. RESULTS: Seizures from patients with unfavorable outcomes exhibited significantly higher maximum activation sizes in various frequency bands. Notably, we provided quantifiable evidence that in seizures associated with unfavorable surgical outcomes, the spread of beta-band power across brain regions is significantly faster, detectable as early as the first second after seizure onset. There was a significant correlation between beta power during seizures and FA in the corresponding areas, particularly in the unfavorable outcome group. Our findings further suggest that integrating structural and functional features could improve the prediction of epilepsy surgical outcomes. DISCUSSION: Our findings suggest that ictal iEEG power dynamics and the structural-functional relationship are mechanistic factors associated with surgical outcomes in TLE.

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE).

BACKGROUND AND OBJECTIVES: New-onset refractory status epilepticus (NORSE) occurs in previously healthy children or adults, often followed by refractory epilepsy and poor outcomes. The mechanisms that transform a normal brain into an epileptic one capable of seizing for prolonged periods despite treatment remain unclear. Nonetheless, several pieces of evidence suggest that immune dysregulation could contribute to hyperexcitability and modulate NORSE sequelae. METHODS: We used single-nucleus RNA sequencing to delineate the composition and phenotypic states of the CNS of 4 patients with NORSE, to better understand the relationship between hyperexcitability and immune disturbances. We compared them with 4 patients with chronic temporal lobe epilepsy (TLE) and 2 controls with no known neurologic disorder. RESULTS: Patients with NORSE and TLE exhibited a significantly higher proportion of excitatory neurons compared with controls, with no discernible difference in inhibitory GABAergic neurons. When examining the ratio between excitatory neurons and GABAergic neurons for each patient individually, we observed a higher ratio in patients with acute NORSE or TLE compared with controls. Furthermore, a negative correlation was found between the ratio of excitatory to GABAergic neurons and the proportion of GABAergic neurons. The ratio between excitatory neurons and GABAergic neurons correlated with the proportion of resident or infiltrating macrophages, suggesting the influence of microglial reactivity on neuronal excitability. Both patients with NORSE and TLE exhibited increased expression of genes associated with microglia activation, phagocytic activity, and NLRP3 inflammasome activation. However, patients with NORSE had decreased expression of genes related to the downregulation of the inflammatory response, potentially explaining the severity of their presentation. Microglial activation in patients with NORSE also correlated with astrocyte reactivity, possibly leading to higher degrees of demyelination. DISCUSSION: Our study sheds light on the complex cellular dynamics in NORSE, revealing the potential roles of microglia, infiltrating macrophages, and astrocytes in hyperexcitability and demyelination, offering potential avenues for future research targeting the identified pathways.

Postoperative Neurologic Outcome in Patients Undergoing Resective Surgery for Parietal Lobe Epilepsy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Parietal lobe epilepsy (PLE) surgery can be an effective treatment for selected patients with intractable epilepsy but can be associated with the risk of serious neurologic deficits. We performed a systematic review of the literature to obtain a comprehensive summary of the frequency and types of new postoperative neurologic deficits in patients undergoing PLE resective surgery. METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published between January 1, 1990, and April 28, 2022. We included studies that reported postoperative neurologic outcome following PLE resective surgery confined to the parietal lobe. We required that studies included ≥5 patients. The data collected included demographic information and specific details of postoperative neurologic deficits. When available, individual patient data were collected. We used the Risk of Bias in Nonrandomized Studies of Interventions tool to assess the risk of bias and Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence. RESULTS: Of the 3,461 articles screened, 33 studies met the inclusion criteria. A total of 370 patients were included. One hundred patients (27.0%) had a new deficit noted postoperatively. Approximately half of the patients with deficits experienced only transient deficits. Motor deficits were the most commonly identified deficit. The rates of motor deficits noted after PLE surgery were 5.7%, 3.2%, and 2.2% for transient, long-term, and duration not specified, respectively. Sensory and visual field deficits were also commonly reported. Gerstmann syndrome was noted postoperatively in 4.9% of patients and was almost always transient. Individual patient data added information on parietal lobe subregion postoperative neurologic outcome. DISCUSSION: Our systematic review provides a comprehensive summary of the frequency and types of neurologic deficits associated with PLE surgery. A significant percentage of postoperative deficits are transient. In addition to the expected sensory and visual deficits, PLE surgery is associated with a notable risk of motor deficits. The available literature has important deficiencies. Our study highlights gaps in the literature and provides recommendations for future directions. TRIAL REGISTRATION INFORMATION: This systematic review was registered on PROSPERO (CRD42022313108, May 26, 2022).

