Review
Pharmacotherapy of focal epilepsy Anand Iyer & Anthony Marson† †
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
The Walton Centre for Neurology and Neurosurgery NHS Foundation Trust, Liverpool, UK
1.
Introduction
2.
Initiating anti-epileptic drug treatment
3.
Initial treatment and monotherapy trials
4.
Refractory epilepsy and add-on trials
5.
Discontinuing therapy and risk of relapse
6.
Conclusion and expert opinion
Introduction: Epilepsy is the most common neurological condition worldwide with significant psychosocial and physical morbidity. Its management requires expertise and good pharmacological knowledge of the available options. Areas covered: This review covers the management of focal epilepsy addressing the common questions arising through the patients’ journey, including timing of starting initial treatment, monotherapy options, add-on treatment for refractory cases and withdrawal of medication during remission. Expert opinion: Initiating anti-epileptic drug (AED) treatment requires assessment of patient preferences and of evidence of benefit and harm. Evidence of benefit will come primarily from randomised controlled trials, although in epilepsy, most trials are undertaken to inform regulatory decision and have important limitations for informing clinical decisions. Evidence about harm may come not only from randomised trials but also from other sources. Most patients will start treatment following a second focal seizure. Carbamazepine and lamotrigine are good initial monotherapy options. Newer AEDs have proof of efficacy as monotherapy but evidence is insufficient to recommend them as first-line treatments. For refractory cases, there are an increasing number of AEDs available, but evidence of efficacy is primarily from placebo-controlled trials, and there is no robust evidence to inform a choice among treatments. Keywords: anti-epileptic drugs, focal epilepsy, monotherapy, refractory, relapse Expert Opin. Pharmacother. (2014) 15(11):1543-1551
1.
Introduction
Epilepsy is the one of the most common neurological disorders; its mean incidence has been reported as 50.4/100,000/year, with peaks of incidence in children and the elderly. Prevalence has been estimated at 0.5 -- 1.0%, although prevalence is higher in low- and middle-income countries [1]. There is a high degree of associated psychological distress, stigma and social disadvantage [1-3]. Epilepsy is also associated with a higher mortality; the standardised mortality rate has been reported to be 2 -- 4 by epidemiological studies, and sudden unexpected death in epilepsy accounts for about 500 deaths a year in the UK [4]. The overall management of epilepsy needs not only expertise but also considerations to the associated comorbidities, and many clinicians treat epilepsy as a syndrome complex, rather than just a diagnosis in itself. Focal epilepsies are the most common type in adults, where seizures arise from focus somewhere within the cerebral cortex, most commonly in a temporal or frontal lobe. Focal seizure types include those without impairment of consciousness/ awareness (also called simple partial seizure), those where alteration of cognition is a major feature (also called complex partial seizure) and those that evolve into bilateral convulsive seizure (also called secondary generalised tonic clonic seizure) [5]. Focal epilepsies can also be classified based on underlying aetiology; the International League against Epilepsy (ILAE) has revised this to include genetic, structural-metabolic (previously known as symptomatic) and unknown (previously known as cryptogenic/idiopathic) [6]. One of the common causes of focal epilepsy is mesial temporal sclerosis [7]. Other structural causes are central nervous system infections, perinatal injury, cortical 10.1517/14656566.2014.922544 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1543
A. Iyer & A. Marson
Article highlights. . . .
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
.
.
.
Initiating pharmacotherapy requires consideration of patient preferences, evidence of benefit and harm. Most patients would start treatment following a second focal seizure. Carbamazepine and lamotrigine remain good initial monotherapy options. There are several medications that can be used for refractory cases; however, there is no robust evidence to inform a choice among these. The authors would use levetiracetam or clobazam as an add-on therapy in selected cases. The decision to withdraw medication depends on several factors and could be considered in selected cases where seizure freedom has been achieved for > 2 years. Changes in trial designs are needed to improve clinical utility and needs integrated partnership among industry, regulators, health services, patients and other stakeholders.
This box summarises key points contained in the article.
dysplasias, neoplasms, vascular malformations, traumatic brain injury and cerebrovascular events. Certain genetic syndromes such as autosomal dominant nocturnal frontal lobe epilepsy have a well-recognised phenotype with onset during childhood or adolescence. Benign epilepsy with centrotemporal spikes (rolandic epilepsy) is the most common epilepsy with a likely genetic aetiology that presents in childhood. This review focuses on the pharmacological treatment of focal epilepsy in adults and children. We address a number of questions, going through the patients’ journey, including timing of starting initial treatment, initial drug selection, add-on treatment for refractory cases and withdrawal of medication during remission. 2.
Initiating anti-epileptic drug treatment
Pharmacotherapy remains the mainstay of treatment for epilepsy. The number of anti-epileptic drugs (AEDs) has increased over the past 10 years and the clinicians and the patients have several options to discuss. This discussion will include the pros and cons of available options before making a joint informed decision. Nevertheless, initiating treatment is a carefully made decision and the risks of withholding treatment to that of adverse effects with treatment need to be weighed thoughtfully. The risks of recurrence after the first unprovoked seizure has been studied in both observational studies and randomised controlled trials (RCTs). Two large RCTs assessing immediate versus delayed treatment following a first seizure are the first seizure trial (FIR.S.T) [8] and the multicenter epilepsy and single seizure study (MESS) [9]. About 24% (52/215) of patients who were randomised to immediate treatment and 42% (85/204) of patients who were 1544
randomised to delayed treatment experienced a recurrence of seizure in the FIR.S.T trial. In comparison, 43% (311/722) of the immediate treatment group and 53% (382/721) of the deferred treatment group experienced recurrence on follow up with the MESS group. Although immediate treatment increased the time to first seizure and also reduced the time to achieve 2-year remission, it did not influence long-term remission from seizures at between 3 and 5 years of follow up (-0.2% [95% confidence interval (CI): -5.8 -- 5.5%]). A prognostic model was developed based on the individual patient data from the MESS study to identify risk factors for seizure recurrence. This showed that the number of seizures of all types, the presence of a neurological disorder and an abnormal electroencephalogram were significant factors in predicting seizure recurrence [10]. In clinical practice, treatment is usually considered after two or more unprovoked seizures. This recommendation is not informed by RCTs that demonstrate the benefits of starting treatment after two or more seizures but is informed by observational studies that demonstrate the high risk of a third seizure after a second seizure [11]. However, based on the prognostic model from the MESS study, patients at higher risk of seizure recurrence can be identified, in whom initiating AED treatment after the first seizure could be discussed. Therefore, the decision to start medications depends on several factors and clinicians should discuss the pros and cons of initiating treatment with the patient in order to make a decision. 3.
Initial treatment and monotherapy trials
The aim of AED treatment is to achieve seizure freedom with minimal, or ideally no, adverse effects. The selection of the appropriate first AED should take into account several variables, including the patient’s age, epilepsy syndrome, seizure severity, likely benefit and tolerability. These decisions will be informed by data from RCTs; however one needs to bear in mind that most RCTs of AEDs are regulatory trials designed to obtain a marketing license, and although they do provide evidence of efficacy, they may provide limited information to inform every day decision making. Numerous AEDs licensed across the world as monotherapy for focal seizures in adults include carbamazepine (CBZ), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), levetiracetam, phenytoin (PHT), sodium valproate (VPA), zonisamide, lacosamide, pregabalin, oxcarbazepine (OXC), felbamate, clobazam, clonazepam, acetazolamide and sulthiame. Providing an overview of evidence from RCTs in order to make overall recommendations in clinical guidelines is a significant challenge. The ILAE have recently produced an updated evidence review, although this falls short of providing guidance [12,13]. This review highlights the variable design and quality of RCTs of AEDs. They highlight the facts that levetiracetam and zonisamide now have class 1 -- 2 evidence based on regulatory trials showing non-inferiority (but not superiority)
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Table 1. Studies of monotherapy in focal epilepsies. Author (year)
RCT class
Medications compared
Numbers recruited
Outcome (adjusted absolute treatment difference)
Baulac et al. (2012) [35] Brodie et al. (2007) [36] Steinhoff et al. (2005) [37] Ramsay et al. (2010) [38] Marson et al. (2007) [14]
Double-blind, parallel group, non-inferiority Double-blind, parallel group, non-inferiority Open-labelled, comparative Double-blind, 28-day trial, non-inferiority Unblinded
Zonisamide versus carbamazepine Levetiracetam versus carbamazepine Lamotrigine versus carbamazepine Topiramate versus phenytoin Carbamazepine, lamotrigine, gabapentin, oxcarbazepine, topiramate
Zonisamide 282 Carbamazepine 301 Levetiracetam 288 Carbamazepine 291 Lamotrigine 88 Carbamazepine 88 Topiramate 130 Phenytoin 131 Total number 1721
Double-blind, non inferiority
Pregabalin versus lamotrigine
Pregabalin 330 Lamotrigine 330
-4.5% 95% CI 12.2 -- 3.1 0.2%, 95% CI -7.8 -- 8.2 No statistically significant difference Hazard ratio 2 95% CI 0.98 -- 4.12 Time to treatment failure lamotrigine was better than carbamazepine Hazard ratio 0.78 95% CI 0.63 -- 0.97 -0.16% 95% CI -0.24 -- 0.09
Kwan et al. (2011) [39]
RCT: Randomised-controlled trial.
