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Generalized Epilepsy Syndromes of Adolescence
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Debopam Samanta, Erin Willis
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Review Article
1
Generalized Epilepsy Syndromes of Adolescence Debopam Samanta1
Erin Willis1
1 Department of Pediatrics, University of Arkansas for Medical
Sciences, Little Rock, Arkansas, United States
Address for correspondence Debopam Samanta, MD, Q1Arkansas Children’s Hospital, 1 Children’s Way, Little Rock, AR, 72202, United States (e-mail:
[email protected]).
J Pediatr Epilepsy 2015;00:1–6.
Abstract
Keywords
► idiopathic generalized epilepsy ► juvenile myoclonic epilepsy ► juvenile absence epilepsy ► generalized tonic– clonic seizures
“Idiopathic” generalized epilepsies (juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic–clonic seizures alone) are the most frequent group of epilepsies with onset during adolescence and constitute 15 to 20% of all epilepsies. These syndromes have overlapping clinical features and genetic origins as well as similar electroencephalographic findings. There are primarily three seizure types that occur with these epilepsy syndromes: generalized tonic–clonic, absence, and myoclonic seizures. Standard neurologic examination and neuroimaging studies do not generally reveal any abnormality. Potential precipitating factors are many, including sleep deprivation, fatigue, alcohol use, photic stimulation, and menstruation. The characteristic electroencephalographic abnormality consists of diffuse, bilateral, symmetric, and synchronous 4 to 6 Hz polyspike and wave complexes. Idiopathic generalized epilepsies are generally associated with low mortality and typically respond well to treatment. The most effective antiepileptic drug for these disorders is sodium valproate, but it should be used with caution in adolescent females who are of childbearing age. Levetiracetam, lamotrigine, topiramate, and zonisamide can also be used as effective monotherapy. Carbamazepine, oxcarbamazepine, phenytoin, gabapentin, and vigabatrin may exacerbate myoclonic and absence seizures in juvenile myoclonic epilepsy.
Introduction In 1989, the International League Against Epilepsy (ILAE) proposed the terminology idiopathic generalized epilepsy (IGE) to describe generalized epilepsies with presumed genetic etiology.1 These epilepsies were defined by age-related onset, particularly clinical and electrographic characteristics along with a presumed genetic etiology. However, a report by the ILAE commission on Classification and Terminology 2005–2009 recommended avoidance of this terminology for description of underlying cause.2 Instead, new terminology of genetic, structural/metabolic, or unknown cause has been proposed to describe etiology. These generalized epilepsies that include juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and epilepsy with generalized tonic–clonic (GTC) seizures alone are considered to be electro clinical syndromes with onset from adolescence to adulthood. These constitute 15 to 20% of all epilepsies.3 They affect all
received June 12, 2014 accepted December 1, 2014
Issue Theme Adolescent epilepsies; Guest Editors: Dr. Gregory B. Sharp, MD, and Dr. Debopam Samanta, MD
races equally and may have a slight predilection for females. These generalized epilepsies are the most frequent group of epilepsies with an adolescent onset. Patients with these epilepsy syndromes have a low threshold for generalized seizures due to genetic predisposition. Magnetic resonance imaging of the brain is usually normal, in contrast to the symptomatic epilepsies where anatomical abnormalities are commonly seen. These disorders can be categorized as ion channelopathies due to recently identified and described genetic mutations that impact sodium, potassium, calcium, or chloride channels affecting gamma aminobutyric acid receptors. These epilepsy syndromes do not follow a welldefined Mendelian pattern and determination of precise mechanism of inheritance needs further investigation. Three primary seizure types—GTC, absence, and myoclonic seizures —are seen with these epilepsy syndromes. These syndromes have overlapping clinical features, genetic origins, and similar
Copyright © 2015 by Georg Thieme Verlag KG, Stuttgart · New York
DOI http://dx.doi.org/ 10.1055/s-0035-1556738. ISSN 2146-4588.
