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Abstract
Juvenile myoclonic epilepsy is one of the most common types of epilepsy seen in an adult epilepsy clinic. Most patients have a good prognosis, particularly when treated with valproate, but a significant minority are more difficult to treat. In this article, we will focus on a management strategy when the initial antiepileptic drug is unsuccessful and outline an approach that translates directly to the clinic.
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Introduction
Although the idiopathic generalised epilepsies generally present in childhood and adolescence, they account for about one-third of patients attending adult epilepsy clinics. Juvenile myoclonic epilepsy (JME) is the most common of these epilepsy syndromes and accounts for 5–10% of all epilepsies.1 All patients with JME have myoclonic seizures, about 30% have absence seizures but these are rarely a significant clinical problem,2 3 and the majority have tonic–clonic seizures.1 Myoclonic seizures are characterised by short, sudden, arrhythmic, mostly symmetrical movements of the arms and trunk. They can be so mild they are misinterpreted as a tremor or so intense that they result in falls. Myoclonic jerks occur particularly within an hour or two of awakening but unless specifically enquired about can be overlooked because some patients just think they are ‘clumsy’ in the mornings. The EEG typically shows 3–6 Hz polyspike and slow wave generalised discharges, with normal background activity, and around 50% are photosensitive4 (figure 1). However, more than 50% have some focal abnormalities such as focal slow waves, sharp waves or asymmetry of generalised discharges.5,–,7
EEG of a patient with juvenile myoclonic epilepsy (JME). A 19-year-old woman had her first tonic–clonic seizure following alcohol and sleep deprivation. In hindsight she had been experiencing early morning myoclonus for 2–3 years prior to this. Her EEG shows bursts of generalised polyspike and slow wave activity with a normal background, typical of JME.
There is generally a good response to appropriate antiepileptic drug (AED) therapy, particularly with valproate.8 9 However, 20–30% of patients remain refractory to treatment.9 It is this significant minority that we will focus on here, offering some practical tips on how to approach the JME patient when the first AED fails.
Which is the best firstline AED for the idiopathic generalised epilepsies?
Valproate is the conventional AED of choice for the treatment of the idiopathic generalised epilepsies. However, with the introduction of newer AEDs such as lamotrigine (now very much an established AED but still considered ‘newer’), topiramate, levetiracetam and zonisamide, the treatment options are greater, just at a time when there are increasing concerns about the adverse effect profile and teratogenicity of valproate. We should also not forget the benzodiazepines—clonazepam and clobazam.
Although randomised controlled trials (RCTs) are the ‘gold standard’ in determining the efficacy and tolerability of an AED, most epilepsy trials have been done to inform decisions made by drug regulatory authorities rather than to help clinicians and patients make day to day decisions; as a result, they have a number of important limitations. They have:
studied highly selected populations unrepresentative of the sort of patients seen in practice
been of short duration
studied different AED doses than those subsequently used in clinical practice
compared the ‘new’ drug versus placebo and not against other AEDs—indeed, comparative RCTs of one drug versus another are particularly rare, especially in the idiopathic generalised epilpsies.10,–,12
While it has been widely accepted that valproate is the first choice AED, until recently there has been remarkably little supportive evidence. Shortly following its license in 1973 there were a series of observational reports that it had a broad spectrum of action and appeared to be particularly effective in generalised seizures.13 Subsequent open label trials14,–,16 and small RCTs17 18 supported this view, but the data were extremely limited.
There are rather few RCTs in patients with idiopathic generalised epilepsies
In fact there are rather few RCTs in patients with idiopathic generalised epilepsies, partly because of the generally good outcome, but also due to difficulties in recruiting children and adolescents into clinical trials. Some comparative studies in newly diagnosed populations have included some idiopathic generalised epilepsy patients but they can be difficult to identify in the entire population studied. Meta-analysis can provide data on larger patient numbers but, as ever, is limited by the quality of the original studies. Another problem is the likely misclassification of epilepsy in the RCTs, and so extrapolating data to the treatment of the idiopathic generalised epilepsies as we now understand them is problematic.19 Prior to the SANAD (Standard and New Antiepileptic Drugs) trial, there were few data other than clinical experience to guide us.
