Juvenile myoclonic epilepsy (JME) is a common type of idiopathic generalized epilepsy (IGE). The major landmark of JME is the occurrence of adolescent-onset myoclonic seizures. JME is both genetically and clinically heterogeneous, suggesting that different pathophysiologic mechanisms might be involved.⁸⁴

The first description of a patient with JME came from the French literature in 1867 by Herpin,³⁸ but the myoclonic jerks were only properly characterized in 1899 by Rabot.⁶³ The intermittent character of these jerks as compared to the myoclonus occurring in progressive myoclonic epilepsy, a neurodegenerative disease, was emphasized by Lundborg⁴⁷ in 1903.

The description of JME as a specific IGE syndrome was established almost at the same time by Janz and Christian in Germany⁴² and by Castells and Mendilaharsu in Uruguay,¹⁶ almost a century after the first patient was reported in the literature. However, because of varying terminologies employed by previous authors, the syndrome was only recognized as JME in the English-speaking literature in the mid-1980s.^5,22

JME is the most common form of IGE, and the myoclonic seizures are the hallmark of the syndrome. Isolated myoclonic jerks of the arms, especially shortly after awakening, are characteristic. Generalized tonic–clonic seizures (GTCSs) occur in most patients, and one third of individuals also have absences. Seizure occurrence is more likely with sleep deprivation, fatigue, and alcohol withdrawal. Onset is usually in adolescence but seizures may begin or be diagnosed only in the early 20s. Patients frequently come to medical attention only after a generalized convulsion, and the history of earlier myoclonic jerks is often obtained retrospectively. More recently, myoclonic epilepsy with adult onset (37 to 39 years) has been highlighted by different groups.^20,30,49

The pathophysiology of JME is unknown. Although clinically a well-defined syndrome, detailed investigations of JME suggest that this stereotyped clinical pattern may be the result of different genetic, pathologic, and pathophysiologic processes.^5a,84

The electroencephalographic (EEG) pattern and other neurophysiologic studies, including those conducted in patients with reflex seizures induced by thinking, writing, or “action programming,” suggest a variable focal or regional frontal hyperexcitability in many cases.⁸⁴ Even so, although subtle frontal morphologic changes can be found, they are not universal in JME, and neither is sensitivity to various cognitive triggers, which may be absent in a typical case or present in a patient with another IGE syndrome. The association with photosensitivity is also variable.

An association with clinical and EEG findings of a clearly focal epilepsy, namely, idiopathic photosensitive occipital epilepsy (IPOE, described below), also raises questions about the nosologic purity of JME as a generalized epilepsy syndrome.

The classic electrophysiological studies conducted by Gloor³¹ led to the corticoreticular theory of generalized epilepsy: This theory postulates an underlying cortical hyperexcitability and abnormal response to thalamocortical input, which would operate in the absence of any lesional substrate. Genetic animal models of generalized epilepsy confirm the role played by thalamocortical circuits in cortical spike-wave
generation, and it has been proposed that genetically determined dysfunction of reticular thalamic neurons is responsible for the abnormal excitation. Since then, evidence has also been accumulating suggesting that subtle but probably significant neurochemical and morphologic alterations exist in both cortex and thalamus in IGE. Meencke and Janz⁵² and Meencke and Veith⁵³ described subtle cortical neuropathologic changes in IGE (“microdysgenesis”) believed to be migrational disturbances, but this has not been confirmed in other small series.⁵⁷

Furthermore, there is much genetic heterogeneity in JME. A positive family history of epilepsy is common, and there is recent evidence that JME constitutes a single gene syndrome in some families,^19,23 although most families show complex inheritance. Some JME cases are apparently sporadic, others occur in families with other IGE syndromes, and occasional families have a pure autosomal dominant JME phenotype. However, the patients in these various groups are otherwise clinically indistinguishable by usual diagnostic criteria. Different genetic results may relate to different diagnostic criteria, including the importance given to detailed classification of EEG patterns, differing estimates of penetrance, and choice of models for linkage analysis.⁹ Linkage to chromosomes 6p and 15q has been described,^25,33,46,79 and mutations in the CACNB4 gene (on chromosome 2q),²⁶ in the CLCN2 gene (on chromosome 3q),^21,35 in the GABRA1 gene (on chromosome 5q),¹⁹ and in the EFHC1 gene (on chromosome 6p)⁷¹ have been identified in JME patients.

