PERAMPANEL
Medical management of refractory epilepsy—Practical treatment with novel antiepileptic drugs Elinor Ben-Menachem Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
SUMMARY
Dr. Elinor Ben-Menachem is Professor of Neurology and Epilepsy at the Institute for Clinical Neurosciences and Physiology, Sahlgrenska Academy, €teborg, University of Go €teborg, Sweden Go
The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review. KEY WORDS: Epilepsy, Treatment, Antiepileptic drugs.
medications, adverse effect profiles of the AEDs, other concomitant diseases, and pharmacokinetic characteristics. The goal of the treatment of refractory epilepsy (as with new-onset epilepsy) is freedom from seizures with as few treatment adverse effects as possible. If the patient becomes seizure-free and does not have adverse effects, the physican should consider not changing the dose of the AED for a few years (or sometimes never depending on the type of seizure syndrome), even if the concentration in the blood is below or slightly above the therapeutic range. If, however, seizures continue, then the AED dose should be increased until the patient is seizure-free or until adverse effects occur. If seizure control is still not achieved, then the drug should be slowly decreased and an alternative monotherapy instituted. If the first drug has had some degree of efficacy, then adding the second drug to the first one would be the most rational approach to begin with. If the second AED causes the patient to become seizure-free, then the first AED might be slowly
Despite adequate treatment with antiseizure drugs, most often called antiepileptic drugs (AEDs), and despite adequate adherence, still about 30–40% of patients will develop refractory epilepsy.1 The choice of an AED for patients who have not responded to the first AED, depends primarily on the seizure diagnosis and epilepsy syndrome. Therefore, as a first step, a serious effort should be made to diagnose the seizure type, localization, and syndrome. In addition to efficacy profiles, considerations when choosing an AED include gender, age, body weight, fertility, lifestyle, other Accepted October 19, 2013. Institute of Clinical Neuroscience and Physiology, Sahlgrenska University Hospital, Goteborg, Sweden Address correspondence to Elinor Ben-Menachem, Institute of Clinical Neuroscience and Physiology, Sahlgrenska University Hospital, 413 45 Goteborg, Sweden. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
3
4 E. Ben-Menachem withdrawn, but this must be up for discussion together with the patient so that the risk/benefit can be evaluated. At the same time, especially with continuing seizures despite treatment with two AEDs (it cannot be stressed enough), the diagnosis should be reevaluated and questions about adherence should be posed. If success is not obtained with the second drug, the patient should be referred to a tertiary epilepsy clinic if necessary for further evaluation and other treatment alternatives discussed. Alternatives include epilepsy surgery, especially in the case of partial onset seizures with mesial temporal lobe focus. It is also important not to overlook the possibility of psychogenic nonepileptic seizures, and these can be excluded by video–electroencephalography (EEG) monitoring. Most difficult to manage are those patients with both nonepileptic seizures and true epilepsy. If the diagnosis of epilepsy is firmly established and an epilepsy surgical intervention will most likely not be fruitful, then further attempts at improving the medical therapy should be pursued. The questions are, however, which drug to choose next and how to combine AEDs to achieve effective seizure reduction. Unfortunately the evidence for how to proceed is lacking. There are some consensus statements as to how to proceed but no definitve studies for guidance.2,3
Seizure Exacerbation When adding a second or third AED, it is important to avoid adding an AED that may worsen or provoke seizures. For example, CBZ (carbamazepine), OXC (oxcarbazepine), PHT (phenytoin), VGB (vigabatrin), and TGB (tiagabine) may worsen myoclonus and absences; GBP (gabapentin), myoclonus; LTG (lamotrigine), myoclonus; and benzodiazepines, tonic seizures.4 Seizure exacerbation is a problem that is encountered mainly in c-aminobutyric acid (GABA)ergic (TGB, GBP, and VGB) and sodium channel blocking AEDs (PHT, CBZ, and LTG), although anecdotal reports have been cited for almost all AEDs.5 Patients with idiopathic epilepsies are most susceptible, whereas adult patients with partial-onset seizure seem to be more immune to this effect.6 Children are different in this regard and should be followed with greater care to avoid seizure exacerbation or even the development of a new seizure type when least expected.7 The natural fluctuation of seizures over the course of a year is a factor that must be taken into account when deciding if seizure exacerbation has really occurred. Baseline seizure information is important to know so that when an increase in seizures occurs, the likelihood of seizure exacerbation due to the AED can be evaluated. When the question arises as to how to be sure that the new AED has indeed elicited a new seizure type or caused an increase in seizures or an EEG change, there is always the possibility that a change in seizure type or Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
an increase in seizures could have happened anyway. Unfortunately, the only way to prove this explicitly is to retest the patient after the drug has first been withdrawn and the situation normalized. This is, however, most often not ethically possible, so ultimately physicians will have to rely on evidence that there is a temporal relationship between the drug use and the appearance of new seizure types while never being absolutely sure. Physicians who are treating pharmacoresistant epilepsy must therefore be made aware that patients, especially children, can develop a new seizure type or cognitive and behavioral changes after being given a new AED. They need to understand that changes in these variables might be due to the new AED or a pharmacodynamic interaction between the new AED and the other AEDs already being given. Physicians should always be vigilant and report suspect occurrences in seizure exacerbation to health authorities such as MedWatch (https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm).
Rational Polytherapy The idea that when adding a new AED to existing therapy one should choose an AED with a different mechanism of action other than the drug or drugs already being given to the patient has been in circulation for >20 years, but there is still no evidence or study to equivocally demonstrate this principle. The idea, nonetheless, seems “rational,” although there are many anecdotal reports to the contrary. As for rational polytherapy and side effects, there is greater support to the idea that adding AEDs with the same mechanism of action can cause an exaggeration of side effects seen with the group of compounds.8 For example, adding a sodium channel blocker such as LCM to another sodium channel blocker such as CBZ might achieve seizure control, but the reports of dizziness could be higher in patients on the CBZLCM combination then on non–sodium channel blocking agent + LCM.9 Another reason that rational polytherapy has not been demonstrated is that many of the AEDs available have other mechanisms of action as well as the one that is thought to be the major mechanism. These other activities may also contribute to the antiepileptic function of an AED that would confuse the purest concept of rational polytherapy. For example LEV is believed to mainly affect the SV2a receptor on the synaptic vesicle, but has even calcium-modulating properties and GABAeric properties.10,11 CBZ, although a sodium channel blocker, has other mechanisms of action as well.12 Therefore, rational polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects, but rational polytherapy for improvement of efficacy based on a known mechanism of action has still not been convincingly demonstrated.
