Juvenile Myoclonic Epilepsy

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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]

For more information, see the following:

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]

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.

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]

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.

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.

History

Juvenile myoclonic epilepsy (JME) is diagnosed on the basis of clinical findings. Video-electroencephalography (EEG) monitoring of typical seizures is the criterion standard, but in the great majority of patients, a working diagnosis of probable JME is made on the basis of the clinical history, often with supportive interictal EEG correlates.

Although observers’ descriptions of seizures are helpful, caution must be used regarding their validity. The most important element in the diagnosis of JME is the patient’s history. Any patient who presents with generalized tonic-clonic seizures (GTCSs) without an aura should be questioned about myoclonic jerks, the time of day when the seizures occurred, and any precipitating factors.

About 17–49% of patients have a family history of epilepsy. Symptoms usually begin in adolescence. The leading symptom is jerky movements that occur in the morning (typically, shortly after awakening) but might occur throughout the day, without loss of consciousness.

Patients may have myoclonic jerks plus other seizure types. In about 60% of patients, JME begins with myoclonic jerks, followed by the onset of relatively uncommon GTCSs a few years later. The finding of myoclonic jerks plus absence seizures and GTCSs is the next most common combination, occurring in approximately 30% of patients with JME. The combination of myoclonic jerks and absence seizures without GTCSs is rare, occurring in only 2% of patients.

Myoclonic seizures

Myoclonic seizures without impairment of consciousness are the cardinal symptoms of JME. Although an occasional strong myoclonic jerk may make patients momentarily seem to be “in a fog,” a key feature is that consciousness is preserved during these jerks.

The jerks are usually brief, bilateral, arrhythmic contractions that mainly involve the shoulders and arms. However, some patients report jerking in the lower limbs, trunk, or head. Some jerks occur unilaterally. In a video-EEG study, Hirano et al characterized myoclonic jerks in patients with JME as being more likely to occur in clusters, with distal predominance, and involving extension muscles.[18]

The frequency and intensity of myoclonic jerks may vary. For instance, they may be perceived only internally, as an electric shock–like sensation. If the jerks are violent, patients may throw objects they are holding or even fall to the floor. Myoclonic jerks can occur in rapid succession and even progress to myoclonic status epilepticus. However, more often a rapid succession of myoclonic jerks evolves into a primary GTCS.

Myoclonic jerks occur as the only seizure type in approximately 17% of patients with JME; the remaining patients have a combination of myoclonic jerks, GTCSs, and absence seizures. Myoclonic seizures tend to subside by the fourth decade,[19] but the other seizure types might persist.

Generalized tonic-clonic seizures

GTCSs occur in more than 90% of patients with JME. The GTCSs seen in JME are typically symmetric, with a prolonged tonic phase that may lead to cyanosis and tongue biting.

GTCSs are sometimes preceded by a series of myoclonic jerks of increasing severity that evolve into an initial clonic phase of a GTCS. The GTCSs often cause a patient with JME to seek medical attention; in this setting, patients should be questioned specifically about myoclonic jerks because most patients do not mention them.

Absence seizures

In JME, typical absence seizures are less common than GTCSs and occur in about a third of patients or less. When absence seizures are a feature of JME, they are often the first clinical manifestation of the syndrome, with myoclonic jerks typically following 1–9 years later. A clue to this diagnosis is the development of GTCSs or myoclonic seizures within a couple of years after starting treatment with ethosuximide. Approximately 3–8% of children who present with absence seizures ultimately receive a diagnosis of JME.

As in all IGEs, absence seizures in JME are typically short, lasting a few seconds, and usually not accompanied by motor signs.

The severity of absence seizures in JME is somewhat age dependent. When they appear in children younger than 10 years, absence seizures of JME are reported less often than those of childhood absence epilepsy. Some recollection of the ictal events is common, particularly in patients that have persistence of these seizures during adulthood. Automatism is rare.

