Continuing Education Activity

A seizure can be defined as transient signs and symptoms associated with 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. It is estimated that as many as 50 million people are affected by epilepsy worldwide.

The pathophysiology of epilepsy will depend on its etiologic factor with thalamocortical interaction being the most understood. Diagnosis of epilepsy is primarily clinical based on typical history and lack of neurologic findings in the interictal state, with electroencephalogram (EEG) as supportive evidence.  Treatment strategies will vary on etiology, as well as the side effect profile of medications and other treatment modalities.  This activity will review the diagnosis and management of idiopathic generalized epilepsy and highlight 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 causing transient signs and symptoms. Epilepsy is brain disorder "characterized by an enduring predisposition to generate epileptic seizures and by the neurobiologic, cognitive, psychological, and social consequences of this condition. The definition of epilepsy requires the occurrence of at least one epileptic seizure."[1][2] A diagnosis of epilepsy is considered in the following circumstances:[3]

• Two unprovoked seizures more than 24 hours apart
• One unprovoked seizure but with a high recurrence risk (such as abnormal baseline EEG)
• 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.[4] This update encompasses scientific advancement and establishes a viable clinical tool for the practicing clinician while remaining applicable for research and development of anti-epileptic therapies. 

The new classification defined by the 2017 ILAE Seizure Classification operates on a three-tier system. The first tier is the location within the brain of the epileptogenic focus.[5] 

Focal Seizures have origins  “within networks limited to one hemisphere. They may be discretely localized or more widely distributed. Focal seizures may originate in subcortical structures.”[5] Focal seizures can be further subclassified according to the following:

1. Motor onset or non-motor onset[5]

• Motor:(with subgroups of automatisms, atonic, clonic, myoclonic, epileptic spasms, hyperkinetic, tonic) 

  • automatism: coordinated, purposeful, repetitive motor activity. A common example is lip-smacking.  
  • atonic: focal loss of tone
  • clonic: focal rhythmic jerking
  • myoclonic: irregular brief focal jerking
  • epileptic spasms: focal flexion or extension of arms with flexion of trunk, 
  • hyperkinetic: activities such as pedaling or thrashing
  • tonic: sustained focal stiffening
• Non-motor (with subgroups autonomic, behavior arrest, cognitive, emotional, sensory).

  • autonomic: a sense of heat or cold, flushing, gastrointestinal sensations, a sense of heat or cold, piloerection (goosebumps), palpitations, sexual arousal, respiratory changes, or other autonomic effects.      
  • behavior arrest: behavioral arrest as the predominant aspect of the entire seizure.
  • cognitive: the patient reports or exhibits deficits in language, thinking or associated higher cortical functions. Examples can also be a feeling of deja vu, jamais vu, hallucinations, or illusions.
  • emotional: emotional changes, such as fear, anxiety, agitation, anger, paranoia, pleasure, joy, laughing (gelastic seizure), or crying (dacrystic seizure). These are often subjective.
  • sensory: somatosensory sensations, such as olfactory, visual, auditory, hot or cold feeling, taste, or vestibular sensations.

2. Intact or non-intact awareness (a surrogate marker for consciousness). Awareness means consciousness during the seizure, not being aware that a seizure has occurred. Impairment of awareness at any point constitutes non-intact awareness. Responsiveness is not a classification criterion by ILAE as focal impaired consciousness seizures can be associated with alertness and responsiveness to commands.

3. Focal to bilateral tonic-clonic. This replaces the term "secondarily generalized tonic-clonic." "Bilateral" describes how the seizure propagates as opposed to "generalized" which describes generalized onset of the seizure location.[5]

Generalized onset seizures have origins “originating at some point within, and rapidly engaging, bilaterally distributed networks."[5] Most generalized seizures are associated with impaired consciousness, so this is a descriptive criterion. They are classified as motor or non-motor. As many seizures evolve into tonic-clonic, it is important to characterize the beginning of a seizure in detail. If a certain type of seizure only occurs when generalized (such as absence seizures), the "generalized" may be omitted.