5 Medical Management of Refractory Epilepsy
AED Synergism The idea of AED synergism is a further development of rational polytherapy. The thought is that adding another AED to one with a different mechanism of action will enhance the efficacy greater than the assumed efficacy addition of both. Attempts to show a difference between additive, synergistic, and antagonistic interactions have not been forthcoming and only a few studies have implied that the addition of one drug to the existing AED increases the efficacy more than the expected.9,13
Choice of AED There are currently 15 newer antiepileptic drugs (AEDs) along with about six older AEDs (depending on how you count them) available to patients and physicians in the United States, European Union (EU), and many other countries. Determining which drug is “best” or which should be used for the first add-on for a specific seizure type can be a confusing decision. Thus there is an urgent need to make some sense of the plethora of clinical trials and flood of information. Most often AED clinical trials are designed for regulatory purposes only, which may not help the physician much in treating his or her patients. Each AED that is marketed by the manufacturer is supposed to be the one with the greatest efficacy and with the fewest side effects, so how can they be sorted out? Because there has been only one published comparative study so far in the literature,14 and large reviews have not been able to define the superiority of one AED over another,15 the physician must make the decision as to which AED to add on to an existing regimen. Due to the paucity of quality evidence, physicians need to bear in mind that regardless of overall recommendations found in guidelines or concensus statements, patient individuality is most important and determines the choice of drug. Expense, availability, ease of use, severity of condition, and other factors may vary considerably for different patients, and therefore the choice is never an easy one. In fact, guidelines and consensus statements will always need to be combined with the skill, knowledge, and the experience of the individual physician. There are no short cuts.16 The following is the main conclusion of the last American Academy of Neurology (AAN) Guideline for refractory epilepsy, which was published in 200617: All of the drugs have demonstrated efficacy as add-on therapy in patients with refractory partial epilepsy. Although the methodology was similar for all studies, it is not possible to determine relative efficacy from comparison of outcomes, because populations differed (as evidenced by differing placebo responder rates), and some drugs were not used in maximum doses, whereas others appear to have been administered above ideal
dose, as evidenced by high dropout and side effect rates. For essentially all drugs, efficacy as well as side effects increased with increasing doses. In all cases where two different titration rates were compared, the slower titration was better tolerated. Therefore, it would seem advisable to start low and go slow, using increasing doses until side effects occur (in other words, push to maximum tolerated dose).
Newly Available Antiepileptic Drugs in the United States Since the Publication of the AAN Guidelines in 2006 Rufinamide Rufinamide (RUF) is a triazole derivative and received orphan drug status for the adjunctive treatment of LennoxGastaut syndrome (LGS) in the United States in 2004 and in 2007 in the EU. It is available for children from 4 years of age and upward. In addition to the LGS indication, it has been approved for adjunctive treatment of partial seizures in adults and adolescents. It is hypothesized that the mechanism of action is on sodium channels, but more research needs to be done in this area. There is evidence of a prolongation of the inactive state of the channel.18 There have been several randomized controlled clinical trials of RUF as add-on for partial-onset seizures and in the LGS population. For LGS, 138 patients were randomized to either RUF or placebo and treated for 3 months. There was a significant reduction in seizures and an increase in the amount of responders during the trial in favor of RUF. For refractory partial seizures, the results showed that 39% of RUF-treated and 16% of placebo-treated patients experienced reduction in seizure frequency of at least 50% relative to baseline (p = 0.096).18,19 Rufinamide can be added to any other AED with minimal interactions occurring, and there are no special black box warnings for the use of RUF in the treatment of epilepsy. Because there has not been a head-to-head study with other AEDs, the exact place of RUF in the treatment of partial-onset epilepsy or LGS is not known. However, a reliable plan to follow when the decision has been made to try RUF is to start at a low dose such as 400 mg and increase every few days to ensure continued tolerability and to test each dose to find the lowest most efficacious dosing level for each patient. Lacosamide The indication for lacosamide (LCM) use is as adjunctive therapy for patients with pharmacoresistant partial epilepsy. Based on recent experimental studies, LCM appears to have a dual mode of action—enhancement of sodium channel slow inactivation and modulation of collapsin Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
6 E. Ben-Menachem response mediator protein-2 (CRMP-2)20—both of which are novel mechanisms for an AED. Without affecting fast inactivation, LCM appears to selectively enhance sodium channel slow inactivation, which may help normalize activation thresholds and decrease pathophysiologic neuronal activity, thereby controlling neuronal hyperexcitability.20 LCM is a functionalized (meaning it passes through the blood–brain barrier) amino acid specifically synthesized as an anticonvulsant drug and has demonstrated antiepileptic activity in several animal seizure models for generalized and complex partial-onset seizures and status epilepticus.20,21 The clinical efficacy of the oral formulation of LCM as adjunctive therapy for partial-onset seizures has been demonstrated in randomized phase II/III clinical trials22,23 and long-term follow-up audits.24 The most frequently reported adverse events in placebocontrolled trials include dizziness, headache, nausea, and diplopia. When used as short-term replacement for oral LCM, intravenous LCM has a comparable safety profile to that of oral LCM. Dose titration starts at 100 mg/day, but in my experience and according to the AAN Guideline recommendation of starting low and going slow, a starting dose of 50 mg with a titration rate of 50 mg/week is the more conservative way to evaluate efficacy and tolerability. New case reports indicate that LCM may have a place in the treatment of refractory status epilepticus.25 Vigabatrin Vigabatrin (VGB), a synthetic GABA derivative, is an enzyme-activated, irreversible inhibitor of GABA transaminase and resulted from a systematic search into possible ways of increasing GABAergic inhibition through interference with GABA metabolism. This mechanism of action is the only significant one ever found.26 Vigabatrin may worsen myoclonic seizures. Immunologic/allergic adverse effects seem to be rare, but sedation, dizziness, headache, depression, and body weight gain are reported.26 Psychosis has been reported in 3–6% of patients.26 In addition it has been discovered that irreversible visual field defects occur in about 30–40% of treated patients and this has resulted in much less prescribing of the drug.27,28 After oral administration of VGB, peak serum concentrations are attained within about 2 h. VGB enters the cerebrospinal fluid (CSF) and produces dose-dependent increases in GABA concentrations in CSF. It is not bound to serum proteins, and no metabolites have been identified in humans. The terminal half-life is between 5 and 8 h. VGB is excreted unchanged primarily in the urine, and thus patients with renal impairment are likely to require lower doses. Due to the irreversible mode of action of the drug, the serum half-life bears practically no relationship to the Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
