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Rufinamide for refractory focal seizures: An open-label, multicenter European study Giangennaro Coppola a,*, Nelia Zamponi b, Gerhard Kluger c, Arndt Mueller c, Anna Rita Mazzottad, Pasquale Parisi d, Claudia Isone a, Elena Santoro a, Paolo Curatolo e, Alberto Verrotti f a
Child and Adolescent Neuropsychiatry, Medical School, University of Salerno, Italy Pediatric Neurology Department, Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy Neuropediatric Clinic and Clinic for Neurorehabilitation, Epilepsy Center for Children and Adolescents, Scho¨n Klinik Vogtareuth, Germany d NESMOS Department, Chair of Pediatrics, Child Neurology, Faculty of Medicine and Psychology, Sapienza University, Italy e Child and Adolescent Neuropsychiatry, Tor Vergata University, Rome, Italy f Department of Pediatrics, University of Chieti, Italy b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 10 June 2012 Received in revised form 18 September 2012 Accepted 22 September 2012
Purpose: The present study aimed to assess the efficacy and tolerability of rufinamide as adjunctive drug for the treatment of a large series of children, adolescents and adults with refractory cryptogenic or symptomatic focal epilepsy. Methods: Patients were recruited in a prospective, add-on, open-label treatment study from six Italian and one German centers for pediatric and adolescent epilepsy care. Inclusion criteria were: (1) age 3 years or more; (2) diagnosis of cryptogenic or symptomatic focal epilepsy refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (3) more than one seizure per month in the last 6 months; (4) use of at least one other AED, but no more than three, at baseline; (5) informed consent from parents and/or caregivers. Results: Sixty-eight patients (40 males, 28 females), aged between 3 and 63 years (mean 19.9 years, median 16.0) SD 12.58, with cryptogenic (28 pts, 41.2%) or symptomatic focal epilepsy (40 pts, 58.8%), were recruited in the study. After a mean follow-up period of 10.4 10.29 months, twenty-two patients (32.3%) had a 50–99% seizure reduction, and none became seizure-free. Twelve patients (17.6%) had a 25– 49% seizure decrease, while in 30 (44.1%) seizure frequency was unchanged. A seizure worsening was reported in 5 patients (7.3%). A better response to rufinamide occurred in frontal lobe seizures (51.6%) and secondary generalized tonic–clonic seizures (50%). Conclusion: Rufinamide was effective against focal-onset seizures, particularly in the treatment of secondary generalized frontal lobe seizures. ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Keywords: Rufinamide Refractory focal seizures Cryptogenic Symptomatic Adjunctive
1. Introduction Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. It was profiled for anticonvulsant activity at the National Institutes of Health and was found to have broad-spectrum anticonvulsant properties at nontoxic doses in animal models.1 In 2005, Eisai filed a new drug application with the U.S. Food and Drug Administration, seeking approval for 2 epilepsy indications: (1) adjunctive treatment of partial-onset seizures
* Corresponding author at: Child and Adolescent Neuropsychiatry, Medical School, University of Salerno, S. Giovanni di Dio e Ruggi d’Aragona Hospital, Largo d’Ippocrate, 84100 Salerno, Italy. Tel.: +39 089 672507; fax: +39 089 672507; mobile: +39 3382747593. E-mail address:
[email protected] (G. Coppola).
