Worth the paper they are printed on? Findings from an independent evaluation of the understandability of patient information leaflets for antiseizure medications.

OBJECTIVE: The Patient Information Leaflet (PIL) is an authoritative document that all people with epilepsy in the EU receive when prescribed antiseizure medication (ASM). We undertook the first independent, comprehensive assessment to determine how understandable they are. Regulators state that when patients are asked comprehension questions about them, ≥80% should answer correctly. Also, recommended is that PILs have a maximum reading requirement of US grade 8. METHODS: Study 1: We obtained 140 current ASM PILs written in English. "Readability" was assessed using four tests, with and without adjustment for influence of familiar, polysyllabic words. A total of 179 online materials on epilepsy were also assessed. Study 2: Two PILs from Study 1 were randomly selected (Pregabalin Focus; Inovelon) and shown to 35 people from the UK epilepsy population. Their comprehension was assessed. Study 3: To understand whether the student population provides an accessible alternative population for future examination of ASM PILs, Study 3 was completed, using the same methods as Study 2, except that participants were 262 UK university students. RESULTS: Study 1: No PIL had a reading level of grade 8. Median was grade 11. Adjusting for context, the PILs were still at grade 10.5. PILs for branded ASMs were most readable. PILs were no more readable than (unregulated) online materials. Study 2: Users struggled to comprehend the PILs' key messages. The eight questions asked about pregabalin were typically answered correctly by 54%. For Inovelon, it was 62%. Study 3: Most student participants comprehended the PILs' key messages. The questions about Inovelon were answered correctly by 90%; for pregabalin it was 86%. SIGNIFICANCE: This is the first independent and comprehensive examination of ASM PILs. It found that PILs being used fail to meet recommendations and regulatory requirements and risk not being understandable to a substantial proportion of users. In finding that people from the epilepsy population differ markedly in comprehension of PILs compared to students, this study highlights the importance of completing user testing with the target population.

HPLC-PDA identification and resolution of rufinamide forced degradation impurities: A congregated chemometric expedite optimization coupled with factorials and desirability.

Rufinamide is used presently to treat Lenaux-Gastaut syndrome. A full factorial design and desirability approach was investigated for the optimization of hydrolytic stress via response surface curves (RSCs). The degradation impurities were identified and resolved using reversed-phase high-performance liquid chromatography (RP-HPLC) on the Qualisil® BDS C8 column. Acetonitrile-water (29:71, v/v) was optimized for the mobile phase and used at a flow rate of 1.0 ml/min with detection at a wavelength of 230 nm. Rufinamide showed appreciable susceptibility to hydrolysis under acidic and alkaline stress, and substantial degradation in the neutral condition. It degraded much less under oxidative stress. Exposure towards thermal and photolytic stress conditions indicated appreciable stability. The developed method was subjected to validation as per the recommendations of the International Conference on Harmonization. The proposed method showed no influence from the excipients and the degradation products. As well as good precision and accuracy in determination, the method showed a linear response between 2 and 12 µg ml-1 . The method was extended for determination in a human plasma sample, which resulted in excellent recovery without interference from matrix effects. The combined use of desirability and design for the optimization of acidic and alkaline hydrolytic stress led to simple and rapid analysis.

Rufinamide, a Triazole-Derived Antiepileptic Drug, Stimulates Ca2+-Activated K+ Currents While Inhibiting Voltage-Gated Na+ Currents.

Rufinamide (RFM) is a clinically utilized antiepileptic drug that, as a triazole derivative, has a unique structure. The extent to which this drug affects membrane ionic currents remains incompletely understood. With the aid of patch clamp technology, we investigated the effects of RFM on the amplitude, gating, and hysteresis of ionic currents from pituitary GH3 lactotrophs. RFM increased the amplitude of Ca2+-activated K+ currents (IK(Ca)) in pituitary GH3 lactotrophs, and the increase was attenuated by the further addition of iberiotoxin or paxilline. The addition of RFM to the cytosolic surface of the detached patch of membrane resulted in the enhanced activity of large-conductance Ca2+-activated K+ channels (BKCa channels), and paxilline reversed this activity. RFM increased the strength of the hysteresis exhibited by the BKCa channels and induced by an inverted isosceles-triangular ramp pulse. The peak and late voltage-gated Na+ current (INa) evoked by rapid step depolarizations were differentially suppressed by RFM. The molecular docking approach suggested that RFM bound to the intracellular domain of KCa1.1 channels with amino acid residues, thereby functionally affecting BKCa channels' activity. This study is the first to present evidence that, in addition to inhibiting the INa, RFM effectively modifies the IK(Ca), which suggests that it has an impact on neuronal function and excitability.

