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JME is a heterogeneous electroclinical epilepsy syndrome.
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The basis of a frontal cortical–subcortical network dysfunction in JME is uncertain.
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This age-related system dysfunction underlies a frontal dysexecutive syndrome.
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How low valproate dose may be effective to attain seizure freedom?
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At least seven factors have been indicative of unfavorable outcome.
Abstract
Purpose
Since its initial 1957 description, juvenile myoclonic epilepsy (JME) has been recognized as a common epileptic syndrome worldwide.
Methods
We reviewed a series of articles on JME to clarify challenges in clinical and pathophysiological findings, treatment and outcome.
Results
Typical JME characteristics include: 1) the age at seizure onset between 10 and 25 years; 2) the triad of myoclonia, generalized tonic-clonic seizures, and absences, of which only myoclonia is a mandatory criterion; 3) cognitive dysfunction that may have impact on interpersonal relationships and social outcome; 4) possibility of seizure control in up to 80% of individuals, in particular with the use of sodium valproate; 5) a tendency for lifelong seizures with an early morning preponderance; 6) after decades from the clinical onset, a possibility to be off medications for a third of the patients, and 7) several prognostic factors.
Conclusion
After 60 years, several challenges remain in this complex epileptic syndrome.
Theodore Herpin initially described the clinical characteristics of juvenile myoclonic epilepsy (JME) in a very intelligent 14-year-old boy, the son of a doctor, using the terms secousses and commotions to describe his cardinal symptoms, the jerks, which started at the age of 13, three months before his attacks [
In his thesis of 1899, entitled De la myoclonie épileptique, Rabot confirmed in five of his patients, the onset of sudden jerks on awakening in adolescence and generalized tonic-clonic (GTC) seizures [
] reporting 47 cases proposed the name “impulsive petit mal” as a clearly definable epileptic syndrome. The German authors recognized general precipitating factors, present in 28/47 cases, such as lack of sleep, sudden awakening and/or excessive alcohol intake [
]. In 2017, the 60th anniversary of JME, the journal Seizure, celebrating its first quarter-century, has contributed write the history of this common epileptic syndrome in 288 articles.
Actually, the prevalence of JME in large cohorts has been estimated to be 2.8–11.9% of all epilepsies and 26.7% of genetic generalized epilepsies [
The official definition of JME in the ILAE classification of epilepsies and epilepsy syndromes states: Impulsive Petit Mal appears around puberty and is characterized by seizures with bilateral, single or repetitive, arrhythmic, irregular myoclonic jerks, predominantly in the arms. Jerks may cause some patients to fall suddenly. No disturbance of consciousness is noticeable. The disorder may be inherited, and sex distribution is equal. Often, there are GTC seizures and, less often, infrequent absences. The seizures usually occur shortly after awakening and are often precipitated by sleep deprivation. Interictal and ictal EEG have rapid, generalized, often irregular spike-waves and polyspike-waves; there is no close phase correlation between EEG spikes and jerks. Frequently, the patients are photosensitive. Response to appropriate drugs is good [
Initially considered to be easily diagnosed, the interest and the spectrum of manifestations of this syndrome have been considerably expanded. Two international experts meetings (Avignon, 2011 and The Hague, 2012) ended with a consensus definition according to which the symptom obligatory for a diagnosis of JME are myoclonic jerks without loss of consciousness predominantly occurring after awakening.
After this mandatory criterion is met, two diagnostic groups could be established, one narrower and one wider. Class I criteria encompass: (1) myoclonic jerks without loss of consciousness exclusively occurring on or up to two hours after awakening; (2) EEG with normal background and typical ictal generalized high amplitude polyspike and slow waves accompanying myoclonic jerks; (3) normal intelligence, and (4) age of onset between 10 and 25 years. The Class II criteria, wider than the first, include: (1) myoclonic jerks predominantly occurring after awakening; (2) myoclonic jerks facilitated by sleep deprivation and stress and provoked by visual stimuli or praxis or GTC seizures preceded by myoclonic jerks; (3) normal background on EEG and at least once interictal generalized spike or polyspike and waves, with some asymmetry allowed, with or without recording of myoclonic jerks; (4) no mental retardation or deterioration, and (5) a wider time window for age at onset of 6–25 years [
