- Email: [email protected]
Do we need any more new antiepileptic drugs?
Epilepsy Research 45 (2001) 3 – 6 www.elsevier.com/locate/epilepsyres
Do we need any more new antiepileptic drugs? Martin J. Brodie * Epilepsy Unit, Uni6ersity Department of Medicine and Therapeutics, Western Infirmary, GlasgowG11 6NT, Scotland, UK
Abstract The last decade has seen the licensing of nine new antiepileptic drugs (AEDs) with more to come. Despite this, only 58 and 63% of patients with localisation-related and newly diagnosed epilepsy, respectively, had been seizure-free for more than a year in separate prospective outcome studies undertaken at the Epilepsy Unit in Glasgow. Data will be presented to support the hypothesis that adolescent and adult epileptic patients comprise two distinct populations. Around 60% will be controlled on monotherapy with the first or second choice AED, while the majority of the remainder is difficult-to-control. It is for this latter group and the many pharmacoresistant paediatric patients with encephalopathic syndromes that we need new AEDs. For a successful clinical outcome, patients must be able to tolerate the treatment. Neurotoxic, sedative, cognitive and psychiatric symptoms, dysmorphic and other long-term side effects, and teratogenesis plague the current crop of AEDs. Pharmacokinetic and pharmacodynamic interactions complicate the situation still further. These problems may, in part, be a consequence of combining drugs with similar mechanisms of action. Unravelling the genetics of the epilepsies will provide a range of tempting targets for pharmacological intervention. We need, also, models of refractory epilepsy to help identify promising therapies. An efficient regulatory trial programme will ensure rapid availability of new AEDs for the many children and adults whose lives continue to be blighted by seizures. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy antiepileptic drugs; Efficacy; Toxicity; Interactions
1. Introduction The last decade has seen the introduction of nine new antiepileptic drugs (AEDs) with more to come. Their licensing status is summarised in Table 1. Some of these have been generally available for routine prescription for nearly 10 years, although not in every country and for every indi-
* Tel.: + 44-141-2112572 ext. 2944; fax: + 44-141-3349329. E-mail address: [email protected] (M.J. Brodie).
cation. What has been their clinical impact? Do we need more? 2. Efficacy Despite the availability of many new AEDs, only 63% of a cohort of 525 patients diagnosed and treated at the Epilepsy Unit in Glasgow, Scotland, since 1984 were seizure-free in a recent prospective analysis (Kwan and Brodie, 2000). Age, sex, family history of epilepsy or febrile convulsions, and a routine surface EEG were not predictive of ‘refractoriness’. Patients with symp-
0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 1 ) 0 0 2 0 3 - 0
4
M.J. Brodie / Epilepsy Research 45 (2001) 3–6 Table 1 Licensing status of new antiepileptic drugs
tomatic or cryptogenic epilepsy were more liable to be uncontrolled than those with idiopathic seizures (40 versus 26% P =0.004), as were those reporting 20 or more seizures before treatment was begun (PB0.001). In a smaller cohort of 470 patients who had never received an AED before, 61% were controlled on monotherapy, 3% on two AEDs and none at all on three (Table 2). In a separate study in 550 adolescents and adult patients with localisation-related epilepsy, only 57% had been seizure-free for at least 1 year at their last clinic visit (Brodie et al., 1999). There was no difference in outcome among patients with symptomatic (58% seizure-free) and cryptogenic (56% seizure-free) epilepsy. However, the underlying cause of symptomatic epilepsy had an influence on prognosis with patients reporting seizures due to mesial temporal sclerosis doing least well (Fig. 1). A larger French study suggested an even poorer outcome for this cohort (Semah et al., 1998). The situation in infant and childhood epilepsy is even less satisfactory. There is a range of devastating encephalopathic syndromes for which there is no consistently effective treatment and so the prognosis for every affected child must remain guarded (Table 3). Many end up severely retarded with a reduced life expectancy and a limited quality of life. Clinical trials with new AEDs in these syndromes may indicate efficacy, but rarely is the patient seizure-free. A possible exception is vigabatrin for infantile spasms, particularly if due to tuberous sclerosis (Appleton et al., 1999). Some of these unusual conditions are part of a range of single gene disorders whose causation is being explored by molecular biological techniques. These studies hold out the promise of future pharmaco-genomic innovation.
