Presynaptic antiseizure medications - basic mechanisms and clues for their rational combinations.

Among clinically highly efficient antiseizure medications (ASMs) there are modifiers of the presynaptic release machinery. Of them, levetiracetam and brivaracetam show a high affinity to the synaptic vesicle protein type 2 A (SV2A), whereas pregabalin and gabapentin are selective ligands for the α2δ1 subunits of the voltage-gated calcium channels. In this paper, we present recent progress in understanding the significance of presynaptic release machinery in the neurochemical mechanisms of epilepsy and ASMs. Furthermore, we discuss whether the knowledge of the basic mechanisms of the presynaptically acting ASMs might help establish a rational polytherapy for drug-resistant epilepsy.

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

Selecting appropriate antiseizure medications (ASMs) for combination therapy in patients with drug-resistant epilepsy (DRE) is a complex task that requires an empirical approach, especially in patients receiving polytherapy. We aimed to analyze the effectiveness of various three-drug combinations in a group of patients with DRE under real-world conditions. This single-center, longitudinal observational study investigated patients with drug-resistant focal epilepsy who received three-drug regimens in the outpatient clinic of Tongji Hospital from September 2019 to December 2022. The effectiveness of each triple regimen was evaluated by the seizure-free rate and within-patient ratio of the seizure frequency (a seizure frequency ratio [SFR]<1 indicated superior efficacy). The independent t-test or Mann-Whitney U test was used for effectiveness analysis, and P values were adjusted by the Benjamini-Hochberg method for multiple comparisons. A total of 511 triple trials comprising 76 different regimens were conducted among 323 enrolled patients. Among these triple regimens, lamotrigine (LTG)/valproic acid (VPA)/topiramate (TPM) was the most frequently prescribed (29.4%, n â€‹= â€‹95). At the last clinical visit, 14.9% (n â€‹= â€‹48) of patients achieved seizure freedom after receiving triple therapy. LTG/VPA/TPM and LTG/VPA/levetiracetam (LEV) exhibited the highest seizure-free rates at 17.9% and 12.8%, respectively. These two regimens also had significantly lower median SFRs of 0.48 (interquartile range [IQR], 0.17-0.85; adjusted P â€‹< â€‹0.001) and 0.63 (IQR, 0.21-1.04; adjusted P â€‹< â€‹0.01), respectively. LTG/VPA/perampanel (PER) was another promising regimen that showed marginal effectiveness (median SFR â€‹= â€‹0.67; adjusted P â€‹= â€‹0.053). LTG/VPA/phenobarbital had the highest incidence of regimen-specific side effects (40.0%, 4/10), while the incidence of side effects from LTG/VPA/LEV was minimal (5.1%, 2/39). In conclusion, LTG/VPA/TPM and LTG/VPA/LEV exhibited superior efficacy and good tolerability in treating patients with DRE. Our results provide preliminary insights into the selection of ASMs for three-drug combination therapies in this clinically challenging population.

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.

The Pharmacoresistant Epilepsy: An Overview on Existant and New Emerging Therapies.

Epilepsy is one of the most common neurological chronic disorders, with an estimated prevalence of 0. 5 - 1%. Currently, treatment options for epilepsy are predominantly based on the administration of symptomatic therapy. Most patients are able to achieve seizure freedom by the first two appropriate drug trials. Thus, patients who cannot reach a satisfactory response after that are defined as pharmacoresistant. However, despite the availability of more than 20 antiseizure medications (ASMs), about one-third of epilepsies remain drug-resistant. The heterogeneity of seizures and epilepsies, the coexistence of comorbidities, and the broad spectrum of efficacy, safety, and tolerability related to the ASMs, make the management of these patients actually challenging. In this review, we analyze the most relevant clinical and pathogenetic issues related to drug-resistant epilepsy, and then we discuss the current evidence about the use of available ASMs and the alternative non-pharmacological approaches.

Perampanel effectiveness and safety as early add-on treatment for focal-onset seizures: PEREAGAL study.

