Pharmacotherapy for tonic-clonic seizures.

Review

Pharmacotherapy for tonic--clonic seizures

Expert Opin. Pharmacother. Downloaded from informahealthcare.com by National University of Singapore on 05/24/14 For personal use only.

Sylvain Rheims† & Philippe Ryvlin 1.

General considerations

Hospices Civils de Lyon and CRNL, INSERM U1028, CNRS 5292, Lyon, France

2.

Pharmacotherapy for pGTCS

3.

Pharmacotherapy for sGTCS

4.

Conclusion

5.

Expert opinion

Introduction: Occurrence of generalized tonic--clonic seizures (GTCS) is one of the most important risk factors of seizure-related complications and comorbidities in patients with epilepsy. Their prevention is therefore an important aspect of therapeutic management both in idiopathic generalized epilepsies and in focal epilepsies. Areas covered: It has been shown that the efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary GTCS (sGTCS) but aggravating primary GTCS (pGTCS). In patients with pGTCS, evidence-based data support the preferential use of valproic acid, lamotrigine, levetiracetam and topiramate. In patients with sGTCS, all AEDs approved in the treatment of focal epilepsies might be used. Expert opinion: Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. Although valproic acid might be the most efficacious drug in idiopathic generalized epilepsies, it should be avoided in women of childbearing age due to its safety profile. In patients with sGTCS, AEDs for which the impact on this seizure type has been formally evaluated and which have demonstrated greater efficacy than placebo might preferentially be used, such as lacosamide, perampanel and topiramate. Keywords: antiepileptic drugs, focal epilepsy, primary generalized epilepsy, tonic--clonic seizures Expert Opin. Pharmacother. [Early Online]

Patients with epilepsy are exposed to multiple seizure-related complications and comorbidities. A large number of contributing or precipitating factors have been individualized and should be taken into account in the therapeutic strategy [1]. Among them, occurrence of generalized tonic--clonic seizures (GTCS) is one of the most important. The large majority of seizure-related injuries occur during GTCS [2,3], which also represents an independent risk factor for psychiatric comorbidities [4,5]. Furthermore, presence and frequency of GTCS are the strongest risk factors of sudden unexpected death in epilepsy (SUDEP), with an odds ratio of > 15 for patients with three or more GTCS per month [6]. With no available effective treatment to prevent SUDEP [7], apart from optimizing antiepileptic drugs (AEDs) [8], prevention of GTCS might be an important parameter to consider for treatment choice in patients with refractory epilepsy. This study aims at reviewing the current evidences upon which therapeutic decisions should rely in patients with GTCS. 1.

General considerations

Although the term ‘GTCS’ refers to seizures with well-defined clinical features, including bilateral symmetric tonic contraction followed by bilateral clonic movements of somatic muscles [9], it encompasses different clinical situations, 10.1517/14656566.2014.915029 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted

1

S. Rheims & P. Ryvlin

2.

Pharmacotherapy for pGTCS

Article highlights. .

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Efficacy of antiepileptic drugs (AEDs) varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with secondary generalized tonic--clonic seizures (GTCS) but aggravating primary GTCS (pGTCS). Treatment of pGTCS primarily relies on valproic acid (VPA), lamotrigine, levetiracetam, topiramate and zonisamide. Carbamazepine, oxcarbazepine and phenytoin might precipitate or aggravate pGTCS. VPA might be the most efficacious drug in idiopathic generalized epilepsies but should be avoided in women of childbearing age due to its safety profile. In patients with secondary GTCS, all AEDs licensed in the treatment of partial seizures with or without secondary generalization might be used.