3. Seizure expression—how to diagnose at an early stage?
Accordingly, JME includes three main types of seizures: myoclonic jerks, GTC seizures, and absences. In most patients, epilepsy begins around puberty with myoclonic jerks preceding the first GTC seizure for a mean period of 3.3 years [
]. In approximately 25%, GTC seizures are observed before the myoclonic jerks, rarely with a latency of several years, and in around one-third of the cases, the major and minor seizures have simultaneous onset [
Fig. 1Course of juvenile myoclonic epilepsy. Regarding seizure types, in most cases myoclonia precede generalized tonic-clonic seizures, although seizure expression can varied from pure myoclonia to the three seizure types. Percentages are from the original Janz and Christian series
Myoclonic jerks in full consciousness, essential to diagnosis, predominate in the upper limbs. They are spontaneous, brief, sudden, isolated, or in short arrhythmic clusters with characteristic chronodependence, generally defined as “epilepsy on awakening” [
]. More common after morning awakening, especially after the lack of sleep or provoked awakening, they may also occur in relaxation periods later in the day. Grossly symmetrical, they may make the patient drop or throw objects, usually those of morning hygiene or breakfast. As praxis-induced reflex seizures, they may predominate in the arm that executes the movement, in general involving the dominant hand. Herpin, in the first reported case, already emphasized this fact, since when the boy threw hand objects, he did especially with his right hand [
]. Rarely, they reach the lower limbs and, occasionally trunk muscles, including the diaphragm, causing an inspiratory noise or the issuance of a brief cry or hiccup, making the seizure similar to a fright reaction [
]; however, this number is probably underestimated, since most of these patients might never seek medical advice.
An accumulation of precipitating factors usually triggers the first GTC seizure, which causes medical referral in most patients. They are present in 80–95% of patients and may follow a prolonged cluster of myoclonic jerks, with increasing amplitude and frequency, in a sequence that culminates in the tonic phase of an intense and particularly long GTC seizure, which may also show focal signs, such as figure four sign and adversive onset [
], clonic-tonic-clonic seizures. Absences are described in 31.9% of the patients (in 12.8% beginning in the first decade of life and 19.1% with juvenile onset), preceding myoclonic jerks in 4.5 ± 2.5 years (Fig. 1) [
]. Eye closure sensitivity, defined as appearance of spike and wave discharges and eyelid myoclonia within two seconds after eye closure, occurs in 15–20% of cases [
]. Praxis induction, the precipitation of epileptic seizures or epileptiform EEG discharges by complex, cognition-guided tasks often involving visuomotor coordination and decision-making, is described in 47% of Japanese patients [
]. Finally, orofacial reflex myoclonic, lightning-like myoclonic in the perioral muscles, tongue, throat and jaw precipitated by language-related activities, mainly reading and talking, is present in 25–30% of JME patients [
4.2 Endophenotyping syndromic manifestations—how many subsyndromes?
Four subsyndromes have been suggested in a long-term prognosis series: (1) classic JME, defined as adolescent onset of isolated awakening myoclonic seizures appearing as the first seizure type or following GTC seizures in 72%; (2) childhood absence epilepsy evolving to JME (18%); (3) JME with adolescent onset of absences (7%); and (4) astatic seizures occurring independently of myoclonic jerks (3%) (Fig. 1) [
The most common interictal EEG pattern in JME is generalized bursts of rapid spike-and-wave 4–6 Hz while polyspike-wave complexes with frontocentral accentuation are the most specific. A burst of 5–20 spikes followed by slow waves of varying frequency and amplitude accompany myoclonia. If 3 Hz spike-and-wave complexes occur, the patient usually has absences as well [
]. Scalp EEG often also shows focal EEG abnormalities seen in up to 45.5% of the cases and a clear frontocentral predominance of ictal EEG activity recorded with the myoclonic jerks has repeatedly been reported [
]. These disorders, suggestive of frontal dysfunctions may lead to poor compliance and unhealthy behaviors affecting their treatment significantly. Several authors suggest a varied degree of executive cognitive dysfunction, which may be clear in a few patients [
4.5 Neuroimaging—is JME a generalized or a focal frontal syndrome?
Consistent with these results, the work presented by Vollmar et al. demonstrates coactivation between the primary motor cortex and supplementary motor area as well as an increase in functional connectivity between the motor and frontal cognitive networks [
]. Another functional MRI study demonstrates the existence of globally dysfunctional neuronal networks with functional connectivity abnormally increased in the premotor area and cognitive prefrontal cortex as well as supplementary motor area and occipital cortex [
4.6 Pathophysiology—does genetics determine microdysgenesis and developmental brain disease?
Although genetic linkage analyses identified about 15 loci linked to JME (the most important possibly being Myoclonin 1/EF-hand domain (C-terminal)-EFHC1, present in 3–9% of consecutive families), its specific pathogenetic mechanism is not entirely known [
]. EFHC1 mutations would induce subtle malformation of cortical development leading to the abnormal epileptogenic circuitry. A controversial histopathological study by Meencke and Janz [
] reporting microdysgenesis in three JME patients out of 15 with primary generalized epilepsy could not be replicated in two JME patients in more recent years [
]. Interestingly, there is evidence from family studies that the behavioral abnormalities in JME are genetically determined, also suggesting an underlying developmental disorder [
