Management of juvenile myoclonic epilepsy - FormSus

Epilepsy & Behavior 28 (2013) S81–S86

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Review

Management of juvenile myoclonic epilepsy Arielle Crespel a, b,⁎, Philippe Gelisse a, b, Ronald C. Reed c, Edoardo Ferlazzo d, e, Judith Jerney f, Bettina Schmitz g, Pierre Genton h a

Epilepsy Unit, Hôpital Gui de Chauliac, Montpellier, France Research Unit “Movement Disorders” (URMA), Department of Neurobiology, Institute of Functional Genomics, CNRS UMR5203 – INSERM U661 – UM1, Montpellier, France Husson University School of Pharmacy, Bangor, ME, USA d Magna Græcia University, Catanzaro, Italy e Regional Epilepsy Centre, “Bianchi-Melacrino-Morelli” Hospital, Reggio Calabria, Italy f Epilepsy Centre, St. John Hospital, Buda Children's Hospital, Budapest, Hungary g Vivantes Humboldt-Klinikum Berlin, Department of Neurology, Stroke Unit, and Center for Epilepsy, Germany h Centre Saint Paul-H. Gastaut, Marseille, France b c

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Article history: Accepted 16 October 2012 Keywords: Juvenile myoclonic epilepsy Management Antiepileptic drugs Lifestyle SUDEP

a b s t r a c t Juvenile myoclonic epilepsy (JME) is a common form of epilepsy and a fairly lifelong disorder that may significantly lower a patient's expectations and potential for a full life. Luckily, it is also a highly treatable disorder, and up to 85% of patients with JME will enjoy satisfactory seizure control. Among anticonvulsants, valproate still stands out as the most efficacious drug, but may be poorly tolerated by some, and is considered unsafe for the fetuses of pregnant women. Alternatives have emerged in recent years, especially levetiracetam, but also topiramate, zonisamide or lamotrigine. In some cases, combination therapy may be useful or even required. One should not forget the potential aggravation induced not only by some commonly used anticonvulsants, especially carbamazepine and oxcarbazepine, but also, in some patients, by lamotrigine. In special settings, older drugs like benzodiazepines and barbiturates may be useful. But the management of JME should also include intervention in lifestyle, with strict avoidance of sleep deprivation and the management of copathologies, including the cognitive and psychiatric problems that are often encountered. With adequate management, there will only remain a small proportion of patients with uncontrolled epilepsy and all of its related problems. Juvenile myoclonic epilepsy is a condition in which the clinician has a fair chance of significantly helping the patient with medication and counseling. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really? © 2013 Elsevier Inc. All rights reserved.

1. Introduction Juvenile myoclonic epilepsy (JME) is a treatable epileptic syndrome. According to the International League Against Epilepsy, “response to appropriate drugs is good” [1]. Juvenile myoclonic epilepsy has a reputation of being benign. However, Gelisse et al. [2] found that the seizures of about 15% of patients with JME are drugresistant, especially the seizures of those in whom all three seizure types coexist (myoclonic jerks (MJs), generalized tonic-clonic seizures (GTCSs), and absence seizures). Independently, the presence of psychiatric problems, e.g., personality disorders, was also found as a factor associated with drug resistance [2]. However, this study was performed at the end of the 1990s, before the extensive use of levetiracetam (LEV), topiramate (TPM), lamotrigine (LTG), and zonisamide (ZNS) in the ⁎ Corresponding author at: Explorations Neurologiques et Epileptologie, Hôpital Gui de Chauliac, 80 avenue Fliche, 34295 Montpellier cedex 05, France. Fax: +33 4 67 33 61 00. E-mail address: [email protected] (A. Crespel). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.01.001

treatment consisting of JME. With treatment of a combination of drugs, the frequency of patients with drug-resistant seizures is probably lower nowadays. The use of different drug combinations may constitute a crucial element in the management of patients with refractory JME. Patients with an abnormal lifestyle, including excessive intake of alcohol or irregular sleep-wake schedules, are at risk of persisting seizures. More than in other types of epilepsy, patients with JME must correct their lifestyle. It was also shown that patients with JME are at risk of sudden unexpected death in epilepsy (SUDEP). Patients with JME can die of a cause closely (trauma, drowning, or status epilepticus) or remotely (e.g., by suicide) related with seizures. Sudden unexpected death in epilepsy was repeatedly reported in IGE, but IGE was not considered a major risk. However, uncontrolled epilepsy, GTCS, lack of compliance, and neurological or mental handicap are risk factors for SUDEP. All these conditions may be present in JME, and Genton and Gelisse reported three cases of SUDEP in JME [3]. This is another reason for working with patients to achieve seizure freedom. In JME, the overall prognosis will remain good with a rational approach to the choice of drug and by avoiding potential aggravation

