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.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy.

OBJECTIVE: This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add-On First Italian Network Study (BRIVAFIRST). METHODS: BRIVAFIRST was a 12-month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5-20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6. RESULTS: A total of 994 participants were included. During the 1-year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5-20, and >20 seizures per month (p < .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p < .001). SSR was reached by 51.2% and 26.5% participants with a history of 1-5 and ≥6 ASMs (p < .001); the corresponding rates of SSF were 24.7% and 4.5% (p < .001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p < .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1-5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs. SIGNIFICANCE: The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Prediction of seizure recurrence risk following discontinuation of antiepileptic drugs.

OBJECTIVE: Discontinuation of antiepileptic drugs (AEDs) in seizure-free patients is an important goal because of possible long-term side effects and the social stigma burden of epilepsy. The purpose of this work was to assess seizure recurrence risk after suspension of AEDs, to evaluate predictors for recurrence, and to investigate the recovery of seizure control after relapse. In addition, the accuracy of a previously published prediction model of seizure recurrence risk was estimated. METHODS: Seizure-free patients with epilepsy who had discontinued AEDs were retrospectively enrolled. The frequency of seizure relapses after AED withdrawal as well as prognosis after recurrence were assessed and the predictive role of baseline clinical-demographic variables was evaluated. The aforementioned prediction model was also validated and its accuracy assessed at different seizure-relapse probability levels. RESULTS: The enrolled patients (n = 133) had been followed for a median of 3 years (range 0.8-33 years) after AED discontinuation; 60 (45%) of them relapsed. Previous febrile seizures in childhood (hazard ratio [HR] 3.927; 95% confidence interval [CI] 1.403-10.988), a seizure-free period on therapy of less than 2 years (HR 2.313; 95% CI 1.193-4.486), and persistent motor deficits (HR 4.568; 95% CI 1.412-14.772) were the clinical features associated with relapse risk in univariate analysis. Among these variables, only a seizure-free period on therapy of less than 2 years was associated with seizure recurrence in multivariate analysis (HR 2.365; 95% CI 1.178-4.7444). Pharmacological control of epilepsy was restored in 82.4% of the patients who relapsed. In this population, the aforementioned prediction model showed an unsatisfactory accuracy. SIGNIFICANCE: A period of freedom from seizure on therapy of less than 2 years was the main predictor of seizure recurrence. The accuracy of the previously described prediction tool was low in this cohort, thus suggesting its cautious use in real-world clinical practice.

Brivaracetam as add-on treatment in focal epilepsy: A real-world time-based analysis.

The study assessed the clinical response to add-on brivaracetam (BRV) in real-world practice by means of time-to-baseline seizure count methodology. Patients with focal epilepsy who were prescribed add-on BRV were identified. Primary endpoint was the time-to-baseline seizure count defined as the number of days until each patient experienced the number of focal seizures that occurred in the 90 days before BRV initiation. Subgroup analysis was performed according to levetiracetam (LEV) status (naive vs prior use). Three-hundred eighty-seven patients were included. The overall median time-to-baseline seizure count was 150 (95% confidence interval [CI] = 130-175) days. The median time-to-baseline seizure count was 198 (lower limit of 95% CI = 168) days for LEV-naive patients, 126 (95% CI = 105-150) days for patients with prior LEV use and withdrawal due to insufficient efficacy, and 170 (95% CI = 128-291) days for patients who discontinued LEV due to adverse events (P = .002). The number of prior antiseizure medications (adjusted hazard ratio [adj HR] = 1.07, 95% CI = 1.02-1.13, P = .009) and baseline monthly seizure frequency (adj HR = 1.004, 95% CI = 1.001-1.008, P = .028) were independently associated with the primary endpoint. Add-on BRV improved seizure control in LEV-naive and LEV-prior patients. The time-to-baseline seizure count represents an informative endpoint alongside traditional study outcomes and designs.

Epilepsy and brain channelopathies from infancy to adulthood.

