Genetic Generalized Epilepsies

It has long been understood that many types of epilepsy have a genetic component, and specific pathogenic variants have been identified for some syndromes (See Tuberous Sclerosis Complex in this issue). There is a five- to tenfold increased risk of genetic generalized epilepsies (GGEs), also termed idiopathic generalized epilepsy,¹ in first-degree relatives of people with these conditions.^2-3 Further evidence of a genetic cause for these epilepsies is the significantly higher concordance rate in monozygotic vs dizygotic twins.⁴ With the GGEs, however, the inheritance pattern is not a simple Mendelian pattern of autosomal dominant/recessive or X-linked, but rather is complex and likely involves epigenetic influences and polygenic etiology. As a result, although pathogenic variants in specific genes are rarely identified, the diagnosis of GGEs remains electroclinical and is essential for appropriate treatment selection, monitoring for comorbidities, and counseling families and patients.⁵

On EEG, these conditions typically have normal background activity with interictal generalized epileptiform discharges. Typically, children with GGEs do not have intellectual disabilities or neurodevelopmental delays. Neuroimaging studies are almost always unremarkable with no visible structural lesions. Genetic testing is rarely confirmatory and usually negative because of the complex inheritance of these conditions. GGEs are differentiated by seizure semiology, seizure triggers, specific EEG patterns, age at onset, and the likelihood of spontaneous remission.^1,5

This article covers the diagnosis and management of GGEs, which together are thought to account for 15% to 20% of all epilepsy.⁶ The GGE syndromes include childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), epilepsy with generalized tonic-clonic seizures (GTCs) alone, and epilepsy with eyelid myoclonia.

Clinical Presentation, Course, and Prognosis

CAE Presentation, Course, and Prognosis

CAE onset is usually between age 4 and 8 years. Absence seizures in CAE can be very brief, lasting a few seconds to half a minute, during which a child may seem to suddenly lose and then regain awareness. Oral automatisms may be present, and seizures often can be provoked by hyperventilation. Usually there are no postictal symptoms. GTCs rarely occur in CAE, usually a few years after onset; in some cases, the appearance of GTCs may indicate a conversion from CAE to JME.^1,7 There may be diagnostic delay and difficulty with CAE because the brief absence seizures may be perceived by parents, teachers, and caregivers as daydreaming or attention problems. By the time of presentation, seizures may be occurring hundreds of times per day.⁵ Most CAE is responsive to pharmacologic treatment and self-limited, with the majority of affected individuals being able to wean off antiseizure medications (ASMs) by adolescence.⁷

JAE Presentation, Course, and Prognosis

In contrast to CAE, onset of JAE is typically in adolescence (age 12-18 years). Brief absence seizures with few postictal symptoms are present but usually less frequent, occurring a few times per day or less, and sometimes with less loss of awareness.⁸ GTCs, however, occur more often in JAE (50%-80% of cases).⁹ Also in contrast to CAE, the seizures of JAE are more likely to be refractory to treatment with ASMs (<50%), and lifelong treatment with ASMs is almost always required.^9-11

JME Presentation, Course, and Prognosis

Onset of JME is also between 12 and 18 years and, although absence seizures and GTCs may occur, the typical seizure type is myoclonic jerks that are most often present in the morning. As with absence seizures, these brief jerks may not initially be recognized as seizures, with individuals being considered “clumsy” or “not morning people” or even evaluated for tremors because the myoclonic jerks lead to dropping things. Seizures in JME may often be provoked by sleep deprivation, flashing lights, or alcohol use,¹² all of which may be difficult for people with JME to avoid without affecting their quality of life, particularly around the time of onset. Most often, JME seizures are responsive to treatment with ASMs; however, as in JAE, lifelong treatment is required in 80% or more of cases.^10-12