BACKGROUND: Perampanel (PER) is an effective adjunctive therapy for controlling focal-onset seizures (FOS), but few studies have examined its effects as an early add-on for the treatment of FOS in daily clinical practice. METHODS: Our retrospective, multicenter, observational study evaluated the effectiveness and safety of PER as an early add-on in 77 patients with FOS, with and without focal to bilateral tonic-clonic seizures (FBTCS) after 3, 6 and 12 months in a real-world setting. RESULTS: After 12 months of treatment (median dose 6 [4,8] mg/day), the retention rate was 79.2 % and 60 % of patients (39/65) experienced a ≥50 % reduction in seizure frequency relative to baseline. The seizure-free rate was 38.5 % for all seizures (25/65) and 60 % for FBTCS (12/20). The responder rate at 12 months was significantly higher when PER was given with one concomitant AED (72.2 %) compared to when PER was given with two concomitant AEDs (44.8 %). Drug-related adverse events (AEs) were reported in 40.3 % of patients, most of them being mild (64.2 %). Twelve patients (15.6 %) discontinued treatment because of AEs. CONCLUSIONS: PER is an effective and safe early add-on for patients with refractory FOS, especially for those with FBTCS.

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

OBJECTIVE: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments. METHODS: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis. We retrospectively reviewed clinical, electroencephalogram, neuroimaging, and genetic information. RESULTS: We identified 29 patients (21 females, eight males). All patients showed severe developmental delay, especially in males. Involuntary movements were observed in 15 patients. No antiepileptic drugs (AEDs) achieved seizure freedom by monotherapy. AEDs achieving ≥ 50% reduction in seizure frequency were sodium valproate in two patients, vigabatrin in one, and lamotrigine in one. Seizure aggravation was observed during the use of lamotrigine, potassium bromide, and levetiracetam. Adrenocorticotrophic hormone (ACTH) was the most effective treatment. The ketogenic diet (KD), corpus callosotomy and vagus nerve stimulation did not improve seizure frequency in most patients, but KD was remarkably effective in one. The degree of brain atrophy on magnetic resonance imaging (MRI) reflected disease severity. Compared with females, males had lower levels of attained motor development and more severe cerebral atrophy on MRI. CONCLUSION: Our patients showed more severe global developmental delay than those in previous studies and had intractable epilepsy, likely because previous studies had lower numbers of males. Further studies are needed to investigate appropriate therapy for CDD, such as AED polytherapy or combination treatment involving ACTH, KD, and AEDs.

Unanticipated improvement in seizure control in drug-resistant epilepsy- real world observations.

OBJECTIVES: To determine the clinical features and anti-seizure medication (ASM) strategies associated with an unanticipated substantial improvement in seizure control in patients with drug-resistant epilepsy (DRE). METHODS: This retrospective analysis of patients attending a tertiary care epilepsy clinic between 2008 and 2017 identified all patients with active DRE (at least 1 seizure per month for 6 months, despite treatment with 2 different ASMs). All treatment interventions were recorded from when DRE was first identified to the end of the study. The primary end points were seizure freedom or meaningful reduction in seizure frequency (greater than 75 %) sustained for at least 12 months after a treatment intervention. RESULTS: Three hundred and twenty-two patients were included in the analysis. Overall, 10 % became seizure free following ASM adjustment and an additional 10 % had a greater than 75 % improvement in seizure control (median follow-up, 4 years). An ASM introduction was ten times more likely than an ASM dose increase to improve seizure control. Combined focal and generalized epilepsy, intellectual disability and prior treatment with more than 5 ASMs were more frequently observed in those with continued pharmacoresistance. ASM responders were more likely to have primary generalized epilepsy. Rational polytherapy (combining ASMs with different mechanisms of action) was almost ubiquitous amongst ASMs responders (95 % taking at least 2 drugs with different mechanistic targets). Of the ASM additions that heralded improved seizure control, 85 % were maintained at submaximal doses. CONCLUSIONS: This retrospective analysis of a large number of 'real-world' patients provides evidence to persist with ASM trials in DRE. Early rotation of ASMs if a clinical response is not observed at a substantial dose and rational ASM polytherapy may yield better clinical outcomes in patients with DRE, although a prospective study would need to be conducted to validate these findings.