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electroencephalographic (EEG) findings. Response to therapy is generally good and associated mortality rates are low. These syndromes will be discussed separately with an emphasis on JME, which is the most common among these epilepsies. JME was recognized more than 200 years ago, but thoroughly described in 1957 by Janz and Christian,4 and in 1958 by Castells and Mendilaharsu.4 JME accounts for 20% of the IGEs and up to 5 to 10% of all cases of epilepsy.5 It is characterized by the presence of myoclonic jerks, GTC seizures, and in some cases absence seizures in otherwise healthy adolescents.
The underlying cause of JME is unknown, but the presence of complex underlying genetic defects can be responsible. Family history of epilepsy is commonly present. It is likely a heterogeneous condition with multiple potentially responsible mutations and susceptibility loci. Though a few of the genes (EFHC1/myoclonin1 gene located on chromosome 6p12-p11, CLCN2, GABRA1, and CACNB4) involved in JME have been identified recently, the vast majority of the involved genes have yet to be discovered.6 Seizures are linked with cortical excitability, most prominently over motor cortex. Manganotti et al7 showed that corticospinal excitability increased after sleep deprivation in JME patients, and this could be demonstrated in response to transcranial magnetic stimulation. Diurnal variability with an increase in cortical excitability early in the morning was also observed.8 These findings may explain the increased seizure susceptibility in response to sleep deprivation and increased seizure occurrence during the morning hours.
alteration or loss of consciousness during myoclonic seizures. Repetitive myoclonic jerks may precede a GTC seizure, and this constellation is often reported as a clonic–tonic–clonic seizure. Otherwise, GTC seizures secondary to JME cannot be distinguished from those related to other IGEs. Loss of consciousness occurs with the GTC seizure, but patients may use the myoclonic jerks as warning symptoms to get to a safe place. Ictal cry, tongue bite, incontinence of urine and stool, muscle soreness, amnesia of the event, and postictal confusion and disorientation can be seen with or following the GTC seizures. Focal ictal symptoms such as head version or asymmetric tonic posturing have been reported.12 Absence seizures are seen less commonly compared with GTC seizures. Associated absence in patients younger than 10 years may have more prominent symptoms of arrest of activity, staring, and unresponsiveness, but older patients usually report only subtle loss of contact and concentration. The absence seizures if present almost always precede the myoclonic or GTC seizures.10 Patients with JME are commonly very sensitive to precipitating factors that may increase seizures such as sleep deprivation, fatigue, alcohol use, photic stimulation, and menstruation. Cognitive effort can cause myoclonic jerks, and Vollmar et al13 found coactivation in the motor cortex and supplementary motor area with increasing cognitive load and increased functional coupling between the motor system and cognitive networks. Praxis-induced reflex epilepsy has also been reported.14,15 The neurologic examination in JME patients is typically normal. Detailed neuropsychological testing may identify executive dysfunction and expressive language deficit that may be attributed to a thalamofrontal circuitry abnormality.16
Clinical Features
Neuroimaging and Electroencephalography
