Adjunctive cenobamate in people with focal onset seizures: Insights from the Italian Expanded Access Program.

OBJECTIVE: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy. METHODS: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses. RESULTS: A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel. SIGNIFICANCE: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.

Automatic Detection of the EEG Spike-Wave Patterns in Epilepsy: Evaluation of the Effects of Transcranial Current Stimulation Therapy.

This study aims to develop a detection method based on morphological features of spike-wave (SW) patterns in the EEG of epilepsy patients and evaluate the effect of cathodal transcranial direct current stimulation (ctDCS) treatment. The proposed method is based on several simple features describing the shape of SW patterns and their synchronous occurrence on at least two EEG channels. High sensitivity, specificity and selectivity values were achieved for each patient and condition. ctDCS resulted in a significant reduction in the number of detected patterns, a decrease in spike duration and amplitude, and an increased spike mobility. The proposed method allows efficient identification of SW patterns regardless of brain condition, although the recruitment of patterns may be modified by ctDCS. This method can be useful in the clinical evaluation of ctDCS effects.

Effectiveness and Safety of Adjunctive Cenobamate in People with Focal-Onset Epilepsy: Evidence from the First Interim Analysis of the BLESS Study.

INTRODUCTION: Despite new anti-seizure medications (ASMs) being introduced into clinical practice, about one-third of people with epilepsy do not reach seizure control. Cenobamate is a novel tetrazole-derived carbamate compound with a dual mechanism of action. In randomized controlled trials, adjunctive cenobamate reduced the frequency of focal seizures in people with uncontrolled epilepsy. Studies performed in real-world settings are useful to complement this evidence and better characterize the drug profile. METHODS: The Italian BLESS ("Cenobamate in Adults With Focal-Onset Seizures") study is an observational cohort study aimed to evaluate the effectiveness, tolerability, and safety of adjunctive cenobamate in adults with uncontrolled focal epilepsy in the context of real-world clinical practice. The study is ongoing and conducted at 50 centers in Italy. This first interim analysis includes participants enrolled until June 2023 and with 12-week outcome data available. RESULTS: Forty participants with a median age of 36.5 (interquartile range [IQR] 26.0-47.5) years were included. The median monthly seizure frequency at baseline was 6.0 (IQR 2.5-17.3) seizures and 31 (77.5%) participants had failed four or more ASMs before cenobamate. At 12 weeks from starting cenobamate, the median reduction in monthly seizure frequency was 52.8% (IQR 27.1-80.3%); 22 (55.0%) participants had a ≥ 50% reduction in baseline seizure frequency and six (15.0%) reached seizure freedom. The median number of concomitant ASMs decreased from 3 (IQR 2-3) at baseline to 2 (IQR 2-3) at 12 weeks and the proportion of patients treated with > 2 concomitant ASMs decreased from 52.5% to 40.0%. Seven (17.5%) patients reported a total of 12 adverse events, 11 of which were considered adverse drug reactions to cenobamate. CONCLUSION: In adults with uncontrolled focal seizures, the treatment with adjunctive cenobamate was well tolerated and was associated with improved seizure control and a reduction of the burden of concomitant ASMs. TRIAL REGISTRATION NUMBER: NCT05859854 (ClinicalTrials.gov Identifier).

Quantitative EEG analysis of brivaracetam in drug-resistant epilepsy: A pharmaco-EEG study.

OBJECTIVE: Brivaracetam (BRV) is a recent antiseizure medication (ASM) approved as an add-on therapy for people with focal epilepsy. BRV has a good efficacy and safety profile compared to other ASMs. However, its specific effects on resting-state EEG activity and connectivity are unknown. The aim of this study is to evaluate quantitative EEG changes induced by BRV therapy in a population of adult people with drug-resistant epilepsy (PwE) compared to healthy controls (HC). METHODS: We performed a longitudinal, retrospective, pharmaco-EEG study on a population of 23 PwE and a group of 25 HC. Clinical outcome was dichotomized into drug-responders (i.e., >50% reduction in seizures' frequency; RES) and non-responders (N-RES) after two years of BRV. EEG parameters were compared between PwE and HC at baseline (pre-BRV) and after three months of BRV therapy (post-BRV). We investigated BRV-related variations in EEG connectivity using the phase locking value (PLV). RESULTS: BRV therapy did not induce modifications in power spectrum density across different frequency bands. PwE presented lower PLV connectivity values compared to HC in all frequency bands. RES exhibited lower theta PLV connectivity compared to HC before initiating BRV and experienced an increase after BRV, eliminating the significant difference from HC. CONCLUSIONS: This study shows that BRV does not alter the EEG power spectrum in PwE, supporting its favourable neuropsychiatric side-effect profile, and induces the disappearance of EEG connectivity differences between PwE and HC. SIGNIFICANCE: The integration of EEG quantitative analysis in epilepsy can provide insights into the efficacy, mechanism of action, and side effects of ASMs.

