Italian report on RARE epilepsies (i-RARE): A consensus on multidisciplinarity.

OBJECTIVE: Rare and complex epilepsies encompass a diverse range of disorders characterized by seizures. We aimed to establish a consensus on key issues related to these conditions through collaboration among experienced neurologists, neuropediatricians, and patient advocacy representatives. METHODS: Employing a modified Delphi method, a scientific board comprising 20 physicians and 4 patient advocacy representatives synthesized existing literature with their expertise to formulate statements on contentious topics. A final 32-member expert panel, representing diverse regions of Italy, validated these statements through a two-round voting process, with consensus defined as an average score ≥7. RESULTS: Sixteen statements reached a consensus, emphasizing the necessity for epidemiological studies to ascertain the true prevalence of rare epilepsies. Etiology emerged as a crucial factor influencing therapeutic strategies and outcome prediction, with particular concern regarding prolonged and tonic-clonic seizures. The importance of early implementation of specific drugs and non-pharmacological interventions in the treatment algorithm for developmental and epileptic encephalopathies (DEEs) was underscored. Multidisciplinary care involving experts with diverse skills was deemed essential, emphasizing non-seizure outcomes in adolescence and adulthood. SIGNIFICANCE: This national consensus underscores the imperative for personalized, comprehensive, and multidisciplinary management of rare epilepsies/DEEs. It advocates for increased research, particularly in epidemiology and therapeutic approaches, to inform clinical decision-making and healthcare policies, ultimately enhancing patients' outcomes. PLAIN LANGUAGE SUMMARY: The modified Delphi method is broadly used to evaluate debated topics. In this work, we sought the consensus on integrated and social care in epilepsy management. Both representatives of high-level epilepsy centers and patients' caregivers were directly involved.

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.

Lamotrigine vs levetiracetam in female patients of childbearing age with juvenile absence epilepsy: A Bayesian reanalysis.

OBJECTIVE: Women of childbearing age with juvenile absence epilepsy (JAE) face treatment challenges due to limited access to safe and effective anti-seizure medications (ASMs). In a previous study we compared the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) in women with idiopathic generalized epilepsy (IGE), highlighting a superiority of LEV in juvenile myoclonic epilepsy. In this study, we specifically reanalyzed, through a Bayesian approach and by expanding the previously published cohort, the comparative effectiveness of these ASMs as initial monotherapy in JAE. METHODS: We conducted a multicenter, retrospective, comparative effectiveness study on women of childbearing age diagnosed with JAE and prescribed LEV or LTG as the initial ASM. Inverse probability treatment weighting (IPTW) Bayesian Cox proportional hazard models were employed to evaluate treatment failure (TF) due to ineffectiveness and ASM retention. The patients' center of provenance and year of prescription were considered as random effect factors. Posterior probabilities and relative log-risk distribution were computed, and the distribution of posterior draws was analyzed to assess the evidence supporting LTG superiority over LEV. RESULTS: Of 123 patients, those treated with LTG (n = 67) demonstrated lower TF and higher ASM retention than those treated with LEV (n = 56), with the IPTW-weighted Bayesian Cox proportional hazards model showing a 99.2% posterior probability of LTG being superior on TF and a 99.5% probability on ASM retention. Additional analyses on ≥50% and ≥75% seizure reduction through IPTW-weighted Bayesian logistic regression largely confirmed these findings, whereas the two ASMs did not show evident differences in terms of seizure freedom. The two ASMs showed comparable safety profiles, with only a minority of patients discontinuing treatment due to side effects. SIGNIFICANCE: Bayesian reanalysis supports LTG as first-line monotherapy for JAE in women of childbearing age, emphasizing the importance of individualized treatment strategies in women with IGE. This study underscores the value of Bayesian methods in refining clinical research and treatment decisions.

