Antiseizure medications for idiopathic generalized epilepsies: a systematic review and network meta-analysis

BackgroundThe effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic–clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs).ObjectiveWe aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication.MethodsBibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564).ResultsNinety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE (N = 378) and the most common syndromes were juvenile myoclonic epilepsy (N = 92), progressive myoclonic epilepsies (N = 59) and absence epilepsies (N = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type.ConclusionsThe identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40263-021-00831-y.

In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance. Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 sodium channel subunits, and the chloride channel CLC-2 were sought. Fifty-five families were studied. 122 (13%) of 937 first- and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance.

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE)

The 2001 classification subcommittee of the International League Against Epilepsy (ILAE) proposed to 'group JME, juvenile absence epilepsy, and epilepsy with tonic clonic seizures only under the sole heading of idiopathic generalized epilepsies (IGE) with variable phenotype'. The implication is that juvenile myoclonic epilepsy (JME) does not exist as the sole phenotype of family members and that it should no longer be classified by itself or considered a distinct disease entity. Although recognized as a common form of epilepsy and presumed to be a lifelong trait, a long-term follow-up of JME has not been performed. To address these two issues, we studied 257 prospectively ascertained JME patients and encountered four groups: (i) classic JME (72%), (ii) CAE (childhood absence epilepsy) evolving to JME (18%), (iii) JME with adolescent absence (7%), and (iv) JME with astatic seizures (3%). We examined clinical and EEG phenotypes of family members and assessed clinical course over a mean of 11 +/- 6 years and as long as 52 years. Forty per cent of JME families had JME as their sole clinical phenotype. Amongst relatives of classic JME families, JME was most common (40%) followed by grand mal (GM) only (35%). In contrast, 66% of families with CAE evolving to JME expressed the various phenotypes of IGE in family members. Absence seizures were more common in family members of CAE evolving to JME than in those of classic JME families (P < 0.001). Female preponderance, maternal transmission and poor response to treatment further characterized CAE evolving to JME. Only 7% of those with CAE evolving to JME were seizure-free compared with 58% of those with classic JME (P < 0.001), 56% with JME plus adolescent pyknoleptic absence and 62% with JME plus astatic seizures. Long-term follow-up (1-40 years for classic JME; 5-52 years for CAE evolving to JME, 5-26 years for JME with adolescent absence and 3-18 years for JME with astatic seizures) indicates that all subsyndromes are chronic and perhaps lifelong. Seven chromosome loci, three epilepsy-causing mutations and two genes with single nucleotide polymorphisms (SNPs) associating with JME reported in literature provide further evidence for JME as a distinct group of diseases.

Purpose:We studied the phenotype and electroencephalographic (EEG) features, and therapeutic aspects of idiopathic generalized epilepsies (IGEs) in South Indian population.Patients and Methods:This prospective cross-sectional hospital-based study was carried out on non-consecutive 287 patients (age 22.2 ± 7.7 years; M:F = 139:148) with IGE syndrome. Their clinical and EEG observations were analyzed.Results:Majority of the patients had onset of seizures <20 years of age (n = 178; 62%). Thirty one patients (10.8%) had family history of epilepsy. Nearly half of them (49.9%) had <5 years of duration of seizures. The type of IGEs included Juvenile myoclonic epilepsy (JME): 115 (40.1%); IGE with generalized tonic-clonic seizures (GTCS) only: 102 (39.02%); childhood absence epilepsy (CAE): 35 (12.2%); GTCS on awakening: 15 (5.2%); Juvenile absence epilepsy (JAE): 11 (3.8%); and unclassified seizures: 9 (3.1%). The triggering factors noted in 45% were sleep deprivation (20%), non-compliance and stress in 5% each. The EEG (n = 280) showed epileptiform discharges in about 50% of patients. Epileptiform discharges during activation was observed in 40/249 patients (16.1%): Hyperventilation in 32 (12.8%) and photic stimulation in 19 (7.6%). The seizures were well controlled with anti-epileptic drugs (AEDs) in 232 (80.8%) patients and among them, 225 (78.4%) patients were on monotherapy. Valproate (n = 131) was the most frequently prescribed as monotherapy.Conclusions:This is one of the largest cohort of patients with IGE. This study reiterates the importance of segregating IGE syndrome and such analysis will aid to the current understanding and management.

