Management of Refractory Epilepsy

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1 Management of Refractory Epilepsy Byung In Lee, M.D. Department of Neurology College of Medicine, Yonsei University Management of drug resistant epilepsy (DRE) requires a systematic approach consisting of (1) investigation of potential causes of DRE, (2) determination of the degree of DRE on the basis of previous drug therapy, (3) rational pharmacotherapy consisting of both monotherapy and combination therapy, and (4) referral to surgery or other alternative therapy. The scheme of rational pharmacotherapy consists of (1) first drug monotherapy (2) second drug monotherapy, (3) two drug combination therapy, (4) triple drug combination therapy, and (5) addition of second-line drug. With the introduction of many new antiepileptic drugs (AEDs) having different mechanisms of action, the combination therapy has become more effective and safer, which made the use of triple drug combination therapy feasible in practice if it includes at least one new AED. It should be acknowleged that the rational combination therapy may achieve a seizure free outcome in a significant proportion of patients with less severe DRE. For patients with surgically remediable epileptic syndromes, a systematic trial of two to three drugs may suffice an earlier referral to surgery. J Korean Neurol Assoc 20(6):443~452, 2002 Key words : Drug-resistant epilepsy (DRE), Monotherapy, Combination therapy, Surgically remediable epileptic syndromes Byung In Lee, M.D. Copyright 2002 by the Korean Neurological Association 443

2 Table 1. Potential causes of drug resistant epilepsies Causes Diagnostic errors Patient s errors Treatment errors Disease itself Comments non-epileptic events wrong diagnosis of seizure types/epileptic syndrome missing of underlying causes/lesions non-compliance inappropriate life style wrong choice of drugs less optimal doses of drugs inadequate dosing schedules refractory epilepsy 444 J Korean Neurol Assoc / Volume 20 / September, 2002

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5 1. Level O : DRE with suboptimal mono-or combination therapy 2. Level 1 : DRE with maximally tolerable first drug monotherapy 3. Level 2 : DRE with maximally tolerable 2nd drug therapy 4. Level 3 : DRE with maximally tolerable duotherapy 5. Level 4 : DRE with maximally tolerable triple therapy 6. Level 5 : Refractory Epilepsy : * if the patient is intolerable to the suboptimal dose of first drug, another drug will be chosen as the first drug second line AED ; clobazam, vigabatrine, felbamate, etc SF; seizure free, SRES ; surgically remediable epileptic syndromes, VNS; vagal nerve stimulation Figure 1. Algorhithm of antiepileptic drug (AED) therapy in drug-resistant epilepsies (DRE). J Korean Neurol Assoc / Volume 20 / September,

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7 Table 2. Considerations for choice of drugs in rational polytherapy 1. drugs having different mechanisms of action 2. drugs have shown best responses in previous exposure 3. drugs having less pharmacokinetic interactions 4. drugs having better pharmacodynamic interactions 5. drugs having higher therapeutic index 6. drugs having different side effect profiles 7. drugs of better cost-effectivenees J Korean Neurol Assoc / Volume 20 / September,

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9 04. Schmidt D. Medical intractability in partial epilepsies. In Luders H. Epilepsy Surgery. New York: Raven Press, Ltd; 1991; Schmidt D. Prognosis of chronic epilepsy with complex 01. Bourgeois BFD. General concepts of medical intractabili- In Luders H. Epilepsy Surgery. New York: Raven ty. Press, Ltd;1991: Aicardi J, Shorvon SD. Intractable epilepsy. In : Engel J. Jr and Pedley TA. Epilepsy: A comprehensive Textbook. Philadelphia-New York: Lippincott-Raven Publishers; 1997: Devinsky O. Patients with refractory epilepsy. N Engl J Med 1999;340: partial seizures. J Neurol Neurosurg Psychiatry. 1984;47: Collaborative Group for the Study of Epilepsy. Prognosis of epilepsy in newly referred patients: a multicenter prospective study of the effects of monotherapy on the long-term course of epilepsy. Epilepsia 1992;33: Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342: Elwes RDC, Johnson AL, Shorvon SD, Reynolds EH. The prognosis for seizure control in newly diagnosed epilepsy. N Engl J Med 1984;311: Semah F, Picot M-C, Adam C, et al. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 1998;51: Alper K, Devinsky O, Perrine K, Vasquez B, Luciano D. Nonepileptic seizures and childhood sexual and physical abuse. Neurology 1993;43: Perucca E, gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998 ; 39: Commission on Classification and Terminology of the ILAE. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;39: Lee BI, Heo K, Kim JS, et al. Syndromic diagnosis at the epilepsy clinic: Role of MRI in lobar epilepsies. Epilepsia 2002:43; Engel J Jr., Cascino GD, Shields WD. Surgically remediable syndromes. In : Engel JJr. and Pedley TA. Epilepsy: A Comprehensive Texbook. Philadelphia-New York: Lippincott Raven Publishers 1997; Gilliam F. Optimizing heath outcomes in active epilepsy. Neurology 2002;58(suppl 5);S9-S Mckee PJW, Brodie MJ. Therapeutic drug monitoring In : Engel J Jr. and Pedley TA. Epilepsy: A Co m p r e h e n s i v e T e x t b o o k. Philadelphia-New York: Lippincott Raven Publishers 1997: Richens A, Davidson DLW, Cartlidage NEF, et al. A multicenter comparative trial of sodium valproate and carba- J Korean Neurol Assoc / Volume 20 / September,