Some of the earlier RCTs compared valproate with other AEDs in the generalised epilepsies but these are of limited practical value. For what it is worth, there was no significant difference between the efficacy of valproate and ethosuximide for the absence epilepsies,10 11 but in practice many patients would require valproate either instead of or in addition to ethosuximide as the latter is ineffective against tonic–clonic seizures which can co-exist with absence seizures or which develop later. A single study found no difference between valproate and phenytoin in patients with primary generalised tonic–clonic seizures12 but the confidence intervals were too wide to exclude the possibility of important differences.
Trials in newly diagnosed patients with different types of epilepsy have shown no significant differences when valproate was compared with carbamazepine,20 21 phenytoin,12 20,–,22 phenobarbitone,20,–,22 oxcarbazepine23 and topiramate.24 But it is important to remember that these were in heterogenous populations, and one cannot extrapolate the results to all epilepsy types, and specifically to JME. In any event, carbamazepine, phenytoin and oxcarbazepine are inappropriate in the idiopathic generalised epilepsies, particularly JME, as they may exacerbate absence or myoclonic seizures.25
The SANAD trial, far larger than previous trials, used a non-blinded pragmatic design to simulate ‘real-life’ clinical practice, not to satisfy the requirements of the drug regulatory authorities.26 Patients with newly diagnosed epilepsy, or a relapse following previous remission, were randomised to a ‘physician's choice' standard AED versus one of the ‘newer’ AEDs. If the drug of choice was valproate, and usually this was in patients with either generalised or unclassified epilepsy, then they were randomised to valproate, lamotrigine or topiramate. The physician was free to treat the patient, with the allocated drug, in an unblinded fashion according to their usual clinical practice. The primary outcomes were time to treatment failure (for whatever reason, including adverse effects or continuing seizures) and time to 12 month remission.
A total of 716 patients were randomised in the valproate part of the trial. Overall, valproate was better tolerated than topiramate and more effective than lamotrigine. In the largest subgroup, those with idiopathic generalised epilepsy, valproate was significantly more effective than both lamotrigine and topiramate. For time to 12 month remission, valproate was significantly better than lamotrigine and also against topiramate in the ‘per protocol’ analysis suggesting that some patients who were randomised to receive topiramate failed on this but achieved remission when switched to valproate (figure 2). While currently published data from SANAD provide overall results for the idiopathic generalised epilepsies, data for subgroups with specific syndromes such as JME are yet to be published but this work is in preparation.
Time to 12 month remission for generalised epilepsy syndromes in the SANAD trial (intention to treat analysis). LTG, lamotrigine; SANAD, Standard and New Antiepileptic Drugs; TPM, topiramate; VPS, valproate.
Currently, therefore, valproate is considered the AED of choice for patients with generalised or unclassified epilepsy, including JME. To further inform our choice of firstline treatments, we need more multicentre RCTs recruiting large numbers of patients with idiopathic generalised epilepsy but who have also had their syndrome appropriately identified at baseline and who can then be analysed in predefined subgroups. This approach is much more efficient than studies concentrating only on specific syndromes within the primary generalised epilepsies.
What to do when the first AED fails
Review the diagnosis
As ever, when treatment fails the first consideration should be whether the diagnosis is correct. Many studies have shown a high rate of misdiagnosis of epilepsy, up to 25% in apparently drug resistant cases.27 Often the correct diagnosis is non-epileptic seizures or syncope, both of which are relatively unlikely to be mistaken for the specific syndrome diagnosis of JME as opposed to epilepsy per se. More of a diagnostic issue tends to be that JME is not recognised initially and treated with AEDs that may be less effective than valproate (table 1). Even frontal lobe epilepsy can be mistaken for JME, as patients may have brief complex partial seizures or jerks reminiscent of absences28 and myoclonus.29 Also, it is well recognised that the EEG in frontal lobe epilepsy can show generalised spike wave.30 31 In cases where there remains clinical uncertainty then prolonged EEG recordings or video-EEG telemetry may be extremely helpful.
