A central role for neuroinflammation in epileptogenesis has recently been suggested by several investigations. This systematic review explores the role of inflammatory mediators in epileptogenesis, its association with seizure severity, and its correlation with drug-resistant epilepsy (DRE). The study analysed articles published in JCR journals from 2019 to 2024. The search strategy comprised the MESH, free terms of “Neuroinflammation”, and selective searches for the following single biomarkers that had previously been selected from the relevant literature: “High mobility group box 1/HMGB1”, “Toll-Like-Receptor 4/TLR-4”, “Interleukin-1/IL-1”, “Interleukin-6/IL-6”, “Transforming growth factor beta/TGF-β”, and “Tumour necrosis factor-alpha/TNF-α”. These queries were all combined with the MESH terms “Epileptogenesis” and “Epilepsy”. We found 243 articles related to epileptogenesis and neuroinflammation, with 356 articles from selective searches by biomarker type. After eliminating duplicates, 324 articles were evaluated, with 272 excluded and 55 evaluated by the authors. A total of 21 articles were included in the qualitative evaluation, including 18 case–control studies, 2 case series, and 1 prospective study. As conclusion, this systematic review provides acceptable support for five biomarkers, including TNF-α and some of its soluble receptors (sTNFr2), HMGB1, TLR-4, CCL2 and IL-33. Certain receptors, cytokines, and chemokines are examples of neuroinflammation-related biomarkers that may be crucial for the early diagnosis of refractory epilepsy or may be connected to the control of epileptic seizures. Their value will be better defined by future studies.

Background and Objectives Autoimmune-associated epilepsy (AAE) with antiglutamic acid decarboxylase 65 (GAD65) antibodies is considered a T-cell–mediated encephalitis that evolves to drug-resistant epilepsy. We do not have an effective therapeutic strategy for these patients. Because the GAD enzyme is primarily responsible for the conversion of glutamate to GABA, the mechanism of epileptogenesis in this condition predicts decreased levels of GABA content in synaptic vesicles. Cenobamate (CNB) acts as a positive allosteric modulator at synaptic and extra synaptic GABAA receptors, producing increased inhibitory neurotransmission in the brain. This mechanism could be especially beneficial in AAE with anti-GAD65 antibodies because it would be able to correct the imbalance due to the GABAergic stimulation deficit in postsynaptic neurons. Methods We recruit a retrospective multicentric consecutive case series of AAE with anti-GAD65 antibodies from 5 epilepsy units in Spain who have received treatment with CNB. Results A total of 8 patients were recruited. This cohort of highly refractory patients have failed a mean of 9.50 (SD = 3.20) ASM without control of seizures for sustained periods of time. The average number of seizures per month during the previous 3 months before CNB treatment was 19.63 (SD = 17.03). After the introduction of CNB improvement was achieved in all our patients, with a median reduction in the number of seizures of 92.22% (interquartile range [IQR]: 57.25–98.75). The mean follow-up was 156.75 days (SD = 68.23). In patients with concomitant treatment with clobazam (CLB), the median percentage of seizure reduction was higher than those not taking CLB: 94.72% (IQR: 87.25–100) vs 41.50% (p = 0.044) and also higher than the control group of patients with refractory epilepsy not related to anti-GAD65 treated with the same combination: 94.72% (IQR: 87.25–100) vs 45.00% (IQR: 25.00–87.00) (p = 0.019). Discussion Treatment with the combination CNB + CLB could be a type of personalized medicine in patients with AAE with anti-GAD65. Our preliminary data will need to be endorsed with new prospective and controlled studies.

La migraña es una enfermedad neurológica altamente prevalente y la búsqueda de un tratamiento eficaz que mejore la calidad de vida del paciente es fundamental. En 2018 se aprobaron en España los anticuerpos monoclonales anti-CGRP como tratamiento preventivo, y han demostrado eficacia al reducir el número de crisis de migraña al mes frente a placebo. Estudio descriptivo y retrospectivo de 14 pacientes con migraña episódica de alta frecuencia y crónica, en seguimiento en nuestra unidad de cefaleas, en los que se ha realizado el cambio de un monoclonal anti-CGRP por ineficacia. Se han recogido datos epidemiológicos y variables relacionadas con la respuesta a ambos fármacos, como los días de cefalea al mes y los días de migraña al mes, además de escalas validadas de calidad de vida (Migraine Disability Assessment Scale y Headache Impact Test-6). El 50% de los pacientes son varones, con una mediana de edad de 46,5, y el 92% estaba diagnosticado de migraña crónica. Se realizó un seguimiento de entre seis y 12 meses tras el cambio de tratamiento en el 91,6%, y se observó mejoría significativa en el 33% de los pacientes. Además, en el 50% se objetivó respuesta inicial tras tres dosis con el primer monoclonal. En nuestra serie, el 66% de los pacientes que no respondieron a un primer fármaco respondió inicialmente al cambio, y esta mejoría se mantuvo en el 36%. Se precisan estudios más amplios para aclarar esta diferencia de respuesta a los distintos anticuerpos monoclonales anti-CGRP.

