Juvenile Myoclonic Epilepsy

Updated: Feb 15, 2022
  • Author: Mona M Sonbol, MD; Chief Editor: Selim R Benbadis, MD  more...
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Overview

Background

Juvenile myoclonic epilepsy (JME) is one of the most common idiopathic (genetic) generalized epilepsy (IGE) syndromes. JME accounts for about 9% of all epilepsies and 27% of all IGEs. [1, 2] The age of onset is typically between 10 and 24 years (“juvenile”). [2] As the entire group of IGE, the general and common features are:

  1. Three seizure types: myoclonic jerks, generalized tonic-clonic seizures (GTCSs), and typical absence seizures in up to a third of cases [2]
  2. Motor seizures often occur shortly after awakening or after precipitating factors such as sleep deprivation, alcohol use, or psychological stress
  3. Normal intelligence and normal neurologic exam
  4. Characteristic EEG features

It is important to view IGE as a spectrum of genetic epilepsies with individual syndromes (such as JME) but with significant overlap. [65] Correctly diagnosing JME or at least the group of IGE can avoid inappropriate and ineffective treatment. [6]

Definition of juvenile myoclonic epilepsy

Since the first description of a probable case of JME in 1867, [1] various names have been applied to this condition. [2, 3, 4, 5] The term “juvenile myoclonic epilepsy” was proposed in 1975 [6] and has been adopted by the International League Against Epilepsy (ILAE). In the “ILAE Definition of the Idiopathic Generalized Epilepsy Syndromes: Position Statement by the ILAE Task Force on Nosology and Definitions,” JME is defined as “the most common adolescent and adult onset IGE syndrome and is characterized by myoclonic and generalized tonic-clonic seizures in an otherwise normal adolescent or adult. Myoclonic seizures typically occur shortly after waking and when tired. Sleep deprivation is an important provoking factor. The EEG shows > 3–5.5 Hz generalized spike-wave and polyspike-wave. Photosensitivity is common, occurring in up to 90% of individuals with appropriate photic stimulation. Life-long treatment is usually required." [68]

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Pathophysiology

Like all idiopathic (genetic) generalized epilepsies (IGEs), juvenile myoclonic epilepsy (JME) is a genetic generalized epilepsy (GGE), and both IGE and GGE are acceptable terms according to ILAE. The pathophysiology is complex, and etiology is multifactorial.

Results from routine pathologic analyses of brain specimens from patients with JME are typically normal. However, histology occasionally reveals increased numbers of partially dystropic neurons in the stratum moleculare, white matter, hippocampus, and cerebellar cortex; an indistinct boundary between the cortex and the subcortical white matter and between lamina 1 and 2 can also be found. These findings are termed microdysgenesia and have been interpreted as a manifestation of minimal developmental disturbances.

Some families have specific mutations that yield the clinical phenotype of JME. (See Etiology.) Known mutations include ion channel proteins, such as the beta-4 subunit of calcium channels and the chloride channel 2 protein.

One study of a large Canadian family with JME demonstrated increased gamma-aminobutyric acid (GABA)-A receptor subunit degradation from a mutation of the alpha1-subunit (A322D) of the GABA-A receptor. [8] This results in a decreased functional lifespan of the GABA-A receptor and consequent CNS hyperexcitability. A review by MacDonald and Kang describes additional mechanisms that might result in hyperexcitability. [9]

In another study, there was a reduction in the regional binding potential to the dopamine transporter (DAT) in the substantia nigra and midbrain (but not in caudate or putamen) in a positron emission tomography (PET) study of patients with JME as compared with healthy controls. [10]

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Etiology

The exact cause of juvenile myoclonic epilepsy (JME) remains unknown. Like the entire group of idiopathic (genetic) generalized epilepsies (IGEs), genetic factors play a definite role, hence the term genetic generalized epilepsy (GGE). JME is the IGE with the best identified specific mutations in various genes. It has a complex mode of inheritance, and most likely, multiple genes result in a similar electroclinical syndrome. [11]

Mutations in genes encoding ion channels have been associated with JME, inclusive of the beta-4 calcium channel subunit (CACNB4), the GABA receptor subunit (GABRA1), and the chloride channel (CLCN2). Each of these channelopathies has been described in a single family, and all are rare causes of JME. [12]

EFHC1, a gene involved in cortical genesis during brain development, is the most common gene mutation found thus far in studies of families with JME. [1, 13, 14] Calcium dysregulation versus abnormalities during cortical development may be the underlying reason for dysfunction in affected patients with JME and mutation in the EFHC1 gene. Gene dysfunction at other loci (EJM2, EJM3) are also being studied.

