A systematic review and meta-analysis of factors related to first line drugs refractoriness in patients with juvenile myoclonic epilepsy (JME)

Abstract

Introduction: Juvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed "Drug-Resistant Epilepsy" (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients.

Material and methods: The systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis.

Results: A total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity.

Conclusion: In aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Fig 1. The PRISMA © flowchart.

Illustration of the progression of our study, outlining the quantity of citations found in titles and abstracts, the removal of duplicates, inclusion of full texts, as well as the exclusion criteria and reasons for exclusions.

Fig 2. Risk of bias graph.

Review of authors’ judgements about each risk of bias item presented as percentages across all included studies.

Fig 3. Forest plot of comparison.

1 ASM Resistant VS ASM Non-Resistant, outcome: 14 Febrile Seizures.

Fig 4. Funnel plot of comparison.

1 ASM Resistant VS ASM Non-Resistant, outcome: 5 Psychiatric disorders.

Fig 5. Meta‐analysis of the prevalence of refractory juvenile myoclonic epilepsy (JME).

The proportion of subjects who were refractory is displayed on the x‐axis. A total of 25 studies describing seizure outcome in 3051 individuals with JME were included. CI, confidence interval; RE, random effects. References denoted as ‘Study’ are available in the S5 Table.

Fig 6. Meta-regression analysis of juvenile myoclonic epilepsy refractoriness based on publication year.

We plotted the proportion of refractory subjects per study against the publication year. Each study is depicted by a circle, and the circle’s size corresponds proportionally to the sample size. Additionally, a meta-regression trend line with a 95% confidence interval (represented by dotted lines) is illustrated as a solid line.