Juvenile myoclonic epilepsy

INTRODUCTION — 

Juvenile myoclonic epilepsy (JME or Janz syndrome), previously "impulsive petit mal," is one of the most common generalized epilepsy syndromes of childhood. It typically occurs in otherwise healthy adolescents and is characterized by the triad of myoclonic jerks, generalized tonic-clonic seizures (GTCS), and absence seizures. Seizures characteristically occur upon awakening or in association with sleep deprivation, and the electroencephalogram (EEG) shows generalized abnormalities [1]. Patients generally respond quickly and completely to standard antiseizure medications (ASMs). Seizure frequency often lessens in adulthood, but many patients require long-term ASM therapy. The underlying cause of JME is unknown, and there are likely complex underlying genetic defects.

The epidemiology, pathophysiology, clinical features, diagnosis, and treatment of JME will be reviewed here. Other epileptic syndromes of childhood are reviewed separately. (See "Epilepsy syndromes in children" and "Childhood absence epilepsy" and "Self-limited focal epilepsies of childhood" and "Focal epilepsy: Causes and clinical features".)

CLASSIFICATION — 

JME is classified as an epilepsy syndrome with presumed polygenic cause according to the International League Against Epilepsy (ILAE) [2-4]. (See "ILAE classification of seizures and epilepsy".)

●JME is one of the idiopathic generalized epilepsies (IGEs) – The ILAE describes a broad group of genetic generalized epilepsies (GGEs) that are characterized by generalized seizure types and generalized spike-wave with a presumed genetic etiology (figure 1). Contained within the GGEs is a subgroup of IGEs comprised of four syndromes [4]:

•Childhood absence epilepsy (CAE)

•Juvenile absence epilepsy (JAE)

•JME

•Epilepsy with generalized tonic-clonic seizures alone (GTCA)

●Shared features of IGEs – The IGEs are the most common epilepsy syndromes within the GGEs and have several shared characteristics, including [4]:

•A relatively good prognosis for seizure control

•Typically normal development

•Clinical overlap among CAE, JAE, and JME

•Possible evolution with age from one to another IGE syndrome

•Similar EEG findings (2.5 to 6 Hz generalized spike-wave that may activate with hyperventilation or photic stimulation)

•Polygenic inheritance likely

PATHOPHYSIOLOGY AND GENETICS — 

JME is included in the group of epilepsy syndromes of unknown cause with a high likelihood of complex genetic defects. (See "ILAE classification of seizures and epilepsy".)

Some JME cases are apparently sporadic, while others occur in families with other idiopathic generalized epilepsy (IGE) syndromes. Occasionally, families have a pure autosomal dominant JME phenotype [5]. The genetic mechanisms that underlie JME are not understood fully, and a polygenic or multifactorial mechanism is likely in most cases.

Several chromosomal loci are suspected of playing a central role in JME; however, only a few are considered to be putative JME-causing genes: EFHC1, CACNB4, CASR, GABRA1, GABRD, and ICK [6,7]. EFHC1 mutations are found in up to 9 percent of classic JME patients of various ethnic backgrounds [8-13]. However, an international consortium failed to replicate previous findings on the role of ICK; no evidence of an enrichment of ICK variants was found in 357 persons with JME [14].

The role of epigenetics in the pathogenesis of JME is unclear. A case-control study reported that, compared with 39 healthy control individuals, methylation of cation-chloride cotransporters SLC12A2 (NKCC1) was lower, whereas methylation of SLC12A5 (KCC2) was higher in 49 patients with JME [15]. Other targets of interest for epigenetic changes in the deoxyribonucleic acid (DNA) of patients with JME have been identified, such as the BRD2 promoter [16]. For that specific candidate, however, a subsequent study failed to replicate results [17]. The significance of these findings and the role of epigenetics in JME thus remain to be clarified.

Seizures in JME are linked with cortical hyperexcitability, most prominent in the motor cortex and accentuated in the mornings and by sleep deprivation [18-21].

