ILAE Guidelines (Newly Diagnosed Epilepsy)
Despite being a relatively common syndrome, there are no randomized trials reporting efficacy or effectiveness as a primary outcome measure in newly diagnosed juvenile myoclonic epilepsy. Valproate has long been regarded as the drug of choice to treat this condition.
‘In the absence of class I, class II and class III RCTs for patients with juvenile myoclonic epilepsy, class IV studies suggest that clonazepam, lamotrigine, levetiracetam, topiramate, valproate and zonisamide may have some efficacy for patients with newly diagnosed juvenile myoclonic epilepsy. Among these anti-epileptic drugs, no clear first-choice anti-epileptic drug exists for initial monotherapy in patients with newly diagnosed or untreated juvenile myoclonic epilepsy based solely on efficacy or effectiveness. Selection of the initial anti-epileptic drug therapy for a patient with newly diagnosed juvenile myoclonic epilepsy requires integration of patient-specific, anti-epileptic drug-specific, and nation-specific variables that can affect overall response to therapy.’
AAN Guidelines (New anti-epileptic drugs)
No syndrome-specific recommendation is made for juvenile myoclonic epilepsy.
In spite of the lack of controlled studies of valproate on juvenile myoclonic epilepsy, this drug continues to be the choice of treatment for juvenile myoclonic epilepsy. In special populations such as women of childbearing age, valproate may be less suitable as the first option because of its potential teratogenicity.
Evidence for valproate effectiveness in the treatment of juvenile myoclonic epilepsy mainly consists of case series that have demonstrated good responses, with seizure-free rates ranging from 54% to 93%. Some studies have reported that seizures in some patients can be controlled with valproate doses as low as 500 mg daily, showing that some patients with IGE are sensitive to a small dose of an effective medication. This may be important when considering the teratogenic potential of valproate, as a dose effect has been observed in some studies. Another study tried to show a dose-response relationship with valproate. Sixteen patients with juvenile myoclonic epilepsy were given two different doses of valproate (1000 mg or 2000 mg daily) in a randomized, double-blind, crossover study. Each patient spent 6 months taking the high or low dose before switching, and there was no significant difference in seizure frequency between the two doses.
One trial studied the efficacy of clonazepam as add-on treatment in 17 patients with juvenile myoclonic epilepsy. Myoclonic jerks were controlled in 15 patients and the remaining two experienced a 75% reduction in seizure frequency. However, clonazepam only controlled generalized-onset tonic–clonic seizures in 6/l4 patients who had this type of seizure before entering the study. While being treated with clonazepam, another patient without a history of generalized-onset tonic–clonic seizures had a convulsion.
It is not established whether lamotrigine is beneficial for idiopathic myoclonic seizures such as those associated with juvenile myoclonic epilepsy. Open-label studies suggest that lamotrigine may benefit all three types of seizures in IGE: generalized-onset tonic–clonic, myoclonic and absence. When used in 12 patients with juvenile myoclonic epilepsy experiencing side-effects of valproate, lamotrigine used in monotherapy controlled all seizure types in five patients. valproate could not be withdrawn in three patients because of re-emergence of myoclonus. Two patients had successful pregnancies while taking lamotrigine. The authors concluded that lamotrigine is a useful alternative in the management of juvenile myoclonic epilepsy.
Morris et al., in an open-label study, studied 63 patients with juvenile myoclonic epilepsy who failed previous treatment with valproate. During treatment with lamotrigine, 44% patients became free of generalized-onset tonic–clonic seizures, 33% free of myoclonic seizures and 60% free of absence seizures. Fourteen per cent of patients had a >50% increase in myoclonic seizures. This worsening of myoclonic seizures induced by lamotrigine in a subset of patients with juvenile myoclonic epilepsy has been reported in several series of patients. It is not clear if these patients have some distinguishing features or represent some genetic heterogeneity.
Prasad et al. compared the efficacy of valproate, lamotrigine, topiramate, phenytoin or carbamazepine in a retrospective cohort study of 72 patients with juvenile myoclonic epilepsy. Seizure control was similar in patients taking valproate or lamotrigine monotherapy, and valproate polytherapy was similar in terms of seizure control to lamotrigine polytherapy. valproate, lamotrigine and topiramate, when compared with phenytoin or carbamazepine, demonstrated significantly better control of myoclonic seizures but not of generalized-onset tonic–clonic seizures.
Open-label studies in patients with refractory primary generalized seizures suggest efficacy particularly in tonic-clonic and myoclonic seizures. The study by Betts et al. included 30 patients with refractory primary generalized epilepsy, with 43% and 30% of patients achieving seizure freedom for 6 and 12 months respectively. The series of 55 refractory patients included in the study by Krauss et al. had 63%, 85% and 34% reduction in monthly generalized-onset tonic–clonic, myoclonic and absence seizures respectively.
A recently completed trial of levetiracetam (3000 mg / day) in IGE in adolescents and adults fulfils class I evidence for myoclonic seizures. This was a double-blind, randomized, placebo-controlled trial of 122 patients. These patients continued to have myoclonic seizures in spite of stable doses of one anti-epileptic drug. To be included in the study, patients were required to have 8 days with myoclonus during the 8-week baseline period. Responder rate was 58.3% in the levetiracetam group compared with 23.3% in the placebo group (P = 0.002). Thirteen out of 61 patients taking levetiracetam had complete control of myoclonic seizures compared with 2 out of 60 patients taking placebo.