Memory and language risk assessment with Wada test in patients candidates for epilepsy surgery. / Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.

AIM: To determine post-surgical cognitive risk and associated factors according to lesion location in a sample of patients evaluated for epilepsy surgery with Wada test at the Fundacion Instituto Neurologico de Colombia. MATERIALS AND METHODS: An observational, retrospective, analytical study was completed in patients with drug-resistant temporal lobe epilepsy candidates for epilepsy surgery treated from 2001 to 2021, who completed the Wada test as part of the pre-surgical evaluation. A descriptive analysis of sociodemographic, clinical, imaging and neuropsychological variables was completed; a multivariate logistic regression was performed analyzing factors associated with resection risk in patients with left lesions. RESULTS A total of 369 patients were included, 54.74% of the cases were women, with a median age of seizure onset of 11 years. 92.66% of the cases had lesional epilepsy and 68.56% were secondary to hippocampal sclerosis. Left hemisphere was the most frequently affected (65.68%) being dominant for memory and language in most of the patients with a proportion of 42.82% and 81.3%, respectively. The median functional adequacy was 43.75 (IQR 0-75) and the functional reserve was 75 (IQR 25 -93.75). In 104 patients, the Wada test determined a resection risk. In patients with a left lesion, it was found that functional reserve (PRadjusted 0.99, CI 95% 0.9997-0.9998) and having a right hemispheric dominance for memory (PRadjusted 0.92, CI 95% 0.547-0.999) were protective factors for post-surgical resection risk. CONCLUSION: Wada test is a useful tool for surgical decision-making in patients with drug-resistant temporal lobe epilepsy. When considering cognitive risk, components such as memory dominance and functional reserve should be considered as protective factors for postsurgical cognitive function preservation in patients with left lesions.

TITLE: Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.Objetivo. Determinar el riesgo cognitivo posquirúrgico y factores asociados según la localización de la lesión en una muestra de pacientes evaluados para cirugía de epilepsia con el test de Wada en la Fundación Instituto Neurológico de Colombia. Materiales y métodos. Se realizó un estudio observacional, retrospectivo y analítico en pacientes con epilepsia farmacorresistente del lóbulo temporal candidatos a cirugía de epilepsia tratados entre 2001 y 2021, que completaron el test de Wada como parte de la evaluación prequirúrgica. Se realizó un análisis descriptivo de variables sociodemográficas, clínicas, imagenológicas y neuropsicológicas. Se realizó una regresión logística multivariada analizando factores asociados al riesgo de resección en pacientes con lesiones izquierdas. Resultados. Se incluyó a 369 pacientes, el 54,74% de los casos fueron mujeres, con una mediana de edad de inicio de las convulsiones de 11 años. El 92,66% de los casos presentó epilepsia lesional; de éstos, el 68,56% fue secundario a esclerosis hipocampal. El hemisferio izquierdo fue el más frecuentemente afectado (65,68%), y éste fue dominante para la memoria y el lenguaje en la mayoría de los pacientes, con una proporción del 42,82 y el 81,3%, respectivamente. La mediana de adecuación funcional fue de 43,75 (rango intercuartílico: 0-75) y la reserva funcional de 75 (rango intercuartílico: 25-93,75). En 104 pacientes, el test de Wada determinó un riesgo de resección. En pacientes con lesiones izquierdas se encontró que la reserva funcional (razón de prevalencia ajustada: 0,99; intervalo de confianza al 95%: 0,9997-0,9998) y tener dominancia del hemisferio derecho para la memoria (razón de prevalencia ajustada: 0,92; intervalo de confianza al 95%: 0,547-0,999) fueron factores asociados para determinar el riesgo de resección posquirúrgico en el test de Wada. Conclusión. El test de Wada es una herramienta útil para la toma de decisiones quirúrgicas en pacientes con epilepsia del lóbulo temporal farmacorresistente. Componentes como la dominancia de la memoria y la reserva funcional en el test de Wada deben considerarse como factores que se deben tener en cuenta en la predicción de la preservación de la función cognitiva posquirúrgica en pacientes con lesiones izquierdas.

