Efficacy, retention, and safety of brivaracetam in adult patients with genetic generalized epilepsy

Epilepsy & Behavior 102 (2020) 106657

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Efficacy, retention, and safety of brivaracetam in adult patients with genetic generalized epilepsy Elena Fonseca a, Lorena Guzmán b, Manuel Quintana a, Laura Abraira a, Estevo Santamarina a, Xavier Salas-Puig a, Manuel Toledo a,⁎ a b

Epilepsy Unit, Neurology Department, Hospital Vall d'Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain Neurophysiology Department, Hospital Vall d'Hebron, Department of Medicine, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain

a r t i c l e

i n f o

Article history: Received 26 August 2019 Revised 18 October 2019 Accepted 19 October 2019 Available online xxxx Keywords: Brivaracetam SV2A Refractory Seizure Genetic generalized epilepsy

a b s t r a c t Objective: The aim of this study was to evaluate the efficacy, tolerability, and retention of brivaracetam (BRV) in genetic generalized epilepsy (GGE) in real-life practice. Methods: This is a retrospective cohort study of adult patients with GGE in whom BRV was started between 2016 and 2018, completing a follow-up period of ≥6 months. Clinical and electroencephalogram (EEG) characteristics were analyzed at baseline and at follow-up as outcome measures. Results: Brivaracetam was started in 37 patients (mean age: 29.9 ± 12.3 years; 73% women). Juvenile myoclonic epilepsy was the most common syndrome (43.2%). The primary indications for starting BRV were lack of efficacy (51.4%) and adverse events (AEs) (27%) of other antiepileptic drugs (AEDs). In total, 32.4% of patients received BRV monotherapy. Retention rate at 6 months was 81.1%; 83.8% of patients were considered responders, and 62.2% achieved seizure freedom. The primary reasons for withdrawal were treatment-emergent adverse events (TEAEs, 57.1%) and lack of efficacy (42.9%). The higher number of prior AED use was a risk factor for a lack of response [median = 4 (interquartile range (IQR): 3–4) vs 2 (IQR: 1–3); p b 0.05]. Patients with a previous response to valproic acid tended to have a higher response rate to BRV (86.7% vs 50%, p = 0.169). Eighty-three point eight percent (83.8%) of previous levetiracetam (LEV) responders also showed a good response to BRV. In terms of patients who presented LEV-related AEs, AE resolution was observed in 79.8%, particularly with regard to psychiatric AEs. Follow-up EEGs were compared with baseline EEGs in 25 patients (67.6%) during follow-up. Most patients showed a reduction (52%) or no change (36%) in interictal epileptiform discharge (IED) frequency. Significance: Brivaracetam shows good responder and retention rates in GGE and is generally well tolerated. It is an appropriate alternative treatment for GGE, especially in refractory epilepsy and when other AEDs are not tolerated. © 2019 Elsevier Inc. All rights reserved.

1. Introduction Genetic generalized epilepsies (GGEs), previously known as idiopathic generalized epilepsies, account for approximately 15% to 20% of all epilepsy syndromes [1,2]. Treatment for these epileptic syndromes remains a clinical challenge, and only a limited number of antiepileptic drugs (AEDs) are approved for the indications, which include valproate (VPA), lamotrigine (LTG), levetiracetam (LEV), topiramate (TPM), benzodiazepines, perampanel (PER), and ethosuximide (ESM). Valproate is still considered the most effective treatment for men or women of nonchildbearing potential [3]. Concern ⁎ Corresponding author at: Pg. Vall d'Hebron, 119-129, 08035 Barcelona, Spain. E-mail addresses: [email protected] (E. Fonseca), [email protected] (M. Quintana), [email protected] (L. Abraira), [email protected] (E. Santamarina), [email protected] (M. Toledo).

https://doi.org/10.1016/j.yebeh.2019.106657 1525-5050/© 2019 Elsevier Inc. All rights reserved.

rises in the case of refractory GGE, which is reported to account for up to 20% of GGE cases [4]. Some specific syndromic diagnosis, the presence of febrile seizures, early onset, multiple seizure types, status epilepticus, developmental delay, and comorbid psychopathology have been described as risk factors to developing drug-resistant GGE. Pharmacological options are very limited in these situations, and there is no surgical approach. Furthermore, resistance to VPA has recently been described as one of the strongest predictors for drug-resistant epilepsy and poor social outcome in patients with GGE [5]. The limitations on the use of VPA, specifically in women of childbearing potential, have increased the concern about patients with drug-refractory epilepsy and their outcomes. The most common AEDs approved for this indication have only been tested as add-on therapy in clinical trials. However, the series in clinical practice have revealed that the new AEDs are widely used as first-line therapy or monotherapy for patients with GGE because of the potential safety concerns associated with the classic AEDs in patients