1. Motor (tonic-clonic, clonic, tonic, myoclonic, myoclonic-tonic-clonic, myoclonic-atonic, atonic, epileptic spasms). See above for a description of terms, and the following are identifying characteristics of specific types of generalized onset motor seizures:

• Tonic-clonic seizure replaces the previous term "grand mal seizure," and is the most recognizable type. If initiated by myoclonic activity, it is classified as myotonic-tonic-clonic. The clonic phase usually decreases over the seizure course. They may be preceded by an "aura" or feeling of impending doom or other autonomic activity, but this does not contribute to focality of the seizure.
• Generalized clonic seizures begin and end with sustained jerking of the head, neck, face, and trunk. This type is most commonly seen in infants.
• Tonic seizures involve sustained extension, less commonly flexion, of a muscle group. It should be distinguished from dystonia and athetoid movement caused by antipsychotic medications.
• Atonic seizures often cause a patient to fall forward or onto the buttocks. In contrast, generalized tonic-clonic seizures generally cause a patient to fall backward. 
• Epileptic spasms cause flexion or extension of proximal muscles and the trunk. They occur most often in clusters and in infants where they are called "infantile spasms."

2. Non-motor or absence (typical, atypical, myoclonic, eyelid myoclonia). The ILAE classification systems retain the distinction between typical and atypical generalized seizures because of different EEG patterns, therapy, and prognosis.[5]

• Typical generalized seizures with non-motor are commonly referred to as absence seizures. They present with sudden onset of cessation of activity, blank stare, and unresponsiveness. They usually last several seconds to half a minute. If performed during the event, EEG would show generalized epileptiform discharges.
• Atypical absence seizures are associated with increased muscle tonic behavior and less abrupt beginning and ending of the event. EEG during the event would show slow, irregular spike-and-wave activity at a rate of <3 per second.
• Myoclonic seizures are characterized by 3-per-second myoclonic jerks ratcheting the arm upwards and correspond to 3-per-second generalized spike-and-wave readings on EEG.
• Eyelid myoclonia are eyelid myoclonic jerks accompanied by upward eye deviation. If accompanied by EEG abnormalities with eye closure and photosensitivity, this triad is called Jeavons syndrome.[5]

Seizures of unknown onset. If seizures are unwitnessed or unable to be accurately described, they are given this designation. They can be motor, non-motor, or unclassified. [6] Unclassified refers to seizures without enough descriptive information to classify or those that do not fit into other categories. Often, this included tonic-clonic seizures for which the start is unwitnessed[5]

There can be significant overlap between the different classifications and differing bystander opinions about the clinical presentations; therefore, the above classifications are only a framework to define seizure origin and type. The recommended classification system first classifies seizures by location (local, generalized, or unknown); then by type of epilepsy disease (focal, generalized, combined, or unknown); and finally, if the seizure and epilepsy type are part of an overall epilepsy syndrome (eg, JME, CAE, JAE).[4]

The 2017 ILAE terminology introduces new terminology, such as developmental and epileptic encephalopathy.[4] Furthermore, the 2017 Classification also includes the following changes:

1. "Partial" becomes "focal";
2. Awareness is used as a classifier of focal seizures;
3. The terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated;
4. New focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional;
5. Atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; [5]
6. Focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure;
7. New generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; 
8. Seizures of unknown onset may have features that can still be classified.
9. Benign is replaced by the terms self-limited or pharmacoresponsive.[7]

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 epilepsy syndromes such as juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and generalized tonic-clonic seizures.[4]

Etiology

The new classification emphasizes etiology as instrumental for diagnosis, prognostic counseling, and management of epilepsy. This is also vital in determining the recurrence risk of single seizures and for making a diagnosis of epilepsy versus seizure from a cause other than underlying brain disorder.[8] These groups can be overlapping in patients with more than one contributing etiology, and etiology should always be considered in conjunction with classification. 