4.7 Treatment—should first choice AED be denied for fertile women?
JME is a heterogeneous epilepsy syndrome considering the response to antiepileptic drugs (AEDs) and long-term consequences. Treatment is based on the balance between the avoidance of precipitating factors and the appropriate use of AEDs. Lifestyle advice is an integral part of the treatment includes recommendations on avoidance of common triggers, such as sleep deprivation, fatigue, alcohol excess, inopportune awakening and emphasis on the importance of compliance with medication. Although no well-designed randomised controlled trials in JME have been done [
]. Despite disparity in response to AEDs, with some patients presenting seizures easy to control and others apparently refractory to all treatment options, available evidence suggests that VPA is superior to most other AEDs for JME treatment, partly because of its relatively high efficacy against GTC, myoclonic, and absence seizures. Table 1 resumes the modern management of JME [
]. Presently, VPA is the first choice AED in men with JME, since evidence suggest that VPA should be avoided in women of childbearing age because of significantly dose-dependent increased risks of fetal malformations and impaired postnatal cognitive development, including autism spectrum disorder (Table 2) [
]. Some AEDs, especially sodium channel blockers such as phenytoin, carbamazepine, oxcarbazepine, lamotrigine but also gabapentin, pregabalin, tiagabine, and vigabatrin can exacerbate JME, particularly myoclonia.
Table 1Antiepileptic drug options, suggested dosage ranges, evidence and precautions for treating juvenile myoclonic epilepsy (modified from Brodie)
General recommendations for women of childbearing potential
Female patients on VPA should be informed about the teratogenic risks, and of possibilities and limitations of prenatal screening, which cannot identify children whose neurodevelopment will be affected
Increased risks of fetal malformations and neurodevelopmental impairment, especially in doses over 700–1000 mg a day
If used in women of childbearing potential, VPA should be prescribed at the lowest effective dose, when possible aiming at doses not exceeding 500–600 mg/day
Lower VPA daily doses of 500 mg, 600 mg or 700 mg or less produced malformation rates of 4.3%, 5.0%, and 5.6%, respectively still higher than 2.3% in general population
Controlled release formulation and divided daily dose of VPA should be prescribed to minimize risks
Not confirmed in a study that reported higher malformation rates observed with in utero exposure to VPA were more likely related to total daily dose, rather than peak serum levels
Levetiracetam and lamotrigine (lower teratogenic risks than phenobarbital and topiramate, AEDs considered reasonable effective in JME)
Women already on valproate while pregnant
The general rule is to continue treatment with VPA in patients discovering that they are pregnant. Switch to another treatment is not recommended during pregnancy in patients with good seizure control
Withdrawal of VPA should be avoided during pregnancy since GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%)
Despite the widespread recognition of the impact of psychopathology in JME treatment and prognosis, psychotherapy results in JME are surprisingly scarce. In a small series of patients, psychotherapy led to seizure freedom in 50% of patients with drug-resistant seizures (Fig. 3) [
Fig. 3Effects of psychotherapy in a series of 58 adolescents and young adults with juvenile myoclonic epilepsy. Fifty percent of 14 patients resistant to pharmacotherapy and supportive counseling aiming at the elimination of seizure precipitants became seizure free in a six months follow-up
4.8 Prognosis—is JME a lifelong condition in which seizure relapse upon AEDs discontinuation is a rule?
JME has been considered as generally responsive to adequate treatment, presenting rates of pharmacoresistance of around 15% and pseudoresistance of 10% of consecutively diagnosed patients (Fig. 4) [
]. Long-term remission is more favorable than previously thought possible. In the series of the original author, after a mean follow-up time of 44.6 years (20–69 years), 59.1% of patients remained free of seizures for at least five years before the last contact. Among these, 28 (71.8%) were still treated, and 11 (28.2%) were off AEDs [
]. Yet 74% of the patients had at least one major unfavorable social outcome as failure to complete high school, unplanned pregnancy, depression, unemployment or living alone [
Fig. 4Prognosis in juvenile myoclonic epilepsy. While most of the patients reach seizure control, a third continue presenting seizures either due to true resistance to pharmacotherapy or pseudoresistance related to inadequate lifestyle, to low compliance, or to an inadequate choice of antiepileptic medications. Percentages are from Gelisse et al.
]. Despite these evidences, anticipation of who will have refractory seizures in JME early phase is still a challenge in this complex epileptic syndrome.
Conflict of interest statement
The author has no conflict of interest to disclose.
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