The various mutations suggested for JME are all believed to influence neuronal excitability but involve different mechanisms. Both direct ion channel mechanisms and nonionic mechanisms have been proposed. How these interact with other possible susceptibility genes and with environmental factors is not yet clear. Vijai et al.⁷⁷ suggested that a potassium channel gene polymorphism may predispose to JME and that later gene expression of KCNQ3 may account for the striking age dependence that is typical of JME. Another potassium channel gene polymorphism in KCNJ10 has been associated with susceptibility to several common seizure types.¹³ Chloride currents, which affect inhibition, are implicated in some studies. Families linked to chromosome 3q and with mutations in the ClCN2 gene, which encodes the ClC-2 voltage-dependent chloride channel, suggest a defect in γ-aminobutyric acid (GABA)-mediated inhibition. Altered GABA-mediated inhibition is also implicated in autosomal dominant JME. The GABRA1 mutation found in autosomal dominant JME encodes a mutant α₁ subunit of the GABA_A receptor, but the functional effect, altered chloride current, and thus altered neuronal inhibition depend on the number of mutant subunits and their position within the pentameric structure of the ligand-gated chloride ion channel.²⁹

Mutations in EFHC1 have more complex effects that may be associated with the pathogenesis of JME.⁷¹ In animals, EFHC1 protein is not an ion channel protein but increases calcium currents in R-type voltage-dependent calcium channels and promotes calcium-related apoptosis; these effects are partly reversed by the mutations associated with JME.⁷¹ Such mutations may thus interfere with apoptotic activity and prevent the normal elimination of neurons during postnatal development of the central nervous system in humans. This may result in increased density of neurons and formation of hyperexcitable circuits. Microdysgenesis, reported in JME, may be a visible manifestation of such a process, which may also be associated with age-dependent seizure onset. Mutations may also destabilize calcium homeostasis with resulting effects on sensitivity to sleep deprivation and other clinical triggers of seizures in JME. However, mutations in EFHC1 were found in only 6 of 44 families, and the authors suggested that unidentified mutations may exist in intronic or regulatory regions.⁷¹ Similarly, the BRD2 gene, in which a mutation in JME was reported by Pal et al.,⁶⁰ is a putative nuclear transcription regulator and a member of a family of genes that are expressed during development and may thus be relevant to the reported abnormalities in imaging and age-related onset of JME.

This is an age-dependent disorder with onset usually in the second decade, but occasionally earlier and not infrequently later. It is important to recognize this group of patients since they are generally fully controlled on valproate in about 80%,¹⁴ but require lifelong treatment.

Myoclonic seizures, mainly involving the arms and occurring preferentially in the postawakening period, are the main feature of JME and are correlated with short bursts of generalized spike-wave or polyspike-wave complexes.²² The myoclonus is quite variable in intensity, often unreported by patients until a GTCS occurs, and then identified only after specific questioning. It is often not considered to represent a major inconvenience to patients, who frequently prefer not to take medication in order to suppress it. Others, however, prefer not to be frequently reminded of their epilepsy by these minor symptoms. When minor manifestations such as myoclonus or absence coexist with major seizures, treatment with antiepileptic drugs (AEDs) such as valproate or clonazepam is mandatory.

The myoclonus usually responds quite readily to antimyoclonic agents such as valproate, clonazepam, piracetam, or levepiracetam, but it may be difficult to control during certain periods of the patient’s life. The reasons for this are not entirely clear, but loss of seizure control may be correlated with emotional factors. The generalized attacks are often precipitated by the concurrence of sleep deprivation and being woken up from sleep, and this sequence should obviously be avoided, if at all possible. Further clinical features are discussed in recent detailed reviews of JME.^75,84

In an effort to better define syndromes for genetic study, Taylor et al.,⁷⁴ working with Berkovic and Scheffer in Australia, showed overlap between the clusters of clinical features used to diagnose JME and IPOE, suggesting a relationship with this focal epilepsy syndrome, especially with respect to visual auras and conscious head version (which are typical of IPOE) in patients with JME. They identified coexistence of myoclonic seizures and occipital EEG spikes in the same individuals in both syndromes. The probands and their families were evaluated in detail by highly skilled observers, and one may suspect that such overlap exists more commonly than is currently realized but that patients are not usually questioned as carefully.