Cenobamate add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: Although most people with epilepsy achieve complete seizure cessation, approximately one-third of those with the condition continue experiencing seizures despite the use of antiseizure medications (ASMs) given as monotherapy or polytherapy. In this review, we summarised the evidence from randomised controlled trials (RCTs) about cenobamate as an add-on treatment for focal epilepsy uncontrolled by one or more concomitant ASMs. OBJECTIVES: To assess the efficacy and tolerability of add-on oral cenobamate for the treatment of drug-resistant focal-onset seizures, defined as seizures persisting despite treatment with one or more ASMs. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE Ovid (September 2022). In addition, we contacted the manufacturer of cenobamate and experts in the field to enquire after any ongoing or unpublished studies. SELECTION CRITERIA: RCTs comparing add-on cenobamate to placebo or another ASM in people with focal epilepsy uncontrolled by one or more concomitant ASMs. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, extracted data, performed risk of bias assessment, and assessed the certainty of the evidence using the GRADE approach. Our primary outcomes were at least a 50% reduction in total seizure frequency, seizure freedom, and the occurrence of adverse events. We used an intention-to-treat approach for our primary analyses. For each outcome we estimated summary risk ratios (RRs) with their 95% confidence intervals (CIs). We summarised the estimates of effects and certainty of the evidence for each outcome in a summary of findings table. MAIN RESULTS: We included two studies (659 adult participants, 442 allocated to cenobamate and 217 to placebo). The overall RR for at least a 50% reduction in seizure frequency for add-on cenobamate at any dose compared to placebo was 2.17 (52% versus 24%, 95% CI 1.66 to 2.84; 2 studies, 605 participants; moderate-certainty evidence). The RR for seizure freedom for add-on cenobamate at any dose compared to placebo was 4.45 (16% versus 5%, 95% CI 2.25 to 8.78; 2 studies, 605 participants; moderate-certainty evidence). The RR for the occurrence of adverse events for add-on cenobamate at any dose compared to placebo was 1.14 (77% versus 67%, 95% CI 1.02 to 1.27; 2 studies, 659 participants; moderate-certainty evidence). We judged the two included RCTs as at low or unclear risk of bias. Both studies were sponsored by the drug company that produces cenobamate. AUTHORS' CONCLUSIONS: Add-on cenobamate is probably better than placebo in reducing the frequency of seizures by at least 50% and in achieving seizure freedom in adults with focal epilepsy uncontrolled by one or more concomitant ASMs (moderate level of certainty). Its use is probably associated with an increased risk of adverse events (moderate level of certainty). Further prospective, controlled trials are required to evaluate the efficacy and tolerability of add-on cenobamate compared to other ASMs. The efficacy and tolerability of cenobamate as adjunctive treatment for focal epilepsy in children should be further investigated. Finally, the long-term efficacy and tolerability of add-on cenobamate treatment in people with other epilepsy types (e.g. generalised epilepsy) or specific epilepsy syndromes, as well as its use as monotherapy, require additional study.

Risk of suicide and suicide-related events in subjects treated with antiseizure medications.

INTRODUCTION: In the United States, it is reported that 1.4% of the general population commits suicide. It has been postulated that antiseizure medications (ASMs) can lead to the development of suicidal ideation and suicidal behavior; however, this risk is still very low and has yet to be precisely established. AREAS COVERED: This narrative review evaluates the risk of suicide-related events (SREs) in subjects taking ASMs for various neurological disorders. Screening tools for suicidal ideation and suicidal behavior are also discussed. References for this article were found using PubMed/MEDLINE. EXPERT OPINION: Although some ASMs can be associated with SREs, this is not yet clearly established. The mechanisms involved in suicide risk in subjects taking ASMs are multifactorial. The bidirectional relationship between depression and epilepsy, as well as other associations, should be kept in mind when interpreting any impact of ASMs in PWE. Screening for SREs, close monitoring of subjects taking ASMs are the most appropriate strategies to minimize suicide risk. More efforts should be made to achieve accurate risk stratification through prognostic models that could be applied to subjects taking ASMs. Studies exploring the association between ASMs and suicide should consider ASMs individually and control for prior SREs.

