Continuing Education Activity
A seizure can be defined as abnormal, hypersynchronous discharge of cortical neurons, and epilepsy is defined as a propensity to have seizures. Idiopathic (genetic) generalized epilepsy is a subtype of generalized epilepsy and consists of childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone. This activity will review the diagnosis and management of idiopathic generalized epilepsy and highlights the importance of an interprofessional team in providing the highest standard of care for patients suffering from this disease.
Objectives:
- Review the latest International League Against Epilepsy classification system for epilepsy.
- Summarize the typical presentation of childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures.
- Identify the most commonly used antiepileptic drugs for this subtype of epilepsy.
- Outline interprofessional team members' roles in providing optimum care to patients with idiopathic (genetic) generalized epilepsy to enhance care coordination and improve clinical outcomes.
Introduction
The definition of a seizure is an abnormal, hypersynchronous discharge of cortical neurons, and epilepsy is defined as a propensity to have seizures.[1] A diagnosis of epilepsy is considered in the following circumstances:[2]
- Two unprovoked seizures more than 24 hours apart
- One unprovoked seizure but with a high recurrence risk (60% and over)
- A diagnosis of an epilepsy syndrome
The terminology and classification of epilepsy have undergone significant change in recent years with the revised International League Against Epilepsy (ILAE) classification of epilepsies in 2017, replacing the 1989 classification.[3] This update aimed to encompass scientific advancement and establish a viable clinical tool for the practicing clinician while remaining applicable for research and development of anti-epileptic therapies.
The classification now operates on a three-tier system with etiological factors considered in tandem throughout (e.g., structural, genetic, infectious, metabolic, immune, and unknown). The first step is defining the seizure type (focal, generalized, unknown). The second step is diagnosing the epilepsy type (focal, generalized, combined generalized and focal, and unknown), and the final step is whether a diagnosis of epilepsy syndrome can be made (conditions with recognizable features such as seizure type, imaging, and electroencephalography (EEG) features). This activity will focus on idiopathic (genetic) generalized epilepsy (IGE), one of the most well-recognized subgroups of generalized epilepsies. Idiopathic generalized epilepsy specifically refers to the epilepsy syndromes such as juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and generalized tonic-clonic seizures.[3]
Etiology
The classification of epilepsies by ILAE stresses that consideration of etiological factors should begin from the first seizure.[3] Six non-hierarchical etiological groups have been established, and patients can fit into more than one. The groups are as follows: genetic, infectious, structural, metabolic, immune, and unknown. Patients with idiopathic (genetic) generalized epilepsy, by definition, have no evidence of structural brain lesions on magnetic resonance imaging (MRI), as well as a lack of symptoms and signs interictally, eliminating most of the etiological groups.[4][5]
A genetic role has been suggested due to twin studies demonstrating higher concordance rates in monozygotic twins than dizygotic twins.[6][7] Research into CAE has implicated chromosomes 20q, 8q24.3, and 1p (CAE, which later evolved into JAE). Research into JME has found that susceptibility polymorphisms BRD2 in chromosome 6p21.3 and Cx-36 in chromosome 15q14 are associated with increased susceptibility of JME.[8][9][10] Despite this, it remains rare that a genetic mutation results in an individual’s diagnosis of epilepsy.[3]
Epidemiology
It is estimated that approximately 50 million people worldwide have epilepsy and that most of these patients do not have access to medical care.[11][12] Recent CDC surveys indicate that the prevalence of epilepsy is underestimated even in Western Countries. A systemic review and meta-analyses of studies worldwide found that the point prevalence of active epilepsy was 6.38 per 1000 persons, and the lifetime prevalence was 7.6 per 1000 persons. The prevalence of epilepsy did not differ between genders or by age group. Generalized seizures and epilepsy of unknown etiology had the highest prevalence.[13] Estimates of the incidence of generalized epilepsies in the United States are at 7.7 per 100000 person-years.[14] JME is the most common of the idiopathic (genetic) generalized epilepsies making up an estimated 3% to 11% of adolescent and adult cases of epilepsy.[15]