Although routine magnetic resonance imaging (MRI) of the brain is typically normal in patients with JME, subtle structural and functional defects are well described using advanced imaging techniques such as diffusion tensor imaging and multivoxel morphometry [22]. Most of these investigations suggest involvement of frontal thalamocortical circuits [23-40] and dysfunction in the dopaminergic and serotoninergic neurotransmission systems [41-44]. In one study, longitudinal imaging in 19 patients with new-onset JME demonstrated abnormal attenuation of normal age-related decline in cortical volume compared with healthy controls over a two-year period [45]. Increased cortical volume and thickness were particularly prominent in fronto-parieto-temporal association areas. These findings are consistent with the neuropsychologic and psychiatric characteristics reported in many JME patients. The underlying pathophysiologic mechanisms are not well understood. (See 'Clinical features' below.)

EPIDEMIOLOGY — 

JME is the most common of the adolescent and adult idiopathic generalized epilepsies (figure 1), accounting for 25 to 30 percent, and is the cause of up to 10 percent of all cases of epilepsy [4,46-48]. Based on a population risk of epilepsy of 1 percent by age 20, the incidence of JME is estimated to be 1 in 1000 to 2000 [49].

The female-to-male ratio in JME is generally considered to be equal, but several studies have reported a female preponderance of up to 2.9:1 [50-52].

CLINICAL FEATURES

Age at onset — The mean age of JME onset is 15 years, ranging from 6 to 40 years [1,53,54]. Most patients are diagnosed between 12 and 18 years of age [55,56].

Seizures

Seizure types — The typical patient with JME is a healthy teenager with one or more of three seizure types: myoclonic jerks, generalized tonic-clonic seizures (GTCS), and absence seizures. In three large observational studies totaling over 580 patients with JME, all patients had myoclonic jerks, 85 to 100 percent had at least one GTCS, and 20 to 40 percent had absence seizures [53,54,57]. Only 5.5 percent of patients had myoclonic jerks as the sole seizure type recognized [54].

●Myoclonic seizures – The hallmark seizures in JME are myoclonic jerks (or myoclonias), which are most frequent in the morning within the first hour after awakening. Myoclonic seizures are seen as isolated jerks usually involving both arms, which can be as subtle as finger twitches. Involvement of the lower limbs leading to falls is uncommon. Consciousness is preserved. The myoclonus in JME is epileptic, as opposed to physiologic or essential. (See "Classification and evaluation of myoclonus", section on 'Causes'.)

With careful history-taking, nearly all patients with JME have myoclonic seizures, but rarely in isolation.

●Generalized tonic-clonic seizures – GTCS occur in almost all patients with JME, often as the index event leading to diagnosis. A GTCS secondary to JME cannot be distinguished from one related to other generalized epilepsy syndromes. Focal ictal symptoms such as head version, asymmetric tonic posturing, or clonic movements have been noted in 16 to 40 percent of patients [53,58].

●Absence seizures – These are the least common seizure type in JME, occurring in 20 to 40 percent of patients [53,54,57,59]. When they do occur, they almost always precede the first myoclonic or generalized seizure, often by as much as five years. The onset of absence seizures at an earlier age may lead to a diagnosis of childhood or juvenile absence epilepsy; a family history of myoclonus or GTCS will suggest the correct diagnosis (see 'Differential diagnosis' below). During video monitoring, clinical manifestations of an absence ictus can vary greatly, ranging from subtle or no overt features to severe impairment of consciousness [60]. Absence phenomenology can vary even within the same patient.

●Other seizure types – Rarer seizure patterns include episodes of status epilepticus (nonconvulsive, generalized tonic-clonic, or myoclonic) [61-64].

Circadian and provoking factors — Myoclonic jerks and GTCS are most common in the mornings and are aggravated by sleep deprivation, alcohol consumption, and sometimes by photic stimulation. Some patients may have reflex seizures triggered by various types of stimuli, such as writing, reading, or praxis (ie, cognitive tasks accompanied by execution of a movement) [21,65-68].

Cognition and behavior — Most patients with JME have normal global cognitive capacities. However, formal neuropsychologic testing demonstrates variable degrees of frontal lobe dysfunction, typically mild to moderate, on tests of verbal fluency, abstract reasoning and mental flexibility, attention, cognitive speed, and planning and organization [31,45,69-73].

Multiple factors likely influence these results, including antiseizure medications (ASMs), seizure frequency, genetic variability, psychosocial conditions, and educational level [69,74-76]. However, in at least one study, cognitive performance was not correlated with disease duration, seizure frequency, seizure types, or treatment [71]. Advanced neuroimaging studies have suggested a potential underlying structural basis for these neuropsychiatric deficits [23,77]. (See 'Pathophysiology and genetics' above.)