Common reasons for failing to recognise juvenile myoclonic epilepsy
Lifestyle advice
The idiopathic generalised epilepsies are particularly susceptible to external provocative factors (table 2). Direct enquiry and modification of such factors is essential and will often remove any need to manipulate AEDs—for example, sleep deprivation, alcohol (often these two are combined), poor compliance with AEDs and stress. One should also not forget to enquire about any change in drug intake, recreational as well as prescription, and so possible interactions.
Questions to ask the apparent ‘drug resistant’ juvenile myoclonic epilepsy patient
Adequate dose of AED?
Inadequate dosing may seem obvious but is a common reason for an AED to apparently fail. A study from over 20 years ago, of patients whose epilepsy was inadequately controlled on phenobarbitone or phenytoin,32 found that simply manipulating the dose of the existing AED was sufficient to enable 30% of patients to achieve remission. This may be an old study examining patients on ‘old’ AEDs but the message remains unchanged.
Add-on or substitute?
Whether to add another AED to failed monotherapy or substitute another monotherapy is an age old question for which there is no ‘one size fits all’ answer. The UK National Institute for Health and Clinical Excellence (NICE) guidelines33 recommend an alternative monotherapy. Indeed, this policy may have several advantages over combination treatment: fewer adverse effects, less overall drug burden, improved compliance and—a factor which cannot be ignored in any health system—lower cost. However, combination therapy in certain circumstances may be more effective than a second (or third) monotherapy, and any adverse effects can be minimised by using lower doses of two different AEDs rather than a high dose of a single AED.
When valproate fails because of lack of efficacy, a switch to another AED in monotherapy is very unlikely to be successful
However, we must consider whether the reason for initial drug failure should affect the decision making process. Common sense tells us that if an adequate dose of an appropriate AED has been ineffective then a second drug in monotherapy is less likely to succeed than if the first AED had failed because of early adverse effects at low dosage. In fact there is empirical evidence that complete remission from seizures declines from around 50% with the first AED tried (often in low dosage), to 11% with the second AED if the first was ineffective. However, the remission rate with the second AED is similar if the first has failed because of adverse effects rather than lack of efficacy.34 One could argue that this may be even more relevant in an epilepsy syndrome such as JME with such a high responsiveness to initial monotherapy with valproate.
When we studied failure of firstline treatment with valproate, we too clearly showed that the reason for failure was a strong predictor of subsequent success with a change in AED.35 When treatment with valproate failed and it was substituted by lamotrigine, six of 44 patients (14%) achieved remission. But remission only occurred in patients who had failed valproate because of adverse effects while no patients achieved remission on lamotrigine if valproate in adequate dosage had failed to control seizures. When lamotrigine was added to valproate, 10 of 83 patients (12%) achieved remission, irrespective of the reason for valproate failure.
Notwithstanding the NICE guidelines, we conclude that in idiopathic generalised epilepsy patients overall, when valproate fails because of lack of efficacy, a switch to another AED in monotherapy is very unlikely to be successful. In this situation, a second AED should be added. If, however, valproate fails because of adverse effects then switching to an alternative AED is appropriate (figure 3).
Management algorithm for the treatment of juvenile myoclonic epilepsy (JME). AED, antiepileptic drug.
Which secondline AED?
There has been a large increase in the number of new AEDs licensed since 1989 when vigabatrin was first introduced into the UK. However, most are only licensed for focal onset seizures and so our treatment options beyond the established AEDs remain relatively limited in JME, although they are improving (table 3).