Pathophysiology
The pathophysiology of epilepsy basically depends on the etiological factor causing the abnormal discharge of cerebral cortical neurons. Thalamocortical interaction that results in typical absence seizures is the most clearly understood mechanism. An alteration in the oscillatory rhythm of the thalamocortical pathway can result in generalized-onset seizures. The primary channel involved is thought to be the transient low-threshold calcium channel (T-calcium) current. Disruption of this current can lead to depolarization and the onset of epileptic activity. Anticonvulsants suppressing T-calcium channels have been shown to prevent absence seizures. Anticonvulsants that increase the thalamocortical circuit's synchronization by increasing T-calcium current have been shown to worsen absence seizures in animal models.[16][17]
History and Physical
Childhood Absence Epilepsy (CAE)
CAE occurs in early childhood, with a peak onset between ages 4 to 7 years. It can occur before or after these ages, but onset is usually before age ten. It is characterized by typical absence seizures initially as the only seizure type. Typical absence seizures are brief (lasting 4 to 30 seconds) vacant episodes (loss of awareness and unresponsiveness) with impairment of consciousness associated with abrupt onset and cessation as well as behavioral arrest or staring with no post-ictal symptoms. There may be associated with orofacial automatisms. Absence seizures can be numerous, with hundreds of them happening per day. They can be induced by hyperventilation for 3 to 4 minutes. Clinical examination is normal.[5]
Juvenile Absence Epilepsy (JAE)
JAE occurs between the ages of 7 to 16 years, with peak onset between 10 to 12 years. The predominant seizure type is absence seizures. These may happen many times a day but is not typically as frequent as CAE. Automatisms occur more frequently (perioral or hand automatisms). Generalized tonic-clonic seizures infrequently occur in most patients, and a small proportion may experience myoclonic seizures. All seizure types are more common when the child is tired or unwell. Hyperventilation for 3 to 4 minutes can trigger an absence seizure but is less likely than CAE.[5]
Juvenile Myoclonic Epilepsy (JME)
JME is a common epilepsy syndrome occurring between the ages of 8 to 26 years, with a peak incidence between 12 and 16 years. It is characterized by three potential seizure types: myoclonic jerks (soon after wakening or when the individual is tired), generalized tonic-clonic seizures, and/or typical absence seizures. Myoclonic seizures are sudden, brief jerks affecting the arms, legs, face, or whole body. Generalized tonic-clonic seizures occur in roughly two-thirds of patients. They are more likely to happen in the morning, especially if the patient has woken up earlier than usual or had a late night the night before. Roughly one-third suffer from typical absence seizures, which are more likely to occur in the morning. Precipitating factors for all seizure types include fatigue, sleep deprivation, alcohol consumption, and up to 40% of patients are photosensitive. Clinical examination is normal.[5]
Generalized Tonic-Clonic Seizures
Patients with generalized tonic-clonic seizures alone present with generalized tonic-clonic seizures exclusively. The most common age group for onset is mid-teens, but onset can be earlier or later. They tend to occur shortly after waking (within 1 to 2 hours) but can occur at other times. Precipitating factors, similarly to JME, include sleep deprivation, fatigue, and excessive alcohol consumption. Physical examination is normal.[5]
Evaluation
Diagnosis of the IGE is primarily a clinical diagnosis based on a typical history with a lack of findings on examination (excluding possibly precipitating an absence seizure with hyperventilation). This has support from electroencephalogram (EEG) evidence. There is normal background activity with generalized spike-and-wave discharges interictally.[4] In CAE and JAE, there are high amplitude ictal spike-wave discharges (2.5 to 4 Hz) lasting longer than 4 seconds. JME characteristically demonstrates generalized spike-wave discharges at 3 to 6 Hz.[5][18] MRI imaging and neuropsychology evaluation will be normal.[5]
Treatment / Management
Treatment of IGE is centered around antiepileptic medication (AED) and patient education to promote an awareness of precipitating factors. The treatment goal is for satisfactory seizure control on minimal therapy, i.e., monotherapy. There are three first-line drugs in use: sodium valproate, ethosuximide, and lamotrigine.