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with GGE. The lack of alternatives in a significant number of unresponsive GGE has driven clinicians to test some of the newer AEDs such as lacosamide (LCM) [6,7] (for which phase II trials have provided safety and efficacy evidence [8]) or zonisamide (ZNS) [9,10,11] for the treatment of GGE, but there is still insufficient evidence for their approval. In light of the above, the development of newer pharmacological strategies is of particular interest. Brivaracetam (BRV) is a recently approved AED as adjuvant therapy for focal onset seizures with or without generalization, in patients with epilepsy aged ≥16 years [12]. It is a synaptic vesicle glycoprotein 2A modulator with high affinity, with 10- to 30-times greater binding potential than LEV [13,14]. In focal onset seizures, clinical trials have shown promising efficacy and safety results, with low discontinuation rates during long-term follow-up [15]. To date, significant experience has been accrued on the efficacy and safety of the drug in focal onset epilepsy. However, the molecular similarity to LEV has driven interest towards its use in GGE. During preclinical development, BRV demonstrated the suppression of spike-and-wave activity in the genetic absence epilepsy rat from Strasbourg model [16]. In humans with GGE, a significant reduction in photoparoxysmal response was seen after treating them with BRV [17]. One of the phase III clinical trials published in 2014 included 36 patients with GGE, in which higher responder and seizure freedom rates were reported compared with placebo [15]. A recent retrospective clinical study in Germany included 61 patients with GGE in which BRV was started. It found a retention rate of 69.2% at 6 months, and discontinuation was mostly due to insufficient efficacy in 20% and adverse events (AEs) in 10% [18]. Another retrospective study from Germany also found a responder rate of 52.6% and 15.8% of patients remained seizure-free at 3 months [19]. The retrospective design, the refractory nature of the patients' profiles, and the lack of EEG confirmatory data are some of the major limitations of the published results. However, the scarce data suggest that BRV might be a suitable option for GGE. We conducted a real-life clinical practice study of patients with GGE in which BRV was used off-label. The purpose of the study was to evaluate its clinical efficacy, tolerability, and EEG outcome, in order to provide additional evidence for its use in this type of epilepsy. 2. Material and method

treatment were retrospectively recorded at a minimum of 6 months follow-up. Efficacy was assessed using responsiveness parameters (patients with a N50% seizure reduction were considered to be responders) and seizure freedom. The retention rate was also retrospectively recorded at 12–24 months follow-up when available. EEG studies were performed at baseline before BRV initiation and a control EEG conducted within the 6 months of follow-up. The Electroencephalogram (EEG) protocol included scalp electrodes using the international 10–20 system with a minimum duration of 30–60 min. Activation procedures were performed (hyperventilation [HV] during 3 min, fixation on–off test, and intermittent photic stimulation [ILS] from 3 to 21 Hz with 5 s intervals). Ictal or interictal patterns were defined and classified as generalized and focal according to the International Federation of Clinical Neurophysiology glossary for epileptiform activity [21]. The frequency of interictal epileptiform discharges (IEDs) was stratified according to the 2012 consensus of the American Clinical Neurophysiology Society [22]. Focal or diffuse slowing and acute sharp waves that did not meet criteria for epileptiform discharges were considered nonepileptiform pathological recordings. Descriptive and frequency statistical analysis was performed, and comparisons were made using the software IBM SPSS Statistics 22.0. Table 1 Demographic and clinical baseline characteristics. EEG findings at baseline. Mean age (years) (±SD) Gender, n (%)

Female Male Epilepsy syndrome, n (%) Juvenile myoclonic epilepsy Generalized tonic–clonic seizures alone Juvenile absence epilepsy Myoclonic absence epilepsy Childhood absence epilepsy Jeavons syndrome Epilepsy duration (years), median (range) Drug-resistant epilepsy, n (%) Mean number of previous AEDs Mean BRV treatment duration (months) Mean BRV daily dose (mg)

