Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

Topiramate ban in women of childbearing potential with idiopathic generalized epilepsy: Does effectiveness offset the teratogenic risks?

Regulatory agencies have recently discouraged the prescription of topiramate (TPM) to women of childbearing potential with epilepsy due to growing evidence of the teratogenic and neurodevelopmental risks associated with its use during pregnancy. It remains, however, unclear whether the use of TPM in this population can be supported to some extent by its high effectiveness. In this multicenter, retrospective, cohort study performed at 22 epilepsy centers, we investigated the comparative effectiveness of TPM and levetiracetam (LEV) given as first-line antiseizure medication in a cohort of women of childbearing potential with idiopathic generalized epilepsy (IGE). A total of 336 participants were included, of whom 24 (7.1%) received TPM and 312 (92.9%) LEV. Women treated with TPM had significantly higher risks of treatment failure and treatment withdrawal and were less likely to achieve seizure freedom at 12 months compared to women treated with LEV. In conclusion, this study highlighted a low tendency among clinicians to use TPM in women of childbearing potential with IGE, anticipating the recently released restrictions on its use. Furthermore, the available data on effectiveness do not appear to support the use of TPM in this population.

Sustained effort network for treatment of status epilepticus/European academy of neurology registry on adult refractory status epilepticus (SENSE-II/AROUSE).

BACKGROUND: Status Epilepticus (SE) is a common neurological emergency associated with a high rate of functional decline and mortality. Large randomized trials have addressed the early phases of treatment for convulsive SE. However, evidence regarding third-line anesthetic treatment and the treatment of nonconvulsive status epilepticus (NCSE) is scarce. One trial addressing management of refractory SE with deep general anesthesia was terminated early due to insufficient recruitment. Multicenter prospective registries, including the Sustained Effort Network for treatment of Status Epilepticus (SENSE), have shed some light on these questions, but many answers are still lacking, such as the influence exerted by distinct EEG patterns in NCSE on the outcome. We therefore initiated a new prospective multicenter observational registry to collect clinical and EEG data that combined may further help in clinical decision-making and defining SE. METHODS: Sustained effort network for treatment of status epilepticus/European Academy of Neurology Registry on refractory Status Epilepticus (SENSE-II/AROUSE) is a prospective, multicenter registry for patients treated for SE. The primary objectives are to document patient and SE characteristics, treatment modalities, EEG, neuroimaging data, and outcome of consecutive adults admitted for SE treatment in each of the participating centers and to identify factors associated with outcome and refractoriness. To reach sufficient statistical power for multivariate analysis, a cohort size of 3000 patients is targeted. DISCUSSION: The data collected for the registry will provide both valuable EEG data and information about specific treatment steps in different patient groups with SE. Eventually, the data will support clinical decision-making and may further guide the planning of clinical trials. Finally, it could help to redefine NCSE and its management. TRIAL REGISTRATION: NCT number: NCT05839418.

Being an adolescent with epilepsy during the transition from pediatric to adult hospital care: A qualitative descriptive study.

BACKGROUND: The transition from pediatric to adult care is challenging for adolescent patients despite numerous recommendations in recent decades. However, the perspective of the patients is sparsely investigated. AIM: To explore the experiences and needs of adolescents with epilepsy (AWE) during the transition from pediatric to adult hospital care. METHODS: We conducted 15 semi-structured interviews with AWEs aged 13-20 years and 10 h of field observations of consultations. Interviews were audio-recorded, transcribed, anonymized, and entered into NVivo (version 12, QSR International) with the transcribed field notes. Data were analyzed using systematic text condensation. RESULTS: Three themes were identified: (1) Navigating epilepsy in everyday life; (2) The difficult balance between concealment and openness about epilepsy; and (3) Being seen as an individual and not an illness. AWEs' needs in transition are closely associated with their experiences and perceptions of illness, treatment, consultations, and seizures. Notably, AWEs reveal a significant concern about being overlooked beyond their medical condition in appointments. CONCLUSIONS: This study highlights the vulnerability and challenges of AWEs transitioning to adult care. Overall, AWEs seek understanding, acceptance, and autonomy in managing their epilepsy and transitioning to adult care. Their experiences underscore the importance of holistic support and communication in healthcare settings. A concerted effort from healthcare professionals (HCP) is necessary to foster the recognition of AWEs as individuals with distinct personalities, needs, and capabilities.

