In response: Nonadherence to treatment causing acute hospitalizations in people with epilepsy: An observational, prospective study

To the Editors: We appreciate the comments by Dr. Wilder-Smith to our article Nonadherence to treatment causing acute hospitalizations in people with epilepsy: An observational, prospective study.1 In 2004, Dr. Wilder-Smith and his group performed a study in Singapore of 41 consecutive seizure admissions in people with epilepsy, exploring the frequency and nature of seizure-provocative factors.2 It was nicely shown that admissions often were associated with seizure-inducing events including treatment noncompliance, “subtherapeutic” doses of antiepileptic drugs (AEDs), and sleep deprivation, sometimes in combination. The discrepancy between uncontrolled seizures and treatment-resistant epilepsy3 was worthily addressed, and the need for educational intervention concerning preventable seizure precipitants was emphasized. In the Singapore study, noncompliance was defined as self-reported failure to take the correct AED dose within a week prior to admission.2 Our study was based on therapeutic drug monitoring (TDM). Nonadherence was defined as an AED concentration/dose ratio of <75% of a trough routine control ratio (probable 50–75%, definite <50%). The two studies are thus not comparable. We consider the method based on recalling back 1 week during an interview taking place after the occurrence of a seizure as very uncertain compared to the more objective TDM approach. Its unreliability appears to be supported by the poor correlation with postictal serum concentrations. Given the pharmacokinetics of the analyzed drugs, a missed single dose up to 1 week prior to measurement, will hardly result in “subtherapeutic” serum concentrations. Furthermore, solitary serum concentration measurements are generally not suited for assessing treatment compliance. The divergence between the studies is more likely based on methodologic issues rather than differences between the populations in Singapore and Norway. In contrast to the Singapore study, our study exclusively brings AED nonadherence into focus. It is true that seizures often are triggered by a cascade of events of which medication failure is only a part. The various factors (e.g., emotional stress, sleep deprivation, and intake of other drugs and alcohol) should be identified and appropriately addressed. We believe that our method using concentration/dose ratios introduces a new standard for measuring AED nonadherence (provided approximate linear pharmacokinetics of the analyzed drugs at therapeutic doses), at least in countries where routine TDM is common. Admittedly, costs and availability of TDM constitute undue disadvantages in many parts of the world. In a global perspective, both studies corroborate the urgent need for appropriate counseling and educational programs for people with uncontrolled seizures. Christian Samsonsen, Geir Bråthen, and Eylert Brodtkorb have received honoraria and/or financial support for attending conferences from GlaxoSmithKline, UCB, and Eisai. Arne Reimers has received speaker's honoraria from GlaxoSmithKline and UCB. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.