Mechanochemical Approach towards Multi-Functionalized 1,2,3-Triazoles and Anti-Seizure Drug Rufinamide Analogs Using Copper Beads.

Highly regiospecific, copper-salt-free and neat conditions have been demonstrated for the 1,3-dipolar azide-alkyne cycloaddition (AAC) reactions under mechanochemical conditions. A group of structurally challenging alkynes and heterocyclic derivatives was efficiently implemented to achieve highly functionalized 1,4-disubstituted-1,2,3-triazoles in good to excellent yield by using the Cu beads without generation of unwanted byproducts. Furthermore, the high-speed ball milling (HSBM) strategy has also been extended to the synthesis of the commercially available pharmaceutical agent, Rufinamide, an antiepileptic drug (AED) and its analogues. The same strategy was also applied for the synthesis of the Cl-derivative of Rufinamide. Analysis of the single crystal XRD data of the triazole was also performed for the final structural confirmation. The Cu beads are easily recoverable from the reaction mixture and used for the further reactions without any special treatment.

Safety and efficacy of rufinamide in children and adults with Lennox-Gastaut syndrome: A post hoc analysis from Study 022.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy with the first symptoms usually appearing during early childhood. Due to the highly variable underlying etiologies, LGS cannot be considered as one disease but as an electro-clinical entity, often challenging to diagnose early and treat accordingly. The anti-seizure medication, rufinamide, is indicated for the adjunctive treatment of patients with LGS aged ≥1 year. This post hoc analysis assessed the safety and efficacy of adjunctive rufinamide for total and tonic-atonic seizures during Study 022 in children (aged <16 years) and adults (aged ≥16 years). METHODS: Randomized, placebo-controlled, phase III Study 022 included patients with a diagnosis of LGS and a history of multiple seizure types (including tonic-atonic or astatic seizures and atypical absence seizures; ≥90 seizures in the month prior to baseline). Assessments included monitoring of treatment-emergent adverse events (TEAEs), percent change in tonic-atonic seizure frequency/28 days during the double-blind phase relative to study baseline (a primary endpoint), and percentage of patients with ≥25%, ≥50%, or ≥75% reduction in seizure frequency relative to baseline. RESULTS: Of 138 enrolled patients, 74 received rufinamide (<16 years, n = 49 [66%]) and 64 received placebo (<16 years, n = 43 [67%]). Incidence of TEAEs was generally similar between age groups. The frequency (per 28 days) of tonic-atonic seizures was reduced with rufinamide (vs. placebo) in both younger and older patients: age <16 years (-41% vs. -6%), age ≥16 years (-55% vs. +16%) (p < 0.025; both age groups). In patients aged <16 years receiving rufinamide, 38% and 17% achieved ≥50% and ≥75% reductions in tonic-atonic seizure frequency vs. 18% and 3% with placebo, respectively. Corresponding responder rates for patients aged ≥16 years were 52% and 32% (rufinamide) vs. 15% and 5% (placebo), respectively. CONCLUSIONS: In this post hoc analysis, adjunctive rufinamide was well tolerated and improved seizure control in patients with LGS, irrespective of age.

Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy.

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r2  = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.