Association of symptoms of psychiatric disease and electroencephalographic patterns in idiopathic generalized epilepsy.

OBJECTIVE: Idiopathic generalized epilepsies (IGE) are genetic epilepsies with alterations of thalamo-frontocortical circuits that play a major role in seizure generation and propagation. Psychiatric diseases and drug resistance are strongly associated, but it remains unknown if they are symptoms of the same pathophysiological process. Hypothesizing that the same network alterations are associated with the frequency of epileptic discharges (ED) and psychiatric symptoms, we here tested the association of self-reported psychiatric symptoms and IGE severity estimated by electroencephalographic (EEG) biomarkers. METHODS: Idiopathic generalized epilepsies patients were asked to fill out four validated psychiatric screening tools assessing symptoms of personality disorders (Standard Assessment of Personality- Abbreviated Scale), depression (Major Depression Inventory), impulsiveness (Barratt Impulsiveness Scale), and anxiety (brief Epilepsy Anxiety Survey Instrument). Blinded to results and clinical data on the patients, we analyzed the patients' EEGs, assessed, and quantified ED. The number and duration of ED divided by the duration of the EEG served as a proxy for the severity of IGE that was correlated with the results of the psychiatric screening. RESULTS: Paired data from 64 patients were available for analysis. The duration of EDs per minute EEG was inversely associated with the time since the last seizure. The number of patients with generalized polyspike trains (n = 2), generalized paroxysmal fast activity (n = 3), and prolonged epileptiform discharges (n = 10) were too low for statistically meaningful analyses. Self-reported symptoms of depression, personality disorder, and impulsivity were not associated with EDs. In contrast, the duration of EDs per minute EEG was associated with self-reported symptoms of anxiety in univariate analyses, not significant, however, following adjustment for time since the last seizure in regression models. SIGNIFICANCE: Self-reported symptoms of psychiatric diseases were not strongly associated with EDs as the best available quantifiable biomarker of IGE severity. As expected, the duration of EDs per minute and anxiety was inversely associated with time since the last seizure. Our data argue against a direct link between the frequency of EDs - as an objective proxy of IGE severity - and psychiatric symptoms.

Postictal Encephalopathy After Status Epilepticus: Outcome and Risk Factors.

BACKGROUND: Postictal encephalopathy is well known after status epilepticus (SE), but its prognostic impact and triggers are unknown. Here, we aimed to establish risk factors for the development of postictal encephalopathy and to study its impact on survival after discharge. METHODS: This retrospective cohort study comprised adult patients diagnosed with first nonanoxic SE at Odense University Hospital between January 2008 and December 2017. Patients with ongoing SE at discharge or unknown treatment success were excluded. Postictal symptoms of encephalopathy were estimated retrospectively using the West Haven Criteria (WHC). WHC grade was determined for postictal day 1 to 14 or until the patient died or was discharged from the hospital. Cumulative postictal WHC during 14 days after SE-cessation was used to quantify postictal encephalopathy. Clinical characteristics, patient demographics, electroencephalographic and imaging features, and details on intensive care treatment were assessed from medical records. RESULTS: Of all eligible patients (n = 232), 198 (85.3%) had at least WHC grade 2 postictal encephalopathy that lasted for > 14 days in 24.5% of the surviving patients. WHC grade at discharge was strongly associated with poor long-term survival (p < 0.001). Postictal encephalopathy was not associated with nonconvulsive SE, postictal changes on magnetic resonance imaging, or distinct ictal patterns on electroencephalography. Although duration of SE and treatment in the intensive care unit showed an association with cumulative postictal WHC grade, they were not independently associated with the degree of encephalopathy when controlling for confounders. In a linear regression model, etiology, duration of sedation, age, and premorbid modified Rankin Scale were significant and consistent predictors for higher cumulative postictal WHC grade. Exploratory analyses showed an association of a cumulative midazolam dosage (mg/kg/h) with higher cumulative postictal WHC grade. DISCUSSION: In this cohort, postictal encephalopathy after SE was common and associated with poor long-term survival. Seizure characteristics were not independently associated with postictal encephalopathy; the underlying etiology, long (high-dose midazolam) sedation, high age, and poor premorbid condition were the major risk factors for its development.

