Reference Section

Modern Approaches to Epilepsy Management

a report by

Professor Martin J Brodie

Vice President, International League against Epilepsy (ILAE)

Martin J Brodie is Vice President of the International League against Epilepsy (ILAE) and chairs its Task Force on Regional Commissions. He is Professor of Medicine and Clinical Pharmacology at the University of Glasgow, Scotland, and directs the Epilepsy Unit in the Western Infirmary, which provides a range of services for people with seizure disorders. Professor Brodie also chairs the Management Group and Scientific Advisory Board of European Concerted Action and Research in Epilepsy (EUCARE) and is Vice Chair of the Executive Committee of the European Epilepsy Academy (EUREPA). His research interests include anti-epileptic drug neuropharmacology, the management of epilepsy and factors affecting outcome, which has resulted in the publication of more than 400 books, editorials, reviews and scientific papers. Professor Brodie has been appointed Ambassador for Epilepsy on behalf of the ILAE and the International Bureau for Epilepsy (IBET).

Seizures are the symptoms of a dysfunctional brain. They manifest in myriad different epilepsy syndromes with an equally wide variety of pathophysiologies.1 The majority of patients with newly diagnosed epilepsy in the developed world will be started on a prophylactic treatment with an antiepileptic drug (AED). AEDs can only suppress seizure activity after epilepsy has developed, but none has been proven to influence the dynamic processes leading to epileptogenesis. When epilepsy remains uncontrolled, it is termed refractory or pharmacoresistant. It has long been recognised that seizures will be or will become refractory to pharmacotherapy in more than 30% of patients2 and that localised related epilepsies are less likely to be controlled than the idiopathic generalised syndromes. Some of these patients will be offered epilepsy surgery or a vagal nerve stimulator. Many epilepsy sufferers will remain seizure-free on the first or second drug chosen. However, combinations of AEDs are usually prescribed in those unresponsive to monotherapy. The major dilemma inherent in this sequential approach of drug prescription lies in the imprecise understanding and definition of pharmacoresistance. Our ignorance of the neurobiological factors underlying the development of drug resistance in localisation-related epilepsy leads to an inability to individualise the prognosis. At present, we can only guess at crude outcomes in patients with identified causative pathologies, such as cortical dysplasia (CD) and mesial temporal sclerosis (MTS), which often but not always carry a poor prognosis.34 Indeed, evidence of MTS has been found in patients without seizures.5 Pharmacoresistance may be regarded as the flip-side of epileptogenesis. Recent research has focused on the role of multidrug transport systems, most notably P-glycoprotein (P-gp), in the pathogenesis of refractory epilepsy. P-gp is an efflux transporter, encoded by the multidrug resistance (MDR1) gene, which contributes to the integrity of the blood-brain barrier and actively extrudes a wide range of pharmacologic agents, including AEDs, from mammalian cells. Speculation suggests that overexpression of P-gp and other drug transport proteins in the region of epileptic foci can prevent

AEDs from reaching their site of action.6 Childelevated expression of these transporters has been reported in the region of both CD and MTS tissue.7 Whether drug transporters represent the cause or effect of recurrent seizures is unclear and perhaps unimportant given that experimental seizures can induce their expression and potentially reinforce inherent or acquired intractability.8
AEDs

In the past decade, nine new AEDs have been licensed, substantially widening physicians choice and the number of possible combinations is now almost limitless. However, there remain a number of issues to be addressed: the number of trials of single AEDs that should be employed before the patient is treated with duotherapy; the number of AEDs, either singly or in combination (and in how many combinations), that need to fail before the seizure disorder can be recognised as refractory and surgery considered; the stage at which epilepsy becomes pharmacoresistant to AED treatment and what determines success or failure with AED therapy; and whether there are clinical features that will allow prediction of subsequent refractoriness. Responses and solutions to these issues depend on an understanding of the natural history of treated epilepsy.
Natural History of Treated Epilepsy

There are two classes of epilepsy patient: easy versus difficult-to-control. A long-term outcome study supports the hypothesis that patients with newly diagnosed epilepsy comprise two distinct populations. Around 60% have a good prognosis (see Table 1). They will become seizure-free on a modest or moderate dose of the first- or second-choice AED as monotherapy without developing intolerable side effects.9 Some of these will remain in remission after withdrawal of AED therapy. The other 30% to 40% have difficult-to-control epilepsy (see Figure 1). These patients often have an underlying structural cerebral abnormality. They are more likely to have had a high number of seizures before treatment was initiated, a feature recognised increasingly as the result rather than the cause of the pathophysiological