10 mazepine in adult onset epilepsy. J Neurol Neurosurg Psychiatry 1994;57: Mattson RH, Cramer JA, Collins JF, et al. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonicclonic seizures in adults. N Engl J Med 1992;327: Dam M, Ekberg R, Loyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;3: Brodie MJ, Richens A, Yuen AWC. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345: Bailer M, Johannessen SI, Kupferberg HJ, et al. Progress report on new antiepileptic drugs : a summary of the fifth Eilat Conference (EILAT V) Epilepsy Res. 2001;43: Chadwick D, for the Vigabatrin European Monotherapy Study Group. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomized double-blind study. Lancet 1999;354: Chadwick DW, Anhut H, Greiner MJ, et al. A doubleblind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;51: Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. B M J 1997;314: Motte J, Trevathan E, Arvidsson JFV, et al. Lamotrigine for generalized seizures associated with the Lennox- Gastaut syndrome. N Engl J Med 1997;337: Beran RG, Berkovic SF, Dunagan FM, et al. Double-bind, placebocontrolled, crossover study of lamotrigine in treatment-resistant generalized epilepsy. Epilepsia ; 39: Glauser TA, Sachdeo RC, Ritter F, Reife R, Lim P, Topiramate in Lennox Gastaut syndrome (abstract). Neurology 1997;48: Biton V, Montouris GD, Riviello JD, Reife R, and The Topiramate YTC Study Group. Topiramate as add-on therapy in generalized seizures of non-focal origin. A n n Neurol 1997;42: Schmidt D, Richter K. Alternative single anticonvulsant drug therapy for refractory epilepsy. Ann. N e u r o l. 1986;19: Beydoun A, Sackelleres JC, Shu V and the Depakote Monotherapy for Partial Seizures Study Group. Safety and efficacy of divalproex sodium monotherapy in partial epilepsy: A double-blind, concentration-response design clinical trial. Neurology. 1997;48: Brodie MJ, Yuen AWC, 105 Study Group. Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26: Brodie MJ, Mumford JP, 012 study group. Double-blind substitution of vigabatrin and valproate in carbamazepineresistant partial epilepsy. Epilepsy Res 1999;34: Kwan P, Brodie MJ. Epielpsy after the first drug fails : substution or add-on? Seizure 2000;9: Marson AG, Kadir ZA, Chadwick DW. New antiepileptic drugs: a systemic review of their efficacy and tolerability. BMJ 1996;313: Chiron C, Dulac O, Beaumont D, et al. Therapentic trial of vigabatrin in refractory infantile spasm. J Child Neurol 1991;6(suppl 2):S52-S Glauser TA, Clark PO, Strawsburg R. A pilot study of topiramate in the treatment of in fantile spasms. E p i l e p s i a 1998;39: Yanai S, Hanai T, Narazaki O. Treatment of infantile spasms with zonidamide. Brain Develop 1999;21: The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut Syndrome). N Engl J Med 1993;328: Korean Topiramate Study Group. Low dose and slow titration of topiramate as adjunctive therapy in refractory partial epilepsies: a multicentre open clinical trial. Seizure 2002;11: Bourgeois BFD. Combination of valproate and ethosuximide : antiepileptic and neurotoxic interaction. J Pharma - col Exp Ther 1988;247: Pisani F, Oteri G, Russo MF, et al. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: Evidence for a pharmacodynamic interaction. Epilepsia 1999;40: McCabe PH, McNew CD, Michel NC. Effect of divalproex-lamotrigine combination therapy in frontal lobe seizures. Arch Neurol 2001;58: Delanty N, French JA,Willams SF. Lamotrigine and topiramate combination therapy: Experience from postmarketing surveillance. Epilepsia 1998;39(suppl 6):131 (abstract). 44. Kanner Am, Balabanov A. Depression and epilepsy : how closely related are they? Neurology 2002;58(suppl 5);S27- S Wilder BJ. Vagal nerve stimulation In : Engel J Jr, Pedley TA. Epilepsy: A comprehensive Textbook. Ph i l a d e l p h i a - New York: Lippincott-Rowen 1997; Vining EPG. Ketogenic diet. In : Engel J Jr., Pedly TA. Epilepsy: A Comprehensive Textbook. P h i l a d e l p h i a - N e w York: Lippincott-Raven 1977; J Korean Neurol Assoc / Volume 20 / September, 2002

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