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Idiopathic Generalized Epilepsy

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The term idiopathic generalized epilepsy (IGE) is used to designate a group of epileptic conditions with a genetic etiology. Patients with IGE have otherwise normal development, don't present with any structural brain damage and usually have a family history of epilepsy.

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Presentation

Clinical manifestations of IGE depend on its subtype. The patient's history may point towards the diagnosis. Some of the syndromes of IGE overlap and therefore may be difficult to distinguish initially.

Benign myoclonic epilepsy in infancy manifests with mild jerks at the start, with their severity increasing progressively. Falls are quite uncommon in this subgroup. Head drops and deviation of the eyes in the upward direction are observed on a daily basis. Some of the patients present with myoclonus triggered by stimuli such as sudden noises or tapping. The degree of cognitive impairment is low, especially in children who respond well to treatment [10].

Generalized epilepsy with febrile seizures plus, an entity in evolution, represents a group of syndromes observed in several family members that have previously experienced febrile seizures. The condition presents with mild convulsions occasionally. Some patients present with seizures resembling the clinical presentation of myoclonic-astatic epilepsy or severe myoclonic epilepsy in infancy (Dravet syndrome). Genes involved in epilepsy may be uncovered by a proper analyses of families with generalized epilepsy with febrile seizures plus.

Epilepsy with myoclonic-astatic seizures (also known as Doose syndrome) is another form of IGE typically starting with a febrile seizure. Myoclonic-astatic seizures consist of symmetric myoclonic jerks followed by periods of absent muscle tone that can result in falls. In some patients, only head nodding may be observed. Absence or myoclonic absence seizures are most commonly observed in children.

Epilepsy with myoclonic absences is characterized by an alteration in consciousness accompanied by rhythmic myoclonic jerks and tonic contractions of the extremities, lasting for 8 to 60 seconds and occurring several times a day. The jerks may be symmetric or asymmetric while the tonic contractions occur primarily in the proximal regions of the arms [11].

Childhood absence epilepsy (or pyknolepsy) consist of changes in consciousness called absences. They may include memory, awareness or responsiveness problems as well as motor features such as automatisms, eye deviations, rhythmic muscle contractions or clonus of the eyelids. All these form a part of simple absence seizures. More massive motor manifestations constitute a part of complex absence seizures.

Juvenile myoclonic epilepsy is a form of IGE represented by myoclonic seizures. These typically occur in the morning with sudden dropping of objects and jerks located in the neck, shoulders, arms or legs. The extensors of the arm are the most frequently involved muscle groups. Falls as well as changes in consciousness are rare, although short absence seizures without automatisms are reported in 30% of the patients [12].

Epilepsy with generalized tonic–clonic seizures is a syndrome with wide range of clinical presentations. Seizures can appear at any time and are aggravated by sleep deprivation and alcohol abuse, similar to almost all other types of epilepsy.