JME peaks at the age of 15 years with a typical presentation between ages 12 and 18 years of age. All patients have myoclonic seizures. GTC seizures are common and occur in 87 to 95%, and absence seizures occur in 10 to 33% of patients.9–11 Early morning (most frequently within the first hour after awakening) myoclonic seizures, a hallmark of JME, usually precede other seizure types. These rapid jerks are most often disregarded as clumsiness and insignificant. Medical attention is commonly not sought until after the first GTC seizure. It is extremely important to ask the patient and family about a history of myoclonic jerks, which otherwise may go unreported. In one study, 5.5% of patients had myoclonic seizures as the only seizure type.10 Myoclonic seizures involve upper extremities more than lower extremities, and are typically bilateral and symmetrical. Repetitive jerks are not uncommon and extensor muscle involvement is usually seen. Falling to the floor is uncommon and typically, the amplitude of the jerk is not massive compared with the myoclonic seizures seen in Lennox–Gastaut syndrome. Upper extremity myoclonic jerks can cause interference with morning activities secondary to clumsiness and dropping objects from the hands. Patients may report sudden abnormal sensations with no physical signs of the seizure. There is no
Standard neuroimaging studies do not generally reveal any abnormality in JME patients, but quantitative voxel-based magnetic resonance imaging, 2-deoxy-2 (F-18) fluoro-Dglucose-positron emission tomography scan, and proton magnetic resonance spectroscopy studies may show frontal lobe dysfunction in some patients.17 In drug-naive JME patients, interictal EEG is abnormal in 50 to 85% of patients, but only 5 to 10% of patients treated with antiepileptic drug (AEDs) will have a persistent EEG abnormality.11 The characteristic EEG abnormality consists of diffuse, bilateral, symmetric, and synchronous 4 to 6 Hz polyspike–wave complexes. Baise-Zung et al18 reported that irregular spike–wave complexes may be more frequently present than classical polyspike and slow wave complexes. Frontocentral predominance of the discharge can be seen and focal abnormalities are evident in one-third of patients. Abnormal epileptiform discharges in response to photic stimulation can be seen in 30 to 50% of patients.19,20 The recorded EEG abnormality during a myoclonic seizure typically consists of an irregular 3 to 4 Hz polyspike–wave discharge with frontocentral predominance.21 Panayiotopoulos et al reported that absence seizures in JME are usually correlated with generalized spike–wave discharges of slightly
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Generalized Epilepsy Syndromes of Adolescence higher frequency than the classic 3 Hz seen in childhood or JAE.22 An ictal EEG pattern of attenuation with low-voltage fast activity followed by spike–wave discharges during a GTC seizure is similar to that seen in other generalized epilepsies. Recent work with dense array EEG suggests that rather than generalized onset, the interictal discharge may localize to a thalamocortical network that involves the medial orbitofrontal cortex and anterior basal-medial temporal lobes.23
Treatment Around 60 to 80% of patients with JME become seizure free in response to AED therapy.24 Valproic acid (VPA) is the most effective choice as it treats absence, myoclonic, and GTC seizures. Standard and New Antiepileptic Drugs study25 suggested that VPA is more effective than lamotrigine (LTG), and better tolerated than topiramate (TPM). Among 716 patients (119 of who had JME) in this study (63% with IGE and 25% with unclassified epilepsy), VPA was found to be least likely to be associated with treatment failure with inadequate seizure control compared with LTG and TPM, and was the preferred drug to achieve a 12-month remission. VPA can cause various adverse effects, including weight gain, hair loss, hepatotoxicity, teratogenicity, tremor, and pancreatitis. Fortunately, JME patients may respond to a lower dose of VPA, which is significantly better tolerated. The use of VPA is sometimes avoided in females owing to potential weight gain and associated increased risk of polycystic ovarian disease and potential teratogenic risks. LTG, another broad-spectrum AED, has been reported to be an efficacious option in JME and other generalized epilepsies, especially when VPA is contraindicated or not tolerated. Morris et al26 evaluated LTG monotherapy as a possible alternative in patients with JME who previously failed treatment with VPA in an open-label study. Improvements in adverse events and global clinical status were seen in 50 and 67% of patients, respectively, and 76% of patients rated LTG as better