Cognitive, adaptive, and behavioral effects of adjunctive rufinamide in Lennox-Gastaut syndrome: A prospective observational clinical study.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe pediatric epilepsy syndrome characterized by multiple drug-resistant seizure types. Children with LGS usually experience cognitive regression, and LGS is almost always associated with moderate to severe cognitive impairment. Rufinamide (RFM) was approved by the European Medicines Agency in 2007 for the adjunctive treatment of seizures associated with LGS in patients ≥4 years of age. The primary objective of our study was to assess cognitive, adaptive, and behavior functioning of patients with LGS after 12 months of RFM therapy. METHODS: This was an observational, multicenter, prospective study involving 16 patients diagnosed with LGS aged between 7 and 58 years (mean = 22 ±â€¯16.3). Fourteen of 16 patients were already on therapy with 3 antiseizure drugs and 2/16 with 4 antiseizure drugs; RFM has been added with 100 mg/week increments up to a dose of 300-2400 mg/day. The participants and their parents underwent a neuropsychological evaluation for the assessment of intellectual, adaptive, and emotional/behavioral functioning (Leiter International Performance Scale-Revised (LEITER-R), Vineland, and Child Behavior CheckList (CBCL), respectively) before the RFM introduction (baseline) and 12 months after the RFM therapy (T2). Physical and neurological examination, electroencephalography (EEG) recording, seizure type and frequency, and adverse reactions were also considered. RESULTS: After 12 months, the total intelligence quotient (IQ) assessed by LEITER-R did not show statistical significant changes, such as there were no statistically significant changes in adaptive functions, assessed by Vineland. Furthermore, there were no statistically significant changes in internalizing and externalizing problems assessed by CBCL. CONCLUSION: Adjunctive treatment with RFM did not negatively affect cognitive, adaptive function, and emotional profile in patients with LGS after 1 year of follow-up.

Rufinamide as add-on therapy in children with epileptic encephalopathies other than Lennox-Gastaut syndrome: A study of 34 patients.

OBJECTIVE: Here, we present a multicenter series of patients with developmental and epileptic encephalopathies (DEE) and related electroclinical patterns (REP) other than Lennox-Gastaut syndrome (LGS) who were treated with rufinamide as add-on therapy. METHODS: Medical records of 34 patients with DEE and REP other than LGS treated with add-on rufinamide seen at four pediatric neurology centers in Argentina between May 2014 and March 2019 were retrospectively analyzed. RESULTS: We evaluated 34 patients (18 males, 16 females), aged between 2 and 15 years with a mean and median age of 6 and 8 years, respectively. The children had different types of childhood-onset refractory DEE and REP other than LGS and were treated with rufinamide for a mean period of 20 months (range, 12-60 months). Twenty-two of 34 patients (64.5%) who received rufinamide as add-on therapy had a greater than 50% decrease in seizures, and two patients (5.8%) became seizure-free. Four patients (11.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in four others (11.7%) and increased in two patients (5.8%). The final mean dosage of rufinamide was 31.5 ±â€¯15.5 mg/kg per day (range, 19-75.4 mg/kg) if combined with valproic acid and of 35.4 ±â€¯11.5 mg/kg per day (range, 8-60.5 mg/kg) without valproic acid. Adverse effects were recorded in nine patients (26.4%). A seizure increase was reported in two of 24 patients (7.3%). CONCLUSION: Rufinamide may be used as a treatment option in DEE and REP other than LGS.

The anti-convulsants lacosamide, lamotrigine, and rufinamide reduce myotonia in isolated human and rat skeletal muscle.

INTRODUCTION: In myotonia congenita, loss of ClC-1 Cl- channel function results in skeletal muscle hyperexcitability and myotonia. Anti-myotonic treatment has typically targeted the voltage-gated sodium channel in skeletal muscle (Nav1.4). In this study we explored whether 3 sodium channel-modulating anti-epileptics can reduce myotonia in isolated rat and human muscle. METHODS: Dissected muscles were rendered myotonic by ClC-1 channel inhibition. The ability of the drugs to suppress myotonia was then assessed from subclinical to maximal clinical concentrations. Drug synergy was determined using isobole plots. RESULTS: All drugs were capable of abolishing myotonia in both rat and human muscles. Lamotrigine and rufinamide completely suppressed myotonia at submaximal clinical concentrations, whereas lacosamide had to be raised above the maximal clinical concentration to suppress myotonia completely. A synergistic effect of lamotrigine and rufinamide was observed. CONCLUSION: These findings suggest that lamotrigine and rufinamide could be considered for anti-myotonic treatment in myotonia congenita. Muscle Nerve 56: 136-142, 2017.

