Impaired GABAergic regulation and developmental immaturity in interneurons derived from the medial ganglionic eminence in the tuberous sclerosis complex.

GABAergic interneurons play a critical role in maintaining neural circuit balance, excitation-inhibition regulation, and cognitive function modulation. In tuberous sclerosis complex (TSC), GABAergic neuron dysfunction contributes to disrupted network activity and associated neurological symptoms, assumingly in a cell type-specific manner. This GABAergic centric study focuses on identifying specific interneuron subpopulations within TSC, emphasizing the unique characteristics of medial ganglionic eminence (MGE)- and caudal ganglionic eminence (CGE)-derived interneurons. Using single-nuclei RNA sequencing in TSC patient material, we identify somatostatin-expressing (SST+) interneurons as a unique and immature subpopulation in TSC. The disrupted maturation of SST+ interneurons may undergo an incomplete switch from excitatory to inhibitory GABAergic signaling during development, resulting in reduced inhibitory properties. Notably, this study reveals markers of immaturity specifically in SST+ interneurons, including an abnormal NKCC1/KCC2 ratio, indicating an imbalance in chloride homeostasis crucial for the postsynaptic consequences of GABAergic signaling as well as the downregulation of GABAA receptor subunits, GABRA1, and upregulation of GABRA2. Further exploration of SST+ interneurons revealed altered localization patterns of SST+ interneurons in TSC brain tissue, concentrated in deeper cortical layers, possibly linked to cortical dyslamination. In the epilepsy context, our research underscores the diverse cell type-specific roles of GABAergic interneurons in shaping seizures, advocating for precise therapeutic considerations. Moreover, this study illuminates the potential contribution of SST+ interneurons to TSC pathophysiology, offering insights for targeted therapeutic interventions.

Genetic causes of infection induced encephalitis.

INTRODUCTION: Patients with encephalitis following a viral infection are often thought to have a para infectious, inflammatory, or autoimmune cause for their presentation. These diagnoses usually result in treatments with immunosuppressant therapies which can have side effects. However, there is an increasing body of evidence demonstrating that patients can have a direct genetic cause mediating viral infection triggered encephalitis, where inflammation is a secondary response. These patients may benefit not from immunosuppressive therapies, but from protection from infection through dedicated immunisation programs and early antiviral therapies at times of infection. METHODS: A small case series of paediatric neurology patients (n = 2) from a single institution with infection induced encephalitis and an underlying genetic cause, is presented. Patients with a confirmed genetic cause of infection induced encephalitis were identified and consented by their treating neurologist for inclusion in this case series. Ethics approval was gained for this case series and review of the surrounding literature. CONCLUSION: A case of both DBR1 and NUP214 genetic changes resulting in infection induced encephalitis is presented. This case series raises awareness of this rare group of disorders and provides clues to their identification. Features to prompt clinician consideration of such genetic conditions are also highlighted. Although rare, identification of these patients is important due to implications on treatment, prognosis, and family planning.

Diagnostic utility of exome sequencing followed by research reanalysis in human brain malformations.

This study aimed to determine the diagnostic yield of singleton exome sequencing and subsequent research-based trio exome analysis in children with a spectrum of brain malformations seen commonly in clinical practice. We recruited children ≤ 18 years old with a brain malformation diagnosed by magnetic resonance imaging and consistent with an established list of known genetic causes. Patients were ascertained nationally from eight tertiary paediatric centres as part of the Australian Genomics Brain Malformation Flagship. Chromosome microarray was required for all children, and those with pathogenic copy number changes were excluded. Cytomegalovirus polymerase chain reaction on neonatal blood spots was performed on all children with polymicrogyria with positive patients excluded. Singleton exome sequencing was performed through a diagnostic laboratory and analysed using a clinical exome sequencing pipeline. Undiagnosed patients were followed up in a research setting, including reanalysis of the singleton exome data and subsequent trio exome sequencing. A total of 102 children were recruited. Ten malformation subtypes were identified with the commonest being polymicrogyria (36%), pontocerebellar hypoplasia (14%), periventricular nodular heterotopia (11%), tubulinopathy (10%), lissencephaly (10%) and cortical dysplasia (9%). The overall diagnostic yield for the clinical singleton exome sequencing was 36%, which increased to 43% after research follow-up. The main source of increased diagnostic yield was the reanalysis of the singleton exome data to include newly discovered gene-disease associations. One additional diagnosis was made by trio exome sequencing. The highest phenotype-based diagnostic yields were for cobblestone malformation, tubulinopathy and lissencephaly and the lowest for cortical dysplasia and polymicrogyria. Pathogenic variants were identified in 32 genes, with variants in 6/32 genes occurring in more than one patient. The most frequent genetic diagnosis was pathogenic variants in TUBA1A. This study shows that over 40% of patients with common brain malformations have a genetic aetiology identified by exome sequencing. Periodic reanalysis of exome data to include newly identified genes was of greater value in increasing diagnostic yield than the expansion to trio exome. This study highlights the genetic and phenotypic heterogeneity of brain malformations, the importance of a multidisciplinary approach to diagnosis and the large number of patients that remain without a genetic diagnosis despite clinical exome sequencing and research reanalysis.

Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes.

Introduction: Constitutive activation of the mTOR pathway, as observed in Tuberous Sclerosis Complex (TSC), leads to glial dysfunction and subsequent epileptogenesis. Although astrocytes are considered important mediators for synaptic clearance and phagocytosis, little is known on how astrocytes contribute to the epileptogenic network. Methods: We employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment. Results: We found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities. Discussion: Our study provides evidence of mechanistic alterations in TSC astrocytes, underscoring the significant impairment of their supportive functions. These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions.

Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years.

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

How have the recent updated epilepsy classifications impacted on diagnosis and treatment?

INTRODUCTION: Epilepsies are a diverse group of disorders which differ regarding prognosis for seizure control and associated comorbidities. Accurate classification is critical to choose the highest yield investigations and best therapeutic options and to provide the most accurate prognoses regarding the expected degree of seizure control, possible remission, and risk of associated comorbidities to patients and their families. This article reviews the recent updates in epilepsy classification to illustrate how accurate classification impacts care for persons with epilepsy. AREAS COVERED: The authors discuss the ILAE 2017 Classification of the Epilepsies along with the modification of the classification for neonatal seizures and epilepsies. They also discuss the ILAE position papers on Epilepsy syndromes in neonates and infants and children of variable age and the Idiopathic Generalized Epilepsies. EXPERT OPINION: Accurate epilepsy classification allows selection of the highest yield investigations, choice of optimal therapies, and accurate prognostication of seizures (likelihood of response to antiseizure treatments and likelihood of remission with age), as well as comorbidities (likelihood, type, and severity). As we move into the era of disease modifying therapy, early accurate identification of underlying causes with timely introduction of specific treatments will be crucial to lessen the severity of epilepsy, with improved seizure control and attenuation of associated comorbidities.

A novel rapamycin cream formulation improves facial angiofibromas associated with tuberous sclerosis complex: a double-blind randomized placebo-controlled trial.

BACKGROUND: Facial angiofibromas (FAs) are a major feature of tuberous sclerosis complex (TSC). Topical rapamycin can successfully treat FAs. A new stabilized cream formulation that protects rapamycin from oxidation has been developed in 0.5% and 1% concentrations. OBJECTIVES: To assess the efficacy and safety of a novel, stabilized topical rapamycin cream formulation. METHODS: This multicentre double-blind randomized placebo-controlled dose-response phase II/III study with a parallel design included participants aged 6-65 years with FAs of mild or moderate severity according to the Investigator's Global Assessment (IGA) scale. Participants were randomized to one of three treatment arms: topical rapamycin 0.5%, topical rapamycin 1% or placebo. Treatment was applied once daily for 26 weeks. Safety and efficacy measures were assessed at days 14, 56, 98, 140 and 182. The primary endpoint was the percentage of participants achieving IGA scores of 'clear' or 'almost clear' after 26 weeks of treatment. Secondary measures included Facial Angiofibroma Severity Index (FASI) and participant- and clinician-reported percentage-based improvement. Safety measures included the incidence of treatment-emergent adverse events and blood rapamycin concentration changes over time. RESULTS: Participants (n = 107) were randomized to receive either rapamycin 1% (n = 33), rapamycin 0.5% (n = 36) or placebo (n = 38). All treated participants were included in the final analysis. The percentage of participants with a two-grade IGA improvement was greater in the rapamycin 0.5% treatment group (11%) and rapamycin 1% group (9%) than in the placebo group (5%). However, this was not statistically significant [rapamycin 0.5%: odds ratio (OR) 1.71, 95% confidence interval (CI) 0.36-8.18 (P = 0.50); rapamycin 1%: OR 1.68, 95% CI 0.33-8.40 (P = 0.53)]. There was a statistically significant difference in the proportion of participants treated with rapamycin cream that achieved at least a one-grade improvement in IGA [rapamycin 0.5%: 56% (OR 4.73, 95% CI 1.59-14.10; P = 0.005); rapamycin 1%: 61% (OR 5.14, 95% CI 1.70-15.57; P = 0.004); placebo: 24%]. Skin adverse reactions were more common in patients following rapamycin application (64%) vs. placebo (29%). CONCLUSIONS: Both rapamycin cream formulations (0.5% and 1%) were well tolerated, and either strength could lead to clinical benefit in the treatment of FA.