Drug resistance in idiopathic generalized epilepsies: Evidence and concepts.

Although approximately 10%-15% of patients with idiopathic generalized epilepsy (IGE)/genetic generalized epilepsy remain drug-resistant, there is no consensus or established concept regarding the underlying mechanisms and prevalence. This review summarizes the recent data and the current hypotheses on mechanisms that may contribute to drug-resistant IGE. A literature search was conducted in PubMed and Embase for studies on mechanisms of drug resistance published since 1980. The literature shows neither consensus on the definition nor a widely accepted model to explain drug resistance in IGE or one of its subsyndromes. Large-scale genetic studies have failed to identify distinct genetic causes or affected genes involved in pharmacokinetics. We found clinical and experimental evidence in support of four hypotheses: (1) "network hypothesis"-the degree of drug resistance in IGE reflects the severity of cortical network alterations, (2) "minor focal lesion in a predisposed brain hypothesis"-minor cortical lesions are important for drug resistance, (3) "interneuron hypothesis"-impaired functioning of γ-aminobutyric acidergic interneurons contributes to drug resistance, and (4) "changes in drug kinetics"-genetically impaired kinetics of antiseizure medication (ASM) reduce the effectiveness of available ASMs. In summary, the exact definition and cause of drug resistance in IGE is unknown. However, published evidence suggests four different mechanisms that may warrant further investigation.

Pseudoresistance in idiopathic/genetic generalized epilepsies - Definitions, risk factors, and outcome.

OBJECTIVE: The aim of the study was to determine risk factors associated with pseudoresistance in a large, representative cohort of patients with Idiopathic/Genetic Generalized Epilepsy (IGE) and the impact of pseudoresistance on socioeconomic parameters. METHODS: We performed a literature review on definitions of pseudoresistance in IGE. In an established cohort of patients with IGE from Funen, patients with current or previous pseudoresistant seizures were retrospectively identified based on a comprehensive evaluation of the patients' medical records and direct patient contact, if required. In addition, clinical characteristics, socioeconomic, and demographic data were assessed. Personal interviews were used to determine the brief version of Barratts (BIS-8) impulsivity score. RESULTS: The literature review provided the following definition of pseudoresistance: Seizures due to (I) lacking adherence to antiseizure medication (ASM), (II) incompliance to general rule of conduct, (III) psychogenic nonepileptic seizures (PNES), (IV) inadequate choice of ASM/dosage, and (V) incorrect classification of epilepsy. Applying criteria I-III to a cohort of patients with IGE (n = 499), 73 patients (14.6%) were currently pseudoresistant and 62 (12.4%) were previously pseudoresistant, but currently seizure free. Current pseudoresistance was associated with younger age, drug/alcohol abuse, lower rate of full-time employment, and higher BIS-8 scores. We found no associations of pseudoresistance with juvenile myoclonic epilepsy, psychiatric disease, specific seizure types, or number of seizure types. Patients with previously pseudoresistant seizures have tried more ASMs and were characterized by male preponderance, higher BIS-8, and higher rates of abuse. Surrogate markers for social outcome did not differ. SIGNIFICANCE: In IGE, pseudoresistance may be defined as PNES or insufficient adherence to medication/conduct and is associated with younger age, drug/alcohol abuse, and higher scores for impulsivity. If transient, its impact on socioeconomic status remains limited but may be associated with a risk of overtreatment with ASM.

The burden of disease of idiopathic/genetic generalized epilepsy - A nationwide online survey.

