Associate Professor of Neurology, Weill Cornell Medical College; Associate Attending Neurologist, NewYork-Presbyterian Hospital; Adjunct Associate Professor, University of Utah
Dr. Afra reports she is on the speakers bureau and is a consultant for UCB and Sunovion, and is a consultant for GW Pharmaceuticals and SK-Pharma.
SYNOPSIS: Juvenile myoclonic epilepsy (JME) is a common form of generalized epilepsy. Although the prognosis of JME is not clear, it is assumed to have a good response to treatment. The authors of this meta-analysis found a higher than expected prevalence of refractoriness in JME, which will affect how neurologists counsel patients with JME.
SOURCE: Stevelink R, Koeleman BPC, Sander JW, et al. Refractory juvenile myoclonic epilepsy: A meta-analysis of prevalence and risk factors. Eur J Neurol 2019;26:856-864.
Juvenile myoclonic epilepsy (JME) is the most common form of genetic generalized epilepsy and affects 5-10% of all people with epilepsy. Generally, it is assumed that treatment response in JME is good. This assumption is reflected in the 1989 International League Against Epilepsy proposal for revised classification of epilepsies as “response to appropriate drug is good.”1 Stevelink et al sought to determine the prevalence and prognostic factors for refractory JME via a meta-analysis of existing literature in accordance with PRISMA guidelines.
The authors performed a literature search in PubMed and EMBASE and identified 1,362 articles that reported treatment outcomes in people with JME (either with retrospective or prospective studies). They removed duplicates, applied inclusion/exclusion criteria (i.e., including articles describing seizure freedom from all seizure types and excluding articles that specifically recruited refractory individuals or those in remission), and selected 43 articles for inclusion. Using a random-effects meta-analysis, they assessed three areas: 1) prevalence of refractory JME, 2) seizure recurrence after antiepileptic drug (AED) withdrawal, and 3) risk factors for refractory JME.
For the meta-analysis of prevalence of refractory JME, the authors used 43 articles describing treatment outcomes for 3,311 subjects. Refractory JME was defined as the persistence of any seizure (i.e., myoclonic, absence, or generalized tonic-clonic) despite AED treatment and regardless of the length of seizure-free follow-up period. Subjects with “pseudorefractory epilepsy” were excluded. The meta-analysis of 43/43 articles (with 3,311 subjects) yielded that 35% (95% confidence interval [CI], 29-41%) of individuals with JME were refractory to treatment. There was wide heterogeneity between studies; however, the proportion of refractoriness was comparable between prospective (36%; 95% CI, 18-56%) and retrospective (35%; 95% CI, 29-42%) studies. The estimates of refractoriness also were comparable when assessing one-, two-, and five-year seizure freedom, suggesting that people who are seizure free at one year are likely to remain so. Additionally, the proportion of seizure-free individuals did not change over time (i.e., with publication year).
For the random-effects meta-analysis of potential risk factors of refractory JME, 21/43 articles that reported seizure outcome in relation to potential risk factors were used. Univariate meta-analysis was performed on 10 risk factors. Six risk factors were determined as significant:
1) having all three seizure types (myoclonic, generalized tonic-clonic, and absence); 2) psychiatric comorbidities; 3) having absence seizures; 4) history of childhood absence epilepsy progressing to JME; 5) early age at epilepsy onset; and 6) praxis-induced seizures (seizures and epileptiform discharges in the EEG induced by complex cognition-guided tasks, such as playing chess, writing, or drawing). Four risk factors were determined as not significant: 1) female gender, 2) epileptiform asymmetry in the EEG, 3) photoparoxysmal response, and 4) family history of epilepsy.
For the meta-analysis of seizure recurrence after AED withdrawal, the authors used 11/43 articles that described seizure outcomes for patients who withdrew from treatment. They included a subset of 246 subjects. The meta-analysis yielded seizure recurrence in 78% (95% CI, 58-94%) of subjects after withdrawal (with wide variation in estimates and high heterogeneity).
JME is a heterogenous disorder in which the prognoses have not been entirely clear.2 Overall, it has been assumed that JME responds well to AEDs.1 Stevelink et al found an unexpectedly high prevalence of refractoriness in JME (35%) based on all seizure types (i.e., absence, myoclonic, and generalized tonic-clonic seizures). This prevalence of refractoriness affecting one-third of people with JME is comparable to other forms of epilepsy (including partial onset epilepsies). The authors reported heterogeneity between studies, possibly because of an overestimation of refractoriness (due to articles from tertiary care centers and selection bias) and underestimation of refractoriness for myoclonic seizures. All these suggest that when counseling patients, clinicians should consider that the commonly held assumption that JME responds well to AEDs may not hold true and that prospective large-scale studies in JME are needed to clarify this matter further.
The authors found that refractoriness was comparable at one, two, and five years. This suggests that people who are seizure-free for at least one year are likely to remain seizure free (i.e., the patients who are not refractory indeed have a good and sustained response to an appropriately chosen AED). Six risk factors for refractoriness, as noted above, should be considered when counseling patients with JME and may be helpful in identifying a subset of refractory patients.
Regarding withdrawal of AEDs after seizure freedom, this study confirmed that there is high probability of seizure recurrence (78%) after AED withdrawal.
Another important finding was there was no decrease in the proportion of refractoriness over the last decade. This highlights the well-known fact that the newer AEDs do not have higher efficacy compared to the standard, sodium valproate. There continues to be a need to develop AEDs and nonpharmacologic treatment modalities with higher efficacy for effective treatment of JME.
- Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389-399.
- Kobayashi E, Zifkin BG, Andermann F, Andermann E. Juvenile Myoclonic Epilepsy. In: Engel JJ, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2018.