side effects reported by patients treated with AEDs. Many patients (and their doctors) believe that these are inevitable accompaniments of successful therapy. Some AEDs produce psychiatric disturbances, particularly depression and psychosis. Idiosyncratic reactions, such as skin rash or the more dangerous blood dyscrasias and hepatotoxicity, stalk the epilepsy literature. Indeed, fatal cases of aplastic anaemia and liver failure have relegated felbamate to drug of last choice for refractory epilepsy (Pellock and Brodie, 1997). Some of the most concerning aspects of AED treatment are insidious, chronic side-effects that can, for instance, change the way a person looks or feels, damage their bones or tendons, and impair their sexual function or fertility (Table 4). Recent examples of this type of problem are polycystic ovarian syndrome associated with sodium valproate administration (Isojarvi et al., 1993) and irreversible visual field constriction due to vigabatrin (Kalviainen et al., 1999). All the established AEDs increase the likelihood of congenital anomalies in infants exposed to these drugs in utero (Crawford et al., 1999). Apart from anatomical abnormalities such as facial clefts, congenital heart disease, and neural tube defects,
3. Toxicity
Table 2 Seizure-freedom in 470 patients with newly diagnosed epilepsya
Many of the established and more modern AEDs suffer from substantial problems with toxicity (Brodie and Dichter, 1996; Dichter and Brodie, 1996). Neurotoxic side effects (e.g. nausea, diplopia, dizziness, headache, fatigue, tiredness, ataxia) are some of the common dose-related
Lamotrigine Gabapentin Topiramate Tiagabine Oxcarbazepine Felbamate Vigabatrin Zonisamide Levetiracetam
Worldwide Worldwide Widely licensed (including UK, USA) Widely licensed (including UK, USA) Widely licensed (including UK, USA) USA and Europe (limited) Limited license (not USA) Japan, South Korea, USA USA and Europe
First drug monotherapy Second drug monotherapy Third drug monotherapy Duotherapy Total seizure-freedom a
Data taken from Kwan and Brodie, 2000.
47% 13% 1% 3% 64%
M.J. Brodie / Epilepsy Research 45 (2001) 3–6
5
Fig. 1. Seizure control in different patient groups according to causation of symptomatic epilepsy MTS, mesial temporal sclerosis; MRI, magnetic resonance imaging. Numbers on top of bars represent percentage of cohort seizure-free MTS * P B0.01 compared with other patient groups.
there is emerging evidence that some babies may have neuropsychological sequelae that interfere with their subsequent intellectual development (Koch et al., 1999). The situation with the newer agents is unclear, although there is warranted hope that some, at least, will prove to be nonteratogenic.
dren with acute lymphoblastic leukaemia (Relling et al., 2000). Endogenous substances, such as hormone and vitamins, also have their turnover accelerated by enzyme inducers, and this may contribute to some of the chronic toxic effects of AEDs listed in Table 4.
5. Conclusions 4. Interactions The older AEDs are notorious for their ability to produce pharmacokinetic interactions amongst themselves, as well as with other medications (Brodie, 1992). Many affect hepatic metabolic enzymes. Phenobarbital, primidone, phenytoin, carbamazepine and, to a more selective extent, topiramate, oxcarbazepine and felbamate all induce the synthesis of one or more isoforms of the cytochrome P450 superfamily (Levy, 1995). This process will accelerate the clearance, shorten the half-life, reduce the concentration, and increase the dosage and, thereby, the cost of other lipidsoluble drugs. The effects of these agents on oral contraceptives and warfarin, for instance, are easy to understand but difficult to combat in clinical practice. Enzyme induction may produce more subtle problems such as reduced survival in chil-
The reason for the poor outcomes and neurotoxic and other side-effects associated with the current crop of AEDs may, in part, be a consequence of their similar mechanisms of action involving, in particular, blockade of voltage-dependent Na+ channels and facilitation of gamma aminobutyric acid inhibitory neuroTable 3 Major therapeutic unmet needs in childhood epilepsy Neonatal seizures Infantile spasms Lennox–Gastaut syndrome Severe myoclonic epilepsies Landau–Kleffner syndrome ESES syndromea Other epileptic encephalopathies a
Continuous spike and wave activity during slow sleep.