When absence seizures of JME begin in children aged 10 years or older, they may be even less severe than they otherwise would be, with merely a brief interruption in the patient’s ability to concentrate. In a video-EEG monitoring study of patients with absence seizures, Sadleir et al found that patients with JME tend to have shorter seizures than patients with other epileptic syndromes with absences.[20]

Precipitating factors for seizures

As in all IGEs, seizures of JME often are precipitated by (1) lack of sleep, (2) psychological stress, (3) alcohol consumption, and (4) noncompliance with medication regimens. These factors can all be a particular problem in adolescents, particularly after moving out of the parents’ household or after matriculation into college.

The time of day is also important because JME has a characteristic circadian pattern of activity. Myoclonic jerks, GTCSs, and absence seizures all tend to occur in the early morning after the patient awakens (though they also occur, to a lesser extent, in the evening when the patient is relaxing). When myoclonic jerks occur in the mornings, patients may have difficulty in eating breakfast or brushing their teeth. In some studies, nearly 90% of patients with JME had myoclonic jerks on awakening; the rest had either random jerks throughout the day or jerks at night.

In a study using transcranial magnetic stimulation (TMS) to examine the diurnal variability of cortical excitability, Badawy et al demonstrated that short and long intracortical inhibition was considerably more impaired in the mornings than in the afternoons in patients with JME.[21] This might suggest a biological basis for the clinical observation of increased seizure frequency within the first hour upon awakening in patients with JME.

Precipitating factors can be summarized as follows:

Physical Examination

As in all idiopathic (genetic) generalized epilepsies (IGEs), physical examination usually does not identify any abnormalities. Intelligence is normal; this observation contrasts with findings with diseases such as progressive myoclonic epilepsies, in which progressive mental deterioration is the rule.

Comorbidities

Comorbidities associated with juvenile myoclonic epilepsy (JME) include psychiatric and neurologic disorders.

Psychiatric comorbidities, including depression, anxiety, and personality disorders, have been described in patients with JME. In one study, 49% of patients with JME had a psychiatric comorbidity. Anxiety and mood disorders were reported in 23% and 19% of patients with JME, respectively. Unfortunately, the psychiatric comorbidities can negatively impact outcome due to poor compliance and unhealthy behaviors.[61]

Neuropsychological testing of patients with JME has demonstrated selected frontal lobe dysfunction in tests such as the Wisconsin Card Sorting test and the Word Fluency test.[23] This dysfunction occurs despite having normal intelligence quotient (IQ) results obtained testing through conventional Wechsler testing. Impairment in executive function has also been reported.[24]

Complications

Both myoclonic status epilepticus and nonconvulsive status epilepticus (NCSE) have been reported in juvenile myoclonic epilepsy (JME). 

The prevalence of NCSE in JME can be estimated at 5.8%, and the incidence at 1.2% per year with a clear preponderance of female gender. 

Absence and myoclonic status epilepticus precipitated by inappropriate antiepileptic drugs can occur in idiopathic generalized epilepsy, including JME, but occurs rarely in JME.[20]

Approach Considerations

Typical electroencephalographic (EEG) abnormalities are highly supportive of the clinical diagnosis of juvenile myoclonic epilepsy (JME). As for all IGEs, neuroimaging studies are usually normal in JME. Many clinicians believe that in the presence of an adequate supportive history, EEG abnormalities, normal intelligence, and normal neurologic findings, neuroimaging studies are unnecessary. However, the clinical scenario might not be as clear as the classical description would suggest.

Electroencephalography

The study of choice for confirming the clinical diagnosis of juvenile myoclonic epilepsy (JME) is sleep-deprived EEG with activation procedures (ie, hyperventilation, photic stimulation). A normal study does not rule out epilepsy or JME, as the sensitivity of a routine study is limited. Repeat routine EEG studies are reported to increase yield following a first non-diagnostic study. This can also be achieved with prolonged (eg, 3-day) EEG. Typical EEG abnormalities are highly supportive of the clinical diagnosis.

