title: Association between antiepileptic drug dose and long-term response in patients with refractory epilepsy.
abstract: Seizures in patients with medically refractory epilepsy remain a substantial clinical challenge, not least because of the dearth of evidence-based guidelines as to which antiepileptic drug (AED) regimens are the most effective, and what doses of these drugs to employ. We sought to determine whether there were regions in the dosage range of commonly used AEDs that were associated with superior efficacy in patients with refractory epilepsy. We retrospectively analyzed treatment records from 164 institutionalized, developmentally disabled patients with refractory epilepsy, averaging 17years of followup per patient. We determined the change in seizure frequency in within-patient comparisons during treatment with the most commonly used combinations of 12 AEDs, and then analyzed the response to treatment by quartile of the dose range for monotherapy with carbamazepine (CBZ), lamotrigine (LTG), valproate (VPA), or phenytoin (PHT), and the combination LTG/VPA. We found that of the 26 most frequently used AED regimens, only LTG/VPA yielded superior efficacy, similar to an earlier study. For the monotherapies, patients who were treated in the lowest quartile of the dose range had significantly better long-term reduction in seizure frequency compared to those treated in the 2nd and 3rd quartiles of the dose range. Patients with paired exposures to CBZ in both the lowest quartile and a higher quartile of dose range experienced an increase in seizure frequency at higher doses, while patients treated with LTG/VPA showed improved response with escalation of LTG dosage. We conclude that in this population of patients with refractory epilepsy, LTG/VPA was the most effective AED combination. The best response to AEDs used in monotherapy was observed at low dosage. This suggests that routine exposure to maximally tolerated AED doses may not be necessary to identify those patients with drug-resistant seizures who will have a beneficial response to therapy. Rather, responders to a given AED regimen may be identified with exposure to low AED doses, with careful evaluation of the response to subsequent titration to identify non-responders or those with exacerbation of seizure frequency at higher doses.
authors.affiliation: Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United States. Electronic address: npoolos@uw.edu.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Poolos
authors.affiliation: Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, WA, United States.
authors.forename: Christina E
authors.initials: CE
authors.lastname: Castagna
authors.affiliation: Rainier Residential Habilitation Center, Buckley, WA, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Williams
authors.affiliation: Fircrest Residential Habilitation Center, Shoreline, WA, United States.
authors.forename: Alison B
authors.initials: AB
authors.lastname: Miller
authors.affiliation: UCB Pharma, SA, Smyrna, GA, United States.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Story
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000627:therapeutic use; D002220:Carbamazepine / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000069279:Drug Resistant Epilepsy / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077213:Lamotrigine; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010672:Phenytoin / Q000008:administration & dosage; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D014227:Triazines / Q000008:administration & dosage*; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D000077213:Lamotrigine
keywords: Dose-response; Lamotrigine; Pharmacodynamic synergy; Refractory epilepsy; Valproate