Adjunctive Therapy In Refractory Epilepsy Research Articles

The cenobamate KORK study—A prospective monocenter observational study investigating cenobamate as an adjunctive therapy in refractory epilepsy, with comparisons to historical cohorts treated with add‐on lacosamide, perampanel, and brivaracetam

AbstractObjectiveIn Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy.MethodsPatients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center.ResultsBetween June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001).SignificanceAdd‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs.Plain Language SummaryThis observational study was carried out in 172 adult patients with difficult‐to‐treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

Fluoxetine as adjunctive therapy in pediatric patients with refractory epilepsy: A retrospective analysis

Approximately 30 % of children with epilepsy develop refractory epilepsy, which has a major impact on neurodevelopmental processes, cognitive functioning, and daily life. Furthermore, children with highly refractory epilepsy are at particular risk of sudden unexpected death. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has shown antiseizure action and was associated with a decreased severity of peri-ictal hypoxemia in adult patients with focal epilepsy. However, therapeutic studies on SSRI use in children are scarce — particularly in epileptic patients.We retrospectively recruited 14 pediatric patients; inclusion criteria were i) refractory epilepsy ii) frequent generalized or focal seizures (more than 1/week) iii) treated with fluoxetine as adjunctive therapy for one month at least. We analyzed their clinical outcome (efficacy and tolerance). The median age at fluoxetine initiation was 9.5 years (2–19), and fluoxetine was combined with a median number of 4 (2–6) anti-seizure medications. The median dose of fluoxetine at the last follow-up was 0.4 mg/kg/day (0.2−0.8).Among the 14 patients, we observed 6 (43 %) good responders. Complete freedom from seizures with cyanosis was reached in 3 (21 %) patients, and only one patient with early-onset epilepsy related to an FHF1 mutation was completely seizure-free. None of the recruited patients experienced seizure worsening, and 8 patients showed no effect on seizure frequency.Fluoxetine as adjunctive therapy in refractory epilepsy could be a beneficial therapeutic option. Future prospective, randomized and controlled studies are needed to study the efficacy of fluoxetine better.

Saudi Arabian Consensus Statement on Vagus Nerve Stimulation for Refractory Epilepsy

Vagus nerve stimulation (VNS) is an approved adjunctive therapy for refractory epilepsy and used in patients who are not candidates for resective epilepsy surgery. In Saudi Arabia, VNS device implantation is being performed since 2008 by several comprehensive epilepsy programs, but with variable protocols. Therefore, to standardize the use of VNS, a task force was established to create a national consensus. This group consisted of epileptologists, epilepsy surgeons and a VNS nurse coordinator working in comprehensive epilepsy centers and dealing with refractory epilepsy cases. The group intensively reviewed the literature using Medline, EMBASE, Web of Science and Cochrane Library, in addition to physician's manual. Evidence is reported as three stages: preimplantation and patient selection, a perioperative phase involving all stakeholders and post-operative care with specific programming pathways.

Efficacy and Tolerability of Perampanel as Adjunctive Therapy in Refractory Epilepsy (P3.5-020)

Efficacy and Tolerability of Perampanel as Adjunctive Therapy in Refractory Epilepsy (P3.5-020)

Lacosamide in Refractory Mixed Pediatric Epilepsy: A Prospective Add-on Study

Lacosamide is a new antiepileptic drug that is currently approved by the US Food and Drug Administration (FDA) for adults 17 years or older for partial-onset seizures. The authors reviewed 21 pediatric patients (<17 years) with various seizure types who were started on oral lacosamide as part of a prospective add-on study as adjunctive therapy for refractory epilepsy. Five patients were excluded due to less than 3 months of meaningful follow-up. Maintenance dosages used ranged from 2.4 to 19.4 mg/kg/d. Eight of 16 (50%) patients had greater than 50% reduction in seizure frequency with adjunctive lacosamide therapy. Eight (50%) patients had generalized epilepsy including 4 with Lennox-Gastaut syndrome. Lacosamide was effective therapy for most seizure types but was particularly effective for partial-onset seizures. Lacosamide was effective in treating 5 of 8 (62.5%) localization-related epilepsies but only 2 of 8 (25%) generalized epilepsies, both Lennox-Gastaut syndrome patients with greater than 90% seizure reduction. None of these very refractory patients remained seizure free.