Quantitative Analysis of Cenobamate and Concomitant Anti-Seizure Medications in Human Plasma via Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry.

Cenobamate (CNB) is a new anti-seizure medication (ASM) recently introduced in clinical practice after approval by the FDA and EMA for the add-on treatment of focal onset seizures in adult patients. Although its mechanism of action has not been fully understood, CNB showed promising clinical efficacy in patients treated with concomitant ASMs. The accessibility of CNB could pave a way for the treatment of refractory or drug-resistant epilepsies, which still affect at least one-third of the patients under pharmacological treatment. In this context, therapeutic drug monitoring (TDM) offers a massive opportunity for better management of epileptic patients, especially those undergoing combined therapy. Here, we describe the first fully validated ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for the quantification of CNB and concomitant ASMs in human plasma, with samples extracted either manually or by means of a liquid handler. Our method was validated according to the most recent ICH International Guideline M10 for Bioanalytical Method Validation and Study Sample Analysis. The method proved to be selective for CNB and displayed a linear range from 0.8 to 80 mg/L; no matrix effect was found (98.2 ± 4.1%), while intra-day and inter-day accuracy and precision were within the acceptance range. Also, CNB short- and long-term stability in plasma under different conditions was assessed. Leftover human plasma samples were employed as study samples for method validation. Our method proved to be highly sensitive and selective to quantify CNB and concomitant ASMs in human plasma; therefore, this method can be employed for a routinely TDM-based approach to support physicians in the management of an epileptic patient.

Overnight switch from carbamazepine to eslicarbazepine in a real-life clinical scenario: a retrospective study.

BACKGROUND: Carbamazepine (CBZ) is a first-choice anti-seizure medication (ASM) whose efficacy is often invalidated by adverse effects (AEs). Eslicarbazepine (ESL) is a structural derivative of CBZ with better pharmacokinetic/tolerability profiles. We describe our experience of the overnight CBZ to ESL switch in people with epilepsy (PwE) to improve seizure control, AEs, and ASMs adherence. METHODS: We retrospectively included 19 PwE (12 females, 53 ± 21 years old) who underwent CBZ to ESL overnight switch due to single/multiple issues: poor efficacy (pEff, N = 8, 42%), tolerability (pToll, N = 11, 58%), adherence (pAdh, N = 2, 10%). 9/19 (47%) had psychiatric comorbidities. Clinical variables, seizure frequency, and AEs were recorded at switch time (T0) after 3.5 ± 3 (T1) and 6.5 ± 1.5 months (T2). RESULTS: At T1, in pEff group, 1/8 (13%) was seizure free, 2/8 (25%) were responders (> 50% seizure reduction), 2/8 (25%) had no seizure changes, 3/8 (37%) had seizure worsening; the latter were those with the most severe epilepsy and encephalopathy. In pToll group, all PwE experienced AEs disappearance/amelioration. In pAdh group, all PwE reported adherence amelioration. Four dropouts. At T2, no changes were recorded within groups, while in the whole sample, 6/15 (40%) were responders, and 4/15 (27%) were seizure-free. No one complained of Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation psychiatric worsening, while 6/19 (32%) experienced mood/behavior benefits. CONCLUSIONS: CBZ to ESL overnight switch offers an opportunity to improve efficacy, tolerability, adherence, and psychiatric symptoms.

Assessing cortical excitability with electroencephalography: A pilot study with EEG-iTBS.

