Idiopathic Generalized Epilepsy


Article Author:
Matthew McWilliam


Article Editor:
Yasir Al Khalili


Editors In Chief:
David Wood
Andrew Wilt
Hajira Basit


Managing Editors:
Avais Raja
Orawan Chaigasame
Khalid Alsayouri
Kyle Blair
Radia Jamil
Erin Hughes
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Navid Mahabadi
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beenish Sohail
Hajira Basit
Phillip Hynes
Sandeep Sekhon


Updated:
9/7/2019 5:44:05 PM

Introduction

The definition of a seizure is an abnormal, hypersynchronous discharge of cortical neurons and epilepsy defined as a propensity to have seizures.[1] A diagnosis of epilepsy is considered in the following circumstances[2]:

  1. 1) two unprovoked seizures more than 24 hours apart
  2. 2) One unprovoked seizure but with a high recurrence risk (60 % and over)
  3. 3) 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), then 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 an epilepsy syndrome can be made (conditions with recognizable features such seizure type, imaging, and EEG features). This activity will focus on idiopathic generalized epilepsy (IGE), one of the most well-recognized subgroups of the generalized epilepsies. Idiopathic generalized epilepsy specifically refers to the epilepsy syndromes: juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), childhood absence epilepsy (CAE), and generalized tonic-clonic seizures alone.[3]

Etiology

The ‘classification of the 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 generalized epilepsy by definition have no evidence of structural brain lesion on MRI, as well as a lack of symptoms and signs inter-ictally, eliminating most of the etiological groups.[4][5] A genetic role has been a suggestion as a result of twin studies which demonstrated higher concordance rates in monozygotic twins in comparison to dizygotic twins.[6][7] Research into CAE has implicated chromosome 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

Estimates are that 50 million people worldwide have epilepsy, the majority of whom do not have access to medical care.[11][12] 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 sexes or by age group. Generalized seizures and epilepsy of unknown etiology had the highest prevalence.[13] Estimates of the incidence of the generalized epilepsies in the US are at 7.7 per 100000 person-years.[14] JME is the most common of the idiopathic generalized epilepsies making up an estimated 3 to 11% of adolescent and adult cases of epilepsy.[15]

History and Physical

Childhood Absence Epilepsy

CAE occurs in early childhood with a peak onset between ages 4 to 7. 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 occurs in between the ages of 7 to 16 with peak onset between the ages of 10 to 12. 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 (peri-oral or hand automatisms). Generalized tonic-clonic seizures infrequently occur in the majority of 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 to than with CAE.[5]

Juvenile Myoclonic Epilepsy

JME is a common epilepsy syndrome occurring between the ages of 8 to 26 with a peak incidence between 12 and 16. It is characterized by three seizure types: myoclonic jerks (soon after wakening 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/whole body. Generalized tonic-clonic seizures occur in roughly two-thirds of patients and 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 Alone

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 IGEs is primarily a clinical diagnosis based on a typical history with lack of findings on examination (excluding possibly being able to precipitate an absence seizure with hyperventilation); this has support from 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][16] MRI Imaging and neuropsychology will be normal.[5]

Treatment / Management

Treatment of IGE is centered around antiepileptic medication (AEDs) and patient education to promote an awareness of precipitants. 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, as well as 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 AED’s used include levetiracetam, clonazepam, and acetazolamide.[5]

Differential Diagnosis

The primary differential diagnosis to consider when considering idiopathic 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 as this could suggest underlying pathology, e.g., mesial temporal atrophy (which can be amenable to surgery) or a neuronal migration disorder.

Syncope is an important condition to consider as it can be confused with generalized tonic-clonic seizures by eye witness 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 associated with generalized tonic-clonic seizures.

Cardiac conditions such as transient AV blocks, Brugada syndrome, and prolonged QT resulting in episodes of ventricular tachycardia or ventricular fibrillation can occur and 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 presyncopal symptoms. An ECG is necessary in all cases where a patient has presented with loss of consciousness.