Etiology is broken into six subgroups:[4]

• structural
• genetic
• infectious
• metabolic
• immune
• 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.[9][10] Recently, a study identified the regulatory effects of cortical regions of basal ganglia and cerebellum among IGE patients and established possible links between the neuroimaging findings and epileptic symptoms.[11] 

A genetic role has been suggested due to twin studies demonstrating higher concordance rates in monozygotic twins than dizygotic twins.[12][13] Research into CAE has implicated chromosomes 20q, 8q24.3, and 1p. Research into JME has found that susceptibility polymorphisms BRD2 in chromosome 6p21.3 and Cx-36 in chromosome 15q14 are associated with increased susceptibility to JME.[14][15][16] Despite this, most epilepsy is not usually linked to known genetic mutations.[4] 

Another factor linked to idiopathic generalized epilepsies is sleep quality and architecture. Studies revealed that sleep deprivation and underlying abnormal sleep architecture are strong triggers for seizures. However, effective antiepileptic treatment can improve sleep architecture in addition to reducing seizure likelihood.[17][18] 

Epidemiology

It is estimated that 65 million people worldwide have epilepsy, and most of these patients do not have access to medical care.[19][20][21] 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 prevalence of active epilepsy was 6.38 per 1000 persons, and the lifetime prevalence was 7.6 per 1000 persons. The prevalence of epilepsy does not differ between genders or by age group. The most common types of seizures and epilepsy are generalized seizures and epilepsy of unknown etiology.[22] Estimates of the incidence of generalized epilepsies in the United States are at 7.7 per 100,000 person-years.[23] 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.[24]

Pathophysiology

The pathophysiology of epilepsy 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.[25][26]

The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei aid in the production of different firing patterns that affect the state of the brain. Particularly, the transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can lead to seizures which rapidly generalize. The study stressed that by studying the role of the thalamus in generalized epilepsy syndromes, there may be new opportunities to better treat pharmaco-resistant generalized epilepsy through thalamic modulation and dietary therapy.[27] Small studies have also shown that children with IGE have abnormal baseline cerebral blood flow compared to children without IGE which may be another potential therapeutic target.[28]

History and Physical

For most patients with IGE, clinical exam will be neurologically non-focal unless there is a structural abnormality that could act as an epileptogenic focus. Examples would be brain tumors or strokes causing corresponding neurological deficits. In addition, most children will show basic cognition equivalent to children without seizures, however, more detailed cognitive testing often reveals decreased higher cortical functions. Children with absence seizures especially tend to exhibit language deficits.[29][30] Studies reveal that a distinct neuropsychological profile consisting of impaired executive functions and reduced psychomotor speed with normal memory, previously described among patients with juvenile myoclonic epilepsy, is also manifested in all IGE patients.[31] In terms of external triggers, precipitating factors for all seizure types include fatigue, sleep deprivation, and alcohol consumption.[10]

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 (usually soon after waking or when the individual is tired), generalized tonic-clonic seizures, and typical absence seizures. Myoclonic seizures are sudden, brief jerks affecting the arms, legs, face, or whole body. Generalized tonic-clonic seizures occur in about two-thirds of patients. Roughly one-third suffer from typical absence seizures, which are more likely to occur in the morning.[10] About 30% of patients with JME show photosensitivity.[32] Family history of epilepsy is related to an earlier age of onset in JME patients.[33] It is thought that patients with IGE have normal cognitive function; however, JME patients have demonstrated lower advanced cognitive function tests than controls. Supplemental functional neuroimaging studies and higher cortical function testing should be done for comprehensive management.[29] The prognosis is good, with 85% to 90% of patients remaining seizure-free with one medication.[29]

Childhood Absence Epilepsy (CAE)

CAE occurs in early childhood, with a peak onset between 4 to 7, usually before age 10. Clinically, CAE patients experience staring and altered awareness. They usually have only absence seizures and fewer than 20 spells per day at the time of diagnosis. The hyperventilation test provokes seizures.[34] Typical absence seizures are brief (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. These episodes may be associated with orofacial automatisms.[10] EEG will show typical 3 Hz spike-and-wave pattern ictally. Ethosuximide is used as first-line treatment and is effective over 50% of the time. However, ethosuximide is ineffective against non-absence seizures, so valproate is the preferred medication if another type is also present. Poor prognosis includes EEGs that have abnormal baseline slowing and generalized-tonic-clonic or myoclonic seizures as well as absence seizures.[35]

If a child develops significant absence seizures before age 4 along with developmental delay and abnormal neurologic exam, the diagnosis of glucose transporter 1 deficiency syndrome (GLUT1 DS) must be considered. This entity responds well to a ketogenic diet.[35]

Juvenile Absence Epilepsy (JAE)