Bilateral median nerve stimulation and High-Frequency Oscillations unveil interhemispheric inhibition of primary sensory cortex.

OBJECTIVE: This study aimed at investigating the effect of median nerve stimulation on ipsilateral cortical potentials evoked by contralateral median nerve electrical stimulation. METHODS: We recorded somatosensory-evoked potentials (SEPs) from the left parietal cortex in 15 right-handed, healthy subjects. We administered bilateral median nerve stimulation, with the ipsilateral stimulation preceding the stimulation on the contralateral by intervals of 5, 10, 20, or 40 ms. We adjusted these intervals based on each individual's N20 latency. As a measure of S1 excitability, the amplitude of the N20 and the area of the High Frequency Oscillation (HFO) burst were analyzed for each condition. RESULTS: The results revealed significant inhibition of N20 amplitude by ipsilateral median nerve stimulation at interstimulus intervals (ISIs) between 5 and 40 ms. Late HFO burst was suppressed at short ISIs of 5 and 10 ms, pointing to a transcallosal inhibitory effect on S1 intracortical circuits. CONCLUSIONS: Findings suggest interhemispheric interaction between the primary somatosensory areas, supporting the existence of transcallosal transfer of tactile information. SIGNIFICANCE: This study provides valuable insights into the interhemispheric connections between primary sensory areas and underscore the potential role of interhemispheric interactions in somatosensory processing.

Futile recanalization is associated with increased risk of post-stroke epilepsy.

BACKGROUND: Endovascular treatment (EVT) is the standard of care of ischaemic stroke due to occlusion of large vessels. Although EVT can significantly improve short- and long-term outcomes, functional dependence can persist despite the achievement of a successful recanalization. The evidence about the predictors of post-stroke epilepsy (PSE) in patients with stroke treated by EVT is limited. We aimed to evaluate the relationship between futile recanalization and the risk of PSE. METHODS: We retrospectively identified consecutive adults with first-ever ischaemic stroke of anterior circulation who were treated with EVT. Futile recanalization was defined as poor 3-month functional status (modified Rankin scale score ≥ 3) despite complete or near-complete recanalization. Study outcome was the occurrence of PSE during the follow-up. RESULTS: The study included 327 patients with anterior circulation ischaemic stroke treated with EVT. Futile recanalization occurred in 116 (35.5%) patients and 26 (8.0%) developed PSE during a median follow-up of 35 [interquartile range, 22.7-55.2] months. Futile recanalization was more common among patients who developed PSE compared to those who did not (76.9% versus 31.9%; p < 0.001). Futile recanalization [hazard ratio (HR) = 5.63, 95% confidence interval (CI): 1.88-16.84; p = 0.002], large artery atherosclerosis (HR = 3.48, 95% CI: 1.44-8.40; p = 0.006), cortical involvement (HR = 15.51, 95% CI: 2.06-116.98; p = 0.008), and acute symptomatic status epilepticus (HR = 14.40, 95% CI: 2.80-73.98; p = 0.001) increased the risk of PSE. CONCLUSIONS: Futile recanalization after EVT is associated with increased risk of PSE in patients with ischaemic stroke due to occlusion of large vessel of the anterior circulation.

Contrast Medium-Induced Transient Cortical Blindness: A Systematic Review of the Literature.