Efficacy and tolerability of perampanel as a first add-on therapy with different anti-seizure drugs.

PURPOSE: To investigate the efficacy and tolerability of perampanel (PER) when administered as a first add-on therapy to patients with focal epilepsy or idiopathic generalized epilepsy (IGE) taking one other antiseizure drug (ASD). METHODS: This multicentre, retrospective, one-year observational study collected data from patients (≥12 years) who initiated treatment with PER as first add-on therapy. Patients had to be experiencing inadequate seizure control on ASD monotherapy and tried ≤3 ASD monotherapies before initiating PER. Multivariate logistic regression analyses were performed, adjusted for the number and type of previous seizures, duration and aetiology of epilepsy. RESULTS: Of the 149 patients included in the study (mean age 41 years; 54.4 % male), 118 (79.2 %) were still receiving PER as first add-on treatment after 12 months. Mean PER dose was 6.2 mg/day. At 12 months, 45.6 % were seizure-free and 84.6 % responders. A significant difference in seizure freedom rate was found between patients with IGE and patients with focal epilepsy, but not in responders. Reduced seizure control was observed when PER was administered with strong enzyme-inducing ASDs; conversely, increased seizure control was seen when the same dose of PER was combined with enzyme-inhibiting ASDs. The most frequent adverse events were dizziness (15.4 %), irritability (14.1 %) and drowsiness (14.1 %); no differences in tolerance were observed among different combinations. CONCLUSION: PER demonstrated a good efficacy and safety profile when used as a first add-on therapy in patients who did not respond to monotherapy. PER dose adjustments may optimize seizure control when combined with strong enzyme-inducing or enzyme-inhibiting ASDs.

Comparative efficacy of unique antiepileptic drug regimens in focal epilepsy: An exploratory study.

OBJECTIVE: To compare efficacy of unique antiepileptic drug (AED) polytherapy regimens among patients with focal epilepsy. METHODS: From a longitudinal study of AED treatment, we identified patients with active focal epilepsy who had attempted at least two unique AED regimens (mono-, duo-, or tri-therapy). Efficacy was defined as the presence of at least one six-month period of continuous seizure freedom during exposure to a regimen. To control for individual variations in response and epilepsy severity, we used within-patient comparison approaches, in which we: 1) compared head-to-head unique regimens tried within the same patients; 2) compared one regimen versus aggregate of other regimens attempted in that patient; and 3) compared aggregated monotherapy versus polytherapy regimens. RESULTS: 757 patients met our criteria and had collectively attempted 170 unique regimens. In the head-to-head analysis, lamotrigine monotherapy was more effective than phenytoin monotherapy. Two regimens were more effective than the aggregate of other regimens attempted: levetiracetam/lamotrigine duotherapy and lamotrigine monotherapy. Two other regimens exhibited slightly better efficacy but did not reach statistical significance: clobazam/levetiracetam/lamotrigine and levetriacetam/oxcarbazepine. Patients who previously attempted at least four regimens had slightly better outcomes on polytherapy than monotherapy, though this was not significant. SIGNIFICANCE: We identified two unique regimens more likely to be associated with ≥6 months of seizure freedom: levetiracetam/lamotrigine duotherapy and lamotrigine monotherapy. Polytherapy may be an effective alternative to monotherapy for patients with focal epilepsy and persistent seizures.