6
M.J. Brodie / Epilepsy Research 45 (2001) 3–6
Table 4 Some chronic side-effects associated with antiepileptic drugs Acne Hirsutism Gum hyperplasia Weight gain Hair loss
Hypocalcaemia Osteomalacia Osteoporosis
Depression Psychosis
Peripheral neuropathy Constricted visual fields Cerebellar atrophy
Polycystic ovaries Decreased libido Impotence Infertility
Dupuytren’s contracture Frozen shoulder
Teratogenesis
Lupus-like syndrome Pseudolymphoma
References
transmission. Current seizure models may not identify AEDs with unique mechanisms of action. Supportive evidence for this statement comes from the discovery process surrounding levetiracetam (Genton and Van Vleymen, 2000). We need new models of refractory epilepsy to help uncover promising therapies. The answer to the question in the title is clearly ‘yes’. We do need more new AEDs, but not an increasing list of ‘me-too’ drugs with similar modes of action. Innovation is essential for future AED development. This needs to be coupled with an understanding of how seizures are generated and propagated together with better insight into the biological basis of pharmacoresistance. Unravelling the genetics of the epilepsies will also provide a range of tempting new targets for pharmacological intervention. An efficient regulatory trial programme is an important component in this process to ensure rapid availability of these new AEDs for the many children and adults whose lives continue to be blighted by seizures.
.
Appleton, R., Peters, A.C.B., Mumford, J.P., Shaw, D.E., 1999. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia 40, 1627 – 1633. Brodie, M.J., 1992. Drug interactions and epilepsy. Epilepsia 33 (suppl 1), S13 – 22. Brodie, M.J., Dichter, M.A., 1996. Antiepileptic drugs. New Engl. J. Med. 334, 168 – 175. Brodie, M.J., Stephen, L.J., Kwan, P., 1999. Localisation related epilepsies: does pathology influence outcome? Epilepsia 40 (suppl 7), S98. The Women with Epilepsy Guidelines Development Group, Crawford, P., Appleton, R., Betts, T., Duncan, J., Guthrie, E., Morrow, J., 1999. Best practice guidelines for the management of women with epilepsy. Seizure 8, 201 – 217. Dichter, M.A., Brodie, M.J., 1996. New antiepileptic drugs. New Engl. J. Med. 334, 1583 – 1590. Genton, P., Van Vleymen, B., 2000. Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles. Epileptic Disord. 2, 99 – 105. Koch, S., Titze, K., Zimmerman, R.B., Schroder, M., Lehmkuhl, U., Ravh, H., 1999. Long-term neuropsychological consequence of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia 40, 1237 – 1243. Levy, R.H., 1995. Cytochrome P450 isoenzymes and antiepileptic drug interactions. Epilepsia 36 (suppl 5), S8 – 13. Kwan, P., Brodie, M.J., 2000. Early identification of refractory epilepsy. New Engl. J. Med. 342, 314 – 319. Isojarvi, J.I., Laatikainen, T.J., Pakarinen, A.J., Juntunen, K.T., Myllyla, W., 1993. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New Engl. J. Med. 329, 1383 – 1388. Kalviainen, R., Nousiainen, I., Mantyjarvi, M., Nikoskelainen, E., Partanen, J., Partanen, K., Riekkinen, P., 1999. Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects. Neurology 53, 922 – 926. Pellock, J.M., Brodie, M.J., 1997. Felbamate: an update. Epilepsia 38, 1261 – 1264. Relling, M.V., Pui, C.-H., Sandlund, J.T., Rivera, G.K., Hancock, M.L., Boyett, J.M., Scheutz, E.G., Evans, W.E., 2000. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 358, 285 – 290. Semah, F., Picot, M.-C., Adam, C., Broglin, D., Arzimanoglou, A., Bazin, B., Cavalcanti, D., Baulac, M., 1998. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51, 1256 – 1262.