PURPOSE: To summarize identified risk factors, the most common clinical presentations, radiological and neurophysiological features, and proposed pathophysiological mechanisms of contrast medium-induced transient cortical blindness (TCB). METHODS: A systematic search of PubMed, Cochrane Central Register of Controlled Trials, and clinicaltrials.gov was performed. A total of 115 patients from 2 retrospective cohort studies, 10 case series, and 52 case reports were included. RESULTS: The available evidence suggests that TCB can manifest after both invasive and noninvasive contrast-enhanced procedures. The pathophysiology of TCB is unclear; however, the primary mechanism suggested involves the direct neurotoxic effect of the contrast medium. Ionic, nonionic, hyperosmolar, isoosmolar, and even ethiodized oil have been implicated. Imaging findings are nonspecific, and absent in about half of patients. Onset is within 30 minutes in about half of patients and resolves within 1 day in about half of patients, but delayed onset after a day and delayed resolution after a week may occur. Higher contrast medium dosage and its injection solely into the posterior circulation were the only risk factors identified in association with TCB. CONCLUSIONS: TCB is a rare, idiopathic, and typically self-limited condition associated with direct posterior cerebral neurotoxicity of iodinated contrast media, and appears to be dose-dependent.

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).

Patient-reported outcomes in epilepsy: a case study exploring their usage and impact.

Background: This study aimed to obtain insights from epilepsy specialists on the use of Patient-Reported Outcome (PRO) measures and how they can affect the management of people with epilepsy and healthcare resource utilization. Methods: The heads of two referral units for people with epilepsy at one tertiary care hospital were invited to respond to a structured survey. Results: Paper-based questionnaires and face-to-face interviews were the main modalities used to measure the quality of life of people with epilepsy. The Quality of Life in Epilepsy Inventory-31 (QOLIE-31), the Adverse Event Profile (adult centre), the Generalized Anxiety Disorder-7, Short-Form Health Survey 36, PSY-Flex, SAFA and Child Behavior Checklist (paediatric centre) were the most used scales. There was consensus about the favourable impact of PRO upon patient management, disease management and measurement of the success of a treatment. Both respondents considered the PRO as important as other main indicators like efficacy and tolerability of the treatment. Lack of time, personnel and economic resources was identified as a barrier on the use of PRO. The PRO could reduce the number of visits, exams and treatments, and increase the time spent on each patient and the number of neuropsychological, psychological and rehabilitation services. The standardized use of PRO was considered useful and the increase in human resources was considered a priority to achieve this goal. Conclusions: Despite the heterogeneity in the actual collection of PRO, there was a uniform perception about their role to optimize the care of people with epilepsy.

Interhemispheric functional connectivity: an fMRI study in callosotomized patients.

Introduction: Functional connectivity (FC) is defined in terms of temporal correlations between physiological signals, which mainly depend upon structural (axonal) connectivity; it is commonly studied using functional magnetic resonance imaging (fMRI). Interhemispheric FC appears mostly supported by the corpus callosum (CC), although several studies investigating this aspect have not provided conclusive evidence. In this context, patients in whom the CC was resected for therapeutic reasons (split-brain patients) provide a unique opportunity for research into this issue. The present study was aimed at investigating with resting-state fMRI the interhemispheric FC in six epileptic patients who have undergone surgical resection of the CC. Methods: The analysis was performed using fMRI of the Brain Software Library; the evaluation of interhemispheric FC and the recognition of the resting-state networks (RSNs) were performed using probabilistic independent component analysis. Results: Generally, bilateral brain activation was often observed in primary sensory RSNs, while in the associative areas, such as those composing the default mode and fronto-parietal networks, the activation was often unilateral. Discussion: These results suggest that even in the absence of the CC, some interhemispheric communication is still present. This residual FC might be supported through extra-callosal pathways that are likely subcortical, making it possible for some interhemispheric integration. Further studies are needed to confirm these conclusions.

Safe delivery, perinatal outcomes and breastfeeding in women with epilepsy.

Safe delivery and optimal peripartum and postpartum care in women with epilepsy (WWE) is a major concern which has received limited attention in recent years. A diagnosis of epilepsy per se is not an indication for a planned cesarean section or induction of labor, even though epidemiological studies indicate that cesarean delivery is more common among WWE compared to the general population. Pregnancy in WWE is associated with an increased risk of obstetrical complications and increased perinatal morbidity and mortality, and these risks may be greater among WWE taking ASMs. Wherever feasible, pregnant WWE should be directed to specialist care. Risk minimization includes, when appropriate, dose adjustment to compensate for pregnancy-related changes in the pharmacokinetics of some ASMs. With respect to postpartum management, WWE should be advised that the benefits of breastfeeding outweigh the small risk of adverse drug reactions in the infant.