Psychiatric comorbidity — Patients with JME are at increased risk for comorbid psychiatric illness and personality disorder. Up to 50 percent of patients meet formal criteria for a psychiatric disorder (mostly anxiety or mood disorder), and 20 to 35 percent have cluster B personality traits such as impulsivity, emotional instability, and difficulty accepting social rules [78-84].

Poorly controlled seizures and ASMs themselves may also put patients at risk for psychiatric side effects and mood disorder [81,85]. Functional magnetic resonance imaging (fMRI) data suggest that frontal-insular network dysfunction may contribute to emotional disturbances [86]. (See "Comorbidities and complications of epilepsy in adults", section on 'Psychiatric disorders'.)

EVALUATION

When to suspect JME — The diagnosis of JME is suspected in every developmentally normal child, adolescent, or young adult with new-onset generalized tonic-clonic seizures (GTCS), particularly if they occur upon awakening in the morning. A history of myoclonic jerks should be sought as this may not be volunteered.

Delays in diagnosis of JME are frequent [57,87,88]. Factors that may contribute to diagnostic delays include:

●Lack of general awareness of the syndrome [88,89]

●The subtlety of some myoclonic jerks and absence seizures, which may go unnoticed until a GTCS occurs

●The focal character of some jerks or EEG features, which are wrongly considered exclusionary for the diagnosis [54,57,87,88,90]

●The relatively nonspecific characteristics of the myoclonic seizures, which may be misdiagnosed as other (epileptic or nonepileptic) paroxysmal events

History — The clinical features are important to differentiate JME from other epileptic and nonepileptic events. The history should focus on event description, including frequency and duration, age of onset, history of other seizure types, and developmental history; JME typically occurs in otherwise healthy school-aged children.

Eyewitness descriptions of events from parents or teachers are critical to the diagnosis. Features that suggest myoclonic seizures should be specifically questioned.

Examination — Most children and adults with suspected JME will have a normal physical and neurologic examination. The goal of the examination is to detect signs of an underlying medical or neurologic disorder other than JME that may be the cause of the events. (See 'Differential diagnosis' below.)

Electroencephalography — The diagnosis of JME in a patient with clinical features is supported by EEG.

An overnight sleep EEG should be performed if a routine EEG is normal in a patient suspected of having JME. The routine interictal EEG is abnormal in approximately 75 percent of patients with JME [53,91,92]. This number increases to nearly 100 percent with overnight recording, when abnormalities are commonly seen in the transition phases from sleep to awakening [91,93,94].

●Interictal findings – The classic interictal EEG pattern in JME is 3 to 6 Hz bilateral polyspike and slow wave discharges (waveform 1) with frontal predominance over a normal background activity.

Less common abnormalities include 2.5 to 4.5 Hz bilateral spike-waves, single spikes, and irregular spike-wave complexes. Photosensitivity is traditionally described in one-third of patients but may be present in up to 90 percent with prolonged continuous photostimulation [95,96].

Focal or asymmetric abnormalities may be found in more than 50 percent of recordings and do not exclude the diagnosis nor predict treatment response [97,98]. In a study of 266 JME patients, focal EEG abnormalities consisted of amplitude asymmetry or focal onset of generalized discharges in 45 percent, independent focal spikes or sharps in 33 percent, and asymmetric photoparoxysmal response in 16 percent [53].

●Ictal findings – An EEG recorded during a myoclonic seizure shows irregular 3 to 4 Hz polyspike-waves with frontocentral predominance. Jerks are usually associated with the spike component of the discharge [99].

During a GTCS, the EEG will show attenuation and low-voltage fast activity with spike-waves of variable frequency and amplitude, indistinguishable from GTCS secondary to other generalized epilepsies.

Absence seizures in JME are usually correlated with generalized spike-wave discharges of slightly higher frequency than the classic 3 Hz seen in childhood or juvenile absence epilepsy [60].

In rare cases, generalized-onset seizures may transition to discharges with a focal predominance [100,101].

Neuroimaging — MRI is not required in the evaluation of a patient with JME when the clinical history and EEG findings are typical. The routine brain MRI in patients with JME is typically normal [22,30]. Abnormalities on brain MRI raise concern for alternative diagnoses.

