Concepts and controversies of juvenile myoclonic epilepsy: still an enigmatic epilepsy

Abstract

Juvenile myoclonic epilepsy (JME) is a clinically and genetically heterogenous, generalized epilepsy syndrome usually starting in adolescence. An age-related, predominantly frontocortical-subcortical network dysfunction is likely to be the substrate of bilateral myoclonic seizures occurring at full consciousness within hours after awakening, which are the clinical hallmark of JME. Although essential features of JME were recognized by Herpin more than 140 years ago, it is still an enigmatic epilepsy syndrome in many ways; advanced imaging techniques reveal multi-focal abnormalities in this paradigmatic generalized epilepsy syndrome; clinical studies reveal a major role of genetics in etiology, but the underlying molecular changes are likely to be highly heterogeneous; many JME patients have psycho-social issues, even though their intelligence is normal; antiepileptic drugs (AEDs), notably valproic acid, achieve seizure remission in two thirds of patients, but more patients seem to relapse after stopping AEDs than in any other epilepsy syndrome. This pessimistic outlook has been challenged in recent population-based studies and needs to be assessed in randomized AED withdrawal trials. This review summarizes recent focus neuroimaging, genetic, and behavioral aspects of JME and re-appraises the entrenched view that remission off AEDs is exceptionally rare in JME.

Keywords::

• behavioral problem
• drug treatment
• epileptogenesis
• genetics
• juvenile myoclonic epilepsy
• neuroimaging
• remission
• valproic acid

Financial & competing interests disclosure

MJ Koepp served on scientific advisory boards and has received honoraria for lectures from of GE Healthcare, UCB Pharma, Novartis, Eisai and Desitin. SF Berkovic served on scientific advisory boards and has received honoraria for lectures from UCB Pharma, Novartis and Eisai. B Wandschneider and RH Thomas report no financial disclosures. D Schmidt served on scientific advisory boards and has received honoraria for lectures from Abbott, Eisai, Novartis, UCB Pharma, Sun Pharma and Viropharm. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Juvenile myoclonic epilepsy (JME) is a clinically heterogenous generalized epilepsy syndrome. Even experts cannot agree on a single syndrome definition of this syndrome.

• JME is a genetically heterogenous generalized epilepsy syndrome. Unbiased whole genome studies will be better suited than single candidate gene studies to explore the genetic basis of JME.

• JME patients present with aberrant functional and structural connectivity in networks that normally mature before and during adolescence. Early studies with longitudinal follow-up in newly diagnosed, drug-naïve JME patients, and in those at a genetic risk of developing JME, will help to disentangle the effects of genetic effects, delayed or altered brain maturation, drugs and seizures.

• Many patients with JME face psychosocial issues even though they have normal intelligence, and present in later life with behavioral and psychosocial characteristics, usually seen only during adolescence.

• Perhaps the most baffling conundrum of JME in older hospital-based observations is that unlike patients with other epilepsies, JME patients enter seizure remission early on antiepileptic drugs (AEDs), but fail to remain seizure-free following discontinuation of AEDs in remission. The speculative explanation for this is that the underlying mechanism of JME differs from that of other epilepsies. However, newer population-based studies have shown a much better prognosis to remain seizure-free off AEDs. This more positive outcome in JME needs to be confirmed in randomized controlled trials of AED withdrawal in JME patients in remission.