Peri-Insular Hemispherotomy: A Systematic Review and Institutional Experience.

INTRODUCTION: Peri-insular hemispherotomy (PIH) is a hemispheric separation technique under the broader hemispherotomy group, a surgical treatment for patients with intractable epilepsy. Hemispherotomy techniques such as the PIH, vertical parasagittal hemispherotomy (VPH), and modified-lateral hemispherotomy are commonly assessed together, despite significant differences in anatomical approach and patient selection. We aim to describe patient selection, outcomes, and complications of PIH in its own right. METHODS: A systematic review of the literature, in accordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was conducted, with searches of the PubMed and Embase databases. A local series including patients receiving PIH and followed up at the Queensland Children's Hospital between 2014 and 2020 was included. RESULTS: Systematic review of the literature identified 393 patients from 13 eligible studies. Engel class 1 outcomes occurred in 82.4% of patients, while 8.6% developed post-operative hydrocephalus. Hydrocephalus was most common in the youngest patient cohorts. Developmental pathology was present in 114 (40.8%) patients, who had fewer Engel 1 outcomes compared to those with acquired pathology (69.1% vs. 83.7%, p = 0.0167). The local series included 13 patients, 11/13 (84.6%) had Engel class 1 seizure outcomes. Post-operative hydrocephalus occurred in 2 patients (15.4%), and 10/13 (76.9%) patients had worsened neurological deficit. CONCLUSION: PIH delivers Engel 1 outcomes for over 4 in 5 patients selected for this procedure, greater than described in combined hemispherectomy analyses. It is an effective technique in patients with developmental and acquired pathologies, despite general preference of VPH in this patient group. Finally, very young patients may have significant seizure and cognitive benefits from PIH; however, hydrocephalus is most common in this group warranting careful risk-benefit assessment. This review delivers a dedicated PIH outcomes analysis to inform clinical and patient decision-making.

Medical treatment in infants and young children with epilepsy: Off-label use of antiseizure medications. Survey Report of ILAE Task Force Medical Therapies in Children.

OBJECTIVE: Antiseizure medications (ASMs) remain the mainstay of epilepsy treatment. These ASMs have mainly been tested in trials in adults with epilepsy, which subsequently led to market authorization (MA). For treatment of - especially young - children with epilepsy, several ASMs do not have a MA and guidelines are lacking, subsequently leading to "off-label" use of ASMs. Even though "off-label" ASM prescriptions for children could lead to more adverse events, it can be clinically appropriate and rational if the benefits outweigh the risks. This could be the case if "on-label" ASM, in mono- or polytherapy, fails to achieve adequate seizure control. METHODS: The Medical Therapies Task Force of the International League Against Epilepsy (ILAE) Commission for Pediatrics performed a survey to study the current treatment practices in six classic, early life epilepsy scenarios. Our aim was not only to study first- and second-line treatment preferences but also to illustrate the use of "off-label" drugs in childhood epilepsies. RESULTS: Our results reveal that several ASMs (e.g. topiramate, oxcarbazepine, benzodiazepines) are prescribed "off-label" in distinct scenarios of young children with epilepsy. In addition, recent scientific guidelines were not always adopted by several survey respondents, suggesting a potential knowledge gap. SIGNIFICANCE: We report the relatively common use of "off-label" prescriptions that underlines the need for targeted and appropriately designed clinical trials, including younger patients, which will also result in the ability to generate evidence-based guidelines.

Clinical seizure semiology is subtle and identification of seizures by parents is unreliable in infants with tuberous sclerosis complex.