duration of pharmacologic effect. Because of the long-lasting GABA transaminase inhibition, the anticonvulsant effect of VGB long outlasts its presence in serum.26 No drug interactions have been observed between VGB and other anticonvulsants or other drug classes except for a decrease in serum PHT concentrations in some patients that was of no clinical significance. In contrast to most other AEDs, monitoring of serum levels of VGB is not suitable as a guide to therapy due to its mechanism of action. For checking adherence a tentative range of 6–278 lM has been suggested. The place of VGB is as monotherapy in the treatment of infantile spasms and as adjunctive therapy for very resistant partial seizures. Because of the occurrence of irreversible visual field deficits, the U.S. Food and Drug Administration (FDA) requires that all people starting VGB regularly undergo automated visual field studies. There are black box warnings for VGB that concern the risks of developing irreversible visual field deficits, and these recommendations for treating patients must be followed closely. Perampanel Perampanel (PER) is a noncompetitive a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)– type glutamate receptor antagonist. It is the first of its kind with this mechanism of action to be approved for the treatment of epilepsy. It has been approved in the EU and the United States (but is not yet available in the United States at the time of writing of this article) as add-on therapy for refractory partial onset seizures with or without generalization. PER has a long half-life of 70–100 h and therefore can be given as a once-daily dose.29 Phase III clinical trials have demonstrated good efficacy with tolerable side effects, mainly dizziness, somnolence, diplopia, and ataxia. These side effects can be addressed by giving the drug directly before bedtime, as there is a peak concentration within 1–2 h after intake and it then subsides after 2–3 h. The recommended doses are between 4 and 12 mg, with most side effects occurring at the higher doses. However, because CBZ will decrease the half-life of PER, people taking CBZ will probably need higher doses. There is a concentration/ effect relationship.30 Eslicarbazepine acetate Eslicarbazepine acetate (ESL) is the third member in a family of dibenz/b,f/asepine AEDs represented by CBZ (first-generation) and oxcarbazepine (OXC, second generation). OXC metabolizes to both R- and S-liscarbazepine, whereas ESL metabolizes to mainly S-liscarbazepine and only to a very minor degree to R-liscarbazepine. The major difference between ESL and CBZ is that ESL does not degrade to the epoxide metabolite, which is one of the major causes of toxicity of CBZ. The mechanism of
7 Medical Management of Refractory Epilepsy action is similar to that of CBZ and OXC, but ESL is thought to even have a modulating action and inhibits the slow activation of the Na+ channel. Metabolism is mainly by glucuronidation, with a minimal engagement of the cytochrome P450 (CYP) liver enzyme system. Therefore, there is less risk for drug–drug interaction when compared to CBZ and OXC. The half-life is 13–20 h in patients taking other AEDs. Therefore, once daily dosing is recommended.31 ESL has been available since 2010 for patients with refractory partial onset seizures as an add-on medication. The phase III double-blind studies show good efficacy and few and tolerable side effects as dizziness, diplopia, and nausea.32 These side effects were most prominent when CBZ was taken concomitantly. Monotherapy studies for new-onset epilepsy are ongoing. Compared to CBZ and OXC, it seems that ESL may have less tendency for hyponatremia and allergic reactions. In the clinical trials and long-term follow-up studies, the cognitive and psychiatric side effects were few.33 Retigabine Retigabine (RET) has been available since 2011. Its generic name in the United States is ezogabine. The indication is as add-on therapy for patients with refractory partial onset seizures. It is the first neuronal KCNQ agonist to be approved as an antiepileptic drug. The antiepileptic effect is through the opening of the voltage-gated potassium channel, thereby enhancing the M-type potassium current. Experimental animal studies have suggested that RET can have a broad spectrum of action.34 RET is metabolized via N-glucuronidation and N-acetylation and not through the CYP system. Therefore, the potential risk for drug–drug interaction is low.35 Phase III clinical trials have been positive in patients with refractory focal onset seizures. The maximum daily dose is 1,200 mg/day, which should be divided into three doses as the half-life is only 8 h. The most common side effects are dizziness, somnolence, fatigue, confusion, dysarthria, ataxia, diplopia, and urinary tract infection, as the risk for urinary retention exists because of the potassium channel activation of the bladder.36 Unfortunately for RET, a serious side effect has been found, and this drug can no longer be recommended for patients not already taking RET. For those who have a positive effect of the drug and no side effects, they can, with caution, be allowed to continue on the drug. The unexpected side effect is the development of a blue hue to the skin and retina after long-term use.33,37 Because of this, use has been restricted to patients who are already taking the drug and who have shown good effect without side effects. All patient on RET should have eye examinations (http://www.fda. gov/Drugs/DrugSafety/ucm349538.htm).
Conclusion In treating a patient with epilepsy, the physician must weigh many factors into his decision for choosing the appropriate AED and also when to go on to surgical evaluation and other therapeutic methodologies when the patient demonstrates that he or she is refractory to two or three appropriate antiseizure drugs. It is, therefore, the responsibility of the treating physician to learn about all anticonvulsants available, both new and old, in order to be able to tailor the treatment according to the requirements of each patient. This is not an easy task, as it is imperative to understand mechanisms of action, metabolism and dosing, interactions, potential side effects and how to deal with them, as well as the appropriate seizure types for each drug, and how to combine the different drugs.