Advanced imaging techniques have demonstrated more subtle structural and functional defects in the frontal thalamocortical circuits. (See 'Pathophysiology and genetics' above.)

DIAGNOSIS

Mandatory criteria — A diagnosis of JME requires [4]:

●Myoclonic seizures

●EEG showing 3 to 5.5 Hz generalized spike-wave or generalized polyspike-wave

Alerts (typically absent in JME) — Alert criteria are absent in most patients with JME; they do not exclude the diagnosis but reduce confidence in diagnostic certainty and should prompt further investigations to rule out other conditions [4]. Alert criteria are:

●Generalized tonic-clonic status epilepticus

●Consistent unifocal semiology (ie, always affecting the same body part on the same side) at onset of generalized tonic-clonic seizures (GTCS)

●Consistent unifocal myoclonia

●Age at onset 8 to 9 years or 25 to 40 years

●Intellectual disability at onset

●Potentially relevant neurologic examination and/or imaging abnormalities, excluding incidental findings

Exclusionary criteria (not present in JME) — The following exclude the diagnosis of JME [4]:

●Any of the following seizure types:

•Myoclonic absence seizures

•Atonic seizures

•Tonic seizures

•Atypical absence seizures

•Focal impaired awareness seizures

•Myoclonia predominantly or exclusively during sleep

•Myoclonic seizures that occur exclusively with specific stimuli, such as reading

•Cortical tremor with myoclonus suggestive of familial adult myoclonic epilepsy (FAME) (see 'Other epilepsies' below)

●EEG findings:

•Habitual myoclonic events captured on EEG in the absence of polyspike and spike-wave discharge

•Focal slowing

•Consistently unilateral focal epileptiform abnormalities

•Generalized slow spike-wave at frequency <2.5 Hz (unless it is at the end of a higher frequency burst)

•Diffuse background slowing that is not limited to the postictal period

●Age at onset less than 8 years or greater than 40 years. Note that childhood absence epilepsy may occasionally evolve to JME; in such cases, onset of absence seizures may be present before age 8 years, but not GTCS or myoclonic seizures.

●Moderate to severe intellectual disability at onset.

●Progressive cognitive decline.

●Progressive myoclonus with impaired fine motor functions.

DIFFERENTIAL DIAGNOSIS

Other epilepsies — The differential diagnosis of JME includes isolated convulsions and other idiopathic generalized epilepsies (IGEs) that occur in adolescents.

Many of these syndromes have overlapping clinical features and resemble each other in the early stages. A thorough patient history, mainly looking for other seizure types, EEG with video recording whenever possible [102], and time are the most helpful tools to distinguish among diagnoses.

●Isolated convulsion – When a child or teenager presents with a first generalized tonic-clonic seizure (GTCS), the history is the most important tool. History taken from both patient and family members should focus on clues to an underlying diagnosis of JME, such as prior staring spells, morning arm jerks, and a family history of jerks or seizures.

●Childhood absence epilepsy (CAE) – CAE is an IGE with a peak age of onset of six to seven years, affecting girls more than boys, characterized by frequent (multiple per day) absence seizures in an otherwise developmentally normal child. GTCS often develop in adolescence. (See "Childhood absence epilepsy".)

Myoclonic jerks do not occur in CAE, but the two syndromes can be confused when JME starts with absence seizures before the onset of myoclonic jerks (as it does in up to one-third of patients).

The absence seizures in JME are typically milder and shorter than those of CAE and have different EEG patterns. (See 'Electroencephalography' above.)

●Juvenile absence epilepsy (JAE) – JAE is an IGE with a peak age of onset of 10 to 12 years, also characterized by typical absence seizures that are generally longer and associated with more severe impairment in consciousness than those in JME. GTCS are more common in JAE than CAE, and myoclonic jerks occur in one-fifth of patients. The latter are typically mild and do not show a morning predominance. Like JME, JAE is usually a lifelong disorder and responds favorably to valproate. (See "Epilepsy syndromes in children", section on 'Absence epilepsies'.)

●Epilepsy with eyelid myoclonia (EEM; Jeavons syndrome) – EEM is a generalized idiopathic epilepsy with onset in the first two decades of life, characterized by eyelid myoclonia, absence seizures, and photosensitivity.

