Variation in prognosis and treatment outcome in juvenile myoclonic epilepsy: a Biology of Juvenile Myoclonic Epilepsy Consortium proposal for a practical definition and stratified medicine classifications

Abstract

Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.

Keywords: classification; definition; drug resistance; juvenile myoclonic epilepsy; prognosis.

Graphical Abstract

Figure 1

Identification of clinical biomarkers by stratified medicine can pave the way to targeted treatments. Stratified medicine adds a step to empirical medicine to associate a patient with a specific therapy that is more likely to be effective and/or safe. Central to the process is the identification of clinical biomarkers that differentiate subgroups of patients with differential treatment response, e.g. response or adverse effects. Based on Trusheim et al.

Figure 2

Proposed predictive model of ASM resistance in JME based on Shakeshaft et al. At each stratum, blue denotes better prognosis, orange worse prognosis, and grey denotes neutral effect on outcome.

Figure 3

Association of valproate with obesity in the BIOJUME data set. WHO categorization of weight in 695 JME patients in the BIOJUME data set by sex (left) and by lifetime exposure to valproate (right). Legend: BMI, body mass index; Overwt, overweight; VPA, valproate; WHO, World Health Organization; wt, weight.