This box summarizes key points contained in the article.

including primary GTCS (pGTCS), as observed in idiopathic generalized epilepsies, or focal seizures evolving to secondary GTCS (sGTCS). It has been shown that the efficacy of AEDs varies across epilepsy syndromes, with some AEDs efficacious against focal seizures with sGTCS but aggravating pGTCS [10-12]. Thus, treatment algorithm in patients with pGTCS differs from those with sGTCS, with large-spectrum AEDs recommended for the former, while most large- and narrow-spectrum AEDs can be used in the latter. Over the last 20 years, the number of drugs licensed for the treatment of seizure disorders has increased exponentially [1,13]. In addition to the five standard AEDs developed before 1970 (phenobarbital, phenytoin [PHT], carbamazepine [CBZ], valproic acid [VPA] and ethosuximide), 15 secondgeneration AEDs are now available (eslicarbazepine acetate, felbamate, gabapentin [GBP], lacosamide, lamotrigine [LTG], levetiracetam [LEV], oxcarbazepine [OXC], perampanel, pregabalin, retigabine, rufinamide, tiagabine, topiramate [TPM], vigabatrin, zonisamide [ZNS]). However, their clinical development systematically followed a highly standardized process characterized by primary evaluation of antiepileptic efficacy as an add-on therapy in adult patients with drugresistant partial epilepsy with or without sGTCS [13,14]. In contrast, evaluation in other epilepsy syndromes, including idiopathic generalized epilepsies, has been conducted as a second development step in a small subset of AEDs [13,14]. The dataset available regarding efficacy of second-generation AEDs in pGTCS, as well as the number of licensed AEDs in this indication remains limited. Several factors contribute to make AEDs’ trials in pGTCS more difficult than in focal onset epilepsies [15]. Specifically, frequency of pGTCS is usually lower than that observed in patients with uncontrolled focal seizures, even in refractory patients, resulting in recruitment issues. For instance, it is not uncommon for patients with refractory juvenile myoclonic epilepsy to suffer frequent myoclonic seizures but only a few annual pGTCS. 2

Treatment of pGTCS primarily relies on five AEDs that have demonstrated efficacy either in monotherapy studies in new-onset pGTCS, in the add-on treatment in drug-resistant pGTCS or in both: VPA, LTG, TPM, ZNS and LEV [1,16]. Other AEDs are either not recommended or have not been evaluated in pGTCS yet. It should, however, be noted that these recommendations rely on a low level of evidence, especially for new-onset pGTCS [17]. In fact, none of the 30 randomized controlled trials (RCTs) and 9 meta-analyses individualized in a recent systematic review of initial monotherapy in adult patients with new-onset pGTCS provided class I or class II evidence [17]. These trials were classified as class III evidences either due to a too short duration of treatment, a forced-exit criterion, or due to an open-label design [17]. Furthermore, in many of these trials, patients with well-defined pGTCS only represented a limited subset of the evaluated population [17]. Indeed, enrolled patients mainly suffered from new onset focal epilepsy and the criteria used to distinguish sGTCS from pGTCS were often unclear. Thus, whether or not data obtained from these RCTs reflected the efficacy of evaluated AEDs in sGTCS rather than in pGTCS remains an open question. RCTs conducted in patients with clearcut pGTCS also suffer from methodological limitations. All of them evaluated AEDs as add-on therapy using doubleblind placebo-controlled design in refractory pGTCS. Such design usually provides class I evidence about efficacy of each AED. However, extrapolation of the results of these RCTs to indirectly compare several AEDs is hampered by several methodological issues [18]. Thus, in the absence of head-to-head trial, it remains difficult to assess the efficacy of AEDs in relation to each other. This issue is aggravated by the fact that none of the standard AEDs, including VPA, has been evaluated using similar methodology and can therefore be included in such indirect comparisons. Initial monotherapy in new-onset pGTCS Class III and class IV evidences support efficacy of VPA, LTG and TPM as initial monotherapy in new-onset pGTCS [16,17]. Among these studies, a specific attention should be paid to the standard and new antiepileptic drugs (SANAD) study [19]. Despite its open-label design, its multigroup comparisons with flexible dosage and a follow-up period of up to 6 years makes it a unique and valuable study. SANAD compared VPA, LTG and TPM in 716 patients with generalized-onset and unclassifiables seizures, including 329 patients suffering from idiopathic generalized epilepsy with GTCS. In these patients, VPA was superior to LTG and TPM in time-totreatment failure and to LTG but similar to TPM for time to 12-month remission. These results were in line with other studies reporting greater efficacy of VPA in comparison with 2.1

Expert Opin. Pharmacother. (2014) 15(10)


RR [95% CI]

p TE

Gabapentine

1.57 [0.74; 3.33]

0.24

Lamotrigine

1.85 [1.42; 2.42] < 0.001 270 2

Levetiracetam

1.58 [1.20; 2.07] < 0.001 164 1

Topiramate

2.89 [1.46; 5.71] < 0.001 80 1


7 89

1

2

3

n

k

117 1

4 5 6

Figure 1. Relative risk for responder rate among patients enrolled in placebo-controlled adjunctive therapy RCTs of antiepileptic drugs in refractory primary generalized tonic--clonic seizures. k: Total number of trials; n: Total number of patients; p TE: Value of the treatment effect test; RCTs: Randomized controlled trials; RR: Relative risk.

