Real-Life Effectiveness and Tolerability of Brivaracetam in Focal to Bilateral and Primary Generalized Tonic-Clonic Seizures

Purpose . Brivaracetam (BRV), an antiseizure medication indicated for focal-onset seizures, has shown e ﬃ cacy in the treatment of focal to bilateral tonic-clonic seizures (FBTCS). We aimed to determine the e ﬀ ectiveness and safety of BRV in patients with FBTCS and generalized tonic-clonic seizures (GTCS). Methods . We performed a multicenter, retrospective, longitudinal study in adult patients with epilepsy who experienced at least one FBTCS or GTCS before starting BRV (baseline visit). Data were collected from consecutive outpatient visits over a 4-year period. All patients had been followed for at least 3 months before the baseline visit and completed a minimum follow-up of 3 months after starting BRV. Response ( ≥ 50% reduction in FBTCS/ GTCS frequency) and retention rates, as well as seizure freedom and presence of adverse events at 3, 6, and 12 months, were recorded as outcome measures. Results . 114 patients were included (mean age 36 3 ± 18 0 years, 52% male, 36.6% genetic generalized epilepsy); 94 had a 12-month follow-up period. At 12 months ’ follow-up, the response rate was 83%, and 73.4% of patients were FBTCS/GTCS-free. Retention was 79% at 12 months. Adverse events occurred in 29.8% of patients, the most common being drowsiness (14.9%). No signi ﬁ cant di ﬀ erences were found in response rates between FBTCS and GTCS. Drug resistance was independently associated with lower response and seizure freedom rates at follow-up. The absence of a titration period predicted seizure freedom and response at 3 months. Conclusions . BRV is an e ﬀ ective and well-tolerated treatment in patients with focal to bilateral tonic-clonic seizures and generalized tonic-clonic seizures.


Introduction
A considerable percentage of patients with epilepsy do not achieve seizure freedom with initial antiseizure medications (ASMs) [1,2].Bilateral tonic-clonic seizures are associated with higher morbidity and mortality in epilepsy patients [3,4]; a higher risk of physical injury, traumatic lesions, and sudden unexpected death [4][5][6][7][8]; and poorer quality of life scores [9].Hence, it is of great clinical interest to control tonic-clonic seizures (both focal to bilateral and primary generalized), to reduce the associated morbidity and mortality.
Brivaracetam (BRV) has been approved as an adjunctive ASM for focal-onset seizures with or without secondary generalization in patients 4 years of age and older [10,11].BRV is a synaptic vesicle glycoprotein 2A modulator with high selective affinity, showing 10-to 30-fold greater binding potential than levetiracetam (LEV) [12,13].The favorable safety profile and absence of a titration period have made BRV a promising option in clinical practice [14][15][16][17].The efficacy of this compound in focal to bilateral tonic-clonic seizures (FBTCS) was observed in post hoc analyses of pooled data from phase III trials [18,19].In retrospective cohort studies, BRV has shown good response and retention rates in genetic generalized epilepsy syndromes [20][21][22][23], although evidence to further support its effectiveness in primary generalized tonic-clonic seizures (GTCS) is still scarce.
We performed a real-life clinical practice study in patients with bilateral tonic-clonic seizures starting treatment with BRV.The aim of the study was to determine the effectiveness and tolerability of BRV in epilepsy patients with FBTCS and GTCS to provide additional evidence for its use in patients with these seizures.

Materials and Methods
2.1.Study Design and Participants.This was a multicenter, longitudinal, retrospective observational study including patients ≥ 15 years of age with a definite epilepsy diagnosis and at least one FBTCS or GTCS prior to starting BRV.The study complies with the STROBE guidelines for observational studies and was approved by the local ethics committee (reference number PR(AG)216/2021).Informed consent was obtained at the moment of data collection.Data were collected from outpatient visits covering a period of 4 years (2016 to 2020) in 3 specialized epilepsy units in Spain: Hospital Universitari Vall d'Hebron (Barcelona), Centro de Neurología Avanzada (Seville), and Hospital Universitario Virgen de la Macarena (Seville).
All patients had been evaluated by experienced epileptologists.The epilepsy diagnosis and classification, seizure types, and epilepsy syndrome were defined according to the current International League Against Epilepsy (ILAE) classifications [24][25][26].Patients who met the criteria for refractory epilepsy according to the 2010 ILAE Task Force consensus proposal were categorized as drug-resistant [27].Patients who declined to participate in the study, those without a definite epilepsy diagnosis, those with progressive neurological diseases, and those with any other condition that prevented them from providing reliable seizure diaries were excluded.Patients with incomplete medical records and those lost to follow-up within 3 months after starting BRV were excluded from the analysis.
All consecutive patients with a definite epilepsy diagnosis, at least one previous FBTCS or GTCS, and starting BRV during the set time period were included in the analysis.All patients had been followed for a minimum of 3 months prior to starting BRV.Their demographic data, epilepsy syndrome diagnoses, and previous ASMs were obtained by medical record review.
The baseline visit was defined as the one at which BRV was started.BRV initial maintenance dosage (including titration period when indicated) was established according to the epileptologists' clinical indications at the baseline visit.Data on FBTCS, GTCS, and overall seizure frequency and therapy regimen were collected from the medical records.Indications for starting BRV were lack of efficacy (defined as seizure recurrence after an adequately applied treatment [27]) and/or presence of treatment-emergent adverse events (TEAEs) leading to treatment modification of the previous ASM trial.Baseline seizure frequency was defined as the mean seizure frequency in the 3 months before the baseline visit.At the follow-up visits, patients were reevaluated by an epileptologist, and the following data were collected: BRV dose at each visit, FBTCS, GTCS and overall seizure frequency since last visit, and TEAEs.Seizure frequency was reported by the patients and in seizure diaries.Data regarding treatment retention or withdrawal and concomitant treatment were also collected.All data were extracted retrospectively after completion of the follow-up period by one designated clinical investigator at each center, who was not actively involved in the clinical decisions or the recording of outcome measures in medical records.Data were then collected in a common database specifically designed for the study, ensuring homogeneity of the data.BRV effectiveness was analyzed at 3, 6, and 12 months' follow-up based on the frequency of FBTCS/GTCS during the months between each follow-up visit compared to the frequency in the 3 months before baseline.Patients with a ≥50% reduction in FBTCS or GTCS episodes were considered BRV responders.