Sodium valproate remains the most effective treatment for generalized seizures, with 75% of patients becoming seizure-free while only on this agent. It is also highly effective as adjuvant therapy. It has the additional benefit of preventing recurrence of absence status and being particularly useful in photosensitive patients.[5] It is associated with weight gain, hair loss, tremor, and gastrointestinal upset most commonly. These side effects are dose-dependent, however, and are reversible. The primary issue is its teratogenicity limiting its use in female patients who may require an AED for life, a particular problem when dealing with JME where it is particularly efficacious.
Ethosuximide is used to treat typical absence seizures and is nearly as effective as sodium valproate; however, it does not prevent generalized tonic-clonic seizures or myoclonic seizures, limiting its use mostly to patients with CAE. Side effects include weight loss, drowsiness, headache, and gastrointestinal upset. Behavioral changes can also occur, and side effects are usually dose-related.[5]
Lamotrigine is the other medication used first-line as it can control typical absence seizures and generalized tonic-clonic seizures with variable efficacy associated with myoclonic seizures. It is a favorable choice in female patients as it does not have the same teratogenic risk as sodium valproate. There is a risk of Stevens-Johnson syndrome, and dose escalation should be gradual. Sodium valproate inhibits its metabolism, so lower doses are required when co-prescribed. Common side effects include headache, gastrointestinal upset, dizziness, ataxia, and tremor. Other AEDs used include levetiracetam, clonazepam, and acetazolamide.[5]
Differential Diagnosis
Focal Epilepsy with Impaired Awareness
The primary differential diagnosis to consider when considering idiopathic (genetic) generalized epilepsy is focal epilepsy with impaired awareness, as this can have implications for treatment. Typical absences can be distinguished from focal seizures with impaired awareness (previously referred to as complex partial seizures) by several features. Typical absences are shorter duration, rarely prolonged, or complicated. They have no associated aura. They can be provoked by hyperventilation (in most cases), and automatisms, while associated with both, rarely involve the trunk or legs in typical absence seizures.[5] It is essential to enquire about aura before the onset of a generalized tonic-clonic seizure, as this could also suggest a focal onset. It is important to establish the possibility of focal onset. This could suggest underlying pathology, e.g., mesial temporal atrophy (which can be amenable to surgery) or a neuronal migration disorder.
Syncope
Syncope is an important condition to consider. It can be confused with generalized tonic-clonic seizures by eyewitness accounts as it can be associated with limb jerking and incontinence (albeit this is less common). Syncope has a distinctive prodrome of visual or auditory fading, nausea, diaphoresis, and pallor. It occurs mainly from standing, whereas seizures can happen in any posture. The episode is shorter, with quicker recovery not associated with the delayed postictal recovery seen with generalized tonic-clonic seizures. Cardiac conditions such as transient atrioventricular (AV) blocks, Brugada syndrome, and prolonged QT resulting in episodes of ventricular tachycardia or ventricular fibrillation, can occur. They should merit consideration in all patients who have had a collapse. Attacks may occur during exercise and can be preceded by palpitations, chest pain, and presyncope symptoms. An electrocardiogram is necessary in all cases where a patient has presented with a loss of consciousness.
Non-epileptic Attack Disorder
Non-epileptic attack disorder is something that clinicians should bear in mind when assessing patients with suspected seizures. It is most common in women and between the ages of 15 and 35. The motor component of the attack can often be associated with flailing asynchronous movements, with side-to-side head movement and pelvic thrusting being common. Patient’s eyes usually remain closed in comparison to generalized tonic-clonic seizures where they are open. There may also be resistance to eye-opening. The episodes can be prolonged, wax and wane, and have abrupt cessation as opposed to generalized tonic-clonic seizures, which abate slowly.