This was a retrospective, observational study following the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines for observational studies that included adult patients with a GGE diagnosis from our Epilepsy Clinic from November 2016 to October 2018. The project was approved by the local ethics committee (reference number PR(AG) 163/2017). All patients were evaluated at baseline by an expert epileptologist. Genetic generalized epilepsy diagnosis, seizure types, and epilepsy syndrome were also adapted according to the 2017 International League Against Epilepsy (ILAE) classification [2]. Drug resistance was assessed according to the 2010 ILAE Task Force [20], and patients who met criteria for refractory epilepsy were categorized as drug-resistant. Patients unwilling to participate, with no definite diagnosis, or with any other conditions that could mask the results of the study were excluded. All consecutive patients with GGE who started BRV with a minimum follow-up of 6 months were included in the analysis. Medical records were reviewed, and demographic data, epilepsy syndrome diagnosis, and previous AEDs were assessed. The effectiveness and tolerability of previous VPA and LEV treatments were reported in detail. Brivaracetam was started at the baseline visit; in most cases, the target dose was started directly without a titration phase. Detailed data on dosage and indication were collected. All patients were reevaluated at least once within the following 6 months by an epileptologist. Seizure control was evaluated using seizure diaries. Data from the medical records regarding treatment retention or withdrawal, treatment-emergent adverse events (TEAEs) according to the World Health Organization criteria, and concomitant

Indication for BRV, n (%)

Seizure-active at baseline, n (%) Seizure types leading to BRV initiation, n (%) Baseline EEG (n=37), n (%)a

Lack of efficacy of previous AEDs AE of previous AEDs Both lack of efficacy and AE of previous AEDs Other Generalized tonic–clonic Absences Myoclonic jerks IEDs Absent Rare Occasional Frequent Abundant Background Absent slowing Focal Diffuse Seizure No recording Yes Response to No change HV Nonphysiological slowing Increase of IEDs Response to No change ILS Nonphysiological slowing Increase of IEDs

29.9 (±12.3) 27 (73) 10 (27) 16 (43.2) 9 (24.3) 7 (18.9) 2 (5.4) 2 (5.4) 1 (2.7) 11.1 (1.2–40.9) 14 (37.8) 2.54 (±1.6) 10.4 (±7.1) 135.1 (±79.2) 19 (51.4) 10 (27) 5 (13.5) 3 (8.1) 24 (64.9) 22 (59.5) 11 (29.7) 4 (10.8) 6 (24) 6 (24) 8 (32) 4 (16) 1 (4) 21 (84) 2 (8) 2 (8) 23 (92) 2 (8) 11 (44) 2 (8) 2 (8) 15 (100) 0 0

BRV: brivaracetam; AEDs: antiepileptic drugs; AE: adverse events; IEDs: interictal epileptiform discharges; HV: hyperventilation; ILS: intermittent light stimulation. a HV and ILS performed in 15 patients.

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Fig. 1. Kaplan–Meier representation of BRV retention by treatment duration. Treatment retention is represented as the percentage of patients that remained under treatment in each period. Tick marks show censored subjects (patients who did not abandon treatment until the last follow-up time). The extended analysis shows a trend towards retaining treatment after completion of the first year.

Categorical variables were reported as frequencies (percentages) and continuous variables as mean ± standard deviation (SD) or median (interquartile range [IQR]), as appropriate. Normality assumption of quantitative variables was checked with the use of quantile–quantile (Q–Q) plots. Statistical significance in the comparisons with the responder rate, seizure-free rate, and TEAEs (outcome measures) at 6 months was assessed by Pearson's chi-square when comparing with categorical variables, except in the case of having an expected count less than 5 in more than 20% of cells in the contingency table, where Fisher's exact test was used. Outcome measures were compared with the Student's t-test for continuous variables that followed approximately a normal distribution (age), and the Mann–Whitney U test was used for the rest of quantitative variables (number of previous AEDs, BRV daily dose). Retention rates during follow-up were analyzed with the Kaplan–Meier product limit survival method using the log-rank test to determine statistical significance between groups; retention rates in quantitative variables were assessed with simple Cox proportional hazard models. Changes in the EEG results between baseline and follow-up were assessed with the McNemar test in dichotomous variables and the McNemar–Bowker test in ordinal variables with more than two groups. A p-value b0.05 was considered statistically significant. 3. Results 3.1. Demographic and clinical characteristics In total, 38 patients with GGE were recruited, and one was lost to follow-up. The 37 patients included in the analysis had a mean age of 29.9 ± 12.3 years (median: 27 years, range: 16–61 years), and 27 patients (73%) were women. The most common syndrome was juvenile myoclonic epilepsy (43.2%), followed by generalized tonic–clonic (24.3%) and juvenile absence epilepsy (18.9%). The primary indications for starting BRV were lack of efficacy of previous AEDs (51.4%) and the