Disclosure Elinor Ben-Menachem has received honoraria from Eisai, the manufacturer of Fycompa for lectures and as an advisory board member. She confirms that she has read the Journal’s position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.
References 1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 2. Legros B, Boon P, De Jonghe P, et al. Opinion of Belgian neurologists on antiepileptic drug treatment in 2006: Belgian study on epilepsy treatment (BESET-2). Acta Neurol Scand 2009;120:402–410. 3. St Louis EK, Gidal BE, Henry TR, et al. Conversions between monotherapies in epilepsy: expert consensus. Epilepsy Behav 2007;11:222–234. 4. Somerville ER. Some treatments cause seizure aggravation in idiopathic epilepsies (especiallyabsence epilepsy). Epilepsia 2009;50 (Suppl. 8):31–36. 5. Sazgar M, Bourgeois BF.Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol 2005;33:227–234. 6. Somerville ER. Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials? Neurology 2002;59:79–83. 7. Yang MT, Lee WT, Chu LW, et al. Anti-epileptic drugs-induced de novo absence seizures. Brain Dev 2003;5:51–56. 8. Brodie MJ, Sills GJ. Combining antiepileptic drugs–rational polytherapy? Seizure 2011;20:369–375. 9. Sake JK, Hebert D, Isoj€arvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs 2010;24:1055–1068. 10. Angehagen M, Margineanu DG, Ben-Menachem E, et al. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. NeuroReport 2003;14 (3):471–475. 11. L€oscher W, H€onack D, Bloms-Funke P. The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. Bin Res 2003;735:208–216. 12. Sitges M, Guarneros A, Nekrassov V. Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H] glutamate: comparison with the Na+ channel-mediated release. Neuropharmacology 2007;53:854–862.
Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
8 E. Ben-Menachem 13. Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 study group. Epilepsy Res 1997;26:423–432. 14. Lindberger M, Alenius M, Frisen L, et al. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin in refractory epilepsy add-on treatment. Epilepsia 2000;41:1289–1295. 15. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 2010;51:7–26. 16. Glauser T, Ben-Menachem E, Bourgeois B. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551–563. 17. French JA, Kanner AM, Bautista J, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261–1273. 18. Arroyo S. Rufinamide. Neurotherapeutics 2007;1:155–162. 19. P alhagen S, Canger R, Henriksen O, et al. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Res 2001;43:115–124. 20. Doty P, Rudd GD, Stoehr T, et al. Lacosamide. Neurotherapeutics 2007;1:145–148. 21. Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007;13:21–42. 22. 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;48:1308–1317. 23. Halasz P, K€alvi€ainen R, Mazurkiewicz-Beldzinska M. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443–453.
Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
24. Novy J, Bartolini E, Bell GS, et al. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epillepsy Res 2013;106:250–256. 25. Kellinghaus C, Berning S, St€ogbauer F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand 2013 Aug 13 [E-pub ahead of print]. 26. Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand Suppl 2011;192:5–15. 27. Willmore LJ, Abelson MB, Ben-Menachem E, et al. Vigabatrin: 2008 update. Epilepsia 2009;50:163–173. 28. Pellock JM. Balancing clinical benefits of vigabatrin with its associated risk of vision loss. Acta Neurol Scand Suppl 2011;192:83–91. 29. Satlin A, Kramer LD, Laurenza A. Development of perampanel in epilepsy. Acta Neurol Scand Suppl 2013;197:3–8. 30. Gidal BE, Ferry J, Majid O, et al. Concentration–effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures. Epilepsia 2013;54:1490–1497. 31. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia 2012;53:935–946. 32. Gil-Nagel A, Elger C, Ben-Menachem E. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind ohase III clinical studies. Epilepsia 2013;54:98–107. 33. Martyn-St James M, Glanville J, McCool R, et al. The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison. Seizure 2012;21:665–678. 34. Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia 2012;53:412–424. 35. Orhan G, Wuttke TV, Nies AT, et al. Retigabine/Ezogabine, a KCNQ/ K(V)7 channel opener: pharmacological and clinical data. Expert Opin Pharmacother 2012;13:1807–1816. 36. Rheims S, Ryvlin P. Retigabine for partial onset seizures. Expert Rev Neurother 2012;12:509–517. 37. Faulkner MA, Burke RA. Safety profile of two novel antiepileptic agents approved for the treatment of refractory partial seizures: ezogabine (retigabine) and perampanel. Expert Opin Drug Saf 2013;12:847–855.
Medical management of refractory epilepsy—Practical treatment with novel antiepileptic drugs Elinor Ben-Menachem Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
SUMMARY
Dr. Elinor Ben-Menachem is Professor of Neurology and Epilepsy at the Institute for Clinical Neurosciences and Physiology, Sahlgrenska Academy, €teborg, University of Go €teborg, Sweden Go
The ultimate treatment goal in epilepsy therapy is always freedom from seizures with as few treatment adverse effects as possible. If seizures persist with the first monotherapy, alternative monotherapy with another antiepileptic drug (AED) should be considered. Continuing seizures should lead to a reevaluation of differential diagnosis and adherence. Epilepsy surgery as an alternative therapy may be suitable in selected cases. If the diagnosis of epilepsy is established and epilepsy surgery is not appropriate, AED treatment should be optimized. Evidence for how to proceed is lacking. Concepts such as rational polytherapy have been advocated but remain speculative concerning better efficacy based on the use of AEDs with differing modes of action. A variety of new AEDs including rufinamide, lacosamide, vigabatrin, perampanel, and retigabine have been recently introduced in the United States. They are briefly characterized in this update review. KEY WORDS: Epilepsy, Treatment, Antiepileptic drugs.