BACKGROUND: Cortical excitability measures neural reactivity to stimuli, usually delivered via Transcranial Magnetic Stimulation (TMS). Excitation/inhibition balance (E/I) is the ongoing equilibrium between excitatory and inhibitory activity of neural circuits. According to some studies, E/I could be estimated in-vivo and non-invasively through the modeling of electroencephalography (EEG) signals and termed 'intrinsic excitability' measures. Several measures have been proposed (phase consistency in the gamma band, sample entropy, exponent of the power spectral density 1/f curve, E/I index extracted from detrend fluctuation analysis, and alpha power). Intermittent theta burst stimulation (iTBS) of the primary motor cortex (M1) is a non-invasive neuromodulation technique allowing controlled and focal enhancement of TMS cortical excitability and E/I of the stimulated hemisphere. OBJECTIVE: Investigating to what extent E/I estimates scale with TMS excitability and how they relate to each other. METHODS: M1 excitability (TMS) and several E/I estimates extracted from resting state EEG recordings were assessed before and after iTBS in a cohort of healthy subjects. RESULTS: Enhancement of TMS M1 excitability, as measured through motor-evoked potentials (MEPs), and phase consistency of the cortex in high gamma band correlated with each other. Other measures of E/I showed some expected results, but no correlation with TMS excitability measures or strong consistency with each other. CONCLUSIONS: EEG E/I estimates offer an intriguing opportunity to map cortical excitability non-invasively, with high spatio-temporal resolution and with a stimulus independent approach. While different EEG E/I estimates may reflect the activity of diverse excitatory-inhibitory circuits, spatial phase synchrony in the gamma band is the measure that best captures excitability changes in the primary motor cortex.

Use, experience and perspectives of high-density EEG among Italian epilepsy centers: a national survey.

INTRODUCTION: High-density EEG (hdEEG) is a validated tool in presurgical evaluation of people with epilepsy. The aim of this national survey is to estimate diffusion and knowledge of hdEEG to develop a network among Italian epilepsy centers. METHODS: A survey of 16 items (and 15 additional items) was distributed nationwide by email to all members of the Italian League Against Epilepsy and the Italian Society of Clinical Neurophysiology. The data obtained were analyzed using descriptive statistics. RESULTS: A total of 104 respondents were collected from 85 centers, 82% from the Centre-North of Italy; 27% of the respondents had a hdEEG. The main applications were for epileptogenic focus characterization in the pre-surgical evaluation (35%), biomarker research (35%) and scientific activity (30%). The greatest obstacles to hdEEG were economic resources (35%), acquisition of dedicated personnel (30%) and finding expertise (17%). Dissemination was limited by difficulties in finding expertise and dedicated personnel (74%) more than buying devices (9%); 43% of the respondents have already published hdEEG data, and 91% of centers were available to participate in multicenter hdEEG studies, helping in both pre-processing and analysis. Eighty-nine percent of respondents would be interested in referring patients to centers with established experience for clinical and research purposes. CONCLUSIONS: In Italy, hdEEG is mainly used in third-level epilepsy centers for research and clinical purposes. HdEEG diffusion is limited not only by costs but also by lack of trained personnel. Italian centers demonstrated a high interest in educational initiatives on hdEEG as well as in clinical and research collaborations.

Autoimmune encephalitis during pregnancy: A diagnostic and therapeutic challenge-A systematic review with individual patients' analysis and clinical recommendations.

Several reports have described the autoimmune encephalitis' (AE) possible onset during pregnancy. In this systematic review, we summarize the available data on the diagnostic and therapeutic approach to AE during pregnancy, highlighting the associated maternal and fetal clinical outcomes. A systematic search of the literature was performed. The following databases were used: PubMed, Google Scholar, EMBASE, and CrossRef. The revision was registered on the PROSPERO platform (CRD42022336357). Forty-nine patients were included. AE onset was mainly observed during the first and the second trimester of pregnancy with psychiatric manifestations and seizures as main onset symptoms. CSF analysis showed AE-specific autoantibody positivity in 33 patients (anti-NMDA receptor as the most frequent). EEG generally showed normal findings. MRI revealed pathological findings in less than half of patients. Tumor screening was positive in 14 cases. First-line immunotherapy (single or combined) was generally employed while second line was administered in a minority of patients. Levetiracetam was the most used antiseizure medication. Cesarean section was performed in 18 women. Most of the women had an excellent early outcome after delivery but 22 showed persistent neurological deficits in long-term follow-up. Fetal outcome was positive in 33 cases, whereas 12 cases of fetal death were reported. A logistic regression showed that no variable significantly influenced the odds of good/bad maternal and fetal clinical outcome. Diagnosis and treatment of AE during pregnancy is challenging. The rate of miscarriage in women with AE seems to be higher than the general population. In addition, mothers may show long-term neurological deficits.

Evaluating the effect of calcifediol supplementation on seizure frequency in people with drug-resistant epilepsy.

The well-known neuroprotective role and involvement of vitamin D in the function of the central nervous system has raised the speculation about the possible antiseizure effect of vitamin D supplementation. This issue is crucial when considering people with epilepsy (PWE), who frequently display vitamin D deficiency, but nowadays data are still unconclusive. In our study, we enrolled 25 adult patients affected by drug-resistant epilepsy and hypovitaminosis D to test the effect of Calcifediol on seizure frequency after 6 months of supplementation. Our findings evidenced that Calcifediol administration completely restored 25-hydroxy vitamin D (25-OHD) and intact parathyroid hormone (iPTH) serum values (p < 0.001 for both) without significant changes of median seizure frequency (-6.1%). Anyway, we observed some rate of PWE responders (32%) to Calcifediol supplementation. Further randomized controlled trials with larger subjects 'samples will be needed to verify the possible antiseizure effect of vitamin D.