Most idiopathic generalized epilepsy (IGE) begins in childhood. Clinicians face many important management decisions for these children; however the existing literature provides little scientific guidance. At the time of presentation, it is unclear how accurately IGE seizures and syndromes are diagnosed and how consistent are the EEG correlates. Investigations beyond EEG are of uncertain value but probably are not needed. Selection of an initial antiepileptic drug (AED) is not based on any adequately powered, blinded, randomized comparative trials; however, reasonable evidence supports the use of valproic acid (VPA), lamotrigine and ethosuccimide as initial treatment for childhood absence epilepsy (CAE). Many large case series suggest the value of VPA for juvenile myoclonic epilepsy (JME) but the relative value of other, newer AEDs has not been established. Once AED treatment is started, it is difficult to establish that absence seizures are completely controlled and the importance of interictal spike-wave discharge remains uncertain. The value of restrictions on the child's activities has not been well studied; however serious accidents appear to be a justifiable concern in children with uncontrolled absence. Assessing the risk from photosensitivity in JME is challenging. The optimal length of treatment for IGE is unclear. There is a high rate of remission in CAE when AEDs are discontinued after 1-2 years of seizure freedom; however, long-term remission in CAE occurs in only 65%. It is usually assumed that treatment for JME is life long, although about 10% appear to have permanent remission in adolescence. Discontinuing AED treatment in JME requires a very individual risk assessment. Long-term social outcome for children with CAE is often unsatisfactory even if the epilepsy remits. The reasons are unclear and successful interventions have not been described. Long-term social outcome for JME has not been adequately described. Further research is needed to justify the direction of many of the necessary management decisions in the diagnosis and treatment of IGE syndromes.

Introduction. Idiopathic generalized epilepsies account for approximately 15-20% of individuals with epilepsy. However, there is no consensus on how to cancel anticonvulsant therapy in patients with these epileptic syndromes after achieving remission, and what can be considered as risk factors for relapse of seizures.&#x0D; Purpose: identification of predictors of seizure recurrence after discontinuation of anticonvulsant therapy in patients with idiopathic generalized epilepsy.&#x0D; Materials and methods. Retrospective analysis of seizure recurrence after discontinuation of anticonvulsant therapy in patients with idiopathic generalized epilepsy. The analysis included two hundred thirty eight patients with genetic generalized epilepsy (GGE), of which 209 (88%) patients were with idiopathic generalized epilepsy (IGE) and 29 (12%) patients with GGE. 143 (68%) patients with IGE achieved remission. An attempt to cancel anticonvulsant was made in 78 (54%) patients.&#x0D; Results. Seizure recurrence was observed in 57 (73%) patients. 90% of seizure relapses occurred in the first 5 years after discontinuation of therapy, half of the relapses occurred in the first year. In group of patients with childhood absence epilepsy (CAE), therapy was discontinued in 6 patients, relapse — 0. 8/14 (57,1%) patients with juvenile absence epilepsy (JAE) had relapse after therapy discontinuation. The relapse in patients with juvenile myoclonic epilepsy (JME) was 23/25 (92%) and in group of patients with isolated generalized tonic-clinic seizure (IGTCS) was in 26/33 (78,8%).&#x0D; Conclusion. Among the epileptic syndromes included in the group of idiopathic generalized epilepsies, CAE has the most favourable prognosis after discontinuation of anticonvulsant therapy, and JME has the least, with a recurrence risk of more than 90%.

ObjectiveTo identify pediatric idiopathic generalized epilepsy (IGE) during 1994–2019 using ICD-10 codes in the Danish National Patient Register and anti-seizure prescriptions in the Danish Prescription Database.Study Design and SettingWe reviewed the medical records in children with ICD-10 codes for IGE before 18 years of age, and pediatric neurologists confirmed that the International League Against Epilepsy criteria were met. We estimated positive predictive values (PPV) and sensitivity for ICD-10 alone, including combinations of codes, anti-seizure prescription, and age at first code registration using medical record-validated diagnoses as gold standard.ResultsWe validated the medical record in 969 children with an ICD-10 code of IGE, and 431 children had IGE (115 childhood absence epilepsy, 97 juvenile absence epilepsy, 192 juvenile myoclonic epilepsy, 27 generalized tonic-clonic seizures alone). By combining ICD-10 codes with antiseizure prescription and age at epilepsy code registration, we found a PPV for childhood absence epilepsy at 44% (95% confidence interval [CI]=34%‒54%) and for juvenile absence epilepsy at 44% (95% CI=36%–52%). However, ethosuximide prescription, age at ethosuximide code registration before age 8 years and a combination of ICD-10 codes yielded a PPV of 59% (95% CI=42%‒75%) for childhood absence epilepsy but the sensitivity was only 17% (20/115 children identified). For juvenile myoclonic epilepsy the highest PPV was 68% (95% CI=62%‒74%) using the code G40.3F plus antiseizure prescription and age at epilepsy code registration after age 8 years, with sensitivity of 85% (164/192 children identified). For generalized tonic-clonic seizures alone the highest PPV was 31% (95% CI=15%‒51%) using G40.3G during 2006–2019 plus antiseizure prescription and age at code registration after age 5 years.ConclusionThe Danish National Patient Register and the Danish Prescription Database are not suitable for identifying children with IGE subtypes, except for juvenile myoclonic epilepsy which can be identified with caution.