Do we need any more new antiepileptic drugs? Martin J. Brodie * Epilepsy Unit, Uni6ersity Department of Medicine and Therapeutics, Western Infirmary, GlasgowG11 6NT, Scotland, UK
Abstract The last decade has seen the licensing of nine new antiepileptic drugs (AEDs) with more to come. Despite this, only 58 and 63% of patients with localisation-related and newly diagnosed epilepsy, respectively, had been seizure-free for more than a year in separate prospective outcome studies undertaken at the Epilepsy Unit in Glasgow. Data will be presented to support the hypothesis that adolescent and adult epileptic patients comprise two distinct populations. Around 60% will be controlled on monotherapy with the first or second choice AED, while the majority of the remainder is difficult-to-control. It is for this latter group and the many pharmacoresistant paediatric patients with encephalopathic syndromes that we need new AEDs. For a successful clinical outcome, patients must be able to tolerate the treatment. Neurotoxic, sedative, cognitive and psychiatric symptoms, dysmorphic and other long-term side effects, and teratogenesis plague the current crop of AEDs. Pharmacokinetic and pharmacodynamic interactions complicate the situation still further. These problems may, in part, be a consequence of combining drugs with similar mechanisms of action. Unravelling the genetics of the epilepsies will provide a range of tempting targets for pharmacological intervention. We need, also, models of refractory epilepsy to help identify promising therapies. An efficient regulatory trial programme will ensure rapid availability of new AEDs for the many children and adults whose lives continue to be blighted by seizures. © 2001 Elsevier Science B.V. All rights reserved. Keywords: Epilepsy antiepileptic drugs; Efficacy; Toxicity; Interactions
1. Introduction The last decade has seen the introduction of nine new antiepileptic drugs (AEDs) with more to come. Their licensing status is summarised in Table 1. Some of these have been generally available for routine prescription for nearly 10 years, although not in every country and for every indi-
* Tel.: + 44-141-2112572 ext. 2944; fax: + 44-141-3349329. E-mail address: [email protected] (M.J. Brodie).
cation. What has been their clinical impact? Do we need more? 2. Efficacy Despite the availability of many new AEDs, only 63% of a cohort of 525 patients diagnosed and treated at the Epilepsy Unit in Glasgow, Scotland, since 1984 were seizure-free in a recent prospective analysis (Kwan and Brodie, 2000). Age, sex, family history of epilepsy or febrile convulsions, and a routine surface EEG were not predictive of ‘refractoriness’. Patients with symp-
0920-1211/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 1 2 1 1 ( 0 1 ) 0 0 2 0 3 - 0
4
M.J. Brodie / Epilepsy Research 45 (2001) 3–6 Table 1 Licensing status of new antiepileptic drugs
tomatic or cryptogenic epilepsy were more liable to be uncontrolled than those with idiopathic seizures (40 versus 26% P =0.004), as were those reporting 20 or more seizures before treatment was begun (PB0.001). In a smaller cohort of 470 patients who had never received an AED before, 61% were controlled on monotherapy, 3% on two AEDs and none at all on three (Table 2). In a separate study in 550 adolescents and adult patients with localisation-related epilepsy, only 57% had been seizure-free for at least 1 year at their last clinic visit (Brodie et al., 1999). There was no difference in outcome among patients with symptomatic (58% seizure-free) and cryptogenic (56% seizure-free) epilepsy. However, the underlying cause of symptomatic epilepsy had an influence on prognosis with patients reporting seizures due to mesial temporal sclerosis doing least well (Fig. 1). A larger French study suggested an even poorer outcome for this cohort (Semah et al., 1998). The situation in infant and childhood epilepsy is even less satisfactory. There is a range of devastating encephalopathic syndromes for which there is no consistently effective treatment and so the prognosis for every affected child must remain guarded (Table 3). Many end up severely retarded with a reduced life expectancy and a limited quality of life. Clinical trials with new AEDs in these syndromes may indicate efficacy, but rarely is the patient seizure-free. A possible exception is vigabatrin for infantile spasms, particularly if due to tuberous sclerosis (Appleton et al., 1999). Some of these unusual conditions are part of a range of single gene disorders whose causation is being explored by molecular biological techniques. These studies hold out the promise of future pharmaco-genomic innovation.
