Advances in Therapy for Refractory Epilepsy.

ObjectiveTuberous sclerosis complex (TSC) is a rare disease with a high risk of epilepsy and cognitive impairment in children. Ketogenic diet (KD) therapy has been consistently reported to be beneficial to TSC patients. In this study, we aimed to investigate the efficacy and safety of KD in the treatment of drug-resistant epilepsy and cognitive impairment in children with TSC.MethodsIn this multicenter study, 53 children (33 males and 20 females) with drug-resistant epilepsy or cognitive impairment caused by TSC were retrospectively recruited from 10 hospitals from January 1, 2010, to December 31, 2020. Intention-to-treat analysis was used to evaluate seizure reduction and cognition improvement as outcomes after KD therapy.ResultsOf the 53 TSC patients included, 51 failed to be seizure-free with an average of 5.0 (range, 4–6) different anti-seizure medications (ASMs), before KD therapy. Although the other two patients achieved seizure freedom before KD, they still showed psychomotor development delay and electroencephalogram (EEG) abnormalities. At 1, 3, 6, and 12 months after the KD therapy, 51 (100%), 46 (90.2%), 35 (68.6%), and 16 patients (31.4%) remained on the diet therapy, respectively. At these time points, there were 26 (51.0%), 24 (47.1%), 22 (43.1%) and 13 patients (25.5%) having ≥50% reductions in seizure, including 11 (21.6%), 12 (23.5%), 9 (17.6%) and 3 patients (5.9%) achieving seizure freedom. In addition, of 51 patients with psychomotor retardation, 36 (36 of 51, 70.6%) showed cognitive and behavioral improvements. During the KD therapy, no serious side effects occurred in any patient. The most common side effects were gastrointestinal disturbance (20 of 53, 37.7%) and hyperlipidemia (6 of 53, 11.3%). The side effects were gradually relieved after adjustment of the ketogenic ratio and symptomatic treatment.ConclusionKD is an effective and safe treatment for TSC-related drug-resistant epilepsy and cognitive impairment in children. KD can reduce seizure frequency and may potentially improve cognition and behavior.

Achieving seizure freedom following failure of several antiseizure medications (ASMs) is rare, with the likelihood of achieving further control decreasing with each successive ASM trial. When cases of drug-resistant epilepsy arise, a diagnostic procedure known as stereoelectroencephalography (sEEG) can be used to identify epileptogenic zones (EZ) within the brain. After localization of these zones, they can be targeted for future surgical intervention. Here, we describe a case of complete seizure freedom off medication after sEEG without resection or other therapeutic intervention. In 2017, a 36-year-old right-handed male presented with drug-resistant epilepsy stemming from prior traumatic brain injury. Due to ongoing seizures, in 2020 a robotic-assisted sEEG electrode placement procedure was employed to localize the seizure onset zone. During sEEG monitoring, a single event was captured where the patient had dysarthric speech, left arm dystonic flexion, and difficulty responding to questioning. Notably, this event had no sEEG correlate, suggesting seizure occurrence in a region not monitored by implanted electrodes, which prompted the placement of scalp electrodes following this event. However, no further clinical events consistent with seizure were provoked through the remainder of recording. Following the 13-day admission, the patient chose to self-discontinue all seizure medications and has remained seizure free as of October 2023, more than 3.5 years later. While sEEG is considered a relatively safe procedure for seizure localization in drug resistant epilepsy, the possibility of microlesions created by sEEG depth electrodes remains largely unexplored. Further evaluation should be performed into potential tissue injury produced by depth electrode insertion.