Hazard ratio (95% confidence interval) LTG
0.70 (0.58, 0.83)
OXC
0.88 (0.69, 1.12)
VPA
1.00 (0.82, 1.24)
TPM
1.13 (0.93, 1.37)
GBP
1.16 (0.96, 1.41)
PHT
1.24 (0.98, 1.57)
PB
1.60 (1.22, 2.10)
0.5 HR < 1CBZ worse
1
2
5
HR > 1CBZ better
Figure 1. Time to treatment failure for partial onset seizures (hazard ratio for each AED compared to standard CBZ) is shown. Reproduced from [15]. AED: Anti-epileptic drug; CBZ: Carbamazepine; GBP: Gabapentin; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VPA: Sodium valproate.
when compared to CBZ for 6-month remission. However these trials do not provide data about longer-term outcomes such as 12 months or longer remission rates that will better inform clinical decisions. Other AEDs (CBZ, LTG, OXC, phenobarbitone [PB], TPM, GBP and PHT) were assessed to have class 3 evidence in focal epilepsy. Data reviewed included those from the SANAD trial which was a large open-label pragmatic RCT that compared CBZ, LTG, OXC, TPM and GBP in 1721 patients with focal onset seizures [14]. LTG was noted to be superior for time to treatment failure compared to CBZ but was non-inferior to CBZ for 12-month remission.
A number of Cochrane reviews have been undertaken in which pairs of AEDs have been compared (Table 1). Data from these reviews have also been summarised in a network meta-analysis [15]. The figures below summarise the main results from this meta-analysis. For time to treatment failure, LTG was significantly better than other AEDs and PB was the worst. No significant differences were identified between CBZ and OXC, VPA, TPM, GBP or PHT. However, the CIs around estimates show that the possibility or important differences existing between treatments have not been included. Similarly, for time to 12-month remission, CBZ was significantly better than GBP and VPA, whereas confidence intervals are wide for comparisons with other treatments (Figures 1 and 2). The National Institute of Clinical Excellence, UK, have recently updated their comprehensive guidelines for the management of the epilepsies in children and adults. In addition to comparing the various RCTs to determine efficacy, they have also considered the cost effectiveness of AEDs used as monotherapy for newly diagnosed focal epilepsy. As firstline treatments they recommend offering either CBZ or LTG for focal epilepsy in children, young people and adults. This reflects the routine clinical practice of the authors. Adverse effects and choice of the initial AEDs Given the lack of strong evidence for differences in efficacy between many potential first-line AEDs, differences in adverse effect and safety profiles can have an important influence on treatment choices. Important adverse effect include those that happen in the short to medium term, long-term effects, idiosyncratic reactions and teratogenicity. A practical list of different AEDs, their mechanisms of action and common adverse effects are detailed in Table 2. Consideration of 3.1
Expert Opin. Pharmacother. (2014) 15(11)
1545
A. Iyer & A. Marson
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Hazard ratio (95% confidence interval) OXC
1.00 (0.82, 1.22)
PB
1.01 (0.77, 1.31)
PHT
1.15 (0.94, 1.41)
LTG
1.15 (0.96, 1.37)
TPM
1.19 (0.99, 1.43)
VPA
1.20 (1.01, 1.42)
GBP
1.38 (1.15, 1.67)
0.5 HR < 1CBZ worse
1
2 HR > 1CBZ better
Figure 2. Time to 12-month remission for partial onset seizures (hazard ratio for each AED compared to standard CBZ) is shown. Reproduced from [15]. AED: Anti-epileptic drug; CBZ: Carbamazepine; GBP: Gabapentin; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VPA: Sodium valproate.
pre-existing morbidities (i.e., behavioural problems, appetite and weight loss), drug interactions (i.e., chemotherapy); other associated medical problems (i.e., renal or hepatic impairment); child-bearing potential and enzyme-inducing effects is essential while making a choice of AED. An important concern is prescribing AEDs to women of child-bearing potential and the risk of associated teratogenicity. The International Registry of Anti-epileptic Drugs and Pregnancy prospectively established the risks of major congenital malformations after monotherapy exposure of four different AED (VPA, CBZ, PB and LTG) [16]. They concluded that VPA had a significant risk of multiple congenital malformations at a dose > 1500 mg/day. Other national registries have reported similar results. The risk of major congenital malformations was more in offsprings of women on AED (5%) than among those with untreated epilepsy (3%). The risk was more in women who were on polytherapy; however this depended on which anticonvulsant was used and was particularly high with VPA. There are also concerns about the impact of in-utero AED exposure on neuro-development. This was assessed prospectively in the Neurodevelopmental Effects of Anti-epileptic Drugs (NEAD) study that compared the cognitive outcome of children after in-utero exposure to monotherapy with VPA, CBZ, LTG or PHT. Analysis of children at 6 years of age showed that those exposed to VPA did poorly on measures of verbal and memory abilities compared with that of other AEDs [17,18]. Therefore, VPA is preferably avoided in young women with child-bearing potential. 4.
Refractory epilepsy and add-on trials
The Cochrane Epilepsy Group has published systematic reviews for several AEDs as add-on therapy in refractory focal 1546
epilepsy. Most of the trials included in these reviews are regulatory trials. These trials have important limitations for clinical decision making as they are placebo-controlled, of short duration (usually 3 months), and enrol patients who may not be representative of the general population seen in clinical practice and often use rapid titration schedules. Also, doses used may not be those subsequently adopted in routine practice. Most of these included RCTs and assessed the following outcomes: i) ‡ 50% reduction in seizure frequency; ii) treatment withdrawal (reason); and iii) side effects. A summary of the common AEDs and their efficacy from these meta-analyses is presented in Table 3. Most of the AEDs that have been studied are found to be superior to placebo for achieving ‡ 50% seizure freedom. There are no data on the long-term efficacy or cost effectiveness from these RCTs. Active--control designs wherein a new AED is compared with a standard AED with long-term follow up (e.g., 12 months) would be more informative but would likely be unattractive to industry and regulators and at present would need to be undertaken post marketing. The choice of an individual AED may be informed by knowledge of mechanism of action or of drug interactions and assumptions about synergy. Table 1 summarises the main mechanisms of action of AEDs. Rational polytherapy has been suggested as an approach for combining AEDs, whereby drugs with differing mechanisms of action may be combined. Theoretically this may improve efficacy, while avoiding toxicity. Similarly drugs with the same mechanism of action are avoided as this may be less effective and more likely to cause toxicity. For example, CBZ may be combined with clobazam, rather than with LTG. Although this approach may appear rational, there is no good evidence that patient outcomes are better if this approach is used. Most recently licensed AEDs Newer AEDs have been in the market for some time and the evidence of their use comes from predominantly adult-based RCTs. These AEDs are retigabine, perampanel, eslicarbazepine and lacosamide. We reviewed randomised, double-blind, placebo-controlled or head-to-head studies of adjunctive therapy that used a parallel group design for each of these AEDs. Retigabine, a novel AED that targets the voltage-gated potassium channels, is licensed as an adjunctive therapy for focal epilepsy in adults. Retigabine has been studied in three randomised, double-blind, parallel trials, compared with placebo [19-21]. Its mean responder rate for doses of 1200 mg/day has been 38.7%, and the mean reduction in the 28 days seizure frequency was 39.7%. Dizziness, somnolence, fatigue, confusion, dysarthria, ataxia and blurred vision were the most common adverse effects. Recent concerns regarding abnormal pigmentation of skin and retina have been reported, and as a result it is unlikely that this drug will be widely used. This finding again highlights the importance of evidence of harm that can be derived from sources outside RCTs. 4.1
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
Table 2. A practical handy list of common AEDs used in focal epilepsy, their mechanisms of action and adverse effects.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
AEDs
Mechanism of action
Carbamazepine
Na, Ca
Lamotrigine
Na
Levetiracetam
Synaptic vesicle protein in presynaptic terminals Na, Ca
Oxcarbazepine
Common adverse effects Rash (5 -- 10%), sedation, headache, diplopia, blurred vision, ataxia, tremor, hyponatraemia (elderly) Rash, headache, nausea, diplopia, dizziness, ataxia, tremor
Somnolence, dizziness, headache, behavioural problems in children
Headache, dizziness, somnolence, ataxia, diplopia, rash (5%), hyponatraemia Phenytoin Na Ataxia, somnolence, gingival hyperplasia, hirsutism Topiramate Na, GABA, AMPA, CA Somnolence, anorexia, mental slowing, word-finding difficulties, metabolic acidosis, nephrolithiasis Sodium valproate Na, GABA Tremor, fatal hepatotoxicity (usually children with pre-existing metabolic defects), hair loss, weight gain Pregabalin GABA Weight gain, somnolence, dizziness, increased appetite Clobazam GABA Somnolence Tiagabine GABA Fatigue, headache, dizziness, tremor Zonisamide Na, Ca, CA, Glu Somnolence, dizziness, anorexia, weight loss, tremor, metabolic acidosis, oligohydrosis, nephrolithiasis Lacosamide Slow Na channel inactivation Dizziness, nausea, headache, diplopia
Additional comments Mood stabiliser, enzyme inducer (phenytoin and phenobarbitone reduce levels) Valproate inhibits lamotrigine metabolism Carbamazepine neurotoxicity when given concomitantly. Needs slow titration of doses. Pregnancy leads to lower lamotrigine levels by nearly half needing frequent adjustments No drug interactions
Combination with monoamine oxidase inhibitors to be avoided Narrow therapeutic range and need for monitoring serum levels Behavioural side effects in children
Limited use in focal epilepsies
Tolerance in some patients Enzyme inducers lower concentration Increased risk of metabolic acidosis with other CA drugs Increases PR interval in some cases
AED: Anti-epileptic drug; AMPA: Antagonism with AMPA receptor; CA: Carbonic anhydrase inhibitor; Ca: Inhibition of L-type calcium channels; GABA: Augmentation of GABA-mediated inhibition; Glu: Inhibition of excitatory glutaminergic transmission; Na: Blockade of voltage-gated sodium channels; NK: Not known.