than VPA. The majority of patients completing the study experienced no deterioration in seizure control when switching from VPA to LTG. Beran et al27 demonstrated that LTG is an effective add-on therapy in patients with refractory generalized epilepsies. Statistically significant reduction in seizures in both absence and GTC seizure types ( 50% decrease in seizures was observed for GTC seizures in 50% of cases) was seen even with low doses of LTG in a doubleblind, placebo-controlled, crossover study in treatment-resistant generalized epilepsy. However, LTG can exacerbate myoclonic seizures and can be less effective in seizure control compared with VPA. LTG is usually well tolerated, but patients should be counseled about the risk of severe and potentially life-threatening skin rash. The incidence of serious rash is higher in pediatric patients than in adults, and may be increased by coadministration with VPA, with higher than recommended starting doses and when the recommended dose titration is exceeded. TPM can be another alternative and may have similar efficacy to VPA. Unfortunately, it also may induce adverse effects including cognitive dysfunction, word finding
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difficulty, weight loss, and kidney stones. Biton et al28 evaluated TPM as add-on therapy in patients with JME in a post hoc analysis of a patient subset from two multicenter, doubleblind, randomized, placebo-controlled, parallel-group trials. A total of 22 patients with JME participating in these trials using TPM (target dose, 400 mg/day in adults) for inadequately controlled GTC seizures were included. A 50% or more reduction in GTC seizures in 8 of 11 TPM-treated patients (73%) and 2 of 11 placebo-treated patients (18%) (p ¼ 0.03) was reported. Reductions in myoclonic, absence, and total generalized seizures were also observed, although TPM versus placebo differences did not achieve statistical significance. Recently, levetiracetam (LEV) and zonisamide (ZNS) have been considered as treatment options as well. LEV has been shown to be efficacious for all seizure types including myoclonic seizures. Adverse effects are less frequently reported and include headache, somnolence, and irritability. Labate et al29 evaluated the efficacy and tolerability of LEV as either “de novo” (monotherapy) or adjunctive therapy in patients with different generalized epilepsies. In total, 82% of 35 patients achieved 50% seizure frequency reduction. Berkovic et al30 evaluated the efficacy and tolerability of adjunctive LEV in patients with uncontrolled GTC seizures associated with IGE in a multicenter, randomized, doubleblind, placebo-controlled, parallel-group study. LEV produced a greater mean reduction in GTC seizure frequency per week over the treatment period (56.5%) compared with placebo (28.2%; p ¼ 0.004). The percentage of patients who achieved 50% reduction in GTC seizure frequency per week (responders) during the treatment period was 72.2% for LEV and 45.2% for placebo (p < 0.001; odds ratio ¼ 3.28; 95% confidence interval ¼ 1.68–6.38). ZNS can also be used with a once-daily dose as an adjunctive medication. Adverse effects include weight loss, cognitive problems, and nephrolithiasis. Kothare et al31 retrospectively analyzed the records of 15 patients (3 males, 12 females, ages 11–20 years) with JME treated with ZNS and suggested that it was effective and well tolerated. They recommended ZNS as an alternative therapy due to the ease of titration, good safety profile, once-daily dosing, lack of significant drug interaction, and short latency for onset of efficacy. The drug of first choice in the treatment of JME is VPA (except in women of childbearing age) with resultant seizure control in up to 80%.32 In most circumstances, adolescent females are considered to be of childbearing age from a practical perspective. LEV and LTG are first-line options in women of childbearing age. TPM and ZNS can also be used as effective monotherapy. Combination therapy should be considered if two monotherapy trials fail. Nicolson and Marson33 recommended combination therapy if an adequate trial of VPA monotherapy fails, rather than switching to alternative monotherapy. The combination of VPA and LTG may have synergistic effects, but there is increased risk of serious skin reactions with rapid titration of LTG in children younger than 12 years. VPA significantly inhibits the metabolism of LTG and may increase LTG serum levels by as much as twofold; thus, the LTG dose needs to be decreased by as much as 50% during Journal of Pediatric Epilepsy