LTG in patients with idiopathic generalized epilepsy, and especially in patients with juvenile myoclonic epilepsy [20]. Importantly, CBZ, OXC and PHT are not considered the standard treatment of choice in pGTCS [1] and guidelines from the International League against Epilepsy [17], as well as those from the NICE in the UK [16] and from SIGN in Scotland [21], recommend using these drugs with caution in patients with pGTCS. Several studies reported that CBZ, OXC and PHT might precipitate or aggravate pGTCS and, more commonly, other generalized seizure types in patients with pGTCS, including myoclonic or absence seizures [10-12]. Importantly, similar observations have been reported with AEDs altering GABAergic transmission, such as tiagabine [22]. It should however be noted that CBZ, OXC and PHT could be efficacious in some patients with pGTCS. These three AEDs have been evaluated in several monotherapy trials which included patients with new-onset GTCS [17]. No significant difference between these drugs and LTG, VPA, TPM or PB was observed neither in term of time to first seizure nor in term of proportion of patients free from GTCS [17]. As a matter of fact, a meta-analysis of individual patient response to LTG or CBZ monotherapy did not show difference in the subgroups of patients with GTCS [23]. Similarly, in patients with GTCS, CBZ and PHT did not differ from VPA [24,25], or OXC from VPA [26], or PHT from TPM [27]. However, the methodological limitations of monotherapy RCTs in GTCS discussed above, and specifically the overrepresentation of patients with partial seizures with sGTCS, drastically limit the interpretability and the impact of these data. The potential impact of misclassification of seizure type have thus been investigated in two meta-analyses which compared VPA and CBZ monotherapy [24] and VPA and PHT monotherapy [25] and which did not find evidence of an interaction between treatment and seizure type. Although there are clinical evidence that individuals with generalized onset seizures are unlikely to be older than 25 -- 30 years at epilepsy onset [28], 49% of patients classified as having GTCS had an age of epilepsy onset over 30 years [25], suggesting that they might have been misclassified. Interestingly, reclassification of individuals with generalized seizures and age at onset

greater than 30 as having partial onset seizures resulted in detection of a significant interaction between treatment and seizure type, with VPA appearing more effective in patients with GTCS than in the original analyses [24,25]. Additional analyses also showed association between age of seizure onset and treatment allocation, suggesting that younger individuals may fare better on VPA, while older individuals fare better on PHT [25]. Pharmacotherapy in drug-resistant pGTCS Four AEDs, LTG, LEV, TPM and GBP, have been evaluated as add-on therapy in drug-resistant pGTCS providing class I evidence of efficacy for LTG, LEV and TPM and class I evidence of lack of efficacy for GBP in this population (Figure 1). In addition, class IV evidences suggest efficacy of ZNS in the same indication. RCTs evaluating lacosamide [29], pregabalin [30] and perampanel [31] in the add-on treatment in patients with drug-resistant pGTCS are ongoing. LTG has been studied in three placebo-controlled trials (Table 1) [32-34], including one which evaluated extendedrelease formulation of LTG (LTG-XR) [34]. In the first study [32], 26 patients with drug-resistant generalized epilepsy were included in a crossover RCT. The study consisted of 2- 8-week treatment periods followed by a 4-week washout period. Only 17 of the 26 included patients suffered from GTCS, the others having absence seizures only or myoclonic seizures only. All patients were taking VPA, with or without other AEDs; LTG was titrated up to 75 mg or 150 mg once-daily depending on concomitant AEDs. Overall, 50% of patients experienced a ‡ 50% reduction in tonic--clonic seizures with LTG compared with placebo (p = 0.03). Seizure-free rate was not provided. The second study was a parallel-groups trial, which included 121 patients with pGTCS with or without other types of generalized seizures [33]. It comprised an 8 weeks baseline, an escalation phase of 7 weeks duration during which study medication was titrated, and a 12-week maintenance phase during which doses of LTG or placebo and concomitant AEDs were maintained. The LTG target daily dose was 200 mg/day in patients taking VPA, 400 mg/day in those taking an enzyme-inducing AED 2.2