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. Often the motor component of the attack can 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 age 12. 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 as to whether these cases represent one of the other idiopathic 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, the 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 manifestation of additional absence seizure at onset are a predictor for an unfavorable outcome.[5][15][17]

Complications

Status epilepticus defines 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 generalized epilepsy and responds rapidly to treatment with IV benzodiazepines. Non-convulsive status epilepticus is more common in idiopathic 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.[18]

Sudden unexpected death in epilepsy (SUDEP) are deaths which 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.[19]

Deterrence and Patient Education

A diagnosis of epilepsy means an individual will need to make adjustments to their life. There are safety precautions of which everyone should be made aware. Patients will require lifestyle training of the following: having a shower is safer than a bath (in case of seizure), they should avoid unprotected heights and unsupervised areas of water, sleep hygiene is vital as a poor night’s sleep will increase the likelihood of seizure, and alcohol intake should be at a minimum. 

Patient’s relatives will require instruction on how to provide first aid to people having generalized seizures and when to call the emergency medical services.

There will be driving restrictions which vary depending on the country or region, and patients will need to understand this. They may need to contact their local motor vehicle authority themselves.

Enhancing Healthcare Team Outcomes

Idiopathic generalized epilepsy requires a vast array of healthcare professionals to provide optimal care to patients. Non-neurologists will be the first point of contact for the vast majority of patients as they will initially present to the emergency department after generalized seizures or to the GP with absence seizures or myoclonic jerks. Patients with absence seizures can pose a particular diagnostic challenge and may present via a more convoluted route after initial concerns raised about reduced performance in school as a result of frequent absence seizures.

Therefore, interprofessional communication skills are paramount. For the neurologist to make a diagnosis history is key, and consequently any referrals sent by other doctors should contain accurate accounts of what the patient or others told them or what they witnessed, including information about onset, prodrome or aura, a clear description of the event, its duration and how the patient was post-ictally. Families need to be encouraged to video future episodes to show the neurologist as this is invaluable and better than any first or second-hand description. Neurophysiologist technicians and doctors are the next part in the diagnostic journey performing and interpreting the EEG. After making a diagnosis, the neurologist can select an appropriate anti-epileptic drug. The patient will need a reliable first port of call with future day to day questions relating to their epilepsy. Nurses play this critical role and help establish a strong patient medical professional relationship to promote better patient care. They are also in a position to assess medication compliance and observe for any adverse reactions to medication; this is where a neuroscience specialty-trained nurse can be a great asset to the team. Pharmacists can provide advice about medication interactions and requirements for drug level monitoring in special circumstances, as well as checking for drug-drug interactions, which can have significant effects on therapy. Nursing and pharmacists need to report to the treating physician any concerns they encounter regarding compliance, treatment, or adverse reactions. Only with this type of open communication in an interprofessional team can these seizure patients obtain the optimal therapy and monitoring for their condition. [Level V]

The hope is that the latest ILAE classification of epilepsies will help facilitate the delivery of the level of care 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 the field of epileptology internationally.[2][3] [Level 1]


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Idiopathic Generalized Epilepsy - Questions

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A 5-year-old female was seen by a child psychology provider and noted to have features of attention-deficit/hyperactivity disorder (ADHD). Her mother reported that the child had intermittent periods of eye fluttering when upset. A pediatric neurologic provider evaluated the patient and started her on guanfacine. According to her mother, the patient started having episodes of staring lasting 8 to 15 seconds with prompt return to baseline. Her mother stopped giving the child guanfacine because of the staring episodes. An EEG was obtained which is shown below. What is the diagnosis?