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.

The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the ß-hydroxybutyrate (ßHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-ßHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the ßHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the ßHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

Long-term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial.

A post hoc analysis of data from Asian patients included in the study BIA-2093-304 was conducted to evaluate the long-term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12-week maintenance period. Patients completing Part I could enter two open-label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400-1600 mg QD). Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL-related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL-related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

Novel Surgical Approaches in Childhood Epilepsy: Laser, Brain Stimulation, and Focused Ultrasound.

Pediatric epilepsy has a worldwide prevalence of approximately 1% (Berg et al., Handb Clin Neurol 111:391-398, 2013) and is associated with not only lower quality of life but also long-term deficits in executive function, significant psychosocial stressors, poor cognitive outcomes, and developmental delays (Schraegle and Titus, Epilepsy Behav 62:20-26, 2016; Puka and Smith, Epilepsia 56:873-881, 2015). With approximately one-third of patients resistant to medical control, surgical intervention can offer a cure or palliation to decrease the disease burden and improve neurological development. Despite its potential, epilepsy surgery is drastically underutilized. Even today only 1% of the millions of epilepsy patients are referred annually for neurosurgical evaluation, and the average delay between diagnosis of Drug Resistant Epilepsy (DRE) and surgical intervention is approximately 20 years in adults and 5 years in children (Solli et al., Epilepsia 61:1352-1364, 2020). It is still estimated that only one-third of surgical candidates undergo operative intervention (Pestana Knight et al., Epilepsia 56:375, 2015). In contrast to the stable to declining rates of adult epilepsy surgery (Englot et al., Neurology 78:1200-1206, 2012; Neligan et al., Epilepsia 54:e62-e65, 2013), rates of pediatric surgery are rising (Pestana Knight et al., Epilepsia 56:375, 2015). Innovations in surgical approaches to epilepsy not only minimize potential complications but also expand the definition of a surgical candidate. In this chapter, three alternatives to classical resection are presented. First, laser ablation provides a minimally invasive approach to focal lesions. Next, both central and peripheral nervous system stimulation can interrupt seizure networks without creating permanent lesions. Lastly, focused ultrasound is discussed as a potential new avenue not only for ablation but also modulation of small, deep foci within seizure networks. A better understanding of the potential surgical options can guide patients and providers to explore all treatment avenues.

Monopolar stereoelectroencephalography-guided radiofrequency thermocoagulation.