presence of AEs under other medications (27%). At baseline, the mean number of previous AEDs used was 2.54 ± 1.6 (median: 2 AEDs, range: 1–8 AEDs), and 37.8% of patients met criteria for drug-resistant epilepsy. 3.2. Outcome measures analysis The mean duration of BRV treatment was 10.4 ± 7.1 months (median: 8 months, range: 1–23 months), and the mean dosage was 135.1 ± 79.2 mg daily (median: 100 mg, range: 50–400 mg) (Table 1). An overnight switch from previous AED to BRV (skipped titration period) was performed in 83.4% (31). At follow-up, 83.8% (31) were considered responders, and 62.2% of patients (23) were seizure-free. The retention rate at 6 months was 81.1% (30). At that point, 32.4% (12) of patients were taking BRV monotherapy and 67.6% (25) in combination with any other AED. The most frequently used combinations were BRV + VPA (48%; 12), BRV + LTG (28%; 7), and BRV + clobazam (16%; 4). Patients who met criteria for drug-resistant epilepsy at baseline presented lower responder (78.6% vs 83.8%) and retention rates (78.6% vs 81.1%) at follow-up. They were also less likely to achieve seizure freedom (42.9% vs 62.2%), although these difference were not statistically significant. An extended analysis was performed in those patients in which a longer follow-up was available (n = 22), showing an estimated retention rate at 12 months of 75.4% and an estimated retention time of 18.9 months (95% Confidence interval (CI) = 16.2–21.6) (Fig. 1). Eighteen point nine percent (18.9%) of patients (7) discontinued treatment. The primary reasons for withdrawal were TEAEs (57.1%; 4) and lack of efficacy (42.9%; 3). In terms of the responders to BRV, 35.5% were on monotherapy and 64.5% on combination therapy. The number of previous AEDs used was a risk factor for a lack of response [median = 4 (IQR: 3–4) vs median = 2 (IQR: 1–3); p b 0.05], although it had no influence on the BRV

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Table 2 Baseline and follow-up clinical characteristics in relation to outcome measures. Total (n) Global Age (mean) years (±SD) Gender Female Male Epilepsy syndrome JME GTCS alone JAE MAE CAE Jeavons syndrome Indication for BRV initiation LE of previous AEDs AEs on previous AEDs LE + AEs on previous AEDs Other Seizure-active or freedom at baseline Seizure-active Seizure-free Seizure types leading to BRV initiation GTC Absences Myoclonic seizures Drug-resistant epilepsy BRV in monotherapy BRV in combination BRV + VPA BRV + LTG BRV + CLB

Responders Retention Seizure-free TEAEs % (n) % (n) % (n) % (n)

37 83.8 (37) 29.9 30.45 (±12.3) (±12.9)

81.1 (37) 30.45 (±12.9)

62.2 (37) 28.7 (±11.9)

27 (37) 30.2 (±10.6)

27 10

85.2 (23) 80 (8)

85.2 (23) 70 (7)

70.4 (19) 40 (4)

25.9 (7) 30 (3)

16 9 7 2 2 1

75 (12) 88.9 (8) 85.7 (6) 100 (2) 100 (2) 100 (1)

68.8 (11) 77.8 (7) 100 (7) 100 (2) 100 (2) 100 (1)

62.5 (10) 66.7 (6) 57.1 (4) 50 (1) 50 (1) 0 (0)

18.8 (3) 44.4 (4) 28.6 (2) 50 (1) 0 (0) 0 (0)

19

78.9 (15)

78.9 (15)

47.4 (9)

31.6 (6)

10

100 (10)

90 (9)

80 (8)

20 (2)

5

60 (3)

80 (4)

60 (3)

20 (1)

3

100 (3)

66.7 (2)

100 (3)

33.3 (1)

24 13

75 (18) 100 (13)

79.2 (19) 84.6 (11)

50 (12) 84.6 (11)

29.2 (7) 23.1 (3)