The age at onset of seizures differentiates CAE from JAE.[36]  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 are not typically as frequent as CAE. Automatisms occur more frequently (especially perioral or hand automatisms). Generalized tonic-clonic seizures infrequently occur, and a small proportion may experience myoclonic seizures. Hyperventilation can trigger an absence seizure but is less likely than in CAE.[10]

Generalized Tonic-Clonic Seizures

Generalized tonic-clonic seizures, formerly grand mal seizures, are described as seizures with a tonic phase followed by clonic muscle contractions. They arise within and rapidly affect the brain's bilateral cortical, subcortical, and brainstem networks.[37] The most common age of onset is mid-teens. They tend to occur shortly after waking (within 1 to 2 hours) but can occur at any time. Precipitating factors, similarly to JME, include sleep deprivation, fatigue, and excessive alcohol consumption.[10]

Evaluation

Diagnosis of IGE is primarily a clinical diagnosis based on history, however, many diagnostic tools also aid in the diagnosis. A brain MRI/MRA with contrast is standard for an initial seizure to rule out structural abnormality and visualize the meninges and vasculature. If there are any signs of infection, such as elevated WBC, fevers, nuchal rigidity, or an immunocompromised state, lumbar puncture (LP) should be performed. Preferably LPs should be done prior to antimicrobial administration, however, given significant morbidity and mortality of meningitis, treatment should not be delayed. The cerebrospinal fluid should be evaluated for WBC, RBC, microbiology, LDH, protein, and microbiology. Certain tests, such as for fungi or tuberculosis, may require additional lab requests and processing. Please see the companion StatPearls article on meningitis for further information.[38]

EEGs are very important in establishing possible epileptogenic foci and characterizing the type of epilepsy. EEGs show interictal epileptiform discharges in about 10% to 50% of patients on the first EEG, and sensitivity increases with the number of EEGs performed and test duration.[9][39][9] Current reviews emphasize the need for longer recordings, especially 24-hour ambulatory EEGs, that show discharges reflecting circadian and sleep-wake cycle-associated changes.[40]

IGE is characterized by generalized spike-and-wave complexes 2 to 5 Hz, usually with frontal prominence. Hyperventilation and photic stimulation increase EEG sensitivity in generalized, but not focal, epilepsy.[39]

In CAE and JAE, there are high amplitude ictal spike-wave discharges (2.5 to 4 Hz) lasting longer than 4 seconds. Recent reviews on CAE revealed interictal findings related to focal polyspike discharges.[41] JME characteristically demonstrates generalized spike-wave discharges at 3 to 6 Hz.[10][42] EEGs on patients with JME show photosensitivity about 30% of the time.[43] The presence of a polyspike train pattern is highly associated with drug-resistant IGE.[44] 

The development of advanced computational techniques to analyze EEG data has been helpful in identifying reliable and reproducible biomarkers of drug resistance in IGE patients. [45] Generalized Polyspike Train is may be used as EEG biomarker [46]  and found to be more prevalent among Drug-Resistant Idiopathic [44] 

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, preferably monotherapy. Currently, there are 26 FDA-approved antiepileptics, and 9 are commonly used for IGE.

Valproate monotherapy is commonly used for IGE with the exception of CAE where ethosuximide is preferred if exclusively absence seizures are present.[47] Topiramate is effective for generalized tonic-clonic seizures alone, while levetiracetam is effective for myoclonic seizures and is often used for IGE in women of childbearing age.[47][48]

Sodium valproate remains the most commonly used AED for generalized seizures, with 75% of patients remaining seizure-free on this alone. It has the additional benefit of preventing the recurrence of absence status epilepticus and is particularly useful in photosensitive patients.[10] Common adverse effects are weight gain, hair loss, tremors, gastrointestinal upset, and teratogenicity. It can also be hepatoxic and interacts with many medications.[47][49]

Ethosuximide is used to treat typical absence seizures; 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.[10]

Lamotrigine is also used first-line as it can control typical absence seizures as well as generalized tonic-clonic seizures with variable efficacy associated with myoclonic seizures. 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 tremors. Overall, ethosuximide and valproic acid are preferable to lamotrigine as initial monotherapy in CAE.[50]

