0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Neurological Review |

Monotherapy in Epilepsy:  Role of the Newer Antiepileptic Drugs FREE

Blanca Vazquez, MD
[+] Author Affiliations

Author Affiliation: Department of Neurology, NYU School of Medicine, New York, NY.


Section Editor: David E. Pleasure, MD

More Author Information
Arch Neurol. 2004;61(9):1361-1365. doi:10.1001/archneur.61.9.1361.
Text Size: A A A
Published online

Background  Monotherapy is the goal for pharmacological treatment of epilepsy. Well-controlled trials have established the efficacy of some of the newer antiepileptic drugs (AEDs) as monotherapy.

Objective  To review clinical data and expert opinions pertinent to the evaluation of most of the newer AEDs as monotherapy for epilepsy.

Data Sources  The MEDLINE database was searched for clinical trials using newer AEDs. Reference sections of review articles were manually searched to identify relevant studies not retrieved in MEDLINE.

Study Selection  The resulting list of references was manually reviewed to identify monotherapy studies.

Results  Lamotrigine and oxcarbazepine demonstrated efficacy in randomized active-control trials in patients with newly diagnosed epilepsy and in substitution trials in patients refractory to conventional AEDs.

Conclusion  Lamotrigine and oxcarbazepine are as effective as conventional AEDs at controlling partial seizures and are better tolerated.

Monotherapy is preferred when treating epilepsy, although previous reports indicate that polytherapy was sometimes the standard of care and given routinely as initial treatment.1 Polytherapy began to be questioned shortly after studies showed that 50% to 75% of patients who started on monotherapy remained seizure free for at least 1 year and that monotherapy is equally or more effective, better tolerated, and associated with fewer drug interactions compared with polytherapy.27 Other advantages of monotherapy include better compliance, lower costs, and improved quality of life.1

The efficacy of conventional antiepileptic drugs (AEDs), including phenytoin, carbamazepine, phenobarbital, and valproate, as monotherapy is accepted,710 but efficacy of monotherapy with some of the newer AEDs has been established in well-controlled trials. To protect patients from the potential dangers of a noneffective agent used as monotherapy, many newer medications were initially studied as adjunctive therapy in refractory patients,1 and when efficacy and tolerability as adjunctive treatments were established, newer medications were then studied as monotherapy.11 However, felbamate and oxcarbazepine were studied as adjunctive therapy and monotherapy simultaneously.1215 Sufficient data are now available to establish the efficacy and tolerability of some of the newer AEDs as monotherapy. This article reviews data pertinent to evaluating the role of the newer AEDs, including felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, and topiramate, as monotherapy.

The long-term, randomized, double-blind, placebo-controlled clinical trial of monotherapy in epilepsy is generally untenable for new AEDs because of possible harm arising from withholding active treatment. Randomized active-control trials comparing monotherapy with a test medication and monotherapy with a reference medication (typically a conventional AED with established efficacy) in newly diagnosed patients are the next best alternative, allowing assessment of efficacy and tolerability under conditions approximating clinical use.11 Because a new drug would not be expected to surpass the high (70%-80%) seizure remission rates achieved with established agents, demonstration of comparable efficacy of the test and reference medications is interpreted as evidence of the test medication’s efficacy.

Randomized, double-blind substitution trials gradually transition refractory patients to monotherapy with either a new AED or a conventional AED as the reference medication.11 As with double-blind, head-to-head monotherapy trials, demonstration of comparable efficacy of the test and reference medications is interpreted as evidence of efficacy of the test medication.