Genetic brain channelopathies result from inherited or de novo mutations of genes encoding ion channel subunits within the central nervous system. Most neurological channelopathies arise in childhood with paroxysmal or episodic symptoms, likely because of a transient impairment of homeostatic mechanisms regulating membrane excitability, and the prototypical expression of this impairment is epilepsy. Migraine, episodic ataxia and alternating hemiplegia can also occur, as well as chronic phenotypes, such as spinocerebellar ataxias, intellectual disability and autism spectrum disorder. Voltage-gated and ligand-gated channels may be involved. In most cases, a single gene may be associated with a phenotypical spectrum that shows variable expressivity. Different clinical features may arise at different ages and the adult phenotype may be remarkably modified from the syndrome onset in childhood or adolescence. Recognizing the prominent phenotypical traits of brain channelopathies is essential to perform appropriate diagnostic investigations and to provide the better care not only in the paediatric setting but also for adult patients and their caregivers. Herein, we provide an overview of genetic brain channelopathies associated with epilepsy, highlight the different molecular mechanisms and describe the different clinical characteristics which may prompt the clinician to suspect specific syndromes and to possibly establish tailored treatments.

Identification of prevalent patients with epilepsy using administrative data: the Tuscany experience.

Overall prevalence of epilepsy ranges from 4 to 10 cases per 1000. Italy lacks recent epidemiological studies on large populations. In the present study, prevalence of epilepsy has been assessed in Tuscany, an Italian Region with 3,750,000 habitants, implementing an algorithm based on administrative data from the Regional Information Health System. To identify patients with epilepsy, we used at least one the following criteria: (a) at least one EEG and at least two dispensations of any antiepileptic drug (AEDS) at a minimum distance of 12 months; (b) at least two dispensations of one "specific" AED (authorized for use only for patients with epilepsy) at a minimum distance of 12 months; and (c) hospital admission for epilepsy or recurrent relapses (cod. ICD-IX-345.*). This algorithm was validated through comparison with lists of true patients with epilepsy and subjects without neurological disorders (gold standard). 35,950 cases were identified. Total crude prevalence was 9.6/1000. Prevalence increased in older patients up to 16/1000 without gender differences. Overall sensitivity of the algorithm was 87.3%, and specificity was 99.9%. This algorithm identifies patients with epilepsy with acceptable sensitivity and specificity and can be used to assess the burden of disease and for monitoring health services.

A prospective study of direct medical costs in a large cohort of consecutively enrolled patients with refractory epilepsy in Italy.

OBJECTIVE: To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. METHODS: Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. RESULTS: Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was € 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second-generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. SIGNIFICANCE: Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities.

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.

Long-term-video monitoring EEG and 18F-FDG-PET are useful tools to detect residual disease activity in anti-LGI1-Abs encephalitis: A case report.

Background: The use of CD20-depleting monoclonal antibodies has shown to improve the long-term outcome of patients with anti-leucine-rich glioma-inactivated protein 1 antibodies (anti-LGI1-Abs) encephalitis after first-line immunotherapy, but currently predictive markers of treatment response and disease activity are lacking. Case presentation: A 75-year-old man presented cognitive impairment and faciobrachial dystonic seizures (FBDS), with mild abnormalities at electroencephalography (EEG), normal brain magnetic resonance and cerebrospinal fluid (CSF) analysis. Anti-LGI1-Abs were detected in serum and CSF, and corticosteroids and intravenous immunoglobulins were administered. Despite partial cognitive improvement, 18F-fluoridesoxyglucose-positron emission tomography (18F-FDG-PET) showed the persistence of temporo-mesial hypermetabolism, and FBDS were still detected by long-term monitoring video EEG (LTMV EEG). Rituximab was therefore administered with FBDS disappearance, further cognitive improvement, and resolution of 18F-FDG-PET temporo-mesial hypermetabolism. Conclusions: Our experience supports the use of 18F-FDG-PET and LTMVEEG as useful tools to measure disease activity, evaluate treatment response and guide therapeutic decisions in the long-term management of anti-LGI1-antibody encephalitis.

Adjunctive Brivaracetam in Older Patients with Focal Seizures: Evidence from the BRIVAracetam add­on First Italian netwoRk Study (BRIVAFIRST).