Myoclonic seizures occur in EEM but are infrequent. EEM is more likely than JME to be associated with mild intellectual disability and treatment resistance. (See "Photosensitive epilepsies", section on 'Epilepsy with eyelid myoclonia (Jeavons syndrome)'.)

●Idiopathic photosensitive occipital epilepsy (IPOE) – IPOE is a reflex focal epilepsy of late-childhood onset characterized by colorful elementary visual auras, often with conscious tonic head and eye version, triggered by photic stimulation. Interictal EEG shows unilateral or bilateral occipital spike-waves and generalized spike-waves.

Myoclonic and generalized seizures are rare in IPOE but can occur, and there may be more clinical overlap between IPOE and JME than previously recognized. As an example, one study compared four families with IPOE to 40 probands with JME and noted overlapping electroclinical features, including visual auras and conscious head version in JME patients, and myoclonic jerks and GTCS without photic stimulation in IPOE patients [103]. (See "Photosensitive epilepsies", section on 'Photosensitive occipital lobe epilepsy'.)

●Progressive myoclonic epilepsy (PME) – Symptomatic myoclonus is a major feature of the rare, genetically heterogeneous syndrome known as PME. The most common causes of PME are Lafora disease, myoclonic epilepsy with ragged red fibers (MERRF), neuronal ceroid lipofuscinosis, dentatorubral pallidoluysian atrophy, and Gaucher disease [104].

In contrast to JME, the myoclonus associated with PME is typically multifocal and induced by action or somatosensory stimulation. PME can also be distinguished from JME by its progressive nature, greater severity of seizures, and accompanying cognitive decline. (See "Symptomatic (secondary) myoclonus", section on 'Progressive myoclonic epilepsy and progressive myoclonic ataxia'.)

●Familial adult myoclonic epilepsy (FAME) – Also known as adult myoclonic epilepsy with cortical tremor, FAME is distinguished from JME by prominent cortical myoclonic tremor, autosomal dominant inheritance, and adolescent to adult onset [4,105,106].

Nonepileptic disorders

●Functional disorders – Patients with functional neurologic disorders may have jerks or twitches that mimic myoclonic seizures [4]. (See "Functional movement disorders", section on 'Functional myoclonus'.)

Functional seizures, also known as psychogenic nonepileptic seizures (PNES), are nonepileptic events resembling seizures or syncopal attacks. They mimic epileptic seizures or syncope but are not associated with abnormal neuronal activity or reduced perfusion to the brain. The diagnosis of functional seizures is generally established by video-electroencephalography (EEG) monitoring. (See "Functional seizures: Etiology, clinical features, and diagnosis" and "Functional seizures: Management and prognosis".)

●Hypnic jerks – Hypnic jerks consist of a sudden, brief jerk of the whole body or one or more segments at sleep onset, often associated with the sense of falling. Hypnic jerks can occur at any age and are a benign phenomenon. (See "Approach to abnormal movements and behaviors during sleep", section on 'Simple or single movements'.)

●Periodic limb movements of sleep (PLMS) – These are characterized by periodic episodes of repetitive and highly stereotyped limb movements during sleep. Myoclonic epilepsy is usually distinguished from PLMS by daytime seizures, myoclonic movements upon awakening, and/or EEG findings recorded during a sleep study. However, distinguishing epilepsy from PLMS occasionally is difficult in a child with only nocturnal symptoms. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep' and "Restless legs syndrome and periodic limb movement disorder in children".)

●Propriospinal myoclonus – Propriospinal myoclonus takes the form of flexion or extension jerks of the trunk that can be spontaneous or stimulus-sensitive (reflex myoclonus). Spinal cord lesions may cause propriospinal myoclonus, leading to myoclonic activity arising during relaxation preceding sleep onset that begins in spinally innervated muscles, with spread to rostral and caudal muscular segments.

●Encephalopathies – Certain toxic (eg, opioids), metabolic (eg, hepatic failure), neurodegenerative (eg, Alzheimer dementia), or genetic (eg, Wilson disease) encephalopathies can cause myoclonus, which may be focal or generalized [4]. In most cases, these are easily distinguished from JME by associated symptoms, signs, and absence of characteristic EEG findings (4 to 6 Hz polyspike and spike-wave).