While clinicians generally accept comparable efficacy of test and reference medications in double-blind comparator trials as evidence of the test medication’s efficacy, regulatory authorities considering whether to approve new medications as monotherapy may not. To be statistically powered to show equivalence between the comparator medications, these trials generally need to include a prohibitively large number of patients. If a study is underpowered, a demonstration of apparent comparable efficacy cannot exclude the possibility that test and reference medications are both ineffective. In this case, a demonstration of superior efficacy of the test medication over the reference medication provides the only incontrovertible evidence of its efficacy. This hurdle is too high for most test AEDs to overcome, although the test drug may be effective as monotherapy in the clinical setting.11

Several alternative study designs compare test medication with a suboptimal treatment, which may be a nontherapeutic dose of the same drug, a different drug, or a placebo. Presurgical trials compare high doses of a test AED with placebo in patients with refractory seizures who need to discontinue their current therapy for evaluation before epilepsy surgery.16 These trials are of short duration because of the risks patients are exposed to in the placebo arm (ie, no AED treatment). This trial design compares the seizure frequency between the study drug and placebo, just as in other placebo-controlled trials. In open-label substitution trials, a high dosage of the test medication is compared with a suboptimal dosage of the same drug or with either a suboptimal drug or an effective dosage of a different one.11 When ethically feasible, a placebo group sometimes takes the place of the active comparator in substitution trials.

These alternative study designs require relatively few patients to demonstrate statistically significant effects of treatment. However, because of short duration and lack of flexibility for titrating doses to optimum levels, the practical relevance of data derived from these studies is limited.

A full discussion of all the complexities of monotherapy trial designs is beyond the scope of this article. The reader is encouraged to refer to other reviews for a more complete discussion of trial designs for monotherapy studies in epilepsy.11,1618

Clinical studies of the newer AEDs as monotherapy were identified through searches of the National Library of Medicine’s PubMed database, using as key words the names of the newer AEDs (ie, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide) and the term “clinical trial.” No date limits were applied. The resulting list of references was manually reviewed to identify monotherapy studies. Reference sections of review articles on AEDs were manually searched to identify relevant studies not identified in the PubMed searches. Data presented at professional meetings in abstract form are not included in this review. Because no clinical studies on zonisamide as monotherapy were identified with the methods described above, that agent is not discussed in this review.

Numerous active-control comparisons of new AEDs with conventional medications have been conducted in patients with newly diagnosed epilepsy, and results of several open-label comparisons are also available.1929 Three of the studies employed a randomized, open-label design,23,28,29 1 randomized study had both an open-label and a double-blind component,19 and the other 7 were randomized, double-blind trials.2022,2427 Most of these studies were of sufficient duration (approximately 1 year) to allow assessment of long-term effects of the drugs on seizure control. Furthermore, many of these studies employed flexible dose-titration schedules, allowing investigators to adjust doses.

Gabapentin, lamotrigine, oxcarbazepine, and vigabatrin have been compared with conventional AEDs in patients with newly diagnosed epilepsy in randomized active-control trials. Except for vigabatrin, which compared with carbamazepine was associated with a higher percentage of discontinuations because of lack of efficacy,28 the studies show that newer agents are as effective in controlling seizures as reference AEDs including carbamazepine, phenytoin, and valproate. Seizure-free rates with both test and reference AEDs ranged from approximately 40% to 75%, consistent with rates historically observed with conventional AEDs.2,810

One randomized, active-control study compared 2 newer AEDs rather than a newer AED with a conventional one.20 That study, a randomized, double-blind, flexible-dose comparison of lamotrigine and gabapentin, demonstrated that both drugs were well tolerated and comparably effective in patients with newly diagnosed partial and tonic-clonic seizures, with 76% of patients in each group remaining seizure free for the last 12 weeks of monotherapy.

The newer AEDs were nearly always better tolerated, as reflected in lower frequencies of adverse events or lower rates of withdrawal from the study because of adverse events. Gabapentin (1 study), lamotrigine (3 studies), oxcarbazepine (1 study), and vigabatrin (2 studies) were each better tolerated than carbamazepine; oxcarbazepine was better tolerated than phenytoin (2 studies).19,2224,2629

Lamotrigine and oxcarbazepine consistently demonstrate efficacy in randomized active-control trials.2027 Furthermore, monotherapy with these drugs is better tolerated than monotherapy with conventional AEDs. Additional study of the other newer AEDs is warranted before definitive conclusions can be drawn about them: gabapentin was effective vs a conventional AED in 1 active-control study19; mixed results have been obtained with vigabatrin28,29; and felbamate, levetiracetam, tiagabine, and topiramate have not been assessed in published, randomized active-control studies in patients with newly diagnosed epilepsy.