Editor's evaluation: Disease-modifying effects of sodium selenate in a model of drug-resistant, temporal lobe epilepsy

Pediatric drug-resistant epilepsy (DRE) is defined as epilepsy that is not controlled by two or more appropriately chosen and dosed anti-seizure medications (ASMs). When alternative therapies or surgical intervention is not viable or efficacious, advanced options like deep brain stimulation (DBS) or responsive neurostimulation (RNS) may be considered. Describe the Stanford early institutional experience with DBS and RNS in pediatric DRE patients. Retrospective chart review of seizure characteristics, prior therapies, neurosurgical operative reports, and postoperative outcome data in pediatric DRE patients who underwent DBS or RNS placement. Nine patients had DBS at 16.0 ± 0.9 years and 8 had RNS at 15.3 ± 1.7 years (mean ± SE). DBS targets included the centromedian nucleus of the thalamus (78% of DBS patients), anterior nucleus of the thalamus (11%), and pulvinar (11%). RNS placement was guided by stereo-EEG and/or intracranial monitoring in all RNS patients (100%). RNS targets included specific seizure onset zones (63% of RNS patients), bilateral hippocampi (25%) and bilateral temporal lobes (12%). Only DBS patients had prior trials of ketogenic diet (56%) and VNS therapy (67%). Four DBS patients (44%) had prior neurosurgical interventions, including callosotomy (22%) and focal resection (11%). One RNS patient (13%) and one DBS patient (11%) required revision surgery. Two DBS patients (22%) developed postoperative complications. Three RNS patients (38%) underwent additional resections; one RNS patient had electrocorticography recordings for seizure mapping before surgery. For patients with a follow-up of at ≥1 year (n = 7 for DBS and n = 5 for RNS), all patients had reduced seizure burden. Clinical seizure freedom was achieved in 80% of RNS patients and 20% had a >90% reduction in seizure burden. The majority (71%) of DBS patients had a ≥50% reduction in seizures. No patients experienced no change or worsening of seizure frequency. In the early Stanford experience, DBS was used as a palliatively for generalized or mixed DRE refractory to other resective or modulatory approaches. RNS was used for multifocal DRE with a clear seizure focus on stereo-EEG and no prior surgical interventions. Both modalities reduced seizure burden across all patients. RNS offers the additional benefit of providing data to guide future surgical planning.

Expression and cellular distribution of multidrug resistance-related proteins in patients with focal cortical dysplasia

Cenobamate in developmental and epileptic encephalopathies and generalized epilepsies: A case report on epilepsy with myoclonic-atonic seizures and systematic review of current evidence.

Effectiveness analysis of three-drug combination therapies for refractory focal epilepsy

To evaluated the effectiveness and safety of single anti-seizure medication (ASM) when used as adjunctive therapy for drug-resistant focal epilepsy. We conducted a comprehensive search of PubMed, EMbase, and the Cochrane Library from their inception until 12 February, 2025, to identify randomized controlled trials (RCTs) meeting our criteria. The trials were analyzed for their use of ASMs in treating drug-resistant focal epilepsy. Inclusion criteria comprised: 1) Participants aged 12years or older with drug-resistant focal epilepsy; 2) Incorporation of an additional single ASM as an adjunct to the existing antiepileptic treatment regimen; 3) Comparison with placebo or continuation of the original antiepileptic regimen without a new ASM; 4) Primary outcome as a 50% response rate, with safety as a secondary outcome, encompassing dizziness, somnolence, headache, ataxia, diplopia, fatigue, and nausea; and 5) Study design limited to RCTs. The surface under the cumulative ranking curve (SUCRA) was employed to rank the effectiveness and safety of the ASMs. A total of 53 RCTs involving 17 ASMs as adjunctive therapy and placebo were analyzed. Compared to placebo, the following ASMs demonstrated statistically significant effectiveness in achieving a 50% response rate: brivaracetam (RR = 2.07, 95% CI: 1.53-2.81), cenobamate (RR = 2.12, 95% CI: 1.56-2.88), eslicarbazepine acetate (RR = 1.95, 95% CI: 1.41-2.70), gabapentin (RR = 2.30, 95% CI: 1.76-3.02), lacosamide (RR = 2.22, 95% CI: 1.47-3.35), lamotrigine (RR = 1.55, 95% CI: 1.00-2.40), levetiracetam (RR = 2.43, 95% CI: 1.88-3.15), oxcarbazepine (RR = 3.03, 95% CI: 2.08-4.40), perampanel (RR = 1.72, 95% CI: 1.21-2.44), pregabalin (RR = 2.06, 95% CI: 1.70-2.50), rufinamide (RR = 2.28, 95% CI: 1.20-4.31), tiagabine (RR = 4.07, 95% CI: 2.03-8.18), topiramate (RR = 3.10, 95% CI: 2.44-3.95), vigabatrin (RR = 2.34, 95% CI: 1.58-3.46), and zonisamide (RR = 2.40, 95% CI: 1.76-3.27). Based on SUCRA rankings, tiagabine (92.7%) exhibited the most favorable therapeutic outcome, followed by topiramate (87.3%), oxcarbazepine (83%), and levetiracetam (62.8%). The ASMs with the least favorable therapeutic effects were placebo (1.1%), lamotrigine (17.8%), and perampanel (24.7%). The network meta-analysis revealed topiramate, tiagabine, oxcarbazepine, and levetiracetam as the four most effective adjuvant ASM treatments for drug-resistant focal epilepsy. However, it is noteworthy that topiramate and oxcarbazepine were associated with a higher incidence of somnolence. Additionally, comprehensive safety data for tiagabine and levetiracetam are lacking, necessitating further research. Larger studies are required to solidify these findings and better understand the safety profiles of all involved ASMs.