Perampanel is a selective competitive AMPA and glutamate receptor antagonist. It has been licensed for the adjunctive treatment of refractory focal epilepsy in adults. Three Phase III studies [22-26] have demonstrated that the responder rates with adjunctive perampanel were 28.5% (4 mg), 33.3 -- 37.6% (8 mg) and 33.9 -- 36.1% (12 mg), and median reductions in seizure frequency were 23.3% (4 mg), 26.3 -- 30.8% (8 mg) and 17.6 -- 34.5% (12 mg), respectively. Common treatment-related adverse effects include dizziness, headache, somnolence and ataxia. There are no clinically significant pharmacokinetic interactions. The once-daily dosing is an advantage with favourable pharmacokinetic profile. Lacosamide has a unique mode of action in that it selectively enhances the slow inactivation of voltage-gated sodium channels. It has been licensed as an add-on therapy for focal epilepsy in people over the age of 16 years. Three RCTs evaluated its efficacy in focal-onset seizures. Chung et al. [27] performed a multicentre, double-blind, placebo-controlled trial, and found responder rates to be 38.3 and 41.2% for doses of 400 and 600 mg/day (n = 405). In another similar trial by Hala´sz et al. [28], responder rates were 40.5% for
doses of 400 mg/day but were not significant for doses of 200 mg/day (35%) in comparison to placebo (25.8%). BenMenachem et al. [29] performed a similar trial and found responder rates of 33, 41 and 38% for doses of 200, 400 and 600 mg/day (n = 418). Common adverse effects reported were dizziness, nausea, fatigue, ataxia, diplopia and nystagmus. No drug interactions are known. It should be used with caution in people with a history of cardiac conduction problems as it is known to increase the PR interval in adults with known cardiac problems. Eslicarbazepine acetate (ESL) also works by blocking voltage-gated sodium channels. It has been licensed for adjunctive therapy in refractory focal seizures in adults. There are no significant pharmacokinetic interactions and elimination is mainly renal. PHT and phenobarbital increase the clearance of ESL, and PHT levels increase with concomitant ESL. Pooled data from Phase III clinical studies have shown responder rates between 17 and 43% for doses ranging from 800 to 1200 mg/day [30]. Common adverse effects include dizziness, somnolence, nausea, diplopia, headache, vomiting, abnormal coordination and blurred vision.
Expert Opin. Pharmacother. (2014) 15(11)
1547
A. Iyer & A. Marson
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Table 3. Summary of the meta-analyses of AED’s used as an add-on therapy for refractory focal epilepsy. AEDs
Number of RCTs (total number of patients)
OR (95% CI) for $ 50% reduction in seizure frequency
OR (95% CI) for treatment withdrawal
Adverse events
Lamotrigine [1,40]
13 (1524)
2.51 (1.86 -- 3.4)
1.13 (0.83 -- 1.54)
2 (961)
2.96 (2.2 -- 4)
2.17 (1.59 -- 2.97)
Levetiracetam [4,42]
11 (1861)
4.91 (2.75 -- 8.77)
0.98 (0.73 -- 1.32)
Topiramate [43]
10 (1312)
2.85 (2.27 -- 3.59)
2.26 (1.55 -- 3.31)
Zonisamide [8,44]
4 (850)
2.44 (1.81 -- 3.30)
1.64 (1.20 -- 2.26)
Vigabatrin [9,45] Tiagabine [10,46]
11 (747) 6
2.58 (1.87 -- 3.57) 3.16 (1.97 -- 5.07)
2.49 (1.05 -- 5.88) 1.81 (1.2502.62)
Eslicarbazepine acetate [11,47] Pregabalin [12,13,48]
4 (1146)
1.86 (1.46 -- 2.36)
2.26 (0.98 -- 5.21)
6 (2009)
2.61 (1.7 -- 4)
2.69 (1.88 -- 3.86)
Ataxia, dizziness, nausea, somnolence, diplopia Ataxia, dizziness, fatigue, nausea, somnolence, diplopia Somnolence, behavioural changes in children Ataxia, dizziness, fatigue, nausea, somnolence, mental slowing Ataxia, dizziness, somnolence, agitation, anorexia Fatigue, drowsiness Dizziness, fatigue, anxiety, tremor Dizziness, nausea, diplopia Ataxia, dizziness, somnolence, weight gain
Oxcarbazepine [2,3,41]
AED: Anti-epileptic drug; OR: Odds ratio; RCT: Randomised-controlled trial.
4.2
Drug choice in refractory focal epilepsy
The previous sections highlight the fact that there is now a large number of AEDs licensed for treating refractory epilepsy but almost no reliable evidence about comparative clinical or cost effectiveness on which to base a treatment choice. This represents a major deficiency in the current AED development paradigms. In the authors practice the most patients with focal epilepsy will be initiated on LTG or CBZ. First-line add-on treatment is usually with levetiracetam or clobazam, unless there are specific reasons, as highlighted above, to choose an alternative.
5.
Discontinuing therapy and risk of relapse
Discontinuing AED therapy depends on several factors -predominantly the epilepsy syndrome, the aetiology and the ease with which seizure remission was achieved. The decision is influenced by the experience of adverse effects from AEDs, compliance, lifestyle (including driving) and the patients’ outlook on continuing or discontinuing treatment and the risk of recurrence. Many patients may be reluctant to discontinue treatment if they have been well controlled, given the potential implications of a seizure relapse such as losing independence due to fear of a relapse and the resultant psychosocial problems. In children and adolescents, several seemingly benign focal epilepsy syndrome such as benign epilepsy with centrotemporal spikes (rolandic epilepsy) and panayiotopoulos syndrome (benign epilepsy with occipital paroxysms) have a higher chance of 1548
spontaneous remission and treatment can be weaned after 2 -- 3 years of being seizure-free. The Medical Research Council (MRC) AED withdrawal study remains the largest RCT assessing AED withdrawal, and compared the policies of either continued AED treatment or slow AED withdrawal in 1013 patients who had been seizure-free for at least 2 years [31,32]. The study indicated that, for patients who remain seizure-free during drug withdrawal, the risk of seizure recurrence in the immediate 12 months was 30%. Once the patient had been seizure-free for 3 months, the risk is reduced to nearly 15%. For patients who have a seizure recurrence during or following drug withdrawal and in whom treatment is reinstated, the risk of seizure recurrence in the next 12 months was 45%, which reduced to 26% if they were seizure-free for 3 months and 18% if they were seizure-free for 6 months. Another prospective, doubleblinded trial randomised patients who were seizure-free for > 2 years on AED monotherapy to AED withdrawal versus non-withdrawal [33]. Seizure relapse at 12 months occurred in 15% of the withdrawal group and 7% of the non-withdrawal group. After withdrawal, seizure relapse rates were 19% at 2 years. More importantly, a recent review suggested that most patients with seizure recurrence after withdrawal will regain control within a year of the medicine being reinstated [34]. However, in 19% of patients this control may not be as optimal as before. Favourable factors indicating lower risk of seizure recurrence are the use of CBZ monotherapy and normal neurological examination. The decision to withdraw AED needs to discussed in detail with the patient and a joint decision based on informed
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
choice must be agreed. If a decision to discontinue AED is made, then this should be undertaken slowly, possibly over a period of months, to minimise the risk of relapse.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
6.
Conclusion and expert opinion
This paper gives an overview of the approach for treating focal epilepsies and an insight into how to apply the available evidence to inform clinical decision making. Any treatment decision should be a joint decision between clinicians and patients, informed by evidence about likely benefit and harm. Given that epilepsy is a long-term, sometimes lifelong, condition, decisions will require evidence about long-term outcomes. This will include evidence about seizure outcomes (ideally seizure remission), adverse effects, neuropsychological outcomes, quality of life and cost effectiveness. We have some data about these outcomes in the longer term for AED monotherapy but almost no evidence for refractory epilepsy. This is due to the fact that the great majority of AED trials have been undertaken to inform drug regulatory decisions. Few trials have been undertaken with the primary intention of informing day-to-day clinical decisions where usually a choice is made among available alternatives. These trials are usually undertaken post marketing and have largely been funded by sources other than the pharmaceutical industry such as the MRC of the Health Technology Assessment Programme in the UK or the Veterans Administration in the USA. The current state of affairs raised a number of important questions. First, should regulatory trials do more to inform clinical decision making? The obvious answer to this question is yes as it is extremely inefficient for both industry and health services for a drug to come to market based on data that does not inform clinician decision making. However, changes to trial design that make them more useful to clinicians and patients might make them less attractive to industry and the regulator. For example, head-to-head actively controlled add-on trials might be difficult to interpret from a regulatory perspective unless superior efficacy is found; non-inferiority is the current benchmark for monotherapy licensing in the EU but is not considered acceptable by the FDA in the USA. Changes in trial design to improve clinical utility will require much closer working between industry, regulators, health services, patients, professional organisations and other stakeholders. This would seem long overdue. Given that we have a number of marketed AEDs based on trials with limited clinical utility, the second question is who should fund post-marketing head-to-head RCTs, industry or another funder such as the public purse or charity. Although one could argue that industry has significant resource to spend, such trials may be unattractive to industry as patents are likely to have expired by the time results are available.