Statistical Analysis.
Descriptive and frequency statistical analyses were performed, and comparisons were made using SPSS Statistics 22.0 software.Categorical variables are reported as the frequency (percentage) and continuous variables as the mean ± standard deviation (SD) or the median (interquartile range (IQR)), as appropriate.The normality assumption for quantitative variables was checked with the use of quantile-quantile (Q-Q) plots.
The Wilcoxon signed ranked test was used to assess changes in seizure frequency from the 3 months before baseline to 3, 6, and 12 months of follow-up.Statistical significance in the comparisons with outcome measures was assessed with the Pearson chi-square or Fisher exact test for categorical variables and the Student t test or Mann-Whitney U test for quantitative variables.Multiple logistic regression models were performed to establish independent predictors of response and seizure-free status at each follow-up visit.
Retention rates during follow-up were analyzed with the Kaplan-Meier product limit survival method using the logrank test to determine statistical significance between groups; retention rates in quantitative variables were assessed with simple Cox proportional hazard models.A multiple Cox regression analysis was performed to obtain predictive factors of treatment discontinuation.A p value <0.05 was considered statistically significant.1.

Acta Neurologica Scandinavica
Twenty-three patients discontinued BRV at some point during follow-up.Retention rates were 92.3%, 88%, and 79% at 3, 6, and 12 months, respectively, with a median dose at withdrawal of 150 mg/day.The main reasons for withdrawal were lack of efficacy in 13 patients (48.1%),TEAEs in 9 (33.3%), both in 2 (7.4%), and other reasons in 3 patients (11.1%).None of the clinical factors were statistically associated with a higher probability of withdrawal, although there was a trend toward a lower retention rate in patients with generalized epilepsy than in those with focal ).There were no differences in terms of epilepsy duration or drug resistance.Patients with generalized epilepsy had a higher monthly frequency of GTCS in the 3 months before baseline than those with focal epilepsy (median 0.7 (IQR 0.3-1.2) vs. 0 (IQR 0-0.7); p < 0 001), but there were no significant differences in the overall seizure frequency relative to baseline between the two groups.Patients with generalized epilepsy had received a larger number of previous ASMs (median 3 (IQR 1-4) vs. 1 (IQR 1-3); p = 0 028).There were no significant differences between the groups regarding BRV dose, titration, indication for starting the treatment, or the form of administration (as add-on therapy or monotherapy).At the follow-up visits, there were no significant differences in response and overall seizure freedom rates between  5 Acta Neurologica Scandinavica patients with focal or generalized epilepsy.However, patients with focal epilepsy had higher freedom rates from tonic-clonic seizures at 3 (76.7% vs. 56.8%;p = 0 039), 6 (75.4% vs. 56.4%;p = 0 044), and 12 months (80.7% vs. 62.2%; p = 0 047) (Figure 2).
Compared to patients with focal epilepsy, those with generalized epilepsy showed a trend toward a lower retention rate at 12 months' follow-up (72.7% vs. 83.2%,p = 0 058).There were no significant differences in the reasons for BRV withdrawal or presence of adverse events between the two groups.

Discussion
This study describes the results of real-life BRV use in a representative sample of patients with generalized convulsive seizures (focal or generalized epilepsy) and a minimum follow-up of three months.In line with previous studies, our results show response rates of around 60% in the overall seizure count during follow-up, and more than 75% in FBTCS/ GTCS [28,18,19,29], with no differences between patients with focal or generalized epilepsy.These results support the potential usefulness of BRV for fast, optimized seizure control.TEAEs: treatment-emergent adverse events.