Falling
  • Myoclonic-astatic seizures consist of symmetric myoclonic jerks followed by periods of absent muscle tone that can result in falls. In some patients, only head nodding may be observed.[symptoma.com]
  • Children with this disorder have incredibly brief ( 100ms) myoclonic jerks followed by equally brief loss of muscle tone, sometimes resulting in dangerous falls. Some patients have much longer lasting seizures of this type.[en.wikipedia.org]
  • Continue reading Fall colors. Just a brief summary of how this post originated. Eckernförde is a small city north of Kiel and the weekly Sunday destination of my daughter and me because of the wave pool.[epilepsygenetics.net]
  • Subjects were instructed to rest with their eyes closed, without thinking of anything in particular or falling asleep. After scanning, subjects were asked whether they had fallen asleep during the scan. Data Processing Preprocessing.[ajnr.org]
  • The seizures start with a loss of consciousness and a sudden contraction of the muscles, which can cause the person to fall down (tonic phase). This is followed by violent convulsions (clonic phase) until the muscles finally relax.[acnr.co.uk]
Seizure
  • All these form a part of simple absence seizures. More massive motor manifestations constitute a part of complex absence seizures. Juvenile myoclonic epilepsy is a form of IGE represented by myoclonic seizures.[symptoma.com]
  • The key secondary endpoint (primary endpoint for European Union registration) was 50% PGTC seizure responder rate (patients achieving 50% reduction in PGTC seizure frequency; maintenance vs baseline).[ncbi.nlm.nih.gov]
  • Unilateral seizures, or hemiconvulsive attacks, are motor seizures with tonic and/or clonic phenomena that involve only one side of the body.[ncbi.nlm.nih.gov]
  • JME first presents between the ages of 12 and 18 with prominent myoclonic seizures. These seizures tend to occur early in the morning. Patients with JME may also have generalized tonic-clonic seizures and absence seizures.[en.wikipedia.org]
  • Clinically, IGE is characterized by the occurrence of any of the following three seizure types: absence seizures, myoclonic seizures and primarily generalized tonic-clonic seizures.[ncbi.nlm.nih.gov]
Tonic-Clonic Seizure
  • seizures; for the use of adjunctive therapy with lamotrigine for the treatment of primarily generalized tonic-clonic seizures; and for the use of levetiracetam as adjunctive therapy for the treatment of myoclonic or primarily generalized tonic-clonic[ncbi.nlm.nih.gov]
  • IGE manifestations include absence seizures, myoclonic jerks and generalized tonic clonic seizures. These may appear alone or in various combinations from patient to patient.[symptoma.com]
  • The patient no longer complained of generalized tonic-clonic seizures. At one year follow-up, this patient receives zonisamide with valproate. She has remained seizure-free.[ncbi.nlm.nih.gov]
  • Correlations between total lifetime generalized tonic-clonic seizures and fractional anisotropy were investigated for both groups.[ncbi.nlm.nih.gov]
  • In this study, 26 patients with idiopathic generalized epilepsy characterized by tonic-clonic seizures and 26 age- and sex-matched healthy controls were recruited.[ncbi.nlm.nih.gov]
Myoclonic Jerking
  • IGE manifestations include absence seizures, myoclonic jerks and generalized tonic clonic seizures. These may appear alone or in various combinations from patient to patient.[symptoma.com]
  • Children with this disorder have incredibly brief ( 100ms) myoclonic jerks followed by equally brief loss of muscle tone, sometimes resulting in dangerous falls. Some patients have much longer lasting seizures of this type.[en.wikipedia.org]
  • IGEs manifest with typical absences, myoclonic jerks, and generalized tonic-clonic seizures, alone or in varying combinations and severity. Absence status epilepticus (ASE) is common.[epilepsy.com]
  • All 86 patients had generalized tonic-clonic seizures, and 17 had additional myoclonic jerks and absences.[ajnr.org]
  • In Gastaut’s series, 98% had nocturnal “grand mal” or tonic–clonic seizures alone, while absences or myoclonic jerks were exceptional. 6 In contrast we were able to identify six cases (18%) with myoclonic jerks and tonic–clonic seizures.[jnnp.bmj.com]
Confusion
  • Early onset of seizures and later recognized episodes of mild confusion before meals together with persistent atypical EEG features and unexpected learning difficulties led to the diagnosis.[ncbi.nlm.nih.gov]
  • Some patients with idiopathic/genetic generalized epilepsy (IGE) experience visual aura, which can confuse the diagnosis. We sought to determine the frequency and characteristics of visual auras in IGE patients.[ncbi.nlm.nih.gov]
  • This past Sunday, daylight saving and the fact that she didn’t like her dinner had confused the little girl, and we had been awake since 4AM. As a consequence, she fell asleep on the way, and I kept driving to let her sleep.[epilepsygenetics.net]
  • If you're confused or don't know what's happening during your seizure -- or don't remember it -- it's an impaired awareness seizure. These used to be called "complex partial seizures." Focal motor seizures.[webmd.com]
  • While the seizure generally only lasts a few minutes, the person will often feel confused or drowsy for a few minutes or up to a few days before returning to normal. [4],[6] Despite treatment, around 20% of people with idiopathic generalised epilepsy[acnr.co.uk]
Dizziness
  • For the safety analysis (placebo, 82; perampanel, 81), the most frequent treatment-emergent adverse events with perampanel were dizziness (32.1%) and fatigue (14.8%).[ncbi.nlm.nih.gov]
  • Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders.[ncbi.nlm.nih.gov]
  • […] week maintenance period when treated with perampanel as an adjunctive therapy, compared to 12% in the placebo group. [3] The adverse event profile is similar to that for other perampanel studies, the most common treatment-emergent adverse events were dizziness[acnr.co.uk]