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Modern Approaches to Epilepsy Management

changes that later manifest as refractory epilepsy. Pharmacoresistant epilepsy may, therefore, be present de novo as well as evolving over time, and can be identified early when treatment with the first well-tolerated AED fails. Between these two subsets, there is a grey zone of patients who will respond to combination therapy (see Figure 2).
Refractory Epilepsy
Figure 1: Probability of Seizure-freedom in Newly Diagnosed Epilepsy According to Number of Antiepileptic Drug Regimens

? Remission Seizure-free (64%) ? Not controlled (36%) Remission

Although criteria for defining refractory epilepsy are elusive, e.g. number of drugs tried, dose of drugs, duration of treatment, etc.,10 a hard core of over 30% of patients continue to have seizures that appear to be pharmacoresistant.11 These patients are usually treated with multiple AEDs, which, in combination, may produce sedative and behavioural toxicity.1213 Some patients with recent-onset seizures appear to have refractory epilepsy de novo even before the first AED is prescribed, whereas others perhaps develop a progressive seizure disorder.14 These observations have important implications for research into the nature of the slow burn that generates treatment resistance in patients with localisation-related epilepsy. High seizure frequency, prolonged seizures and episodes of status epilepticus can lead to cognitive decline.15 In some patients epilepsy is progressive, resulting in a catalogue of detrimental changes including dendritic sprouting, synaptic reorganisation, glial proliferation and cell death.16 A long period of imperfect seizure control can produce disturbed psychosocial integration, which results, for instance, in poor academic achievement, diminished self esteem, dependent behaviour and a restricted lifestyle, all of which lead to an unsatisfactory, downwardspiralling quality of life.1718 In addition, this patient population shows excess mortality, particularly due to sudden unexpected death.18,19 Refractory epilepsy, therefore, may be best understood as a condition comprising a constellation of features with recurrent seizures being just one of its manifestations.18 Factors that constitute refractory epilepsy are: intractable seizures; excessive drug burden; neurobiochemical plasticity changes; cognitive deterioration; psychosocial dysfunction; dependent behaviour; restricted lifestyle; unsatisfactory quality of life; and increased mortality.

?
Source: P Kwan and M J Brodie, Early Identification of Refractory Epilepsy, N Engl. J. Med., 342 (2000), pp. 314319.

Figure 2: Natural History of Treated Epilepsy

100 80 Percentage of patients 60 40 20 0 1 (470) 2 (190) 3 (65) 4 (25)

Antiepileptic drug regimens

Dotted lines represent 95% confidence intervals. Source: P Kwan and M J Brodie, Early Identification of Refractory Epilepsy, N Engl. J. Med., 342 (2000), pp. 314319.

Table 1: Success of Antiepileptic Drug Regimens in 470 Patients with Newly Diagnosed, Previously Untreated Epilepsy
Variable No. of patients %

Seizure-free on first monotherapy Seizure-free on second monotherapy Seizure-free on third monotherapy Seizure-free on two drugs Total seizure-free

222 61 6 12 301

47 13 1 3 64

Source: P Kwan and M J Brodie, Early Identification of Refractory Epilepsy, N Engl. J. Med., 342 (2000), pp. 314319.

Combination Therapy

Combining AEDs requires an understanding of their pharmacology, in particular their mechanisms of

action.20 Other issues that need to be considered in planning a treatment schedule for the individual patient include spectrum of efficacy, side-effect profile and propensity for adverse interactions.21 Although the mechanisms of action of all AEDs are not fully understood, they fall into a number of general categories (see Table 2).22 Drugs such as phenytoin, carbamazepine and lamotrigine act

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Reference Section

Table 2: Common Mechanisms of Antiepileptic Drug Action

Sodium channels Calcium channels Potassium channels Inhibitory transmission Excitatory transmission

Phenytoin Carbamazepine Sodium valproate Ethosuximide Phenobarbital Benzodiazepines Lamotrigine Oxcarbazepine Zonisamide Vigabatrin Tiagabine Gabapentin Felbamate Topiramate Levetiracetam