There are no class I or II data for the use of topiramate in myoclonic seizures. Sixteen patients with myoclonic seizures were included in one class I study, including patients with primary generalized-onset tonic–clonic seizures. However, no conclusions (other than lack of worsening) could be made. In the open-label portion of the study, 67% of the patients with myoclonic seizures were responders. One study reported outcome of a subset of 22 patients with juvenile myoclonic epilepsy included in two controlled trials aimed to study the efficacy and tolerability of topiramate in primary generalized-onset tonic–clonic seizures. Eight out of 11 topiramate-treated patients (73%) had at least 50% reduction in the number of generalized-onset tonic–clonic seizures, compared with 2/l1 placebo-treated patients (18%) (P = 0.03). Reductions in myoclonic, absence and total generalized seizures were also observed, although topiramate vs. placebo differences did not achieve statistical significance.
A recent study reported 28 patients who were randomized (unblinded) to valproate or topiramate therapy for juvenile myoclonic epilepsy. Nineteen patients were randomized to topiramate and nine patients to valproate. Among patients completing 26 weeks of treatment, 8 of 12 (67%) in the topiramate group and 4 of 7 (57%) in the valproate group were seizure free during the 12-week maintenance period. Median daily dose was 250 mg topiramate or 750 mg valproate.
In a review of 72 consecutive patients with juvenile myoclonic epilepsy receiving valproate, lamotrigine, topiramate, phenytoin or carbamazepine, topiramate provided good control of generalized-onset tonic–clonic seizures (<1 seizure per year) in three of four patients on monotherapy and 9 of 11 patients on polytherapy including topiramate. Relative control of myoclonic seizures (defined as <5 seizures or clusters / month) was achieved with topiramate monotherapy in three of four patients and 8 of 15 patients on topiramate polytherapy. topiramate monotherapy did not benefit one patient with juvenile myoclonic epilepsy and absence seizures; topiramate polypharmacy provided good (<5 seizures a month) control in three of five patients.
In a preliminary report of patients with refractory primary generalized epilepsy treated with zonisamide, two of three patients with myoclonic seizures had a >50% reduction in seizures. On a database review of patients with juvenile myoclonic epilepsy treated with lamotrigine, topiramate and zonisamide, four patients were on zonisamide. Generalized tonic-clonic seizures were substantially reduced, but myoclonic seizures increased in these patients on zonisamide, while absence seizures remained unchanged. One retrospective study looked into the efficacy and tolerability of zonisamide in the treatment of juvenile myoclonic epilepsy. Fifteen patients taking zonisamide as monotherapy (13 patients) or as add-on treatment to valproate (two patients) were included in the study. Overall, 80% of patients on zonisamide monotherapy showed good control, defined as >50% seizure reduction. Mean follow up was 12 months. Sixty-nine per cent, 62% and 38% of patients were free of generalized-onset tonic–clonic, myoclonic, and absence seizures, respectively.
Another recent retrospective study analysed the efficacy of zonisamide as add-on treatment in seven patients with refractory juvenile myoclonic epilepsy. Six patients had a history of generalized-onset tonic–clonic seizures. Five of six patients had >50% reduction in frequency of generalized-onset tonic–clonic seizures, with two patients becoming free of this seizure type. Six patients had active myoclonus when started on zonisamide. All six patients had >50% reduction in myoclonus, and two became free of this seizure type. Of the four patients who were having absence seizures when zonisamide was started, all four experienced >50% reduction in seizure frequency, and one became free of absences. These results were sustained over more prolonged follow-up in five of seven patients, with one patient improving further over time. Four patients initially had minor side-effects that resolved during the maintenance period. The authors concluded that zonisamide may be effective and well tolerated as add-on therapy in patients with refractory juvenile myoclonic epilepsy.
Common Clinical Practice
In juvenile myoclonic epilepsy, counselling on lifestyle is essential. The importance of regular sleep habits must be stressed, and drinks containing excessive caffeine should not be consumed in the evening. Excessive alcohol intake must be avoided also. If patients are photosensitive, they should avoid relevant visual stimuli and wear dark glasses in brightly lit surroundings. Such measures will decrease the necessity of high-dose medical treatment, but the use of anti-epileptic drugs is still necessary. As mentioned earlier, total control of seizures on valproate monotherapy may be achieved in up to 84% of patients. Daily dosage in adults ranges between 1000 and 2000 mg, although some patients may be controlled on significantly lower doses and theoretically ‘sub-therapeutic’ blood levels. If an extended-release formulation is used, the whole daily dose may be given in the evening. Clonazepam may also be useful, best in association with valproate. Among newer anti-epileptic drugs, lamotrigine is often used in association with valproate and levetiracetam has shown its efficacy against myoclonic and also generalized-onset tonic–clonic seizures. Lamotrigine is an interesting option when valproate causes significant side-effects or when there is concern about teratogenicity (women of fertile age). Topiramate and zonisamide may be useful, especially in drug-resistant patients.
There is a widespread belief that lifelong treatment is mandatory in juvenile myoclonic epilepsy because of very frequent relapses at attempts to terminate treatment. If the decision is made for long-term maintenance of treatment, low-dose controlled-release valproate with a single evening intake may be an adequate option.