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by inadequate AEDs. Juvenile myoclonic epilepsy stands out as a pharmacodependent form of epilepsy. In this review, we discuss some issues surrounding the management of patients with JME: drug choice, paradoxical aggravation by AEDs, lifestyle, and best treatment strategies for women of childbearing potential with epilepsy. 2. Choice of antiepileptic drugs Choice of treatment in JME is based on clinical experience, retrospective studies, and prospective open-label trials. But randomized blinded clinical trials comparing old or new antiepileptic drugs are clearly lacking. Juvenile myoclonic epilepsy has a particular pharmacological sensitivity. If some antiepileptic drugs (AEDs) can be used with success, the potential aggravating effect of others must be kept in mind. 2.1. Valproate Valproate (VPA) has a very specific efficacy in the treatment of JME, and this was stressed in the first reports on JME following the availability of the compound. Valproate quickly became the drug of choice for the treatment of JME. A few studies used monotherapy of VPA in patients with JME and showed similar very high rates of total control of seizures. In North America, high control rates of 90% [4] or 86% [5] were reported in the 1980s, compared with 84.5% in a European study by Genton et al. [6]. The superiority of VPA in the treatment of IGE was clearly demonstrated in the SANAD study [7]. In adults, the dosage ranges between 1000 and 2000 mg/day. Electroencephalogram abnormalities can persist even if good control is obtained with VPA, but this persistence of EEG abnormalities does not have a bad prognostic significance [8]. In the case of initial nonefficacy of VPA in the treatment of JME, increasing dosage until the occurrence of side effects does not appear to result in decreased seizure frequency [9]. Valproate is still considered as the first-line treatment in JME in men and women without childbearing potential. 2.2. Lamotrigine Open-label studies showed the efficacy of LTG in the treatment of JME, used in association or not with VPA [10–12]. Nicolson and Marson studied the efficacy of LTG after VPA failure (side effects or no efficacy). They observed a remission in 13.6% of the patients but only for those who had stopped using VPA because of its side effects and not because of its lack of efficacy [13]. Bodenstein-Sachar et al. found similar results particularly in patients with JME but without GTCS [14]. Lamotrigine is helpful in treating JME but appears to be less effective than VPA [7,15]. However, LTG has the potential to aggravate IGE, with promyoclonic effects which may occur after a long delay [16]. Therefore, LTG should not be considered as a first-line option compared with VPA, but it remains useful in younger women because of the potential teratogenicity of VPA [17], and also in patients with comorbidities like migraine (with aura) [18] and psychiatric disorders (bipolar depression) [19]. 2.3. Levetiracetam The increasing use of LEV in the treatment of JME is now well-founded. Since 1996, its efficacy has been shown respectively against photoparoxysmal responses [20] and myoclonus [21]. Several open studies demonstrated the specific efficacy of LEV in the treatment of JME with patients who became seizure-free on polytherapy and monotherapy. In the open study of Labate et al. [22], 8 patients received monotherapy, and 13 patients received add-on therapy with LEV; 62.5% of the patients became seizure-free on monotherapy and 61.5% on add-on therapy. In the monotherapy group, the seizure frequency decreased more than 50% for one patient, was unchanged for one, and worsened for one. In the add-on group, the seizure frequency decreased more than 50% for three patients, was unchanged for one,