Also, industry funding will carry the taint of industry involvement and suspicion if bias, even if rigorously carried out. It may be preferable, therefore, for health services or payors to fund such trials who stand to gain from results that will help ensure the most cost-effective use of health service resource. For example, in the UK, the Department of Health has an extensive Health Technology Assessment Programme that funds a large number of RCTs. When starting AED treatment, as a general principle, it is important whenever possible to classify the epilepsy syndrome as this may inform initial treatment choice, but more importantly it may inform likely prognosis with whatever treatment is chosen. CBZ and LTG are recommended first-line treatments. A number of newer AEDs are licensed for use as monotherapy but none have convincing evidence of clinical or cost effectiveness. Although some of the newer AEDS may be better tolerated than older standard treatments, it is disappointing to highlight that none of the new AEDs has been shown to have superior efficacy. There is an ever-increasing number of AEDs available to use as add-on treatment in refractory epilepsy. Unfortunately, there is no reliable evidence from RCTs to inform a choice among alternatives as few head-to-head trials have been undertaken. Treatment choices might be informed by knowledge of adverse events and drug interactions. The authors use levetiracetam or clobazam as first-line add-on treatments. We do have some evidence from RCTs to inform as to whether to discontinue or withdraw AED treatment once a sustained period of remission has been achieved, but the decision is complex, and ultimately it should be the patients’ decision. In the authors practice, the default decision is to stay on AED treatment, unless the patient has made a clear decision to attempt AED withdrawal. In conclusion, we have some evidence from RCTs and other sources to inform decisions at a number of stages in the patients’ journey. However, the evidence base is largely inadequate which is to the detriment of patient and the economy as there is uncertainty about the most effective treatment or policy. Clinicians, patients, industry, regulators, health services and other stakeholders need to work together more effectively to generate an evidence base that is fit for purpose and to ensure that future treatments are more adequately assessed.
Declaration of interest A Marson has received research funding from GSK, UCB, Eisai and Honoraria for Sanofi. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Pharmacother. (2014) 15(11)
1549
A. Iyer & A. Marson
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
2.
Ngugi AK, Kariuki SM, Bottomley C, et al. Incidence of epilepsy: a systematic review and meta-analysis. Neurology 2011;77:1005-12 Jacoby A, Snape D, Baker GA. Epilepsy and social identity: the stigma of a chronic neurological disorder. Lancet Neurol 2005;4:171-8
3.
Hermann B, Jacoby A. The psychosocial impact of epilepsy in adults. Epilepsy Behav 2009;15:S11-16
4.
Shankar R, Cox D, Jalihal V, et al. Sudden unexpected death in epilepsy (SUDEP): Development of a safety checklist. Seizure 2013;22(10):812-7
5.
6.
Blume WT, Lu¨ders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:1212-18 Panayiotopoulos CP. The new ILAE report on terminology and concepts for the organization of epilepsies: critical review and contribution. Epilepsia 2012;53:399-404
7.
Blumcke I. Neuropathology of focal epilepsies: a critical review. Epilepsy Behav 2009;15:34-9
8.
Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonicclonic seizure. First Seizure Trial Group (FIR.S.T. Group). Neurology 1993;43:478-83 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures.
.
9.
.
10.
1550
..
Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet 2005;365:2007-13 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures. Kim LG, Johnson TL, Marson AG, et al. MRC MESS Study group. Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results
from the MESS trial. Lancet Neurol 2006;5:317-22 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures.
11.
Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seiures after two unprovoked seizures. N Engl J Med 1998;7:429-34
12.
Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094-120
13.
.
14.
..
15.
..
16.
Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551-63 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000-15 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Tudur Smith C, Marson AG, Chadwick DW, Williamson PR. Multiple treatment comparisons in epilepsy monotherapy trials. Trials 2007;8:34 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;10:609-17
Expert Opin. Pharmacother. (2014) 15(11)
17.
.
Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012;11:803-13 This is an important paper detailing the teratogenic effects of anti-epileptic medications.
18.
Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12:244-52
19.
Porter RJ, Partiot A, Sachdeo R, et al. on behalf of the 205 Study Group. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007;68:1197-204
20.
French JA, Abou-Khalil BW, Leroy RF, et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology 2011;76:1555-63
21.
Splinter MY. Ezogabine (retigabine) and its role in the treatment of partial-onset seizures: a review. Clin Ther 2012;34:1845-1856.e1
22.
French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2012;54:117-25
23.
Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: Interim results from phase III, extension study 307. Epilepsia 2012;54:126-34
24.
Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408-15
25.
Rektor I. Perampanel, a novel, noncompetitive, selective AMPA receptor antagonist as adjunctive therapy for treatment-resistant partial-onset seizures. Expert Opin Pharmacother 2013;14:225-35
26.
Hsu WW, Sing CW, He Y, et al. Systematic review and meta-analysis of the efficacy and safety of perampanel in
Pharmacotherapy of focal epilepsy
the treatment of partial-onset epilepsy. CNS Drugs 2013;27:817-27 27.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
28.
29.
30.
31.
32.
..
33.
Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51:958-67
34.
Schmidt D, Loscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience. Acta Neurol Scand 2005;111:291-300
35.
Baulac M, Brodie MJ, Patten A, et al. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012;11:579-88
Hala´sz P, Ka¨lvia¨inen R, Mazurkiewicz-Beldzin´ska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443-53 Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308-17 Verrotti A, Loiacono G, Rossi A, Zaccara G. Eslicarbazepine acetate: an update on efficacy and safety in epilepsy. Epilepsy Res 2014;108:1-10 Chadwick D. Does withdrawal of different antiepileptic drugs have different effects on seizure recurrence? Further results from the MRC Antiepileptic Drug Withdrawal Study. Brain 1999;122(Pt 3):441-8 Bonnett LJ, Shukralla A, Tudur-Smith C, et al. Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review. J Neurol Neurosurg Psychiatry 2011;82:1328-33 This is an important paper discussing the risk of seizure recurrence after medication withdrawal and its implications. Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia 2008;49:455-63
36.
37.
38.
39.
Brodie MJ, Perucca E, Ryvlin P, et al. for the Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402-8 Steinhoff BJ, Ueberall MA, Siemes H, et al. The LAM-SAFE. Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults. Seizure 2005;14:597-605 Ramsay E, Faught E, Krumholz A, et al. Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial. Epilepsia 2010;51:1970-7 Kwan P, Brodie MJ, Kalviainen R, et al. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011;10:881-90
40.
Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2001(3):CD001909
41.
Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000(3):CD002028
Expert Opin. Pharmacother. (2014) 15(11)
42.
Mbizvo GK, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database Syst Rev 2012;9:CD001901
43.
Jette N, Hemming K, Hutton JL, Marson AG. Topiramate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2008(3):CD001417
44.
Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2005(4):CD001416
45.
Hemming K, Maguire MJ, Hutton JL, Marson AG. Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev 2013;1:CD007302
46.
Pulman J, Hutton JL, Marson AG. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2014;2:CD001908
47.
Chang XC, Yuan H, Wang Y, et al. Eslicarbazepine acetate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2011(12):CD008907
48.
Lozsadi D, Hemming K, Marson AG. Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2008(1):CD005612
Affiliation
Anand Iyer1,2 & Anthony Marson†1 † Author for correspondence 1 The Walton Centre for Neurology and Neurosurgery NHS Foundation Trust, Liverpool, UK E-mail: [email protected] 2 Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
1551
Pharmacotherapy of focal epilepsy Anand Iyer & Anthony Marson† †
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
The Walton Centre for Neurology and Neurosurgery NHS Foundation Trust, Liverpool, UK
1.
Introduction
2.
Initiating anti-epileptic drug treatment
3.
Initial treatment and monotherapy trials
4.
Refractory epilepsy and add-on trials
5.
Discontinuing therapy and risk of relapse
6.