Politerapia racional en epilepsia infantil / Rational polytherapy in infantile epilepsy

Se acepta globalmente que el tratamiento inicial de la epilepsia debe realizarse en monoterapia. Sin embargo, dado que hasta un 30% de los pacientes son refractarios a una o varias monoterapias, es común asociar pautas combinadas de dos o más fármacos antiepilépticos (FAE). En estos supuestos de politerapia, hay que considerar el mecanismo de acción de cada FAE, su espectro, su seguridad, y sus interacciones farmacocinéticas y farmacodinámicas. La politerapia racional es un concepto terapéutico basado en la combinación de FAE con mecanismos de acción complementarios que actúan sinérgicamente para maximizar su e cacia y minimizar los potenciales efectos adversos. Para diseñar una buena politerapia racional en epilepsia es básico conocer los distintos mecanismos de acción de cada FAE y analizar la evidencia empírica existente para con cada una de las posibles combinaciones de FAE. Se sugiere que puede ser útil combinar FAE inhibidores de canales de sodio con FAE gabaérgicos, o con FAE con múltiples mecanismos de acción, y evitar aquellas combinaciones que potencien la toxicidad. Sin embargo, existe muy escasa evidencia empírica y clínica respecto a la politerapia racional y sólo está demostrado el sinergismo entre valproato y lamotrigina. La politerapia racional supone una estrategia diseñada para mejorar el balance entre e cacia y tolerabilidad de las distintas combinaciones de FAE. Sin embargo, dada la ausencia de ensayos clínicos en politerapia racional, sólo podemos hacer sugerencias sobre asociaciones de FAE potencialmente útiles o perjudiciales en base a las características farmacocinéticas y farmacodinámicas de los diversos FAE implicados.

Abstract It is an accepted fact that antiepileptic treatment must be started with monotherapy, but 30% of patients do not respond to it or to several monotherapies; in that moment an association of two or more antiepileptic drugs (AEDs) is commonly utilized. It is necessary to consider the mechanism of action of each AED, its spectrum, the safety and pharmacodynamic and pharmacokinetic interactions, and to select the association of AEDs in accordance with these factors. Rational polytherapy is a concept that is predicated on the combination of drugs with complementary mechanisms of action that work synergistically to maximize efficacy and minimize the potential for adverse events. Furthermore, rational polytherapy requires a detailed understanding of the mechanisms of action subclasses among available AEDs and an appreciation of the empirical evidence that supports the use of specific combinations. These theoretical foundations suggest a sodium channel inhibitor should be associated with a GABAergic agent or with an AED with multiple mechanisms and that we should avoid the association between AEDs with additional toxicity or that are likely to interact. However, the experimental and clinical evidence in support of rational polytherapy is sparse, with only the combination of sodium valproate and lamotrigine demonstrating synergism. Rational polytherapy is a theoretical approach designed for improving the balance between efficacy and tolerability of several AEDs combinations. However, the absence of clinical trials only allows us to make suggestions about possible bene cial or harmful associations depending on the pharmacodynamic and pharmacokinetic characteristics of AEDs.

Pharmacological Treatment of Drug-Resistant Epilepsy in Adults: a Practical Guide.

More than 30 % of adults with epilepsy do not fully control on the currently available antiepileptic drugs (AEDs). For these and many other patients, combinations of agents, often possessing different mechanisms of actions, are employed with the aim of achieving seizure freedom or the best available prognosis in terms of reduced seizure numbers and severity. This review discusses my own approach to optimising outcomes in as many of these patients as possible by adjusting the drug burden using a combination of two, three or sometimes four or more AEDs. Modes of drug action are reviewed and practical strategies for treating different patients with drug-resistant epilepsy have been explored. Only for sodium valproate with lamotrigine is there good evidence of synergism. The final part of this practical paper consists of six individual illustrative cases with appropriate comments.

Synergism of perampanel and zonisamide in the rat amygdala kindling model of temporal lobe epilepsy.