3


Table 1. Characteristics of RCTs evaluating antiepileptic drug in the add-on therapy in refractory primary generalized tonic--clonic seizures. Gabapentine


Chadwick et al. 1996 [39]

Number of patients Mean age of patients (years) Mean duration of epilepsy (years) Baseline monthly seizure frequency (median) Median percent reduction from baseline in 28-day seizure frequency Responder rate (%) Seizure-free rate (%)

Lamotrigine Biton et al. 2005 [33]

Biton et al. 2010 [34]

Levetiracetam

Topiramate

Berkovic et al. 2007 [35]

Biton et al. 2005 [33]

GBP

Placebo

LTG

Placebo

LTG-XR

Placebo

LEV

Placebo

TPM

Placebo

58 30 22 3.9

71 29 20 3.3

58 NA NA 2.3

59 NA NA 3

76 29.4 13.9 3

77 28.4 14.6 2.5

80 26.9 16.3 2.5

84 30.6 18 2.5

39 26.8 NA 5

41 25.6 NA 4.5

29.3

15.2

66.5

34.2

75.4

32.1

77.6

44.6

56.7

9

27.5 NA

17.5 NA

64 21

39 17

69.6 20

31.9 9.7

72.2 24.1

45.2 7.1

56 13

20 5

GBP: Gabapentin; LEV: Levetiracetam; LTG: Lamotrigine; LTG-XR: Extended-release formulation of lamotrigine; NA: Not available; RCT: Randomized controlled trial; TPM: Topiramate.

and 300 mg/day in those taking an AED other than VPA or an enzyme-inducing AED. The mean age ± standard deviation (SD) of patients was 26.9±14.6 years in the LTG group and 24.9±13.8 years in the placebo group, with about 20% of patients under 12 years. The median number of pGTCS per month during the baseline period was 2.6. Sixty-four per cent of patients allocated to LTG demonstrated ‡ 50% reduction of pGTCS during the double-blind period, in comparison to 39% of those assigned to placebo (p < 0.05). The proportion of seizure-free patients did not differ between LTG and placebo groups (38% and 24%, respectively). Efficacy did not appear to differ by age group (2 to 12 years [n = 12 LTG and n = 11 placebo], 12 years [n = 46 LTG and n = 48 placebo]), although sample sizes were too small to allow definitive conclusions. No patient in the LTG group prematurely withdrew from the study because of increased seizure frequency, including myoclonic seizures. Using the same design than the previous study, a RCT evaluating LTG-XR showed very similar results [34]. A total of 153 patients with pGTCS were randomized to receive either LTG-XR (n = 76) or placebo (n = 77). In the study, 93% of patients were ‡ 16 years old. LTG-XR was titrated over a period of 7 weeks up to 200 mg/day once daily in patients taking VPA, up to 500 mg/day once daily in those taking an enzyme-inducing AED and up to 400 mg/day once daily in patients taking an AED other than VPA and enzymeinducing AED. The median number of pGTCS per month during the baseline period was three. Over the whole treatment period (escalation + maintenance phase), 69.6% of patients receiving LTG and 31.9 of those taking placebo showed ‡ 50% reduction in pGTCS frequency (p < 0.001). The percentage of patients with 100% reduction in pGTCS seizure frequency was 45.6% for LTG-XR compared with 14.3% for placebo (p < 0.0001). When LTG and LTG-XR data obtained from RCTs with similar design were pooled 4

