Summary
The pharmacological treatment of epilepsy has made considerable progress during the last decade, due to improved knowledge of the clinical pharmacology of individual drugs, acquisition of new information on the factors affecting response and need for drug treatment, and development of promising new agents. Once a clinical diagnosis of epilepsy has been made (which generally requires the occurrence of more than one seizure), treatment should be started with a single drug selected on the basis of seizure type and tolerability profile. Although there are important regional differences in prescribing patterns and individual circumstances may dictate alternative choices, carbamazepine is generally regarded as the preferred treatment for partial seizures (with or without secondary generalisation) while valproic acid (sodium valproate) is usually the first choice in most forms of generalised epilepsies.
To achieve therapeutic success, the daily dosage must be tailored to meet individual needs, and there is suggestive evidence that in some patients the dosage prescribed initially may be unnecessarily large. Plasma antiepileptic drug concentrations may aid in the individualisation of dosage, but should not be regarded as a substitute for careful monitoring of clinical response.
Although overall about 70% of patients can be completely controlled, response rate is influenced by a number of factors, the most important of which are seizure type and syndromic form. The importance of a correct syndromic classification for rational drug selection has been poorly assessed and represents a major area for future research. Patients who do not respond to the highest tolerated dose of the initially prescribed drug may be switched to monotherapy with an alternative agent or may be given add-on treatment with a second drug. Appropriate prospective trials are required to assess the merits of either strategy. If add-on therapy is selected and the patient becomes seizure free, it may be possible to discontinue the drug prescribed initially and reinstitute monotherapy. Only a minority of patients are likely to require multiple drug therapy, and it remains to be established whether specific drug combinations are more effective than others.
Until further information becomes available, the new agents should be reserved for patients failing to respond to the conventional treatments of first choice. Patients whose seizures cannot be controlled by available drugs should be reassessed, and polytherapy should be maintained only when there is clear evidence that benefits outweigh possible adverse effects. In many patients who have been seizure free for at least 2 years it may be possible to gradually discontinue all medications. The decision to withdraw treatment is determined largely by the risk of seizure relapse which, in turn, is primarily dependent on the syndromic form.
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References
Berg AT, Shinnar S. The risk of seizure recurrence following a first unprovoked seizure: a quantitative review. Neurology 1991; 41: 965–72
Camfield P, Camfield C, Dooley JM, et al. Epilepsy after a first unprovoked seizure in childhood. Neurology 1985; 35: 1657–60
Hirtz DG, Ellenberg JH, Nelson KB. The risk of recurrence of nonfebrile seizures in children. Neurology 1984; 34: 637–41
Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-84. Epilepsia 1993; 34: 453–68
van den Berg BJ, Yerushalmy J. Studies on convulsive disorders in young children: I. Incidence of febrile and nonfebrile convulsions by age and other factors. Pediatr Res 1969; 3: 298–304
Annegers J, Shirts SB, Hauser WA, et al. Risk of recurrence after an initial unprovoked seizure. Epilepsia 1986; 27: 43–50