+++ +++ +

+ + +++ + + + ++ ++ +++ +++ + +++ +++ ++ ++ ++ + + +

+++ +++ ++

+ ++ ++

+ + ++ +

++ ++ +

Key: +++ = primary action; ++ = probable action; + = possible action

primarily by limiting sustained repetitive firing via blockade of voltage-gated sodium channels. This property is shared by some of the newer AEDs, such as oxcarbazepine and zonisamide. Ethosuximide uniquely reduces low-threshold T-calcium currents. A number of AEDs, such as the barbiturates and the benzodiazepines, vigabatrin and tiagabine, enhance the inhibitory action of -aminobutyric acid. Effects on calcium and potassium channels and reduction of glutamate-mediated excitation also contribute to the antiepileptic properties of many drugs. Many of the newer AEDs, especially gabapentin, topiramate, felbamate, zonisamide and, probably also, lamotrigine and levetiracetam, have multiple pharmacological effects. Theoretically, seizure freedom can be achieved by combining drugs with different, overlapping or similar mechanisms of actions with the aim of finding a complementary formula for the individual patient.23 In patients with multiple-seizure types or difficultto-control epilepsy, AEDs with differing pharmacological properties should be chosen. Patients with a single-seizure type may, in addition, respond to a pairing that influences an individual ion channel or neurotransmitter system in different ways. Although robust data evaluating the effectiveness of AED combinations is scarce, some regimens, such as sodium valproate with ethosuximide for absence seizures,24 sodium valproate with lamotrigine for partial-onset and generalised seizures25,26 and lamotrigine with topiramate for a range of seizure types,27 have been suggested in clinical and laboratory studies to have additive or even synergistic effects.20 There is emerging evidence that a wide range of combinations of two or perhaps three AEDs can be effective in some patients with difficult-tocontrol epilepsy.28,29

Epilepsy Management Practical and Theoretical Considerations

These theoretical considerations have practical implications for the management of newly diagnosed epilepsy. The most suitable AED for each patient should be chosen to maximise the chance of remission without producing side effects given that lifelong treatment may be required in a patient with often mild epilepsy.30 In clinical practice, first-line AEDs are not all the same. Important differences between them may not be detected by regulatory trials, which are designed primarily to satisfy licensing requirements and often diverge considerably from clinical reality. Evidence from randomised trials should be complemented by long-term studies that reflect everyday clinical practice. Efficacy and tolerability, i.e. effectiveness, should both be taken into account when choosing an AED since many patients with newly diagnosed epilepsy will control on a modest dose of the first drug tried. Safety and lack of long-term sequelae are important factors for this patient population.21 Failure on the first AED due to lack of efficacy implies refractoriness, since only 11% of such patients subsequently become seizure-free.2 It is unclear whether substituting or adding another AED is a more effective strategy in this situation.31 For practical purposes, a patient may be regarded as having refractory epilepsy when seizure control is not obtained with consecutive trials of two AEDs. The challenge facing the clinician is to improve the outcome for patients not responding to monotherapy by combining more appropriately modern AEDs with complementary modes of action or offering them early resective surgery. If a structural abnormality, such as MTS, can be identified on brain

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Modern Approaches to Epilepsy Management

imaging, surgery should be considered.32,33 For the majority of patients in whom epilepsy cannot be cured by surgery, combination therapy should be employed early in the management process.29 At this time, too, it would be appropriate to reassess the security of the diagnosis, the accuracy of the seizure and/or syndrome classification, the results of brain imaging, the patients compliance with medication and the possible presence of negative lifestyle factors such as covert alcohol or drug abuse.
Staged Approach to Epilepsy Management

polytherapy will be tolerated and, therefore, effective.34 Drug burden is a function of dose as well as number of AEDs and reducing the dose of one or more AEDs may help accommodate the introduction of a second or third drug. Some patients do well on duotherapy. A few will become seizure-free on three AEDs, but treatment with four or more is not likely to be successful.29
Conclusion