Interictal EEG

The typical interictal EEG abnormality consists of a generalized greater than or equal to 3- to 5.5-Hz spike or polyspike and slow-wave discharges lasting 1–20 seconds seen in both wakefulness and sleep (see the image below). Usually, 1–3 spikes precede each slow wave. Focal or multi-focal spikes and spike-wave discharges are observed in up to 20% of patients, and can lead to a wrong diagnosis of focal epilepsy, as can asymmetries.[68] When absence seizures are also present, 3-Hz spike-and-wave (SW) activity may be seen in addition to the polyspike-and-wave (PSW) pattern. Occasionally, isolated fragments of generalized spikes can also be seen.



View Image

Findings in a man with a history of generalized tonic-clonic seizures (mostly nocturnal) and myoclonic jerks (mostly in the morning) since the age of ....

Treatment with medications clinically effective in JME might also reduce the frequency of interictal abnormalities. Levetiracetam adjunctive therapy in patients with JME increased the likelihood of a normal EEG from 8% to 53% after maintenance therapy was achieved. There was a decrease in frequency of interictal discharges and suppression of the paroxysms induced by photic stimulation.[25]

Ictal EEG

The ictal EEG associated with myoclonic jerks typically reveals 10- to 16-Hz polyspike discharges. These may be preceded by SW activity and are often followed by 1- to 3-Hz slow waves. The number of spikes is typically 5-20 and tends to be proportionately correlated with the clinical intensity of the seizure. These epileptic discharges may briefly persist, even after clinical activity has ceased. Seizures in patients with JME tend to be associated with polyspikes and disorganization of the paroxysm.[26]

Absence seizures of JME may be associated with ictal EEG patterns consisting of 3-Hz SW activity. Sometimes, these are preceded by 4- to 6-Hz PSW discharges, which slow to 3 Hz as the patient loses consciousness.

Background

Background activity of the EEG is normal in JME.

Activation

Hyperventilation and photic stimulation often facilitate the appearance of epileptiform discharges. Photic stimulation frequently precipitates SW patterns or a photo-paroxysmal response, which is seen in more than a third of patients and can be detected in up to 90% of untreated patients.[68]

SW patterns by photic stimulation occur in 30% of patients with JME, compared with 18% of patients with childhood absence epilepsy, 13% of patients with epileptic seizures on awakening, and 7.5% of patients with juvenile absence epilepsy.

Hyperventilation can provoke clinical absence seizures.[68]

Other EEG findings

In addition to generalized epileptiform discharges, focal abnormalities may be found in a subset of patients with JME, with reported rates ranging from 4% to 55%. These include focal slow waves, generalized discharges that evolve from a focal onset, and focal spikes or SW discharges. Focal spikes or SW discharge mostly occur in the frontal regions.[68] EEG discharges can also be asymmetric[72] and lead to a wrong diagnosis of focal epilepsy. One published series of idiopathic primary generalized epilepsy patients evaluated with video EEG reported focal interictal epileptiform discharges and semiologic features of focal seizure in 35% of patients. However, no seizures with focal electrographic onset were reported in that study.[28]

The etiology of these focal abnormalities is unclear. A possible explanation is structural changes in the cerebral cortex secondary to recurrent seizures or head injury; another is fluctuation in the refractoriness of the cortex to the influence of a spike/wave generator.

Morning EEG

A morning EEG has been proposed as a superior strategy to detect generalized epileptiform discharges in patients with JME. In this particular study, a morning awake EEG detected interictal epileptiform discharges in 69% of patients, whereas an afternoon awake EEG in the same patients demonstrated epileptiform discharges in fewer than 20% of patients.[29]

Video EEG

Video EEG monitoring in patients with atypical features of JME might be needed. In a one study, most people with JME only required no more than 2 days of stay to demonstrate diagnostic abnormalities in the EEG.[30]

A combined magnetoencephalography and EEG study demonstrated interictal spikes with localizations mainly in the central and premotor regions in patients with JME as compared with other absence syndromes.[31]

Magnetic Resonance Imaging

As in all idiopathic (genetic) generalized epilepsies (IGEs), magnetic resonance imaging (MRI) of the brain usually yields unremarkable results. This observation reflects the fact that juvenile myoclonic epilepsy (JME) is an idiopathic generalized epilepsy and is not caused by conditions  leading to focal cortical brain pathology such as brain tumors or encephalitis. However, quantitative morphometric studies using a voxel-based technique have shown some differences among patients with JME.