Innovative LC-MS/MS method for therapeutic drug monitoring of fenfluramine and cannabidiol in the plasma of pediatric patients with epilepsy.

We present a novel liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying fenfluramine (FFA), its active metabolite norfenfluramine (norFFA), and Epidyolex®, a pure cannabidiol (CBD) oral solution in plasma. Recently approved by the EMA for the adjunctive treatment of refractory seizures in patients with Dravet and Lennox-Gastaut syndromes aged above 2 years, FFA and CBD still do not have established therapeutic blood ranges, and thus need careful drug monitoring to manage potential pharmacokinetic and pharmacodynamic interactions. Our method, validated by ICH guidelines M10, utilizes a rapid extraction protocol from 100 µL of human plasma and a reversed-phase C-18 HPLC column, with deuterated internal standards. The Thermofisher Quantiva triple-quadrupole MS coupled with an Ultimate 3000 UHPLC allowed multiple reaction monitoring detection, ensuring precise analyte quantification. The assay exhibited linear responses across a broad spectrum of concentrations: ranging from 1.64 to 1000 ng/mL for both FFA and CBD, and from 0.82 to 500 ng/mL for norFFA. The method proves accurate and reproducible, free from matrix effect. Additionally, FFA stability in plasma at 4 °C and -20 °C for up to 7 days bolsters its clinical applicability. Plasma concentrations detected in patients samples, expressed as mean ± standard deviation, were 0.36 ± 0.09 ng/mL for FFA, 19.67 ± 1.22 ng/mL for norFFA. This method stands as a robust tool for therapeutic drug monitoring (TDM) of FFA and CBD, offering significant utility in assessing drug-drug interactions in co-treated patients, thus contributing to optimized patient care in complex therapeutic scenarios.

A profile of azetukalner for the treatment of epilepsy: from pharmacology to potential for therapy.

INTRODUCTION: Epilepsies are a group of heterogeneous brain disorder, and antiseizure medications (ASMs) are the mainstay of treatment. Despite the availability of more than 30 drugs, at least one third of individuals with epilepsy are drug-resistant. This emphasizes the need for novel compounds that combine efficacy with improved tolerability. AREAS COVERED: A literature review on the pharmacology, efficacy, tolerability, and safety of azetukalner (XEN1101), a second-generation opener of neuronal potassium channels currently in Phase 3 development as ASM. EXPERT OPINION: Results from the phase 2b clinical trial strongly support the ongoing clinical development of azetukalner as a new ASM. Its pharmacokinetic properties support convenient once-daily dosing, eliminating the need for titration at initiation or tapering at the conclusion of treatment. CYP3A4 is the main enzyme involved in its metabolism and drug-drug interactions can affect the drug exposure. Preliminary analysis of an ongoing open-label study reveals no reported pigmentary abnormalities. The upcoming Phase 3 clinical trials are expected to provide further insight into the efficacy, tolerability, and safety of azetukalner in treating focal-onset and primary generalized tonic-clonic seizures. Structurally distinct from currently marketed ASMs, azetukalner has the potential to be the only-in-class Kv7.2/7.3 opener on the market upon regulatory approval.

Current challenges in focal epilepsy treatment: An Italian Delphi consensus.

