Variation in prognosis and treatment outcome in juvenile myoclonic epilepsy: a Biology of Juvenile Myoclonic Epilepsy Consortium proposal for a practical definition and stratified medicine classifications
Guido RubboliChristoph P. BeierKaja Kristine SelmerMarte SyvertsenAmy ShakeshaftAmber CollingwoodAnna HallDanielle M. AndradeChoong Yi FongJoanna GescheDavid A. GreenbergKhalid HamandiKheng Seang LimChing Ching NgAlessandro OrsiniLisa J. StrugNaim PanjwaniFan LinDanielle M. AndradeJana ZárubováZuzana ŠobíškováCechovazPracovisteMichaela KajšováGuido RubboliRikke S. MøllerElena GardellaChristoph P. BeierJoanna GescheM MirandaInga TalvikPasquale StrianoAlessandro OrsiniChoong Yi FongChing Ching NgKheng Seang LimKaja Kristine SelmerMarte SyvertsenPronab BalaAmy KitchingKate IrwinLorna WaldingLynsey AdamsUma JegathasanRachel SwinglerRachel WaneJulia AramNikil SudarsanDee MullanRebecca RamsayVivien RichmondM. SargentPaul FrattaroliMatthew D. TaylorMarie HomeSal UkaSusan KilroyTonicha NortcliffeKheng Seang LimKelly HolroydKhalid HamandiAlison McQueenDympna McaleerDina JayachandranDawn EggintonBridget MacDonaldMichael ChangDavid DeekolluAlok GauravCaroline HamiltonJaya Natarajan Inyan TakonJanet CottaNick MoranJeremy D.P. BlandRosemary BelderbosHeather CollierJoanne HenryMatthew J. MilnerSam WhiteMichalis KoutroumanidisWilliam SternMark P. RichardsonJennifer M. QuirkJavier Peña CeballosAnastasiaPapathanasiouIoannis StavropoulosDora A. LozsádiAndrew SwainCharlotte QuaminaJennifer CrooksTahir MajeedSonia RajShakeelah PatelMichael C. YoungMelissa MaguireMunni RayCaroline PeaceyLinetty MakawaAsyah ChhibdaEve SacreShanaz BegumMartin O’MalleyLap YeungClaire HollidayLouise WoodheadKaren Helton RhodesRhys H. ThomasShan EllawelaJoanne GlentonVerity CalderJohn M. DavisPaul McAlindenSarah FrancisLisa RobsonKaren LanyonGraham A. MackayElma StephenColeen ThowMargaret ConnonMartin KirkpatrickSusan MacFarlaneAnne Scott MacLeodDebbie RiceSiva KumarCarolyn CampbellVicky CollinsWilliam WhitehouseChristina GiavasiBoyanka PetrovaThomas D. BrownCatie PictonMichael O’DonoghueCharlotte WestHelen NavarraSean SlaghtCatherine EdwardsAndrew GribbinLiz NelsonStephen WarrinerHeather Angus‐LeppanLoveth EhioroboBintou CamaraT SamakomvaRajiv MohanrajVictoria A. ParkerRajesh K. PandeyLisa CharlesCatherine CotterArchana DesurkarAlison HydeRachel HarrisonMarkus ReuberR. T. CleggJ SidebottomMayeth RectoPatrick EastonCharlotte WaiteAlice HowellJacqueline SmithR. T. CleggShyam MariguddiZena HaslamElizabeth Caruana GaliziaHannah R. CockMark MenciasSamantha TruscottDéirdre DalyHilda MhanduNooria SaidMark I. ReesSeo‐Kyung ChungWilliam Owen PickrellBeata Fonferko‐ShadrachMark D. BakerAmy B. HeagleLouise SwainKirsty O’BrienFraser ScottNaveed GhausGail CastleJacqui BartholomewAnn NeedleJulie BallAndrea CloughShashikiran SastryCharlotte Busby Amit AgrawalDebbie DickersonAlmu DuranMuhammad Shamim KhanLaura ThrasyvoulouEve IrvineSarah TittensorJacqueline DaglishSumant KumarClaire BackhouseClaire MewiesJulia AramNikil SudarsanDee MullanRebecca RamsayVivien RichmondDenise SkinnerM. SargentRahul BharatSarah-Jane SharmanArun SaraswatulaHelen CockerillDavid A. GreenbergPasquale StrianoRhys H. ThomasJana ZarubovaMark P. RichardsonLisa J. StrugDeb K. Pal
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Abstract Reliable definitions, classifications and prognostic models are the cornerstones of stratified medicine, but none of the current classifications systems in epilepsy address prognostic or outcome issues. Although heterogeneity is widely acknowledged within epilepsy syndromes, the significance of variation in electroclinical features, comorbidities and treatment response, as they relate to diagnostic and prognostic purposes, has not been explored. In this paper, we aim to provide an evidence-based definition of juvenile myoclonic epilepsy showing that with a predefined and limited set of mandatory features, variation in juvenile myoclonic epilepsy phenotype can be exploited for prognostic purposes. Our study is based on clinical data collected by the Biology of Juvenile Myoclonic Epilepsy Consortium augmented by literature data. We review prognosis research on mortality and seizure remission, predictors of antiseizure medication resistance and selected adverse drug events to valproate, levetiracetam and lamotrigine. Based on our analysis, a simplified set of diagnostic criteria for juvenile myoclonic epilepsy includes the following: (i) myoclonic jerks as mandatory seizure type; (ii) a circadian timing for myoclonia not mandatory for the diagnosis of juvenile myoclonic epilepsy; (iii) age of onset ranging from 6 to 40 years; (iv) generalized EEG abnormalities; and (v) intelligence conforming to population distribution. We find sufficient evidence to propose a predictive model of antiseizure medication resistance that emphasises (i) absence seizures as the strongest stratifying factor with regard to antiseizure medication resistance or seizure freedom for both sexes and (ii) sex as a major stratifying factor, revealing elevated odds of antiseizure medication resistance that correlates to self-report of catamenial and stress-related factors including sleep deprivation. In women, there are reduced odds of antiseizure medication resistance associated with EEG-measured or self-reported photosensitivity. In conclusion, by applying a simplified set of criteria to define phenotypic variations of juvenile myoclonic epilepsy, our paper proposes an evidence-based definition and prognostic stratification of juvenile myoclonic epilepsy. Further studies in existing data sets of individual patient data would be helpful to replicate our findings, and prospective studies in inception cohorts will contribute to validate them in real-world practice for juvenile myoclonic epilepsy management.Keywords:
Juvenile myoclonic epilepsy
Idiopathic generalized epilepsy
Levetiracetam
Myoclonic epilepsy
“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.
Juvenile myoclonic epilepsy
Zonisamide
Levetiracetam
Generalized epilepsy
Vigabatrin
Myoclonic Jerk
Idiopathic generalized epilepsy
Myoclonic epilepsy
Epilepsy syndromes
Abnormality
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Juvenile myoclonic epilepsy is a common idiopathic generalized epileptic syndrome that includes generalized myoclonic seizures and commonly generalized tonic-clonic and generalized absence seizures. Before the emergence of the newer antiepileptic drugs (AEDs) in the 1990s, valproate was the usual first-line treatment in both men and women. However, the frequent adverse effect of weight gain and the risk of teratogenicity have resulted in a search for alternative first-line therapies in women. Four new AEDs- lamotrigine, topiramate, levetiracetam, and zonisamide-have been used as monotherapy or adjunctive therapy for juvenile myoclonic epilepsy in small patient series. Because they are not associated with weight gain and because they may have less risk of teratogenicity than valproate, they have been proposed as alternative first-line agents in women who have childbearing potential. However, the new AEDs may not be effective for all the seizure types of juvenile myoclonic epilepsy, and valproate appeared overall more effective in a large comparative trial in idiopathic generalized epilepsy. In addition, valproate is often effective at lower doses that have less teratogenicity, and an extended-release preparation may be less likely to produce weight gain. The current review presents evidence and arguments supporting the use of a new AED and those supporting the use of valproate as the first-line treatment in a girl with newly diagnosed juvenile myoclonic epilepsy. The review then concludes with a compromise approach.
Juvenile myoclonic epilepsy
Levetiracetam
Zonisamide
Myoclonic epilepsy
Generalized epilepsy
Valproic Acid
Idiopathic generalized epilepsy
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To determine the pattern of treatment response in patients with idiopathic generalized epilepsy (IGE) and whether routinely assessed clinical and neurophysiological parameters allow predicting response to lamotrigine, levetiracetam, or valproic acid.In 328 adult patients with IGE, demographic data, imaging, EEG data, current and prior antiepileptic treatment, treatment outcome, and side effects were analyzed from the patients' medical files and patient interviews.Seizure freedom with acceptable side effects at the first attempt was achieved in 61 (18.6%) patients. One hundred four (31.7%) patients tried ≥3 antiepileptic drugs before achieving seizure control at the last follow-up. Lamotrigine, levetiracetam, and valproic acid showed differential response rates (39.8% vs 47.5% vs 71.1%) that were most pronounced in patients with juvenile myoclonic epilepsy. The risk of having side effects was higher with valproic acid (23.7%) than with lamotrigine (10.4%) or levetiracetam (20.4%) treatment, contributing to the low retention rate of valproic acid (53.7%). Treatment resistance was associated with established risk factors. Multivariate analyses aiming at identifying clinical indicators for response to specific drugs did not reveal putative biomarkers when corrected for drug resistance.Despite a high rate of seizure control, the chance of achieving seizure control and acceptable side effects at first attempt was low due to an inverse association of effectiveness and side effects of the 3 most commonly used drugs. Routinely assessed clinical parameters were not indicative for response to specific drugs.This study provides Class II evidence that for patients with IGE, various clinical factors do not predict a response to specific antiepileptic drugs.