and worsened for one; a high dosage of LEV (2000 to 3000 mg/day) was used. In the long-term open study of Specchio et al. [23], 5 of the 10 newly-diagnosed patients (50%) became seizure-free on monotherapy, and 11 of the 38 patients with resistant or intolerant seizures (28.5%) became seizure-free on polytherapy. Thirty-seven percent of patients had no myoclonias, and 72.9% had no GTCS. They observed a significant decrease in the number of days with myoclonus and the monthly frequency of GTCS after LEV treatment. The patients received between 1000 and 3000 mg/day of LEV (mean: 2208 mg/day). In a following study, Specchio et al. [24] studied the effect of LEV on EEG abnormalities and photoparoxysmal response (PPR) in 48 patients. Electroencephalogram was normalized in 23 patients after LEV treatment. Suppression of PPR was observed in 13 of the 17 patients with PPR before LEV treatment. When the EEG was normalized, there were significantly more days without myoclonias compared to patients with unchanged EEG. A multicenter, randomized, double-blind, placebo-controlled study of LEV in idiopathic generalized epilepsies was published in 2007 by Berkovic et al. [25]. Among 164 patients, 54 patients had JME: 24 received LEV, while 30 received placebo. They obtained a significantly better response in patients on LEV than in patients on placebo. In 2008, Verotti et al. [26] published an open study on 32 patients with new-onset JME using LEV treatment as the first monotherapy. At 12 months, all patients were responders with 90.6% of them seizure-free. Sharpe et al., in their 2008 retrospective study of 32 patients with JME, showed that 80% of patients were seizure-free after LEV monotherapy (initial or conversion). They used a dosage between 12 and 50 mg/kg/day [27]. Of the 122 patients with IGE and myoclonias in whom a first treatment failed, Noachtar et al. gave placebo to 60 and LEV to 62 [28]. A very significant response to LEV was demonstrated for myoclonias. The analysis of the two randomized, double-blind, placebo-controlled studies of Berkovic et al. [25] and Noachtar et al. [28] by Rosenfeld et al. [29] in 2009 showed a rate of responders of 61% in patients with JME, with 20.8% of them seizure-free. Thus, LEV is one of the options in the treatment of JME [30] and is an alternative choice to VPA as a first-line or add-on treatment, especially in women of childbearing potential. No study comparing VPA and LEV is available. 2.4. Topiramate Topiramate (TPM) is useful in the treatment of JME. Its efficacy in add-on therapy was shown in the first studies [31,32]. Biton and Bourgeois in 2006 [33] made a retrospective analysis of 22 patients with JME who participated in two prospective, double-blind, add-on studies of TPM versus placebo in the treatment of IGE and found a reduction of GTCSs. In the SANAD study, Marson et al. in 2007 [7] demonstrated the efficacy of TPM in the treatment of IGE. Topiramate was more efficacious than LTG, but was less tolerated than VPA and LTG. Levisohn and Holland in 2007 [34] observed that TPM was slightly more efficacious than VPA in a randomized, open-label study comparing 28 adolescent and adult patients; 19 were on TPM (median dosage of 250 mg/day) and 9 on VPA (median dosage of 750 mg/day). In 2005, Sousa et al. confirmed the efficacy of TPM against GTCS and myoclonias in an open study of 15 patients with uncontrolled JME [35]. But in some patients, TPM may produce neuropsychiatric side effects (alteration of attention, short-term memory, processing speed, and verbal fluency) [36] and lead to treatment failure [7]. Nevertheless, when it is well tolerated, TPM is a suitable alternative to VPA, particularly in patients who are overweight or have associated migraine. 2.5. Zonisamide (ZNS) In 2004, Kothare et al. used zonisamide (ZNS) in 15 patients with JME. Thirteen patients received ZNS as first monotherapy and 2 as add-on therapy. They reported a good control of seizures, with 80% of responders in the monotherapy group. Sixty-nine percent of patients were GTCS-free, 62% were seizure-free for myoclonias, and 38% were seizure-free for