BACKGROUND: Epilepsy, a globally prevalent neurological condition, presents distinct challenges in management, particularly for focal-onset types. This study aimed at addressing the current challenges and perspectives in focal epilepsy management, with focus on the Italian reality. METHODS: Using the Delphi methodology, this research collected and analyzed the level of consensus of a panel of Italian epilepsy experts on key aspects of focal epilepsy care. Areas of focus included patient flow, treatment pathways, controlled versus uncontrolled epilepsy, follow-up protocols, and the relevance of patient-reported outcomes (PROs). This method allowed for a comprehensive assessment of consensus and divergences in clinical opinions and practices. RESULTS: The study achieved consensus on 23 out of 26 statements, with three items failing to reach a consensus. There was strong agreement on the importance of timely intervention, individualized treatment plans, regular follow-ups at Epilepsy Centers, and the role of PROs in clinical practice. In cases of uncontrolled focal epilepsy, there was a clear inclination to pursue alternative treatment options following the failure of two previous therapies. Divergent views were evident on the inclusion of epilepsy surgery in treatment for uncontrolled epilepsy and the routine necessity of EEG evaluations in follow-ups. Other key findings included concerns about the lack of pediatric-specific research limiting current therapeutic options in this patient population, insufficient attention to the transition from pediatric to adult care, and need for improved communication. The results highlighted the complexities in managing epilepsy, with broad consensus on patient care aspects, yet notable divergences in specific treatment and management approaches. CONCLUSION: The study offered valuable insights into the current state and complexities of managing focal-onset epilepsy. It highlighted many deficiencies in the therapeutic pathway of focal-onset epilepsy in the Italian reality, while it also underscored the importance of patient-centric care, the necessity of early and appropriate intervention, and individualized treatment approaches. The findings also called for continued research, policy development, and healthcare system improvements to enhance epilepsy management, highlighting the ongoing need for tailored healthcare solutions in this evolving field.

Brivaracetam use in clinical practice: a Delphi consensus on its role as first add-on therapy in focal epilepsy and beyond.

BACKGROUND: Antiseizure medications remain the cornerstone of treatment for epilepsy, although a proportion of individuals with the condition will continue to experience seizures despite appropriate therapy. Treatment choices for epilepsy are based on variables related to both the individual patient and the available medications. Brivaracetam is a third-generation agent antiseizure medication. METHODS: We carried out a Delphi consensus exercise to define the role of brivaracetam in clinical practice and to provide guidance about its use as first add-on ASM and in selected clinical scenarios. A total of 15 consensus statements were drafted by an expert panel following review of the literature and all were approved in the first round of voting by panelists. The consensus indicated different clinical scenarios for which brivaracetam can be a good candidate for treatment, including first add-on use. RESULTS: Overall, brivaracetam was considered to have many advantageous characteristics that render it a suitable option for patients with focal epilepsy, including a fast onset of action, favorable pharmacokinetic profile with few drug-drug interactions, broad-spectrum activity, and being well tolerated across a range of doses. Brivaracetam is also associated with sustained clinical response and good tolerability in the long term. CONCLUSIONS: These characteristics also make it suitable as an early add-on for the elderly and for patients with post-stroke epilepsy or status epilepticus as highlighted by the present Delphi consensus.

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Diagnosing epileptic seizures in patients with Alzheimer's disease and deciding on the appropriate treatment plan.

INTRODUCTION: Alzheimer's disease (AD) is the predominant cause of dementia and a significant contributor to morbidity among the elderly. Patients diagnosed with AD face an increased risk of epileptic seizures. AREAS COVERED: Herein, the authors review the challenges in the diagnosis of seizures in patients with AD, the risks of seizures related to medications used in AD and the pharmacological treatment of seizures in AD. The authors also provide the reader with their expert opinion on the subject matter and future perspectives. EXPERT OPINION: Healthcare professionals should maintain a vigilant approach to suspecting seizures in AD patients. Acute symptomatic seizures triggered by metabolic disturbances, infections, toxins, or drug-related factors often have a low risk of recurrence. In such cases, addressing the underlying cause may suffice without initiating antiseizure medications (ASMs). However, unprovoked seizures in certain AD patients carry a higher risk of recurrence over time, warranting the use of ASMs. Although data is limited, both lamotrigine and levetiracetam appear to be reasonable choices for controlling seizures in elderly AD patients. Decisions should be informed by the best available evidence, the treating physician's clinical experience, and the patient's preferences.