OBJECTIVE: Stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) has the advantage of producing a lesion in the epileptogenic zone (EZ) at the end of SEEG. The majority of published SEEG-guided RFTCs have been bipolar and usually performed between contiguous contacts of the same electrode. In the present study, the authors evaluate the safety, efficacy, and benefits of monopolar RFTC at the end of SEEG. METHODS: This study included a series of 31 consecutive patients who had undergone RFTC at the end of SEEG for drug-resistant focal epilepsy in the period of January 2013-December 2019. Post-RFTC seizure control was assessed after 2 months and at the last follow-up visit. Twenty-one patients underwent resective epilepsy surgery after the SEEG-guided RFTC, and the postoperative seizure outcome among these patients was compared with the post-RFTC seizure outcome. RESULTS: Four hundred forty-six monopolar RFTCs were done in the 31 patients. Monopolar RFTCs were performed in all cortical areas, including the insular cortex in 11 patients (56 insular RFTCs). There were 31 noncontiguous lesions (7.0%) because of vascular constraints. The volume of one monopolar RFTC, as measured on T2-weighted MRI immediately after the procedure, was between 44 and 56 mm3 (mean 50 mm3). The 2-month post-RFTC seizure outcomes were as follows: seizure freedom in 13 patients (41.9%), ≥ 50% reduced seizure frequency in 11 (35.5%), and no significant change in 7 (22.6%). Seizure outcome at the last follow-up visit (mean 18 months, range 2-54 months) showed seizure freedom in 2 patients (6.5%) and ≥ 50% reduced seizure frequency in 20 patients (64.5%). Seizure freedom after monopolar RFTC was not significantly associated with the number or location of coagulated contacts. Seizure response after monopolar RFTC had a high positive predictive value (93.8%) but a low negative predictive value (40%) for seizure outcome after subsequent resective surgery. In this series, the only complication (3.2%) was a limited intraventricular hematoma following RFTC performed in the hippocampal head, with spontaneous resolution and no sequelae. CONCLUSIONS: The use of monopolar SEEG-guided RFTC provides more freedom in terms of choosing the SEEG contacts for thermocoagulation and a larger thermolesion volume. Monopolar thermocoagulation seems particularly beneficial in cases with an insular EZ, in which vascular constraints could be partially avoided by making noncontiguous lesions within the EZ.

A systematic review of the Mozart effect in adult and paediatric cases of drug-resistant epilepsy: A sound approach to epilepsy management.

OBJECTIVES: In recent years, adjunctive therapies for epilepsy management are being explored due to considerable side effects carried by antiepileptic drugs (AEDs) and widespread reports of drug-resistant epilepsy. One such approach is non-invasive musical neurostimulation. Within this context, Mozart's sonata K448 has received particular attention following reports of reduced seizure frequency and a decrease in epileptiform discharges during and after music exposure; often described as the 'Mozart effect'. However, controversy exists around the effectiveness of K448 in epilepsy and the strength and quality of the evidence supporting it. Therefore, this study aims to systematically review the available literature around the Mozart effect, in both adult and paediatric cases of epilepsy. METHODS: We carried out a literature search on PubMed, Science Direct, Scopus and Web of Science using the query string ALL= (Mozart AND epileps*). Selected clinical studies were classified based on the age of the population studied, as paediatric (0-18 years), adult (19 years or older) or a combination of the two. All the studies were evaluated using the Johns Hopkins Nursing Evidence-Based Practice (JHNEBP) rating scale to determine the strength of the evidence (level) and the quality of the research evidence. RESULTS: Out of 538 records, 25 studies were selected, grouped based on the age of the population studied and evaluated using the JHNEBP rating scale. Ten level 1 studies, which represent the strongest evidence, were identified, including six RCTs and three meta-analyses. Nine of these ten studies show a decrease in epileptiform discharges and in seizure frequency following exposure to Mozart's K448. One multiverse analysis reported lack of statistically significant evidence to support the use of K448 in epilepsy or any other medical condition. CONCLUSIONS: A growing body of evidence supports the Mozart effect on epilepsy, with notable studies including RCTs and comprehensive meta-analyses. This review identified nine level 1 studies, conducted by research groups worldwide, which endorse the use of Mozart's music to reduce seizures and epileptiform discharges in adult and paediatric epilepsy patients. However, existing research exhibits limitations like varying protocols, small sample sizes and diverse treatment regimens. Additionally, studies that combine adult and paediatric patients fail to take account of developmental differences between these two groups - particularly with regards to brain maturation and neurophysiology - which could negatively impact upon the accuracy of findings by obscuring important age-related differences in response to intervention. Adequately addressing these limitations will be crucial to demonstrating proof of concept; otherwise, a potentially valuable, non-invasive, accessible, and affordable therapeutic option for drug-resistant epilepsy will remain on the medical fringe. Further research with larger samples and stricter protocols, particularly considering patient age and drug regimens, is required.