Conclusion and expert opinion
Introduction: Epilepsy is the most common neurological condition worldwide with significant psychosocial and physical morbidity. Its management requires expertise and good pharmacological knowledge of the available options. Areas covered: This review covers the management of focal epilepsy addressing the common questions arising through the patients’ journey, including timing of starting initial treatment, monotherapy options, add-on treatment for refractory cases and withdrawal of medication during remission. Expert opinion: Initiating anti-epileptic drug (AED) treatment requires assessment of patient preferences and of evidence of benefit and harm. Evidence of benefit will come primarily from randomised controlled trials, although in epilepsy, most trials are undertaken to inform regulatory decision and have important limitations for informing clinical decisions. Evidence about harm may come not only from randomised trials but also from other sources. Most patients will start treatment following a second focal seizure. Carbamazepine and lamotrigine are good initial monotherapy options. Newer AEDs have proof of efficacy as monotherapy but evidence is insufficient to recommend them as first-line treatments. For refractory cases, there are an increasing number of AEDs available, but evidence of efficacy is primarily from placebo-controlled trials, and there is no robust evidence to inform a choice among treatments. Keywords: anti-epileptic drugs, focal epilepsy, monotherapy, refractory, relapse Expert Opin. Pharmacother. (2014) 15(11):1543-1551
1.
Introduction
Epilepsy is the one of the most common neurological disorders; its mean incidence has been reported as 50.4/100,000/year, with peaks of incidence in children and the elderly. Prevalence has been estimated at 0.5 -- 1.0%, although prevalence is higher in low- and middle-income countries [1]. There is a high degree of associated psychological distress, stigma and social disadvantage [1-3]. Epilepsy is also associated with a higher mortality; the standardised mortality rate has been reported to be 2 -- 4 by epidemiological studies, and sudden unexpected death in epilepsy accounts for about 500 deaths a year in the UK [4]. The overall management of epilepsy needs not only expertise but also considerations to the associated comorbidities, and many clinicians treat epilepsy as a syndrome complex, rather than just a diagnosis in itself. Focal epilepsies are the most common type in adults, where seizures arise from focus somewhere within the cerebral cortex, most commonly in a temporal or frontal lobe. Focal seizure types include those without impairment of consciousness/ awareness (also called simple partial seizure), those where alteration of cognition is a major feature (also called complex partial seizure) and those that evolve into bilateral convulsive seizure (also called secondary generalised tonic clonic seizure) [5]. Focal epilepsies can also be classified based on underlying aetiology; the International League against Epilepsy (ILAE) has revised this to include genetic, structural-metabolic (previously known as symptomatic) and unknown (previously known as cryptogenic/idiopathic) [6]. One of the common causes of focal epilepsy is mesial temporal sclerosis [7]. Other structural causes are central nervous system infections, perinatal injury, cortical 10.1517/14656566.2014.922544 © 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1543
A. Iyer & A. Marson
Article highlights. . . .
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
.
.
.
Initiating pharmacotherapy requires consideration of patient preferences, evidence of benefit and harm. Most patients would start treatment following a second focal seizure. Carbamazepine and lamotrigine remain good initial monotherapy options. There are several medications that can be used for refractory cases; however, there is no robust evidence to inform a choice among these. The authors would use levetiracetam or clobazam as an add-on therapy in selected cases. The decision to withdraw medication depends on several factors and could be considered in selected cases where seizure freedom has been achieved for > 2 years. Changes in trial designs are needed to improve clinical utility and needs integrated partnership among industry, regulators, health services, patients and other stakeholders.
This box summarises key points contained in the article.
dysplasias, neoplasms, vascular malformations, traumatic brain injury and cerebrovascular events. Certain genetic syndromes such as autosomal dominant nocturnal frontal lobe epilepsy have a well-recognised phenotype with onset during childhood or adolescence. Benign epilepsy with centrotemporal spikes (rolandic epilepsy) is the most common epilepsy with a likely genetic aetiology that presents in childhood. This review focuses on the pharmacological treatment of focal epilepsy in adults and children. We address a number of questions, going through the patients’ journey, including timing of starting initial treatment, initial drug selection, add-on treatment for refractory cases and withdrawal of medication during remission. 2.
Initiating anti-epileptic drug treatment
Pharmacotherapy remains the mainstay of treatment for epilepsy. The number of anti-epileptic drugs (AEDs) has increased over the past 10 years and the clinicians and the patients have several options to discuss. This discussion will include the pros and cons of available options before making a joint informed decision. Nevertheless, initiating treatment is a carefully made decision and the risks of withholding treatment to that of adverse effects with treatment need to be weighed thoughtfully. The risks of recurrence after the first unprovoked seizure has been studied in both observational studies and randomised controlled trials (RCTs). Two large RCTs assessing immediate versus delayed treatment following a first seizure are the first seizure trial (FIR.S.T) [8] and the multicenter epilepsy and single seizure study (MESS) [9]. About 24% (52/215) of patients who were randomised to immediate treatment and 42% (85/204) of patients who were 1544
randomised to delayed treatment experienced a recurrence of seizure in the FIR.S.T trial. In comparison, 43% (311/722) of the immediate treatment group and 53% (382/721) of the deferred treatment group experienced recurrence on follow up with the MESS group. Although immediate treatment increased the time to first seizure and also reduced the time to achieve 2-year remission, it did not influence long-term remission from seizures at between 3 and 5 years of follow up (-0.2% [95% confidence interval (CI): -5.8 -- 5.5%]). A prognostic model was developed based on the individual patient data from the MESS study to identify risk factors for seizure recurrence. This showed that the number of seizures of all types, the presence of a neurological disorder and an abnormal electroencephalogram were significant factors in predicting seizure recurrence [10]. In clinical practice, treatment is usually considered after two or more unprovoked seizures. This recommendation is not informed by RCTs that demonstrate the benefits of starting treatment after two or more seizures but is informed by observational studies that demonstrate the high risk of a third seizure after a second seizure [11]. However, based on the prognostic model from the MESS study, patients at higher risk of seizure recurrence can be identified, in whom initiating AED treatment after the first seizure could be discussed. Therefore, the decision to start medications depends on several factors and clinicians should discuss the pros and cons of initiating treatment with the patient in order to make a decision. 3.
Initial treatment and monotherapy trials
The aim of AED treatment is to achieve seizure freedom with minimal, or ideally no, adverse effects. The selection of the appropriate first AED should take into account several variables, including the patient’s age, epilepsy syndrome, seizure severity, likely benefit and tolerability. These decisions will be informed by data from RCTs; however one needs to bear in mind that most RCTs of AEDs are regulatory trials designed to obtain a marketing license, and although they do provide evidence of efficacy, they may provide limited information to inform every day decision making. Numerous AEDs licensed across the world as monotherapy for focal seizures in adults include carbamazepine (CBZ), lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), levetiracetam, phenytoin (PHT), sodium valproate (VPA), zonisamide, lacosamide, pregabalin, oxcarbazepine (OXC), felbamate, clobazam, clonazepam, acetazolamide and sulthiame. Providing an overview of evidence from RCTs in order to make overall recommendations in clinical guidelines is a significant challenge. The ILAE have recently produced an updated evidence review, although this falls short of providing guidance [12,13]. This review highlights the variable design and quality of RCTs of AEDs. They highlight the facts that levetiracetam and zonisamide now have class 1 -- 2 evidence based on regulatory trials showing non-inferiority (but not superiority)
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Table 1. Studies of monotherapy in focal epilepsies. Author (year)
RCT class
Medications compared
Numbers recruited
Outcome (adjusted absolute treatment difference)
Baulac et al. (2012) [35] Brodie et al. (2007) [36] Steinhoff et al. (2005) [37] Ramsay et al. (2010) [38] Marson et al. (2007) [14]
Double-blind, parallel group, non-inferiority Double-blind, parallel group, non-inferiority Open-labelled, comparative Double-blind, 28-day trial, non-inferiority Unblinded
Zonisamide versus carbamazepine Levetiracetam versus carbamazepine Lamotrigine versus carbamazepine Topiramate versus phenytoin Carbamazepine, lamotrigine, gabapentin, oxcarbazepine, topiramate
Zonisamide 282 Carbamazepine 301 Levetiracetam 288 Carbamazepine 291 Lamotrigine 88 Carbamazepine 88 Topiramate 130 Phenytoin 131 Total number 1721
Double-blind, non inferiority
Pregabalin versus lamotrigine
Pregabalin 330 Lamotrigine 330
-4.5% 95% CI 12.2 -- 3.1 0.2%, 95% CI -7.8 -- 8.2 No statistically significant difference Hazard ratio 2 95% CI 0.98 -- 4.12 Time to treatment failure lamotrigine was better than carbamazepine Hazard ratio 0.78 95% CI 0.63 -- 0.97 -0.16% 95% CI -0.24 -- 0.09
Kwan et al. (2011) [39]
RCT: Randomised-controlled trial.
Hazard ratio (95% confidence interval) LTG
0.70 (0.58, 0.83)
OXC
0.88 (0.69, 1.12)
VPA
1.00 (0.82, 1.24)
TPM
1.13 (0.93, 1.37)
GBP
1.16 (0.96, 1.41)
PHT
1.24 (0.98, 1.57)
PB
1.60 (1.22, 2.10)
0.5 HR < 1CBZ worse
1
2
5
HR > 1CBZ better
Figure 1. Time to treatment failure for partial onset seizures (hazard ratio for each AED compared to standard CBZ) is shown. Reproduced from [15]. AED: Anti-epileptic drug; CBZ: Carbamazepine; GBP: Gabapentin; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VPA: Sodium valproate.
when compared to CBZ for 6-month remission. However these trials do not provide data about longer-term outcomes such as 12 months or longer remission rates that will better inform clinical decisions. Other AEDs (CBZ, LTG, OXC, phenobarbitone [PB], TPM, GBP and PHT) were assessed to have class 3 evidence in focal epilepsy. Data reviewed included those from the SANAD trial which was a large open-label pragmatic RCT that compared CBZ, LTG, OXC, TPM and GBP in 1721 patients with focal onset seizures [14]. LTG was noted to be superior for time to treatment failure compared to CBZ but was non-inferior to CBZ for 12-month remission.