with and without secondary generalization in adults and adolescents 12 years of age and older, and (2) adjunctive treatment of seizures associated with Lennox–Gastaut syndrome in children 4 years and older and adults. Rufinamide seems so far to play a preferential role for the treatment of generalized epileptic seizures and syndromes such as Lennox–Gastaut syndrome2–4 for which it was granted orphan drug status in 2004, and epileptic encephalopathies other than LGS such as West syndrome and refractory myoclonic astatic epilepsy (Doose syndrome).5,6 Preliminary data reported poor results in patients with Dravet syndrome and malignant migrating partial epilepsy in infancy.7,8 Rufinamide has been approved for adjunctive treatment of partial seizures in adults and adolescents, though an efficacy between 11.0% and 20.4% resulted in these patients.9–12 A metanalysis of rufinamide for the treatment of partial seizures in pediatric population regards no more than 60 cases, pooled out from a few series.5,13–15
1059-1311/$ – see front matter ß 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.seizure.2012.09.015
Please cite this article in press as: Coppola G, et al. Rufinamide for refractory focal seizures: An open-label, multicenter European study. Seizure: Eur J Epilepsy (2012), http://dx.doi.org/10.1016/j.seizure.2012.09.015
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Overall, the responder rate was of 23%13 and an extension follow-up study of the same series reported the worst outcome in patients with partial seizures (11.8%) after 18 months.14 In contrast, a retrospective study of 77 patients with various refractory epilepsy syndromes (48 of them receiving rufinamide as adjunctive therapy), reported the highest responder rate in cryptogenic focal epilepsies (83.3%), and an overlapping responder rate in tonic–atonic and partial seizures (48.6% vs. 46.7%, respectively). Unfortunately, the subgroup of patients with cryptogenic focal seizure was very small (12 cases) in this study.15 Respect to the origin of focal seizures, those from the frontal lobe, were particularly sensitive to rufinamide treatment, even in patients with multifocal epileptic encephalopathy.5 This study reports results from an open-label study of a large series of children, adolescents and adults with refractory cryptogenic or symptomatic focal epilepsy treated with rufinamide as adjunctive drug. 2. Methods Patients were recruited in a prospective, open-label, add-on treatment study from six Italian and 1 German centers for pediatric and adolescent epilepsy care. The patients were selected according to the following criteria: (1) age 3 years or more; (2) diagnosis of cryptogenic or symptomatic focal epilepsy refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (3) more than one seizure per month in the previous 6 months; (4) therapy with one other AED, but no more than three, at baseline; (5) informed consent from parents and/or caregivers, who had to be able to administer the study drug and record seizures in a diary. Moreover, female patients of child bearing age were required not to be pregnant and to be using an adequate form of contraception. Exclusion criteria included: (1) progressive neurological or systemic disease; (2) significantly abnormal liver, kidney and blood laboratory values; (3) poor compliance from parents/ caregivers. The Institutional Review Board from each epilepsy unit approved the study; no support was received from pharmaceutical companies. Pseudo-seizures were excluded by means of video-EEG recordings and/or long-term monitoring EEGs. CT and MRI were performed in all cases. Seizure number was recorded by parents and/or caregivers at home and at school. Seizure frequency, type and duration were recorded in an epilepsy diary reviewed at each follow-up visit. All seizures were classified according to the International League against Epilepsy Revised Classification of Seizures,16 while diagnostic criteria for focal epilepsy were based on the International League Against Epilepsy classification17 as follows: localization-related epilepsies and syndromes are epileptic disorders in which seizure semiology or findings at investigation disclose a localized origin of the seizures. There was an initial observation period of 6 months (baseline) that could be shortened to 3 months if seizures occurred almost daily. Before the beginning of rufinamide adjunctive therapy, each patient underwent the following blood tests: white, red and platelet cell count, transaminases, gGT, urea, serum glucose, protrombin and thromboplastin time, fibrinogen, total cholesterol, tryglicerides, thyroid hormones, urinalysis, AED blood level. Wake and sleep EEG recordings and EKG were performed in all patients. After the observation period, rufinamide was added to the baseline therapy at the starting dose of 10 mg/kg body weight, evenly divided in two daily doses and then titrated by 10 mg/kg per day approximately every 3 days up to a maximum of 1000 mg/day in children aged 3 years with a body weight less than 30 kg. If baseline therapy included valproic acid, rufinamide could be titrated up to a maximum of 600 mg/day, because of the