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Juvenile myoclonic epilepsy
Zonisamide
Levetiracetam
Idiopathic generalized epilepsy
Generalized epilepsy
Seizure types
Childhood absence epilepsy
Epilepsy syndromes
Oxcarbazepine
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The prognosis of idiopathic generalized epilepsy syndromes (IGES) in the adult setting may vary from that in children owing to differences in genetic, environmental and lifestyle factors.All patients diagnosed with epilepsy at the Epilepsy Unit, Western Infirmary, Glasgow, between 1981 and 2001 were reviewed.Of 890 patients, 118 (13%) met the criteria for IGES. Outcomes were known for 103, 66 (64%) of whom achieved remission. The responder rate with sodium valproate was superior (66% vs 45%, P = 0.073) to that with lamotrigine (LTG) particularly in patients with juvenile myoclonic epilepsies (75% vs 39%, P = 0.014). History of febrile seizures was the only factor associated with reduced likelihood of remission (P = 0.032)Idiopathic generalized epilepsy syndromes constituted 13% of cases in a largely adult cohort of newly diagnosed epilepsy, most of whom achieved remission usually with a single antiepileptic drug. History of febrile seizures was associated with a poorer outcome.
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Idiopathic generalized epilepsy
Generalized epilepsy
Epilepsy syndromes
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Childhood epilepsies comprise a broad range of disorders which vary from benign to progressive and disabling. Accurate diagnosis of epilepsy type and determination of aetiology, when possible, are essential for appropriate treatment. The most common seizure type encountered in children is febrile seizures. These represent a benign condition which is not, in fact, epilepsy and usually does not require antiepileptic medication. When partial seizures occur in childhood, benign syndromes with spontaneous remission, such as rolandic epilepsy, must be distinguished from symptomatic epilepsies which may be refractory to medical management. Complex partial seizures in young children may appear different than in adults. The adverse effect profiles and dosing regimens of antiepileptic drugs in children are also different than in adults, and influence the choice of treatment. Epilepsy surgery should be considered for some children with intractible partial seizures. Generalized epilepsies also have a broader spectrum in children. The idiopathic generalized absence epilepsies are usually easy to control with medication. They range from childhood absence epilepsy which tends to remit in adolescence to juvenile myoclonic epilepsy which is a lifelong condition. In contrast, the seizures of West syndrome and Lennox-Gastaut syndrome are difficult to control, and treatment involves therapeutic modalities rarely used in adults such as ACTH and the ketogenic diet. Many childhood epilepsy syndromes have a familial predisposition, and the genetic bases for several disorders have been described.
Juvenile myoclonic epilepsy
Idiopathic generalized epilepsy
Epilepsy syndromes
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Ketogenic Diet
Myoclonic epilepsy
Lennox–Gastaut syndrome
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A combination of valproates in dose 15-25 mg per day and levetiracetam in dose 20-25 mg per day was used in the treatment of 23 patients with different forms of epilepsy (juvenile myoclonic epilepsy, juvenile absence epilepsy, convulsive idiopathic generalized epilepsy and children absence epilepsy). The use of these drugs was effective in all forms of epilepsy. There were positive changes in the frequency of seizures and epileptic activity in the EEG.
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Generalized epilepsy
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The choice of an antiepileptic drug (AED) in patients with epilepsy is mainly based on efficacy and safety of each drug. However, these criteria of drug selection should be further evaluated according to the epileptic syndromes, and adjusted to the sex and age of the patient. Unfortunately, very few studies have been conducted based on these latter criteria. We conducted a survey on the management of epilepsy treatment in adults. This survey was undertaken in France, and led to the establishment of a French consensus on antiepileptic drug treatment in adult patients with newly diagnosed epilepsy. Patients were grouped into 18 categories according to the epileptic syndrome (absence epilepsy, juvenile myoclonic epilepsy, undetermined idiopathic generalized epilepsy, symptomatic or cryptogenic partial epilepsy and unclassified epilepsy), and to the patient's gender and age. Our survey suggests that there is a consensus among French epileptologists for the choice of AEDs, mainly based on the epilepsy syndrome. Gender also plays a crucial role. Sodium valproate and lamotrigine are the two drugs of choice for generalized epilepsies, as well as for undetermined epilepsies. Lamotrigine is often prefered for women of childbearing age. First line AEDs in partial epilepsy are carbamazepine (particularly for men), lamotrigine (particularly for women), and gabapentin (in the elderly). In cases of failure and/or intolerance to one of these AED, the principal alternatives are oxcarbazepine, sodium valproate and topiramate.
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Epilepsy syndromes
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Idiopathic generalized epilepsy
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Lacosamide
Juvenile myoclonic epilepsy
Levetiracetam
Zonisamide
Valproic Acid
Idiopathic generalized epilepsy
Myoclonic Jerk
Generalized epilepsy
Myoclonic epilepsy
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