22 11 4 14

77.3 (17) 90.9 (10) 100 (4) 78.6 (11)

77.3 (17) 81.8 (9) 100 (4) 78.6 (11)

68.2 (15) 54.5 (6) 50 (2) 42.9 (6)

31.8 (7) 27.3 (3) 0 (0) 21.4 (3)

12 25 12 7 6

91.7 (11) 80 (20) 75 (9) 85.7 (6) 66.7 (4)

91.7 (11) 76 (19) 66.7 (8) 85.7 (6) 50 (3)

83.3 (10) 52 (13) 50 (6) 42.9 (3) 50 (3)

16.7 (2) 32 (8) 33.3 (4) 28.6 (2) 33.3 (2)

At baseline, IEDs were observed in 76% of patients, the majority of which were occasional (32%) or rare (24%). Follow-up EEGs were compared with the baseline EEG in 25 patients (67.6%) during the sixmonth follow-up. The median time interval between baseline and follow-up EEG was 17.3 months (IQR range: 8.1–24.1). At follow-up, most patients showed an improvement (52%) or no change (36%) in IED frequency (Table 4). No significant changes were found in the background activity or in HV/ILS response. 3.3. Adverse events Treatment-emergent adverse events were reported in 10 patients (27%). They were a major reason for treatment discontinuation, with a significant fall in the retention rate during follow-up (p = 0.037) (Fig. 3). The most common TEAEs were daytime drowsiness (30%), dizziness (20%), and weight gain (20%). Other TEAEs, such as bradypsychia (9.1%), depression (9.1%), anxiety (9.1%), and tremor (9.1%), were less frequently reported. Treatment-emergent adverse events occurred in 20% of patients in whom BRV was started due to AEs or both lack of efficacy and TEAEs related to other AEDs. Treatment-emergent adverse event rates were similar when BRV was used in monotherapy or in combination. 4. Discussion

Outcome measures (responder, retention, seizure freedom, and TEAEs) are represented as % in each group. No statistically significant differences were found for these clinical items. TEAEs: treatment-emergent adverse events; LE: lack of efficacy; JME: juvenile myoclonic epilepsy; GTCS alone: generalized tonic–clonic seizures alone; JAE: juvenile absence epilepsy; MAE: myoclonic absence epilepsy; CAE: childhood absence epilepsy; GTC: generalized tonic–clonic; CLB: clobazam.

retention rate. However, responders had a higher retention rate (81.1% vs 50%, p b 0.05) with a significantly higher mean retention time in the extension follow-up [20.2 (95% CI = 17.7–22.8) vs 8.7 (95% CI = 4.3–13) months; p b 0.05]. Age, gender, previous AED, reason for BRV indication, and EEG outcome had no influence on the BRV response and retention rates. Patients with prior active seizures did not show significantly worse response and retention rates, and no differences were found depending on either the epileptic syndrome or the seizure types at baseline (Table 2). Nineteen patients (51.3%) switched from VPA to BRV because of lack of efficacy (52.6%), drug intolerance (15.8%) or both (15.8%), and pregnancy risk (15.8%). Patients who had a previous response to VPA tended to have a higher response rate to BRV (86.7% vs 50%, p = 0.169). In total, 83.8% of subjects had previously used LEV. These patients started BRV because of lack of efficacy (51.6%), drug intolerance (29%) or both (12.9%), and because of other situations (6.5%). Eighty-nine point five percent (89.5%) of previous LEV responders also responded to BRV. Regarding patients who experienced LEV-related AEs, 84.2% were responders, and the AEs were resolved with BRV in 79.8% of cases. Specifically, in 19 patients with a history of LEV-related psychiatric AEs, these events were resolved with BRV in 73.7% of cases (Table 3 and Fig. 2).

This study shows the real-life experience of the off-label use of BRV in a sample of 37 adult patients with a confirmed diagnosis of GGE, encompassing the most common GGE syndromes. In line with previous studies, our results show promising efficacy, safety, and retention data for this subset of patients [15,18,19]. According to our results, BRV can be an efficacious alternative to other AEDs, including VPA, and tolerability includes improvement of LEV-related psychiatric symptoms [23,24,25,26]. The supportive EEG data of a large number of our patients confirm the global good clinical response observed in the study patients. Our results show a higher seizure freedom and responder and retention rates than the results published by previous authors. This may be due to treatment dosage, since the first published clinical trial used lower doses (100 to 150 mg) and recorded a responder rate of 46.8% in the maintenance period [15]. Recent studies published in 2017 and 2018 used higher BRV doses similar to ours (median dose: 100 mg, Table 3 Outcome measures by previous treatment with VPA and LEV.