Microdeletions at 15q13.3, 15q11.2, and 16p13.11 have also been found to be associated with JME.

Genetic risk factors

Although JME is known to be an inherited disorder, the exact mode of inheritance is not clear. About a third of patients with JME have a positive family history of epilepsy. About 17-49% of patients with JME have relatives who have epileptic seizures, including parents (about 4%) and children (about 7%). The risk of expressing clinical JME is higher in relatives of people with JME.

Although investigators in most studies have presumed that JME is an autosomal dominant condition (ie, 50% risk of inheritance), it has incomplete penetrance, which means that some individuals who inherit the JME gene or genes do not express clinical JME. However, their children may inherit the JME genes and express clinically obvious disease. To an untrained observer, the disease seems to skip generations. For relatives of a patient with JME, the risk of having clinically obvious JME is small: 3.4% in parents, 7% in siblings, and 6.6% in children.

Despite similar genetic burden, the phenotype of JME might vary among relatives, as in a case of identical twins in which the proband had JME (myoclonus and GTCSs) but the identical twin only had childhood absence epilepsy. A French-Canadian study of probands with JME demonstrated only an absence syndrome in 27% of relatives with seizures. [15]  Certainly, disease burden does vary across the spectrum of individuals with JME.

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Epidemiology

The incidence of juvenile myoclonic epilepsy (JME) in the general population is estimated to be 1 case per 1000–2000 people internationally. JME represents approximately 5–10% of all epilepsies; however, the exact figures may be higher, as the condition is often misdiagnosed.

Age-related differences in incidence

JME typically begins in adolescence. Although the reported age of onset varies from 6 years up to 36 years, symptoms typically begin in adolescents, with a peak age most commonly of 12–18 years. Why the onset of this genetic disorder is delayed until adolescence is unclear.

Myoclonic jerks, GTCSs, and absence seizures all have an age-related onset in JME. If absence seizures are a feature, they usually begin between the ages of 5 years and 16 years. Myoclonic jerks may follow 1-9 years later, usually around the age of 15 years. GTCSs typically appear a few years later than myoclonic jerks.

Sexual differences in incidence

Findings from some studies suggest that JME is slightly more prevalent among females than males. The reason is unknown. However, data from other studies indicate similar prevalences in both sexes.

Racial differences in incidence

No systematic racial differences have been observed. However, it is likely that some specific genetic mutations among the different types described in families with JME might be more prevalent among different racial groups. For example, the myoclonin (EFHC1) mutation has been found in 9–20% of Mexican-American families with JME but in only 3% of Japanese families with this disorder. [11]

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Prognosis

In general, excellent seizure control can be achieved in juvenile myoclonic epilepsy (JME) patients with relatively low doses of appropriate anticonvulsants (eg, valproic acid). The risk of recurrence is higher than 80% if anticonvulsants are withdrawn; hence, lifelong treatment is usually necessary.

While for many patients this is a lifelong disorder, the burden of JME seizures appears to decrease in adulthood and senescence.

In one observational study, a minority of patients (16/175 patients or 9%) were seizure free without seizure medications for greater than 2 years. [70] In another observational study of 24 patients over ~24 years of follow-up, 11 patients had discontinued ASMs for the last 5–23 years. Of those patients, 6 remained seizure free. [17] .Based on Kaplan-Meier estimate, the chances of remission for at least 5 years without ASMs is 6% for JME. [71]

Whether patients outgrow JME, as compared with other primary generalized epilepsies, at a late age (ie, > 60 y) is unknown. An epidemiologic study is needed to settle this issue. Rare cases of late-onset JME have been reported as late as the eighth decade of life. [16]

Camfield and Camfield conducted a long-term population-based study of patients with JME. Between 1977 and 1985, the 24 patients in Nova Scotia who developed JME by age 16 years were contacted 25 years later. In 17%, all seizure types in JME had resolved; in 13%, only myoclonus persisted. Nevertheless, many patients’ lives were complicated by depression, social isolation, unemployment, and social impulsiveness. [17]

Sudden unexpected death in epilepsy (SUDEP) and accidental morbidity and mortality have been observed in JME, as in other epileptic syndromes involving GTCSs.

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Patient Education

The Epilepsy Foundation has a large selection of brochures and informational booklets for patients and their families. The American Epilepsy Society is the professional organization for people treating patients with epilepsy or for those doing research in this field.

For patient education resources, see the Brain and Nervous System Center, as well as Epilepsy.

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