Drug resistant epilepsy (DRE) is defined as the persistence of seizures despite at least two syndrome-adapted antiseizure drugs (ASD) used at efficacious daily dose. Despite the increasing number of available ASD, about a third of patients with epilepsy still suffer from drug resistance. Several factors are associated with the risk of evolution to DRE in patients with newly diagnosed epilepsy, including epilepsy onset in the infancy, intellectual disability, symptomatic epilepsy and abnormal neurological exam. Pharmacological management often consists in ASD polytherapy. However, because quality of life is driven by several factors in patients with DRE, including the tolerability of the treatment, ASD management should try to optimize efficacy while anticipating the risks of drug-related adverse events. All patients with DRE should be evaluated at least once in a tertiary epilepsy center, especially to discuss eligibility for non-pharmacological therapies. This is of paramount importance in patients with drug resistant focal epilepsy in whom epilepsy surgery can result in long-term seizure freedom. Vagus nerve stimulation, deep brain stimulation or cortical stimulation can also improve seizure control. Lastly, considering the effect of DRE on psychologic status and social integration, comprehensive care adaptations are always needed in order to improve patients’ quality of life.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark

A french real-world experience with cenobamate in patients with drug-resistant focal epilepsy: A retrospective observational study

Epilepsy is a neurological disease characterized by seizures, which affects up to 65 million people worldwide (1). About two-thirds of patients with epilepsy are able to achieve seizure control with current antiseizure medication (ASM) (2), whereas one-third of epilepsy patients are difficult to treat, i.e., patients with drug-resistant epilepsy (DRE). In addition, ASM can induce (serious) adverse events and a significant reduction of the quality of life (QoL), leading to ASM retention rates around 50% (3). DRE can induce neurobiochemical alterations and emotional and physical dysfunctions. The multifaceted status of DRE patients underscores the emphasis on non-pharmacological options, and therapies that target multiple mechanisms are likely to be more effective to treat DRE (4), thereby acting as a “magic shotgun” rather than a “magic bullet.” If epilepsy surgery is not an option in a patient with DRE, vagus nerve stimulation (VNS) (5) or dietary treatments, such as the ketogenic diet (KD), are valuable alternative options (5–7). Initial studies with dietary treatments report on the classical KD, consisting of 80% fat and 20% protein plus carbohydrate (4:1 KD) or 75% fat and 25% protein plus carbohydrate (3:1 KD) (8). A KD using medium-chain triglycerides (MCTs) leads to more ketones/kcal of energy and a more efficient absorption (9). Therefore, the MCT diet is less restrictive since it consists of a lower amount of fat and a higher intake of protein and carbohydrate (10). The modified Atkins diet (MAD) (11) and the low-glycemic index treatment (LGIT) (12) are other dietary therapies mimicking the seizure reduction result of the KD, but they are less restrictive. Clinical studies show that both modalities (VNS and KD) lead to a seizure frequency reduction (SFR) by at least 50% in half of the DRE patients. A recent study proposed a treatment algorithm for pediatric DRE, including non-pharmacological treatment options such as VNS and the KD (13). Interestingly, the KD therapy has some advantages in comparison to VNS: the SFR is slightly higher for patients on the KD (14); the KD is non-invasive, and there are few to no neurotoxic effects when compared to multiple ASM (6). Nevertheless, there are barriers and disadvantages in putting the KD into practice, such as palatability issues, compliance issues, side effects (usually mild), variable response rates, and restrictions to the daily life of the patient (15). Overall, a multidisciplinary team (pediatric neurologist, dietician/nutritionist, and a primary care-giver) is indispensable when dietary treatments are initiated and also during maintenance (16). Currently, we are unable to pinpoint the mechanism(s) of action of the KD, and it is possible that dietary therapies will be classified as “magic shotguns” (17–20). Therefore, our aim was to elaborate on the newest pathways involved, such as the gut microbiome and serine synthesis.