A systematic review and meta-analysis of factors related to first line drugs refractoriness in patients with juvenile myoclonic epilepsy (JME).

INTRODUCTION: Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients. MATERIAL AND METHODS: The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis. RESULTS: A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity. CONCLUSION: In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Disparities in Teleneurology Use in Medicaid Beneficiaries With Epilepsy by Practice Setting: Promoting Health Equity in Academic Centers.

BACKGROUND AND OBJECTIVES: Medicaid beneficiaries in many American academic medical centers can receive care in a separate facility than those not covered by Medicaid. We aimed to identify possible disparities in care by evaluating the association between facility type (integrated faculty practice or Medicaid-only outpatient clinic) and telehealth utilization in people with epilepsy. METHODS: We performed retrospective analyses using structured data from the Mount Sinai Health System electronic medical record data from January 2003 to August 2021. We identified people of all ages with epilepsy who were followed by an epileptologist after January 3, 2018, using a validated ICD-9-CM/10-CM coded case definition. We evaluated associations between practice setting and telehealth utilization, an outcome measure that captures the evolving delivery of neurologic care in a post-coronavirus disease 2019 era, using multivariable logistic regression. RESULTS: We identified 4,586 people with epilepsy seen by an epileptologist, including Medicaid beneficiaries in the Medicaid outpatient clinic (N = 387), Medicaid beneficiaries in the faculty practice after integration (N = 723), and non-Medicaid beneficiaries (N = 3,476). Patients not insured by Medicaid were significantly older (average age 40 years vs 29 in persons seen in Medicaid-only outpatient clinic and 28.5 in persons insured with Medicaid seen in faculty practice [p < 0.0001]). Medicaid beneficiaries were more likely to have drug-resistant epilepsy (DRE), with 51.94% of people seen in Medicaid-only outpatient clinic, 41.63% of Medicaid beneficiaries seen in faculty practice, and 37.2% of non-Medicaid beneficiaries having DRE (p < 0.0001). Medicaid outpatient clinic patients were less likely to have telehealth visits (phone or video); 81.65% of patients in the Medicaid outpatient clinic having no telehealth visits vs 71.78% of Medicaid beneficiaries in the faculty practice and 70.89% of non-Medicaid beneficiaries (p < 0.0001). In an adjusted logistic regression analysis, Medicaid beneficiaries had lower odds (0.61; 95% CI 0.46-0.81) of using teleneurology compared with all patients seen in faculty practice (p = 0.0005). DISCUSSION: Compared with the Medicaid-only outpatient clinic, we found higher telehealth utilization in the integrated faculty practice with no difference by insurance status (Medicaid vs other). Integrated care may be associated with better health care delivery in people with epilepsy; thus, future research should examine its impact on other epilepsy-related outcomes.

An observational time-series study on the behavioral effects of adjunctive artisanal cannabidiol use by adults with treatment resistant epilepsies.

BACKGROUND: For approximately 30% of people with epilepsy, seizures are not well-controlled by anti-seizure medication (ASM). This condition, called treatment resistant epilepsy (TRE), is associated with increased morbidity and mortality, and substantially impacts the quality of life of both the individual and their family. Non-responsiveness to ASMs leads many people with TRE to seek alternative therapies, such as cannabinoid-based medication, particularly cannabidiol (CBD), with or without medical or professional advice. This is due in part to widespread reporting in the media about the benefits of CBD for seizures in some forms of epilepsy. METHODS: Adults with TRE, opting to add CBD to their existing treatment regime, completed this prospective, observational, longitudinal, quasi-experimental, time-series study. We hypothesized that adjunctive CBD use would positively impact participants' quality of life and psychological well-being in comparison to a baseline period without CBD use. Participants were followed for a period of approximately six months - for approximately one month of baseline prior to the initiation of CBD use and approximately five months after the initiation of CBD use. Participants provided urine samples and completed behavioral questionnaires that assessed quality of life, anxiety/depression, and adverse events during baseline and at two times during CBD use. RESULTS: Complete case analyses (n = 10) showed a statistically significant improvement in quality of life, a statistically significant decrease in anxiety symptoms, and a statistically significant decrease in the experience of adverse events over time (p < 0.05). Improvements noted in the experience of depression symptoms did not reach statistical significance. Urinalysis revealed the majority of participants had no CBD/metabolites in their system at the beginning of the study, and confirmed the presence of CBD/metabolites in participants' urine after CBD was added to their treatment regime. Analysis of missing data using multiple imputation supported the findings of the complete case analysis. INTERPRETATION: For a small group of individuals with TRE of varying etiologies, adjunctive use of artisanal CBD was associated with improvements in the behavioral and psychological symptoms of TRE, as well as improved medication tolerability.