A number of Cochrane reviews have been undertaken in which pairs of AEDs have been compared (Table 1). Data from these reviews have also been summarised in a network meta-analysis [15]. The figures below summarise the main results from this meta-analysis. For time to treatment failure, LTG was significantly better than other AEDs and PB was the worst. No significant differences were identified between CBZ and OXC, VPA, TPM, GBP or PHT. However, the CIs around estimates show that the possibility or important differences existing between treatments have not been included. Similarly, for time to 12-month remission, CBZ was significantly better than GBP and VPA, whereas confidence intervals are wide for comparisons with other treatments (Figures 1 and 2). The National Institute of Clinical Excellence, UK, have recently updated their comprehensive guidelines for the management of the epilepsies in children and adults. In addition to comparing the various RCTs to determine efficacy, they have also considered the cost effectiveness of AEDs used as monotherapy for newly diagnosed focal epilepsy. As firstline treatments they recommend offering either CBZ or LTG for focal epilepsy in children, young people and adults. This reflects the routine clinical practice of the authors. Adverse effects and choice of the initial AEDs Given the lack of strong evidence for differences in efficacy between many potential first-line AEDs, differences in adverse effect and safety profiles can have an important influence on treatment choices. Important adverse effect include those that happen in the short to medium term, long-term effects, idiosyncratic reactions and teratogenicity. A practical list of different AEDs, their mechanisms of action and common adverse effects are detailed in Table 2. Consideration of 3.1
Expert Opin. Pharmacother. (2014) 15(11)
1545
A. Iyer & A. Marson
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Hazard ratio (95% confidence interval) OXC
1.00 (0.82, 1.22)
PB
1.01 (0.77, 1.31)
PHT
1.15 (0.94, 1.41)
LTG
1.15 (0.96, 1.37)
TPM
1.19 (0.99, 1.43)
VPA
1.20 (1.01, 1.42)
GBP
1.38 (1.15, 1.67)
0.5 HR < 1CBZ worse
1
2 HR > 1CBZ better
Figure 2. Time to 12-month remission for partial onset seizures (hazard ratio for each AED compared to standard CBZ) is shown. Reproduced from [15]. AED: Anti-epileptic drug; CBZ: Carbamazepine; GBP: Gabapentin; LTG: Lamotrigine; OXC: Oxcarbazepine; PB: Phenobarbitone; PHT: Phenytoin; TPM: Topiramate; VPA: Sodium valproate.
pre-existing morbidities (i.e., behavioural problems, appetite and weight loss), drug interactions (i.e., chemotherapy); other associated medical problems (i.e., renal or hepatic impairment); child-bearing potential and enzyme-inducing effects is essential while making a choice of AED. An important concern is prescribing AEDs to women of child-bearing potential and the risk of associated teratogenicity. The International Registry of Anti-epileptic Drugs and Pregnancy prospectively established the risks of major congenital malformations after monotherapy exposure of four different AED (VPA, CBZ, PB and LTG) [16]. They concluded that VPA had a significant risk of multiple congenital malformations at a dose > 1500 mg/day. Other national registries have reported similar results. The risk of major congenital malformations was more in offsprings of women on AED (5%) than among those with untreated epilepsy (3%). The risk was more in women who were on polytherapy; however this depended on which anticonvulsant was used and was particularly high with VPA. There are also concerns about the impact of in-utero AED exposure on neuro-development. This was assessed prospectively in the Neurodevelopmental Effects of Anti-epileptic Drugs (NEAD) study that compared the cognitive outcome of children after in-utero exposure to monotherapy with VPA, CBZ, LTG or PHT. Analysis of children at 6 years of age showed that those exposed to VPA did poorly on measures of verbal and memory abilities compared with that of other AEDs [17,18]. Therefore, VPA is preferably avoided in young women with child-bearing potential. 4.
Refractory epilepsy and add-on trials
The Cochrane Epilepsy Group has published systematic reviews for several AEDs as add-on therapy in refractory focal 1546
epilepsy. Most of the trials included in these reviews are regulatory trials. These trials have important limitations for clinical decision making as they are placebo-controlled, of short duration (usually 3 months), and enrol patients who may not be representative of the general population seen in clinical practice and often use rapid titration schedules. Also, doses used may not be those subsequently adopted in routine practice. Most of these included RCTs and assessed the following outcomes: i) ‡ 50% reduction in seizure frequency; ii) treatment withdrawal (reason); and iii) side effects. A summary of the common AEDs and their efficacy from these meta-analyses is presented in Table 3. Most of the AEDs that have been studied are found to be superior to placebo for achieving ‡ 50% seizure freedom. There are no data on the long-term efficacy or cost effectiveness from these RCTs. Active--control designs wherein a new AED is compared with a standard AED with long-term follow up (e.g., 12 months) would be more informative but would likely be unattractive to industry and regulators and at present would need to be undertaken post marketing. The choice of an individual AED may be informed by knowledge of mechanism of action or of drug interactions and assumptions about synergy. Table 1 summarises the main mechanisms of action of AEDs. Rational polytherapy has been suggested as an approach for combining AEDs, whereby drugs with differing mechanisms of action may be combined. Theoretically this may improve efficacy, while avoiding toxicity. Similarly drugs with the same mechanism of action are avoided as this may be less effective and more likely to cause toxicity. For example, CBZ may be combined with clobazam, rather than with LTG. Although this approach may appear rational, there is no good evidence that patient outcomes are better if this approach is used. Most recently licensed AEDs Newer AEDs have been in the market for some time and the evidence of their use comes from predominantly adult-based RCTs. These AEDs are retigabine, perampanel, eslicarbazepine and lacosamide. We reviewed randomised, double-blind, placebo-controlled or head-to-head studies of adjunctive therapy that used a parallel group design for each of these AEDs. Retigabine, a novel AED that targets the voltage-gated potassium channels, is licensed as an adjunctive therapy for focal epilepsy in adults. Retigabine has been studied in three randomised, double-blind, parallel trials, compared with placebo [19-21]. Its mean responder rate for doses of 1200 mg/day has been 38.7%, and the mean reduction in the 28 days seizure frequency was 39.7%. Dizziness, somnolence, fatigue, confusion, dysarthria, ataxia and blurred vision were the most common adverse effects. Recent concerns regarding abnormal pigmentation of skin and retina have been reported, and as a result it is unlikely that this drug will be widely used. This finding again highlights the importance of evidence of harm that can be derived from sources outside RCTs. 4.1
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
Table 2. A practical handy list of common AEDs used in focal epilepsy, their mechanisms of action and adverse effects.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
AEDs
Mechanism of action
Carbamazepine
Na, Ca
Lamotrigine
Na
Levetiracetam
Synaptic vesicle protein in presynaptic terminals Na, Ca
Oxcarbazepine
Common adverse effects Rash (5 -- 10%), sedation, headache, diplopia, blurred vision, ataxia, tremor, hyponatraemia (elderly) Rash, headache, nausea, diplopia, dizziness, ataxia, tremor
Somnolence, dizziness, headache, behavioural problems in children
Headache, dizziness, somnolence, ataxia, diplopia, rash (5%), hyponatraemia Phenytoin Na Ataxia, somnolence, gingival hyperplasia, hirsutism Topiramate Na, GABA, AMPA, CA Somnolence, anorexia, mental slowing, word-finding difficulties, metabolic acidosis, nephrolithiasis Sodium valproate Na, GABA Tremor, fatal hepatotoxicity (usually children with pre-existing metabolic defects), hair loss, weight gain Pregabalin GABA Weight gain, somnolence, dizziness, increased appetite Clobazam GABA Somnolence Tiagabine GABA Fatigue, headache, dizziness, tremor Zonisamide Na, Ca, CA, Glu Somnolence, dizziness, anorexia, weight loss, tremor, metabolic acidosis, oligohydrosis, nephrolithiasis Lacosamide Slow Na channel inactivation Dizziness, nausea, headache, diplopia
Additional comments Mood stabiliser, enzyme inducer (phenytoin and phenobarbitone reduce levels) Valproate inhibits lamotrigine metabolism Carbamazepine neurotoxicity when given concomitantly. Needs slow titration of doses. Pregnancy leads to lower lamotrigine levels by nearly half needing frequent adjustments No drug interactions
Combination with monoamine oxidase inhibitors to be avoided Narrow therapeutic range and need for monitoring serum levels Behavioural side effects in children
Limited use in focal epilepsies
Tolerance in some patients Enzyme inducers lower concentration Increased risk of metabolic acidosis with other CA drugs Increases PR interval in some cases
AED: Anti-epileptic drug; AMPA: Antagonism with AMPA receptor; CA: Carbonic anhydrase inhibitor; Ca: Inhibition of L-type calcium channels; GABA: Augmentation of GABA-mediated inhibition; Glu: Inhibition of excitatory glutaminergic transmission; Na: Blockade of voltage-gated sodium channels; NK: Not known.