BACKGROUND: The management of epilepsy in older adults has become part of daily practice because of an aging population. Older patients with epilepsy represent a distinct and more vulnerable clinical group as compared with younger patients, and they are generally under-represented in randomized placebo-controlled trials. Real-world studies can therefore be a useful complement to characterize the drug's profile. Brivaracetam is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A and approved as adjunctive therapy for focal seizures in adults with epilepsy. OBJECTIVE: The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive brivaracetam in older patients (≥65 years of age) with epilepsy treated in a real-world setting. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a 12-month retrospective multicenter study including adult patients prescribed adjunctive brivaracetam. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events and the incidence of adverse events. Data were compared for patients aged ≥65 years of age ('older') vs those aged <65 years ('younger'). RESULTS: There were 1029 patients with focal epilepsy included in the study, of whom 111 (10.8%) were aged ≥65 years. The median daily dose of brivaracetam at 3 months was 100 [interquartile range, 100-175] mg in the older group and 100 [100-200] mg in the younger group (p = 0.036); it was 150 [100-200] mg in both groups either at 6 months (p = 0.095) or 12 months (p = 0.140). At 12 months, 49 (44.1%) older and 334 (36.4%) younger patients had a reduction in their baseline seizure frequency by at least 50% (p = 0.110), and the seizure freedom rates were 35/111 (31.5%) and 134/918 (14.6%) in older and younger groups, respectively (p < 0.001). During the 1-year study period, 20 (18.0%) patients in the older group and 245 (26.7%) patients in the younger group discontinued brivaracetam (p = 0.048). Treatment withdrawal because of insufficient efficacy was less common in older than younger patients [older: n = 7 (6.3%), younger: n = 152 (16.6%); p = 0.005]. Adverse events were reported by 24.2% of older patients and 30.8% of younger patients (p = 0.185); the most common adverse events were somnolence, nervousness and/or agitation, vertigo, and fatigue in both study groups. CONCLUSIONS: Adjunctive brivaracetam was efficacious, had good tolerability, and no new or unexpected safety signals emerged when used to treat older patients with uncontrolled focal seizures in clinical practice. Adjunctive brivaracetam can be a suitable therapeutic option in this special population.

Brivaracetam as add-on treatment in patients with post-stroke epilepsy: real-world data from the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST).

OBJECTIVE: Post-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy and accounts for about 10-15% of all newly diagnosed epilepsy cases. However, evidence about the clinical profile of antiseizure medications in the PSE setting is currently limited. Brivaracetam (BRV) is a rationally developed compound characterized by high-affinity binding to synaptic vesicle protein 2A. The aim of this study was to assess the 12-month effectiveness and tolerability of adjunctive BRV in patients with PSE treated in a real-world setting. METHODS: This was a subgroup analysis of patients with PSE included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). The BRIVAFIRST was a 12-month retrospective, multicentre study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of seizure response (≥50% reduction in baseline seizure frequency), seizure-freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. RESULTS: Patients with PSE included in the BRIVAFIRST were 75 and had a median age of 57 (interquartile range, 42-66) years. The median daily doses of BRV at 3, 6, and 12 months from starting treatment were 100 (100-150) mg, 125 (100-200) mg and 100 (100-200) mg, respectively. At 12 months, 32 (42.7%) patients had a reduction in their baseline seizure frequency by at least 50%, and the seizure freedom rates was 26/75 (34.7%). During the 1-year study period, 10 (13.3%) patients discontinued BRV. The reasons of treatment withdrawal were insufficient efficacy in 6 (8.0%) patients and poor tolerability in 4 (5.3%) patients. Adverse events were reported by 13 (20.3%) patients and were rated as mild in 84.6% and moderate in 15.4% of cases. SIGNIFICANCE: Adjunctive BRV was efficacious and generally well-tolerated when used in patients with PSE in clinical practice. Adjunctive BRV can be a suitable therapeutic option for patients with PSE.

Brivaracetam as Early Add-On Treatment in Patients with Focal Seizures: A Retrospective, Multicenter, Real-World Study.

INTRODUCTION: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Most real-world research on BRV has focused on refractory epilepsy. The aim of this analysis was to assess the 12-month effectiveness and tolerability of adjunctive BRV when used as early or late adjunctive treatment in patients included in the BRIVAracetam add-on First Italian netwoRk Study (BRIVAFIRST). METHODS: BRIVAFIRST was a 12-month retrospective, multicenter study including adult patients prescribed adjunctive BRV. Effectiveness outcomes included the rates of sustained seizure response, sustained seizure freedom, and treatment discontinuation. Safety and tolerability outcomes included the rate of treatment discontinuation due to adverse events (AEs) and the incidence of AEs. Data were compared for patients treated with add-on BRV after 1-2 (early add-on) and ≥ 3 (late add-on) prior antiseizure medications. RESULTS: A total of 1029 patients with focal epilepsy were included in the study, of whom 176 (17.1%) received BRV as early add-on treatment. The median daily dose of BRV at 12 months was 125 (100-200) mg in the early add-on group and 200 (100-200) in the late add-on group (p < 0.001). Sustained seizure response was reached by 97/161 (60.3%) of patients in the early add-on group and 286/833 (34.3%) of patients in the late add-on group (p < 0.001). Sustained seizure freedom was achieved by 51/161 (31.7%) of patients in the early add-on group and 91/833 (10.9%) of patients in the late add-on group (p < 0.001). During the 1-year study period, 29 (16.5%) patients in the early add-on group and 241 (28.3%) in the late add-on group discontinued BRV (p = 0.001). Adverse events were reported by 38.7% and 28.5% (p = 0.017) of patients who received BRV as early and late add-on treatment, respectively. CONCLUSION: Brivaracetam was effective and well tolerated both as first add-on and late adjunctive treatment in patients with focal epilepsy.