Multimodal Approach for the Treatment of Complex Hypothalamic Hamartomas.

Hypothalamic hamartomas (HHs) are rare congenital lesions formed by heterotopic neuronal and glial cells attached to the mammillary bodies, tuber cinereum, and hypothalamus.They often present with an intractable epilepsy typically characterized by gelastic seizures but commonly associated with other types of refractory seizures. The clinical course is progressive in most of the cases, starting with gelastic seizures in infancy and deteriorating into complex seizure disorders that result in catastrophic epilepsy associated with cognitive decline and behavioral disturbances.Hamartomas are known to be intrinsically epileptogenic and the site of origin for the gelastic seizures. As antiepileptic drugs are typically ineffective in controlling HH-related epilepsy, different surgical options have been proposed as a treatment to achieve seizure control. Resection or complete disconnection of the hamartoma from the mammillothalamic tract has proved to achieve a long-lasting control of the epileptic syndrome.Usually, symptoms and their severity are typically related to the size, localization, and type of attachment. Precocious puberty appears mostly in the pedunculated type, while epileptic syndrome and behavioral decline are frequently related to the sessile type. For this reason, different classifications of HHs have been developed based on their size, extension, and type of attachment to the hypothalamus.The bigger and more complex hypothalamic hamartomas typically present with severe refractory epilepsy, behavioral disturbances, and progressive cognitive decline posing a formidable challenge for the control of these symptoms.We present here our experience with the multimodal treatment for complex hypothalamic hamartomas. After an in-depth review of the literature, we systematize our approach for the different types of hypothalamic hamartomas.

Association between Genetic Polymorphism of SCN1A, GABRA1 and ABCB1 and Drug Responsiveness in Vietnamese Epileptic Children.

Background and Objectives: Drug resistant epilepsy (DRE) is a major hurdle in epilepsy, which hinders clinical care, patients' management and treatment outcomes. DRE may partially result from genetic variants that alter proteins responsible for drug targets and drug transporters in the brain. We aimed to examine the relationship between SCN1A, GABRA1 and ABCB1 polymorphism and drug response in epilepsy children in Vietnam. Materials and Methods: In total, 213 children diagnosed with epilepsy were recruited in this study (101 were drug responsive and 112 were drug resistant). Sanger sequencing had been performed in order to detect six single nucleotide polymorphisms (SNPs) belonging to SCN1A (rs2298771, rs3812718, rs10188577), GABRA1 (rs2279020) and ABCB1 (rs1128503, rs1045642) in study group. The link between SNPs and drug response status was examined by the Chi-squared test or the Fisher's exact test. Results: Among six investigated SNPs, two SNPs showed significant difference between the responsive and the resistant group. Among those, heterozygous genotype of SCN1A rs2298771 (AG) were at higher frequency in the resistant patients compared with responsive patients, playing as risk factor of refractory epilepsy. Conversely, the heterozygous genotype of SCN1A rs3812718 (CT) was significantly lower in the resistant compared with the responsive group. No significant association was found between the remaining four SNPs and drug response. Conclusions: Our study demonstrated a significant association between the SCN1A genetic polymorphism which increased risk of drug-resistant epilepsy in Vietnamese epileptic children. This important finding further supports the underlying molecular mechanisms of SCN1A genetic variants in the pathogenesis of drug-resistant epilepsy in children.