Since the majority of patients becoming seizure-free on a single AED will do so at modest or moderate dosage, the emphasis for this patient population should be tolerability and safety.9 If the first AED produces a rash or another idiosyncratic reaction or side effects at low or moderate dosage or fails to improve seizure control, an alternative should be substituted. If the first or second drug is well tolerated, the dose can be increased by increments towards the limit of tolerability aiming for optimal control. If control is greatly improved but seizurefreedom proves elusive, another AED with a different mechanism of action should be added. The dose of the original drug should be reduced, particularly if the patient has or develops side effects. If seizures are not fully controlled on the first two drugs as monotherapy or the initial choice and first combination, work-up for epilepsy surgery should be considered, particularly if a potentially operable structural abnormality, such as MTS, has been identified.32,33 If the first AED combination is not effective, a sequence of combinations with potential complementary modes of action should be tried. If one of these pairs is particularly well tolerated and substantially reduces seizure frequency and/or severity, triple therapy can be attempted by adding a small dose of a third AED with different pharmacological properties. There is a caveat, however. The greater the drug burden, the less likely
References

Are there identifiable clinical, molecular or genetic markers that will refine prediction of outcome? If these processes can be monitored, we can begin to develop compounds that do not just prevent seizures, but will hinder or reverse the insidious processes underlying the genesis of refractory epilepsy. In addition, certain proteins are providing scope for pharmacologic exploitation, and the recent identification of polymorphism-related P-gp expression may aid prediction of a patients innate drug resistance.6 This is, however, the tip of the iceberg. Many genes influence the disposition of and response to AEDs. It is unlikely that a single polymorphism in the MDR1 gene alone will be predictive of outcome. By characterising polymorphisms in all genes that encode proteins that influence AED pharmacokinetics or pharmacodynamics, we may be able to predict efficacy and acceptable tolerability with a specific drug in a designated patient with a defined epilepsy syndrome.35 This may in turn advance our understanding of epileptogenesis itself. Hopefully, the many decades of trial and error in choosing AED therapy will slowly give way to a more scientific rationale in the choice of antiseizure drugs for people with localisation-related epilepsy and antiepileptogenic agents for those at risk of developing it. A staged approach to the pharmacological management and, when appropriate, surgical workup for each epilepsy syndrome will optimise the chance of perfect seizure control and help more patients achieve a fulfilling life. s