OBJECTIVE: Anticonvulsive monotherapy fails to be effective in one third of patients with epilepsy resulting in the need for polytherapy regimens. However, with the still limited knowledge, drug choices for polytherapy remain empirical. Here we report experimental data from a chronic epilepsy model for the combination of perampanel and zonisamide, which can render guidance for clinical studies and individual drug choices. METHODS: The anticonvulsant effects of the combination of perampanel and zonisamide were evaluated in a rat amygdala kindling model. Furthermore, the potential for motor impairment was evaluated. The type of interaction was quantitatively assessed based on isobolographic analysis. RESULTS: When administered alone, zonisamide dose-dependently increased the afterdischarge threshold in fully kindled rats. Moreover, data confirmed efficacy of perampanel to inhibit seizure initiation and progression with an impact on propagation of activity from the focus. Pronounced threshold increases were observed following administration of a constant zonisamide dosage combined with different doses of perampanel. Isobolographic analysis of drug responses, which is based on individual drug dose-effect data, revealed a synergistic interaction substantiating the high efficacy of the combination. Furthermore, rotarod data indicated that the combination has a favorable tolerability profile when zonisamide is coadministered with low doses of perampanel. Plasma concentration analysis argued against a pharmacokinetic interaction as a basis for the synergism. SIGNIFICANCE: The findings clearly indicate a pronounced synergistic anticonvulsant effect for the combination of the noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist perampanel with zonisamide, which modulates voltage-sensitive sodium channels and T-type calcium currents. Consequently, polytherapy using these two antiepileptic drugs might be efficacious for clinical management of partial-onset seizures. The findings indicate that the impact of dose ratios on tolerability needs be taken into account. With regard to conclusions about the extent of the synergism and its implications further antiepileptic drug combinations need to be evaluated allowing direct comparison.

Single versus combinatorial therapies in status epilepticus: Novel data from preclinical models.

Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. The mechanisms involved in RSE are incompletely understood. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. The pilocarpine and lithium-pilocarpine rat models are widely used in this respect. In these models, resistance to diazepam and other antiseizure drugs (ASDs) develops during SE so that an SE that is longer than 30 min is difficult to suppress. Furthermore, because all ASDs used in SE treatment are much more rapidly eliminated by rodents than by humans, SE recurs several hours after ASD treatment. Long-term consequences include hippocampal damage, behavioral alterations, and epilepsy with spontaneous recurrent seizures. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group. Based on data from diverse seizure models, we hypothesized that cholinergic mechanisms are involved in the mechanisms underlying ASD resistance of SE. We, therefore, developed an intravenous drug cocktail, consisting of diazepam, phenobarbital, and the anticholinergic scopolamine. This drug combination irreversibly terminated SE when administered 60, 90, or 120 min after SE onset. The efficacy of this cocktail in terminating SE was comparable with the previously reported efficacy of polytherapies with the glutamate receptor antagonist ketamine. Furthermore, when injected 60 min after SE onset, the scopolamine-containing cocktail prevented development of epilepsy and hippocampal neurodegeneration, which was not observed with high doses of diazepam or a combination of phenobarbital and diazepam. Our data add to the existing preclinical evidence that rational polytherapy can be more effective than monotherapy in the treatment of SE and that combinatorial therapy may offer a clinically useful option for the treatment of RSE. This article is part of a Special Issue entitled "Status Epilepticus".

Adjunctive use of ezogabine/retigabine with either traditional sodium channel blocking antiepileptic drugs (AEDs) or AEDs with other mechanisms of action: Evaluation of efficacy and tolerability.

Integrated data from three double-blind, randomized, placebo-controlled trials were analyzed to evaluate the efficacy and tolerability of ezogabine (EZG; US adopted name)/retigabine (RTG; international non-proprietary name) when used in combination with ≥1 sodium channel blocking antiepileptic drug (AED), ≥1 non-sodium channel blocking AED, or ≥1 AED from both the sodium channel and non-sodium channel mechanistic groups. Efficacy and tolerability appeared to be similar across all three groups of patients.

Rational Polytherapy with Antiepileptic Drugs.

Approximately 30-40% of patients do not achieve seizure control with a single antiepileptic drug (AED). With the advent of multiple AEDs in the past 15 years, rational polytherapy, the goal of finding combinations of AEDs that have favorable characteristics, has become of greater importance. We review the theoretical considerations based on AED mechanism of action, animal models, human studies in this field, and the challenges in finding such optimal combinations. Several case scenarios are presented, illustrating examples of rational polytherapy.