Determination of the economically justifiable price of cenobamate in the treatment of focal-onset seizures in adult patients with drug-resistant epilepsy in Spain.

OBJECTIVE: To determine the economically justifiable price (EJP) of cenobamate to become a cost-effective alternative compared with third-generation anti-seizure medications in the treatment of focal-onset seizures (FOS) in adult patients with drug-resistant epilepsy (DRE) in Spain. METHODS: Cost-effectiveness analysis compared cenobamate with brivaracetam, perampanel, eslicarbazepine acetate, and lacosamide. Markov model simulation of treatment pathway over a 60-year time horizon is presented. We determined the effectiveness and quality-adjusted life-years (QALYs) of health status and disutilities associated with treatment-related adverse events. Acquisition costs and use of medical resources were obtained from published literature and expert opinion. Base-case of cenobamate's EJP calculated applying a willingness-to-pay (WTP) threshold of €21,000/QALY. Analyses were performed at different thresholds, including dominant price scenario. Result robustness was assessed through sensitivity analyses. RESULTS: Base-case shows that cenobamate's daily EJP of €7.30 is cost-effective for a threshold of €21,000/QALY. At a daily price of €5.45, cenobamate becomes dominant over all treatment alternatives producing cost-savings for the national health system (NHS). Sensitivity analyses supported the robustness of base-case findings. CONCLUSIONS: Treatment with cenobamate produces incremental clinical benefit over third-generation ASMs, and at the base-case, EJP could represent a cost-effective option for the adjunctive treatment of FOS in adult patients with DRE in Spain.

Identifying key unmet needs and value drivers in the treatment of focal-onset seizures (FOS) in patients with drug-resistant epilepsy (DRE) in Spain through Multi-Criteria Decision Analysis (MCDA).

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. Approximately 40% of patients with epilepsy are pharmacoresistant after their seizures failed at least two antiseizure medications (ASMs). Adult patients experiencing focal-onset seizures (FOS) account for approximately 60% of all patients with epilepsy and they are more likely to become drug-resistant epilepsy (DRE) than those with generalized onset. Drug-resistant epilepsy is associated with mortality, morbidity, and reduced quality of life. The information available on the clinical management, health outcomes, and unmet needs of the disease within the Spanish healthcare environment is very limited. Multi-Criteria Decision Analysis (MCDA) allows determination of what represents value in a given indication considering all relevant criteria for healthcare decision-making in a transparent and systematic manner and from the perspective of relevant stakeholders. PURPOSE: The aim of this study was to identify the burden of DRE (clinical, quality of life, and economic) and the unmet needs in Spain and to determine what represents value in the treatment of FOS in DRE patients from the perspective of Spanish epileptologists. METHODS: The steps taken to carry out the MCDA were based on previously published good methodological practices. A systematic literature review (combining biomedical databases and gray literature sources) was performed between March and April 2020. Results were reviewed and validated with three epileptologists in June 2020 and used to develop a MCDA value framework, adapted for FOS in DRE, composed of 12 quantitative criteria and 3 contextual criteria. A group of six Spanish epileptologists from four Spanish regions were trained in MCDA methodology before individually validating value criteria (and their definitions based on literature review findings) and assigned relative weights using an ordinal 6-points scale. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology. RESULTS: Drug-resistant epilepsy is considered a very severe health problem with important unmet needs affecting a considerably sized population. While safety and impact on quality of life of available ASMs are considered adequate, efficacy remains insufficient for patients to achieve seizure freedom and maintain it over time. Hence, the therapeutic benefit of pharmacological treatments currently used is regarded as suboptimal. Drug-resistant epilepsy management is associated with moderate pharmacological, relevant direct medical and high indirect costs. Quality of evidence available for current treatments is moderate. It is considered that DRE does not currently stand as a key priority for the Spanish healthcare system. CONCLUSIONS: Drug-resistant epilepsy is considered a very severe health problem associated with relevant unmet needs. These include the lack of availability of specific treatment protocols, the need to improve early diagnosis by increasing the number of referrals to specialized epilepsy units and the availability of specific ASMs with improved efficacy and safety profiles, allowing to reach treatment objectives. Reflective MCDA provided a standardized, transparent approach to evaluate multiple criteria ascertaining what represents value from a holistic point of view and from the perspective of clinical experts, facilitating decision-making.

Beneficial Effects of Metformin on the Central Nervous System, with a Focus on Epilepsy and Lafora Disease.

