ILAE Task Force Research Articles

Interpretation of treatment of seizures in the neonate: guidelines and consensus-based recommendations-special report from the ILAE Task Force on Neonatal Seizures(2023)

Interpretation of treatment of seizures in the neonate: guidelines and consensus-based recommendations-special report from the ILAE Task Force on Neonatal Seizures(2023)

Genetic and phenotypic landscape of pediatric-onset epilepsy in 142 Indian families: Counseling and therapeutic implications.

The application of genomic technologies has led to unraveling of the complex genetic landscape of disorders of epilepsy, gaining insights into their underlying disease mechanisms, aiding precision medicine, and providing informed genetic counseling. We herein present the phenotypic and genotypic insights from 142 Indian families with epilepsy with or without comorbidities. Based on the electroclinical findings, epilepsy syndrome diagnosis could be made in 44% (63/142) of the families adopting the latest proposal for the classification by the ILAE task force (2022). Of these, 95% (60/63) of the families exhibited syndromes with developmental epileptic encephalopathy or progressive neurological deterioration. A definitive molecular diagnosis was achieved in 74 of 142 (52%) families. Infantile-onset epilepsy was noted in 81% of these families (61/74). Fifty-five monogenic, four chromosomal, and one imprinting disorder were identified in 74 families. The genetic variants included 65 (96%) single-nucleotide variants/small insertion-deletions, 1 (2%) copy-number variant, and 1 (2%) triplet-repeat expansion in 53 epilepsy-associated genes causing monogenic disorders. Of these, 35 (52%) variants were novel. Therapeutic implications were noted in 51% of families (38/74) with definitive diagnosis. Forty-one out of 66 families with monogenic disorders exhibited autosomal recessive and inherited autosomal dominant disorders with high risk of recurrence.

ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE Task Force on Nosology and Definitions

Treatment of Seizures in the Neonate: Special Report From the ILAE Task Force on Neonatal Seizures, 2022

Treatment of Seizures in the Neonate: Special Report From the ILAE Task Force on Neonatal Seizures, 2022

Epilepsy with myoclonic absences: A case series

Epilepsy with myoclonic absences (EMA) is a very rare childhood generalized epilepsy syndrome (<1% of all generalized epilepsies) associated with frequent myoclonic absence seizures that was described in 1969 by Tassinari et al. [ [1] Tassinari C.A. Lyagoubi S. Santos V. et al. Study on spike and wave discharges in man. II. Clinical and electroencephalographic aspects of myoclonic absences. Rev Neurol. 1969; 121: 379-383 PubMed Google Scholar ]. Seizures are characterized by bilateral rhythmic jerks of the upper limbs, superimposed on tonic abduction of the arms [ [2] Bureau M. Tassinari C.A. Epilepsy with myoclonic absences. Brain Dev. 2005; 27: 178-184 Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar ]. Ictal EEG consists of 3-Hz generalized spike-and-wave complexes that are time-locked with the upper limb myoclonus, while the EMG generally shows myoclonic jerks followed by tonic contraction of both deltoids. These seizures differ from typical absences of childhood absence epilepsy, since myoclonic jerks are generally not seen in typical absences and, if present, are subtle and spare the arms. The lack of an atonic component also distinguishes these seizures from myoclonic-atonic seizures [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. A recent position paper by the International League Against Epilepsy for the classification of epilepsy syndromes with onset in childhood retained EMA as an independent epilepsy syndrome and defined its diagnostic criteria [ [3] Specchio N. Wirrell E.C. Scheffer I.E. et al. International league against epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022; 63: 1398-1442 Crossref PubMed Scopus (46) Google Scholar ]. The mandatory requirements are myoclonic absences as the predominant type of seizures, and regular 3 Hz generalized spike-and-wave complexes synchronous with myoclonus.