together, the relative risk of the responder rate over the double-blind period was 1.85 (95% CI: 1.42; 2.42). Two placebo-controlled study evaluated efficacy of LEV in the add-on therapy in refractory generalized epilepsies [35,36]. One of them focused on pGTCS [35], whereas the other concentrated on myoclonic seizures and did not provide specific efficacy data for pGTCS [36]. The former was a multi-centre placebo-controlled parallel-group study [35]. After an 8-week baseline period, comprising a 4-week historical baseline period and a 4-week, prospective, single-blind, placebo baseline period, patients entered a double-blind treatment period which consisted of a 4-week up-titration period, followed by a 20-week evaluation period. To qualify for randomization, patients had to have experienced ‡ 3 GTCS during the 8-week combined baseline period. The target LEV dose was 3000 mg/day but patients who could not tolerate the target LEV dose could fall back to a dose of 2000 mg/day. A total of 164 patients were randomized, including 80 to LEV and 84 to placebo. Mean age ± SD at epilepsy onset was 11.6 ± 6.2 years and mean ± SD epilepsy duration was 17.2 ± 12.3. Only 16 of the 164 patients were under 16 years of age. Juvenile myoclonic epilepsy and GTCS on awakening were the most frequently identified syndromes (32.9% and 29.9% of patients, respectively). The median weekly seizure frequency for GTCS during the combined baseline period was 0.62. During the whole-treatment period, the median percentage reduction from baseline in GTCS frequency per week 77.6% in patients assigned to LEV and 44.6% in those receiving placebo (p < 0.001). The 50% responder rate was 72.2% in the LEV group and 45.2% in the placebo group (p < 0.001). In addition, 24.1% of patients receiving LEV and 7.1% of those receiving placebo were free of GTCS during the entire treatment period (p = 0.004). Increase in GTCS frequency ‡ 25% was observed in 10.1% of patients randomized to LEV and in 15.5% of those randomized to placebo.




TPM efficacy in refractory pGTCS has been evaluated in two identical RCTs conducted in the US and in Europe [37,38], the results of which were published for the US study only [37]. In the latter, eighty patients who experienced three or more pGTCS during an 8-week baseline phase were randomly assigned to treatment with either TPM (n = 39) or placebo (n = 41). The median number of pGTCS per month during the baseline period was 4.5 in the TPM group and 5.0 in the placebo group. The median percentage reduction from baseline in the average monthly pGTCS rate during the double-blind phase was significantly greater in the TPM group (56.7%) than in placebo-treated patients (9.0%) (p = 0.019). Similarly, the proportion of responders significantly differed between the two groups, with 56% of patients receiving TPM showing ‡ 50% reduction in pGTCS frequency in comparison to 20% of those assigned to placebo (p = 0.001). Moreover, a greater percentage of TPM-treated (13%; 5/39) than placebo-treated (5%; 2/41) patients were free of pGTCS during the treatment period, although this difference did not achieve statistical significance (p = 0.225). GBP has been evaluated in a single placebo-controlled trial in patients with refractory pGTCS and did not prove superiority over placebo in this population [39]. After a 12-week baseline period, 129 adult patients entered a 14-week efficacy assessment phase, which comprised a 2-week titration period where GBP daily dose was increased up to 1200 mg/day and a 12-week maintenance phase. Seventy-one patients were allocated to placebo and 58 to GBP. The baseline pGTCS frequency per 28 days was 3.3 in patients receiving placebo and 3.9 in those receiving GBP. The responder rate was 27.5% in the GBP group and 17.5% in the placebo group (p = 0.317). Similarly, the percent change in seizure frequency from baseline to treatment period did not significantly differ between placebo and GBP, with 15.2% and 28.3% reduction, respectively (p = 0.169). Although ZNS has mainly been evaluated in new-onset or drug-resistant partial epilepsies through well-designed RCTs, which resulted in its approval in these indications in the US and/or in Europe, several uncontrolled observations, including small case series and retrospective reports, have also suggested its efficacy in patients with pGTCS [15]. Extensive clinical experience has thus been reported from Japan, where ZNS is licensed for a broad range of seizures, including pGTCS [40]. In Japanese pre-registration studies, the 50% responder rate in patients with idiopathic generalized epilepsy was 66% [40]. A post-marketing surveillance prospective study reported similar figures, with 83 of the 122 patients with pGTCS achieving 50% or greater decrease in seizure frequency after a follow-up of 1 -- 3 years [41]. Some retrospective US or European studies also reported efficacy data resulting from off-label use of ZNS in refractory pGTCS. In such a series, where 56 patients with drug-resistant pGTCS received ZNS up to 300 -- 500 mg/day, 20 of them (36%) were seizure-free for > 6 months and 15 additional patients (37%) achieved ‡ 50% seizure reduction for 6 months [42].