Evaluation of Levetiracetam as Adjunctive Treatment for Refractory Canine Epilepsy: A Randomized, Placebo‐Controlled, Crossover Trial

There is little evidence-based information available to guide treatment of refractory epilepsy in dogs. The antiepileptic drug levetiracetam (LEV) is administered to dogs, although its safety and efficacy are unknown. To evaluate the safety and efficacy of LEV as adjunctive therapy for refractory epilepsy in dogs. Thirty-four client-owned dogs with idiopathic epilepsy. Randomized, blinded trial involving dogs resistant to phenobarbital and bromide. Dogs received LEV (20 mg/kg PO q8h) or placebo for 16 weeks, and after a 4-week washout were crossed over to the alternate treatment for 16 weeks. Owners kept records on seizure frequency and adverse events. Hemogram, chemistry profile, urinalysis, and serum antiepileptic drug concentrations were evaluated at established intervals. Twenty-two (65%) dogs completed the study. Weekly seizure frequency during the 1st treatment period decreased significantly during LEV administration relative to baseline (1.9 ± 1.9 to 1.1 ± 1.3, P = .015). The reduction in seizures with LEV was not significant when compared to placebo (1.1 ± 1.3 versus 1.5 ± 1.7, P = .310). The most common adverse event was ataxia, with no difference in incidence between LEV and placebo (45 versus 18%, P = .090). No changes in laboratory parameters were identified and owners reported an improved quality of life (QOL) with LEV compared to placebo (QOL score 32.7 ± 4.3 versus 29.4 ± 4.5, P = .028). Adjunctive treatment with LEV appears safe in epileptic dogs. Efficacy of LEV over placebo was not demonstrated, although the power of the study was limited. Further evaluation of LEV as treatment for epilepsy in dogs is warranted.

Pharmacoeconomics of anti-epileptic drugs as adjunctive therapy for refractory epilepsy

Epileptic seizures are associated with significant morbidity, impaired quality of life, mortality and substantial healthcare costs. Treatment with anti-epileptic drugs is the mainstay of therapy, with pharmacotherapy aiming to achieve seizure freedom or seizure reduction. Given that approximately 30% of patients are not controlled with monotherapy regimens, adjunctive therapy with multiple anti-epileptic drugs can be envisaged. This article aims to review economic evaluations of anti-epileptic drugs as adjunctive therapy for refractory epilepsy in adult patients. Studies were included if they examined the costs and consequences of different pharmacotherapeutic adjunctive therapies for refractory epilepsy. Uncertainty surrounds the cost–effectiveness of anti-epileptic drugs as adjunctive therapy for refractory epilepsy owing to methodological limitations and design differences between studies. Although cost–effectiveness estimates vary between studies, adjunctive therapy of refractory epilepsy appears to be cost effective, depending on the cost–effectiveness threshold used by pricing/reimbursement agencies. However, there is a need for more, better-designed and comprehensive economic evaluations of adjunctive therapy for refractory epilepsy with anti-epileptic drugs.

Add-on lamotrigine in pediatric epilepsy in India

Lamotrigine is a newer antiepileptic drug useful as oral adjunctive therapy in refractory epilepsy. Indian data on use of lamotrigine is limited. This study was conducted to evaluate add-on lamotrigine in Indian children with epilepsy. Twenty children (median age 90 months) receiving lamotrigine as add-on therapy for mean 26.7 (19.1) months, were followed for a median period of 7.9 (6-10) months. Follow-up was done every two weeks. The most common seizures types were either generalized tonic-clonic (6, 30%) or myoclonic (8, 40%). The average dose used was 3.86 mg/kg/day (with concomitant valproate). Good response (>50% reduction) or complete seizure control was seen in 72% patients. Side effects were seen in 27.5% patients and were mild in more than half of these. Lamotrigine was stopped in two patients due to adverse reactions, which resolved on stopping the drug. Lamotrigine was observed to be an effective, add-on, broad-spectrum antiepileptic with 'mild' side effects in Indian children.

Vagus nerve stimulation for refractory epilepsy in children: More to VNS than seizure frequency reduction

Vagus nerve stimulation (VNS) is used increasingly as adjunctive therapy for refractory epilepsy. Studies of VNS in children report mainly seizure frequency reduction as a measure of efficacy and clinical details are often scanty. We report our experience with VNS in children with refractory epilepsy and emphasize the positive effects of VNS in terms of seizure severity. We reviewed 26 consecutive children who had VNS with a minimum follow-up period of 18 months. We examined their clinical characteristics, seizure types, seizure frequency, epilepsy syndrome diagnosis, and response to VNS in terms of seizure frequency and seizure severity. Fifty-four percent of patients responded to VNS with >or=50% seizure frequency reduction. Patients with Lennox-Gastaut syndrome (LGS) and tonic seizures had a higher responder rate; 78% (seven of nine patients) (p < 0.01). Status epilepticus (SE) episodes were reduced or ceased in the four patients with recurrent SE. Seizure severity, duration, and recovery time decreased in all responders. Increased alertness was reported in all responders and three nonresponders. Decreased seizure severity, recovery time, abolition of daytime drop attacks, and reduced hospitalization due to SE improved patients' lives over and above the benefit from seizure frequency reduction.