Hemimegalencephaly and Epileptic Encephalopathy Associated with a Variant of Uncertain Significance of the TRIO Gene

Objectives: Electrical status epilepticus during sleep (ESES) is a type of EEG pattern seen in children with childhood-onset epileptic seizures and cognitive, language and motor regression. ESES has been associated with different etiologies, with or without structural abnormalities of the brain. To replace the term “ESES”, the recent Position Paper of the ILAE Taskforce on Nosology and Definitions introduced the term Epileptic Encephalopathy with Spike-Wave Activity during Sleep (EE-SWAS), which represents an activation of epileptiform activity, typically 1.5-2.5 Hz during NREM sleep, in a previously normal child and leads to cognitive and motor regression. Pathogenic variants in the TRIO gene are associated with autosomal dominant mental retardation type 44 (MRD44), which is characterized by mildly delayed global development resulting in variable intellectual deficits, learning difficulties, and variable dysmorphic features mostly represented by facial asymmetry, microcephaly, abnormalities of the fingers, and dental anomalies. Materials and methods: We present the case of a 13-year-old girl with onset of atonic seizures at the age of 3 who had undergone different types of antiepileptic drug (AED) therapies and was seizure-free 4 years later. She had an acquired impaired cognitive status as well as hemimegalencephaly, multiple hypopigmented patches on her legs and a large patch of hypopigmentation on the left side of her face extending towards the scalp (Becker’s nevus), dental anomalies (gingival hyperplasia, ogival palate), periventricular gliosis and electroencephalographic and (EEG) findings consistent with SWAS. Outcomes: Genetic testing confirmed a heterozygous variant of uncertain significance (VUS) of the TRIO gene, possibly associated with autosomal dominant MRD44. Although our patient presented with some phenotypic similarities to MRD44, her cognitive impairment improved with control of the SWAS pattern and AED adjustments. Conclusion: Association of structural anomalies of white matter, hemimegalencephaly, and encephalopathy with SWAS and a VUS mutation of the TRIO gene might suggest a different genetic neurocutaneous syndrome altogether.

International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: Position paper by the ILAE Task Force on Nosology and Definitions

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations.

International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions.

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients.

Exploring the influence of telehealth on patient engagement with a multidisciplinary Non-Epileptic Seizure (NES) Clinic during the COVID-19 pandemic

The ILAE task force has identified a gap in treatment access for patients with nonepileptic seizures (NES) [1]. Access to multidisciplinary treatment clinics for adults with NES is limited with only 18 institutions delivering care across the United States [2]. Patient engagement has been low in the University of Colorado, NES Clinic treatment program despite our clinic’s status as the only clinic of its kind in the mountain west. We analyzed patient factors of those who engaged in treatment before and after COVID-19 regulations were imposed and found a 23.6% increase in treatment engagement using telehealth. Those who engaged using telehealth were more likely to be of white race, of non-Hispanic ethnicity, publicly insured, employed, have a Charlson Comorbidity Index (CCI) of zero, a daily seizure rate of 0–1, did not have suicidal ideation or attempts, and live greater than 25 miles from the NES clinic. Delivering NES treatment via telehealth reduced the logistical and psychological barriers to initiating recovery and with a severe lack of accessible treatments for patients with NES, barrier reduction is necessary. This study describes patient factors that result in higher engagement with NES treatment using telehealth and emphasizes the importance of telehealth utilization to improve access to available treatment.

Global Survey of Guidelines for the Management of Epilepsy in Pregnancy: A report from the International League Against Epilepsy Task Force on Women and Pregnancy.

The ILAE Task Force on Women and Pregnancy conducted a survey among ILAE Chapters of their use of guidelines or recommendations for the management of women with epilepsy during pregnancy. A web‐based questionnaire including 10 questions was sent to the 118 ILAE Chapters in December 2017 with repeated reminders until the end of February 2018. In total, 77 chapters (65%) responded, although not to all questions. Out of those responding, 68% reported having guidelines or recommendations, 34% of which were from 2014 or earlier. At least 20% of the guidelines did not include information on possible risk to cognitive development, information regarding specific risks with specific antiepileptic drugs, nor recommendations regarding selection of antiepileptic drugs. Among those responding to the question, 91% reported that recommendations were made regarding folate supplementation, but the recommended dose ranged from 0.4 mg/d to 4 mg/d or more; 34% did not include recommendations regarding drug level monitoring during pregnancy, and 19% did not include guidelines on breastfeeding. Our survey demonstrates that there is a need for the development of up‐to‐date, globally applicable recommendations for the management of epilepsy during pregnancy.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and psychosis in children and teenagers.