Other studies with smaller sample size reported similar data [15,43]. 3.

Pharmacotherapy for sGTCS

All AEDs approved in the US and/or in Europe in the treatment of focal epilepsies, either as initial monotherapy or as add-on therapy in refractory patients, are considered to be effective to prevent sGTCS. All of them have indeed been evaluated in patients with focal-onset seizures with or without sGTCS, and AEDs’ efficacy profile is considered to be equivalent on simple/complex partial seizures and on sGTCS. It should, however, be noted that data specifically informing on efficacy of AEDs to prevent sGTCS are usually much more scarce than those about complex partial seizures. According to the recommendations of regulatory authorities in terms of trial design and outcomes, Phase III add-on RCTs are designed to evaluate efficacy and safety of new AEDs within a representative sample of patients with drugresistant focal epilepsy [14]. No specific emphasis has, therefore, been put on sGTCS in add-on RCTs inclusion criteria, and the primary efficacy outcome is chosen in these RCTs to appropriately evaluate the impact of the tested AED on focal seizures with or without sGTCS. In this context, a very large number of Phase III pivotal trials of second-generation AEDs in the add-on therapy in drug-resistant partial epilepsy did not provide any specific data regarding sGTCS. For instance, sGTCS efficacy outcomes were reported in none of the RCTs, which have evaluated LTG [44] or retigabine [45-47], and in only one of the three pivotal RCTs of lacosamide [48-50] and eslicarbazepine acetate (Table 2) [51-54]. Furthermore, the proportion of patients with partial seizures and sGTCS included in these studies remained limited. For instance, in Phase III pivotal trials of LEV [55,56], pregabalin [57-59] or perampanel [60-62], the average proportion of patients who demonstrated at least one sGTCS during the baseline period was 34% (range from 23 to 41%) (Table 2). Interpretation of efficacy data of sGTCS is also rendered difficult by other methodological issues. The treatment effect size is usually small because of the monthly sGTCS rate, which is highly variable and often low in included patients (Table 2). In addition, in the subgroups of patients with high sGTCS frequency, the regression to the mean effect might be higher than for partial seizures. Indeed, according to the impact of sGTCS on quality of life, patients might be more prone to be included in Phase III RCTs when they experience aggravation of sGTCS frequency. In addition, tapering of an ongoing AED might sometimes be required before inclusion within the trial, a modification which might result in transient occurrence and/or increased rate of sGTCS. In this context, assessing whether or not some AEDs might be more efficacious than other on sGCTS appears difficult. In the absence of randomized head-to-head comparison of the available treatments in the add-on therapy of drug-resistant partial seizures with or without secondary generalization, meta-


5

6

No informative RCT Sperlling et al. 2010 [75] Sperlling et al. 2010 [75] Halford et al. 2011 [76] No informative RCT Elger et al. 2009 [53] No informative RCT Chung et al. 2010 [49] no informative RCT Shorvon et al. 2000 [56] Cereghino et al. 2000 [55] Barcs et al. 2000 [77] French et al. 2012 [60] French et al. 2013 [61] Krauss et al. 2012 [62] Lee et al. 2009 [59] No informative RCT Brodie et al. 2009 [78] Biton et al. 2011 [79] Kalviainen et al. 1998 [80] Uthman et al. 1998 [81] Privitera et al. 1996 [82] Korean study group 1999 [83] Sharief et al. 1996 [84] Faught et al. 1996 [85] Ben-Menachem et al. 1996 [86] Guberman et al. 2002 [87] French et al. 1996 [88] Schmidt et al. 1993 [89]

Brivaracetam Carisbamate


NA 187; 192 188; 185 180; 182 NA 100; 98; 102 NA 204; 97 NA 106; 106 98; 101 169; 178; 174 133; 134 129; 121 180; 172; 169 119 NA 156 176 77 61; 88; 57 48; 48; 47 91 23 45.45; 46 28 171 93 73