Epilepsy With GTCs Alone Presentation, Course, and Prognosis

Onset of epilepsy with GTCs alone has been seen from age 5 to 41 years, although there is discussion of whether this comprises a single or multiple type(s) of epilepsy based on age.¹³ By definition, GTCs are the only seizure type that occurs in epilepsy with GTCs alone. Some individuals with epilepsy with GTCs alone have seizures only on awakening,¹⁴ which has also been proposed as a separate diagnostic entity. Response to treatment with ASMs occurs in approximately two-thirds of cases, and it is unclear whether the condition is self-limited.¹³ Typically, ASMs are not discontinued, but in a study of 26 children with mean onset at age 5 years, 16 were weaned of ASMs and all remained seizure free for 2 to 9 years of follow-up.¹³

Epilepsy With Eyelid Myoclonias Presentation, Course, and Prognosis

Epilepsy with eyelid myoclonias, also termed Jeavons syndrome, has onset from age 1 to 16 years and is less common than the other GGEs discussed. The hallmark of epilepsy with eyelid myoclonias is seizures consisting of brief episodes of eyelid fluttering; these may occur hundreds of times per day, can often be provoked by voluntarily closing the eyes, and are usually photosensitive. Other seizure types are frequently present, including GTCs and absence seizures.^14,15 The absence seizures and GTCs can usually be controlled with ASMs, but the eyelid myoclonia is typically pharmacoresistant.^14,15 Mild-to-moderate intellectual disability is present in 23% to 35% of cases, and this is usually more severe when certain pathogenic variants are present (see Genetic Testing).^16-18

Diagnosis

The diagnosis and differentiation of GGEs are electroclinical. Genetic testing only rarely identifies causative pathogenic variants, and the complex inheritance patterns observed suggest polygenic and epigenetic factors are key elements in the etiology of GGEs.⁴ As noted, neuroimaging studies are usually normal, and these are warranted only when intellectual disability, pharmacoresistance, or an atypical course of disease are present. Similarly, genetic testing is needed only in specific situations (see Genetic Testing).

Clinical History and Examination

Careful history taking is required to elicit both seizure semiology (eg, absence, GTCs, myoclonic jerks, or eyelid flutters) and understand which seizures occur most commonly in any individual. The age of onset should be carefully assessed considering that, as described, seizures may not initially have been recognized as such. When seizures most often occur and whether they are provoked is also essential to learn. Having the patient voluntarily close their eyes or hyperventilate for up to 3 minutes to see if a seizure is triggered has diagnostic value.

EEG

Anyone with suspected GGE should have an EEG study because the pattern of epileptogenic discharges during seizures and interictal spikes differs among the GGEs (Table 1). Additionally, photic stimulation, voluntary eye closIng, and hyperventilation in young patients with predominantly absence seizures should be included in the EEG study. If a GGE is suspected and a first EEG study is not diagnostic, a sleep-deprived EEG may help differentiate GGEs from focal epilepsies. In CAE, there are 3-Hz spike-wave discharges during absence seizures,^8,19 whereas in JAE, spike-wave discharges during absence seizures are at 4 to 5 Hz.⁸ In JME, there are high-amplitude spike-wave and polyspike-wave bursts during myoclonic seizures.¹² Generalized interictal spike-wave fragments occur in CAE, JAE, JME, and epilepsy with GTCs alone.^8,12,13,19 Interictal polyspike-wave fragments are also commonly observed in JAE and JME. Generalized 3 to 6 Hz spike-wave and polyspike-wave, as well as fixation-off sensitivity, is seen in epilepsy with eyelid myoclonia.¹⁴

Genetic Testing

Pathogenic variants in SLC2A1, which encodes glucose transporter type 1 (GLUT1), are present in 10% of children with absence epilepsy that has onset before age 4 years; genetic testing should be considered for all children this young with primarily absence seizures.²⁰ Chromosomal microarray may also be useful because some common copy variants are risk factors for CAE.²¹ Although monogenic inheritance for several genes has been associated with epilepsy with eyelid myoclonias (eg, CHD2, SYNGAP1, or KCNB1) or JME (eg, GABRA1),^17-19 testing for these with epilepsy gene panels is not necessary unless atypical features, developmental impairments, or neuropsychiatric decline occurs.