significantly reduced clearance of rufinamide in combination with valproic acid, especially in children. In patients more than 30 kg body weight, rufinamide could be titrated up to 1800 mg/day if bodyweight was comprised between 30.0 and 50.0 kg, up to 2400 mg/day for body weight of 50.1–70.0 kg, and up to 3200 mg for body weight of more than 70.1 kg, regardless of the current therapy. During titration and maintenance periods, anticonvulsant drug daily doses including rufinamide could be changed whenever necessary depending on clinical and adverse side effects. Rescue drugs were allowed if necessary. EEG, adverse effects and blood levels of concomitant anticonvulsant drugs were monitored in all patients. Patients were followed on a weekly basis during the titration period, either by means of visits to the clinic or by telephone. Patients subsequently visited the clinic at 3-month intervals during the maintenance treatment, with a monthly follow-up by telephone between visits to the clinic whenever necessary. At each time interval, the following laboratory examinations were performed on all patients: complete peripheral blood counts, urinary analysis and measurement of blood creatinine, alanine and aspartate aminotransferase levels, erythrocyte and leukocyte count, amylase and blood urea nitrogen, total cholesterol, tryglicerides, thyroid hormones, together with AED serum level. Parents/caregivers were informed of the potential clinical adverse effects and were asked to notify the physician of these. Efficacy was assessed by comparing the frequency of countable seizures at baseline (4 weeks before rufinamide therapy) with the frequency in the last 4 weeks of observation. Response to treatment was evaluated by counting seizure frequency, in relation to the baseline phase, using the following categories: (1) seizure control (100% seizure remission); (2) 50– 99% decrease in number of seizures; (3) 25–49% decrease in number of seizures; and (4) worsened when the seizure rate and/or severity increased by 25% as compared to baseline period. Statistical evaluation was performed by means of chi-square exact test and the Fisher’ exact test. Data were expressed as mean SD and median values. Significance was set at p < 0.05. 3. Results The final sample included sixty-eight patients (40 males, 28 females), aged between 3 and 63 years (mean 19.9 years, median 16.0) SD 12.58, with cryptogenic (28 pts, 41.2%) or symptomatic focal epilepsy (40 pts, 58.8%). Characteristics of the patients, including age at therapy onset, psychomotor development/mental level, neurological examination and CT/MRI findings are summarized in Table 1. Duration of epilepsy ranged between 2 and 50 years (mean 15.6 10.8, median 12.5). The baseline seizure frequency was: 1/month (2), 1–5/week (6), 1–10/day (42), and >10/day in 18 patients. The follow-up period lasted from 6 to 52 months (mean 10.4 10.29, median 8.0). In order to understand a potential relationship between rufinamide efficacy and the site of seizureonset, seizures were distinguished as follows: frontal in 30 (44.1%), temporal in 26 (38.2%), occipital in 7 (10.3%), and parietal in 7 (7.3%). Patients showed the following seizure types, often combined in a given patient: elementary/complex focal seizures (34), secondary generalized tonic–clonic seizures (54). Rufinamide’ mean maintenance dose per kg was 27.8 10.6, median 27.6 (range 5.7–60 mg). The results are summarized in Table 2. Twenty-one patients (30.9%) had a 50–99% seizure reduction, and none became seizurefree. In other 12 cases (17.6%), a 25–49% decrease in seizure frequency was reported, while in 30 (44.1%) seizure frequency was unchanged. Seizure worsening was reported in 5 patients (7.3%): seizures started from the temporal lobe in all cases and rufinamide
Please cite this article in press as: Coppola G, et al. Rufinamide for refractory focal seizures: An open-label, multicenter European study. Seizure: Eur J Epilepsy (2012), http://dx.doi.org/10.1016/j.seizure.2012.09.015
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YSEIZ-2025; No. of Pages 4 G. Coppola et al. / Seizure xxx (2012) xxx–xxx Table 1 Characteristics of patients (n = 68).
Table 3 Relationship between outcome and site of seizure onset.
Sex, male/female Age, mean SD (range) Psychomotor development/mental retardation Mild delay Moderate delay Severe/profound Normal Cerebral palsy Tetraparesis/spastic dyplegia Spastic diplegia Hemiparesis Hypotonia Ataxia Normal CT/MRI findings Localized brain atrophy Neuronal migration disorder Hemimegalencephaly Tuberous sclerosis Aicardi syndrome Rasmussen syndrome Normal
40/28 19.9 12.58 (3–63 years)
9 3 3 1 52 27 7 1 3 1 1 28
Table 2 Response to treatment related to epilepsy type.
*
Cryptogenic no. of pts (28)
Symptomatic no. of pts (40)
– 8 8 10 2
– 13 4 20 3
(28.6%)* (28.6%) (35.7%) (7.1%)
p = 0 .79 at Fisher exact test.
Seizure control 50–99%
14 15 21 18
was discontinued within 4 weeks. The first of two cryptogenic patients had secondary generalized tonic–clonic seizures (SGTCS), never experienced before, while the second had a seizure increase together with headache and feeling of fear. Of other three symptomatic cases, one developed an early increase in seizure frequency, and another one, with left polar and insular focal cortical dysplasia and previous tonic seizures, manifested atypical absences and gelastic seizures. A third male aged 12 years and half, with an ischemic temporal lesion, showed an initial seizure decrease with disappearance of an EEG bitemporal status, followed by a seizure worsening in the next few weeks. Better response to rufinamide of frontal lobe seizures (51.6%) and SGTCS (50%) (p = 0.003 at Chi-square test) was observed (see Table 3). No significant correlation was found between rufinamide efficacy and seizure frequency during baseline period, epilepsy duration, age less or more than 18 years, type of etiology (cryptogenic vs. symptomatic and hypoxic-ischemic and/or hemorragic vs. malformative), degree of psychomotor delay/ mental retardation, abnormal neurological examination and rufinamide daily dose. Furthermore, a better response (50–99% seizure reduction) was achieved when rufinamide was added to one AED (62.5%) than to two or three AEDs (19.2% and 32.3%, respectively), and when baseline therapy included valproic acid combined with non-enzymatic inducing AEDs. Twenty-two patients (32.3%) reported adverse side effects (Table 4). Vomiting was the most common side effect; it appeared early during the titration phase in three of them and was controlled by decreasing rufinamide daily dosage. In another patient, vomiting appeared at the daily dose of 2400 mg (32 mg/kg), leading to drug discontinuation. Overall, adverse side effects were mild and transient, disappearing within the first treatment weeks. Blood levels of concomitant AEDs were generally not modified by adding rufinamide. All patients had normal laboratory test values during the treatment period.