Psychosis related to epilepsy or antiepileptic treatment can occur in teenagers and very rarely in children. Postictal, interictal and antiepileptic-drug-induced psychosis have all been reported in young people. Whether ictal psychosis occurs in this age group remains open to debate. Neuronal antibody encephalitis such as anti-NMDA receptor encephalitis can present with seizures and psychosis, both of which can resolve with prompt, appropriate immunotherapy. In addition, there have been several reports in which the terms psychosis or psychotic features have been used loosely to describe behavioural disturbance in children with epilepsy; in these cases there have apparently been no diagnostic features of psychosis, implying that these terms should not have been used. The management of epilepsy-related psychosis in young people is similar to that in adults. Antipsychotic medication should not be withheld if it is needed on clinical grounds. If the psychosis has been induced by antiepileptic medication then a medication review is necessary.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Anxiety, depression and childhood epilepsy.

Anxiety and depression are relatively common in children with epilepsy: anxiety has been reported in 15-36% and depression in 8-35% of patients. In some cases these conditions may be related specifically to the epilepsy or its treatment. For example, some antiepileptic drugs are known to be associated with depression in adults and are likely to have a similar effect in young people. Emotional reactions to the epilepsy, for example anxieties and social phobia related specifically to the seizures, might be expected and require appropriate management. However, there is a growing recognition of the bidirectional relationship between epilepsy and psychiatric disorders, including depression, largely based on adult data. Cognitive behavioural therapy and serotonin reuptake inhibitors are used for treatment of both anxiety and depression in children with epilepsy. There is a need for greater understanding of the causes of these conditions in young people and there is also a need for better evidence for optimal treatment.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epidemiology of psychiatric/behavioural disorder in children with epilepsy.

Psychiatric/behavioural problems can have a major effect on quality of life. Epidemiological studies in Europe, Scandinavia and the USA have confirmed a high rate of psychiatric disorder in children with epilepsy, typically around 35 to 50%. In children with additional impairment, particularly those with intellectual disability, the rates are even higher, over 50%. Determining the causes of these high rates and deciding on the best strategies, either for prevention or for optimal management, remain major challenges.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): When should pharmacotherapy for psychiatric/behavioural disorders in children with epilepsy be prescribed?

The most important factor in deciding whether psychotropic medication should be prescribed is a meticulous assessment of the possible causes of the behavioural/psychiatric disturbance. This assessment should include a consideration of the possible roles of the epilepsy itself, treatment of the epilepsy, associated brain damage or dysfunction, reactions to the epilepsy and causes that are unrelated to the epilepsy or its treatment. If the epilepsy itself or antiepileptic drug treatment are responsible for the disorder then a review of antiepileptic medication is required. Contrary to popular myth, most psychotropic medications are not contraindicated in children with epilepsy. Treatment with methylphenidate, dexamfetamine, atomoxetine, clonidine or low-dose risperidone are unlikely to precipitate seizures. The selective serotonin reuptake inhibitors might protect against seizures but some of these are powerful enzyme inhibitors, implying that careful monitoring to avoid antiepileptic drug toxicity is recommended. In many cases, the appropriate approach will be through other interventions such as behavioural management or providing the young person with empowering strategies, implying that psychotropic pharmacotherapy should not be the first-line treatment. However, if assessment indicates that psychotropic medication is necessary, it can be of great benefit.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural and psychiatric disorders associated with childhood epilepsy syndromes.

The categorisation of the childhood epilepsies into a number of different syndromes has allowed greater insight into the prognosis, not only with regard to seizure control but also in relation to cognitive and behavioural outcome. The role of genetics in determining both the syndrome and the behavioural outcome remains promising, although the promise is still largely unfulfilled. The behavioural/psychiatric outcome of a selection of the large number of childhood epilepsy syndromes is presented. The rate of autism in West syndrome, particularly in children who have tuberous sclerosis with temporal tubers, is high. In Dravet syndrome there is a loss of skills, with an associated increase in behavioural problems. The frequency of both subtle and overt seizures in the Lennox-Gastaut syndrome almost certainly accounts for the apparent poor motivation; however, a marked improvement in seizure control with treatment can also result in behavioural problems, probably as a result of the "release phenomenon". A number of cognitive problems can arise in the so-called "benign" syndrome of epilepsy with centrotemporal spikes (BECTS) and the rate of ADHD is high. Autistic features and ADHD have been described in the Landau-Kleffner syndrome and other syndromes associated with electrical status epilepticus of slow-wave sleep (ESES). Early effective treatment may reverse some of these features. There is clear evidence for a behavioural syndrome in relation to juvenile myoclonic epilepsy (JME), in which both clinical descriptions and functional neuroimaging indicate frontal lobe deficits.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and ADHD