For example, decreased gray matter volume was found in thalami, insula cortices, and cerebellar hemispheres bilaterally in patients with JME. An increase in gray matter volume was observed in the right superior frontal, orbitofrontal, and medial frontal gyri of patients with JME as compared with age-matched controls. Patients with JME who are photosensitive had decreased gray matter volume in the visual cortex as compared with a control group; this was not found in patients with JME who were not photosensitive.[32, 33]

Some patients with brain MRIs, particularly if the MRIs are high-definition (or high-Tesla) studies, have shown minor abnormalities of cortical development. Tae et al reported reduction in the cortical thicknesses of frontal and temporal gyri in patients with JME.[34] However, these observations were not confirmed in the study by Roebling et al.[35]

Progressive thalamic atrophy was also reported in patients with JME by the same group.[36] The decreased thalamic volume has been confirmed by several other groups and might be related to executive function impairment.[37, 38, 39] Furthermore, studies using diffusion tension imaging (DTI) have also confirmed that abnormalities in the degree of thalamocortical fiber orientation and tissue anisotropy correlate with the frequency of generalized tonic-clonic seizures (GTCSs).[40]

Magnetic resonance spectroscopy (MRS) has also confirmed abnormalities in the thalamus and thalamocortical system of patients with JME.[41, 42] Functional MRI (fMRI) studies have not shown significant abnormalities in patients with JME.[35]  However, it has been noted that during working memory tasks, the motor cortex co-activated with the supplementary motor cortex in addition to areas of higher cognitive function including the frontal and parietal lobes; interestingly, this co-activation is decreased with increased valproic acid dosages.[67]

Positron emission tomography (PET) imaging has revealed neurotransmitter and metabolic changes in the dorsolateral prefrontal cortex, which is in keeping with JME patients’ previously noted psychiatric comorbidities.[67] H-magnetic resonance spectroscopy reveals progressive thalamic dysfunction, which can extend to the occipital lobe in those with photosensitivity.[65] Based on studies of neurotransmitters using PET imaging, the serotonin system may also be affected in JME. The dopaminergic system also appeared to be affected with impaired signaling in the substantia nigra and midbrain, but was normal in the caudate and putamen.[67]

Using proton magnetic resonance spectroscopy, studies have found that patients with JME have lower N-acetyl aspartate (NAA) both in the thalamus and prefrontal areas.[67]

Overall, with more sophisticated imaging there have been some noted abnormalities in JME, most significantly in the thalami, prefrontal cortex, and motor cortex with co-activation with the supplementary motor cortex and the frontal and parietal lobes. In addition, neurotransmitters such as dopamine, serotonin, and NAA may play a role in JME.

Despite these minor quantitative differences, the guidelines of the International League Against Epilepsy (ILAE) do not recommend routine neuroimaging studies in patients with JME.[43]

Transcranial Magnetic Stimulation

Although not standard of care at this time, transcranial magnetic stimulation (TMS) has also been used in this setting. Studies using TMS show abnormalities in cortical excitability in patients with juvenile myoclonic epilepsy (JME).[44]

Approach Considerations

Medical therapy with anticonvulsants typically is needed (see Medication). Avoidance of precipitating events such as alcohol use and sleep deprivation may be useful but is not by itself sufficient to control the seizures of juvenile myoclonic epilepsy (JME).

Go to Antiepileptic Drugs and Epilepsy and Seizures for complete information on these topics.