TREATMENT — 

Patients with JME usually respond quickly and completely to broad-spectrum antiseizure medication (ASM) therapy, but most require long-term treatment.

First-line pharmacotherapy

Valproate — Valproate is considered to be the first-line treatment of choice for most patients [107,108]. It is a broad-spectrum ASM that controls all three seizure types in JME and has the best established efficacy in JME [47,109]. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

In a randomized study of 716 patients with idiopathic generalized epilepsy (IGE), 119 of whom had JME, valproate controlled seizures in 80 percent of patients and was more effective than lamotrigine or topiramate [108]. Valproate was also better tolerated than topiramate. Observational data also support a superior efficacy of valproate compared with levetiracetam [47,109], with lamotrigine [107,109], and with topiramate [107] in patients with JME.

However, because of its teratogenic risks, shared decision-making is required in individuals of childbearing potential [110]. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

Valproate has additional side effects such as weight gain and hair loss that make it unacceptable in some patients.

The demonstrated efficacy of valproate in patients with JME most often outweighs these potential side effects; however, those who are considering becoming pregnant or who cannot guarantee reliable contraception may choose an alternative treatment [111]. Individuals of childbearing potential who choose treatment with valproate should be counseled regarding effective contraception. (See "Management of epilepsy during preconception, pregnancy, and the postpartum period", section on 'Contraception'.)

The risks regarding valproate in pregnancy are discussed separately. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

Limited retrospective observational data suggest children born to men taking valproate in the three months before conception have a slightly higher rate of neurodevelopmental disorders, but not congenital malformations, compared with children born to men taking lamotrigine or levetiracetam [112]. Based largely on this finding, the European Medicines Agency in 2024 recommended precautionary measures in prescribing valproate for male patients [113], and the UK Medicines and Healthcare products Regulatory Agency (MHRA) severely restricted prescribing valproate for men younger than 55 years of age [114]. However, the data suggesting an association of valproate use in male parents with neurodevelopmental disorders are not compelling and require confirmation [115].

Alternatives to valproate — For patients in whom valproate is contraindicated or not tolerated (eg, female patients of childbearing potential), we suggest treatment with levetiracetam, lamotrigine, or topiramate [116-122]. These are broad-spectrum agents with observational evidence of efficacy in JME. Dosing of these ASMs is provided separately. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

Some observational data suggest that levetiracetam may be more efficacious than lamotrigine in patients with JME [109]. In a retrospective report of 543 female patients with IGE syndromes who were treated with levetiracetam or lamotrigine as initial monotherapy, levetiracetam was associated with a lower risk of treatment failure compared with lamotrigine in a subset of 259 females with JME (adjusted hazard ratio [HR] 0.47, 95% CI 0.32-0.68) [122]. In addition, lamotrigine is associated with exacerbation of myoclonic seizures in some patients with JME [123,124].

With insufficient studies comparing one drug to another, the choice of an alternative ASM should account for patient comorbidities, side effect profile, and patient preferences, among other factors. As an example, in a patient who is overweight with comorbid migraines, topiramate may be a good treatment choice [125]. (See "Initial treatment of epilepsy in adults", section on 'Selection of an antiseizure medication'.)

Avoidance of seizure triggers — Patients should be counseled to avoid common seizure precipitants, such as sleep deprivation, alcohol or drug consumption, medication nonadherence, and flickering lights in those with photosensitivity.

Failure of initial monotherapy therapy

Additional trial of monotherapy — ASM substitution is appropriate if the first ASM is poorly tolerated at a lower dose or fails to improve seizure control. Patients whose seizures fail to respond to adequate doses of first-line therapy are less likely to become seizure-free on a second single agent than those who are switched because of adverse drug reactions [107,126].

For the additional trial, we prioritize valproate therapy if it was not used as initial therapy; otherwise, we choose one of the valproate alternatives (levetiracetam, lamotrigine, or topiramate) as discussed above. (See 'First-line pharmacotherapy' above.)

Combination therapy — Combination (adjunctive) therapy should be considered when:

●The first ASM is adequately dosed, well-tolerated, and improves but does not abolish seizures.

●Two different ASMs (monotherapy) fail to improve seizure control [125].