Adjunctive Perampanel in Older Patients With Epilepsy: A Multicenter Study of Clinical Practice.

BACKGROUND: Clinical data regarding use of newer antiseizure medications (ASMs) in an older population are limited. In randomized-controlled, placebo-controlled trials, older patients are under-represented, and protocols deviate markedly from routine clinical practice, limiting the external validity of results. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Perampanel is a third-generation ASM and the first and only non-competitive alfa-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor antagonist. OBJECTIVE: The aim of this study was to assess the effectiveness and tolerability of adjunctive perampanel over a 1-year period in a population of older patients with epilepsy treated in a real-world setting. METHODS: Older (≥ 65 years of age) patients prescribed add-on perampanel at 12 Italian epilepsy centers were retrospectively identified. Seizure occurrence, adverse events (AEs), and drug withdrawal were analyzed. Effectiveness outcomes included the rates of seizure response (≥ 50% reduction in baseline monthly seizure frequency), seizure freedom, and treatment discontinuation. Safety and tolerability outcomes were the rate of treatment discontinuation due to AEs and the incidence of AEs. RESULTS: A total of 92 patients with a median age of 69 (range 65-88) years were included. The median daily dose of perampanel at 12 months was 6 mg (interquartile range 4-6 mg). At 12 months, 53 (57.6%) patients were seizure responders, and 22 (23.9%) patients were seizure free. Twenty (21.7%) patients discontinued perampanel; the reasons for treatment withdrawal were insufficient efficacy (n = 6/20; 30.0%), AEs (n = 12/20; 60.0%), and a combination of both (n = 2/20; 10%). The most common AEs included irritability (8.7%), somnolence (4.3%), and dizziness/vertigo (4.3%). The rate of behavioral and psychiatric AEs was higher in patients with history of psychiatric comorbidities (p = 0.044). There were no differences in the occurrence of behavioral and psychiatric AEs according to the concomitant use of levetiracetam (p = 0.776) and history of cognitive decline (p = 0.332). CONCLUSIONS: Adjunctive perampanel was associated with improvement in seizure control and good tolerability in a real-life setting and can represent a viable therapeutic option in older patients with epilepsy.

Adjunctive Brivaracetam in Focal Epilepsy: Real-World Evidence from the BRIVAracetam add-on First Italian netwoRk STudy (BRIVAFIRST).

BACKGROUND: In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. OBJECTIVE: This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. METHODS: The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure-freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. RESULTS: A total of 1029 patients with a median age of 45 years (33-56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs (p < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% (p < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%;  p = 0.341) and seizure response (39.7% vs. 26.9%; p = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p = 0.017). CONCLUSION: The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.

Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy.

PURPOSE: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). METHODS: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. RESULTS: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed. CONCLUSION: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy.

The characteristics of 1,124 consecutive adults and children with refractory epilepsy attending 11 tertiary referral centers in Italy were investigated at enrollment into a prospective observational study. Among 933 adults (age 16-86 years), the most common syndromes were symptomatic (43.7%) and cryptogenic (39.0%) focal epilepsies, followed by idiopathic (8.1%) and cryptogenic/symptomatic generalized (6.2%) epilepsies. The most common syndrome among 191 children was symptomatic focal epilepsy (35.1%), followed by cryptogenic focal (18.8%), cryptogenic/symptomatic generalized (18.3%), undetermined whether focal or generalized (16.8%), and idiopathic generalized (7.3%). Primarily and secondarily generalized tonic-clonic seizures were reported in 27.8% of adults and 16.8% of children. The most commonly reported etiologies were mesial temporal sclerosis (8.0%) and disorders of cortical development (6.2%) in adults, and disorders of cortical development (14.7%) and nonprogressive encephalopathies (6.8%) in children. More than three-fourths of subjects in both age groups were on antiepileptic drug (AED) polytherapy.