medications, adverse effect profiles of the AEDs, other concomitant diseases, and pharmacokinetic characteristics. The goal of the treatment of refractory epilepsy (as with new-onset epilepsy) is freedom from seizures with as few treatment adverse effects as possible. If the patient becomes seizure-free and does not have adverse effects, the physican should consider not changing the dose of the AED for a few years (or sometimes never depending on the type of seizure syndrome), even if the concentration in the blood is below or slightly above the therapeutic range. If, however, seizures continue, then the AED dose should be increased until the patient is seizure-free or until adverse effects occur. If seizure control is still not achieved, then the drug should be slowly decreased and an alternative monotherapy instituted. If the first drug has had some degree of efficacy, then adding the second drug to the first one would be the most rational approach to begin with. If the second AED causes the patient to become seizure-free, then the first AED might be slowly
Despite adequate treatment with antiseizure drugs, most often called antiepileptic drugs (AEDs), and despite adequate adherence, still about 30–40% of patients will develop refractory epilepsy.1 The choice of an AED for patients who have not responded to the first AED, depends primarily on the seizure diagnosis and epilepsy syndrome. Therefore, as a first step, a serious effort should be made to diagnose the seizure type, localization, and syndrome. In addition to efficacy profiles, considerations when choosing an AED include gender, age, body weight, fertility, lifestyle, other Accepted October 19, 2013. Institute of Clinical Neuroscience and Physiology, Sahlgrenska University Hospital, Goteborg, Sweden Address correspondence to Elinor Ben-Menachem, Institute of Clinical Neuroscience and Physiology, Sahlgrenska University Hospital, 413 45 Goteborg, Sweden. E-mail: [email protected] Wiley Periodicals, Inc. © 2014 International League Against Epilepsy
3
4 E. Ben-Menachem withdrawn, but this must be up for discussion together with the patient so that the risk/benefit can be evaluated. At the same time, especially with continuing seizures despite treatment with two AEDs (it cannot be stressed enough), the diagnosis should be reevaluated and questions about adherence should be posed. If success is not obtained with the second drug, the patient should be referred to a tertiary epilepsy clinic if necessary for further evaluation and other treatment alternatives discussed. Alternatives include epilepsy surgery, especially in the case of partial onset seizures with mesial temporal lobe focus. It is also important not to overlook the possibility of psychogenic nonepileptic seizures, and these can be excluded by video–electroencephalography (EEG) monitoring. Most difficult to manage are those patients with both nonepileptic seizures and true epilepsy. If the diagnosis of epilepsy is firmly established and an epilepsy surgical intervention will most likely not be fruitful, then further attempts at improving the medical therapy should be pursued. The questions are, however, which drug to choose next and how to combine AEDs to achieve effective seizure reduction. Unfortunately the evidence for how to proceed is lacking. There are some consensus statements as to how to proceed but no definitve studies for guidance.2,3
Seizure Exacerbation When adding a second or third AED, it is important to avoid adding an AED that may worsen or provoke seizures. For example, CBZ (carbamazepine), OXC (oxcarbazepine), PHT (phenytoin), VGB (vigabatrin), and TGB (tiagabine) may worsen myoclonus and absences; GBP (gabapentin), myoclonus; LTG (lamotrigine), myoclonus; and benzodiazepines, tonic seizures.4 Seizure exacerbation is a problem that is encountered mainly in c-aminobutyric acid (GABA)ergic (TGB, GBP, and VGB) and sodium channel blocking AEDs (PHT, CBZ, and LTG), although anecdotal reports have been cited for almost all AEDs.5 Patients with idiopathic epilepsies are most susceptible, whereas adult patients with partial-onset seizure seem to be more immune to this effect.6 Children are different in this regard and should be followed with greater care to avoid seizure exacerbation or even the development of a new seizure type when least expected.7 The natural fluctuation of seizures over the course of a year is a factor that must be taken into account when deciding if seizure exacerbation has really occurred. Baseline seizure information is important to know so that when an increase in seizures occurs, the likelihood of seizure exacerbation due to the AED can be evaluated. When the question arises as to how to be sure that the new AED has indeed elicited a new seizure type or caused an increase in seizures or an EEG change, there is always the possibility that a change in seizure type or Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
an increase in seizures could have happened anyway. Unfortunately, the only way to prove this explicitly is to retest the patient after the drug has first been withdrawn and the situation normalized. This is, however, most often not ethically possible, so ultimately physicians will have to rely on evidence that there is a temporal relationship between the drug use and the appearance of new seizure types while never being absolutely sure. Physicians who are treating pharmacoresistant epilepsy must therefore be made aware that patients, especially children, can develop a new seizure type or cognitive and behavioral changes after being given a new AED. They need to understand that changes in these variables might be due to the new AED or a pharmacodynamic interaction between the new AED and the other AEDs already being given. Physicians should always be vigilant and report suspect occurrences in seizure exacerbation to health authorities such as MedWatch (https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm).
Rational Polytherapy The idea that when adding a new AED to existing therapy one should choose an AED with a different mechanism of action other than the drug or drugs already being given to the patient has been in circulation for >20 years, but there is still no evidence or study to equivocally demonstrate this principle. The idea, nonetheless, seems “rational,” although there are many anecdotal reports to the contrary. As for rational polytherapy and side effects, there is greater support to the idea that adding AEDs with the same mechanism of action can cause an exaggeration of side effects seen with the group of compounds.8 For example, adding a sodium channel blocker such as LCM to another sodium channel blocker such as CBZ might achieve seizure control, but the reports of dizziness could be higher in patients on the CBZLCM combination then on non–sodium channel blocking agent + LCM.9 Another reason that rational polytherapy has not been demonstrated is that many of the AEDs available have other mechanisms of action as well as the one that is thought to be the major mechanism. These other activities may also contribute to the antiepileptic function of an AED that would confuse the purest concept of rational polytherapy. For example LEV is believed to mainly affect the SV2a receptor on the synaptic vesicle, but has even calcium-modulating properties and GABAeric properties.10,11 CBZ, although a sodium channel blocker, has other mechanisms of action as well.12 Therefore, rational polytherapy is sometimes rational for drug combinations chosen to minimize adverse effects, but rational polytherapy for improvement of efficacy based on a known mechanism of action has still not been convincingly demonstrated.