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the titration and ultimately. Noachtar et al34 reported a randomized, double-blind, placebo-controlled multicenter trial that assessed the efficacy and tolerability of adjunctive treatment with LEV in patients with IGE who experienced myoclonic seizures despite antiepileptic monotherapy. A reduction of 50% in the number of days per week with myoclonic Q2seizures was seen in 58.3% of patients in the LEV group compared with 23.3% in the placebo group (p < 0.001) during the treatment period. LEV-treated patients were more likely to respond to treatment than patients receiving placebo, and achieved higher freedom from all seizures including myoclonic seizures during the study period. Clonazepam is a useful adjunct for myoclonus and can be used in combination with LTG to avoid LTG’s myoclonic inducing effects. Phenobarbital is the most cost-effective drug and can be used to control the seizures in patients with JME who have difficulty affording other expensive medicines. Surgical alternatives in refractory cases are rarely contemplated but may include vagus nerve stimulation and callosotomy. Deep brain stimulation is an experimental technique that may prove useful in managing refractory cases of JME.35 Carbamazepine, oxcarbamazepine, phenytopatieinQ3, gabapentin, and vigabatrin may exacerbate myoclonic and absence seizures in patients with JME. These AEDs may induce absence or myoclonic status epilepticus. Though carbamazepine and phenytoin may control GTC seizures in some refractory patients, use of these drugs should be avoided if possible owing to this potential adverse outcome.36,37 A careful and informed approach is needed in treating females of childbearing age. Though VPA is most effective in controlling seizures, a dose > 1,000 mg/day is associated with 6 to 11% risk of birth defects.38 In the neurodevelopmental effects of AEDs study, children exposed to VPA had a mean intelligence quotient that was 11 (97 vs. 108) points compared with patients exposed to LTG.39 They also did poorly on measures of verbal and nonverbal performance, memory abilities, and executive function. Risk of major birth malformations associated with exposure to LTG is 2.7%.40 There are also concerns for decreased serum level during pregnancy and possible worsening of seizure control with LTG. Regardless of the AEDs involved, polytherapy (6%) is associated with a higher risk of malformation than monotherapy (3.7%). In general, women with JME should not be discouraged from having children, but preconceptual planning, and better seizure control with a minimum dose of a single AED, is encouraged.
AED therapy was successfully discontinued in 6 patients (28.6%).42 The occurrence of GTC seizures preceded by bilateral myoclonic seizures, a long duration of epilepsy with unsuccessful treatment, and AED polytherapy were identified as significant predictors for a poor long-term seizure outcome, whereas complete remission of GTC seizures in response to AED therapy significantly increased the chance for complete seizure freedom. The occurrence of photoparoxysmal responses on EEG also significantly increased the risk of seizure recurrence after AED discontinuation in this study. Another study from Germany showed that 59.1% of 66 patients remained seizure free for at least 5 years before the last contact during a mean follow-up of 44.6 years (20–69 years).43 Among the seizure-free patients, 28 (71.8%) were still taking AEDs and 11 (28.2%) were off medication for at least the last 5 years. Absence seizures at onset of JME were noted to be an independent predictor of an unfavorable outcome regarding seizure freedom in this report.