side effects reported by patients treated with AEDs. Many patients (and their doctors) believe that these are inevitable accompaniments of successful therapy. Some AEDs produce psychiatric disturbances, particularly depression and psychosis. Idiosyncratic reactions, such as skin rash or the more dangerous blood dyscrasias and hepatotoxicity, stalk the epilepsy literature. Indeed, fatal cases of aplastic anaemia and liver failure have relegated felbamate to drug of last choice for refractory epilepsy (Pellock and Brodie, 1997). Some of the most concerning aspects of AED treatment are insidious, chronic side-effects that can, for instance, change the way a person looks or feels, damage their bones or tendons, and impair their sexual function or fertility (Table 4). Recent examples of this type of problem are polycystic ovarian syndrome associated with sodium valproate administration (Isojarvi et al., 1993) and irreversible visual field constriction due to vigabatrin (Kalviainen et al., 1999). All the established AEDs increase the likelihood of congenital anomalies in infants exposed to these drugs in utero (Crawford et al., 1999). Apart from anatomical abnormalities such as facial clefts, congenital heart disease, and neural tube defects,
3. Toxicity
Table 2 Seizure-freedom in 470 patients with newly diagnosed epilepsya
Many of the established and more modern AEDs suffer from substantial problems with toxicity (Brodie and Dichter, 1996; Dichter and Brodie, 1996). Neurotoxic side effects (e.g. nausea, diplopia, dizziness, headache, fatigue, tiredness, ataxia) are some of the common dose-related
Lamotrigine Gabapentin Topiramate Tiagabine Oxcarbazepine Felbamate Vigabatrin Zonisamide Levetiracetam
Worldwide Worldwide Widely licensed (including UK, USA) Widely licensed (including UK, USA) Widely licensed (including UK, USA) USA and Europe (limited) Limited license (not USA) Japan, South Korea, USA USA and Europe
First drug monotherapy Second drug monotherapy Third drug monotherapy Duotherapy Total seizure-freedom a
Data taken from Kwan and Brodie, 2000.
47% 13% 1% 3% 64%
M.J. Brodie / Epilepsy Research 45 (2001) 3–6
5
Fig. 1. Seizure control in different patient groups according to causation of symptomatic epilepsy MTS, mesial temporal sclerosis; MRI, magnetic resonance imaging. Numbers on top of bars represent percentage of cohort seizure-free MTS * P B0.01 compared with other patient groups.
there is emerging evidence that some babies may have neuropsychological sequelae that interfere with their subsequent intellectual development (Koch et al., 1999). The situation with the newer agents is unclear, although there is warranted hope that some, at least, will prove to be nonteratogenic.
dren with acute lymphoblastic leukaemia (Relling et al., 2000). Endogenous substances, such as hormone and vitamins, also have their turnover accelerated by enzyme inducers, and this may contribute to some of the chronic toxic effects of AEDs listed in Table 4.
5. Conclusions 4. Interactions The older AEDs are notorious for their ability to produce pharmacokinetic interactions amongst themselves, as well as with other medications (Brodie, 1992). Many affect hepatic metabolic enzymes. Phenobarbital, primidone, phenytoin, carbamazepine and, to a more selective extent, topiramate, oxcarbazepine and felbamate all induce the synthesis of one or more isoforms of the cytochrome P450 superfamily (Levy, 1995). This process will accelerate the clearance, shorten the half-life, reduce the concentration, and increase the dosage and, thereby, the cost of other lipidsoluble drugs. The effects of these agents on oral contraceptives and warfarin, for instance, are easy to understand but difficult to combat in clinical practice. Enzyme induction may produce more subtle problems such as reduced survival in chil-
The reason for the poor outcomes and neurotoxic and other side-effects associated with the current crop of AEDs may, in part, be a consequence of their similar mechanisms of action involving, in particular, blockade of voltage-dependent Na+ channels and facilitation of gamma aminobutyric acid inhibitory neuroTable 3 Major therapeutic unmet needs in childhood epilepsy Neonatal seizures Infantile spasms Lennox–Gastaut syndrome Severe myoclonic epilepsies Landau–Kleffner syndrome ESES syndromea Other epileptic encephalopathies a
Continuous spike and wave activity during slow sleep.