Efficacy and safety of Cenobamate: a multicenter, retrospective evaluation of real-world clinical practice.

Randomized studies in drug-resistant epilepsy (DRE) typically involve addition of a new anti-seizure medication (ASM). However, in clinical practice, if the patient is already taking multiple ASMs, then substitution of one of the current ASMs commonly occurs, despite little evidence supporting this approach. Longitudinal prospective study of seizure outcome after commencing a previously untried ASM in patients with DRE. Multivariable time-to-event and logistic regression models were used to evaluate outcomes by whether the new ASM was introduced by addition or substitution. A total of 816 ASM changes in 436 adult patients with DRE between 2010 and 2018 were analyzed. The new ASM was added on 407 (50.1%) occasions and substituted on 409 (49.9%). Mean patient follow-up was 3.2years. Substitution was more likely if the new ASM was enzyme-inducing or in patients with a greater number of concurrent ASMs. ASM add-on was more likely if a γ-aminobutyric acid (GABA) agonist was introduced or if the patient had previously trialed a higher number of ASMs. The rate of discontinuation due to lack of tolerability was similar between the add-on and substitution groups. No difference between the add-on and substitution ASM introduction strategies was observed for the primary outcome of ≥50% seizure reduction at 12months. Adding or substituting a new ASM in DRE has the same influence on seizure outcomes. The findings confirm that ASM alterations in DRE can be individualized according to concurrent ASM therapy and patient characteristics.

Introduction Anti-seizure medications (ASMs) are commonly used to prevent recurring epileptic seizures, but around a third of people with epilepsy fail to achieve an adequate response. Vagus nerve stimulation (VNS) is clinically recommended for people with drug-resistant epilepsy (DRE) who are not suitable for surgery, but the cost-effectiveness of the intervention has not recently been evaluated. The study objective is to estimate costs and quality-adjusted life-years (QALYs) associated with using VNS as an adjunct to ongoing ASM therapy, compared to the strategy of using only ASMs in the treatment of people with DRE, from an English National Health Service perspective. Methods A cohort state transition model was developed in Microsoft Excel to simulate costs and QALYs of the VNS + ASM and ASM only strategies. Patients could transition between five health states, using a 3-month cycle length. Health states were defined by an expected percentage reduction in seizure frequency, derived from randomized control trial data. Costs included the VNS device as well as its installation, setup, and removal; ASM therapy; adverse events associated with VNS (dyspnea, hoarseness, and cough); and health-state costs associated with epilepsy including hospitalizations, emergency department visits, neurologist visits, and primary care visits. A range of sensitivity analyses, including probabilistic sensitivity analysis, were run to assess the impact of parameter and structural uncertainty. Results In the base case, VNS + ASM had an estimated incremental cost-effectiveness ratio (ICER) of £17,771 per QALY gained compared to ASMs alone. The cost-effective ICER was driven by relative reductions in expected seizure frequency and the differences in health care resource use associated therewith. Sensitivity analyses found that the amount of resource use per epilepsy-related health state was a key driver of the cost component. Conclusions VNS is expected to be a cost-effective intervention in the treatment of DRE in the English National Health Service.