Prognosis
Relatively recently, JAE has been categorized as a separate syndrome. Clinical symptoms have many overlapping features with childhood absence epilepsy and JME. The average age of onset is at age 12 years with most cases beginning near or after puberty.3 The absences in JAE are different from childhood absence epilepsy. The absences tend to occur less frequently (one per day to several per weak) with less severe loss of consciousness. A retropulsive component (backward motion of the eyes) is more commonly present in JAE. Absence seizures in JAE generally last for 10 to 60 seconds,
Although 60 to90% of patients with JME become seizure free with AEDs, breakthrough seizures are not uncommon secondary to medication noncompliance, sleep deprivation, or alcohol use. In the past, multiple studies have suggested that JME is a lifelong condition with a relapse rate of around 90% following discontinuation of medication.41 A recent study followed up 31 patients with JME for at least 25 years (mean 39.1 years) and found that 21 (67.7%) became seizure free, and Journal of Pediatric Epilepsy
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Epilepsy with GTC Seizures Only This syndrome has recently been described by the ILAE as a separate syndrome. The predominant seizure type, as the name suggests, is GTC. The peak age of onset, similar to JME, is at 15 years.3 “Epilepsy with GTC seizures on awakening” is a subcategory of this epilepsy syndrome in which more than 90% of seizures occur within 1 to 2 hours after awakening or at the end of the day during relaxation before sleep. Patients within this particular subcategory tend to have a longer duration of epilepsy, higher relapse rate, and stronger relationship to seizure-provoking factors compared with the group with GTC occurrence at random times.44 Seizureprovoking factors are similar to other generalized epilepsies and include photic stimulation, alcohol consumption, and sleep deprivation. These patients frequently have a positive family history of epilepsy. EEG during the interictal period reveals generalized 4 to 5 Hz spike and polyspike–wave complexes. Treatment options are similar to other generalized epilepsies. The prognosis is better than focal with or without secondary generalized epilepsy. Failure to remit within 2 years of diagnosis reduces the chance of remission in following years.45 Up to 95% of patients can be seizure free for 5 years within 20 years of epilepsy onset, but close to 20% may experience relapse even after a 5-year seizure-free period.46
Juvenile Absence Epilepsy
Generalized Epilepsy Syndromes of Adolescence typically longer than the absences in childhood absence epilepsy. GTC seizures are seen in 47 to 80% of patients, and myoclonic jerks in 10 to 15% of patients with JAE.47,48 The associated 3 to 4 Hz generalized spike and wave discharges tend to be slightly faster, less rhythmic, and less organized compared with the spike and wave complexes seen in childhood absences. Photosensitivity is rarely present. A positive family history of epilepsy is present in one-third of patients with JAE.47,48 Although genetics plays a large role, exact genetic mutation is largely undiscovered. VPA is the most effective AED, but owing to concern for adverse effects, other AEDs including LEV and LTG can be used. Avoidance of sleep deprivation and alcohol consumption is also of paramount importance. Owing to the frequent occurrence of GTC seizures, ethosuximide is not recommended as a first-line medication. More than 80% of JAE patients are pharmacoresponsive, but seizure-free rates tend to be less compared with patients with childhood onset.47 Patients with GTC seizures tend to have a worse prognosis.
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References 1 Commission on Classification and Terminology of the International
League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30(4):389–399
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2 Berg AT, Berkovic SF, Brodie MJ, et al. Revised terminology and
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The literature is scant concerning medically intractable generalized epilepsy, but tertiary epilepsy centers routinely encounter patients who are medically refractory. “Pseudoresistance” due to inappropriate choice of medication, wrong diagnosis (i.e., frontal lobe epilepsy masquerading as generalized epilepsy due to secondary bilateral synchrony), and medication noncompliance should be carefully watched for. After confirmation of true medical refractoriness, other options such as vagus nerve stimulation or therapy with ketogenic or modified Atkins diet can be considered. Unfortunately, these patients are not candidates for epilepsy surgery.49 In conclusion, the diagnosis of generalized epilepsy with adolescent onset as a group is of critical importance. Exact syndrome differentiation among these epilepsy syndromes is commonly impossible owing to overlapping clinical and EEG features; it is also of lesser practical significance secondary to treatment with similar AEDs. In clinical practice, adolescents with infrequent GTCs with normal EEG should not be automatically categorized as focal epilepsy with secondary generalization until proven otherwise. Staring spells in this age group may potentially represent localization related or absence seizures. Keeping an open mind and using a broadspectrum AED may be prudent until further characterization of the seizures is possible. Explanation of the genetic predisposition to lower seizure threshold rather than an “idiopathic” nature may be more acceptable to patients and families. Detailed discussion regarding trigger factors and avoidance, treatment options and compliance, and prognosis may decrease morbidity from these epilepsy syndromes.
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the corresponding details for accuracy. whether the edited sentence retains the intended sense. whether the “phenytopatiein” is correctly spelt. and 44 were similar. We have retained ref. 3 and deleted ref. 44. Please check for accuracy.