Phase-amplitude coupling between low- and high-frequency activities as preoperative biomarker of focal cortical dysplasia subtypes.

OBJECTIVE: To evaluate whether ictal phase-amplitude coupling (PAC) between high-frequency activity and low-frequency activity could be used as a preoperative biomarker of Focal Cortical Dysplasia (FCD) subtypes. We hypothesize that FCD seizures present unique PAC characteristics that may be linked to their specific histopathological features. METHODS: We retrospectively examined 12 children with FCD and refractory epilepsy who underwent successful epilepsy surgery. We identified ictal onsets recorded with stereo-EEG. We estimated the strength of PAC between low-frequencies and high-frequencies for each seizure by means of modulation index. Generalized mixed effect models and receiver operating characteristic (ROC) curve analysis were used to test the association between ictal PAC and FCD subtypes. RESULTS: Ictal PAC was significantly higher in patients with FCD type II compared to type I, only on SOZ-electrodes (p < 0.005). No differences in ictal PAC were found on non-SOZ electrodes. Pre-ictal PAC registered on SOZ electrodes predicted FCD histopathology with a classification accuracy > 0.9 (p < 0.05). CONCLUSIONS: The correlations between histopathology and neurophysiology provide evidence for the contribution of ictal PAC as a preoperative biomarker of FCD subtypes. SIGNIFICANCE: Developed into a proper clinical application, such a technique may help improve clinical management and facilitate the prediction of surgical outcome in patients with FCD undergoing stereo-EEG monitoring.

A real-life pilot study of the clinical application of pharmacogenomics testing on saliva in epilepsy.

Response to antiseizure medications (ASMs) can be influenced by several gene polymorphisms, causing either lower efficacy or higher occurrence of adverse drug reactions (ADRs). We investigated the clinical utility of salivary pharmacogenomic testing on epilepsy patients. A commercialized pharmacogenomic salivary test was performed in a cohort of epileptic patients. Genetic variants on five genes (i.e., CYP1A2, CYP2C9, CYP2C19, EPHX1, and ABCB1) involved in common ASMs metabolism were selected. Twenty-one individuals (median age [Q1 -Q3 ]: 15 [6.5-28] years) were enrolled. Six patients harboring the homozygous *1F allele in CYP1A2 could have reduced chance of response to stiripentol due to fast metabolism. CYP2C9 had reduced activity in 10 patients (alleles *2 and *3), potentially affecting phenytoin (PHT), phenobarbital (PB), primidone, lacosamide (LCM), and valproic acid metabolism. Seven patients, carrying the *2 allele of CYP2C19, had an increased risk of ADRs with clobazam (CLB), PB, PHT, LCM, brivaracetam; while one individual with the *17 allele in heterozygosity reported a CLB fast metabolism. Six patients showed a CC polymorphism of EPHX1 associated with the impaired efficacy of carbamazepine. ABCB1 polymorphisms related to drug-resistance (3435 CC) or drug-sensitive phenotype (CT or TT) were found in 6 out of 7 patients. Pharmacogenomic testing on saliva proved easy and safe in clinical practice to convey information for the management of epileptic patients, especially those resistant to treatment or sensitive to severe ADRs.

EPIAMNE: A New Scoring System for Differentiating Transient EPIleptic AMNEsia from Transient Global Amnesia.

Transient epileptic amnesia (TEA) is a rare cause of acute amnestic syndromes (AAS), often misdiagnosed as transient global amnesia (TGA). We proposed a scoring system­the EPIlepsy AMNEsia (EPIAMNE) score­using quantitative EEG (qEEG) analysis to obtain a tool for differentiating TEA from TGA. We retrospectively reviewed clinical information and standard EEGs (stEEG) of 19 patients with TEA and 21 with TGA. We computed and compared Power Spectral Density, demonstrating an increased relative theta power in TGA. We subsequently incorporated qEEG features in EPIAMNE score, together with clinical and stEEG features. ROC curve models and pairwise ROC curve comparison were used to evaluate and compare the diagnostic accuracy for TEA detection of EPIAMNE score, presence of symptoms atypical for TGA (pSymAT) and identification of anomalies (interictal epileptiform or temporal focal spiky transients) at stEEG (PosEEG). Area Under the Curve (AUC) of EPIAMNE score revealed to be higher than PosEEG and pSymAT (AUCEPIAMNE = 0.95, AUCpSymAT = 0.85, AUCPosEEG = 0.67) and this superiority proved to be statistically significant (p-valueEPIAMNE-PosEEG and p-valueEPIAMNE-pSymAT < 0.05). In conclusion, EPIAMNE score classified TEA with higher accuracy than PosEEG and pSymAT. This approach could become a promising tool for the differential diagnosis of AAS, especially for early TEA detection.