Workup

Electroencephalogram (EEG) is the laboratory test of choice for the diagnosis of IGE. However, EEG does not always allow distinction between the different syndromes, especially the overlapping ones. EEG changes are usually non-specific, with specific changes attributed to the different subtypes occurring in some cases. EEG usually shows bilateral, synchronous generalized spike-and-wave (GSW) or polyspike-and-wave discharges with a normal background. Asymmetries or pseudofocalities may also be observed in some patients [13] [14] [15] [16].

Interictal EEG in benign myoclonic epilepsy in infancy is usually normal. Fast generalized spike or polyspike-wave discharges may be observed during the myoclonic episodes. The use of video-EEG is recommended for their recording [17].

In order to differentiate IGE from focal epilepsy with rapid secondary generalization, physical examination, EEG studies (interictal EEG, video EEG) or radiographic tests should be performed.

Generalized Epileptiform Discharges
  • Circadian variations of generalized epileptiform discharges are well described, and these can be useful in diagnostic confirmation.[ncbi.nlm.nih.gov]
3-4 Hz Spikes
  • 4 Hz spikes and waves in all regions of the brain 1 st -line : valproic acid Avoid triggers : sleep deprivation, alcohol, drugs, flickering lights 60% are seizure -free under treatment Transition to juvenile myoclonic epilepsy possible Juvenile myoclonic[amboss.com]
  • Her EEG showed 34 Hz spike and wave discharges. She had a daughter with childhood absence epilepsy, and two sisters and a cousin with seizures (fig 2 , family 1).[jnnp.bmj.com]
Polyspike-and-Slow-Waves
  • Bursts of 2–5 Hz spikes and waves or polyspikes; slow waves synchronous to atonic phase Background slowing with theta rhythm 70% remission with normal development and cognition 30% have an unfavorable prognosis ( status epilepticus, cognitive impairment[amboss.com]
  • EEG findings About half of patients had an abnormal EEG viz. spikes, polyspikes and slow waves. Stephan (2000) [25] had described similar observations in patients with JME.[annalsofian.org]
Spike-and-Slow-Waves
  • […] and slow waves during clonic phase 70% are seizure -free under treatment In some cases, no medical therapy is necessary avoid triggers Epilepsy with myoclonic-atonic seizures ( Doose syndrome ) 2–6 years Sex: Myoclonic and atonic (astatic) seizures Frequent[amboss.com]
  • Panayiotopoulos et al. (1994) [21] observed that 51.5% of patients had spike/multiple spike-slow wave discharges. In a study by Jain et al. (2003), [7] EEG was abnormal in 90% of drug-naïve JME.[annalsofian.org]
Occipital Intermittent Rhythmic Delta Activity
  • Other characteristic EEG features include polyspikes, polyspike-wave discharges, occipital intermittent rhythmic delta activity, and photoparoxysmal response.[ncbi.nlm.nih.gov]

Treatment

Different groups of antiepileptic medications are indicated in the management of IGE.

Valproate is the drug of choice for all IGE syndromes as it is effective for all types of seizures. However, valproate is not well tolerated by all patients. Moreover, valproate is considered as a teratogen. Pregnant woman or those planning pregnancy should use levetiracetam instead of valproate.

Drugs such as carbamazepine, oxcarbazepine and pregabalin, frequently used in focal and partial seizures, may aggravate absence seizures and/or myoclonus. They should, thus, be avoided in IGE syndromes with similar manifestations.

