- •JME is a heterogeneous electroclinical epilepsy syndrome.
- •The basis of a frontal cortical–subcortical network dysfunction in JME is uncertain.
- •This age-related system dysfunction underlies a frontal dysexecutive syndrome.
- •How low valproate dose may be effective to attain seizure freedom?
- •At least seven factors have been indicative of unfavorable outcome.
2. Nosology—how to define?
3. Seizure expression—how to diagnose at an early stage?
4. Extending clinical manifestations
4.1 Endophenotyping seizure expression—how many reflex traits?
4.2 Endophenotyping syndromic manifestations—how many subsyndromes?
4.3 EEG—how focal it can be?
4.4 Psychopathology—a wolf in sheep’s clothing?
4.5 Neuroimaging—is JME a generalized or a focal frontal syndrome?
4.6 Pathophysiology—does genetics determine microdysgenesis and developmental brain disease?
4.7 Treatment—should first choice AED be denied for fertile women?
|Antiepileptic drug||Daily usual doses in adults||Evidence||Precautions|
|Valproate||400–3000 mg||Most effective choice based on clinical experience; positive psychotropic effects||Monitor weight gain (in about a third of patients; more common in women) and dysmetabolic syndrome|
|Phenobarbital||60–180 mg||Before the availability of VPA, efficacy in up to 80% of patients||Sedation; strong CYP-450 inductor|
|Levetiracetam||500–3000 mg||Likely to be less efficacious than VPA in controlling absence seizures, which coexist with other seizure types in around 30% of patients with JME||Monitor psychiatric side effects which may manifest at the initial maintenance dose|
|Lamotrigine||100–400 mg||Probably less effective than VPA. Synergistic effect with VPA. May worsen myoclonic seizures||Slow titration due to allergic risks|
|Topiramate||100–400 mg||May be effective in GTCS||Monitor neuropsychiatric adverse effects|
|Zonisamide||100–500 mg||May be effective in myoclonia and GTCS||Sedation, depression, gastrointestinal problems, allergic rash|
|Perampanel||6–12 mg||May be effective as adjunctive in GTCS||Monitor adverse behavioral effects|
|Clobazam||10–40 mg||May be effective as adjunctive||Sedation|
|Clonazepam||4–8 mg||May be effective as adjunctive||Sedation, tolerance|
|Acetazolamide||500–1000 mg||May be effective as adjunctive||Tolerance|
|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 |
|Other treatment options||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%) |
4.8 Prognosis—is JME a lifelong condition in which seizure relapse upon AEDs discontinuation is a rule?
Conflict of interest statement
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