Data from active-control studies are supplemented by a placebo-controlled trial of the efficacy of lamotrigine (median dose, 15 mg/kg per day) for absence seizures in 45 children aged 3 to 15 years with newly diagnosed epilepsy.30 A placebo control group was feasible because of the relatively benign nature of absence seizures; withholding effective treatment from the placebo group for the brief, 4-week treatment period would not endanger patients because this trial employed an escape design. When patients entered the double-blind phase, their absence seizures were fully controlled. Patients would exit the double-blind arm as soon as they were no longer seizure free. Therefore, the only patients exposed to placebo for 4 weeks were those who remained seizure free. Lamotrigine was significantly more effective than placebo, with 64% of patients receiving lamotrigine monotherapy free of absence seizures during the 4-week double-blind phase compared with 21% of placebo recipients. Lamotrigine was well tolerated, and no patient withdrew from the study because of adverse events.

Several double-blind and open-label substitution trials have been conducted with the newer AEDs.13,3138 These trials generally enrolled patients with epilepsy refractory to conventional AEDs and were initiated with add-on phases during which patients were introduced to increasing doses of the test AED while their current AED was discontinued. A period of monotherapy with the test drug ensued. Patients with worsening epilepsy (usually measured by an increase in seizure frequency, severity, or the emergence of a new seizure type) or patients who did not tolerate the test AED were withdrawn from the study.

Active-control substitution trials were conducted with felbamate (2 studies) and lamotrigine (1 study), both of which were significantly more effective as monotherapy than low-dose or a minimally effective dose of valproate.13,31,32 In the only long-term, placebo-controlled substitution trial, 3000 mg of levetiracetam was significantly more effective than placebo during 12 weeks of monotherapy.35 Substitution trials comparing low and high doses of the test AED have been carried out with oxcarbazepine (300 mg/d vs 2400 mg/d), tiagabine (6 mg/d vs 36 mg/d), and topiramate (100 mg/d vs 1000 mg/d).3638 In all comparisons, the high dose of study medication was more effective at controlling seizures or prolonging time in the study. Generally, overall retention rates in these studies are low, and occurrence of adverse effects may be due to the high doses and rapid titration used.

Overall, substitution trials are consistent with randomized active-control trials in demonstrating efficacy of newer AEDs. The data for felbamate, lamotrigine, and levetiracetam are most robust because they were obtained from studies using an active comparator or a placebo control group.13,31,32,35 The other studies, which either were open-label and did not include a comparator or compared low and high doses of the test AED, should be interpreted cautiously because of the lack of a reference treatment.33,34,3638

Substitution trials extend the data from the trials in patients with newly diagnosed epilepsy by showing that seizures can be controlled with the newer medications in many patients refractory to conventional AEDs. The findings should be generalized to clinical practice carefully because these treatment-resistant patients may not be representative of typical clinical populations of patients with epilepsy.

Presurgical trials have been conducted with felbamate, gabapentin, oxcarbazepine, and tiagabine.15,37,39,40 In 3 placebo-controlled studies (felbamate, oxcarbazepine, and tiagabine), the test AED was more effective than placebo at reducing seizure frequency or prolonging time in the study.15,37,39 In the fourth comparison, a higher daily dose of gabapentin (3600 mg) was more effective than a lower dose (300 mg) in prolonging time in the study.40 Presurgical trials, while having the benefit of a placebo group, provide limited information because their design does not mimic clinical practice. These trials are of short duration (ie, 8-10 days), the inpatient setting is more controlled (ie, supervised) than an outpatient setting, study medication is administered via unorthodox conditions (ie, with rapid-dose escalation after abrupt withdrawal of the patient’s usual AED), and AED doses cannot be titrated as they would be in clinical practice.