First-line drugs for childhood absence epilepsy include ethosuximide, valproate, topiramate or lamotrigine. Levetiracetam and zonisamide can also be used.

Treatment of IGE should always include patient counseling in order to establish and control the triggering factors for such seizures.

Prognosis

Although studies on the prognosis of IGE are lacking compared to other epilepsy syndromes, IGE seems to have a better prognosis. However, lifelong treatment may be necessary, especially in JME patients. With the aid of anti-epileptic drugs, JME patients usually achieve remission easily; however, on stopping the anti-epileptic medications, less than 20% of them remain in remission, thus highlighting the need for life-long treatment. A higher rate of remission has been observed in childhood absence epilepsy. Appearance of myoclonus or generalized tonic-clonic seizures is a poor indicator for remission. The social outcome in IGE patients may be unsatisfactory even with good seizure control. Using EEG as an indicator of prognosis is not entirely supported by studies. Research into accurately defining the prognostic criteria is ongoing.

Etiology

Although the mode of inheritance remains uncertain, at least two or more genes are likely to be involved in IGE inheritance. However, the exact genes have not been found yet. In different studies, mutations in α1 and γ2 GABA-A-receptor subunit as well as in CLC-2 voltage-gated chloride channel (CLCN2) gene have been identified [1] [2] [3].

It has been suggested that the mother has a greater role in the inheritance of IGE [4] [5].

Epidemiology

IGE represents 15-20% of all epileptic conditions.

IGE usually manifests between early childhood and adolescence with different ages of onset depending on the type of IGE. IGE affects otherwise healthy individuals. No major difference in sex and racial distributions of the condition are observed.

Juvenile absence epilepsy (JAE) and juvenile myoclonic epilepsy usually appear between the age of 10 and 18 years. There is however, a childhood form of JAE affecting children between 6 and 8 years.

Benign myoclonic epilepsy as well as epilepsy with myoclonic-astatic seizures typically begin at 5 months to 5 years, while epilepsy with generalized tonic-clonic seizures has an onset between 6 and 28 years, peaking at 17 years.

Sex distribution
Age distribution

Pathophysiology

As mentioned, IGE includes several subtypes- benign myoclonic epilepsy in infancy; generalized epilepsy with febrile seizures plus, an entity in evolution; epilepsy with myoclonic absences; epilepsy with myoclonic-astatic seizures; childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and epilepsy with generalized tonic–clonic seizures. It is still unclear if they all have similar mutations and pathophysiologic mechanisms [6] [7] [8] [9].

Prevention

In terms of prevention, several measures can be undertaken in order to minimize the risk of epilepsy. These include reducing the risk factors for brain injury, heart attack and stroke, maintaining an up-to-date vaccination calendar as well as following all recommendations in pregnancy.

Summary

According to the International League Against Epilepsy (ILAE), the category of idiopathic generalized epilepsy (IGE) includes eight different syndromes: benign myoclonic epilepsy in infancy, epilepsy with myoclonic absences, epilepsy with myoclonic-astatic seizures, epilepsy with generalized tonic–clonic seizure, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy open link, and generalized epilepsy with febrile seizures plus, an entity in evolution.

All of them are genetic disorders although the exact etiology remains unclear. IGE is equally present in males and females. No wide differences in disease prevalence have been observed amongst different races. The disease usually persists for life.

The different subtypes of IGE are differentiated mainly on the basis of their clinical presentation. IGE manifestations include absence seizures, myoclonic jerks and generalized tonic clonic seizures. These may appear alone or in various combinations from patient to patient. In most of the cases, the onset is in early childhood or adolescence although the condition has been observed in adults as well.

Electroencephalogram is the most useful, easy to perform and accessible test for IGE confirmation, although the distinction of different subtypes, especially overlapping ones based on EEG alone may be difficult.

Further research in genetic studies will allow the creation of more accurate classification and discrimination criteria for the various forms of idiopathic generalized epilepsy. Current classification criteria still hinge on identifying the clinical features appropriate for the specific syndrome.