Metformin is a drug in the family of biguanide compounds that is widely used in the treatment of type 2 diabetes (T2D). Interestingly, the therapeutic potential of metformin expands its prescribed use as an anti-diabetic drug. In this sense, it has been described that metformin administration has beneficial effects on different neurological conditions. In this work, we review the beneficial effects of this drug as a neuroprotective agent in different neurological diseases, with a special focus on epileptic disorders and Lafora disease, a particular type of progressive myoclonus epilepsy. In addition, we review the different proposed mechanisms of action of metformin to understand its function at the neurological level.

La importancia de la resección amigdalar en el tratamiento quirúrgico de la epilepsia temporal mesial / The importance of amygdala removal in the surgical treatment of mesial temporal lobe epilepsy

Pese a que desde hace tiempo se conoce que lesiones amigdalares en animales de experimentación producen un modelo de epilepsia, la participación de la amígdala en el complejo de la esclerosis temporal mesial es poco conocida y casi toda la atención se centra en el hipocampo. Este trabajo tiene como propósito enfatizar el papel de la resección de la amígdala para conseguir que el paciente quede sin crisis. Para ello presentamos dos casos de pacientes mujeres de 50 y 42 años con crisis desde la infancia y diagnosticadas de esclerosis temporal mesial. Ambas fueron intervenidas por nosotros en el año 2000 mediante amigdalohipocampectomía con resección parcial amigdalar más lobectomía temporal izquierda y derecha respectivamente. Las dos pacientes no presentaron nuevas crisis parciales complejas durante los primeros 6 años, empeorando posteriormente por lo que fueron reintervenidas para monitorización con electrodos subdurales y profundos. En ambas se evidenció un inicio ictal compatible con el electrodo situado en la amígdala. La subsiguiente resección del tejido donde se situó el electrodo amigdalar dejó a las dos pacientes libres de crisis. En estas dos pacientes fue preciso completar la resección amigdalar para conseguir que quedaran libres de crisis. La resección amigdalar es parte importante de la técnica quirúrgica en la epilepsia temporal mesial. Es posible que la amígdala tenga un papel mucho más relevante de lo actualmente considerado en el origen de las crisis

Even though amygdalar lesions are a known epilepsy model in laboratory animals, the role of the amygdala in mesial temporal sclerosis is not well-known. To date, most interest has been paid to the role of the hippocampal formation. The aim of this article is to emphasize the role of the amygdala in order to render a patient seizure free. Two patients are presented who were 50 and 42 years old at the time of surgery. They suffered from seizures since childhood and were diagnosed with mesial temporal sclerosis. A temporal lobectomy with hippocampectomy and partial amygdalectomy was performed on both patients in the year 2000, with one patient operated on the right side and the other one on the left side. Both patients were seizure free after surgery for 6 years, but presented again with seizures after that time. They were evaluated again for surgery, and subdural grids were placed, together with a deep electrode in the remnants of the amygdala. The amygdalar electrode showed to be the seizure onset in the two cases, and its resection rendered both patients seizure free. These two patients show that a complete amygdalar resection is necessary to render some patients seizure free. It might be the amygdala has a greater role than previously thought

[The importance of amygdala removal in the surgical treatment of mesial temporal lobe epilepsy]. / La importancia de la resección amigdalar en el tratamiento quirúrgico de la epilepsia temporal mesial.

Even though amygdalar lesions are a known epilepsy model in laboratory animals, the role of the amygdala in mesial temporal sclerosis is not well-known. To date, most interest has been paid to the role of the hippocampal formation. The aim of this article is to emphasize the role of the amygdala in order to render a patient seizure free. Two patients are presented who were 50 and 42 years old at the time of surgery. They suffered from seizures since childhood and were diagnosed with mesial temporal sclerosis. A temporal lobectomy with hippocampectomy and partial amygdalectomy was performed on both patients in the year 2000, with one patient operated on the right side and the other one on the left side. Both patients were seizure free after surgery for 6 years, but presented again with seizures after that time. They were evaluated again for surgery, and subdural grids were placed, together with a deep electrode in the remnants of the amygdala. The amygdalar electrode showed to be the seizure onset in the two cases, and its resection rendered both patients seizure free. These two patients show that a complete amygdalar resection is necessary to render some patients seizure free. It might be the amygdala has a greater role than previously thought.

Early add-on lacosamide in a real-life setting: results of the REALLY study.