ADHD occurs in about 30% of children with epilepsy. The causes of ADHD features include some antiepileptic drugs, the epilepsy itself and underlying brain dysfunction. Management of the ADHD will depend on the cause. Treatment with methylphenidate is effective in about 70% of cases; standard treatments with methylphenidate, dexamfetamine and atomoxetine are very unlikely to exacerbate seizures.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Subtle behavioural and cognitive manifestations of epilepsy in children.

A subtle behavioural or cognitive manifestation of epilepsy can be defined in two ways. First, epileptiform discharges not presenting as obvious seizures may nevertheless affect cognition and/or behaviour. Second, the actual seizures may be obvious but the way they affect cognition or behaviour may not be. There is a growing body of evidence indicating that the epileptiform discharges in benign epilepsy with centrotemporal spikes can affect behaviour and cognition. The focal discharges in other forms of epilepsy can also be associated with behavioural change. The Landau-Kleffner syndrome, the CSWS syndrome, transitory cognitive impairment and transient epileptic amnesia provide further examples of cognitive and behavioural manifestations resulting from subtle manifestations of the epilepsy. Prompt, effective antiepileptic treatment with medication or surgery can improve behaviour and cognition in at least some cases.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Epilepsy and autism.

A high proportion of children with epilepsy have autism spectrum disorder. Although estimates vary, depending both on the population studied and the definitions used, a figure of around 20% has typically been reported. Autism can have a major impact on the life of the child and family. Despite the importance of this comorbidity and although many studies have been performed, a full understanding of the possible links between epilepsy and autism remains elusive. In a minority of cases, for example in the Landau-Kleffner syndrome, the autistic features can be the result of the epilepsy itself. However, there has been a failure to demonstrate that the epilepsy itself plays a major role in most cases. The current evidence seems to point to a common underlying predisposing factor. The discovery of a growing number of genetic defects leading to both conditions would support this explanation of the link.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Adverse cognitive and behavioural effects of antiepileptic drugs in children.

The literature was evaluated for cognitive and more general behavioural effects. We distinguished the older antiepileptic drugs (AEDs), from the newer and newest AEDs. The striking finding was the lack of information on children. From the available evidence it would appear that there may be negative cognitive effects with phenobarbital, phenytoin, topiramate and zonisamide, and adverse behavioural effects with phenobarbital, valproate, gabapentin, topiramate, levetiracetam and zonisamide. There is inconclusive data on ethosuximide, clobazam, vigabatrin, felbamate, pregabalin, stiripentol, rufinamide, lacosamide and retigabine. The following drugs appear to be neutral with regard to cognitive effects: valproate, carbamazepine, gabapentin and oxcarbazepine. Carbamazepine appears to be neutral with regard to behavioural effects. Positive cognitive effects have been reported with lamotrigine and levetiracetam. Positive behavioural effects have been reported with lamotrigine. Recommendations are provided.

Psychiatric and Behavioural Disorders in Children with Epilepsy (ILAE Task Force Report): Behavioural effects of epilepsy surgery.

There are relatively few studies of the behavioural outcome of epilepsy surgery in children that have used standardised behavioural measures before and after the procedure. Those investigations that have used such measures are often on mixed groups with mixed pathology, implying that the numbers, when stratified, are very small. They are also often retrospective. Furthermore, because placebo surgery is generally not an option, the studies have been open and they are usually uncontrolled. The few available data suggest that, although individual children may benefit or deteriorate, there is little overall group effect of temporal or extratemporal surgery on behavioural/psychiatric outcome. Hemispherectomy has traditionally been associated with the expectation of marked behavioural improvement but firm data are lacking. Multiple subpial transection performed for electrical status epilepticus of slow-wave sleep in the Landau-Kleffner syndrome can result in marked improvements in cognition and behaviour. Vagus nerve stimulation appears to improve quality of life and mood/behaviour but again the quality of the data has been questioned. There is a need for large, prospective, multicentre, collaborative studies using standardised cognitive and behavioural measures before and after surgery to provide an adequate database on the outcome of various categories of procedures, pathologies and patients.