Previous VPA Never Yes, responder Yes, nonresponder AEs on VPA Previous LEV Never Yes, responder Yes, nonresponder AEs on LEV Psychiatric Others

Total (n)

Responders % (n)

Retention % (n)

Seizure-free % (n)

TEAEs % (n)

18

88.9 (16)

77.8 (14)

72.2 (13)

15

86.7 (13)

93.3 (14)

60 (9)

4

50 (2)

50 (2)

25 (1)

27.8 (5) 33.3 (5) 0 (0)

8

87.5 (7)

87.5 (7)

37.5 (3)

50 (4)

6

100 (6)

100 (6)

50 (3)

19

89.5 (17)

84.2 (16)

78.9 (15)

12

66.7 (8)

66.7 (8)

41.7 (5)

33.3 (2) 31.6 (6) 16.7 (2)

19

84.2 (16)

68.4 (13)

78.9 (15)

80 (4)

100 (5)

60 (3)

5

26.3 (5) 40 (2)

Previous efficacy and AEs to these AEDs are shown, as well as their relationship to BRV responder, retention, seizure freedom, and TEAE rates. VPA: valproic acid; LEV: levetiracetam; AEDs: antiepileptic drugs; BRV: brivaracetam; TEAEs: treatment-emergent adverse events; AEs: adverse events.

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Fig. 2. Graphic representation of responder rates to BRV in patients by previous response to either VPA or LEV. It is shown how response to BRV is maintained in previously nonresponder patients to these AEDs.

range from 100 to 200 mg) and showed slightly better retention rates (68.4% at 3 months and 69.2% at 6 months) [18,19]. This would suggest that the correct BRV dosage should be reached in all patients in order to achieve seizure control. In our study, almost 40% of patients were found to be drug-resistant, and 65% were seizure-active at baseline. Patients with drug-resistant epilepsy showed a tendency towards lower BRV responder and retention rates. These findings are consistent with a recent series published in 2018 of 61 patients with GGE, 90% of which were found to have drugresistant epilepsy [18]. Therefore, BRV could become an option in those cases, especially when other AEDs are contraindicated or not tolerated. Patients who had previously shown a good response to other AEDs such as VPA and LEV had good BRV response and retention rates. In addition, our analysis also shows favorable outcome measures in those patients treated with BRV monotherapy, which had not been assessed in previous series, providing further evidence that BRV is useful in GGE. The addition of routine EEG findings during follow-up in the majority of patients gives the study a more complete clinical approach. In previous studies, EEG features had not been assessed. Our results show that during follow-up, the frequency of IEDs and the background activity did not increase in up to 88% of patients. Even though EEG is not accepted as a biomarker for clinical response, the data are supportive of the good clinical outcome. Other drugs such as carboxamides have shown a deleterious effect on baseline EEG in patients with GGE. However, IEDs in follow-up EEGs were compared retrospectively with the baseline EEGs performed previously with a variable interval and under different medications. Also, its methodological design did not allow to further investigate background slowing and other EEG features that can be clinically relevant in this scenario, so these results should be interpreted with caution.

In line with previous studies, approximately one-third of our cases reported TEAEs, with no severe TEAEs. Interestingly, low TEAE rates and good outcome measures were reported in the subgroup of patients who had presented LEV-related TEAEs, particularly psychiatric TEAEs. The better tolerability of BRV compared with LEV has been consistently reported in clinical series with different epileptic syndromes [23,24,25]. This could indicate that BRV might be a suitable option for patients with psychiatric TEAEs related to other approved AEDs in GGE. However, the presence of TEAEs was a major reason for treatment withdrawal. The TEAEs leading to discontinuation are more likely to occur within the first 6 months after treatment initiation, whereas some TEAEs are tolerable for some patients when seizure control is reached beyond 6 months. Long-term response was also reported in previous studies in patients who received BRV treatment for longer than 6 months [18,19]. Table 4 EEG outcome during BRV treatment. Follow-up EEG IEDs % (n) Absent (12) Baseline EEG IEDs % (n)

Absent (6) Rare (6) Occasional (8) Frequent (4) Abundant (1)

83.3 (5) 33.3 (2) 37.5 (3) 25 (1)

Rare (10)

16.7 (1) 50 (3) 62.5 (5) 25 (1) 100 (1) 0

Occasional (0)

Frequent (2)

Abundant (1)

0

0

0

0

16.7 (1)

0

0

0

0

0

25 (1)

25 (1)

0

0

0

Baseline and follow-up EEG IED frequencies are compared in each row. IEDs: interictal epileptiform discharges.