absences. The daily dose ranged between 200 and 500 mg [37]. A complete resolution of EEG discharges has been observed in a patient with JME who became seizure-free with ZNS [38]. In a retrospective analysis of 7 patients with refractory JME, O'Rourke et al. in 2007 showed that ZNS treatment led to more than 50% reduction of seizure frequency in 83.3% of treated patients for GTCS and in 100% for myoclonias and absences [39]. Two patients became seizure-free. Marinas et al. in 2009 used ZNS to treat 13 patients with IGE, six of whom had JME. In these patients with JME, 3 became seizure-free, 2 had no change, and one experienced side effects and stopped using ZNS [40]. All these retrospective studies showed good results for treating JME with ZNS, but prospective controlled studies are clearly missing. 2.6. Other treatments Before the availability of VPA, phenobarbital (PB) and primidone were commonly used in the treatment of JME with efficacy in up to 86% of cases, while a regimen containing predominantly phenytoin (PHT) controlled seizures only in 67% of the patients and left 33% unchanged or worsened [41]. Other authors described efficacy with acetazolamide [42], methsuximide [43], and piracetam in the dosage of 3200 mg/day with sustained antimyoclonic efficacy [44]. Some publications have also stressed the possibility of adding clonazepam to VPA to improve efficacy [45]. Recently, lacosamide (LCM) was used in three patients with JME [46]. Two patients received LCM as monotherapy and one as add-on. A good effect was observed, but these preliminary data await confirmation. 3. Paradoxical aggravation of JME due to the choice of inadequate drugs Juvenile myoclonic epilepsy may be aggravated by AEDs. Kivity and Rechtman reported that phenytoin (PHT) at high doses is highly toxic in JME and may clearly exacerbate MJs [47]. Sözüer et al. reported that PHT exacerbated MJs in four of six patients [48]. Genton et al. reported that PHT was not very efficacious: among 16 subjects exposed to PHT alone or in association with other AEDs, seizures in six were aggravated (38%) including one in monotherapy, two in association with PB, one in association with VPA, one in association with CBZ and PB, and one in association with CBZ and VPA [49]. Only two were improved (12%), whereas 8 (50%) did not notice any change in seizure frequency. In this study, CBZ aggravated symptoms in nearly 68% of patients exposed to it, whereas 14% of them have been improved (two in monotherapy, one in association with VPA, and one in association with VPA and PB). No effect was seen in the remaining five cases (one in monotherapy, three in association with VPA, and one in association with PB). Following change of treatment including withdrawal of PHT and CBZ, all patients who had aggravation were clearly improved by VPA as monotherapy or in association with LTG, PB, or BZP. Previously, Sözüer et al. had reported aggravation with CBZ in a series of 19 patients with JME. Sixteen experienced increased MJs with CBZ monotherapy, and four also experienced absences [48]. In 2000, Osorio et al. observed status epilepticus occurring in 4 patients with JME refractory to IV benzodiazepines secondary to concurrent phenytoin or carbamazepine treatment; when PHT or CBZ was withdrawn and VPA was initiated, seizure control was achieved [50]. Oxcarbazepine (OXC) is a drug chemically related to CBZ. Oxcarbazepine appears to have a significant potential to aggravate JME. Gelisse et al. reported a clear aggravation in four patients with JME: aggravation of MJs in all, increased GTCSs in three, and absence seizures in two [51]. This aggravation followed the prescription of OXC with a close time relation after its introduction. However, Carignani and Rosso in 1997 reported a good response with OXC in six patients with JME. Oxcarbazepine was used at dosages≤45 mg/kg/day. The authors mentioned that exacerbation of spike-wave activity and MJs did not occur in their cases [52]. The main problem with the patients reported by these authors is the lack of characterization of the epilepsy. There is no detail. The