Antiepileptic drugs used in the treatment of juvenile myoclonic epilepsy
Lamotrigine
Lamotrigine was licensed in the UK in 1990 and has become an established firstline monotherapy AED. It soon became clear, after some early open label and observational studies,36,–,38 that it could be an alternative to valproate for the idiopathic generalised epilepsies but there have only been two published randomised trials exclusively in patients with generalised epilepsy.39 40 The first, a study in children with newly diagnosed absence seizures, showed in an initial open label dose escalation phase that 30 of the 42 patients (71%) became seizure free on lamotrigine. They were then randomised in a double blind fashion to continue with the same dose or to taper to zero.39 Nine of the 14 patients (60%) randomised to continue remained seizure free compared with three of the 14 (21%) on placebo, but clearly the small numbers in this study limit its applicability. The second, a double blind, placebo, controlled, crossover trial of add-on lamotrigine in 26 patients with refractory generalised epilepsy showed a responder rate (>50% reduction in seizures) of 33% compared with placebo in absence seizures and 50% in tonic–clonic seizures.40 Twenty-three of the 26 patients elected to take lamotrigine in an open label extension, with an 80% response rate and 25% became seizure free.
There have been reports of worsening of myoclonus with lamotrigine, initially in patients with symptomatic generalised epilepsy,41 but it is now a well recognised phenomenon in the idiopathic generalised epilepsies.42 This together with data from SANAD already referred to casts doubt over lamotrigine as a firstline add-on AED in the idiopathic generalised epilepsies, particularly JME.
Topiramate
Topiramate was licensed in the UK in 1996. Animal studies suggested efficacy in generalised epilepsy43 and so it was used in clinical practice in the idiopathic generalised epilepsies fairly early. Some observational studies reported reasonable responses in small numbers of patients.44 45
It was the first of the newer AEDs to be used in a larger RCT in the idiopathic generalised epilepsies, specifically versus placebo in 80 patients with drug refractory seizures.46 This showed a responder rate (>50% reduction in seizures) of 46% compared with 17% for placebo, and a post hoc analysis of the data for the 22 patients with JME showed a 73% reduction in tonic–clonic seizures compared with 18% for placebo.47 It was concluded that topiramate was effective and well tolerated as add-on therapy in drug resistant idiopathic epilepsy but this trial was of only 12 weeks duration.
One comparative monotherapy trial included a subgroup of 180 patients with idiopathic generalised epilepsy among 613 patients with newly diagnosed epilepsy.24 Patients were randomised to the standard AED of choice of the physician (valproate or carbamazepine) or topiramate in a target dose of 100 or 200 mg daily. There was no statistically significant difference between either of the topiramate dosage groups and the standard AEDs in efficacy measures. The lower target dose of 100 mg daily (not surprisingly) was associated with fewer discontinuations due to adverse effects.
Levetiracetam
Levetiracetam was licensed in the UK in 2000 and has undoubtedly been the most widely used of the newer AEDs. It has a novel mechanism of action primarily involving an interaction with the synaptic vesicle protein 2A (SV2A); preclinical studies have found that binding affinity for SV2A is strongly correlated with anticonvulsant potency in models of partial and generalised epilepsy.48 There is some RCT evidence for levetiracetam as add-on therapy in treatment resistant idiopathic generalised tonic–clonic seizures49 and myoclonic seizures.50 A pooled analysis of the data from the two studies showed a median 67% reduction in seizure days per week (vs 14% for placebo; p<0.001) for patients with JME, a 61% responder rate (>50% reduction in seizures) versus 25% for placebo (p<0.001) and 21% seizure freedom for the evaluation period (3% for placebo; p=0.002).51 Levetiracetam is therefore effective for myoclonic seizures as part of an idiopathic generalised epilepsy, usually JME, and in idiopathic generalised tonic–clonic seizures.
However, as mentioned previously, such short term RCTs tell us little about the tolerability of an AED or of its longer term efficacy; the levetiracetam studies had a treatment period of only 24 weeks, including the titration phase. Also, while tonic–clonic seizures may be relatively easy to monitor during follow-up in an RCT, myoclonus and absences are much more difficult to evaluate.