Prognosis
The prognosis for CEA is very good, with most children (80% to 90%) achieving remission by 12 years of age. Typical absence seizures are responsive to one or two AEDs in most cases. Prognosis becomes less favorable depending on how it is defined (particularly age of onset) and whether other seizure types develop. However, there is debate regarding whether these cases represent one of the other idiopathic (genetic) generalized epilepsies such as JAE or JME.[5] As with CEA, a high proportion of patients with JAE achieve seizure freedom (over 80%) with appropriate treatment. However, epilepsy is usually lifelong, with no significant medication-free remission expected to occur. JME is also considered lifelong epilepsy with a tendency for relapse after drug withdrawal. However, it is controllable with appropriate therapy. Some research has suggested that the manifestation of an additional absence seizure at onset is a predictor for an unfavorable outcome.[5][15][19]
Complications
Status epilepticus is defined as a seizure lasting more than five minutes or two or more seizures occurring within short succession (5 minutes) without complete recovery between seizures. It can happen in all forms of epilepsy and can be convulsive or non-convulsive. Convulsive status is uncommon in idiopathic (genetic) generalized epilepsy and responds rapidly to treatment with IV benzodiazepines. Non-convulsive status epilepticus is more common in idiopathic (genetic) generalized epilepsy and characteristically demonstrates frequent episodes of absence seizure with a clear onset and offset, with associated myoclonus being common. It often terminates with a generalized tonic-clonic seizure. Non-convulsive status epilepticus also responds rapidly to treatment with IV benzodiazepines.[20]
Sudden unexpected death in epilepsy (SUDEP) are deaths that are not attributable to any specific medical condition, trauma, drowning, or status epilepticus. The underlying cause of this remains unknown, but some studies have suggested that the risk of SUDEP was lower in idiopathic/cryptogenic epilepsy when compared to symptomatic epilepsies. Furthermore, research has determined that female patients are less at risk for this complication.[21]
Deterrence and Patient Education
A diagnosis of epilepsy means an individual will need to make adjustments to their life. It is a lifelong disease with well-known precipitant factors and a need for strict medication compliance. Patients and family members require education on safety precautions, along with lifestyle training such as showering rather than bathing, avoiding unprotected heights, and unsupervised areas of water. They require counseling on sleep hygiene as a poor night’s sleep will increase the likelihood of seizure. Thye should be counseled against alcohol consumption as well as other illicit drug use at every visit. Driving restrictions vary depending on the country or region they reside in, and patients and parents will need to understand the reasoning for this restriction. In some cases, they may need to contact their local motor vehicle authorities.
Enhancing Healthcare Team Outcomes
Idiopathic (genetic) generalized epilepsy requires an integrated approach by an interprofessional care team to provide optimal care to patients. Patients with absence seizures can pose a particular diagnostic challenge. They may present via a more convoluted route after initial concerns raised about reduced performance in school due to frequent absence seizures. A high index of suspicion is required by primary care providers in the communities, including primary care clinicians, school nurses, and social workers so that patients with this disorder are identified early. The hope is that the latest ILAE classification of epilepsies will help facilitate care delivery outlined above and improve research in the future. The classification was born from extensive peer-reviewed scientific evidence since the previous iteration in 1989. It was submitted for public scrutiny in 2013 and incorporated feedback from experts in epileptology internationally.[2][3] [Level 1]
Once the diagnosis is made, the patient needs regular follow-up with the neurologist and primary care clinicians. Care coordination between medical providers can help decrease complications and ensure optimal treatment. Social workers can help identify barriers to optimal clinical care and communicate these findings to the clinical team. Specialty-trained nurses should provide education on safety precautions, medication compliance, and monitoring for adverse outcomes. The clinical pharmacists augment this role by educating the patient and family on possible adverse reactions of AEDs and communicating these findings to the clinical team if they occur. Simple dose adjustments can be made to ensure adverse outcomes are minimized, which will, in turn, increase compliance with therapy.
With ongoing treatment, the patient will need a reliable first port of call with future day-to-day questions relating to their epilepsy diagnosis and treatment. Nurses play this critical role and help establish a strong patient medical professional relationship to promote better patient care. They can also assess medication compliance and observe for any adverse reactions to medications at follow-up visits. Pharmacists can assist the clinical team during long-term care with drug level monitoring and checking for drug-drug interactions. Open communication in an interprofessional team will lead to optimal therapy and outcomes. [Level 5]
Idiopathic (Genetic) Generalized Epilepsy