A paradox exists in the development of pharmacologic treatment for epilepsy. Nearly all clinical trials evaluate the efficacy and safety of novel compounds as adjunctive therapy, yet the preferred medication treatment for epilepsy is monotherapy. Obstacles to monotherapy trials include ethical issues regarding placebo comparators and a lack of universal acceptance of "noninferiority" trials or clinical data compared with historical controls. Consequently, most antiepileptic drugs (AEDs) come to market with adjunctive indications, and it is only later, if ever, that they achieve a monotherapy indication from the US Food and Drug Administration.
The following 9 studies evaluate AEDs as monotherapy in special populations with epilepsy, such as those with cryptogenic or symptomatic focal onset, new-onset, or refractory epilepsy; patients who have seizures after a stroke; and veterans. Of these studies, 4 are prospective: oral topiramate vs phenytoin in patients with new-onset epilepsy, levetiracetam vs long-acting valproate (VPA) and carbamazepine (CBZ) in patients with newly diagnosed epilepsy (KOMET), the effects on cognition and behavior of lamotrigine vs carbamazepine in children with partial epilepsy, and initial monotherapy of lamotrigine vs levetiracetam. Only the topiramate study was blinded. The remaining 5 studies are retrospective.
Topiramate vs Phenytoin
Rapid oral initiation of topiramate (N = 132) was compared with rapid oral initiation of phenytoin (N = 127) in 259 patients with new-onset epilepsy in a 28-day, double-blind, randomized study. At 28 days, generalized tonic clonic or partial seizures were more common in the topiramate group (18%) compared with the phenytoin group (10.9%), and noninferiority of topiramate to phenytoin was not established. Topiramate was better tolerated, with 6% discontinuing the study because of an adverse event compared with 12.5% of patients taking phenytoin. Rash developed in only 1 patient receiving topiramate compared with 10 who were taking phenytoin.
Eugene Ramsay, MD, University of Miami School of Medicine, Miami, Florida, and lead author, observed, "This study suggests that there are alternate ways of successfully treating people with seizures in the emergency room. [Phenytoin] is not the only drug we have to consider."
Levetiracetam vs Extended-Release Valproate
In KOMET, a 52-week, open-label, prospective, randomized, parallel-group, community-based study, levetiracetam was compared with VPA extended-release (ER) or CBZ controlled-release (CR). At 269 centers in Europe and Australia, patients with newly diagnosed epilepsy (N = 1688) were first divided into the "best-recommended treatment" group, either VPA-ER or CBZ-CR. Patients were then randomized to either VPA-ER or levetiracetam, or CBZ-CR or levetiracetam. Target doses were 1000 mg/day VPA-ER, 600 mg/day CBZ-CR, and 1000 mg/day levetiracetam. In the CBZ-CR group, 86.5% had partial seizures, and in the VPA-ER group, 65.8% had primary generalized seizures. The time to withdrawal was similar in all groups, but the time to first seizure was significantly shorter in patients taking levetiracetam compared with those taking VPA-ER or CBZ-CR (hazard ratio 1.20 [95% confidence interval], P = .022). Seizure freedom at 12 months was not significantly different between VPA-ER and CBZ-CR combined (26.6%) and levetiracetam (28.3%). Discontinuation rates for VPA-ER and CBZ-CR combined were 26.1% compared with 24% for levetiracetam, which was not significantly different. The results suggest broad-spectrum efficacy of levetiracetam with tolerability similar to that of VPA-ER and CBZ-CR.
Lamotrigine vs CBZ
A 32-week, multicenter, open-label, observational study comparing the cognitive and behavioral effects of lamotrigine (3-6 mg/kg/day) with CBZ (10-20 mg/kg/day) was completed by 67 of 84 (79.8%) previously untreated children with partial seizures. Both drugs resulted in a similar proportion of children who were seizure-free: lamotrigine 69.8% and CBZ 70.7%. Neuropsychological data available from 53 of 84 (63%) patients failed to demonstrate significant differences in cognition or behavior between the 2 groups, with the sole exception of "delinquency," which was significantly worse with CBZ.
Lamotrigine vs Levetiracetam
In 58 centers, 409 patients with newly diagnosed epilepsy or a first seizure and high recurrence risk participated in an open-label, prospective, 26-week comparison of lamotrigine (200 mg/day) and levetiracetam (2000 mg/day). The primary endpoint, proportion of seizure-free patients until 6 weeks after randomization, was similar in both groups: lamotrigine 74.9% and levetiracetam 79.1%. Quality-of-life changes were not significantly different between the 2 treatments. Both drugs had a similar number of at least one adverse event: lamotrigine 70.6% and levetiracetam 74.5%. Tiredness and aggression occurred significantly more often in patients taking levetiracetam (32.8% and 8.8%, respectively) than in patients taking lamotrigine (16.4% and 2.5%, respectively).