Benzodiazepines
The two main benzodiazepines that have been used as add-on therapy in the idiopathic generalised epilepsies are clonazepam and clobazam. Both were licensed in Europe in 1975 and clonazepam has been widely used for epilepsy, particularly where myoclonus is a feature.
There is evidence of efficacy of clonazepam in generalised tonic–clonic seizures,52 absence seizures and myoclonus.53 Although an effective treatment for myoclonus in the idiopathic generalised epilepsies, some have noted the disadvantage of losing the warning myoclonus prior to a generalised tonic–clonic seizure in JME.54 In practice, however, clonazepam is limited by its sedative effects which are fairly common and can be quite severe.
Clobazam differs from other benzodiazepines in that it has a 1,5 substitution instead of the usual 1,4 diazepine structure. This structural difference results in an 80% reduction in its anxiolytic properties, and a 10-fold reduction in its sedative effects.55 It acts at the γ-aminobutyric acid (GABA)-A receptor but its different action from the other benzodiazepines may reflect the differential binding to the various GABA-A receptor subunits, and its actions away from the GABA-A receptor. It is an effective AED for use either intermittently—for example, in catamenial epilepsy56—or as an adjunctive add-on in partial or generalised epilepsies.
The development of tolerance has been a major concern with all of the benzodiazepines. Intermittent therapy, drug holidays, initiation at very low dose and the use of very high doses have all been attempted to minimise this problem. The frequency of tolerance with clobazam has been reported to be as high as 36%57 but the evidence to support this statement is weak; in a comparative study in newly diagnosed children there was in fact no significant difference in the development of tolerance with clobazam compared with carbamazepine and phenytoin (8%, 4% and 7%, respectively).58
Zonisamide
Zonisamide has been used in Asia since 1989 but was only licensed in the UK and the USA in 2000. It has multiple mechanisms of action and so is thought to have a broad spectrum of efficacy. Despite this, the evidence supporting its use in generalised epilepsy is limited. Most of the reports in refractory idiopathic generalised epilepsies are just abstracts describing small numbers of patients in retrospective studies.59
Are any specific AED combinations indicated?
When adding a second AED there are several factors to be considered, including pharmacokinetic interactions (between the two AEDs and also between any co-existing medication and the new AED), the adverse effect profile of each, and the spectrum of efficacy.
Traditionally the most commonly used combination in patients with an idiopathic generalised epilepsy is valproate with lamotrigine. But one does need to be aware of the interaction between these two drugs; valproate inhibits the metabolism of lamotrigine thereby increasing its serum levels. It is therefore essential when adding lamotrigine to valproate that the initial dose is low, with slow titration to minimise the risk of rash and other toxic effects of lamotrigine. We start with 25 mg on alternate days (or 10 mg daily) for 2 weeks, increasing to 25 mg daily for 2 weeks and then subsequent fortnightly increases if seizures have not been controlled. The risk of hypersensitivity to lamotrigine appears to be higher when it is added to valproate compared with when it is given alone, even with cautious titration, and so patients must be forwarned.35 When used in combination with valproate, fairly low doses of lamotrigine may therefore be therapeutic and there have been reports of a synergistic effect when these two AEDs are combined.60 61
When considering combination therapy in any patient, one needs to consider a variety of non-drug factors also, such as gender, age and comorbidity. If a patient has migraine, then clearly topiramate may be a good option because it helps migraine as well as epilepsy. Topiramate (and now zonisamide) can also be very useful in those patients who find valproate reasonably effective but have difficulty with weight gain. In women of childbearing potential it is advisable to use monotherapy where possible to reduce the teratogenic risks (see below).