BACKGROUND AND OBJECTIVES: Many patients with epilepsy are treated with antiepileptic drug (AED) polytherapy. Several factors influence the choice of early add-on therapy, and deciding on the most appropriate drug can be difficult. This study aimed to assess the efficacy and tolerability of lacosamide as early add-on therapy in patients with partial-onset seizures. METHODS: REALLY (REtrospective study of lAcosamide as earLy add-on aLong one Year) was a multicenter, retrospective, 1-year, real-life study. Patients included were aged older than 16 years, had partial-onset seizures, and were treated with lacosamide as add-on therapy after one or two prior AEDs. Data were collected retrospectively from clinical records. The primary study objective was to assess the efficacy of lacosamide over 12 months (seizure-free and responder rates), and the secondary objective was to assess the tolerability of lacosamide at 3, 6, and 12 months [adverse events (AEs) and discontinuation]. RESULTS: One hundred and ninety-nine patients were enrolled in the study; 89 patients (44.7 %) had tried one AED and 110 patients (55.3 %) had tried two AEDs before lacosamide. At 12 months, the proportion of patients who were seizure free was 44.9 %, and 76 % of patients were responders. The seizure-free rate at 12 months for patients who had previously received one or two AEDs was 58 and 34.3 %, and the responder rate at 12 months was 83.0 and 70.4 %, respectively. The AE rate was 21.5 % at 3 months, 27.1 % at 6 months, and 31.2 % at 12 months, with 7.0 % of patients discontinuing treatment because of an AE. The most common AE reported was dizziness (11.6 %). Cryptogenic epilepsy, a higher number of prior AEDs, and the use of a sodium channel blocker at onset were associated with a worse outcome. The number of concomitant AEDs decreased over 1 year (Z = 5.89; p < 0.001). Twenty-two patients were converted to lacosamide monotherapy with at least one evaluation ≥6 months from the beginning of monotherapy conversion. CONCLUSIONS: Lacosamide was effective and well tolerated as early add-on treatment in patients who had received one or two previous AEDs.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide.

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage-titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required.

Temporal lobe epilepsy: clinical semiology and age at onset.

The objective of this study was to define the clinical semiology of seizures in temporal lobe epilepsy according to the age at onset. We analyzed 180 seizures from 50 patients with medial or neocortical temporal lobe epilepsy who underwent epilepsy surgery between 1997-2002, and achieved an Engel class I or II outcome. We classified the patients into two groups according to the age at the first seizure: at or before 17 years of age and 18 years of age or older. All patients underwent intensive video-EEG monitoring. We reviewed at least three seizures from each patient and analyzed the following clinical data: presence of aura, duration of aura, ictal and post-ictal period, clinical semiology of aura, ictal and post-ictal period. We also analyzed the following data from the clinical history prior to surgery: presence of isolated auras, frequency of secondary generalized seizures, and frequency of complex partial seizures. Non-parametric, chi-square tests and odds ratios were used for the statistical analysis. There were 41 patients in the "early onset" group and 9 patients in the "later onset" group. A relationship was found between early onset and mesial temporal lobe epilepsy and between later onset and neocortical temporal lobe epilepsy (p = 0.04). The later onset group presented a higher incidence of blinking during seizures (p = 0.03), a longer duration of the post-ictal period (p = 0.07) and a lower number of presurgical complex partial seizures (p = 0.03). The other parameters analyzed showed no significant differences between the two groups. We conclude that clinical and semiological differences exist between patients with temporal lobe epilepsy according to the age at onset. [Published with video sequences].

Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation.

Progressive myoclonus epilepsy of Lafora type (LD, MIM 254780) is a fatal autosomal recessive disorder characterized by the presence of progressive neurological deterioration, myoclonus, epilepsy and polyglucosan intracellular inclusion bodies, called Lafora bodies. Lafora bodies resemble glycogen with reduced branching, suggesting an alteration in glycogen metabolism. Linkage analysis and homozygosity mapping localized EPM2A, a major gene for LD, to chromosome 6q24. EPM2A encodes a protein of 331 amino acids (named laforin) with two domains, a dual-specificity phosphatase domain and a carbohydrate binding domain. Here we show that, in addition, laforin interacts with itself and with the glycogen targeting regulatory subunit R5 of protein phosphatase 1 (PP1). R5 is the human homolog of the murine Protein Targeting to Glycogen, a protein that also acts as a molecular scaffold assembling PP1 with its substrate, glycogen synthase, at the intracellular glycogen particles. The laforin-R5 interaction was confirmed by pull-down and co-localization experiments. Full-length laforin is required for the interaction. However, a minimal central region of R5 (amino acids 116-238), including the binding sites for glycogen and for glycogen synthase, is sufficient to interact with laforin. Point-mutagenesis of the glycogen synthase-binding site completely blocked the interaction with laforin. The majority of the EPM2A missense mutations found in LD patients result in lack of phosphatase activity, absence of binding to glycogen and lack of interaction with R5. Interestingly, we have found that the LD-associated EPM2A missense mutation G240S has no effect on the phosphatase or glycogen binding activities of laforin but disrupts the interaction with R5, suggesting that binding to R5 is critical for the laforin function. These results place laforin in the context of a multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin is involved in the regulation of glycogen metabolism.