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.

Background and Objective Most second and third generation antiseizure medications (ASMs) are associated with cognitive adverse events, which are a major concern for patients. However, the profile of cognitive adverse events differs between ASMs. This study investigated the effects of cenobamate on cognition in patients with drug-resistant epilepsy (DRE) within the Spanish Expanded Access Program (EAP). Methods This was a retrospective, observational study. Inclusion criteria were age ≥ 18 years, DRE with focal seizures, and availability of cognition assessments and EAP authorization. Data were sourced from the clinical records of patients who took part in the Spanish cenobamate EAP. Primary endpoints included cognition (based on 20 neuropsychological outcomes, including verbal and visuospatial episodic memory, verbal fluency, executive function, working memory, attention, and speed of processing), seizure frequency, and concomitant antiseizure medication (ASM) usage at 6 months. Results The study included 20 patients; 10 patients (50%) had daily seizures, 7 (35%) had weekly seizures and 3 (15%) had monthly seizures. The median number of prior antiseizure medications (ASMs) and concomitant ASMs were 10 and 3, respectively. Mean cenobamate doses were 12.5 mg/day at baseline and 191.2 mg/day at 6 months. There was a statistically significant improvement in cognitive scores between baseline and 6 months for two measures of verbal episodic memory (p = 0.0056 and p = 0.0013) and one measure of visuospatial episodic memory (p = 0.011), and a significant worsening in cognitive score for attention (p = 0.030). At 6 months, 14 patients (70%) had a ≥ 50% reduction in seizure frequency, 3 patients (15%) had a ≥ 90% reduction, and 1 patient (5%) was seizure free. There were significant decreases in the mean number of concomitant ASMs (p = 0.0009), the sum of the ratios of prescribing daily dose/daily defined dose (total ratio of DDD) for concomitant ASMs (p < 0.0001), and concomitant ASM drug load (p = 0.038) between baseline and 6 months. Total ratio of DDD was significantly lower at 6 months for perampanel (p = 0.0016), benzodiazepines (p = 0.035), and sodium channel blockers (p = 0.0005) compared with baseline. Based on analysis of covariance, cognitive tests related to verbal or visuospatial episodic memory (e.g., RT of FCSRT, or ROCFT), executive functions (e.g., TMT-B), and processing speed (some 5-Digit Test subtests) appeared to be closely related to the reduction in pharmacological burden rather than the improvement in seizure control. Conclusions Significant improvements in cognition, seizure frequency, and concomitant ASM usage were observed after the introduction of cenobamate in patients with DRE in a real-world setting. Covariance analysis supports the reduction in concomitant ASMs as the most important factor driving cognitive improvements with cenobamate. As this was an exploratory study with an uncontrolled, retrospective design and a low number of patients, further studies are required to confirm the findings.

Objective To evaluate cognitive function in patients with rheumatoid arthritis (RA) and inflammatory activity. Patients and methods We performed a cross-sectional study of a cohort of patients with RA initiating their first biological treatment due to moderate-to-high inflammation and a healthy control group (no inflammatory diseases) matched for age, sex and educational level. All participants underwent a comprehensive neuropsychological assessment, with cognitive impairment defined as a Montreal Cognitive Assessment (MoCA) score<26. Additional assessments included various cognitive tests (STROOP, forward and backward digit spans), anxiety and depression scales (Hospital Anxiety and Depression Scale), quality of life measures (Quality of Life-Rheumatoid Arthritis) and average inflammatory activity according to the 28-joint Disease Activity Score (DAS28)-C-reactive protein (CRP) into high activity (DAS28≥3.2) and low activity (DAS28<3.2) groups, also CRP levels and interleukin 6 (IL-6) levels were measured using an ELISA. Results The study population comprised 140 participants, 70 patients with RA and 70 controls. Patients more frequently experienced cognitive impairment than controls (60% vs 40%; p=0.019) and had lower mean (SD) values in the MoCA (23.6 (3.9) vs 25.1 (3.4); p=0.019. As for subtests of the MoCA, involvement was more marked in patients than in controls for the visuospatial-executive (p=0.030), memory (p=0.026) and abstraction (p=0.039) domains. Additionally, patients scored lower on executive function, as assessed by the backward digit span test (4.0 (1.7) vs 4.7 (1.9); p=0.039). Cognitive impairment is associated with age and a lower educational level in the general population, and among patients with RA with educational level, obesity and average inflammatory activity (DAS28, CRP, and IL-6). Conclusions Patients with RA with high inflammatory activity are more susceptible to cognitive impairment, which specifically affects the domains of visuospatial, memory, abstraction and executive function.