Anticonvulsant Therapy

The selection of antiepileptic drugs for the treatment of juvenile myoclonic epilepsy (JME) depends on several factors, including the patient’s comorbidities, preferences, previous history of adverse events, and gender. The US Food and Drug Administration (FDA) has not approved any anticonvulsant solely for the treatment of JME, but several are approved for “primary generalized tonic clonic seizures,” which essentially means IGE. ASMs are considered "broad spectrum" if they work in IGE and focal epilepsies.[63] In 2006, the FDA approved the adjunctive use of levetiracetam for the treatment of JME. Divalproex sodium has been approved as adjunctive therapy for patients with multiple seizure types that include primary generalized epilepsies.

In most patients with JME, seizures are well controlled with monotherapy. Valproic acid has been considered the treatment of choice for JME for many years due to high response rates, but epileptologists are increasingly using other choices as first-line therapies. Approximately 90% of patients with JME become seizure free with valproate monotherapy. Several studies using lamotrigine, topiramate, levetiracetam, and zonisamide have shown similar efficacy to that achieved with divalproex sodium, and in some cases better tolerability.[45]

Levetiracetam is useful for the treatment of myoclonic seizures.[46, 47] Noachtar et al demonstrated in a randomized, double-blinded, placebo-controlled trial that levetiracetam adjunctive therapy reduced all seizure types and myoclonic seizures in patients with JME.[48] Meta-analysis of 2 randomized controlled trials affirm that JME is highly responsive to treatment with levetiracetam.[49] Small, uncontrolled studies of levetiracetam monotherapy in JME suggest efficacy and tolerability.[50, 51]

Lamotrigine may also be a consideration in the treatment of JME. This agent is ideal for patients who cannot tolerate the adverse effects of valproate (eg, weight gain, tremor, stomach upset, and hair loss) or leviteracetam. In some patients, lamotrigine monotherapy controls seizures completely. However, lamotrigine can exacerbate myoclonic jerks. Data from an open-label study suggested that lamotrigine was better tolerated than valproate, with similar efficacy.[52] A European expert opinion study showed that lamotrigine was first-line choice for JME in adolescent females, whereas valproate was the first-line choice in adolescent males.[53]

Topiramate is useful in the treatment of primary generalized seizures; it may effectively prevent the seizures of JME.[54]  Findings from an open-label study also suggested that zonisamide might be effective and well tolerated in patients with JME.[55]

Perampanel can also be considered as adjunctive treatment in IGEs in those patients who are refractory to other ASMs and is usually well tolerated.[73]

In general, low doses of appropriate anticonvulsants are needed to successfully treat JME. Although treatment with phenytoin, carbamazepine, or phenobarbital may control some seizure components of JME (albeit at high doses), these drugs may increase seizure frequency and occasionally precipitate new seizure types, such as absence seizures. Rarely, they may be considered in combination if the patient’s condition does not respond effectively to other first line drugs.[56]  Other antiepileptic medications noted to exacerbate JME include gabapentin, pregabalin, vigabatrin, oxcarbazepine, and tiagibine. Innapproriate antiepileptic medication selection in JME has been reported to potentiate status epilepticus.

Clonazepam is often used during seizure exacerbations in patients with JME; however, it is inadequate and undesirable as long-term treatment. Side effects limit the use of benzodiazepines such as clonazepam and clobazam.[63] However, clobazam is considered a broad spectrum ASM and can be considered as adjunctive therapy in refractory cases. 

A patient’s medication should rarely be changed when he or she is not having seizures and there are no medication side effects or signs of toxicity. In medical school, physicians are taught to treat patients and not proposed serum target concentrations.  The routine checking of levels in a patient without side effects whose seizures are controlled is of little benefit to the patient, and sometimes detremental if it leads to an unnecessary dosing adjustment.  An effective low-dose regimen is not unusual; in fact, many patients with JME need relatively low levels of anticonvulsants to achieve adequate seizure control (as long as it is an appropriate medication for the syndrome).