Because currently available AEDs are generally not distinguishable on the basis of efficacy data from clinical trials, factors such as mechanism of action, spectrum of activity, neuropsychiatric profile, sedative burden, long-term adverse effects, and ease of dosing need to be considered in choosing AEDs for monotherapy.6 Many of these features are not directly assessed in clinical trials. Taking into account these features and others, the newer AEDs lamotrigine, gabapentin, oxcarbazepine, and vigabatrin are considered to have better profiles as AED monotherapies than the conventional AEDs phenobarbital, phenytoin, carbamazepine, and valproate. Specific advantages of the newer AEDs include better tolerability, predictable kinetics, and broad-spectrum efficacy or well-defined spectrum of efficacy.

In addition to these characteristics of AEDs, medication effects in special patient populations warrant consideration.6 It is important to be aware that some AEDs (phenobarbital, phenytoin, carbamazepine, oxcarbazepine, felbamate, and topiramate) increase the metabolism of hormonal contraceptives, while others (valproic acid, vigabatrin, lamotrigine, gabapentin, tiagabine, and levetiracetam) do not interact with hormonal contraceptives.41 Drugs with cognitive adverse effects should be avoided in elderly patients, who may be particularly susceptible to central nervous system toxicity.

Finally, there is evidence to suggest that the majority of patients who achieve seizure freedom with AEDs do so with monotherapy. The results of a prospective study evaluating AED response in patients with newly diagnosed epilepsy suggest that, regardless of the drug, only a relatively small percentage of patients who do not achieve seizure control with monotherapy will achieve control with polytherapy. Of the 64% of patients naïve to AEDs before the start of the study who became seizure free, 61% achieved seizure freedom with monotherapy, while the remaining 3% were seizure free with a 2-drug regimen.42 The finding that only 3% of the 64% of patients who were seizure free required polytherapy suggests that, for most patients who are responsive to pharmacotherapy, monotherapy is an effective treatment regimen.

Leaders in the field of epilepsy recommend valproate and lamotrigine as first-line monotherapy for generalized tonic-clonic seizures; valproate, ethosuximide, and lamotrigine for absence seizures; and valproate and lamotrigine for myoclonic seizures. Lamotrigine was recommended as first-line treatment for idiopathic generalized epilepsy among women of reproductive age, including those who are pregnant or breastfeeding; elderly patients; and those with intellectual impairment.43 Oxcarbazepine is currently approved by the Food and Drug Administration as monotherapy for partial seizures in adults, and lamotrigine is Food and Drug Administration-approved for conversion to monotherapy in adults with partial seizures.

Long-term, randomized, double-blind, placebo-controlled trials are not appropriate to evaluate monotherapy because of the risks involved in withholding active treatment from a patient. Therefore, several alternative designs are generally used. It is important to keep the strengths and weaknesses of these trial designs in mind when interpreting results and evaluating options for monotherapy.

Results of several clinical trials demonstrate that the newer AEDs can be as effective as monotherapy for epilepsy. Efficacy is particularly well established for lamotrigine and oxcarbazepine, and compared with conventional AEDs such as carbamazepine, phenytoin, and valproate, both are equally effective at controlling seizures and are better tolerated. Data for the other newer AEDs are both less voluminous and less consistent than those for lamotrigine and oxcarbazepine, and additional clinical study is warranted before the place of these medications can be established.

Correspondence: Blanca Vazquez, MD, NYU Comprehensive Epilepsy Center, 403 East 34th St, RIV Fourth Floor, New York, NY 10016-4998 (blancavs@netscape.net).

Accepted for Publication: Feburary 4, 2004.