To analyse prognostic factors for long term seizure remission in patients with childhood (CAE) and juvenile absence epilepsy (JAE). A retrospective analysis of a hospital based prevalence cohort. The cohort consisted of 163 patients (104 females, 59 males) treated at the Universitatsklinik fur Neurologie, Innsbruck between 1970 and 1997. All had absences according to the ILAE classification. Follow up was in 1999 to 2000. We assessed multiple clinical and EEG factors as predictors of outcome and compared a classification according to the predominant pattern of seizure recurrence (pyknoleptic, PA or non pyknoleptic absence, NPA) with the ILAE classification with respect to prognosis. The mean age at seizure onset was 10.9 years (range, 3 to 27); age at follow up was 36.7 years (range, 13 to 81); duration of follow up was 25.8 years (range, 3 to 69). Sixty four patients (39 %) had CAE and 64 (39 %) JAE, while 35 (22%) had typical absences but could not be clearly defined as either CAE or JAE, and were therefore called "the overlap group". Patients with JAE or patients in the overlap group developed more often generalized tonic clonic seizures (GTCS) (p<0.001) and myoclonic attacks (p<0.05) during the course of the disease. At follow up 36 (56 %) of patients with CAE, 40 (62%) with JAE and 19 (54 %) of the overlap group were seizure free for at least two years (p=ns). When classified according to the predominant absence pattern at seizure onset 42 (51%) patients with PA and 53 (65%) with NPA were in remission (p=ns). In a stepwise binary logistic regression analysis the pattern of absence (PA or NPA) together with the later development of additional seizure types (myoclonias or GTCS), but not the CAE/JAE classification was predictive for long term lack of remission with a correct prediction of 66% of all patients. Only 58% of patients with absences were in remission after a long term follow up. CAE and JAE are closely related syndromes with large overlap of the age of onset. A classification according to the predominant seizure pattern at onset, together with later development of myoclonic attacks or GTCS is useful in predicting seizure remission in absence epilepsies.

IntroductionJuvenile Myoclonic Epilepsy (JME) is a prevalent form of epileptic disorder, specifically categorized within the realm of Genetic Generalized Epilepsy (GGE). Its hallmark features encompass unprovoked bilateral myoclonus and tonic-clonic seizures that manifest during adolescence. While most JME patients respond favorably to anti-seizure medication (ASM), a subset experiences refractory JME, a condition where seizures persist despite rigorous ASM treatment, often termed “Drug-Resistant Epilepsy” (DRE). This systematic review and meta-analysis aims to determine the prevalence of refractory JME, and further to identify socio-demographic, electrophysiological and clinical risk factors associated with its occurrence. Pinpointing these factors is crucial as it offers the potential to predict ASM responsiveness, enabling early interventions and tailored care strategies for patients.Material and methodsThe systematic review and meta-analysis followed the Cochrane Handbook and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The study evaluated outcomes post ASM treatment in JME cohorts by searching papers published up to September 2023 in PubMed/MEDLINE, Scopus, and Google Scholar databases. Predefined inclusion criteria were met by 25 eligible studies, forming the basis for analysis.ResultsA total of 22 potential risk factors for refractory JME were documented. Notably, robust risk factors for treatment resistance included Psychiatric Disorder (Odds Ratio (OR), 3.42 [2.54, 4.61] (95% Confidence Inverval (Cl)), Febrile Seizures (OR, 1.83 [1.14, 2.96] (95% Cl)), Alcohol Consumption (OR, 16.86 [1.94, 146.88] (95%Cl)), Aura (OR, 2.15 [1.04, 4.47] (95%Cl)), childhood absence epilepsy (CAE) evolving into JME (OR, 4.54 [1.61, 12.78] (95%CI)), occurrence of three seizure types (OR, 2.96 [1.96, 4.46] (95%CI)), and Focal EEG abnormalities (OR, 1.85 [1.13, 3.01] (95%Cl)). In addition, there were some non-significant risk factors for DRE because of noticeable heterogeneity.ConclusionIn aggregate, over 36% of JME patients demonstrated drug resistance, with seven significant risk factors closely linked to this refractoriness. The interplay between these factors and whether they denote treatment non-response or heightened disease burden remains an open question and more studies would be required to fully examine their influence.

Clinical study of idiopathic generalized epilepsy syndromes

Typical absence epilepsy presenting prior to age of 3 years: An uncommon form of idiopathic generalized epilepsy

O.308 Use of gold implants in paralytic lagophtalmos

Juvenile myoclonic epilepsy is a genetically transferred generalized epilepsy that affects approximately 7% of adolescents and adults with epilepsy. Juvenile myoclonic epilepsy always has a myoclonic component alone or in combination with generalized tonic-clonic seizure or absence seizure. The myoclonic component is most prominent on waking or in a drowsy state. The electroencephalogram may be normal between seizures. Life-long treatment with valproate is effective in more than 80% of patients. The author describes the clinical features, diagnosis, and treatment of juvenile myoclonic epilepsy in a typical patient.

Zonisamide for refractory juvenile absence epilepsy