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Fig. 3. Kaplan–Meier representation of BRV retention according to the presence of TEAEs. Tick marks show censored subjects (patients who did not abandon treatment until the last followup time). A significant decrease in retention rate during treatment duration is shown in the TEAEs group (p b 0.05) in the first 6 months of treatment. However, the extended analysis shows a trend towards treatment retention even in the TEAEs group after the 12-month period.

The main limitation of this study is its retrospective design. There is selection bias since our sample only includes adult patients with a wide age range probably older than the overall population with GGE and with a longer duration of epilepsy. In addition, the mean number of previous AEDs was N2. All these factors imply a high proportion of patients with drug-refractory epilepsy in this study. Efficacy compared with VPA or LEV cannot be assumed because only a small proportion of patients switched to BRV due to lack of efficacy. Furthermore, the short followup period could represent a bias since some TEAEs could appear after the first 6 months, and serious AEs might, therefore, be underrepresented. Also, there is a wide range of follow-up period, so the extension analysis must be interpreted carefully. Nevertheless, every patient was assessed by trained epileptologists, and findings from clinical trials suggest that there is a low likelihood of experiencing serious TEAEs in the long-term use of BRV. Larger prospective, randomized, and controlled trials with a longer follow-up and a methodical EEG analysis are needed in order to study the efficacy of BRV in GGE.

Declaration of competing interest

5. Conclusion

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Seizure control in GGE can be achieved under BRV treatment. It has significant responder and retention rates at 6 months of follow-up, and nearly two-thirds of patients remain seizure-free. It also offers a good safety profile, particularly in patients with previous intolerance to LEV. Brivaracetam can, therefore, be considered a suitable option for GGE treatment, especially when other AEDs are not well tolerated. Ethical publication statement We confirm that we have read the Journal's position on issues concerning ethical publication and affirm that this report is consistent with those guidelines.

E. Fonseca, L. Guzmán, and L. Abraira declare travel support from UCB Pharma. M. Toledo declares funding and honoraria from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve. E. Santamarina declares funding and honoraria from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve. X. Salas-Puig declares funding and honoraria from UCB Pharma, BIAL Pharmaceutical, EISAI Inc., and Esteve. M. Quintana has no conflict of interest to declare. Acknowledgments This article received medical writing support from UCB Pharma. UCB Pharma was not involved in the study design, the collection, analysis or interpretation of the data gathered, the writing of the report or the decision to submit the article for publication. Funding sources

References [1] Jallon P, Latour P. Epidemiology of idiopathic generalized epilepsies. Epilepsia 2005; 46:10–4. [2] Scheffer IE, Berkovic S, Capovilla G, Connolly MB, French J, Guilhoto L, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017;58:512–21. [3] Coppola G, Piccorossi A, Operto FF, Verrotti A. Anticonvulsant drugs for generalized tonic–clonic epilepsy. Expert Opin Pharmacother 2017;18:925–36. [4] Vorderwülbecke BJ, Kowski AB, Kirschbaum A, Merkle H, Senf P, Janz D, et al. Longterm outcome in adolescent-onset generalized genetic epilepsies. Epilepsia 2017;58: 1244–50. [5] Gesche J, Khanevski M, Solberg C. Resistance to valproic acid as predictor of treatment resistance in genetic generalized epilepsies. Epilepsia 2017;58:E64–9.