5 Medical Management of Refractory Epilepsy
AED Synergism The idea of AED synergism is a further development of rational polytherapy. The thought is that adding another AED to one with a different mechanism of action will enhance the efficacy greater than the assumed efficacy addition of both. Attempts to show a difference between additive, synergistic, and antagonistic interactions have not been forthcoming and only a few studies have implied that the addition of one drug to the existing AED increases the efficacy more than the expected.9,13
Choice of AED There are currently 15 newer antiepileptic drugs (AEDs) along with about six older AEDs (depending on how you count them) available to patients and physicians in the United States, European Union (EU), and many other countries. Determining which drug is “best” or which should be used for the first add-on for a specific seizure type can be a confusing decision. Thus there is an urgent need to make some sense of the plethora of clinical trials and flood of information. Most often AED clinical trials are designed for regulatory purposes only, which may not help the physician much in treating his or her patients. Each AED that is marketed by the manufacturer is supposed to be the one with the greatest efficacy and with the fewest side effects, so how can they be sorted out? Because there has been only one published comparative study so far in the literature,14 and large reviews have not been able to define the superiority of one AED over another,15 the physician must make the decision as to which AED to add on to an existing regimen. Due to the paucity of quality evidence, physicians need to bear in mind that regardless of overall recommendations found in guidelines or concensus statements, patient individuality is most important and determines the choice of drug. Expense, availability, ease of use, severity of condition, and other factors may vary considerably for different patients, and therefore the choice is never an easy one. In fact, guidelines and consensus statements will always need to be combined with the skill, knowledge, and the experience of the individual physician. There are no short cuts.16 The following is the main conclusion of the last American Academy of Neurology (AAN) Guideline for refractory epilepsy, which was published in 200617: All of the drugs have demonstrated efficacy as add-on therapy in patients with refractory partial epilepsy. Although the methodology was similar for all studies, it is not possible to determine relative efficacy from comparison of outcomes, because populations differed (as evidenced by differing placebo responder rates), and some drugs were not used in maximum doses, whereas others appear to have been administered above ideal
dose, as evidenced by high dropout and side effect rates. For essentially all drugs, efficacy as well as side effects increased with increasing doses. In all cases where two different titration rates were compared, the slower titration was better tolerated. Therefore, it would seem advisable to start low and go slow, using increasing doses until side effects occur (in other words, push to maximum tolerated dose).
Newly Available Antiepileptic Drugs in the United States Since the Publication of the AAN Guidelines in 2006 Rufinamide Rufinamide (RUF) is a triazole derivative and received orphan drug status for the adjunctive treatment of LennoxGastaut syndrome (LGS) in the United States in 2004 and in 2007 in the EU. It is available for children from 4 years of age and upward. In addition to the LGS indication, it has been approved for adjunctive treatment of partial seizures in adults and adolescents. It is hypothesized that the mechanism of action is on sodium channels, but more research needs to be done in this area. There is evidence of a prolongation of the inactive state of the channel.18 There have been several randomized controlled clinical trials of RUF as add-on for partial-onset seizures and in the LGS population. For LGS, 138 patients were randomized to either RUF or placebo and treated for 3 months. There was a significant reduction in seizures and an increase in the amount of responders during the trial in favor of RUF. For refractory partial seizures, the results showed that 39% of RUF-treated and 16% of placebo-treated patients experienced reduction in seizure frequency of at least 50% relative to baseline (p = 0.096).18,19 Rufinamide can be added to any other AED with minimal interactions occurring, and there are no special black box warnings for the use of RUF in the treatment of epilepsy. Because there has not been a head-to-head study with other AEDs, the exact place of RUF in the treatment of partial-onset epilepsy or LGS is not known. However, a reliable plan to follow when the decision has been made to try RUF is to start at a low dose such as 400 mg and increase every few days to ensure continued tolerability and to test each dose to find the lowest most efficacious dosing level for each patient. Lacosamide The indication for lacosamide (LCM) use is as adjunctive therapy for patients with pharmacoresistant partial epilepsy. Based on recent experimental studies, LCM appears to have a dual mode of action—enhancement of sodium channel slow inactivation and modulation of collapsin Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
6 E. Ben-Menachem response mediator protein-2 (CRMP-2)20—both of which are novel mechanisms for an AED. Without affecting fast inactivation, LCM appears to selectively enhance sodium channel slow inactivation, which may help normalize activation thresholds and decrease pathophysiologic neuronal activity, thereby controlling neuronal hyperexcitability.20 LCM is a functionalized (meaning it passes through the blood–brain barrier) amino acid specifically synthesized as an anticonvulsant drug and has demonstrated antiepileptic activity in several animal seizure models for generalized and complex partial-onset seizures and status epilepticus.20,21 The clinical efficacy of the oral formulation of LCM as adjunctive therapy for partial-onset seizures has been demonstrated in randomized phase II/III clinical trials22,23 and long-term follow-up audits.24 The most frequently reported adverse events in placebocontrolled trials include dizziness, headache, nausea, and diplopia. When used as short-term replacement for oral LCM, intravenous LCM has a comparable safety profile to that of oral LCM. Dose titration starts at 100 mg/day, but in my experience and according to the AAN Guideline recommendation of starting low and going slow, a starting dose of 50 mg with a titration rate of 50 mg/week is the more conservative way to evaluate efficacy and tolerability. New case reports indicate that LCM may have a place in the treatment of refractory status epilepticus.25 Vigabatrin Vigabatrin (VGB), a synthetic GABA derivative, is an enzyme-activated, irreversible inhibitor of GABA transaminase and resulted from a systematic search into possible ways of increasing GABAergic inhibition through interference with GABA metabolism. This mechanism of action is the only significant one ever found.26 Vigabatrin may worsen myoclonic seizures. Immunologic/allergic adverse effects seem to be rare, but sedation, dizziness, headache, depression, and body weight gain are reported.26 Psychosis has been reported in 3–6% of patients.26 In addition it has been discovered that irreversible visual field defects occur in about 30–40% of treated patients and this has resulted in much less prescribing of the drug.27,28 After oral administration of VGB, peak serum concentrations are attained within about 2 h. VGB enters the cerebrospinal fluid (CSF) and produces dose-dependent increases in GABA concentrations in CSF. It is not bound to serum proteins, and no metabolites have been identified in humans. The terminal half-life is between 5 and 8 h. VGB is excreted unchanged primarily in the urine, and thus patients with renal impairment are likely to require lower doses. Due to the irreversible mode of action of the drug, the serum half-life bears practically no relationship to the Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