Acta Neurologica Scandinavica
The starting BRV dose in our sample was similar to those described in previous postcommercialization studies [29,30], and doses remained stable during follow-up.Our sample includes patients who received high doses of BRV, mostly due to the proportion of drug-resistant patients included.Overall, a higher starting BRV dose was independently associated with higher response rates and seizure freedom.In addition, most patients skipped the titration phase, and this was independently associated with a response against tonic-clonic seizures at 3 months' followup.These findings support previous reports suggesting that therapeutic doses should be started from the first day to quickly achieve seizure control without increasing the risk of TEAEs [15,31].This is particularly relevant in the case of tonic-clonic seizures, which carry a higher risk of injuries and unexpected sudden death.However, in our study, a titration phase was still considered in some patients at clinicians' criteria, mostly in those patients with high ASM over-load and those with a previous history of TEAEs with other ASMs, and therefore, no definite conclusions can be reached regarding this matter from our results.
A large percentage of patients with drug-resistant epilepsy used BRV in combination with other ASMs.As would be expected, drug resistance was the main clinical factor independently associated with lower response and seizure freedom rates [32].However, half the patients with drugresistant epilepsy were free of tonic-clonic seizures during follow-up, and up to 24% were free of all seizures.These results uphold the potential benefit of this treatment even in patients with refractory epilepsy and failure to several ASMs [33,34].
The retention rate in our sample was similar to values reported in previous series but was slightly higher than those described in previous postcommercialization studies having longer follow-up periods [19,23,29,35,36].This difference could be attributable to the shorter follow-up of Figure 2: Response (a) and tonic-clonic seizure freedom (b) rates in patients with focal or generalized epilepsy.Similar response rates were observed in the two groups at 3-, 6-, and 12-month follow-ups, whereas tonic-clonic seizure freedom rates were higher in patients with focal epilepsy.Tonic-clonic seizure freedom rates above 55% were seen in both groups throughout follow-up.TCS: tonic-clonic seizures.
7 Acta Neurologica Scandinavica our study, which was mainly focused on the first months after starting treatment.
Similar to the findings in postcommercialization studies, adverse events occurred in almost 30% of our patients, and in most cases, they were mild and did not lead to treatment discontinuation.Nonetheless, TEAEs were the main reason for discontinuation, as has been reported [23,[34][35][36].Some clinical trials have described higher TEAE [16,19], but they were mainly considered mild and did not require treatment discontinuation.The retrospective design of most postcommercialization studies may have underestimated adverse events of less clinical relevance.
Our study included patients with genetic generalized epilepsy in which BRV was initiated off-label.The frequency of GTCSs and the number of previous ASMs were higher in these patients at baseline.This likely represents a selection bias, as this is a more difficult-to-treat patient population, especially in women of childbearing potential in whom avoiding valproate may have influenced baseline seizure control.Accordingly, this group of patients had lower seizure freedom rates during follow-up compared to patients with focal epilepsy.However, overall seizure freedom rates were above 55% both in patients with GTCS and those with FBTCS throughout the follow-up.The effectiveness results provide further evidence of the potential benefit of BRV in tonic-clonic seizures, whether patients have a focal or generalized epilepsy type [28,11,20,23].
The retrospective design, wide age range, and high percentage of drug-resistant patients, as well as the differing epilepsy syndromes and etiologies of the patients included, are some of the main limitations of this study.The retrospective design might have also introduced a selection bias in those cases in which reliable seizure frequency could not be obtained or those with progressive conditions.In addition, the short follow-up period may have overestimated some outcome measures such as seizure frequency and retention rates, whereas some TEAEs may have been underrepresented.Also, the observational design did not allow to control some confounding factors and cointerventions such as other ASM modifications during follow-up.Nevertheless, the results provide real-life data regarding the usefulness of BRV to control FBTCS/GTCS in focal and generalized epilepsies.Larger prospective, randomized, placebo-controlled trials with longer follow-up periods are needed to confirm these results.

Conclusions
Brivaracetam is an effective and well-tolerated ASM in patients with focal or generalized epilepsy experiencing bilateral tonic-clonic seizures.As the therapeutic effect can be achieved from the first day of treatment, brivaracetam can be considered a promising option to avoid the complications associated with these seizures.

Figure 1 :
Figure1: Brivaracetam dose and seizure frequency at follow-up.The figure shows increasing doses in the first 3 to 6 months of treatment, with stabilization at 6-12 months.Median seizure frequency (both FBTCS/GTCS and overall seizures) is seen to decrease since the baseline visit.FBTCS/GTCS remain near 0 after 3 months of treatment.BRV: brivaracetam; FBTCS/GTCS: focal to bilateral tonic-clonic seizures/ generalized tonic-clonic seizures.

Table 1 :
Demographic and clinical characteristics and BRV initiation at baseline visit.

Table 2 :
Seizure frequency and response rates at follow-up.

Table 4 :
Treatment-emergent adverse events during follow-up.