Hopkins A, Garman A, Clarke C. The first seizure in adult life: value of clinical features, electroencephalography and computerized tomographic scaning in prediction of seizure recurrence. Lancet 1988; 1: 721–6
Hauser WA, Rich SS, Annegers JF, et al. Seizure recurrence after a 1st unprovoked seizure: an extended follow-up. Neurology 1990; 40: 1163–70
Shinnar S, Berg AT, Moshe SL, et al. The risk of recurrence following a first unprovoked seizure in childhood: a prospective study. Pediatrics 1990; 85: 1076–85
van Donselaar CA, Geerts AT, Schimsheimer RJ. Idiopathic first seizure in adult life: who should be treated?. BMJ 1991; 302: 620–3
Boulloche I, Leloup P, Mallet E, et al. Risk of recurrence after a single unprovoked generalized tonic-clonic seizure. Dev Med Child Neurol 1989; 31: 629–32
Hart YM, Sander JWAS, Johnson AL, et al. National general practice study of epilepsy: recurrence after a first seizure. Lancet 1990; 336: 1271–4
Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985; 313: 145–51
Collaborative Group for Epidemiology of Epilepsy. Adverse reactions to antiepileptic drugs: a multicenter survey of clinical practice. Epilepsia 1986; 27: 323–30
First Seizure Trial Group. Randomized clinical trial on the efficacy of antiepileptic drugs in reducing the risk of relapse after a first unprovoked tonic-clonic seizure. Neurology 1993; 43: 478–83
Camfield P, Camfield C, Dooley J, et al. A randomized study of carbamazepine versus no medication after a first unprovoked seizure in childhood. Neurology 1989; 39: 851–2
Musicco M, Beghi E, Solari A, et al. Effect of antiepileptic treatment initiated after the first unprovoked seizure on the long-term prognosis of epilepsy. Neurology 1994; 44 Suppl. 27: A337–8
Willmore LJ. Postraumatic epilepsy. Neurol Clin 1992; 10: 868–78
Yablon SA. Post-traumatic seizures. Arch Phys Med Rehab 1993; 4: 983–1001
Hauser WA. Prevention of post-traumatic epilepsy. N Engl J Med 1990: 323: 540–2
Murri L, Parenti G, Annegers JF, editors. Pharmacological prophylaxis of post-traumatic epilepsy. Padova: Piccin Editore, 1991
Reynolds EH, Shorvon SD. Monotherapy or polytherapy for epilepsy?. Epilepsia 1981; 22: 1–10
Beghi E, Di Mascio R, Tognoni G. Drug treatment of epilepsy. Outlines, criticism and perspectives. Drugs 1986; 31: 249–65
Smith DB, Delgado-Escueta AV, Cramer JA, et al. Historical perspective on the choice of antiepileptic drugs for the treatment of seizures in adults. Neurology 1983; 33 Suppl. 1: 2–7
Chadwick D. Standard approach to antiepileptic drug treatment in the United Kingdom. Epilepsia 1994; 35 Suppl. 4: S3–S10
Pellock JM. Standard approach to antiepileptic drug treatment in the United States. Epilepsia 1994; 35 Suppl. 4: S11–8
Callaghan N, O’Hare J, O’Driscoll D, et al. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol 1982; 24: 830–6
Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982; 32: 157–63
Turnbull DM, Rawlins MD, Weightman D, et al. A comparison of phenytoin and valproate in previously untreated adult epileptic patients. J Neurol Neurosurg Psychiatry 1982; 45: 55–9
Turnbull DM, Howell D, Rawlins MD, et al. Which drug for the adult epileptic patients: phenytoin or valproate?. BMJ 1985; 290: 815–7
Chadwick D, Turnbull DM. The comparative efficacy of antiepileptic drugs for partial and tonic-clonic seizures. J Neurol Neurosurg Psychiatry 1985; 48: 1073–7
Callaghan N, Kenny RA, O’Neill B, et al. A prospective study between carbamazepine, phenytoin and sodium valproate as monotherapy in previously untreated and recently diagnosed patients with epilepsy. J Neurol Neurosurg Psychiatry 1985; 48: 639–44
Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic/clonic seizures in adults. N Engl J Med 1992; 327: 765–71
Feksi AT, Kaamugisha J, Sander JWAS, et al. Comprehensive primary health care antiepileptic drug treatment programme in rural and semi-urban Kenya. Lancet 1991; 337: 406–9
Heller AJ, Stewart J, Hughes E, et al. Comparative efficacy and toxicity of phenobarbital, phenytoin, carbamazepine, and valproate in adults and children with newly diagnosed previously untreated epilepsy: a randomized long-term trial. J Neurol Neurosurg Psychiatry. In press
Richens A, Davidson DLW, Cartlidge NEF, et al. A multicentre comparative trial of sodium valproate and carbamazepine in adult-onset epilepsy. J Neurol Neurosurg Psychiatry 1994; 57: 682–7
Richens A, Perucca E. Clinical pharmacology and medical treatment. In: Laidlaw J, Richens A, Chadwick D. editors. A textbook of epilepsy. Edinburgh: Churchill-Livingstone, 1993: 495–559
Perucca E. The general principles of drug treatment. In: Shorvon SD, Dreifuss FE, Fish DF, et al., editors. The treatment of epilepsy. Oxford: Blackwell Scientific Publications Ltd. In press
Porter RJ. How to use antiepileptic drugs. In: Levy RH, Mattson R, Meldrum B, et al., editors. Antiepileptic drugs. New York: Raven Press, 1989: 117–31
Okuma T, Kumashiro H. Natural history and prognosis of epilepsy: report of a multi-institutional study in Japan. Epilepsia 1981; 22: 35–53
Holowach-Thurston J, Thurston DL, Hixon BB, et al. Prognosis of childhood epilepsy. Additional follow-up of 148 children 15 to 23 years after withdrawal of anticonvulsant therapy. N Engl J Med 1982; 306: 831–6
Rodin E, Klutke G, Chayasirisobohon C. Epileptic patients who are refractory to anticonvulsant medications. Neurology 1982; 32: 1382–4
Todt H. The late prognosis of epilepsy in childhood: results of a prospective follow-up study. Epilepsia 1984; 25: 137–44
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: 45–51
Lombroso CT. A prospective study of infantile spasms: clinical and therapeutic correlations. Epilepsia 1983; 24: 135–58
Matsumoto A, Watanabe K, Sugiura M, et al. Long-term prognosis of convulsive disorders in the first year of life: mental and physical development and seizure persistence. Epilepsia 1983; 24: 321–9
Viani F, Beghi E, Atza G, et al. Classifications of epileptic syndromes: advantages and limitations for evaluation of childhood epileptic syndromes in clinical practice. Epilepsia 1988; 29: 440–5
Perucca E. Recipes for clinical practice. In: Trimble MR, editor. A re-appraisal of some new antiepileptic drugs. London: John Wiley, 1994: 145–61
Eadie MJ. Neurological diseases. In: Speight TM, editor. Avery’s drug treatment. Principles and practice of clinical pharmacology and therapeutics. Auckland: ADIS Press Limited, 1987: 1078–1136
Levy RH, Mattson R, Meldrum B, et al., editors. Antiepileptic Drugs. New York: Raven Press, 1989
Reynolds EH, Elwes RDC, Shorvon SD. Why does epilepsy become intractable?. Lancet 1983; 2: 952–4
Shorvon SD, Reynolds EH. Unnecessary polypharmacy for epilepsy. BMJ 1977; 1: 1635–7
Schmidt D, Haenel F. Therapeutic plasma levels of phenytoin, phenobarbital, and carbamazepine. Individual variation in relation to seizure frequency and type. Neurology 1984; 34: 1252–5
Baruzzi A, Procaccianti G, Tinuper P, et al. Antiepileptic drug withdrawal in childhood epilepsy: preliminary results of a prospective study. In: Faienza C, Prati GL. editors. Diagnostic and therapeutic problems in pediatric epileptology. Amsterdam: Elsevier, 1988: 117–23
Schmidt D, Einicke I, Haenel F. The influence of seizure type on the efficacy of plasma concentrations of phenytoin, phenobarbital and carbamazepine. Arch Neurol 1986; 43: 263–5