Rufinamide in children and adults in routine clinical practice.

OBJECTIVE: To explore the long-term effectiveness of rufinamide in managing Lennox-Gastaut Syndrome (LGS), other epileptic encephalopathies, and intractable focal epilepsies in adults and children in routine clinical practice. METHODS: A multicentre, retrospective chart review of patients prescribed adjunctive rufinamide at seven Spanish epilepsy centres, with assessments at six and 12 months. RESULTS: We evaluated data from 58 patients (40 male, age range 7-57 years), 25 of whom were diagnosed with LGS, 12 with other epileptic encephalopathies and 21 of whom were diagnosed with focal epilepsies, mainly frontal lobe. The mean daily rufinamide dose was 32.0 mg/kg (range 12.5-66.7 mg/kg) in children and 24.7 mg/kg (range 5.0-47.0 mg/kg) in adults, and the most commonly used concomitant antiepileptic drugs were levetiracetam and valproate. Rufinamide was discontinued in 25 patients (43.1%) during the 1-year follow-up, and the most common reason was lack of effectiveness (n = 12, 20.7% of total). The frequency of generalized tonic-clonic seizures was significantly reduced from baseline at 6 and 12 months (P = 0.001), both in patients with generalized epilepsies and in patients with focal epilepsies. Significant seizure frequency reduction from baseline was observed at 12 months (P = 0.01) for tonic/atonic seizures and at 6 months (P = 0.001) for focal seizures. Side effects were reported in 21 patients (36.2%): nausea, vomiting and weight loss were most frequent. CONCLUSIONS: Rufinamide was well tolerated and was effective in reducing frequency of generalized tonic-clonic, tonic/atonic and focal seizures in both children and adults with severe refractory epilepsies, primarily LGS.

Real-world data on rufinamide treatment in patients with Lennox-Gastaut syndrome: Results from a European noninterventional registry study.

INTRODUCTION: Rufinamide is approved for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients aged ≥4years. The objective of this study was to provide real-world, long-term data on patients with LGS initiating rufinamide as add-on therapy and patients with LGS receiving other antiepileptic drugs (AEDs). METHODS: A Phase IV, noninterventional, multicenter registry study was conducted in patients with LGS aged ≥4years requiring modification to any AED treatment, including initiation of add-on rufinamide therapy. Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs), and efficacy was assessed using a generic seizure frequency scale. RESULTS: A total of 111 patients from 64 sites in 8 European countries were included, of whom 64 initiated rufinamide ("rufinamide" group) and 21 did not receive rufinamide at any time during the study ("no-rufinamide" group). Mean ages were 16.1years (rufinamide) and 15.0years (no rufinamide). The median duration of follow-up was >2years (range: 1.3-46.4months). Antiepileptic drug-related TEAEs were reported for 40.6% (rufinamide) and 33.3% (no rufinamide) of patients and led to discontinuation of 7.8% and 4.8%, respectively. The most frequently reported rufinamide-related TEAEs (≥5% patients) were somnolence (7.8%) and decreased appetite (6.3%). There were no unexpected safety/tolerability findings. At month 12, the proportion of patients with improvement in all seizures ("much improved" or "very much improved") was 28.6% (12/42) for the rufinamide group and 14.3% (2/14) for the no-rufinamide group. CONCLUSION: The study provided valuable information on LGS and its management, and evidence that rufinamide has a consistent and generally favorable safety/tolerability profile when used in routine clinical practice. CLINICALTRIALS. GOV IDENTIFIER: NCT01991041.

Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience.