Special considerations in pregnant women

All women of childbearing age who are taking anticonvulsants should also take folic acid 1 mg/d. It is also beneficial to provide counsel regarding pregancy planning so that adjustments to an antiepileptic drug regimen can occur in anticipation of a potential pregnancy. As a general consideration, monotherapy is preferred to polytherapy, as is the minimal dose required to control the patient's seizures.

In general, most epileptologists believe that the anticonvulsants that help that patient the most should be continued during pregnancy. Frequent monitoring of drug levels is recommended, as pregnancy induces clinically significant changes in drug metabolism, clearance, and volume of distribution. Women with JME are no different from other women who need to take anticonvulsants.

A great majority of children born to women taking anticonvulsant monotherapy are healthy. Valproic acid and divalproex sodium, however, clearly pose a recognized risk of birth defects that is higher than the risk associated with other anticonvulsants. Exposure in utero probably contributes to neural tube defects (at a rate of 10–20 times the general population) and facial clefts, possibly contributes to hypospadias, and potentially impacts cognition. Multiple studies have shown valproic acid inferiority in comparison to other ASMs. VPA is not the drug of choice in women of childbearing age, so levetiracetam or lamotrigine are typically used instead.

With regards to topiramate, data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry reported that the prevalence of oral clefts was 1.1% for infants exposed to TPM in the first trimester of pregnancy, versus 0.12% in the unexposed reference group.[57]  The NAAED Pregnancy Registry also reported a prevalence of 19.7% for small-for-gestational-age newborns exposed to TPM in utero versus 5.4% for newborns without exposure.

Experience is limited with levetiracetam (category C), with one larger prospective database following 197 patients finding no detectable increased fetal risk. Greater data is available with lamotrigine. The North American AED Pregnancy registry prospectively found no increased risk of major congenital malformations; a 10.1 fold risk of cleft palate was noted, however it should be noted that the study included montherapy and polytherapy.[57]  This has failed to be replicated in larger prospective monotherapy reports. The United Kingdom pregnancy registry, a prospective database of 1151 patients on lamotrigine monotherapy, found no significantly increased risk of major congenital malformations or cleft palate.[58]

Surgical Care

Surgical treatment is not indicated, because juvenile myoclonic epilepsy (JME) is a primary generalized epilepsy. Some uncontrolled studies have suggested that vagus nerve stimulation (VNS) might be helpful for patients with intractable seizures of primary generalized onset, such as JME. VNS may have similar or better efficacy in IGE as compared to focal epilepsy, but this is an off-label use in the United States.[63]

Modification of Activity

Seizure precautions include warnings about unpredictable lapses of consciousness due to seizures during a variety of activities, including the following:

Such precautions, including restrictions on driving, must be observed until seizures that impair consciousness are controlled (ie, the patient is seizure free) for the recommended period—typically 3-12 months, though the length varies from state to state in the United States. Patients with seizures cannot have a commercial driving license until they complete a seizure-free period of 5 years. In addition, patients with seizures are not permitted to fly aircraft.

Studies have shown that patients with JME experience decreases in quality of life similar to those experienced by patients with other epileptic syndromes.[59]

Patients with suspected seizures manifesting as lapses of consciousness during wakefulness should be educated and warned about seizure precautions. Documenting on the patient’s chart that driving and occupational hazards for people with seizures were discussed is helpful. Physicians should be aware of state regulations regarding driving, which vary considerably among states and nations.

Warnings should be tailored to each specific patient, and they should include factors such as seizure control, time of the occurrence of seizures, medication compliance, and the patient’s occupation, among other concerns.

Consultations

Juvenile myoclonic epilepsy (JME) is rarely diagnosed in the primary care setting. Most often, an epileptologist diagnoses and manages the condition, sometimes unfortunately after several years of inadequate treatment with medications such as carbamazepine or phenytoin.

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and prevent complications.

The US Food and Drug Administration (FDA) has not approved any anticonvulsant solely for the treatment of juvenile myoclonic epilepsy (JME). In 2006, the FDA approved the adjunctive use of levetiracetam for the treatment of JME. Divalproex sodium has been approved as adjunctive therapy for patients with multiple seizure types that include absence seizures. However, many patients with JME do not have absence seizures.