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authors mentioned that some patients had hemiclonic or hemitonic seizures at the onset of the disorder, which is a very atypical presentation for JME, and focal epilepsy cannot be ruled out. Lamotrigine is a therapeutic option for patients with JME but this drug can aggravate MJs [53] or GTCSs [54]. Crespel et al. reported de novo appearance of MJs in juvenile IGE in five women among 93 patients treated with LTG (5.4%) with a phenotype close to JME at the time of aggravation [16]. Two distinct profiles of aggravation were observed: (1) a dose-related aggravation of MJs during or at the end of LTG titration that may respond to LTG dosage reduction by 25 to 50%; and (2) a severe aggravation of MJs occurring several months after LTG titration and evolving into myoclonic status requiring cessation of LTG. Status epilepticus has been reported in patients with JME treated with inappropriate AEDs. Larch et al. reported two cases of myoclonic status epilepticus (one treated with CBZ and one treated with PHT) [55]. Thomas et al. reported three cases of myoclonic status epilepticus and one case of absence status [56]. All were treated with CBZ: two in monotherapy, 1 in combination with PB and vigabatrin (VGB), and one in combination with PB and PHT. Potential precipitating factors for the status were: initiation of CBZ in one case, of VGB in one case, sleep deprivation in one case, and an unknown cause in the latter. Vigabatrin is not considered a good drug for treating JME even if Pedersen et al. have reported partial efficacy in three of their patients [57]. However, VGB may aggravate absence epilepsies and is not indicated in IGEs [58]. 4. Treatment of status epilepticus Myoclonic status epilepticus or mixed myoclonic–absence status is uncommon in JME, often precipitated by sleep deprivation and inadequate AEDs or resulting from drug withdrawal (Fig. 1). Such episodes of status respond well to benzodiazepines [55] or valproate [59]. 5. Treatment of JME in women with childbearing potential Pregnancy is a therapeutic challenge in women with epilepsy, and the risk/benefit ratio for the mother and fetus must be considered regarding the choice of the AED. None of the AEDs can be categorized as safe during pregnancy. Lamotrigine and levetiracetam seem to be comparatively safer to use in pregnancy than others [60]. There is a significant decrease in the plasma concentration during pregnancy in patients treated with LTG and restoration of prepartum levels after delivery. Dosage adjustments may be necessary. Lamotrigine is contraindicated while breastfeeding. Valproate (VPA) is associated with an increased risk of major malformations and has also been associated with an increased risk of impaired postnatal cognitive development [61]. It is recommended to avoid VPA during pregnancy or to use it in monotherapy at low dosages (≤750 mg/day) if GTCSs are difficult to control with other drugs. For ZNS and TPM (which is FDA Pregnancy Category D), the available information is relatively sparse. These drugs should only be given when there is no alternative. Treatment in women of reproductive age remains a clinical challenge. Enzyme-inducing drugs can reduce the efficacy of combined hormonal contraception. Topiramate does not interact with oral contraceptives if the daily dose is below 200 mg, but at a higher dose, it may decrease the efficacy of combined oral contraceptives [62]. Valproate, ZNS, and LTG do not affect hormonal contraception. But combined oral contraceptives reduce the plasma concentration of LTG. Women using LTG should be advised that seizure frequency may increase when initiating this method of contraception. 6. Nonpharmacological approach 6.1. Lifestyle Lifestyle is a crucial element in the successful management of patients with JME. Without a good lifestyle, obtaining good control of

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Fig. 1. The EEG (15 mm/s; 10 μV/mm; international 10–20 electrode system with right deltoid and left deltoid) of a 24-year-old woman with juvenile myoclonic epilepsy and bipolar disorder. Confusional state 5 days after withdrawal of clonazepam (14 mg/day) and introduction of oxazepam (200 mg/day) followed by catatonic stupor with subtle myoclonus of the face and the arms. Left segment: absence status with continuous activity with bilateral spike–waves and sharp notched theta or delta waves. Right segment: after treatment with IV clonazepam (1 mg) leading to cessation of the status. The patient was able to speak normally. Note that the EEG did not completely return to normal.

seizures remains difficult. Lifestyle is part of the treatment, and this point must be particularly discussed with the patient. In spite of adequate treatment, seizures may be precipitated by various stimuli such as fatigue, sleep deprivation, alcohol intake, and drugs. Patients must regulate their wake-sleep rhythm in order to have sufficient time of sleep and the most possible natural awakening. Sleep deprivation and provoked awakening are two major conditions precipitating seizures. Seizures principally occur within 2 h after awakening (30 min to 1 h), which is why the patient must have a sufficient time to prepare, must be careful in this period, and must not engage in dangerous activities like taking a bath. Alcoholic drinks may be permitted only in small quantities. Energy drinks should be discouraged in some patients, especially adolescents consuming a large amount at night or in combination with alcohol [63]. Low medication adherence may also be a factor of pseudo-drug resistance. In many countries, patients with epilepsy can drive if their seizures are controlled. Patients must be advised not to drive when fatigued, deprived of sleep, and in the awakening period. 6.2. Photosensitivity Juvenile myoclonic epilepsy is the epilepsy syndrome with the closest relation with photosensitivity, both as an EEG phenomenon and clinically. When flashing lights trigger seizures, some precautions are necessary such as wearing sunglasses on sunny days when the sun is reflected on the water or dappled through trees. Nowadays, flat