duration of pharmacologic effect. Because of the long-lasting GABA transaminase inhibition, the anticonvulsant effect of VGB long outlasts its presence in serum.26 No drug interactions have been observed between VGB and other anticonvulsants or other drug classes except for a decrease in serum PHT concentrations in some patients that was of no clinical significance. In contrast to most other AEDs, monitoring of serum levels of VGB is not suitable as a guide to therapy due to its mechanism of action. For checking adherence a tentative range of 6–278 lM has been suggested. The place of VGB is as monotherapy in the treatment of infantile spasms and as adjunctive therapy for very resistant partial seizures. Because of the occurrence of irreversible visual field deficits, the U.S. Food and Drug Administration (FDA) requires that all people starting VGB regularly undergo automated visual field studies. There are black box warnings for VGB that concern the risks of developing irreversible visual field deficits, and these recommendations for treating patients must be followed closely. Perampanel Perampanel (PER) is a noncompetitive a-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)– type glutamate receptor antagonist. It is the first of its kind with this mechanism of action to be approved for the treatment of epilepsy. It has been approved in the EU and the United States (but is not yet available in the United States at the time of writing of this article) as add-on therapy for refractory partial onset seizures with or without generalization. PER has a long half-life of 70–100 h and therefore can be given as a once-daily dose.29 Phase III clinical trials have demonstrated good efficacy with tolerable side effects, mainly dizziness, somnolence, diplopia, and ataxia. These side effects can be addressed by giving the drug directly before bedtime, as there is a peak concentration within 1–2 h after intake and it then subsides after 2–3 h. The recommended doses are between 4 and 12 mg, with most side effects occurring at the higher doses. However, because CBZ will decrease the half-life of PER, people taking CBZ will probably need higher doses. There is a concentration/ effect relationship.30 Eslicarbazepine acetate Eslicarbazepine acetate (ESL) is the third member in a family of dibenz/b,f/asepine AEDs represented by CBZ (first-generation) and oxcarbazepine (OXC, second generation). OXC metabolizes to both R- and S-liscarbazepine, whereas ESL metabolizes to mainly S-liscarbazepine and only to a very minor degree to R-liscarbazepine. The major difference between ESL and CBZ is that ESL does not degrade to the epoxide metabolite, which is one of the major causes of toxicity of CBZ. The mechanism of
7 Medical Management of Refractory Epilepsy action is similar to that of CBZ and OXC, but ESL is thought to even have a modulating action and inhibits the slow activation of the Na+ channel. Metabolism is mainly by glucuronidation, with a minimal engagement of the cytochrome P450 (CYP) liver enzyme system. Therefore, there is less risk for drug–drug interaction when compared to CBZ and OXC. The half-life is 13–20 h in patients taking other AEDs. Therefore, once daily dosing is recommended.31 ESL has been available since 2010 for patients with refractory partial onset seizures as an add-on medication. The phase III double-blind studies show good efficacy and few and tolerable side effects as dizziness, diplopia, and nausea.32 These side effects were most prominent when CBZ was taken concomitantly. Monotherapy studies for new-onset epilepsy are ongoing. Compared to CBZ and OXC, it seems that ESL may have less tendency for hyponatremia and allergic reactions. In the clinical trials and long-term follow-up studies, the cognitive and psychiatric side effects were few.33 Retigabine Retigabine (RET) has been available since 2011. Its generic name in the United States is ezogabine. The indication is as add-on therapy for patients with refractory partial onset seizures. It is the first neuronal KCNQ agonist to be approved as an antiepileptic drug. The antiepileptic effect is through the opening of the voltage-gated potassium channel, thereby enhancing the M-type potassium current. Experimental animal studies have suggested that RET can have a broad spectrum of action.34 RET is metabolized via N-glucuronidation and N-acetylation and not through the CYP system. Therefore, the potential risk for drug–drug interaction is low.35 Phase III clinical trials have been positive in patients with refractory focal onset seizures. The maximum daily dose is 1,200 mg/day, which should be divided into three doses as the half-life is only 8 h. The most common side effects are dizziness, somnolence, fatigue, confusion, dysarthria, ataxia, diplopia, and urinary tract infection, as the risk for urinary retention exists because of the potassium channel activation of the bladder.36 Unfortunately for RET, a serious side effect has been found, and this drug can no longer be recommended for patients not already taking RET. For those who have a positive effect of the drug and no side effects, they can, with caution, be allowed to continue on the drug. The unexpected side effect is the development of a blue hue to the skin and retina after long-term use.33,37 Because of this, use has been restricted to patients who are already taking the drug and who have shown good effect without side effects. All patient on RET should have eye examinations (http://www.fda. gov/Drugs/DrugSafety/ucm349538.htm).
Conclusion In treating a patient with epilepsy, the physician must weigh many factors into his decision for choosing the appropriate AED and also when to go on to surgical evaluation and other therapeutic methodologies when the patient demonstrates that he or she is refractory to two or three appropriate antiseizure drugs. It is, therefore, the responsibility of the treating physician to learn about all anticonvulsants available, both new and old, in order to be able to tailor the treatment according to the requirements of each patient. This is not an easy task, as it is imperative to understand mechanisms of action, metabolism and dosing, interactions, potential side effects and how to deal with them, as well as the appropriate seizure types for each drug, and how to combine the different drugs.
Disclosure Elinor Ben-Menachem has received honoraria from Eisai, the manufacturer of Fycompa for lectures and as an advisory board member. She confirms that she has read the Journal’s position on issues involved in ethical publication and affirms that this report is consistent with those guidelines.