OBJECTIVE: The objectives of this study were to assess the accuracy of parental seizure detection in infants with antenatally diagnosed tuberous sclerosis complex (TSC), and to document the total seizure burden (clinical and subclinical) in those patients who met criteria for prolonged electroencephalography (EEG) recording. METHODS: Consecutive infants at a single institution with antenatally diagnosed TSC who met criteria for prolonged video-EEG (vEEG) were recruited to this study. The vEEG data were reviewed and when a seizure was identified on EEG, the video and audio recording was assessed for evidence of clinical seizure and, if present, whether there was evidence of parent seizure identification. RESULTS: Nine infants were enrolled, for whom 674 focal seizures were identified in eight of nine patients across 24 prolonged vEEG recordings, with vEEG total duration of 634 h 49 min (average seizure frequency of 1 focal seizure/h). Only 220 of 674 (32.6%) were clinical seizures, 395 of 674 (58.6%) were subclinical seizures, and 59 of 674 seizures could not be classified. Only 63 of 220 clinical seizures (28.6%) were identified by parents, with 157 of 220 (71.4%) not identified. Thirty clusters of epileptic spasms were detected in one patient. At least one clinical epileptic spasm occurred in 2 of 30 clusters (6.7%), 24 of 30 clusters of epileptic spasms (80%) were electrographic only, and classification was uncertain for 4 of 30 clusters (13.3%). No clinical epileptic spasms were detected by parents. Clinical seizure frequency was significantly underestimated by parents for all patients. SIGNIFICANCE: This study demonstrates that in infants with TSC who met criteria for prolonged vEEG, (1) parents significantly under recognize total clinical seizure count, (2) parents fail to identify epileptic spasms, and (3) seizure frequency is high. This highlights that epilepsy treatment decisions should not be based solely on parental clinical seizure identification. Prolonged vEEG monitoring may have an important role in the routine epilepsy care of infants with TSC, as demonstrating undetected high clinical seizure frequency may allow improved epilepsy management decisions.

Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox-Gastaut syndrome: Interim analysis of an open-label extension study.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of fenfluramine in patients with Lennox-Gastaut syndrome (LGS). METHODS: Eligible patients with LGS who completed a 14-week phase 3 randomized clinical trial enrolled in an open-label extension (OLE; NCT03355209). All patients were initially started on .2 mg/kg/day fenfluramine and after 1 month were titrated by effectiveness and tolerability, which were assessed at 3-month intervals. The protocol-specified treatment duration was 12 months, but COVID-19-related delays resulted in 142 patients completing their final visit after 12 months. RESULTS: As of October 19, 2020, 247 patients were enrolled in the OLE. Mean age was 14.3 ± 7.6 years (79 [32%] adults) and median fenfluramine treatment duration was 364 days; 88.3% of patients received 2-4 concomitant antiseizure medications. Median percentage change in monthly drop seizure frequency was -28.6% over the entire OLE (n = 241) and -50.5% at Month 15 (n = 142, p < .0001); 75 of 241 patients (31.1%) experienced ≥50% reduction in drop seizure frequency. Median percentage change in nondrop seizure frequency was -45.9% (n = 192, p = .0038). Generalized tonic-clonic seizures (GTCS) and tonic seizures were most responsive to treatment, with median reductions over the entire OLE of 48.8% (p < .0001, n = 106) and 35.8% (p < .0001, n = 186), respectively. A total of 37.6% (95% confidence interval [CI] = 31.4%-44.1%, n = 237) of investigators and 35.2% of caregivers (95% CI = 29.1%-41.8%, n = 230) rated patients as Much Improved/Very Much Improved on the Clinical Global Impression of Improvement scale. The most frequent treatment-emergent adverse events were decreased appetite (16.2%) and fatigue (13.4%). No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed. SIGNIFICANCE: Patients with LGS experienced sustained reductions in drop seizure frequency on fenfluramine treatment, with a particularly robust reduction in frequency of GTCS, the key risk factor for sudden unexpected death in epilepsy. Fenfluramine was generally well tolerated; VHD or PAH was not observed long-term. Fenfluramine may provide an important long-term treatment option for LGS.

miRNAs and isomiRs: Serum-Based Biomarkers for the Development of Intellectual Disability and Autism Spectrum Disorder in Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterized by a high incidence of epilepsy and neuropsychiatric manifestations known as tuberous-sclerosis-associated neuropsychiatric disorders (TANDs), including autism spectrum disorder (ASD) and intellectual disability (ID). MicroRNAs (miRNAs) are small regulatory non-coding RNAs that regulate the expression of more than 60% of all protein-coding genes in humans and have been reported to be dysregulated in several diseases, including TSC. In the current study, RNA sequencing analysis was performed to define the miRNA and isoform (isomiR) expression patterns in serum. A Receiver Operating Characteristic (ROC) curve analysis was used to identify circulating molecular biomarkers, miRNAs, and isomiRs, able to discriminate the development of neuropsychiatric comorbidity, either ASD, ID, or ASD + ID, in patients with TSC. Part of our bioinformatics predictions was verified with RT-qPCR performed on RNA isolated from patients' serum. Our results support the notion that circulating miRNAs and isomiRs have the potential to aid standard clinical testing in the early risk assessment of ASD and ID development in TSC patients.

