Abstracts

Rationale: For most antiepileptic drugs (AEDs), the effectiveness of increasing AED doses or serum levels higher than recommended is not known. We compared the rates of efficacy (measured by 6-month seizure-freedom) and intolerable side effects in adult patients with epilepsy who were “pushed” to high serum concentrations (levels) or doses of their AEDs by their physicians in an attempt to improve seizure control. Methods: We reviewed levels, dose, age, duration of use, concomitant AEDs, efficacy (measured as becoming seizure-free for at least 6 months in response to an increase in dose or level of an AED) and intolerability (whether or not the occurrence of side effects led to a change in dose or discontinuation of a drug) for 1505 patients ≥16 years old, who took any AED as mono- or adjunctive therapy for any period of time while under treatment at our center from 1/1/2000 - 12/31/2004. Determinations of intolerability and efficacy were based on the assessment of the treating physician. For each commonly used AED (carbamazepine [CBZ], clobazam [CLB], felbamate [FBM], gabapentin [GP], levetiracetam [LEV], lamotrigine [LTG], oxcarbazepine [OXC], phenobarbital [PB], phenytoin [PHT], topiramate [TPM], valproate [VPA] and zonisamaide [ZNS]), we compared the rates of 6-month seizure-freedom and intolerability across a range of increasing serum levels (or doses if the number of levels were inadequate). Those who were seizure-free but stopped an AED before 6 months due to side effects were excluded from the seizure-freedom analysis. Results: Table 1 shows the rates of 6-month seizure-freedom and intolerability seen at higher level-ranges (for CBZ, FBM, LTG, PB, PHT, VPA) and dose-ranges (CLB, GP, LEV, OXC, TPM, ZNS). Patients on LTG, CBZ and PHT showed some benefit from being pushed to serum levels higher than the commonly used “reference ranges”. 29.4% (5/17) of patients with the very high LTG serum levels of 20-24.9 achieved 6-month seizure-freedom. 16% (8/50) of patients on CBZ with levels 11-12.9, and 7.1% (1/14) of patients with levels ≥13.0 became seizure-free for more than 6 months. 18.2% (6/33) of patients on PHT with levels ≥25 became seizure-free, but none pushed to levels ≥30. Higher than recommended doses seemed to provide some efficacy with GP (including ≥5600 mg/day) and LEV (though not at ≥5000 mg/day). For most AEDs, increasing rates of intolerable side effects were seen with rising levels and doses. Efficacy and tolerability data across all levels and doses will be presented graphically for each AED. Conclusions: This study suggests that “pushing” some AEDs to higher than recommended doses and levels still results in prolonged seizure freedom in a significant minority of patients. This study helps define the dose or level of each AED at which further increases are unlikely to be of benefit.