OBJECTIVE: Reports of studies evaluating rufinamide as an add-on therapy in children and adolescents with refractory epilepsy are restricted to a few publications. Prospective multicenter studies including children and adults have yielded important information about several types of epilepsies and syndromes. We evaluated the use of rufinamide in a single pediatric center with a large cohort and long-term follow-up period. METHODS: We retrospectively included patients taking rufinamide from November 2008 to March 2013. Response was defined by a seizure reduction of ≥50% compared to baseline. RESULTS: Three hundred patients with a median age of 9.1 years (range 0.4-29.6 years) were reviewed. Median follow-up was 9 months (range 1-37 months). Epilepsy etiology was classified as genetic (23.7%), structural/metabolic (41%), and unknown cause (35.3%). Overall, rufinamide treatment led to a median seizure frequency reduction of 59.2% from responders to baseline. Seizure reduction was greater in patients with genetic etiology compared to structural/metabolic (66.2% vs. 45.5% responders, p = 0.005). Rufinamide was discontinued in 110 (36.7%) of 300 patients: 63 (21%) due to unsatisfactory response, 47 (15.7%) due to side effects, and in 18 (6%) of those due to both. Most common adverse effects were sleepiness, vomiting, mood changes, nausea, and loss of appetite. Median time to loss of efficacy was 11.6 months (range 3-28 months). SIGNIFICANCE: Rufinamide provides satisfactory seizure reduction as an adjunctive treatment in refractory epilepsy. Results need to be interpreted in the setting of data acquisition, including inherent biases of retrospective studies. Patients with a known genetic etiology may have better responses than patients with structural/metabolic etiology.

Exposure to rufinamide and risks of CNS adverse events in drug-resistant epilepsy: a meta-analysis of randomized, placebo-controlled trials.

AIM: Epilepsy is a complex disease necessitating continuous development of new therapeutic strategies to encounter drug-resistant cases. Among new adjuvant antiepileptic drugs, rufinamide is structurally distinct from other antiepileptic drugs. It is used to treat partial-onset seizures and seizures associated with Lennox-Gastaut syndrome (LGS) in adult and children. To date, there has been no attempt to evaluate systematically the risks of adverse events with rufinamide. METHODS: We performed a quantitative risk analysis of central nervous system (CNS) adverse events of rufinamide from all randomized, double-blind, add-on, placebo-controlled trials. The meta-analysis was undertaken with fixed effects models. RESULTS: Of the 886 publications reviewed, 99 papers were retrieved and five articles met the inclusion criteria. One thousand two hundred and fifty-two patients were included. Our study showed that exposure to rufinamide was associated with a significant increase in risk of somnolence [relative ratio (RR) 1.87; 95% confidence interval (CI) 1.33, 2.62; P = 0.0003], dizziness (RR 2.66; 95% CI 2.00, 3.55; P = 0.00001), fatigue (RR 2.14; 95% CI 1.57, 2.91; P = 0.01) and headache (RR 1.28; 95% CI 1.02, 1.59, P = 0.03). In addition, exposure to rufinamide was associated with higher treatment discontinuation rates as compared with placebo (RR 2.65; 95% CI 1.74, 4.03; P = 0.00001). CONCLUSIONS: The risk of CNS adverse events appears to be increased in patients exposed to rufinamide as well as the treatment discontinuation rates. However, although statistical associations were significant, additional long term safety studies are required to confirm the clinical significance of these findings, as most reports described only mild and moderate adverse events.

Brivaracetam and rufinamide combination increased seizure threshold and improved neurobehavioral deficits in corneal kindling model of epilepsy.

BACKGROUND: Besides seizures, a myriad of overlapping neuropsychiatric and cognitive comorbidities occur in patients with epilepsy, which further debilitates their quality of life. This study provides an in-depth characterization of the impact of brivaracetam and rufinamide individually and in combination at 10 and 20 mg/kg doses, respectively, on corneal kindling-induced generalized seizures and behavioral alterations. Furthermore, observed convulsive frequency and behavioral changes were correlated to post-kindling-induced changes in the activity of markers of oxidative stress. METHODS: Adult C57BL/6 mice were kindled via twice-daily transcorneal 50-Hz electrical stimulations (3 mA) for 3 s for 12 days until animals reached a fully kindled state. After the kindling procedure, animals were tested using a set of behavioral tests, and neurochemical alterations were assessed. RESULTS: Corneal-kindled animals exhibited intense generalized convulsions, altered behavioral phenotypes typified by positive symptoms (hyperlocomotion), negative symptoms (anxiety and anhedonia), and deficits in semantic and working memory. BRV 10 + RFM 20 dual regime increased convulsive threshold and propensity toward the start of stage 4-5 seizures and improved phenotypical deficits, that is, anxiety, depression, and memory impairments. Moreover, this combination therapy mitigated kindling-induced redox impairments as evidenced by reduced malondialdehyde and acetylcholinesterase levels and increased glutathione antioxidant activity in the brain of animals subjected to repetitive brain insult. CONCLUSION: Based on our outcomes, this dual therapy provides supporting evidence in alleviating epilepsy-induced neurobehavioral comorbidities and changes in redox homeostasis.