Both carbamazepine and oxcarbazepine have been shown to worsen seizures in JME. However, carbamazepine has been used as an alternative treatment option for refractory IGE under close supervision, particularly for patients with generalized tonic-clonic seizures.[51][52]

Cenobamate was FDA-approved for focal-onset seizures in 2019 and has recently been found to reduce the frequency of attacks among patients with generalized epilepsy and combined generalized and focal epilepsy. Its proposed mechanism of action is blocking persistent sodium currents and increasing GABA-A activity.[53] 

Perampanel is a novel class of drug, an AMPA receptor antagonist, that decreases post-synaptic glutamate activity. Glutamate is the primary transmitter involved in generalization of seizures, so this AED class has significant therapeutic potential.  Currently, it is used for generalized tonic-clonic seizures and is generally well tolerated. Adverse effects include fatigue, dizziness, behavioral disturbances, and falls. Use in IGEs aside from GTC is still being studied.[54]

Other medications used in drug-resistant IGE include levetiracetam, clonazepam, and the recently approved brivaracetam.[10][55]

Resective surgery is not generally a potential treatment option for IGE due to a lack of a specific epileptogenic focus, so neuromodulation interventions have been used instead. The first neuromodulatory device used for epilepsy treatment is the vagus nerve stimulator procedure (VNS) which has been used for over 20 years in over 100,000 patients. It is thought to work by desynchronizing cortical activity and is well-tolerated among children with medically intractable primary generalized epilepsy.[56][57] Other neuromodulatory techniques. that are currently being studied include deep brain stimulation (DBS), responsive neurostimulation (RNS), and transcranial magnetic stimulation.[58] 

A ketogenic diet (high-fat, low carbohydrate, adequate protein) has been used to treat refractory seizures since at least 1921, and fasting has been noted to improve since the time of Hippocrates. Effectiveness is linked to decreased fluctuations in blood glucose, but the exact therapeutic mechanism is not completely understood. Proposed mechanisms include: mitochondrial regulation; effects of ketone bodies on neuronal function and neurotransmitter release; antiepileptic effects of fatty acids; membrane potential hyperpolarization; increased GABA synthesis; and decreased release of glutamate, norepinephrine, and adenosine. When experienced dieticians are involved, nutritional deficiencies are rare, and the primary obstacle is helping patients adhere to a strict diet. Although primarily studied in children, ketogenic diets have also been effective for intractable seizures in adults.[59][60]

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 seizures are usually short, with an abrupt start and stop, and no associated aura. They can often be provoked by hyperventilation and often are associated with automatism of the face. Up to 30% of initial seizures are misclassified, and EEGs can be very useful in differentiating seizure types.

Syncope

Lack of cerebral blood flow, such as with hypotension or cardiac arrhythmia, can often cause generalized tonic-clonic seizures but are not associated with underlying epilepsy. This is especially common if a patient is secured in an upright position when a syncopal event occurs, such as with a fastened seatbelt in a car. An electrocardiogram is necessary in all cases where a patient presents with a loss of consciousness.

Non-epileptic seizures 

An important distinction for IGE is the differentiation of true epileptic seizures from psychogenic nonepileptic seizures (formerly called pseudoseizures). Psychogenic nonepileptic seizures (PNES) are episodic motor, sensory, mental or autonomic manifestations resembling epileptic seizures but without corresponding neuronal activity on EEG. Patients often have a history of abuse or trauma, and this is considered a form of conversion disorder. PNES affects 20% to 30% of patients at epilepsy centers, and patients can be on high doses of AEDs with corresponding adverse effects. In addition, between 5% to 40% of patients with PNES also have epilepsy, further compounding the diagnosis.[61] Please see our companion StatPearls article "Psychogenic Nonepileptic Seizures" for further information.[62]

Absence Status Epilepticus

De novo late-onset absence status epilepticus (ASE) occurring during elderly with clinical and EEG features suggestive of late-onset IGE such as generalized tonic-clonic seizures, and myoclonic seizures. Late-onset IGE should be thoroughly evaluated by accurate clinical and family history taking aimed at identifying seizures. In elderly patients presenting with de novo late-onset ASE, a diagnosis of late-onset IGE should be considered in the differential diagnosis, especially among atypical cases including the absence of triggering factors, coexistence of generalized tonic-clonic or myoclonic seizures, and interictal generalized epileptiform discharges.[63]  