Perampanel is a selective competitive AMPA and glutamate receptor antagonist. It has been licensed for the adjunctive treatment of refractory focal epilepsy in adults. Three Phase III studies [22-26] have demonstrated that the responder rates with adjunctive perampanel were 28.5% (4 mg), 33.3 -- 37.6% (8 mg) and 33.9 -- 36.1% (12 mg), and median reductions in seizure frequency were 23.3% (4 mg), 26.3 -- 30.8% (8 mg) and 17.6 -- 34.5% (12 mg), respectively. Common treatment-related adverse effects include dizziness, headache, somnolence and ataxia. There are no clinically significant pharmacokinetic interactions. The once-daily dosing is an advantage with favourable pharmacokinetic profile. Lacosamide has a unique mode of action in that it selectively enhances the slow inactivation of voltage-gated sodium channels. It has been licensed as an add-on therapy for focal epilepsy in people over the age of 16 years. Three RCTs evaluated its efficacy in focal-onset seizures. Chung et al. [27] performed a multicentre, double-blind, placebo-controlled trial, and found responder rates to be 38.3 and 41.2% for doses of 400 and 600 mg/day (n = 405). In another similar trial by Hala´sz et al. [28], responder rates were 40.5% for
doses of 400 mg/day but were not significant for doses of 200 mg/day (35%) in comparison to placebo (25.8%). BenMenachem et al. [29] performed a similar trial and found responder rates of 33, 41 and 38% for doses of 200, 400 and 600 mg/day (n = 418). Common adverse effects reported were dizziness, nausea, fatigue, ataxia, diplopia and nystagmus. No drug interactions are known. It should be used with caution in people with a history of cardiac conduction problems as it is known to increase the PR interval in adults with known cardiac problems. Eslicarbazepine acetate (ESL) also works by blocking voltage-gated sodium channels. It has been licensed for adjunctive therapy in refractory focal seizures in adults. There are no significant pharmacokinetic interactions and elimination is mainly renal. PHT and phenobarbital increase the clearance of ESL, and PHT levels increase with concomitant ESL. Pooled data from Phase III clinical studies have shown responder rates between 17 and 43% for doses ranging from 800 to 1200 mg/day [30]. Common adverse effects include dizziness, somnolence, nausea, diplopia, headache, vomiting, abnormal coordination and blurred vision.
Expert Opin. Pharmacother. (2014) 15(11)
1547
A. Iyer & A. Marson
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
Table 3. Summary of the meta-analyses of AED’s used as an add-on therapy for refractory focal epilepsy. AEDs
Number of RCTs (total number of patients)
OR (95% CI) for $ 50% reduction in seizure frequency
OR (95% CI) for treatment withdrawal
Adverse events
Lamotrigine [1,40]
13 (1524)
2.51 (1.86 -- 3.4)
1.13 (0.83 -- 1.54)
2 (961)
2.96 (2.2 -- 4)
2.17 (1.59 -- 2.97)
Levetiracetam [4,42]
11 (1861)
4.91 (2.75 -- 8.77)
0.98 (0.73 -- 1.32)
Topiramate [43]
10 (1312)
2.85 (2.27 -- 3.59)
2.26 (1.55 -- 3.31)
Zonisamide [8,44]
4 (850)
2.44 (1.81 -- 3.30)
1.64 (1.20 -- 2.26)
Vigabatrin [9,45] Tiagabine [10,46]
11 (747) 6
2.58 (1.87 -- 3.57) 3.16 (1.97 -- 5.07)
2.49 (1.05 -- 5.88) 1.81 (1.2502.62)
Eslicarbazepine acetate [11,47] Pregabalin [12,13,48]
4 (1146)
1.86 (1.46 -- 2.36)
2.26 (0.98 -- 5.21)
6 (2009)
2.61 (1.7 -- 4)
2.69 (1.88 -- 3.86)
Ataxia, dizziness, nausea, somnolence, diplopia Ataxia, dizziness, fatigue, nausea, somnolence, diplopia Somnolence, behavioural changes in children Ataxia, dizziness, fatigue, nausea, somnolence, mental slowing Ataxia, dizziness, somnolence, agitation, anorexia Fatigue, drowsiness Dizziness, fatigue, anxiety, tremor Dizziness, nausea, diplopia Ataxia, dizziness, somnolence, weight gain
Oxcarbazepine [2,3,41]
AED: Anti-epileptic drug; OR: Odds ratio; RCT: Randomised-controlled trial.
4.2
Drug choice in refractory focal epilepsy
The previous sections highlight the fact that there is now a large number of AEDs licensed for treating refractory epilepsy but almost no reliable evidence about comparative clinical or cost effectiveness on which to base a treatment choice. This represents a major deficiency in the current AED development paradigms. In the authors practice the most patients with focal epilepsy will be initiated on LTG or CBZ. First-line add-on treatment is usually with levetiracetam or clobazam, unless there are specific reasons, as highlighted above, to choose an alternative.
5.
Discontinuing therapy and risk of relapse
Discontinuing AED therapy depends on several factors -predominantly the epilepsy syndrome, the aetiology and the ease with which seizure remission was achieved. The decision is influenced by the experience of adverse effects from AEDs, compliance, lifestyle (including driving) and the patients’ outlook on continuing or discontinuing treatment and the risk of recurrence. Many patients may be reluctant to discontinue treatment if they have been well controlled, given the potential implications of a seizure relapse such as losing independence due to fear of a relapse and the resultant psychosocial problems. In children and adolescents, several seemingly benign focal epilepsy syndrome such as benign epilepsy with centrotemporal spikes (rolandic epilepsy) and panayiotopoulos syndrome (benign epilepsy with occipital paroxysms) have a higher chance of 1548
spontaneous remission and treatment can be weaned after 2 -- 3 years of being seizure-free. The Medical Research Council (MRC) AED withdrawal study remains the largest RCT assessing AED withdrawal, and compared the policies of either continued AED treatment or slow AED withdrawal in 1013 patients who had been seizure-free for at least 2 years [31,32]. The study indicated that, for patients who remain seizure-free during drug withdrawal, the risk of seizure recurrence in the immediate 12 months was 30%. Once the patient had been seizure-free for 3 months, the risk is reduced to nearly 15%. For patients who have a seizure recurrence during or following drug withdrawal and in whom treatment is reinstated, the risk of seizure recurrence in the next 12 months was 45%, which reduced to 26% if they were seizure-free for 3 months and 18% if they were seizure-free for 6 months. Another prospective, doubleblinded trial randomised patients who were seizure-free for > 2 years on AED monotherapy to AED withdrawal versus non-withdrawal [33]. Seizure relapse at 12 months occurred in 15% of the withdrawal group and 7% of the non-withdrawal group. After withdrawal, seizure relapse rates were 19% at 2 years. More importantly, a recent review suggested that most patients with seizure recurrence after withdrawal will regain control within a year of the medicine being reinstated [34]. However, in 19% of patients this control may not be as optimal as before. Favourable factors indicating lower risk of seizure recurrence are the use of CBZ monotherapy and normal neurological examination. The decision to withdraw AED needs to discussed in detail with the patient and a joint decision based on informed
Expert Opin. Pharmacother. (2014) 15(11)
Pharmacotherapy of focal epilepsy
choice must be agreed. If a decision to discontinue AED is made, then this should be undertaken slowly, possibly over a period of months, to minimise the risk of relapse.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
6.
Conclusion and expert opinion
This paper gives an overview of the approach for treating focal epilepsies and an insight into how to apply the available evidence to inform clinical decision making. Any treatment decision should be a joint decision between clinicians and patients, informed by evidence about likely benefit and harm. Given that epilepsy is a long-term, sometimes lifelong, condition, decisions will require evidence about long-term outcomes. This will include evidence about seizure outcomes (ideally seizure remission), adverse effects, neuropsychological outcomes, quality of life and cost effectiveness. We have some data about these outcomes in the longer term for AED monotherapy but almost no evidence for refractory epilepsy. This is due to the fact that the great majority of AED trials have been undertaken to inform drug regulatory decisions. Few trials have been undertaken with the primary intention of informing day-to-day clinical decisions where usually a choice is made among available alternatives. These trials are usually undertaken post marketing and have largely been funded by sources other than the pharmaceutical industry such as the MRC of the Health Technology Assessment Programme in the UK or the Veterans Administration in the USA. The current state of affairs raised a number of important questions. First, should regulatory trials do more to inform clinical decision making? The obvious answer to this question is yes as it is extremely inefficient for both industry and health services for a drug to come to market based on data that does not inform clinician decision making. However, changes to trial design that make them more useful to clinicians and patients might make them less attractive to industry and the regulator. For example, head-to-head actively controlled add-on trials might be difficult to interpret from a regulatory perspective unless superior efficacy is found; non-inferiority is the current benchmark for monotherapy licensing in the EU but is not considered acceptable by the FDA in the USA. Changes in trial design to improve clinical utility will require much closer working between industry, regulators, health services, patients, professional organisations and other stakeholders. This would seem long overdue. Given that we have a number of marketed AEDs based on trials with limited clinical utility, the second question is who should fund post-marketing head-to-head RCTs, industry or another funder such as the public purse or charity. Although one could argue that industry has significant resource to spend, such trials may be unattractive to industry as patents are likely to have expired by the time results are available.