Pharmacokinetics and Drug Interactions with Zonisamide

Polypharmacy is a widely employed treatment strategy in epilepsy, particularly for individuals with poorly controlled seizures. Drug combinations should be carefully considered to minimize the potential for unfavorable interactions. Older-generation antiepileptic drugs (AEDs) are well known for their pharmacokinetic interaction potential, which generally results from alterations in the metabolism of concomitant drugs due to effects on the cytochrome P450 (CYP) and uridine glucuronyl transferase enzyme systems. Newer agents, such as zonisamide, are less likely to cause adverse drug interactions. A series of interaction studies has revealed zonisamide to be without effect on the steady-state pharmacokinetics of carbamazepine, phenytoin, sodium valproate, or lamotrigine. However, zonisamide is principally inactivate by CY3A4-dependent reduction. Consequently, carbamazepine, phenytoin, and phenobarbital all increase its clearance, an interaction that may necessitate a dosage increase, but which will also permit more rapid attainment of steady-state zonisamide concentrations. Otherwise, zonisamide is essentially devoid of clinically significant interactions with other AEDs, oral contraceptives and, indeed, all other classes of therapeutic agents investigated to date. As a result, it is reasonable to conclude that zonisamide has a favorable pharmacokinetic profile and that it may be a useful and uncomplicated agent when employed as adjunctive therapy in refractory epilepsy.

Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation

This study evaluated the effects of lamotrigine as adjunctive therapy for refractory epilepsy in patients with mental retardation. Patients with epilepsy and mental retardation having uncontrolled seizures despite treatment with other antiepileptic drugs were eligible ( n=67). The open-label study comprised a Baseline Phase, an Escalation Phase during which lamotrigine was titrated to a target dose, an 8-week Maintenance Phase during which doses of lamotrigine and concomitant antiepileptic drugs were maintained, and a 12-week Optimization Phase during which doses of lamotrigine and other antiepileptic drugs could be adjusted. Almost half (44%) of patients experienced a 50% reduction in seizure frequency during the Maintenance Phase after addition of lamotrigine; 15% of patients became seizure-free. A similar pattern of results was reported for the Optimization Phase. Investigator-rated clinical status was improved relative to baseline in 66 and 74% of patients at the end of the Maintenance and Optimization Phases, respectively. Most patients experienced improvements in seizure frequency, duration, and intensity during the Maintenance Phase (62 to 72%) and the Optimization Phase (65 to 74%). Many patients were rated as having improved social functioning during the Maintenance Phase (42%) and the Optimization Phase (46%). The Aberrant Behavior Checklist score for lethargy and the mean Habilitative Improvement Scale score were improved at the ends of the Maintenance and Optimization Phases relative to baseline ( P⩽0.04). One limitation of this study is its open-label design, which limits the ability definitively to attribute the clinical improvements to lamotrigine. Adjunctive lamotrigine in patients with refractory epilepsy and mental retardation appears to decrease seizure frequency and improve behavior while permitting a reduction in dose of concomitant antiepileptic drugs.

Lamotrigina en epilepsia parcial y generalizada refractarias

Lamotrigine (LTG) is a new antiepileptic drug that it has proved to be efficacious in treating patients with partial and generalized tonic-clonic seizures in adjunctive and monotherapy. It has similar efficacy in comparison with carbamazepine and phenytoin with a minor number of adverse experiences. We report the use of LTG in adjunctive therapy in 106 adults patients with refractory epilepsy (efficacy and safety) with partial and generalized seizures, with follow-up to 3.4 years. The LTG mean doses used was 273 mg/day. 66% of patients experienced a > or = 50% reduction in seizure frequency, with 30% in remission. Both partial, secondarily generalized and generalized seizures showed significant reductions with LTG treatment. LTG was well tolerated in our patients. Side effects were minor. No case of rash was seen. LTG is a excellent agent for adjunctive therapy in refractory epilepsy.

The place of clobazam in the treatment of epilepsy: An update

The 1,4-benzodiazepines have a recognized place in the treatment of epilepsy, mainly in status epilepticus, as adjunctive therapy in refractory epilepsy, in hypsarrythmia and in myoclonic epilepsy. Clobazam, the only marketed 1,5-benzodiazepine, has been shown in eight controlled studies involving 291 patients to be significantly superior to placebo, while in 35 open studies embracing 2259 patients, it has produced an overall reduction in seizure frequency of 65 per cent, with some 18 per cent of patients being rendered seizure free. The main indication for its use is as oral adjunctive therapy in refractory epilepsy. It has a rapid onset of action, is well tolerated, and many studies indicate it has a psychotropic action and/or produces minimal, or no cognitive impairment. The most common side-effect reported is transient sedation, while the overall incidence of adverse effects in the open studies is 38 per cent. In the controlled investigations 4 per cent of patients had to be withdrawn because of adverse side-effects, while in the open studies the figure was 9 per cent. In general, there are no significant interactions with other antiepileptic drugs, although changes in a few have been described. Withdrawal seizures can occur and require gradual termination of clobazam. The main disadvantage of clobazam is the development of tolerance, which develops in approximately 32 per cent of patients, and there is no way of predicting when the phenomenon is likely to occur nor in which individuals. A dose of 20 to 30 mg given preferably at night is recommended, possibly commencing at 10 mg.