Jeavons Syndrome

Epilepsy with eyelid myoclonias, or Jeavons syndrome, may account for up to 13% of generalized epilepsies but is frequently under-reported and under-recognized. The diagnosis of this condition is usually delayed and typically presents as idiopathic generalized epilepsy manifested by the triad of eyelid myoclonia with or without absence seizures, eyelid closure-elicited EEG activity, and photosensitivity. Most patients develop medically refractory epilepsy and seizures that tend to persist throughout life.[64][65]

Prognosis

The prognosis for CAE is very good, with most children (80% to 90%) achieving remission by 12 years of age. Recent studies showed terminal remission after 27 years of treatment which, therefore, concluded that remission of IGE is primarily a function of time.[66] On the other hand, favorable long-term seizure outcomes in adult-onset IGE patients, as seen by the high rates of early remission pattern as compared to younger onset patients.[67] 

Typical absence seizures are responsive to one or two AEDs in most cases. Prognosis becomes less favorable if other seizure types develop. There is debate about whether these cases represent one of the other IGEs such as JAE or JME.[10] In CAE and JAE, more than 80% of patients achieve remission with appropriate treatment. 

Once patients have a significant seizure-free interval, neurologists often attempt to decrease or taper off AEDs to minimize adverse effects depending on the underlying epilepsy type and other clinical factors. The appropriate time to taper AEDs after a seizure-free interval is debatable and must be done with careful monitoring.

Complications

Seizures and epilepsy have signnificant associated morbidity. Recurrent seizures are associated with a 12-month follow-up of 40% to 60% risk of bodily injury such as burns, fractures, and concussions. This shows the importance of adequate seizure control.[21]

A dreaded complication of seizures is status epilepticus (SE) which is defined as seizure activity lasting longer than five minutes or two or more seizures occurring within 5 minutes without complete recovery between seizures. It can occur in all forms of epilepsy and can be convulsive or non-convulsive. Surprisingly, convulsive status is uncommon in IGE and responds rapidly to treatment with IV benzodiazepines. Non-convulsive SE is more common in IGE and characteristically demonstrates frequent episodes of absence seizures with a clear onset and offset, with associated myoclonus being common and often terminates with a generalized tonic-clonic seizure. Non-convulsive SE also responds rapidly to treatment with IV benzodiazepines [68] or valproate.[69] Convulsive SE is associated with clear mortality and is considered a medical emergency. The long-term effects of non-convulsive SE are less well-defined.

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.[70]

Drug-resistant epilepsy can serve as a challenge to review the initial diagnosis and consider alternative therapeutic strategies among. Refractory seizures are not only therapeutically challenging but can also serve as a cardinal sign that should not be ignored in syndromes commonly deemed drug-responsive, and the consideration of nonepileptic seizures must also be considered.[71][72] 

Deterrence and Patient Education

Epilepsy can be a lifelong disease with significant medical burdern and a need for strict medication compliance. The quality of life of IGE patients is associated with poor seizure control, psychiatric comorbidity,  unemployment, and other adverse outcomes.[73] 

Patients and family members require education on safety precautions, along with lifestyle training such as showering rather than bathing, and 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 a seizure. They 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.[74]

Enhancing Healthcare Team Outcomes

IGE requires an integrated approach by an interprofessional care team to provide optimal care. Patients with absence seizures can pose a particular diagnostic challenge. A high index of suspicion is required by primary care providers in the communities, including primary care clinicians, school nurses, and social workers for patients with this disorder to beidentified early. The hope is that the latest ILAE classification of epilepsies will help facilitate the care delivery outlined above and improve research in the future. 

Once the diagnosis is made, the patient needs regular follow-up with a neurologist and primary care clinician. Patients with IGE may have significant executive dysfunction in multiple domains. This requires screening for executive dysfunctions and a possible role for cognitive retraining.[75] 

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 assist the clinical team with drug-level monitoring and checking for drug interactions. Open communication in an interprofessional team leads to optimal therapy and outcomes.[Level 5]

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Disclosure: Matthew McWilliam declares no relevant financial relationships with ineligible companies.

Disclosure: Yasir Al Khalili declares no relevant financial relationships with ineligible companies.