AED NA 186 189 185 NA 102 NA 104 NA 112 95 173 121 136 185 59 NA 157 181 77 91 47 86 24 45 28 92 90 71

Placebo

Number of randomized patients

NA 78; 95; 56; NA NA NA 84; NA 28; NA 49; 51; 44; 68; 45 NA 47 76 38 NA 12; NA 14 14; 11 55 31 8 15; 13

17; 11

68; 60 52 43 71; 62

21

47

80 81 64

AED NA 75 84 70 NA NA NA 45 NA 24 NA 51 56 48 69 25 NA 54 65 35 NA 17 NA 8 14 13 36 29 7

Placebo

Number of patients with sGTCs during baseline

Baseline characteristics

NA NA NA NA NA 3.2; NA 3.3; NA NA NA 3.5; 3.4; 3.4; 3.4; NA NA 1 NA 1.4 1.6; NA NA NA NA NA 0 NA NA

AED

1.8; 1.5

2; 2.4 4.1 3.8 3.7; 2.7

5

2.5; 1.5

NA NA NA NA NA 2.5 NA 4 NA NA NA 3.5 4.1 3.5 3.4 NA NA 1.6 NA 0.7 2 NA NA NA NA NA 0 NA NA

Placebo

Baseline monthly sGTCs frequency (median)

NA NA NA NA NA NA NA 56; NA NA NA NA 67; 50; 44; 62 NA NA NA 32 NA 67; NA 71 71; 82 49 48 25 87.77

47; 54

60 47 49; 63

70

AED NA NA NA NA NA NA NA 33 NA NA NA NA 38 25 45 80 NA NA NA 26 NA 35 NA 38 21 23 33 52 57

Placebo

Responder rate (%)

AED: Antiepileptic drug; NA: Not available; RCT: Randomized controlled trial; sGTCS: Secondary generalized tonic--clonic seizures; pGTCS: Primary generalized tonic--clonic seizures.

Vigabatrin Zonisamide

Topiramate

Tiagabine

Pregabalin Retigabine Rufinamide

Oxcarbazepine Perampanel

Divalproex sodium Eslicarbazepine Gabapentin Lacosamide Lamotrigine Levetiracetam

RCT

AED

Table 2. Evaluation of sGTCS in RCTs evaluating AEDs in the add-on therapy in patients with refractory partial epilepsy.


NA -28; -56 -36; -29 -18; NA NA -16; -64; -20 NA NA NA -37; -28 -85; -65 -71; -86; -94 -56; -40 -34; -35 -2; -30; -38 -70 NA -38 -40 -21.8 -43; -44; -47 -66; -44; -78 -100 -84 -62; -100; -89 -90 -50 NA -23

AED

NA -11 -28 -11 NA -28 NA NA NA -17 -24 -13 -16 -14 -7 -68 NA -38 -25 0 -60 -40 -40 -9 -1 -19 -1 NA -61

Placebo

Median percent reduction from baseline in 28-day seizure frequency




analyses of RCTs provide the best possible tool to inform clinical decisions regarding treatment choices. Over the last 15 years, several meta-analyses have provided indirect comparisons of the efficacy of second-generation AEDs in this indication but failed to demonstrate consistent differences [18,63-66]. However, the latter have assessed the impact of treatment on partial seizures with or without sGCTS, without specifically investigating the impact of AEDs on sGTCS. This issue remains, therefore, to be specifically addressed. 4.

Conclusion

Because of the complications related to GTCS, including increased risk of SUDEP, their prevention is an important aspect of therapeutic management both in idiopathic generalized epilepsies and in partial epilepsies. In patients with pGTCS, evidence-based data support the preferential use of VPA, LTG, LEV and TPM. In contrast, GBP proved to be inefficacious and CBZ and PHT might aggravate seizures in some patients. In patients with sGTCS, all AEDs licensed in the treatment of partial seizures with or without secondary generalization might be used. Both in pGTCS and sGTCS, additional data are required, specifically to inform about the relative efficacy of AEDs in relation to each other. 5.