televisions and flat screens for computers are less provocative than the old cathode TV tubes. However, the increasing size of screens as well as the contrast and changing colors of the programs cancel this positive development, unfortunately [64]. When playing video games on the TV or computer, it is better to play in a well-lit room and at maximal possible distance to the screen and not to play when drowsy and asthenic. In patients suffering clinically from their photosensitivity, the use of blue lenses can be an interesting option in those whose photoparoxysmal EEG responses are clearly suppressed by wearing blue lenses [65]. Patients should be warned that with the blue lenses, traffic lights are more difficult to discriminate. Valproate and LEV are both very effective in the treatment of photosensitivity, and management is therefore similar to the treatment of JME; other drugs do suppress the photosensitivity as well [66]. 6.3. Psychotherapy Juvenile myoclonic epilepsy may be associated with some degree of social and cognitive dysfunction and some degree of personality disorders. According to Janz and Christian [67], patients with JME have inadequate social behavior, emotional instability, and immaturity, which can lead to social maladjustment, low medication adherence, and inadequate lifestyle. Early descriptions were confirmed by studies using modern psychiatric criteria [68–70]. The presence of psychiatric disorders seems to be a marker of drug resistance [2,70,71]. Their identification and treatment should be early since they have a fundamental role


in the prognosis. In patients with refractory JME, psychotherapy may be helpful. Martinović reported that psychotherapy led to seizure freedom in 50% of patients with drug-resistant seizures [72]. He investigated 22 patients with JME with uncontrolled seizures. After a structured counseling, eight patients became seizure-free. Of the patients who were not seizure-free, seven had an antistress treatment which resulted in three becoming seizure-free. Seven had an individual cognitive behavioral therapy which resulted in four becoming seizure-free. 6.4. Vagus nerve stimulation Vagus nerve stimulation (VNS) is an adjunctive treatment in refractory epilepsy. Some authors consider VNS a favorable treatment option for patients with drug-resistant IGE. Ng and Devinsky reported that, among 14 patients with IGE, 57.1% achieved a 50% or greater reduction in seizure frequency [73]. These authors did not precisely state how many patients had JME. Kostov et al. reported on 12 patients with drug-resistant IGE, including seven with JME [74]. Five out of these 7 patients were responders (>50% seizure reduction), with one remaining on VNS alone with a >75% reduction in GTCSs and a >50% reduction in typical absence seizures and MJs. These studies are not sufficient for VNS to qualify as a recommended treatment option in JME. 7. Treatment of JME: the long-term outcome There are no data showing that JME, once controlled, may have a fluctuating course with loss of control over time. Lifestyle issues usually get milder with aging, and factors that might trigger seizures, such as sleep schedule irregularities, tend to disappear in adulthood. Recent long-term studies, detailed elsewhere in this volume, have shown that some patients have a more severe condition that may pose therapeutic problems over many years, and that some have a very benign course, with isolated jerks (and those patients can often do without drug therapy), while the majority will enjoy a fairly mild course, bordering on long-term, even final remission in some. As a milder disease is usually found in patients who are in their fourth decade of life onwards, a reasonable therapeutic compromise is to maintain treatment in most patients beyond early adulthood, e.g., with low-dose VPA, with a single evening intake [75]. 8. Copathologies Copathologies can influence the choice of antiepileptic drug by virtue of the known positive or negative side effects of AEDs. One may thus prefer LTG, TPM, or VPA in the case of migraine or LTG in the case of depression. In the case of obesity, TPM is an interesting option [30]. Copathologies are conditions that may interfere with prognosis of JME and must be diagnosed in patients with refractory JME because they can be aggravating or revealing conditions. Genton et al. reported one patient with hypothyroidism in whom thyroid replacement therapy quickly led to improvement [6]. Hyperthyroidism has also been reported as an aggravation factor in JME [76]. Similarly, patients with well-controlled seizures can relapse with GTCSs when they suffer from obstructive sleep apnea syndrome due to severe sleep deprivation. Psychiatric disorders are also a factor that can lead to drug resistance or aggravation in patients with well-controlled seizures [2]. 9. Conclusion With proper management, the majority of patients with JME can have lives much less impacted by seizures. When the epilepsy remains active in spite of apparently adequate drug choice and management, the diagnosis of JME must be reviewed, and the lifestyle issues and adherence must be verified. Several AEDs are useful. Valproate appears to be the first-line treatment option. If VPA is ineffective in controlling seizures in adequate