Disproportionality analysis of the safety profile of rufinamide in the real world: an evaluation of the FDA Adverse Event Reporting System database.

BACKGROUND: Rufinamide (RUF) is an antiepileptic drug recently introduced for managing seizures in Lennox-Gastaut syndrome (LGS), but its adverse reactions are not well understood. This study aims to evaluate RUF's safety profile using data from the FDA Adverse Event Reporting System (FAERS). METHODS: Disproportionality analysis was conducted to assess RUF-associated adverse drug events (ADEs), using reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma-Poisson shrinker (MGPS). RESULTS: We collected 338 ADE reports related to RUF. Nervous system disorders were the most frequently reported signals, and several new ADEs were detected, including atonic seizures, sudden unexplained death in epilepsy, seizure clusters, multi-drug resistance, and Stevens-Johnson syndrome. Nearly half of the ADEs in pediatric patients were psychological or neurological. Disproportionality analysis within 4 weeks of treatment showed high RORs for QT shortening, sudden death, and atonic seizures. CONCLUSIONS: Our study revealed prospective signals of new ADEs linked to RUF as well as revealed that both prescribers and patients were more conscious of the risks involved in its clinical use.

Indirect comparison of clobazam and other therapies for Lennox-Gastaut syndrome.

OBJECTIVE: In the absence of head-to-head trials, it is not feasible to make direct comparisons of antiepileptic therapies for the treatment of Lennox-Gastaut syndrome (LGS). We conducted indirect comparisons of the relative efficacies of clobazam, felbamate, lamotrigine, topiramate, and rufinamide as adjunctive treatments for LGS. METHODS: Clinical studies of LGS patients were identified in a 2009 Cochrane review and by electronic database search. Five randomized controlled trials were included in this systematic review, which reports findings from indirect comparisons between clobazam and other approved adjunctive LGS therapies (felbamate, lamotrigine, topiramate, rufinamide) in the United States and Europe. As outcomes were not uniformly reported across studies, the primary efficacy endpoint from each trial was transformed into Cohen's d effect size, to facilitate indirect comparisons. Typical interpretations of Cohen's d results are as follows: d < 0.2, change not detectable; 0.2 ≤ d < 0.5, small change; 0.5 ≤ d < 0.8, moderate change; and 0.8 ≤ d, large change. RESULTS: High-dosage clobazam (1.0 mg/kg/day) was found to have the strongest treatment effect vs placebo (effect size 0.80), with moderate effects (effect sizes >0.50) for medium-dosage clobazam (0.5 mg/kg/day) and rufinamide. Felbamate, lamotrigine, and topiramate had low effect sizes. Indirect comparisons of numbers of total seizures and tonic-atonic seizures ('drop attacks') demonstrated superiority of both clobazam dosages over all comparators. CONCLUSIONS: High- and medium-dosage clobazam was estimated to be more efficacious than other LGS treatments. Our analysis relied on published data and could not draw on direct head-to-head data of clobazam with alternatives. Further comparative research is ongoing to assess the usefulness of clobazam for LGS.

Short-term efficacy and tolerability of rufinamide adjunctive therapy in children with refractory generalised epilepsy.