6
M.J. Brodie / Epilepsy Research 45 (2001) 3–6
Table 4 Some chronic side-effects associated with antiepileptic drugs Acne Hirsutism Gum hyperplasia Weight gain Hair loss
Hypocalcaemia Osteomalacia Osteoporosis
Depression Psychosis
Peripheral neuropathy Constricted visual fields Cerebellar atrophy
Polycystic ovaries Decreased libido Impotence Infertility
Dupuytren’s contracture Frozen shoulder
Teratogenesis
Lupus-like syndrome Pseudolymphoma
References
transmission. Current seizure models may not identify AEDs with unique mechanisms of action. Supportive evidence for this statement comes from the discovery process surrounding levetiracetam (Genton and Van Vleymen, 2000). We need new models of refractory epilepsy to help uncover promising therapies. The answer to the question in the title is clearly ‘yes’. We do need more new AEDs, but not an increasing list of ‘me-too’ drugs with similar modes of action. Innovation is essential for future AED development. This needs to be coupled with an understanding of how seizures are generated and propagated together with better insight into the biological basis of pharmacoresistance. Unravelling the genetics of the epilepsies will also provide a range of tempting new targets for pharmacological intervention. An efficient regulatory trial programme is an important component in this process to ensure rapid availability of these new AEDs for the many children and adults whose lives continue to be blighted by seizures.
.
Appleton, R., Peters, A.C.B., Mumford, J.P., Shaw, D.E., 1999. Randomised, placebo-controlled study of vigabatrin as first-line treatment of infantile spasms. Epilepsia 40, 1627 – 1633. Brodie, M.J., 1992. Drug interactions and epilepsy. Epilepsia 33 (suppl 1), S13 – 22. Brodie, M.J., Dichter, M.A., 1996. Antiepileptic drugs. New Engl. J. Med. 334, 168 – 175. Brodie, M.J., Stephen, L.J., Kwan, P., 1999. Localisation related epilepsies: does pathology influence outcome? Epilepsia 40 (suppl 7), S98. The Women with Epilepsy Guidelines Development Group, Crawford, P., Appleton, R., Betts, T., Duncan, J., Guthrie, E., Morrow, J., 1999. Best practice guidelines for the management of women with epilepsy. Seizure 8, 201 – 217. Dichter, M.A., Brodie, M.J., 1996. New antiepileptic drugs. New Engl. J. Med. 334, 1583 – 1590. Genton, P., Van Vleymen, B., 2000. Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles. Epileptic Disord. 2, 99 – 105. Koch, S., Titze, K., Zimmerman, R.B., Schroder, M., Lehmkuhl, U., Ravh, H., 1999. Long-term neuropsychological consequence of maternal epilepsy and anticonvulsant treatment during pregnancy for school-age children and adolescents. Epilepsia 40, 1237 – 1243. Levy, R.H., 1995. Cytochrome P450 isoenzymes and antiepileptic drug interactions. Epilepsia 36 (suppl 5), S8 – 13. Kwan, P., Brodie, M.J., 2000. Early identification of refractory epilepsy. New Engl. J. Med. 342, 314 – 319. Isojarvi, J.I., Laatikainen, T.J., Pakarinen, A.J., Juntunen, K.T., Myllyla, W., 1993. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. New Engl. J. Med. 329, 1383 – 1388. Kalviainen, R., Nousiainen, I., Mantyjarvi, M., Nikoskelainen, E., Partanen, J., Partanen, K., Riekkinen, P., 1999. Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects. Neurology 53, 922 – 926. Pellock, J.M., Brodie, M.J., 1997. Felbamate: an update. Epilepsia 38, 1261 – 1264. Relling, M.V., Pui, C.-H., Sandlund, J.T., Rivera, G.K., Hancock, M.L., Boyett, J.M., Scheutz, E.G., Evans, W.E., 2000. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet 358, 285 – 290. Semah, F., Picot, M.-C., Adam, C., Broglin, D., Arzimanoglou, A., Bazin, B., Cavalcanti, D., Baulac, M., 1998. Is the underlying cause of epilepsy a major prognostic factor for recurrence? Neurology 51, 1256 – 1262.