Elwes RDC, Johnson AL, Shorvon SD, et al. The prognosis for seizure control in newly diagnosed epilepsy. N Engl J Med 1984; 311: 944–7
Elwes RDC, Johnson AL, Reynolds EH. The course of untreated epilepsy. BMJ 1988; 297: 948–50
Goddard GV, McIntyre DC, Leech CK. A permanent change in brain function resulting from daily electrical stimulation. Exp Neurol 1969; 25: 295–330
Sander JWAS. Some aspects of prognosis in the epilepsies: a review. Epilepsia 1993; 34: 1007–16
Annegers J, Hauser WA, Elveback LR. Remission of seizures and relapse in patients with epilepsy. Epilepsia 1979; 20: 729–37
Goodridge DMG, Shorvon SD. Epileptic seizures in a population of 6000. BMJ 1983; 287: 641–7
Watts AE. The natural history of untreated epilepsy in a rural community in Africa. Epilepsia 1992; 33 (3): 464–8
Commission on Classification and Terminology of the International League against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989; 30: 389–99
Shorvon SD. Chronic epilepsy. BMJ 1991; 302: 363–6
Perucca E, Richens A. Antiepileptic drugs: clinical aspects. In: Richens A, Marks V, editors. Therapeutic drug monitoring. Edinburgh: Churchill-Livingstone, 1981: 320–48
Thompson AH, Brodie MJ. Pharmacokinetic optimisation of anticonvulsant therapy. Clin Pharmacokinet 1992; 23: 216–30
Chadwick DW. Overuse of monitoring of blood concentrations of antiepileptic drugs. BMJ 1987; 294: 723–4
Pellock JM, Willmore LJ. A rational guide to routine blood monitoring in patients receiving antiepileptic drugs. Neurology 1991; 41: 961–4
Kalviainen R, Keranen T, Riekkinen PJ. Place of newer antiepileptic drugs in the treatment of epilepsy. Drugs 1994; 46: 1009–24
Peters DH, Sorkin EM. Zonisamide: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy. Drugs 1993; 45: 760–87
Grant SM, Heel RC. Vigabatrin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 1991; 41: 889–926
Goa KL, Ross SR, Chrisp P. Lamotrigine: a review of its pharmacological properties and clinical efficacy in epilepsy. Drugs 1993; 46: 152–76
Cramer JA, Mattson RH, Prevey ML, et al. How often is medication taken as prescribed?. JAMA 1989; 261: 3273–7
Hakkarainen H. Carbamazepine vs diphenyl-hydantoin vs their combination in adult epilepsy. Neurology 1980; 30: 354
Rowan AJ, Meijer JWA, de Beer-Pawlikowski N, et al. Valproate ethosuximide combination therapy for refractory absence seizures. Arch Neurol 1983; 40: 797–802
Schmidt D. Two antiepileptic drugs for intractable epilepsy with complex partial seizures. J Neurol Neurosurg Psychiatry 1982; 45: 1119–24
Gram L, Drachmann Bentsen K, Parnas J, et al. Controlled trials in epilepsy: a review. Epilepsia 1992; 23: 491–519
Perucca E. The clinical pharmacology of new antiepileptic drugs. Pharmacol Res 1993; 28: 89–106
Walker MC, Sander JW. Developments in antiepileptic drug therapy. Curr Opin Neurol Neurosurg 1994; 7: 131–9
Walker MC, Sander JW. Overtreatment with antiepileptic drugs: how extensive is the problem?. CNS Drugs 1994; 2: 335–40
Loscher W, Schmidt D. Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation?. Epilepsy Res 1994; 17: 95–134
Macdonald RL, Kelly KM. Mechanism of action of new anticonvulsant drugs. In: Trimble MR, editor. A re-appraisal of some new antiepileptic drugs. London: John Wiley, 1994: 35–50
Porter RJ, Rogawsky MA. New antiepileptic drugs: from serependity to rational discovery. Epilepsia 1992; 33 Suppl. 1: S1–6
Robinson MK, Black AB, Schapel GS, et al. Combined gammavinyl GABA (vigabatrin) and lamotrigine therapy in management of refractory epilepsy. Epilepsia 1993: 34 Suppl. 2: 109
Stolarek I, Blacklaw J, Forrest G, et al. Vigabatrin and lamotrigine in refractory epilepsy. J Neurol Neurosurg Psychiatry 1994; 57: 921–4