Retrospective Studies
A retrospective chart review of 531 patients (98% males, mean age 57) at the Veterans Administration Los Angeles Healthcare System, Los Angeles, California, identified 426 patients receiving monotherapy. The majority of patients had partial-onset seizures resulting from traumatic brain injury. The AEDs used were phenytoin (47%), CBZ (15%), levetiracetam (12%), topiramate (6%), valproic acid (4%), phenobarbital (2%), oxcarbazepine (1%), ethosuximide (1%), primidone (1%), and other (6%). Based on the number of AED withdrawals, lamotrigine, levetiracetam, phenytoin, and topiramate had > 75% efficacy.
Another Veterans Administration study evaluated the use of levetiracetam monotherapy in 75 patients with partial seizures, 57 of whom were elderly (age ≥ 60). Of the 75 patients, 80% or more were seizure-free, including the elderly. Lethargy and psychiatric side effects were the most common adverse events, occurring in less than 20% of both groups.
In 65 patients with cryptogenic and symptomatic focal epilepsy (25 newly diagnosed patients and 40 patients switched to levetiracetam from another drug), monotherapy with levetiracetam resulted in an overall responder rate of 75.4% at 6 months, with seizure freedom in 41.5% of patients. Seizure freedom was higher in the newly diagnosed patients (64%) who received levetiracetam as first-line therapy than in those converted to levetiracetam (27.5%). Retention rate for patients receiving levetiracetam monotherapy at 18 months was 69.2%: 84% in the first-line group and 60% in the conversion group. Dropouts were primarily because of lack of efficacy rather than side effects.
A retrospective review of 307 patients treated at Wake Forest University with levetiracetam (median dose 2000 mg/day) for an average duration of 48 months revealed that 132 (43%) became seizure-free, which included 54% of patients with no prior AED treatment and 36% of patients with refractory disease who were taking 2 or more AEDs. Most patients (91%) had partial epilepsy. Of the 173 patients with refractory epilepsy, 17 (9.8%) became seizure-free when treated with levetiracetam monotherapy. Adverse events resulted in discontinuation of therapy in 47 patients (15.3%). These included anger/hostility (N = 10), sedation (N = 8), irritability (N = 8), poor memory/concentration (N = 8), and depression (N = 4). Psychiatric problems were present at baseline in 120 of the patients (39%).
The effect of levetiracetam monotherapy was evaluated in the special population of patients early after stroke (≤14 days) and late after stroke (>14 days). Of 490 patients (220 males, 270 females, mean age 74.7) with ischemic stroke, 61 (12.4%) had poststroke seizures, 31 (50.8%) of whom had early and 30 of whom (49.2%) had late poststroke seizures. Of the 31 patients with early poststroke seizures, 16 were treated with levetiracetam monotherapy (1000-2000 mg/day), and only 2 (12.5%) had further seizures. The remaining 15 of 31 patients did not receive AED treatment, and further seizures occurred in 6 (40%). Of the 30 patients with late-onset poststroke seizures, 16 were treated with levetiracetam monotherapy (1000-2000 mg/day), and epilepsy developed in 4 (25%). The remaining 14 of 30 patients were not treated with AEDs, and epilepsy developed in 8 (57%).
Conclusions
These studies support the effectiveness of AEDs as monotherapy and failed to show superiority for the "newer" AEDs. For example, oral topiramate did not prove superior or even equivalent to oral phenytoin loading in the prevention of recurrent seizures, but it may be a good choice for patients allergic to phenytoin because of the lower risk for rash. The KOMET study suggests that levetiracetam is a broad-spectrum AED and compares well with long-acting VPA and CBZ. Results may have been better with an ER formulation of levetiracetam, which was not available when the study was initiated. A formal study of cognitive and behavioral effects showed similar efficacy and little difference in cognitive and behavioral adverse events between lamotrigine and CBZ. In an efficacy study of 2 newer drugs, both lamotrigine and levetiracetam treatment resulted in similar numbers of patients who were seizure-free.
The retrospective studies also supported the effectiveness of AEDs in monotherapy, focusing primarily on levetiracetam. In the Veterans Administration study of 531 patients, > 75% efficacy was achieved with monotherapy with lamotrigine, levetiracetam, phenytoin, and topiramate. In another Veterans Administration study, levetiracetam monotherapy was similarly effective in all patients and in the elderly subgroup. In a study of newly diagnosed and refractory patients, the retention rate of patients receiving levetiracetam monotherapy at 18 months was 69%. Even in patients with refractory epilepsy, a small number may become seizure-free on monotherapy. Levetiracetam monotherapy may be effective in both early and late poststroke seizures, but these results were compared with no treatment rather than with treatment using other AEDs.
Overall, the data suggest that commonly used AEDs, even those that have not received formal US Food and Drug Administration approval for monotherapy, may be effective when used alone. The many advantages of monotherapy compared with polytherapy, including a lower incidence of side effects, lower cost, and improved compliance, warrant consideration of monotherapy with both "new" and "old" AEDs for patients with epilepsy.