Expert opinion

Therapeutic management of patients with GTCS primarily relies on the efficacy data discussed above. However, some additional aspects should be taken into account to refine clinical decisions in these patients, especially in order to stratify treatment choices according to patients’ individual characteristics, including patients’ age, gender and comorbidities. Primary GTCS The armamentum of AEDs available to prevent pGTCS is limited, mainly relying on fives AEDs, VPA, LTG, LEV, TPM and ZNS, both because of the limited number of AEDs, which have been evaluated in this indication, and because of the risk of epilepsy aggravation with several other AEDs. Specifically, with the exception of LTG, sodium-channels blockers should be avoided in patients with idiopathic generalized epilepsy, including those with pGTCS [1,16,17,21]. However, LTG should be used with caution in patients with idiopathic generalized epilepsy in whom pGTCS are associated with other types of seizures, because myoclonic seizures might be aggravated by LTG [20] and LTG efficacy on absence seizures is limited [67]. Although a RCT evaluating pregabalin in pGTCS is ongoing, the negative GBP trials both in pGTCS [39] and in absence of seizures [68] might suggest that AED acting on the a2-subunit of calcium channels might be inefficacious in idiopathic generalized epilepsy. Although the level of evidence about the relative efficacy of these five AEDs in relation to each other remains low, VPA 5.1

might be the most efficacious drug in idiopathic generalized epilepsies. Despite its methodological limitations, the SANAD study thus supports the view that the efficacy profile of VPA is superior to that of LTG or TPM [19]. By extrapolation, it might be speculated that the situation might be similar between VPA and LEV. Interestingly, a second SANAD study is ongoing [69]. Using the same pragmatic design that SANAD-I, SANAD-II will compare LTG and VPA with LEV in primary generalized seizures and might therefore bring important information. Unfortunately, ZNS has not been included in this new study [69]. In absence of other ongoing study evaluating ZNS in pGTCS, the level of evidence of its efficacy in this indication will probably remain low. However, both the Japanese studies and the experience of off-label use reported by several authors might suggest that ZNS should be considered as an interesting option in pGTCS. Importantly, therapeutic management of patients with epilepsy does not only rely on the efficacy profile of AEDs [1]. Other key points, including the safety profiles of AEDs, should indeed modulate therapeutic decision and AEDs’ choices. Thus, according to the higher rates of major congenital malformations with use of VPA during pregnancy compared with other AEDs [70], and specifically LTG, as well as the risk of cognitive impairment after fetal exposure to VPA [71], LTG should be preferred to VPA in women of childbearing age [1]. Taking into account the potential negative impact of VPA on cognitive performances [67], a similar evaluation of the benefit-risk ratio favoring LTG over VPA might be made in children or adolescents with pGTCS. According to recent reassuring data concerning the relative low risk of complications of prenatal exposure to LEV [72], this latter might be preferred to VPA after LTG failure. In contrast, comparison of the benefit-risk ratios of VPA, TPM and ZNS remains an open question, especially in women of childbearing age. Secondary GTCS As discussed above, no evidence-based data supports differences between AEDs to prevent sGTCS. However, this conclusion might predominantly reflect the limitations of the current RCTs design for evaluating AEDs efficacy on sGTCS, reinforcing the need to develop alternative designs for the evaluation of new therapeutic interventions in epilepsy [73], especially in at-risk patients of seizure-related complications and/or comorbidities [74]. Despite the paucity of data, it might, however, be discussed to prefer the use of the AEDs for which the impact on sGTCS has been formally evaluated and which have demonstrated greater efficacy than placebo. As shown in Table 2, perampanel, lacosamide or TPM might fulfill these criteria. 5.2

Declaration of interest S Rheims has received speaker fees from UCB pharma, consultant fees from EISAI and funding for attending


7


scientific congress from GlaxoSmithKline and Cyberonics. P Ryvlin has received speaker or consultant fees from Pfizer, Sanofi-Aventis, GlaxoSmithKline, Jansen-Cilag, UCB pharma, EISAI and Valeant. The authors have no other Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.


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Affiliation

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Sylvain Rheims† MD PhD & Philippe Ryvlin † Author for correspondence Hospices Civils de Lyon and CRNL, INSERM U1028, CNRS 5292, Unite´ 301, Hoˆpital Neurologique, 59 Bd Pinel, 69003, Lyon, France E-mail: [email protected]

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