Women of childbearing potential
When treating women of childbearing potential, one needs to take several factors into account as well as those for all patients, including the interaction or otherwise of the AED with hormonal contraceptives, and the potential adverse effects of the treatment on the developing fetus. This subject has been recently reviewed in Practical Neurology.62 Our view is that a risk–benefit discussion needs to take place on continuing treatment with the most effective AED for JME (and the dose of that drug) or switching to another AED which may be less effective but potentially less harmful in pregnancy. Add to this the complicating factor of the comparative risk of a major congenital malformation on low dose valproate versus high dose lamotrigine (which may be required for a similar level of seizure control), or even levetiracetam (with only early pregnancy data available), then we can see the complexity of discussion that is required.
Surgery
Resective surgery is not a treatment option for refractory idiopathic generalised epilepsy. Palliative procedures such as callosotomy or multiple subpial transections are usually reserved for patients with severe symptomatic epilepsy with multiple seizure types.
Practice Points
Review the diagnosis of JME if the patient is apparently not responding adequately to treatment.
Lifestyle issues and compliance are crucial in the management of JME and can be challenging, particularly in adolescents.
Valproate is the most effective AED for JME and remains the firstline choice in men.
If valproate is ineffective in controlling seizures in adequate dosage, then consider early combination therapy.
Vagal nerve stimulation is now established as a treatment for refractory focal epilepsy and is recommended by NICE.33 A few small observational reports have suggested that it may be of similar or greater efficacy in idiopathic generalised epilepsy as in focal epilepsy,63 64 and may be considered an option in those patients with JME resistant to AED treatment.
Deep brain stimulation is now well established in the treatment of Parkinson's disease and several small studies have examined various targets in patients with epilepsy. Results in such unblinded studies have been promising, and data from the SANTE (Stimulation of the Anterior nucleus of the Thalamus in Epilepsy) trial showed a significant seizure reduction in the treatment group (median reduction of 40% vs 14% in the sham group). There was at least a 50% reduction in seizures in 54% of patients, and 14 (13%) patients achieved 6 months remission.65 More data from such trials in the future will tell us whether this is a realistic treatment option for patients with refractory non-resectable epilepsy, including the idiopathic generalised epilepsies.
Conclusions
The most important factor in determining the appropriate AED in patients with JME, as is the case with epilepsy in general, is to get the diagnosis right. A relatively common reason for ‘pseudorefractory’ epilepsy is the patient with unrecognised JME who has never been treated with valproate. For patients with a diagnosis of JME, it still remains important to re-evaluate the syndromic diagnosis for those who appear to be refractory to valproate, and particularly consider the possibility of a frontal lobe epilepsy. We also have to recognise the importance of treatment adherence and of lifestyle management in these patients who are often young and may lead less than ideal lifestyles. For patients with JME who fail to achieve seizure control on monotherapy with an AED other than valproate, switching to valproate is recommended although women of childbearing age might prefer to attempt another non-valproate monotherapy. For patients with JME who definitely fail to gain seizure control on appropriately high doses of valproate without adverse effects, there is probably little to be gained from trying an alternative monotherapy and so add-on therapy is recommended. There is not much evidence to inform a choice from between the treatment options. This choice might be dominated by risk of adverse events, the evidence for which is poorer than is the evidence for efficacy. Such adverse effects include sedation with clobazam, agitation with levetiracetam, renal stones with topiramate and zonisamide, and teratogenicity with a combination of valproate and lamotrigine. We use lamotrigine or levetiracetam as first choice add-ons to valproate, but accept than any recommendation is—at present—based on anecdote.
It is clear there is a dearth of data from pragmatic trials in epilepsy, despite the many hundreds that have been published over the past two decades. For patients starting monotherapy we need head to head long term pragmatic trials assessing levetiracetam and zonisamide versus valproate—perhaps a SANAD II. For patients with refractory JME we need head to head trials of add-on treatments as well as regulatory trials assessing potential new treatments.
Acknowledgments
This article was reviewed by Simon Shorvon, London. Thanks to Dr Manohar Deshpande for providing the EEG.
References
Footnotes
Competing interests AN and AGM have received honoraria and/or hospitality from the pharmaceutical companies that manufacture all of the drugs discussed in this article.
Provenance and peer review Commissioned; externally peer reviewed.