References 1. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–319. 2. Legros B, Boon P, De Jonghe P, et al. Opinion of Belgian neurologists on antiepileptic drug treatment in 2006: Belgian study on epilepsy treatment (BESET-2). Acta Neurol Scand 2009;120:402–410. 3. St Louis EK, Gidal BE, Henry TR, et al. Conversions between monotherapies in epilepsy: expert consensus. Epilepsy Behav 2007;11:222–234. 4. Somerville ER. Some treatments cause seizure aggravation in idiopathic epilepsies (especiallyabsence epilepsy). Epilepsia 2009;50 (Suppl. 8):31–36. 5. Sazgar M, Bourgeois BF.Aggravation of epilepsy by antiepileptic drugs. Pediatr Neurol 2005;33:227–234. 6. Somerville ER. Aggravation of partial seizures by antiepileptic drugs: is there evidence from clinical trials? Neurology 2002;59:79–83. 7. Yang MT, Lee WT, Chu LW, et al. Anti-epileptic drugs-induced de novo absence seizures. Brain Dev 2003;5:51–56. 8. Brodie MJ, Sills GJ. Combining antiepileptic drugs–rational polytherapy? Seizure 2011;20:369–375. 9. Sake JK, Hebert D, Isoj€arvi J, et al. A pooled analysis of lacosamide clinical trial data grouped by mechanism of action of concomitant antiepileptic drugs. CNS Drugs 2010;24:1055–1068. 10. Angehagen M, Margineanu DG, Ben-Menachem E, et al. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. NeuroReport 2003;14 (3):471–475. 11. L€oscher W, H€onack D, Bloms-Funke P. The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. Bin Res 2003;735:208–216. 12. Sitges M, Guarneros A, Nekrassov V. Effects of carbamazepine, phenytoin, valproic acid, oxcarbazepine, lamotrigine, topiramate and vinpocetine on the presynaptic Ca2+ channel-mediated release of [3H] glutamate: comparison with the Na+ channel-mediated release. Neuropharmacology 2007;53:854–862.
Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
8 E. Ben-Menachem 13. Brodie MJ, Yuen AW. Lamotrigine substitution study: evidence for synergism with sodium valproate? 105 study group. Epilepsy Res 1997;26:423–432. 14. Lindberger M, Alenius M, Frisen L, et al. Gabapentin versus vigabatrin as first add-on for patients with partial seizures that failed to respond to monotherapy: a randomized, double-blind, dose titration study. GREAT Study Investigators Group. Gabapentin in refractory epilepsy add-on treatment. Epilepsia 2000;41:1289–1295. 15. Beyenburg S, Stavem K, Schmidt D. Placebo-corrected efficacy of modern antiepileptic drugs for refractory epilepsy: systematic review and meta-analysis. Epilepsia 2010;51:7–26. 16. Glauser T, Ben-Menachem E, Bourgeois B. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia 2013;54:551–563. 17. French JA, Kanner AM, Bautista J, et al. Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology; Quality Standards Subcommittee of the American Academy of Neurology; American Epilepsy Society. Efficacy and tolerability of the new antiepileptic drugs II: Treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004;62:1261–1273. 18. Arroyo S. Rufinamide. Neurotherapeutics 2007;1:155–162. 19. P alhagen S, Canger R, Henriksen O, et al. Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy. Epilepsy Res 2001;43:115–124. 20. Doty P, Rudd GD, Stoehr T, et al. Lacosamide. Neurotherapeutics 2007;1:145–148. 21. Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev 2007;13:21–42. 22. 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;48:1308–1317. 23. Halasz P, K€alvi€ainen R, Mazurkiewicz-Beldzinska M. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia 2009;50:443–453.
Epilepsia, 55(Suppl.1):3–8, 2014 doi: 10.1111/epi.12494
24. Novy J, Bartolini E, Bell GS, et al. Long-term retention of lacosamide in a large cohort of people with medically refractory epilepsy: a single centre evaluation. Epillepsy Res 2013;106:250–256. 25. Kellinghaus C, Berning S, St€ogbauer F. Intravenous lacosamide or phenytoin for treatment of refractory status epilepticus. Acta Neurol Scand 2013 Aug 13 [E-pub ahead of print]. 26. Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand Suppl 2011;192:5–15. 27. Willmore LJ, Abelson MB, Ben-Menachem E, et al. Vigabatrin: 2008 update. Epilepsia 2009;50:163–173. 28. Pellock JM. Balancing clinical benefits of vigabatrin with its associated risk of vision loss. Acta Neurol Scand Suppl 2011;192:83–91. 29. Satlin A, Kramer LD, Laurenza A. Development of perampanel in epilepsy. Acta Neurol Scand Suppl 2013;197:3–8. 30. Gidal BE, Ferry J, Majid O, et al. Concentration–effect relationships with perampanel in patients with pharmacoresistant partial-onset seizures. Epilepsia 2013;54:1490–1497. 31. Bialer M, Soares-da-Silva P. Pharmacokinetics and drug interactions of eslicarbazepine acetate. Epilepsia 2012;53:935–946. 32. Gil-Nagel A, Elger C, Ben-Menachem E. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind ohase III clinical studies. Epilepsia 2013;54:98–107. 33. Martyn-St James M, Glanville J, McCool R, et al. The efficacy and safety of retigabine and other adjunctive treatments for refractory partial epilepsy: a systematic review and indirect comparison. Seizure 2012;21:665–678. 34. Gunthorpe MJ, Large CH, Sankar R. The mechanism of action of retigabine (ezogabine), a first-in-class K+ channel opener for the treatment of epilepsy. Epilepsia 2012;53:412–424. 35. Orhan G, Wuttke TV, Nies AT, et al. Retigabine/Ezogabine, a KCNQ/ K(V)7 channel opener: pharmacological and clinical data. Expert Opin Pharmacother 2012;13:1807–1816. 36. Rheims S, Ryvlin P. Retigabine for partial onset seizures. Expert Rev Neurother 2012;12:509–517. 37. Faulkner MA, Burke RA. Safety profile of two novel antiepileptic agents approved for the treatment of refractory partial seizures: ezogabine (retigabine) and perampanel. Expert Opin Drug Saf 2013;12:847–855.
