Revising the "Rule of Three" for inferring seizure freedom

Summary Purpose: How long after starting a new medication must a patient go without seizures before they can be regarded as seizure‐free? A recent International League Against Epilepsy (ILAE) task force proposed using a “Rule of Three” as an operational definition of seizure freedom, according to which a patient should be considered seizure‐free following an intervention after a period without seizures has elapsed equal to three times the longest preintervention interseizure interval over the previous year. This rule was motivated in large part by statistical considerations advanced in a classic 1983 paper by Hanley and Lippman‐Hand. However, strict adherence to the statistical logic of this rule generally requires waiting much longer than recommended by the ILAE task force. Therefore, we set out to determine whether an alternative approach to the Rule of Three might be possible, and under what conditions the rule may be expected to hold or would need to be extended. Methods: Probabilistic modeling and application of Bayes’ rule. Key Findings: We find that an alternative approach to the problem of inferring seizure freedom supports using the Rule of Three in the way proposed by the ILAE in many cases, particularly in evaluating responses to a first trial of antiseizure medication, and to favorably‐selected epilepsy surgical candidates. In cases where the a priori odds of success are less favorable, our analysis requires longer seizure‐free observation periods before declaring seizure freedom, up to six times the average preintervention interseizure interval. The key to our approach is to take into account not only the time elapsed without seizures but also empirical data regarding the a priori probability of achieving seizure freedom conferred by a particular intervention. Significance: In many cases it may be reasonable to consider a patient seizure‐free after they have gone without seizures for a period equal to three times the preintervention interseizure interval, as proposed on pragmatic grounds in a recent ILAE position paper, although in other commonly encountered cases a waiting time up to six times this interval is required. In this work we have provided a coherent theoretical basis for modified criterion for seizure freedom, which we call the “Rule of Three‐To‐Six.”