Levetiracetam Modulates EEG Microstates in Temporal Lobe Epilepsy.

To determine the effects of Levetiracetam (LEV) therapy using EEG microstates analysis in a population of newly diagnosed Temporal Lobe Epilepsy (TLE) patients. We hypothesized that the impact of LEV therapy on the electrical activity of the brain can be globally explored using EEG microstates. Twenty-seven patients with TLE were examined. We performed resting-state microstate EEG analysis and compared microstate metrics between the EEG performed at baseline (EEGpre) and after 3 months of LEV therapy (EEGpost). The microstates A, B, C and D emerged as the most stable. LEV induced a reduction of microstate B and D mean duration and occurrence per second (p < 0.01). Additionally, LEV treatment increased the directional predominance of microstate A to C and microstate B to D (p = 0.01). LEV treatment induces a modulation of resting-state EEG microstates in newly diagnosed TLE patients. Microstates analysis has the potential to identify a neurophysiological indicator of LEV therapeutic activity. This study of EEG microstates in people with epilepsy opens an interesting path to identify potential LEV activity biomarkers that may involve increased neuronal inhibition of the epileptic network.

Functional Source Separation-Identified Epileptic Network: Analysis Pipeline.

This proof-of-concept (PoC) study presents a pipeline made by two blocks: 1. the identification of the network that generates interictal epileptic activity; and 2. the study of the time course of the electrical activity that it generates, called neurodynamics, and the study of its functional connectivity to the other parts of the brain. Network identification is achieved with the Functional Source Separation (FSS) algorithm applied to electroencephalographic (EEG) recordings, the neurodynamics quantified through signal complexity with the Higuchi Fractal Dimension (HFD), and functional connectivity with the Directed Transfer Function (DTF). This PoC is enhanced by the data collected before and after neuromodulation via transcranial Direct Current Stimulation (tDCS, both Real and Sham) in a single drug-resistant epileptic person. We observed that the signal complexity of the epileptogenic network, reduced in the pre-Real, pre-Sham, and post-Sham, reached the level of the rest of the brain post-Real tDCS. DTF changes post-Real tDCS were maintained after one month. The proposed approach can represent a valuable tool to enhance understanding of the relationship between brain neurodynamics characteristics, the effects of non-invasive brain stimulation, and epileptic symptoms.

A Rare Neuro-Ophthalmological Condition in a Patient with Lung Adenocarcinoma: The Eight-and-a-Half Syndrome, Case Report and Review of the Literature.

The eight-and-a-half syndrome is a rare neuro-ophthalmological condition caused by a structural lesion in the dorsal portion of the pons, involving critical areas of the brainstem, i.e., medial longitudinal fasciculus (MLF), abducens nucleus, facial genu, and colliculus. It is characterized by internuclear ophthalmoplegia with horizontal gaze palsy and peripheral facial palsy. Although the syndrome is most frequently caused by vascular or demyelinating diseases, several different underlying causes might occur. Herein, we describe a case of the eight-and-a-half syndrome caused by a lung adenocarcinoma metastasis localized in the lower pontine tegmentum. Then, we review the current literature on the underlying causes of the eight-and-a-half syndrome.

Understanding and managing the impact of the COVID-19 pandemic and lockdown on patients with epilepsy.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic represented a relevant issue for people with epilepsy (PwE). Medical care and social restrictions exposed PwE to a high risk of seizure worsening. Medical institutions answered to the pandemic assuring only emergency care and implementing a remote assistance that highlighted the technological obsolescence of the medical care paradigms for PwE. AREA COVERED: We reviewed the literature on the COVID-19-related factors influencing the epilepsy course, from the evidence of seizure risk in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected PwE to anti-Sars-Cov-2 drugs interactions with antiseizure medications and the perceived changes of seizures in PwE. EXPERT OPINION: COVID-19 pandemic was a problematic experience for PwE. We must make treasure of the lessons learned during this period of social restrictions and employ the recent technological advances to improve PwE assistance, in particular telemedicine and electronic media for patients' education.