In most patients with JME, seizures are well controlled with monotherapy. Valproic acid has been considered the treatment of choice for JME for many years, but epileptologists are increasingly using other choices as first-line therapies, including leviteracetam monotherapy. Approximately 90% of patients with JME become seizure free with valproate monotherapy.

Valproic acid

Clinical Context:  Increases levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. 

Generics are available in rapid-release capsules, oral solution, and IV formulations.

Studies of combination therapy suggest that in practice, patients starting divalproex monotherapy need a low starting dose and target doses close to about 10 mg/kg/d. In the elderly, clearance of unbound drug is decreased; lowered doses are needed. Children often require higher doses per weight than adults do; some children given combination therapy (with enzyme-inducing antiepileptic drugs [EIAEDs]) may need doses as high as 60 mg/kg/day.

Divalproex sodium (Depakote, Depakote ER, Depakote Sprinkles)

Clinical Context:  Divalproex sodium is indicated for monotherapy or adjunctive therapy in both focal-onset and generalized-onset seizures and adjunctively in many seizure types, including absence seizures. In clinical practice, it is often a first-line anticonvulsant in JME. It is metabolized to valproic acid. 

Depakote and generics are available as delayed-release capsules, tablets, and sprinkles.

Lamotrigine (Lamictal)

Clinical Context:  Lamotrigine is FDA-approved as monotherapy and add-on therapy in patients with focal-onset seizures and as add-on therapy only in patients with generalized tonic-clonic seizures and patients with Lennox-Gastaut syndrome (LGS); it is also indicated for conversion to monotherapy after failure of at least 1 enzyme-inducing antiseizure medication (eg, carbamazepine, phenytoin, phenobarbital). Several reports suggest that it is efficacious in JME and some of its seizure types; the present authors found benefit in some patients.

Lamotrigine is a well-tolerated anticonvulsant; it requires slow up-titration because of the risk of rash. It probably has fewer cognitive (ie, sedative) effects than most anticonvulsants do; some patients with JME have worsening of myoclonic jerks at low doses. In most patients, increasing the dose results in clinically significant improvement.

Serum concentrations of lamotrigine are useful in monitoring compliance and adjusting the dose; a few months into treatment, serum concentrations may decrease slightly because of enzymatic inducement in the liver. Conversion from enzyme-inducing antiseizure medications can be faster than recommended. Conversion from (or add-on therapy with) valproic acid requires slow titration because valproic acid inhibits metabolism of lamotrigine. Starting at high doses may increase the incidence of rash.

No IV formulation is available.

Topiramate (Topamax, Eprontia, Trokendi XR, Qudexy XR)

Clinical Context:  Topiramate is indicated and FDA-approved as monotherapy and adjunctive therapy for adults and children aged 2 years and older with focal-onset seizures or primary GTCSs. It is also approved as add-on therapy for patients with Lennox-Gastuat syndrome (LGS). Some patients with JME have primary GTCSs, but may also have myoclonic and absence seizures. Topiramate is available as 25-, 100-, or 200-mg tablets and as 15-. 25-, 50-, 100-, 150-, or 200-mg sprinkle capsules. An oral solution (Eprontia) is also available. Extended-release capsules (Trokendi XR) are available for children aged 6 years and older.

Zonisamide (Zonegran)

Clinical Context:  Zonisamide is indicated for adjunctive treatment of focal-onset seizures with or without secondary generalization. Evidence suggests effectiveness in myoclonic and other generalized seizure types as well.

It may stabilize neuronal membranes by acting at sodium and calcium channels. Zonisamide does not affect GABA activity.