Background: There is growing evidence that neuroinflammation is involved in epileptogenesis. Identifying its biomarkers can be important for distinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from drug-resistant epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved epilepsy patients divided into three groups: healthy controls (HC), seizure-free epilepsy (SFE), and DRE. Demographic and clinical data and plasmatic and/or CSF levels of 24 different inflammation-related molecules were collected for each patient and were analyzed through univariate and multivariate analysis. Results: The study included 68 patients: 38 in the DRE group, 14 in the SFE group, and 16 in the HC group. A new Inflammatory Drug-Resistant Epilepsy Index (IDREI) was created using key variables with significant or trending significance. This index combined pro-inflammatory mediators (ICAM-1 and NfL) and anti-inflammatory factors (IL-10 and IL-4), showing statistical significance (p = 0.002). ROC curve analysis for the IDREI gave an AUC of 0.731 (95% CI: 0.608–0.854). A multivariate logistic regression model’s ROC analysis resulted in a higher AUC of 0.891 (95% CI: 0.791–0.991). Conclusions: The IDREI molecular index shows promise in predicting epilepsy and drug-resistant epilepsy (DRE). Additional prospective studies are required to assess its clinical utility.

Objective: Patients with drug‐resistant epilepsy (DRE) typically take multiple anti‐seizure medications (ASMs) and are at risk of treatment‐related adverse events (AEs). This study assessed the impact of cenobamate monotherapy or dual therapy in patients with drug‐resistant epilepsy. Methods: This was a multicenter (six Spanish epilepsy units), retrospective, observational study in patients with drug‐resistant epilepsy who had received treatment with cenobamate as monotherapy (after conversion from polytherapy) or in dual therapy for at least three consecutive months, between April 2017 and November 2024. Results: In total, 125 patients (mean age 46 ± 15.9 years; median epilepsy duration 16 years, range: 1–65) were included. Median follow‐up was 11 months (range 3–80). Patients had received a median of 5 (range 2–19) previous anti‐seizure medications and were receiving a median of 2 (range 0–3) concomitant anti‐seizure medications at cenobamate initiation; the most common concomitant anti‐seizure medications were lacosamide (36%), brivaracetam (29.6%), and clobazam (26.4%). The median cenobamate dose at the last visit was 200 mg/day (range 100–400 mg/day). By the last visit, 31.5% of patients had achieved seizure freedom, and 75.8%, 58.1%, and 49.2% had achieved ≥50%, ≥75%, and ≥90% reductions in seizure frequency, respectively. During cenobamate treatment, 52% of patients discontinued one, 32% discontinued two, and 4% discontinued three concomitant anti‐seizure medications. In total, 63/125 patients (50.4%) had adverse events during cenobamate treatment, all mild or moderate; 40.8% of patients had adverse events at the last visit. The most reported adverse events were somnolence (22.4%), dizziness (10.4%), fatigue (7.2%), and instability (4.8%). Significance: This study highlights the real‐world effectiveness and safety of cenobamate, either as monotherapy (after conversion from polytherapy) or in dual therapy, in patients with drug‐resistant epilepsy. Cenobamate allows for a significant treatment simplification, resulting in fewer treatment‐related adverse events without compromising seizure reduction.

Background: Neuroinflammation contributes to epileptogenesis across the different etiological categories of epilepsy. Identifying its biomarkers can be important for dis-tinguishing epilepsy patients from healthy individuals and differentiating well-controlled epilepsy from Drug Resistant Epilepsy (DRE). Methods: An observational case-control study at Malaga’s Regional University Hospital involved epilepsy patients, divided into three groups: Healthy controls (HC), Sei-zure-Free Epilepsy (SFE) and DRE. Demographic and clinical data and plasmatic and/or CSF level of 24 different inflammation-related molecules were collected for each patient and were analysed through a univariate and multivariate analysis. Results: The study included 68 patients: 38 in the DRE group, 14 in the SFE group, and 16 in the HC group. A new Inflammatory Drug-Resistant Epilepsy Index (IDREI) was created using key variables with significant or trending significance. This index com-bined pro-inflammatory mediators (ICAM-1 and NfL) and anti-inflammatory factors (IL-10 and IL-4), showing statistical significance (p=0.002). ROC curve analysis for the IDREI gave an AUC of 0.731 (95% CI: 0.608−0.854). A multivariate logistic regression model's ROC anaysis resulted in a higher AUC of 0.891 (95% CI: 0.791−0.991). Conclusions: IDREI is a molecular index that effectively predicts epilepsy and DRE. Further prospective studies are needed to evaluate its clinical utility.