Pisani F, Di Perri R, Perucca E, et al. Interaction of lamotrigine with sodium valproate. Lancet 1993; 341: 1224
Goa KL, Sorkin EM. Gabapentin: a review of its pharmacological properties and clinical potential in epilepsy. Drugs 1993; 46: 409–27
Grant SM, Faulds D. Oxcarbazepine: a review of its pharmacology and therapeutic potential in epilepsy, trigeminal neuralgia and affective disorders. Drugs 1992; 43: 873–88
Patsalos PN, Duncan JS. New antiepileptic agents: a review of their current status and clinical potential. CNS Drugs 1994; 2: 40–77
Pellock JM. The use of new anticonvulsant drugs in children. In: Trimble MR, editor. A re-appraisal of some new antiepileptic drugs. London: John Wiley, 1994: 127–43
Pisani F, Perucca E, Avanzini G, et al. New antiepileptic drugs. Amsterdam: Elsevier, 1991: 1–196
Duncan JS. Vigabatrin. In: Trimble MR, editor. A re-appraisal of some new antiepileptic drugs. London: John Wiley, 1994: 5
Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400
Leppik IE. Lamotrigine. In: Trimble MR, editor. A re-appraisal of some new antiepileptic drugs. London: John Wiley, 1994: 91–102
Editorial. Oxcarbazepine. Lancet 1989; 334: 196–8
Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut Syndrome). N Engl J Med 1993; 328: 29–33
Palmer KJ, McTavish D. Felbamate: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs 1993; 45: 1041–65
Appleton RE, Montiel-Viesca F. Vigabatrin in infantile spasms — why add-on?. Lancet 1992; 341: 962
Chadwick D. A practical guide to discontinuing antiepileptic drugs. CNS Drugs 1994; 2: 423–8
Pedley TA. Discontinuing antiepileptic drugs. N Engl J Med 1988; 318: 982–4
Chadwick D, Reynolds EH. When do epileptic patients need treatment? Starting and stopping medication. BMJ 1985; 290: 1885–8
Oller-Daurella L, Oiler LF-V. Suppression of antiepileptic treatment. Eur Neurol 1987; 27: 106–13
Berg AT, Shinnar S. Relapse following discontinuation of antiepileptic drugs: a meta-analysis. Neurology 1994; 44: 601–8
Shinnar S, Vining EPG, Mellits ED, et al. Discontinuing antiepileptic medication in children with epilepsy after two years without seizures. A prospective study. N Engl J Med 1985; 313: 976–80
Callaghan N, Ganett A, Goggin T. Withdrawal of anticonvulsant drugs in patients free of seizures for two years. N Engl J Med 1988; 318: 942–6
Medical Research Council Antiepileptic Drug Withdrawal Study Group. Randomized study of antiepileptic drug withdrawal in patients in remission. Lancet 1991; 337: 1175–80
Shinnar S, Berg AT, Moshè SL, et al. Discontinuing antiepileptic drugs in children with epilepsy: a prospective study. Ann Neurol 1994; 35: 534–45
Emerson R, D’Souza BJ, Vining EP, et al. Stopping medication in children with epilepsy. Predictors of outcome. N Engl J Med 1988; 304: 1125–9
Bouma PAD, Peters ACB, Arts RJH, et al. Discontinuation of antiepileptic therapy: a prospective study in children. J Neurol Neurosurg Psychiatry 1987; 50: 1579–83
Tennison M, Greenwood R, Lewis D, et al. Discontinuing antiepileptic drugs in children with epilepsy. A comparison of a six-week and a nine-month taper period. N Engl J Med 1994; 330: 1407–10
Arts WFM, Visser LH, Loonen MCB, et al. Follow-up of 146 children with epilepsy after withdrawal of antiepileptic therapy. Epilepsia 1988; 29: 244–50
Viani F. Le epilessie nell’infanzia: diagnosi e terapia. In: Assael BM, editor. Fisiopatologia e Terapia in Pediatria. Milano: Edizioni Congress Studio, 1987: 119–37
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Beghi, E., Perucca, E. The Management of Epilepsy in the 1990s. Drugs 49, 680–694 (1995). https://doi.org/10.2165/00003495-199549050-00004
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DOI: https://doi.org/10.2165/00003495-199549050-00004