Seizure control 100% 50–99% 25–49% Unchanged Increased
3
(32.5%)* (10%) (50%) (7.5%)
Brain area Frontal* 16 Others 7 23 Total Seizure type SGTCS8 33 E/CPS 10 Total 43
25–49%
Unchanged
Increased
Total
(51.6%) (17.9%) (32.9%)
7 (22.6%) 5 (12.8%) 12 (17.14%)
7 (22.6%) 23 (58.9%) 30 (42.8%)
1 (3.23%) 4 (10.3% 5 (7.1%)
31 (100%) 39 (100%) 70 (100%)
(61.1%) (29.4%) (48.9%)
5 (9.3%) 7 (20.6%) 12 (13.6%)
16 (29.6%) 15 (44.1%) 31 (35.2%)
– 2 (5.9%) 2 (2.3%)
54 (100%) 34 (100%) 88 (100%)
E/CPS, elementary/complex partial seizures; SGTCS, secondary generalized tonic– clonic seizures. * Exact chi square: p = 0.003. 8 Exact chi square: p = 0.005. Table 4 Adverse effects occurring on rufinamide add-on therapy. Adverse effects Vomiting Decreased appetite Headache Weight loss Drowsiness Mild ataxia Dizziness Irritability Anxiety and agitation Dyplopia Faticability Total
No. of patients 4 3 3 2 2 2 2 1 1 1 1 22 (32.3%)
4. Discussion In this multicenter, open label, adjunctive study, rufinamide significantly reduced the overall seizure frequency in approximately 30% of pediatric and adult patients with refractory cryptogenic or symptomatic focal seizures, after a mean followup period of 10.4 months. This figure is rather in agreement with previous reports.3,13,15 None of our patients achieved seizure freedom. Interestingly, frontal seizures responded to adjunctive rufinamide better than those starting from the occipital and parietal lobes. With respect to the seizure type, secondary generalized tonic–clonic seizures have improved more than others with this drug. A favorable response to rufinamide has already been reported in patients with multifocal epileptic encephalopathies and bi(frontal) spike-wave discharges 5. Notably, all of them had drop-attacks, as reflected in other studies in which atonic seizures were considerably improved by rufinamide adjunctive therapy.2,13,15 Furthermore, no significant correlation was found in our series between rufinamide efficacy and age under or over 18 years, seizure frequency before adding rufinamide, and epilepsy duration, as well as neurological examination and mental level. Indeed, a better response to rufinamide was observed when this drug was associated with valproic acid. In this regard, valproic acid may increase rufinamide plasma concentration, especially in children.18 Unfortunately, we could not assess rufinamide blood level in our patients. Eight of thirteen symptomatic patients with a more than 50% seizure decrease, had seizures originating in the frontal lobe. Three of them had a cortical migration disorder (1, perisilvian polymicrogyria and schizencephaly) or a genetic disorder (1, tuberous sclerosis; 2, Aicardi syndrome). Another patient with Rasmussen syndrome, improved by more than half once rufinamide was added to levetiracetam and
Please cite this article in press as: Coppola G, et al. Rufinamide for refractory focal seizures: An open-label, multicenter European study. Seizure: Eur J Epilepsy (2012), http://dx.doi.org/10.1016/j.seizure.2012.09.015
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clobazam. In a further patient of 19 years, with focal seizures due to previous anatomical right hemispherectomy because of cerebral malaria and infarction, secondary generalized seizures significantly improved, once rufinamide was added to clobazam and potassium bromide. In our experience, adverse side effects were reported by 30% of our patients, according with a 25–55% from literature; drowsiness, vomiting and headache were the most common. Tolerability profile was overall favorable; adverse effects were generally mild and transient, mostly disappearing by slowing drug titration or daily dose. Our study is one of the first performed in children and adolescents with focal epilepsy; nevertheless, it has some important limitations: (1) short follow-up: in fact it was 10.4 months with a minimum of 6 months; the short follow-up period may be counterbalanced by the high baseline seizure frequency (1–10/day or more) in 60/68 patients, (2) wide age range of the patients: in spite of this wide range, clinical spectrum of our patients remained clearly limited to refractory crypto-symptomatic focal-onset epilepsy and (3) presence of multifocal interictal discharges in some patients: in contrast it should be underlined that ictal EEG recordings showed persisting seizure onset from a specific brain area. In conclusion, rufinamide was effective against refractory focal seizures, though generalized epileptic syndromes like Lennox– Gastaut syndrome and other epileptic encephalopathies seem to preferentially respond to this drug. Of note, frontal lobe seizures with secondary generalization showed a good response. No correlation was found between age at therapy onset or seizure etiology and rufinamide efficacy. Rufinamide was generally well tolerated. Studies assessing the long term retention rate in patients treated with this drug for refractory or less severe focal seizures are warranted. Conflicts of interest statement None of the authors has any conflict of interest to disclose. References 1. White HS, Franklin MR, Kupferberg HJ, Schmutz M, Stables JP, Wolf HH. The anticonvulsant profile of rufinamide (CGP 33101) in rodent seizure models. Epilepsia 2008;49:1213–20.
2. Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox–Gastaut syndrome. Neurology 2008;70:1950–8. 3. Coppola G, Grosso S, Franzoni. Veggiotti P, Zamponi N, Parisi P, et al. Rufinamide in children and adults with Lennox–Gastaut syndrome: first Italian multicenter experience. Seizure 2010;19:587–91. 4. Kluger G, Glauser T, Krauss G, Seeruthun R, Perdomo C, Arroyo S. Adjunctive rufinamide in Lennox–Gastaut syndrome: a long-term, open-label extension study. Acta Neurologica Scandinavica 2010;122:202–8. 5. Coppola G, Grosso S, Franzoni E, Veggiotti P, Zamponi N, Parisi P, et al. Rufinamide in refractory childhood epileptic encephalopathies other than Lennox–Gastaut syndrome. European Journal of Neurology 2011;18:246–51. 6. Von Stu¨pnagel C, Coppola G, Striano P, Mu¨ller A, Staudt M, Kluger G. First longterm experience with the orphan drug rufinamide in children with myoclonicastatic epilepsy (Doose syndrome). European Journal of Paediatric Neurology 2012 [Epub ahead of print]. 7. Mueller A, Boor R, Coppola G, Striano P, Dahlin M, von Stuelpnagel C, et al. Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome. Epilepsy & Behavior 2011;21:282–4. 8. Vendrame M, Poduri A, Loddenkemper T, Kluger G, Coppola G, Kothare SV. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Disorders 2011;13:18–21. 9. Palhagen S, Canger R, Henriksen O, van Parys JA, Rivie´re ME, Karolchyk MA. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Research 2001;43:115–24. 10. Elger CE, Stefan H, Mann A, Narurkar M, Sun Y, Perdomo C. A 24-week multicenter, randomized, double-blind, parallel-group, dose-ranging study of rufinamide in adults and adolescents with inadequately controlled partial seizures. Epilepsy Research 2010;88:255–63. 11. Brodie MJ, Rosenfeld WE, Vazquez B, Sachdeo R, Perdomo C, Mann A, et al. Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: a randomized placebo-controlled trial. Epilepsia 2009;50:1899– 909. 12. Biton V, Krauss G, Vasquez-Santana B, Bibbiani F, Mann A, Perdomo C, et al. A randomized, double-blind, placebo-controlled, parallel-group study of rufinamide as adjunctive therapy for refractory partial-onset seizures. Epilepsia 2011;52:234–42. 13. Kluger G, Kurlemann G, Haberlandt E, Ernst JP, Runge U, Schneider F, et al. Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience. Epilepsy & Behavior 2009;14:491–5. 14. Kluger G, Haberlandt E, Kurlemann G, Ernst JP, Runge U, Schneider F, et al. First European long-term experience with the orphan drug rufinamide in childhoodonset refractory epilepsy. Epilepsy & Behavior 2010;17:546–8. 15. Vendrame M, Loddenkemper T, Gooty VD, Takeoka M, Rotenberg A, Bergin AM, et al. Experience with rufinamide in a pediatric population: a single center’s experience. Pediatric Neurology 2010;43:155–8. 16. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. 17. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99. 18. Perucca E, Cloyd J, Critchley D, Fuseau E. Rufinamide: clinical pharmacokinetics and concentration–response relationships in patients with epilepsy. Epilepsia 2008;49:1123–41.
Please cite this article in press as: Coppola G, et al. Rufinamide for refractory focal seizures: An open-label, multicenter European study. Seizure: Eur J Epilepsy (2012), http://dx.doi.org/10.1016/j.seizure.2012.09.015