1. J Engel, A Proposed Diagnostic Scheme for People with Epileptic Seizures and with Epilepsy: Report on the ILAE Task Force on Classification and Terminology, Epilepsia, 42 (2001), pp. 18. 2. P Kwan and M J Brodie, Early Identification of Refractory Epilepsy, N Engl. J. Med., 342 (2000), pp. 314319. 3. F Semah, M-C Picot, C Adam, et al., Is the Underlying Cause of Epilepsy a Major Prognostic Factor for Recurrence?, Neurology, 42 (1998), pp. 1,2561,262. 4. L J Stephen, P Kwan and M J Brodie, Does the Cause of Localisation-related Epilepsy Influence the Response to Antiepileptic Drug Treatment?, Epilepsia, 42 (2001), pp. 357362. 5. S R Benbadis, J Wallace, F R Murtagh, C Martinez, W O Tatum and F L Vale, MRI Evidence of Mesial Temporal Sclerosis in Subjects Without Seizures, Seizure, 11 (2002), pp. 340343. 6 W Lscher and H Potschka, Role of Multidrug Transporters in Pharmacoresistance to Antiepileptic Drugs, J.
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Pharmacol. Exp. Ther., 301 (2002), pp. 714. 7. S M Sisodiya, W-R Lin, B N Harding, M V Squier and M Thom, Drug Resistance in Epilepsy: Expression of Drug Resistance Proteins in Common Causes of Refractory Epilepsy, Brain, 125 (2002), pp. 2231. 8. P Kwan, G J Sills, E Butler, T W Gant, B S Meldrum and M J Brodie, Regional Expression of Multidrug Resistance Genes in Genetically Epilepsyprone Rat Brain Following a Single Audiogenic Seizure, Epilepsia, 43 (2002), pp. 1,3181,323. 9. P Kwan and M J Brodie, Effectiveness of First Antiepileptic Drug, ibid., 42 (2001), pp. 1,2551,260. 10. E Perucca, Pharmacoresistance in Epilepsy: How Should it be Defined?, CNS Drugs, 10 (1998), pp. 171179. 11. M J Brodie and M A Dichter, Antiepileptic Drugs, N. Engl. J. Med., 334 (1996), pp. 168175. 12. J Vermeulen and A P Aldenkamp, Cognitive Side-effects of Chronic Antiepileptic Drug Treatment: A Review of 25 Years of Research, Epilepsy Res., 22 (1995), pp. 6595. 13. P Kwan and M J Brodie, Neuropsychological Effects on Epilepsy of Antiepileptic Drugs, Lancet, 357 (2001), pp. 216222. 14. S Arroyo, M J Brodie, G Avanzini, et al., Is Refractory Epilepsy Preventable?, Epilepsia, 43 (2002), pp. 437444. 15. O Devinsky, Patients with Refractory Seizures, N. Engl. J. Med., 340 (1999), pp. 1,5651,570. 16. B S Meldrum, Why and When are Seizures Bad for the Brain?, Trends Pharmacol. Sci., 22 (2001), pp. 445446. 17. M Sillanp, M Jalava, O Kaleva and S Shinnar, Long-term Prognosis of Seizures with Onset in Childhood, N. Engl. J. Med., 338 (1998), pp. 1,7151,722. 18. P Kwan and M J Brodie, Refractory Epilepsy: A Progressive, Intractable but Preventable Condition?, Seizure (in press). 19. L Nilsson, B Y Farahmand, P G Persson, I Thiblin and T Tomson, Risk Factors for Sudden Unexpected Death in Epilepsy: A Case Control Study, Lancet, 353 (1999), pp. 888893. 20. C L Deckers, S J Czuczwar, Y A Hekster, A Keyser, H Kubova, H Meinardi, P N Patsalos, W O Renier and C M Van Rijn, Selection of Antiepileptic Drug Polytherapy Based on Mechanisms of Action: The Evidence Reviewed, Epilepsia, 41 (2000), pp. 1,3641,374. 21. M J Brodie and P Kwan, The Star Systems: Overview and Use in Determining Antiepileptic Drug Choice, CNS Drugs, 15 (2001), pp. 112. 22. P Kwan, G J Sills and M J Brodie, The Mechanisms of Action of Commonly Used Antiepileptic Drugs, Pharmacol. Ther., 90 (2001), pp. 2134. 23. M J Brodie, Management Strategies for Refractory Localization-related Seizures, Epilepsia, 42 (2001) Suppl. 3, pp. 2730. 24. A J Rowan, J W A Meijer, N De Beer-Pawlikowski, et al., Valproate Ethosuximide Combination Therapy for Refractory Absence Seizures, Arch. Neurol., 40 (1983), pp. 797802. 25. M J Brodie, A W Yuen and the 105 Study Group, Lamotrigine Substitution Study: Evidence for Synergism with Sodium Valproate?, Epilepsy Res., 26 (1997), pp. 423432. 26. F Pisani, G Otero, M F Russo, R Di Perri, E Perucca and A Richens, The Efficacy of Valproate-lamotrigine Comedication in Refractory Complex Partial Seizures: Evidence for a Pharmacodynamic Interaction, Epilepsia, 40 (1999), pp. 1,1411,146. 27. L J Stephen, G J Sills and M J Brodie, Lamotrigine and Topiramate May be a Useful Combination, Lancet, 351 (1998), pp. 958959. 28. L J Stephen, P Kwan and M J Brodie, Does the Cause of Localisation-related Epilepsy Influence the Response to Antiepileptic Drug Treatment?, Epilepsia, 42 (2001), pp. 357362. 29. L J Stephen and M J Brodie, Seizure-freedom with More Than one Antiepileptic Drug, Seizure, 11 (2002), pp. 349351. 30. M J Brodie and J A French, Management of Epilepsy in Adolescents and Adults, Lancet, 356 (2000), pp. 323329. 31. P Kwan and M J Brodie, Epilepsy After the First Drug Fails: Substitution or Add-on?, Seizure, 9 (2000), pp. 464468. 32. J Engel, Jr, Surgery for Seizures, N. Engl. J. Med., 334 (1996), pp. 647652. 33. S Wiebe, W T Blume, J P Girvin and M Elasziw, for the Effectiveness and Efficacy of Surgery for Temporal Lobe Epilepsy Study Group, A Randomized, Controlled Trial of Surgery for Temporal Lobe Epilepsy, ibid., 345 (2001), pp. 311318. 34. C L Deckers, Y A Hekster, A Keyser, H Meinardi and W O Renier, Reappraisal of Polytherapy in Epilepsy: A Critical Review of Drug Load and Adverse Effects, Epilepsia, 38 (1997), pp. 570575. 35. K K Jain, Will Neurogenomics Revolutionize Neurotherapeutics?, Exp. Rev. Neurotherapeut., 1 (2001), pp. 13.
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