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    Contributed by Arayamparambil Anilkumar MD
Attributed To: Contributed by Arayamparambil Anilkumar MD



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A 15-year-old boy presents to the emergency department with his mother after he was seen shaking for 2 minutes. Collateral history is provided by his mother, who describes that he was fine and then suddenly collapsed, let out a cry and dropped to the kitchen floor. He later became stiff with his arms flexed for about half a minute followed by rhythmic jerking of all four limbs for roughly two minutes. The jerking limb movements gradually abated. His eyes remained open throughout, but the mother was uncertain if his gaze was fixed in a particular direction or not. He was incontinent of urine. He remained drowsy for several hours after. Neurological examination and EKG were normal. What is the most likely cause of this episode?



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A 7-year-old boy presents to the clinic with his mother for frequent episodes of a sudden loss of awareness. The episodes can happen many times a day and are characterized by an abrupt cessation of activity and appearing vacant. The episodes end abruptly and rarely last more than 5 seconds. Occasionally he is noted to blink during these episodes. His neurological examination is normal. During activation testing (hyperventilation) he is noted to have one of his typical vacant episodes. What is the typical ictal pattern expected to be seen on the electroencephalogram (EEG)?



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A 24-year-old recently married nurse presents to the clinic for episodes of jerky movements. She has no significant medical history. She reports sudden jerking movements of her arms early in the morning while having breakfast. She often drops cups and plates as a result. She states this has been the case for several years and when asked what prompted this particular visit she said she had an episode the morning after her wedding whereby she fell to the floor, and her whole body shook for about 5 minutes. She had wet herself and bitten her tongue. Her partner had to call the ambulance. Neurological examination is normal. A CT scan of the head and routine blood tests were normal. Which of the following is the most appropriate medication that can be prescribed to this patient?



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A 7-year-old boy accompanied by his mother presents to the clinic after concerns were raised by his teachers. They report that he appears to be 'daydreaming' frequently. His mother is concerned that he is no longer progressing at the same rate as his classmates and fears he may have some sort of learning disability. Her pregnancy and delivery were normal. He has achieved all of the appropriate milestones to date. On examination, he is happy and friendly, making good eye contact and interacting well. It is noted that despite concerns regarding his performance, he is achieving and developing appropriately for his age. He has no focal neurological deficit, but an episode of vacancy occurs after hyperventilating for a few minutes. What is the most likely diagnosis?



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A 29-year-old female is brought in to the emergency department as a medical emergency with suspected status epilepticus. She has a prior medical history of type one diabetes, anxiety, depression, and hypothyroidism. She is brought in on high flow oxygen and an intravenous line in preparation for benzodiazepine administration. On examination, bizarre pelvic thrusting with asynchronous limb movement is noticed. The shaking appears to start and stop abruptly. Her pupillary response is checked, but there is resistance to eye-opening. What is the most likely diagnosis?



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A male patient with a history of previous left middle cerebral artery's territory infarct presents to the emergency department with suspected status epilepticus. On assessment, he is having a generalized tonic-clonic seizure and is centrally cyanosed. The best bystander estimate is that this has been going on for 10 minutes without intervention. Which of the following is considered first-line treatment for this patient's condition?



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A 14-year-old boy, known sleepwalker, presents to the clinic after two episodes of nocturnal enuresis. He also has become concerned that he is experiencing daytime somnolence. On further questioning, it was found that he had a painful tongue the morning after these episodes. He has occasionally been waking suddenly during the night but has not been sleepwalking these days. He has not noticed any jerky movements or vacant episodes. Neurological examination is normal. He is sent for an electroencephalography (EEG) which was noted to have a normal background with bursts of generalized spike-waves. While awaiting routine follow up he reports having an episode consistent with a generalized tonic-clonic seizure about 1 hour after getting up. Which of the following is the most likely diagnosis in this patient?



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Idiopathic Generalized Epilepsy - References

References

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Fiest KM,Sauro KM,Wiebe S,Patten SB,Kwon CS,Dykeman J,Pringsheim T,Lorenzetti DL,Jetté N, Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies. Neurology. 2017 Jan 17;     [PubMed]
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Duble SN,Thomas SV, Sudden unexpected death in epilepsy. The Indian journal of medical research. 2017 Jun;     [PubMed]

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