Also, industry funding will carry the taint of industry involvement and suspicion if bias, even if rigorously carried out. It may be preferable, therefore, for health services or payors to fund such trials who stand to gain from results that will help ensure the most cost-effective use of health service resource. For example, in the UK, the Department of Health has an extensive Health Technology Assessment Programme that funds a large number of RCTs. When starting AED treatment, as a general principle, it is important whenever possible to classify the epilepsy syndrome as this may inform initial treatment choice, but more importantly it may inform likely prognosis with whatever treatment is chosen. CBZ and LTG are recommended first-line treatments. A number of newer AEDs are licensed for use as monotherapy but none have convincing evidence of clinical or cost effectiveness. Although some of the newer AEDS may be better tolerated than older standard treatments, it is disappointing to highlight that none of the new AEDs has been shown to have superior efficacy. There is an ever-increasing number of AEDs available to use as add-on treatment in refractory epilepsy. Unfortunately, there is no reliable evidence from RCTs to inform a choice among alternatives as few head-to-head trials have been undertaken. Treatment choices might be informed by knowledge of adverse events and drug interactions. The authors use levetiracetam or clobazam as first-line add-on treatments. We do have some evidence from RCTs to inform as to whether to discontinue or withdraw AED treatment once a sustained period of remission has been achieved, but the decision is complex, and ultimately it should be the patients’ decision. In the authors practice, the default decision is to stay on AED treatment, unless the patient has made a clear decision to attempt AED withdrawal. In conclusion, we have some evidence from RCTs and other sources to inform decisions at a number of stages in the patients’ journey. However, the evidence base is largely inadequate which is to the detriment of patient and the economy as there is uncertainty about the most effective treatment or policy. Clinicians, patients, industry, regulators, health services and other stakeholders need to work together more effectively to generate an evidence base that is fit for purpose and to ensure that future treatments are more adequately assessed.
Declaration of interest A Marson has received research funding from GSK, UCB, Eisai and Honoraria for Sanofi. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Expert Opin. Pharmacother. (2014) 15(11)
1549
A. Iyer & A. Marson
Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
2.
Ngugi AK, Kariuki SM, Bottomley C, et al. Incidence of epilepsy: a systematic review and meta-analysis. Neurology 2011;77:1005-12 Jacoby A, Snape D, Baker GA. Epilepsy and social identity: the stigma of a chronic neurological disorder. Lancet Neurol 2005;4:171-8
3.
Hermann B, Jacoby A. The psychosocial impact of epilepsy in adults. Epilepsy Behav 2009;15:S11-16
4.
Shankar R, Cox D, Jalihal V, et al. Sudden unexpected death in epilepsy (SUDEP): Development of a safety checklist. Seizure 2013;22(10):812-7
5.
6.
Blume WT, Lu¨ders HO, Mizrahi E, et al. Glossary of descriptive terminology for ictal semiology: report of the ILAE task force on classification and terminology. Epilepsia 2001;42:1212-18 Panayiotopoulos CP. The new ILAE report on terminology and concepts for the organization of epilepsies: critical review and contribution. Epilepsia 2012;53:399-404
7.
Blumcke I. Neuropathology of focal epilepsies: a critical review. Epilepsy Behav 2009;15:34-9
8.
Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonicclonic seizure. First Seizure Trial Group (FIR.S.T. Group). Neurology 1993;43:478-83 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures.
.
9.
.
10.
1550
..
Marson A, Jacoby A, Johnson A, et al. Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial. Lancet 2005;365:2007-13 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures. Kim LG, Johnson TL, Marson AG, et al. MRC MESS Study group. Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results
from the MESS trial. Lancet Neurol 2006;5:317-22 This study provides evidence about the risk of seizure recurrence after a first seizure and the evidence to start pharmacotherapy after unprovoked seizures.
11.
Hauser WA, Rich SS, Lee JR, et al. Risk of recurrent seiures after two unprovoked seizures. N Engl J Med 1998;7:429-34
12.
Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2006;47:1094-120
13.
.
14.
..
15.
..
16.
Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551-63 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007;369:1000-15 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Tudur Smith C, Marson AG, Chadwick DW, Williamson PR. Multiple treatment comparisons in epilepsy monotherapy trials. Trials 2007;8:34 This study provides evidence of monotherapy in focal seizures and provides the available evidence and trials. Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol 2011;10:609-17
Expert Opin. Pharmacother. (2014) 15(11)
17.
.
Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol 2012;11:803-13 This is an important paper detailing the teratogenic effects of anti-epileptic medications.
18.
Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol 2013;12:244-52
19.
Porter RJ, Partiot A, Sachdeo R, et al. on behalf of the 205 Study Group. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007;68:1197-204
20.
French JA, Abou-Khalil BW, Leroy RF, et al. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology 2011;76:1555-63
21.
Splinter MY. Ezogabine (retigabine) and its role in the treatment of partial-onset seizures: a review. Clin Ther 2012;34:1845-1856.e1
22.
French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2012;54:117-25
23.
Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: Interim results from phase III, extension study 307. Epilepsia 2012;54:126-34
24.
Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012;78:1408-15
25.
Rektor I. Perampanel, a novel, noncompetitive, selective AMPA receptor antagonist as adjunctive therapy for treatment-resistant partial-onset seizures. Expert Opin Pharmacother 2013;14:225-35
26.
Hsu WW, Sing CW, He Y, et al. Systematic review and meta-analysis of the efficacy and safety of perampanel in
Pharmacotherapy of focal epilepsy
the treatment of partial-onset epilepsy. CNS Drugs 2013;27:817-27 27.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Memorial University of Newfoundland on 07/31/14 For personal use only.
28.
29.
30.
31.
32.
..
33.
Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia 2010;51:958-67
34.
Schmidt D, Loscher W. Uncontrolled epilepsy following discontinuation of antiepileptic drugs in seizure-free patients: a review of current clinical experience. Acta Neurol Scand 2005;111:291-300
35.
Baulac M, Brodie MJ, Patten A, et al. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol 2012;11:579-88
Hala´sz P, Ka¨lvia¨inen R, Mazurkiewicz-Beldzin´ska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443-53 Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007;48:1308-17 Verrotti A, Loiacono G, Rossi A, Zaccara G. Eslicarbazepine acetate: an update on efficacy and safety in epilepsy. Epilepsy Res 2014;108:1-10 Chadwick D. Does withdrawal of different antiepileptic drugs have different effects on seizure recurrence? Further results from the MRC Antiepileptic Drug Withdrawal Study. Brain 1999;122(Pt 3):441-8 Bonnett LJ, Shukralla A, Tudur-Smith C, et al. Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC Antiepileptic Drug Withdrawal Study and a systematic review. J Neurol Neurosurg Psychiatry 2011;82:1328-33 This is an important paper discussing the risk of seizure recurrence after medication withdrawal and its implications. Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia 2008;49:455-63
36.
37.
38.
39.
Brodie MJ, Perucca E, Ryvlin P, et al. for the Levetiracetam Monotherapy Study Group. Comparison of levetiracetam and controlled-release carbamazepine in newly diagnosed epilepsy. Neurology 2007;68:402-8 Steinhoff BJ, Ueberall MA, Siemes H, et al. The LAM-SAFE. Study: lamotrigine versus carbamazepine or valproic acid in newly diagnosed focal and generalised epilepsies in adolescents and adults. Seizure 2005;14:597-605 Ramsay E, Faught E, Krumholz A, et al. Efficacy, tolerability, and safety of rapid initiation of topiramate versus phenytoin in patients with new-onset epilepsy: a randomized double-blind clinical trial. Epilepsia 2010;51:1970-7 Kwan P, Brodie MJ, Kalviainen R, et al. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011;10:881-90
40.
Ramaratnam S, Marson AG, Baker GA. Lamotrigine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2001(3):CD001909
41.
Castillo S, Schmidt DB, White S. Oxcarbazepine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2000(3):CD002028
Expert Opin. Pharmacother. (2014) 15(11)
42.
Mbizvo GK, Hutton JL, Marson AG. Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. Cochrane Database Syst Rev 2012;9:CD001901
43.
Jette N, Hemming K, Hutton JL, Marson AG. Topiramate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2008(3):CD001417
44.
Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2005(4):CD001416
45.
Hemming K, Maguire MJ, Hutton JL, Marson AG. Vigabatrin for refractory partial epilepsy. Cochrane Database Syst Rev 2013;1:CD007302
46.
Pulman J, Hutton JL, Marson AG. Tiagabine add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2014;2:CD001908
47.
Chang XC, Yuan H, Wang Y, et al. Eslicarbazepine acetate add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2011(12):CD008907
48.
Lozsadi D, Hemming K, Marson AG. Pregabalin add-on for drug-resistant partial epilepsy. Cochrane Database Syst Rev 2008(1):CD005612
Affiliation
Anand Iyer1,2 & Anthony Marson†1 † Author for correspondence 1 The Walton Centre for Neurology and Neurosurgery NHS Foundation Trust, Liverpool, UK E-mail: [email protected] 2 Alder Hey Children’s NHS Foundation Trust, Liverpool, UK
1551