Levetiracetam (Keppra, Keppra XR, Elepsia XR, Spritam)

Clinical Context:  Levetiracetam is indicated as adjunctive therapy for myoclonic seizures in adults and adolescents and in primary GTCSs in addition to the treatment of focal-onset seizures. Levetiracetam is also approved specifically as adjunctive therapy for JME. The medication comes in many forms including oral solution, tablet (extended release, short acting, and disintegrating), and IV. The mechanism of action is unknown but is presumed to involve binding to the SV2A site in synaptic terminals. 

Perampanel (Fycompa)

Clinical Context:  Perampanel is indicated as adjunctive treatment for patients with generalized tonic-clonic seizures aged 12 years and older. The medication is available as both a suspension and a tablet. It is a noncompetitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons. Glutamate is a primary excitatory neurotransmitter in the CNS and is implicated in various neurological disorders caused by neuronal overexcitation. 

Clobazam (ONFI, Sympazan)

Clinical Context:  Clobazam is indicated as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome (LGS), but can be used off-label as an adjunctive treatment for patients with refractory epilepsy as it is a broad spectrum antiseizure medication.

Class Summary

Anticonvulsants are the mainstay of therapy for JME. These agents are given to prevent myoclonic jerks or seizures, generalized tonic-clonic seizures (GTCSs), and absence seizures.

Author

Mona M Sonbol, MD, Resident Physician, Department of Neurology, University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Catalyst; Jazz; LivaNova; Neurelis; SK Life Science; Stratus; Synergy; UCB<br/>Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard, Xenon<br/>Received income in an amount equal to or greater than $250 from: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Catalyst; Jazz; LivaNova; Neurelis; SK Life Science; Stratus; Synergy; UCB<br/>Received research grant from: Cerevel Therapeutics; Ovid Therapeutics; Neuropace; Jazz; SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Longboard, Xenon<br/>Received income in an amount equal to or greater than $250 from: Catalyst; Ceribell; Jazz; LivaNova; Neurelis; Neuropace; SK Life Science; Stratus; Synergy; UCB.

Additional Contributors

Elizabeth Carroll, DO, Resident Physician, Department of Neurology, University of South Florida College of Medicine

Disclosure: Nothing to disclose.

James Selph, MD, Assistant Professor of Neurology, University of South Carolina School of Medicine; Director of Neurophysiology Lab and Services, Palmetto Richland Hospital

Disclosure: Nothing to disclose.

Jose E Cavazos, MD, PhD, FAAN, FANA, FACNS, FAES, Professor with Tenure, Departments of Neurology, Neuroscience, and Physiology, Assistant Dean for the MD/PhD Program, Program Director of the Clinical Neurophysiology Fellowship, University of Texas School of Medicine at San Antonio

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Brain Sentinel, consultant.<br/>Stakeholder (<5%), Co-founder for: Brain Sentinel.

Ramon Diaz-Arrastia, MD, PhD, Professor, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School; Director, North Texas TBI Research Center, Comprehensive Epilepsy Center, Parkland Memorial Hospital

Disclosure: Nothing to disclose.

Souvik Sen, MD, MPH, MS, FAHA, Professor and Chair, Department of Neurology, University of South Carolina School of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Mark Spitz, MD Professor, Department of Neurology, University of Colorado Health Sciences Center

Mark Spitz, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, and American Epilepsy Society

Disclosure: pfizer Honoraria Speaking and teaching; ucb Honoraria Speaking and teaching; lumdbeck Honoraria Consulting

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Findings in a man with a history of generalized tonic-clonic seizures (mostly nocturnal) and myoclonic jerks (mostly in the morning) since the age of 14 years. Carbamazepine exacerbated his myoclonic seizures. Sleep-deprived EEG was digitally recorded and then plotted by using an analog paper machine. The patient was getting drowsy when this burst of polyspike and slow wave was recorded.

Findings in a man with a history of generalized tonic-clonic seizures (mostly nocturnal) and myoclonic jerks (mostly in the morning) since the age of 14 years. Carbamazepine exacerbated his myoclonic seizures. Sleep-deprived EEG was digitally recorded and then plotted by using an analog paper machine. The patient was getting drowsy when this burst of polyspike and slow wave was recorded.