Lamotrigine, levetiracetam, topiramate, zonisamide, and benzodiazepines are all options for combination therapy. Some considerations include:

●Two large randomized studies have shown that levetiracetam is an effective add-on therapy for patients with IGE [127,128]. In a secondary analysis of the 167 patients with JME included in these two studies, a >50 percent seizure reduction was achieved in 61 percent of patients treated with adjunctive levetiracetam compared with 25 percent treated with adjunctive placebo [129].

●Small studies support a role for zonisamide in JME, particularly for generalized tonic-clonic seizures (GTCS) and myoclonic seizures [130-132]. However, risks of metabolic acidosis, nephrolithiasis, bone disease, and reduced growth rates may limit its utility in children.

●Clobazam or clonazepam may be useful as adjunctive therapy for myoclonic jerks in patients who are otherwise well controlled on lamotrigine [125].

●The combination of valproate and lamotrigine may have synergistic effects, but caution must be taken given the increased risk of serious skin reactions with rapid titration of lamotrigine, particularly in children younger than 12 years.

Drug-resistant epilepsy — Drug-resistant epilepsy (DRE) is defined as the failure of adequate trials of two tolerated, appropriately chosen and administered ASMs, whether as monotherapy or in combination, to achieve seizure freedom. (See "Evaluation and management of drug-resistant epilepsy", section on 'Definition'.)

●Prevalence – In different studies and systematic reviews, DRE developed in 29 to 36 percent of patients with JME [133-135], despite evidence that most patients with JME achieve seizure control with valproate (see 'First-line pharmacotherapy' above) and achieve long-term seizure remission. (See 'Seizure remission' below.)

●Risk factors – In systematic reviews and meta-analyses of mainly retrospective studies, risk factors for DRE included the following [134-136]:

•Alcohol consumption

•Childhood absence epilepsy (CAE) evolving into JME

•Presence of absence seizures

•Psychiatric disorder or comorbidities

•Occurrence of three seizure types

•Aura symptoms

•Focal EEG abnormalities

•History of febrile seizures

•Family history of epilepsy

•History of status epilepticus

•Catamenial epilepsy

•Ethnicity

●Evaluation – When possible, patients with apparent DRE should be referred for evaluation by an epilepsy specialist, ideally at a comprehensive epilepsy center.

It is important to differentiate true DRE versus apparent DRE (pseudoresistance). Reasons for apparent treatment failure that do not reflect drug resistance include inappropriate ASM choice, inappropriate ASM dose, treatment nonadherence, and lifestyle factors such as alcohol use or sleep deprivation. Addressing these factors is reviewed separately. (See "Evaluation and management of drug-resistant epilepsy", section on 'Apparent intractability'.)

●Treatment – For patients who have true DRE, treatment options include combination therapy (see 'Combination therapy' above), empiric trials with other ASMs appropriate for JME, neurostimulation (eg, vagus nerve stimulation), and the ketogenic diet [136,137]. Failure of levetiracetam and lamotrigine should prompt the addition of valproate, even in women of childbearing potential.

Ablative surgery is not considered appropriate for JME, which is a generalized type of epilepsy.

Treatment options for DRE are discussed in detail separately. (See "Evaluation and management of drug-resistant epilepsy", section on 'Treatment options'.)

Antiseizure medications to avoid — As a general rule, carbamazepine, phenytoin, and oxcarbazepine should be avoided because they may aggravate absence seizures and myoclonic jerks. However, they may control GTCS in some refractory cases [138].

Gabapentin, pregabalin, tiagabine, and vigabatrin are also contraindicated in JME because of their potential to aggravate all seizure types, including myoclonic or absence status epilepticus [125,139].

LONG-TERM OUTCOMES

Seizure remission — While JME is a lifelong disorder, most patients have a substantial alleviation of seizures by their fourth decade, achieving a five-year remission and requiring lower doses of antiseizure medication (ASM) [59,140]. Approximately 25 percent of patients achieve long-term remission off medication [61,135,141,142].

For adults and children who are seizure-free for at least two years on ASM therapy, it is reasonable to begin a discussion about ASM continuation versus a trial of discontinuation. However, patients should be counseled about the relatively high risk of seizure recurrence after ASM withdrawal, particularly those with identified risk factors. Discussions about ASM withdrawal must be individualized and weigh the risks of seizure recurrence against the possible benefits of ASM withdrawal. Shared decision-making and patient counseling is paramount in this process.

In a meta-analysis of 24 studies with individual patient data for 368 people with JME who underwent attempted ASM withdrawal, independent risk factors for recurrence of seizures were [135]:

●Younger age at the start of withdrawal

●Shorter seizure-free interval

●Greater number of ASMs in use before the start of withdrawal

Psychosocial outcomes — Psychosocial outcomes are generally favorable. In one long-term follow-up study, 87 percent of patients had graduated from high school, 70 percent had been married, and 70 percent declared they were "very satisfied with their health, work, friendships, and social life" [61].

However, psychosocial complications (eg, unwanted pregnancy, living alone, unemployment, depression) are described in up to one-third of patients and are more common in those with uncontrolled seizures [61,140,143,144].

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Classification – Juvenile myoclonic epilepsy (JME) is classified as an idiopathic generalized epilepsy (IGE) syndrome. It is believed to have a complex underlying genetic basis; however, the exact mechanisms are not well understood. (See 'Classification' above and 'Pathophysiology and genetics' above.)

●Seizures – JME is typically diagnosed in otherwise healthy young teenagers and is characterized by one or more of the following seizure types:

•Myoclonic jerks – These are the hallmark seizures in JME and often begin before the first generalized tonic-clonic seizure.

•Generalized tonic-clonic seizures (GTCS) – These occur in almost all patients with JME, often as the index event leading to diagnosis.

•Absence seizures – These occur in 20 to 40 percent of patients beginning up to five years before other seizure types. Delays in diagnosis are common since absence seizures and myoclonic jerks often go unnoticed until a first GTCS.

Myoclonic jerks and GTCS are most common in the mornings and are aggravated by sleep deprivation, alcohol consumption, and sometimes by photic stimulation. Some patients may have reflex seizures triggered by various types of stimuli. (See 'Clinical features' above.)

●Cognitive, behavioral, and psychiatric comorbidity – Cognitive, behavioral, and social difficulties may occur, either directly related to underlying cerebral dysfunction or as a result of uncontrolled seizures or medication side effects. (See 'Cognition and behavior' above.)

Patients with JME are at increased risk for comorbid psychiatric illness and personality disorder. (See 'Psychiatric comorbidity' above.)

●Evaluation and diagnosis – The diagnosis of JME is suspected in a developmentally normal child, adolescent, or young adult with new-onset generalized tonic-clonic seizures, particularly if they occur upon awakening in the morning, or (less commonly) those with new-onset absence seizures. The diagnosis of JME is established by a careful history, supportive clinical features, and typical EEG findings. Brain MRI is typically normal and is not required for diagnosis.

•EEG – The classic interictal EEG pattern in JME is 3 to 6 Hz generalized spike-wave or generalized polyspike-wave discharges with frontal predominance over a normal background activity. Sensitivity of the EEG rises to nearly 100 percent with overnight recording. (See 'Electroencephalography' above.)

•Diagnosis – The diagnosis of JME requires the presence of myoclonic seizures and an EEG showing 3 to 6 Hz generalized spike-wave or generalized polyspike-wave. Alert criteria (typically absent in JME) and exclusionary criteria for JME are listed above (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of JME includes other IGEs with onset in childhood and progressive myoclonic epilepsy (PME), as well as nonepileptic paroxysmal disorders characterized by jerks or twitches that may mimic myoclonic seizures. (See 'Differential diagnosis' above.)

●Treatment – Patients with JME require treatment with a broad-spectrum antiseizure medication (eg, valproate, levetiracetam, lamotrigine, topiramate). For most patients, we suggest initial treatment with valproate (Grade 2C). Valproate has the best established efficacy for JME, resulting in seizure control in up to 80 percent of patients. However, because of its teratogenic risks, valproate should be used with caution in females of childbearing potential, particularly those who are considering becoming pregnant or who cannot guarantee reliable contraception practices. (See 'Valproate' above.)

Some patients require combination therapy after two single-agent treatment failures. Rare patients have drug-resistant epilepsy. (See 'Failure of initial monotherapy therapy' above.)

●Long-term outcomes – JME is a lifelong disorder. However, most patients have a substantial alleviation of seizures by their fourth decade, achieving a five-year remission and requiring lower doses of antiseizure medication. Approximately 25 percent of patients achieve long-term remission off medication. (See 'Long-term outcomes' above.)