Patient Information

30% of all epilepsy cases are attributed to idiopathic generalized epilepsy (IGE). They are a group of genetic disorders and show no gender or racial predilection. IGE is usually a condition that stays lifelong. Most of the syndromes included in the term IGE start at an early age. Typical clinical manifestations include myoclonic jerks, and generalized tonic-clonic seizures, either alone or in combination with variable severity. The EEG is the laboratory test of choice for IGE. Typical EEG changes include generalized discharges of spikes, polyspikes, or spike/polyspike-waves either ictally or inter-ictally. They could be triggered by episodes of hyperventilation or sleep deprivation. Normal EEG does not exclude the diagnosis IGE. Routine EEG test may be completed by video-EEG or EEG during sleep and awakening if the results obtained are uncertain.

Antiepileptic drugs should be carefully chosen as a few, used in the treatment of focal epilepsies, are contraindicated for IGE. Treatment is often lifelong.

IGEs syndromes included in the lists of the International League Against Epilepsy (ILAE) are: benign myoclonic epilepsy in infancy, epilepsy with myoclonic absences, epilepsy with myoclonic-astatic seizures, epilepsy with generalized tonic–clonic seizures, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized epilepsy with febrile seizures plus. Proper identification of the syndrome based on the clinical features is essential in determining the prognosis of disease. It is hoped that the advent of genetic studies will allow for the creation of more specific classification criteria to aid in prompt diagnosis and prognosis.

References

Article

  1. Berkovic SF, Howell RA, Hay DA, et al. Epilepsies in twins: genetics of the major epilepsy syndromes. Ann Neurol. 1998;43: 435–45.
  2. Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31: 184–9.
  3. Janz D, Beck-Mannagetta G, Sander T. Do idiopathic generalized epilepsies share a common susceptibility gene? Neurology. 1992;42(suppl 5):48–55.
  4. Ottman R, Annegers JF, Hauser WA, et al. Higher risk of seizures in offspring of mothers than of fathers with epilepsy. Am J Hum Genet. 1988;43: 257–64.
  5. Doose H, Gerken H, Horstmann T, et al. Genetic factors in spike-wave absences. Epilepsia. 1973;14: 57–75.
  6. Wallace RH, Marini C, Petrou S, et al. Mutant GABAA receptor γ2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet. 2001;28: 49–52.
  7. Kananura C, Haug K, Sander T, et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch Neurol. 2002;59: 1137–41.
  8. Haug K, Warnstedt M, Alekov AK, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet. 2003;33: 527–32.
  9. Cossette P, Liu L, Brisebois K, et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet. 2002;31: 184–9.
  10. Ricci S, Cusmai R, Fusco L, et al. Reflex myoclonic epilepsy in infancy: a new age-dependent idiopathic epileptic syndrome related to startle reaction. Epilepsia. 1995;36: 342–8.
  11. Manonmani V, Wallace S. Epilepsy with myoclonic absences. Arch Dis Child 1994;70: 288–90.
  12. Janz D. Epilepsy with impulsive petit mal (juvenile myoclonic epilepsy). Acta Neurol Scand. 1985;72: 449–59.
  13. Aliberti V, Grunewald RA, Panayiotopoulos CP, et al. Focal electroencephalographic abnormalities in juvenile myoclonic epilepsy. Epilepsia. 1994;35: 297–301.
  14. Lancman ME, Asconape JJ, Penry JK. Clinical and EEG asymmetries in juvenile myoclonic epilepsy. Epilepsia.1994;35: 302–306
  15. Pedersen SB, Petersen KA. Juvenile myoclonic epilepsy: clinical and EEG features. Acta Neurol Scand. 1998;97:160–163.
  16. Yenjun S, Harvey AS, Marini C, et al. EEG in adult-onset idiopathic generalized epilepsy. Epilepsia. 2003;44:252–256.
  17. Dravet C, Bureau M. Benign myoclonic epilepsy in infancy. Available at: http://www.epilepsy.org. Accessed March 3, 2003.

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Last updated: 2019-07-11 20:07