E. Fonseca et al. / Epilepsy & Behavior 102 (2020) 106657 [6] Miskin C, Khurana DS, Valencia I. Efficacy and tolerability of lacosamide in the treatment of children with refractory generalized epilepsy. J Child Neurol 2016;31: 925–8. [7] Abarrategui B, García-García ME, Toledano R, Parejo-Carbonell B, Gil-Nagel A, García-Morales I. Lacosamide for refractory generalized tonic–clonic seizures of non-focal origin in clinical practice: a clinical and VEEG study. Epilepsy Behav Case Rep 2017;24:63–5. [8] Wechsler RT, Yates SL, Messenheimer J, Leroy R, Beller C, Doty P. Lacosamide for uncontrolled primary generalized tonic–clonic seizures: an open-label pilot study with 59-week extension. Epilepsy Res 2017;130:13–20. [9] Ramirez-García T, Serrano-Castro PJ, Alonso-Morillejo E, Perea-Justicia P, IglesiasEspinosa M, Parrón-Carreño T. Cognitive profile of zonisamide and valproic acid in the treatment of idiopathic generalized epilepsy: a comparative observational study. Neurol Ther 2016;5:59–68. [10] Marinas A, Villanueva V, Giráldez BG, Molins A, Salas-Puig J, Serratosa JM. Efficacy and tolerability of zonisamide in idiopathic generalized epilepsy. Epileptic Disord 2009;11:61–6. [11] Joo EY, Kim SH, Seo DW, Hong SB. Zonisamide decreases cortical excitability in patients with idiopathic generalized epilepsy. Clin Neurophysiol 2008;119:1385–92. [12] Strzelczyk A, Klein KM, Willems LM, Rosenow F, Bauer S. Brivaracetam in the treatment of focal and idiopathic generalized epilepsies and of status epilepticus. Expert Rev Clin Pharmacol 2016;9:637–45. [13] Dupuis N, Matagne A, Staelens L, Dournaud P, Desnous B, Gressens P, et al. Antiictogenic and antiepileptogenic properties of brivaracetam in mature and immature rats. Epilepsia 2015;56:800–5. [14] Wood MD, Gillard M. Evidence for a differential interaction of brivaracetam and levetiracetam with the synaptic vesicle 2A protein. Epilepsia 2017;58:255–62. [15] Kwan P, Trinka W, Van Paesschen W, Rektor I, Johnson ME, Lu S. Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: results of a phase III, double-blind, randomized, placebo-controlled, flexible-dose trial. Epilepsia 2014;55:38–46.

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[16] Matagne A, Kenda B, Michel P, Klitgaard H. UCB 34714, a new pyrrolidone derivative, suppresses seizures epileptogenesis in animal models of chronic epilepsy in vivo. Epilepsia 2003;44(Suppl. 8):53–3, A072. [17] Kasteleijn-Nolst Trenite DG, Genton P, Parain D, Masnou P, Steinhoff BJ, Jacobs T, et al. Evaluation of brivaracetam, a novel SV2A ligand, in the photosensitivity model. Neurology 2007;69:1027–34. [18] Strzelczyk A, Kay L, Bauer S, Immisch I, Klein KM, Knake S, et al. Use of brivaracetam in genetic generalized epilepsies and for acute, intravenous treatment of absence status epilepticus. Epilepsia 2018;59:1549–56. [19] Steinig I, Von Podewils F, Möddel G. Postmarketing experience with brivaracetam in the treatment of epilepsies: a multicenter cohort study from Germany. Epilepsia 2017;58:1208–16. [20] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010;51:1069–77. [21] Noachtar S, Binnie C, Ebersole J. A glossary of terms most commonly used by clinical electroencephalographers and proposal for the report form for the EEG findings. Electroencephalogr Clin Neurophysyiol Suppl 1999;52:21–41. [22] Hirsch LJ, LaRoche N, Gaspard E, Gerard E, Svoronos A, Herman ST, et al. American Clinical Neurophysiology Society's standardized critical care EEG terminology: 2012 version. J Clin Neurophysiol 2013;30:1–27. [23] Hirsch M, Hintz M, Specht A, Schulze-Bonhage A. Tolerability, efficacy and retention rate of brivaracetam in patients previously treated with levetiracetam: a monocenter retrospective outcome analysis. Seizure 2018;61:98–103. [24] Villanueva V, López-González FJ, Mauri JA, Rodriguez-Uranga J, Olivé-Gadea M, Montoya J, et al. BRIVA-LIFE—a multicenter retrospective study of the long-term use of brivaracetam in clinical practice. Acta Neurol Scand 2019;134:360–8. [25] Zhu LN, Chen D, Chen T, Xu D, Chen SH, Liu L. The adverse event profile of brivaracetam: a meta-analysis of randomized controlled trials. Seizure 2017;45:7–16. [26] Ortega G, Abraira L, Martí G. Anger assessment in patients treated with brivaracetam. Clin Neuropharmacol 2018;41:6–9.