We evaluated the efficacy and tolerability of rufinamide adjunctive therapy in children with refractory generalised epilepsy. The study cohort consisted of 20 patients with Lennox-Gastaut syndrome, 5 with Dravet syndrome, and 28 with unclassified refractory generalised epilepsy. Patients with more than 50% seizure reduction at three and six months were defined as responders. The overall response rate was 37.7% at three months and 34.0% at six months. At three months, patients with Lennox-Gastaut syndrome (40.0%) and epilepsy with spasms/tonic seizures (38.5%) showed higher response rates than those with Dravet syndrome (20.0%) and epilepsy with myoclonic seizures (20.0%). High response rates in patients with Lennox-Gastaut syndrome (30.0%) and epilepsy with spasms/tonic seizures (38.5%) were sustained throughout the six-month study. The accuracy of, and differences between, responder rates should, however, be interpreted with caution due to the small number of patients. Overall, rufinamide appeared to be effective and reasonably well tolerated in this group of children with refractory generalised epilepsies, although a subgroup of patients with Dravet syndrome and epilepsy with myoclonic seizures were less responsive to rufinamide treatment.

Pharmacological diversity amongst approved and emerging antiseizure medications for the treatment of developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are rare neurodevelopmental disorders characterised by early-onset and often intractable seizures and developmental delay/regression, and include Dravet syndrome and Lennox-Gastaut syndrome (LGS). Rufinamide, fenfluramine, stiripentol, cannabidiol and ganaxolone are antiseizure medications (ASMs) with diverse mechanisms of action that have been approved for treating specific DEEs. Rufinamide is thought to suppress neuronal hyperexcitability by preventing the functional recycling of voltage-gated sodium channels from the inactivated to resting state. It is licensed for adjunctive treatment of seizures associated with LGS. Fenfluramine increases extracellular serotonin levels and may reduce seizures via activation of specific serotonin receptors and positive modulation of the sigma-1 receptor. Fenfluramine is licensed for adjunctive treatment of seizures associated with Dravet syndrome and LGS. Stiripentol is a positive allosteric modulator of type-A gamma-aminobutyric acid (GABAA) receptors. As a broad-spectrum inhibitor of cytochrome P450 enzymes, its antiseizure effects may additionally arise through pharmacokinetic interactions with co-administered ASMs. Stiripentol is licensed for treating seizures associated with Dravet syndrome in patients taking clobazam and/or valproate. The mechanism(s) of action of cannabidiol remains largely unclear although multiple targets have been proposed, including transient receptor potential vanilloid 1, G protein-coupled receptor 55 and equilibrative nucleoside transporter 1. Cannabidiol is licensed as adjunctive treatment in conjunction with clobazam for seizures associated with Dravet syndrome and LGS, and as adjunctive treatment of seizures associated with tuberous sclerosis complex. Like stiripentol, ganaxolone is a positive allosteric modulator at GABAA receptors. It has recently been licensed in the USA for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder. Greater understanding of the causes of DEEs has driven research into the potential use of other novel and repurposed agents. Putative ASMs currently in clinical development for use in DEEs include soticlestat, carisbamate, verapamil, radiprodil, clemizole and lorcaserin.

Proposed anti-seizure medication combinations with rufinamide in the treatment of Lennox-Gastaut syndrome: Narrative review and expert opinion.

Lennox-Gastaut syndrome (LGS) is a severe, chronic, complex form of early childhood-onset epilepsy characterized by multiple seizure types, generalized slow (≤2.5 Hz) spike-and-wave activity and other electroencephalography abnormalities, and cognitive impairment. A key treatment goal is early seizure control, and several anti-seizure medications (ASMs) are available. Due to the low success rate in achieving seizure control with monotherapy and an absence of efficacy data supporting any particular combination of ASMs for treating LGS, a rational approach to selection of appropriate polytherapy should be applied to maximize benefit to patients. Such "rational polytherapy" involves consideration of factors including safety (including boxed warnings), potential drug-drug interactions, and complementary mechanisms of action. Based on the authors' clinical experience, rufinamide offers a well-considered first adjunctive therapy for LGS, particularly in combination with clobazam and other newer agents for LGS, and may be particularly useful for reducing the frequency of tonic-atonic seizures associated with LGS.