Guberman  A Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 1998;25S3- S8
PubMed
Mattson  RHCramer  JACollins  JF  et al.  Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313145- 151
PubMed Link to Article
Beghi  ETognoni  G Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Epilepsia 1988;29236- 243
PubMed Link to Article
Schmidt  D Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24368- 376
PubMed Link to Article
Theodore  WHPorter  RJ Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13320- 324
PubMed Link to Article
Brodie  MJ Monostars: an aid to choosing an antiepileptic drug as monotherapy. Epilepsia 1999;40(suppl 6)S17- S22
PubMed Link to Article
Schneiderman  JH Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 1998;25S9- S13
PubMed
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;3345- 51
PubMed Link to Article
Heller  AJChesterman  PElwes  RDC  et al.  Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;5844- 50
PubMed Link to Article
de Silva  MMacArdle  BMcGowan  M Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347709- 713
PubMed Link to Article
Perucca  ETomson  T Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999;33247- 262
PubMed Link to Article
Theodore  WHRaubertas  RFPorter  RJ  et al.  Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991;32392- 397
PubMed Link to Article
Faught  ESachdeo  RCRemler  MP  et al.  Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology 1993;43688- 692
PubMed Link to Article
Glauser  TANigro  MSachdeo  R  et al. Oxcarbazepine Pediatric Study Group, Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology 2000;542237- 2244
PubMed Link to Article
Schachter  SCVazquez  BFisher  RS  et al.  Oxcarbazepine: double-blind, randomized, placebo-control monotherapy trial for partial seizures. Neurology 1999;52732- 737
PubMed Link to Article
Pledger  G Monotherapy trials: presurgical studies. Epilepsy Res 2001;4567- 71
PubMed Link to Article
Kwan  PBrodie  MJ Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 2003;60(suppl 4)S2- S12
PubMed Link to Article
Beydoun  AKutluay  E Conversion to monotherapy: clinical trials in patients with refractory partial seizures. Neurology 2003;60(suppl 4)S13- S25
PubMed Link to Article
Chadwick  DWAnhut  HGreiner  MJ  et al.  A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;511282- 1288
PubMed Link to Article
Brodie  MJChadwick  DWAnhut  H  et al.  Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002;43993- 1000
PubMed Link to Article
Brodie  MJOverstall  PWGiorgi  LThe UK Lamotrigine Elderly Study Group, Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999;3781- 87
PubMed Link to Article
Brodie  MJRichens  AYuen  AW Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345476- 479
PubMed Link to Article
Reunanen  MDam  MYuen  AWC A randomised open multicenter comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res 1996;23149- 155
PubMed Link to Article
Dam  MEkberg  RLoyning  YWaltimo  OJakobsen  K A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;370- 76
PubMed Link to Article
Christe  WKramer  GVigonius  U  et al.  A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26451- 460
PubMed Link to Article
Bill  PAVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27195- 204
PubMed Link to Article
Guerreiro  MMVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27205- 213
PubMed Link to Article
Kälviäinen  RÄikiä  MSaukkonen  AMMervaala  ERiekkinen  PJ  Sr Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy: a randomized, controlled study. Arch Neurol 1995;52989- 996
PubMed Link to Article
Tanganelli  PRegesta  G Vigabatrin vs carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study. Epilepsy Res 1996;25257- 262
PubMed Link to Article
Frank  LMEnlow  THolmes  GL  et al.  Lamictal monotherapy for typical absence seizures in children. Epilepsia 1999;40973- 979
PubMed Link to Article
Sachdeo  RKramer  LDRosenberg  ASachdeo  S Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol 1992;32386- 392
PubMed Link to Article
Gilliam  FVazquez  BSackellares  JC  et al.  An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;511018- 1025
PubMed Link to Article
Brodie  MJYuen  AW Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26423- 432
PubMed Link to Article
Jozwiak  STerczynski  A Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure 2000;9486- 492
PubMed Link to Article
Ben-Menachem  EFalter  UThe European Levetiracetam Study Group, Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;411276- 1283
PubMed Link to Article
Beydoun  ASachdeo  RCRosenfeld  WE  et al.  Oxcarbazepine monotherapy for partial-onset seizures. Neurology 2000;542245- 2251
PubMed Link to Article
Schachter  SC Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 1995;36(suppl 6)S2- S6
PubMed Link to Article
Sachdeo  RCReife  RALim  PPledger  G Topiramate monotherapy for partial onset seizures. Epilepsia 1997;38294- 300
PubMed Link to Article
Devinsky  OFaught  REWilder  BJ  et al.  Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995;20241- 246
PubMed Link to Article
Bergey  GKMorris  HHRosenfeld  W  et al.  Gabapentin monotherapy: an 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49739- 745
PubMed Link to Article
Crawford  P Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16263- 272
PubMed Link to Article
Kwan  PBrodie  MJ Early identification of refractory epilepsy. N Engl J Med 2000;342314- 319
PubMed Link to Article
Karceski  SMorrell  MCarpenter  D The expert consensus guideline series: treatment of epilepsy. Epilepsy Behav 2001;2(suppl 6)A1- A50
Link to Article