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dosage or is poorly tolerated, other drugs or combination therapy must be considered. Lamotrigine, levetiracetam, topiramate, zonisamide, and phenobarbital are other potential options in monotherapy or in combination with VPA, with LEV as the preferred option for many. Comorbidities must be considered and treated. Lifestyle remains essential and is an integral part of JME treatment and can be a true challenge in some patients, particularly in adolescents. An opinion poll about the popular, modern therapeutic options in JME was performed among participants of the 2011 Avignon workshop, and its results are detailed elsewhere in this volume. Ethical approval We confirm that we have read the ethical publication guidelines for this Journal and affirm that this report is consistent with those guidelines. Conflict of interest statement Dr. Crespel has received support from pharmaceutical companies for teaching programs (Sanofi-Aventis, UCB). Dr. Crespel served as a board member for Eisai-France. Dr. Gelisse has received support from pharmaceutical companies for teaching programs (Sanofi-Aventis, UCB, Psicofarma). He received a research grant from the French League Against Epilepsy and the Janssen-Cilag company. He was a paid consultant for Eisai-France in 2011. Dr. Reed has no conflicts of interest to declare. Dr. Ferlazzo has received speaker honoraria from Novartis and UCB. Dr. Jerney has received speaker honoraria from UCB and support for teaching programs from Eisai. Dr Schmitz has received research grants and served on advisory board of Desitin, Eisai, UCB-Pharma, Novartis, Glaxo-Smith-Kline, Pfizer and Sanofi. Dr. Genton has received speaker honoraria from Sanofi-Aventis, UCB, and Eisai. References [1] 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. [2] Gelisse P, Genton P, Thomas P, Rey M, Samuelian JC, Dravet C. Clinical factors of drug resistance in juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 2001;70: 240–3. [3] Genton P, Gelisse P. Premature death in juvenile myoclonic epilepsy. Acta Neurol Scand 2001;104:125–9. [4] Delgado-Escueta AV, Enrile-Bacsal F. Juvenile myoclonic epilepsy of Janz. Neurology 1984;34:285–94. [5] Penry JK, Dean JC, Riela AR. Juvenile myoclonic epilepsy: long-term response to therapy. Epilepsia 1989;30(Suppl. 4):19–23. [6] Genton P, Gelisse P, Thomas P. Juvenile myoclonic epilepsy today: current definition and limits. In: Schmitz B, Sander T, editors. Juvenile myoclonic epilepsy: the Janz syndrome. Petersfield and Philadelphia: Wrightson Medical Publishing; 2000. p. 11–32. [7] Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1016–26. [8] Sundqvist A, Nilsson BY, Tomson T. Valproate monotherapy in juvenile myoclonic epilepsy: dose-related effects on electroencephalographic and other neurophysiologic tests. Ther Drug Monit 1999;21:91–6. [9] Sundqvist A, Tomson T, Lundkvist B. Valproate as monotherapy for juvenile myoclonic epilepsy: dose–effect study. Ther Drug Monit 1998;20:149–57. [10] Buchanan N. The use of lamotrigine in juvenile myoclonic epilepsy. Seizure 1996;5: 149–51. [11] Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res 1998;29:147–54. [12] Morris GL, Hammer AE, Kustra RP, Messenheimer JA. Lamotrigine for patients with juvenile myoclonic epilepsy following prior treatment with valproate: results of an open-label study. Epilepsy Behav 2004;5:509–12. [13] Nicolson A, Marson AG. When the first antiepileptic drug fails in a patient with juvenile myoclonic epilepsy. Pract Neurol 2010;10:208–18. [14] Bodenstein-Sachar H, Gandelman-Marton R, Ben-Zeev B, Chapman J, Blatt I. Outcome of lamotrigine treatment in juvenile myoclonic epilepsy. Acta Neurol Scand 2011;124:22–7.

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