Objective: To prospectively evaluate possible decline of cognitive functions in adult patients with juvenile idiopathic arthritis (JIA) and identify associated factors. Patients and methods: We performed a 24-month prospective observational study of adults (≥16 years) with JIA. The primary outcome measure was decline in cognitive function defined as a worsening of ≥2 points on the scales of the subsets administered to evaluate the different cognitive areas using the Wechsler Adult Intelligence Scale (WAIS) after 24 months: attention/concentration (digit span); verbal function (vocabulary); visual-spatial organization (block design); working memory (letter-number sequencing); and problem solving (similarities). Other variables included average inflammatory activity using C-reactive protein and composite activity indexes, comorbidity, and treatment. Logistic regression was performed to identify factors associated with cognitive decline. Results: The study population comprised 52 patients with JIA. Of these, 15 (28.8%) had cognitive decline at V24. The most affected functions were working memory (17.3%), attention/concentration (9.6%), verbal function (7.7%), visual-spatial organization (7.7%), and problem solving (3.8%). There were no significant differences in the median direct or scale scores for the cognitive functions evaluated between V0 and V24 for the whole sample. The factors associated with cognitive decline in patients with JIA were average C-reactive protein (OR [95% CI], 1.377 [1.060–1.921]; p = 0.039), depression (OR [95% CI], 3.691 [1.294–10.534]; p = 0.015), and treatment with biologics (OR [95% CI], 0.188 [0.039–0.998]; p = 0.046). Conclusion: Cognitive decline was detected in almost one third of adults with JIA after 24 months of follow-up. Systemic inflammatory activity in JIA patients was related to cognitive decline. Patients treated with biologics had a lower risk of decline in cognitive functions.

Introduction Cognitive adverse events are a common issue in patients receiving later-generation antiseizure medications (ASMs). In this study, we assessed the long-term effects of cenobamate on cognitive endpoints in patients with drug-resistant focal epilepsy. Methods In this retrospective, observational study, the clinical records of adult patients who received cenobamate as part of the Spanish Expanded Access Program were reviewed. Seizure frequency, concomitant ASM usage, and data from 20 neuropsychological tests were collected at 6 and 18 months after cenobamate initiation. Results Among 14 patients included in the study, eight (57%) had daily seizures at baseline, three (21%) had seizures at least weekly, and three (21%) had seizures at least monthly. The median number of prior ASMs was 10; the median number of concomitant ASMs was three. The median cenobamate dose was 12.5 mg/day at baseline, 200 mg/day at month 6, and 250 mg/day at month 18. At month 18, 10 patients (71%) had at least a 50% reduction in seizure frequency, seven (50%) had at least a 90% reduction, and two (14%) achieved seizure freedom. Significant improvements in cognitive scores from baseline to month 18 were observed for verbal episodic memory (two measures; p = 0.016 and p = 0.0013), visuospatial episodic memory (p = 0.014), and processing speed (p = 0.0018). The mean number of concomitant ASMs (p = 0.0018) and the concomitant ASM drug load (p = 0.0001) decreased significantly between baseline and month 18. The sum of the ratios of prescribed daily dose/daily defined dose (total ratio of defined daily dose) for all concomitant ASMs (p < 0.0001), for perampanel (p = 0.017), and for sodium channel blockers (p = 0.0003) also decreased between baseline and month 18. Conclusion In this exploratory, real-world study, we observed significant improvements in seizure frequency, concomitant ASM usage, and cognition at up to 18 months of cenobamate treatment in patients with drug-resistant focal epilepsy.

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.