Figures

Tables

References

Guberman  A Monotherapy or polytherapy for epilepsy? Can J Neurol Sci 1998;25S3- S8
PubMed
Mattson  RHCramer  JACollins  JF  et al.  Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures. N Engl J Med 1985;313145- 151
PubMed Link to Article
Beghi  ETognoni  G Prognosis of epilepsy in newly referred patients: a multicenter prospective study. Epilepsia 1988;29236- 243
PubMed Link to Article
Schmidt  D Reduction of two-drug therapy in intractable epilepsy. Epilepsia 1983;24368- 376
PubMed Link to Article
Theodore  WHPorter  RJ Removal of sedative-hypnotic antiepileptic drugs from the regimens of patients with intractable epilepsy. Ann Neurol 1983;13320- 324
PubMed Link to Article
Brodie  MJ Monostars: an aid to choosing an antiepileptic drug as monotherapy. Epilepsia 1999;40(suppl 6)S17- S22
PubMed Link to Article
Schneiderman  JH Monotherapy versus polytherapy in epilepsy: a framework for patient management. Can J Neurol Sci 1998;25S9- S13
PubMed
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;3345- 51
PubMed Link to Article
Heller  AJChesterman  PElwes  RDC  et al.  Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995;5844- 50
PubMed Link to Article
de Silva  MMacArdle  BMcGowan  M Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996;347709- 713
PubMed Link to Article
Perucca  ETomson  T Monotherapy trials with the new antiepileptic drugs: study designs, practical relevance and ethical implications. Epilepsy Res 1999;33247- 262
PubMed Link to Article
Theodore  WHRaubertas  RFPorter  RJ  et al.  Felbamate: a clinical trial for complex partial seizures. Epilepsia 1991;32392- 397
PubMed Link to Article
Faught  ESachdeo  RCRemler  MP  et al.  Felbamate monotherapy for partial-onset seizures: an active-control trial. Neurology 1993;43688- 692
PubMed Link to Article
Glauser  TANigro  MSachdeo  R  et al. Oxcarbazepine Pediatric Study Group, Adjunctive therapy with oxcarbazepine in children with partial seizures. Neurology 2000;542237- 2244
PubMed Link to Article
Schachter  SCVazquez  BFisher  RS  et al.  Oxcarbazepine: double-blind, randomized, placebo-control monotherapy trial for partial seizures. Neurology 1999;52732- 737
PubMed Link to Article
Pledger  G Monotherapy trials: presurgical studies. Epilepsy Res 2001;4567- 71
PubMed Link to Article
Kwan  PBrodie  MJ Clinical trials of antiepileptic medications in newly diagnosed patients with epilepsy. Neurology 2003;60(suppl 4)S2- S12
PubMed Link to Article
Beydoun  AKutluay  E Conversion to monotherapy: clinical trials in patients with refractory partial seizures. Neurology 2003;60(suppl 4)S13- S25
PubMed Link to Article
Chadwick  DWAnhut  HGreiner  MJ  et al.  A double-blind trial of gabapentin monotherapy for newly diagnosed partial seizures. Neurology 1998;511282- 1288
PubMed Link to Article
Brodie  MJChadwick  DWAnhut  H  et al.  Gabapentin versus lamotrigine monotherapy: a double-blind comparison in newly diagnosed epilepsy. Epilepsia 2002;43993- 1000
PubMed Link to Article
Brodie  MJOverstall  PWGiorgi  LThe UK Lamotrigine Elderly Study Group, Multicentre, double-blind, randomized comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. Epilepsy Res 1999;3781- 87
PubMed Link to Article
Brodie  MJRichens  AYuen  AW Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy. Lancet 1995;345476- 479
PubMed Link to Article
Reunanen  MDam  MYuen  AWC A randomised open multicenter comparative trial of lamotrigine and carbamazepine as monotherapy in patients with newly diagnosed or recurrent epilepsy. Epilepsy Res 1996;23149- 155