Treatment and Counseling

ASMs

ASMs most commonly used for the GGEs are summarized in Table 2. Valproic acid is a first-line treatment for all the GGEs,^{9,12-14,22,23} although use may be limited by concern for side effects as well as teratogenicity or neuropsych-iatric effects on the fetus of a childbearing person taking this medication.^24,25 Teratogenicity should be discussed with caregivers and with patients as soon as appropriate, and even before menarche because later decisions will be affected for individuals with childbearing potential. This is particularly important for JAE, JME, epilepsy with GTCs alone, and epilepsy with eyelid myoclonias, which all often require lifelong ASM treatment as discussed.

For CAE, ethosuximide is also a first-line agent that is often tried before valproic acid because of better tolerability.²² When ethosuximide does not control seizures, levetiracetam or clobazam are options if there is a desire to avoid valproic acid.²³ However, because treatment is typically time-limited in CAE, valproic acid may be a reasonable treatment option even in those who may later become pregnant.

If treatment with ASMs does not control seizures in CAE, genetic testing including SLC2A1 (ie, GLUT1 deficiency) should be considered. The ketogenic diet is a first-line treatment for GLUT1 deficiency, which usually does not respond to ASMs.²¹

Levetiracetam and lamotrigine are second-line agents for JME and epilepsy with GTCs alone. However, sodium channel blockers, including lamotrigine, oxcarbazepine, and carbamazepine should be used with caution as these may worsen seizures in JME or even cause myoclonic status epilepticus in some patients.²³

Second-line agents for JAE, epilepsy with GTCs alone, or epilepsy with myoclonias include ethosuximide, levetiracetam, lamotrigine, topiramate, and clobazam. Phenytoin, carbamazepine, oxcarbazepine, gabapentin, pregabalin, and vigabatrin may exacerbate seizures in JAE, epilepsy with GTCs alone, and epilepsy with eyelid myoclonias.^23,26

Counseling

Patients, families, and caregivers should be educated and counseled about inciting events that can be avoided (ie, light stimulation, sleep deprivation, alcohol consumption, and hyperventilation). Avoiding these triggers may be difficult, especially for adolescents and young adults. Adherence to treatment may be encouraged with discussions about the importance of seizure control for desired activities such as driving. As noted, discussions about eventual desires for a family should be had with anyone considering treatment with valproic acid who may decide choose to carry a pregnancy at some point.

Any support needs in school and work environments should be documented and education about seizure first-aid provided. Education about sudden unexplained death in epilepsy (SUDEP) is also paramount. Education about SUDEP should both inform families, caregivers, and patients (when age appropriate) that it is a rare possibility (approximately 1 in 1,000) that is also potentially preventable and may increase with the GGEs, moreso when GTCs are present or if seizures are pharmacoresistant.^27,28

Summary

Different GGEs are both common and rare and together account for 15% to 20% of epilepsy. Diagnosis is electroclinical with an EEG study and careful evaluation of seizure types and patterns, and age at onset. CAE is the only GGE that is usually self-limited, resolving by adolescence in the majority of cases. Pharmacoresistance, developmental delay, intellectual disability or regression, and atypical patterns warrant further evaluation with neuroimaging and genetic testing. Treatment with ASMs usually controls seizures in CAE and JME, although it is needed lifelong for JME typically. Response to ASMs occurs less often for epilepsy with GTCs, JAE, and epilepsy with myoclonias. Patient and family education and counseling are also essential parts of managing GGEs; topics should include factors that can provoke seizures, ASM side effects and teratogenicity, treatment adherence, school and work accommodations, seizure first aid, and the relative risk of SUDEP.