A Multi-Disciplinary Team Approach to Genomic Testing for Drug-Resistant Epilepsy Patients-The GENIE Study.

BACKGROUND: The genomic era has led to enormous progress in clinical care and a multi-disciplinary team (MDT) approach is imperative for integration of genomics into epilepsy patient care. METHODS: The MDT approach involved patient selection, genomic testing choice, variant discussions and return of results. Genomics analysis included cytogenomic testing and whole exome sequencing (WES). Neurologist surveys were undertaken at baseline and after genomic testing to determine if genomic diagnoses would alter their management, and if there was a change in confidence in genomic testing and neurologist perceptions of the MDT approach. RESULTS: The total diagnostic yield from all genomic testing was 17% (11/66), with four diagnoses from cytogenomic analyses. All chromosomal microarray (CMA) diagnoses were in patients seen by adult neurologists. Diagnostic yield for WES was 11% (7/62). The most common gene with pathogenic variants was DCX, reported in three patients, of which two were mosaic. The genomic diagnosis impacted management in 82% (9/11). There was increased confidence with integrating genomics into clinical care (Pearson chi square = 83, p = 0.004) and qualitative comments were highly supportive of the MDT approach. CONCLUSIONS: We demonstrated diagnostic yield from genomic testing, and the impact on management in a cohort with drug-resistant epilepsy. The MDT approach increased confidence in genomic testing and neurologists valued the input from this approach. The utility of CMA was demonstrated in epilepsy patients seen by adult neurologists as was the importance of considering mosaicism for previously undiagnosed patients.

Efficacy and Safety of Fenfluramine for the Treatment of Seizures Associated With Lennox-Gastaut Syndrome: A Randomized Clinical Trial.

Importance: New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. Objective: To evaluate the efficacy and safety of fenfluramine in patients with LGS. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. Interventions: Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. Main Outcomes and Measures: Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. Results: A total of 263 patients (median [range] age, 13 [2-35] years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21 [26%] vs 5 [6%]; P = .001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%]), with a decrease in frequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0.2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. Conclusions and Relevance: Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures. Trial Registration: ClinicalTrials.gov Identifier: NCT03355209.

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

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.

Methodology for classification and definition of epilepsy syndromes with list of syndromes: Report of the ILAE Task Force on Nosology and Definitions.

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers.

ILAE definition of the Idiopathic Generalized Epilepsy Syndromes: Position statement by the ILAE Task Force on Nosology and Definitions.

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications.

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.

Status Epilepticus Australasian Registry for Children: A pilot prospective, observational, cohort study of paediatric status epilepticus.

OBJECTIVE: Paediatric status epilepticus (SE) has potential for long-term sequelae. Existing data demonstrate delays to aspects of care. The objective of the present study was to examine the feasibility of collecting data on children with paediatric SE and describe current management strategies in pre-hospital and in-hospital settings. METHODS: A pilot, prospective, observational cohort study of children 4 weeks to 16 years of age with SE, in four EDs in Australia. Clinical details including medications administered, duration of seizure and short-term outcomes were collected. Follow up occurred by telephone at 1 month. RESULTS: We enrolled 167 children with SE. Mean age was 5.4 years (standard deviation [SD] 4.1), and 81 (49%) male. Median seizure duration was 10 min (interquartile range 7-30). Midazolam was the first medication administered in 87/100 (87%) instances, mean dose of 0.21 mg/kg (SD 0.13). The dose of midazolam was adequate in 30 (35%), high (>0.2 mg/kg) in 44 (51%) and low (<0.1 mg/kg) in 13 (15%). For second-line agents, levetiracetam was administered on 33/55 (60%) occasions, whereas phenytoin and phenobarbitone were administered on 11/55 (20%) occasions each. Mean dose of levetiracetam was 26.4 mg/kg (SD 13.5). One hundred and four (62%) patients were admitted to hospital, with 13 (8%) admitted to ICU and seven (4%) intubated. CONCLUSION: In children presenting with SE in Australia medical management differed from previous reports, with midazolam as the preferred benzodiazepine, and levetiracetam replacing phenytoin as the preferred second-line agent. This pilot study indicates the feasibility of a paediatric SE registry and its utility to understand and optimise practice.