PubMed Link to Article
Dam  MEkberg  RLoyning  YWaltimo  OJakobsen  K A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989;370- 76
PubMed Link to Article
Christe  WKramer  GVigonius  U  et al.  A double-blind controlled clinical trial: oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Res 1997;26451- 460
PubMed Link to Article
Bill  PAVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in adults with previously untreated epilepsy. Epilepsy Res 1997;27195- 204
PubMed Link to Article
Guerreiro  MMVigonius  UPohlmann  H  et al.  A double-blind controlled clinical trial of oxcarbazepine versus phenytoin in children and adolescents with epilepsy. Epilepsy Res 1997;27205- 213
PubMed Link to Article
Kälviäinen  RÄikiä  MSaukkonen  AMMervaala  ERiekkinen  PJ  Sr Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy: a randomized, controlled study. Arch Neurol 1995;52989- 996
PubMed Link to Article
Tanganelli  PRegesta  G Vigabatrin vs carbamazepine monotherapy in newly diagnosed focal epilepsy: a randomized response conditional cross-over study. Epilepsy Res 1996;25257- 262
PubMed Link to Article
Frank  LMEnlow  THolmes  GL  et al.  Lamictal monotherapy for typical absence seizures in children. Epilepsia 1999;40973- 979
PubMed Link to Article
Sachdeo  RKramer  LDRosenberg  ASachdeo  S Felbamate monotherapy: controlled trial in patients with partial onset seizures. Ann Neurol 1992;32386- 392
PubMed Link to Article
Gilliam  FVazquez  BSackellares  JC  et al.  An active-control trial of lamotrigine monotherapy for partial seizures. Neurology 1998;511018- 1025
PubMed Link to Article
Brodie  MJYuen  AW Lamotrigine substitution study: evidence for synergism with sodium valproate? Epilepsy Res 1997;26423- 432
PubMed Link to Article
Jozwiak  STerczynski  A Open study evaluating lamotrigine efficacy and safety in add-on treatment and consecutive monotherapy in patients with carbamazepine- or valproate-resistant epilepsy. Seizure 2000;9486- 492
PubMed Link to Article
Ben-Menachem  EFalter  UThe European Levetiracetam Study Group, Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;411276- 1283
PubMed Link to Article
Beydoun  ASachdeo  RCRosenfeld  WE  et al.  Oxcarbazepine monotherapy for partial-onset seizures. Neurology 2000;542245- 2251
PubMed Link to Article
Schachter  SC Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 1995;36(suppl 6)S2- S6
PubMed Link to Article
Sachdeo  RCReife  RALim  PPledger  G Topiramate monotherapy for partial onset seizures. Epilepsia 1997;38294- 300
PubMed Link to Article
Devinsky  OFaught  REWilder  BJ  et al.  Efficacy of felbamate monotherapy in patients undergoing presurgical evaluation of partial seizures. Epilepsy Res 1995;20241- 246
PubMed Link to Article
Bergey  GKMorris  HHRosenfeld  W  et al.  Gabapentin monotherapy: an 8-day, double-blind, dose-controlled, multicenter study in hospitalized patients with refractory complex partial or secondarily generalized seizures. Neurology 1997;49739- 745
PubMed Link to Article
Crawford  P Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs 2002;16263- 272
PubMed Link to Article
Kwan  PBrodie  MJ Early identification of refractory epilepsy. N Engl J Med 2000;342314- 319
PubMed Link to Article
Karceski  SMorrell  MCarpenter  D The expert consensus guideline series: treatment of epilepsy. Epilepsy Behav 2001;2(suppl 6)A1- A50
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 12

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles