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 patients generally respond quickly and completely to standard antiseizure medications. Seizure frequency often lessens in adulthood but many patients require long-term antiseizure medication therapy. The underlying cause of JME is not known 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".)

EPIDEMIOLOGY — JME accounts for 25 to 30 percent of the idiopathic generalized epilepsies and up to 10 percent of all cases of epilepsy [1]. 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 [2].

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 [3-5].

The mean age of onset is 15 years, with a range of 5 to 34 years [6-9]. The majority of patients are diagnosed between the ages of 12 and 18 years.

PATHOPHYSIOLOGY AND GENETICS — JME was classified as an idiopathic generalized epilepsy (IGE) in 1989 by the International League Against Epilepsy (ILAE) [10]. In its 2010 proposal, the ILAE proposed changing the term "idiopathic" to "genetic" when applied to epilepsy syndromes [11]. In a 2017 position paper on epilepsy classification, and following the desire to retain the term IGE expressed by many, the ILAE reaffirmed the use of the term IGE for the following four epilepsy syndromes [12]:

●Childhood absence epilepsy

●Juvenile absence epilepsy

●Juvenile myoclonic epilepsy

●Epilepsy with generalized tonic-clonic seizures alone (previously termed generalized tonic-clonic seizures on awakening)

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".)

The genetic mechanisms that underlie JME are not understood fully, and a polygenic or multifactorial mechanism is likely in most cases. Some JME cases are apparently sporadic, others occur in families with other IGE syndromes, and occasionally families have a pure autosomal dominant JME phenotype [13]. A number of chromosomal loci are suspected of playing a central role in JME; however, only a few are considered as putative JME-causing genes: EFHC1, CACNB4, CASR, GABRA1, GABRD, and ICK [14,15]. EFHC1 mutations are found in up to 9 percent of classic JME patients of various ethnic backgrounds [16-21]. 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 [22].

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 [23]. Other targets of interest for epigenetic changes in the DNA of patients with JME have been identified, such as the BRD2 promoter [24]. For that specific candidate, however, a subsequent study failed to replicate results [25]. The significance of these findings and the role of epigenetics in JME thus remains 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 [26-29].

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 [30]. Most of these investigations suggest involvement of frontal thalamocortical circuits [31-48] and dysfunction in the dopaminergic and serotoninergic neurotransmission systems [49-52]. 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 [53]. Increased cortical volume and thickness were particularly prominent in fronto-parieto-temporal association areas. These findings are consistent with the neuropsychological and psychiatric characteristics reported in many JME patients. The underlying pathophysiological mechanisms are not well understood. (See 'Clinical features' below.)

CLINICAL FEATURES

Seizures — The typical patient with JME is a healthy young teenager with one or more of three seizure types: myoclonic jerks, generalized tonic-clonic seizures (GTCS), and absence seizures. In three large observational studies totalling 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 [6,7,9]. Only 5.5 percent of patients had myoclonic jerks as the only seizure type recognized [9]. Approximately one-half of patients have a family history of one or more of the three seizure types.

●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 almost never in isolation.

●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 or asymmetric tonic posturing or clonic movements have been noted in 16 to 40 percent of patients [6,54].

●Absence seizures are the least common seizure type in JME, occurring in 20 to 40 percent of patients [6,7,9]. 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; only 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 show great variation, ranging from subtle or no overt features to severe impairment of consciousness [55]. Absence phenomenology can vary even within the same patient.

Myoclonic jerks and GTCS are most common in the mornings and are aggravated by sleep deprivation, alcohol consumption, and sometimes by photic stimulation.

Absence seizures typically precede the onset of myoclonic jerks and GTCS by three to five years, starting as early as age six years [9]. Delays in diagnosis are common, often because absence seizures and myoclonic jerks go unrecognized by the patient and family until a GTCS occurs.

Rarer seizure patterns include episodes of nonconvulsive, generalized tonic-clonic, myoclonic, or mixed myoclonic-absence status epilepticus [56-59]. Rare patients may have reflex seizures triggered by various types of stimuli, such as writing, reading, or praxis (ie, higher mental activities accompanied by execution of a movement) [29,60-62].

Some authors distinguish various subtypes of JMEs based on different clinical phenotypes and their evolution [16,63]. These categories include classic JME (accounting for 72 percent in a series of 257 patients), childhood absence epilepsy evolving to JME (18 percent), JME with adolescent absences (7 percent), and JME with astatic (atonic, drop attack) seizures (3 percent) [63].

Cognition and behavior — Most patients with JME have normal global cognitive capacities. However, formal neuropsychological 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 [39,53,64-68]. These results are likely influenced by multiple factors, including antiseizure medications, seizure frequency, genetic variability, psychosocial conditions, and educational level [64,69-71]. However, in at least one study, cognitive performance was not correlated with disease duration, seizure frequency, seizure types, or treatment [66]. Advanced neuroimaging studies have suggested an underlying structural basis for these neuropsychiatric deficits [31,72]. (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 [73-79]. Poorly controlled seizures and antiseizure medications themselves may also put patients at risk for psychiatric side effects and mood disorder [76,80]. Functional magnetic resonance imaging (MRI) data suggest that frontal-insular network dysfunction may contributed to emotional disturbances [81]. (See "Comorbidities and complications of epilepsy in adults", section on 'Psychiatric disorders'.)

ELECTROENCEPHALOGRAPHY — The diagnosis of JME in a patient with clinical features is supported by electroencephalography (EEG). If routine EEG is normal in a patient suspected of having JME, an overnight sleep EEG should be performed.

Interictal EEG — The routine interictal EEG is abnormal in about 75 percent of patients with JME [6,82,83]. This number increases to nearly 100 percent with overnight recording, when abnormalities are commonly seen in the transition phases from sleep to awakening [82,84,85]. For this reason, a normal EEG in a patient suspected of having JME should prompt an overnight recording.

The classic interictal EEG pattern in JME is 4 to 6 Hz bilateral polyspike and slow wave discharges 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 [86,87].

Focal or asymmetric abnormalities may be found in more than 50 percent of recordings and do not exclude the diagnosis, nor do they predict treatment response [88,89]. 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 [6].

Ictal EEG — 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 [90].

During a generalized tonic-clonic seizure (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 [55].

In rare cases, focal findings on EEG evolve from generalized-onset seizures [91,92].

NEUROIMAGING — Magnetic resonance imaging (MRI) is not required in the evaluation of a patient with JME when the clinical history and EEG findings are typical. The routine structural MRI in patients with JME is normal [30,38]. An abnormal structural MRI raises concern for an alternative diagnosis. More subtle structural and functional defects in the frontal thalamocortical circuits have been demonstrated using advanced imaging techniques. (See 'Pathophysiology and genetics' above.)

DIAGNOSIS — Formal diagnostic criteria have not been established for JME. The diagnosis is established by a careful history, supportive clinical features and typical EEG findings. In a survey of 69 adult and pediatric epileptologists, all respondents agreed that a diagnosis of JME can be made with a history of myoclonus, a single generalized tonic-clonic seizure (GTCS), and a typical EEG pattern [93]. Most required a history of myoclonic jerks, the presence of two out of three seizure types, a normal neurological examination, and a normal background EEG pattern. The majority did not require an MRI for diagnosis. Thus, if the history and EEG findings are all consistent with the diagnosis, further studies may not be necessary. If a routine EEG is normal in a patient suspected of having JME, an overnight sleep EEG should be performed. (See 'Electroencephalography' above.)

The diagnosis of JME should be considered in every developmentally normal child with absence seizures beginning in the second half of the first decade and isolated generalized convulsive seizures, particularly if they occur upon awakening in the mornings. A detailed history of myoclonic jerks should be sought as this may not be volunteered.

Delays in diagnosis are frequent [7,94,95]. Factors that may contribute to diagnostic delays include:

●Lack of general awareness of the syndrome [95,96]

●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 [7,9,94,95,97]

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

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of JME includes isolated convulsions, other idiopathic generalized epilepsies that occur in adolescents, such as childhood or juvenile absence epilepsy (JAE) and eyelid myoclonia with absences (EMA), partial epilepsies that share overlapping electroclinical features, such as idiopathic photosensitive occipital epilepsy (IPOE), and symptomatic myoclonus related to a more severe epilepsy syndrome, such as progressive myoclonic epilepsy (PME).

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 [98], and time are the most helpful tools to distinguish between 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 – Childhood absence epilepsy (CAE, pyknolepsy) is an idiopathic generalized epilepsy 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 normal child. GTCS often develop in adolescence (see "Epilepsy syndromes in children", section on 'Absence epilepsies'). Myoclonic jerks do not occur in CAE, but the two syndromes can be confused when JME starts with absence seizures prior to the onset of myoclonic jerks (as it does in up to one third of patients). However, the absence seizures in JME are typically milder and shorter compared with those of CAE and have different EEG patterns. (See 'Electroencephalography' above.)

●Juvenile absence epilepsy – JAE is an idiopathic generalized epilepsy 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 in 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 life-long disorder and responds favorably to valproate. (See "Epilepsy syndromes in children", section on 'Absence epilepsies'.)

●Eyelid myoclonia with absences – EMA 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 EMA but are infrequent. EMA is more likely than JME to be associated with mild intellectual disability and treatment resistance [99].

●Idiopathic photosensitive occipital epilepsy – 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 [100].

●Progressive myoclonic epilepsy – 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 [101]. In contrast to JME, the myoclonus associated with PME is typically multifocal and induced by action or by 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'.)

TREATMENT — Patients with JME generally respond quickly and completely to broad spectrum antiseizure medication therapy, but many require long-term treatment.

Valproate — Valproate is recommended as the first-line treatment of choice for most patients [102,103]. It is a broad spectrum antiseizure medication that controls all three seizure types in JME, and has the best established efficacy in JME [104,105].

In a large randomized study of 716 patients with idiopathic generalized epilepsy (119 of whom had JME), valproate controlled seizures in 80 percent of patients and was more effective than lamotrigine or topiramate [103]. Valproate was also better tolerated than topiramate.

Valproate should be used with caution in postpubertal girls, particularly those who are considering becoming pregnant or who cannot guarantee reliable birth control practices, because of its teratogenic risks [106]. Valproate has additional side effects such as weight gain and hair loss that make it unacceptable in some patients. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

The teratogenic risks of valproate and its efficacy in JME emphasize the importance of shared decision-making in girls with JME. A special report on the use of valproate in girls and women issued by the Commission on European Affairs of the International League Against Epilepsy and the European Academy of Neurology states that valproate may be offered as a first-line treatment for epilepsy syndromes for which it is the most effective treatment, including genetic generalized syndromes associated with tonic-clonic seizures [107]. In clinical practice, the well-demonstrated efficacy of valproate in patients with JME most often outweighs these potential side effects when this is discussed with patients and their parents or guardians, and valproate remains a first-choice therapy in a majority of girls with JME. Options for effective contraception in the setting of antiseizure medication therapy should also be reviewed when appropriate. (See "Seizures and epilepsy in children: Initial treatment and monitoring", section on 'Additional considerations in adolescent girls'.)

Other antiseizure medications — For patients in whom valproate is contraindicated or not tolerated, we suggest treatment with levetiracetam, lamotrigine or topiramate [108-113]. All of these are broad spectrum agents with observational evidence of efficacy in JME. Small studies also support a role for zonisamide, particularly for generalized tonic-clonic seizures (GTCS) and myoclonic seizures [114-116]. However, risks of metabolic acidosis, nephrolithiasis, bone disease, and reduced growth rates may limit its utility in children.

With insufficient studies comparing one drug to another, the choice of an alternative antiseizure medication should take into account patient comorbidities, side effect profile and patient preferences among other factors. As an example, in an overweight patient with comorbid migraines, topiramate may be a good treatment choice [117]. (See "Initial treatment of epilepsy in adults", section on 'Selection of an antiseizure medication'.)

One note of caution is that lamotrigine is associated with exacerbation of myoclonic seizures in some patients with JME [118,119].

Adjunctive therapy — Combination therapy should be considered after two single medication failures [117]. Lamotrigine, levetiracetam, topiramate, zonisamide, and benzodiazepines are all options for adjunctive therapy. Some considerations include:

●Patients who fail 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 [102,120].

●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.

●Two large randomized studies have shown that levetiracetam is an effective add-on therapy for patients with idiopathic generalized epilepsy [121,122]. 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 [123].

●Failure of levetiracetam and lamotrigine should prompt the addition of valproate, even in women of childbearing potential.

●Clobazam or clonazepam may be especially useful as adjunctive therapy for myoclonic jerks in patients who are otherwise well controlled on lamotrigine [117].

●Vagal nerve stimulation may be indicated in the rare severely refractory cases [124]. (See "Vagus nerve stimulation therapy for the treatment of epilepsy".)

Lifestyle modification — 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.

Antiseizure medications to avoid — As a general rule, carbamazepine, phenytoin, and oxcarbazepine should be avoided because they may aggravate absence seizures and myoclonic jerks, although they may control GTCS in a certain number of refractory cases [125]. 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 [117,126].

PROGNOSIS — JME is a life-long disorder. The majority of patients require continued drug treatment for years, even after prolonged remission of seizures [63]. However, most patients have a substantial alleviation of seizures by their fourth decade, achieving a five-year remission and requiring lower doses of medication [127]. Approximately 25 percent of patients achieve long-term remission off medication [56,128,129]. A meta-analysis of prevalence and risk factors in 3311 patients with JME showed that seizures of any type were refractory to treatment in 35 percent [130]. Risk factors for treatment resistance included having three seizure types, absence seizures, psychiatric comorbidities, a history of childhood absence epilepsy, praxis-induced seizures, and early age at epilepsy onset [127,129-131].

Other outcomes are also 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 that they were "very satisfied with their health, work, friendships, and social life" [56]. 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 [56,127,131,132].

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

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

●JME is typically diagnosed in otherwise healthy young teenagers and is characterized by one or more of the following seizure types: myoclonic jerks, absence seizures, and generalized tonic-clonic seizures (GTCS). (See 'Clinical features' above.)

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

•GTCS occur in almost all patients, often as the index event leading to diagnosis.

•Absence seizures are present 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.

●The classic interictal electroencephalography (EEG) pattern in JME is 4 to 6 Hz bilateral polyspike and slow 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.)

●The diagnosis of JME is established by a careful history, supportive clinical features and EEG. Magnetic resonance imaging (MRI) is typically normal and is not required for diagnosis. (See 'Diagnosis' above.)

●The differential diagnosis of JME includes other idiopathic generalized epilepsies with onset in childhood and progressive myoclonic epilepsy (PME). (See 'Differential diagnosis' above.)

●In patients with JME, we recommend initial treatment with a broad spectrum antiseizure medication (eg, valproate, levetiracetam, lamotrigine, topiramate) (Grade 1A). Valproate has the best established efficacy and results in seizure control in 80 percent of patients. Valproate should be used with caution in postpubertal girls, particularly those who are considering becoming pregnant or who cannot guarantee reliable birth control practices, because of its teratogenic risks. Patients generally respond quickly and completely to antiseizure medication therapy, but many require long-term treatment. Some patients require combination therapy after two single-agent treatment failures. Rare patients have drug-resistant epilepsy. (See 'Treatment' above.)

●Cognitive, behavioral, and social difficulties may occur, either directly related to underlying cerebral dysfunction or as a result of medication side effects. (See 'Clinical features' above and 'Prognosis' above.)