The aim of the study was to assess the self-reported burden of disease in people with idiopathic/genetic generalized epilepsy and risk factors associated with high disease burden. We performed a nationwide online survey on epilepsy characteristics/treatment, quality of life/daily living followed by Standardized Assessment of Personality-Abbreviated Scale, Major Depression Inventory, Barratt Impulsiveness Scale (brief) and the brief Epilepsy Anxiety Survey Instrument. The survey was sent to 275 representative patients with IGE ('Funen cohort') and later publicly distributed via the Danish Epilepsy Association. The characteristics of the responders of the 'Funen cohort' (n = 119) did not differ from non-responders and previously assessed data. Out of 753 persons accessing the public survey, 167 had probable IGE. As compared to the 'Funen cohort', patients from the public survey reported similar age, time since last seizure, years with disease, seizure types, and IGE syndromes but more current and previously tried anti-seizure medications (ASMs). In both cohorts, patients had higher scores for depression, impulsivity, and personality disorders as compared to Danish normal values irrespective of seizure control or medication. Higher depression and anxiety scores but neither impulsivity nor personality disorders were associated with ongoing seizures. Overall health condition was estimated as bad by 28%. In the last four weeks, 20.4% reported limitations of activities of daily living due to epilepsy; 27.8% felt fed up because of their epilepsy. Patients with high subjective disease burden had more current ASMs, shorter time since last seizure and increased scores for depression, anxiety, impulsivity, and personality disorders. In conclusion, having IGE was associated with higher scores for impulsivity, depression, and personality disorders irrespective of seizure control and current treatment. High subjective disease burden was common and associated with ongoing seizures, absence/myoclonic seizures and high scores for impulsivity, depression, anxiety, and personality disorders.

Neurofilament light chain as biomarker in idiopathic intracranial hypertension.

BACKGROUND: Damage of the optic nerve is the major complication of idiopathic intracranial hypertension. A biomarker indicative for optic nerve damage would help identifying high-risk patients requiring surgical procedures. Here, we studied the potential of cerebrospinal fluid neurofilament to predict idiopathic intracranial hypertension-induced optic nerve damage. METHODS: In two centers, serum and cerebrospinal fluid of 61 patients with clinically suspected idiopathic intracranial hypertension were prospectively collected. Neurofilament concentrations were measured and related to ophthalmological assessment. RESULTS: The average cerebrospinal fluid neurofilament concentration in patients with moderate and severe papilledema was increased compared to patients with minor and no papilledema (1755 ± 3507 pg/ml vs. 244 ± 102 pg/ml; p < 0.001). Cerebrospinal fluid neurofilament concentrations correlated with the maximal lumbar puncture opening pressure (r = 0.67, p < 0.001). In patients fulfilling the Friedman criteria for idiopathic intracranial hypertension with or without papilledema (n = 35), development of bilateral visual field defects and bilateral atrophy of the optic nerve were associated with increased average age-adjusted cerebrospinal fluid neurofilament concentrations. At last follow-up (n = 30), 8/13 of patients with increased, but only 3/17 with normal, cerebrospinal fluid neurofilament had developed bilateral visual field defects and/or bilateral optic nerve atrophy resulting in a sensitivity of 72.7% and a specificity of 73.7% of cerebrospinal fluid neurofilament to detect permanent optic nerve damage. CONCLUSIONS: Cerebrospinal fluid neurofilament is a putative biomarker for optical nerve damage in idiopathic intracranial hypertension.

Severe hypersomnia after unilateral infarction in the pulvinar nucleus- a case report.

BACKGROUND: Although a central role of the thalamus for sleep regulation is undisputed, the exact localization of the crucial structures within the thalamus remains controversial. CASE PRESENTATION: Here we report a 35 year old woman with no prior comorbidities who developed severe and persistent hypersomnia with long sleep time after a small right-sided MRI-verified thalamic stroke affecting the dorsal part of the pulvinar and the dorsolateral boarders of the dorsomedial nuclei. CONCLUSION: The observed symptoms suggest a crucial role of posterior thalamus but not the midline parts of the thalamus in sleep-wake control.

High long-term mortality after incident status epilepticus in adults: Results from a population-based study.

OBJECTIVE: To determine annual incidence, etiology, severity, and short- and long-term mortality of first-time, nonanoxic status epilepticus (SE) in adults in a population-based retrospective cohort study. METHODS: We systematically identified all episodes of SE in the year 2014 on the island of Funen. Patients with SE due to anoxia, patients with recurrent SE, and patients <18 years old were excluded. Nonconvulsive SE in coma was diagnosed according to the Salzburg criteria. Etiology, semiology, modified Rankin Scale (mRS) at discharge, survival, and the Status Epilepticus Severity Score were retrospectively determined from patients' records. Patients with first-time nonanoxic SE diagnosed during 2008-2013 from our database (n = 88) were used to confirm the results. RESULTS: The incidence of first-time, nonanoxic SE in 2014 was 10.7/100 000 persons at risk (n = 41). Median Status Epilepticus Severity Score was 3; in-hospital mortality was 24.4%. After median follow-up of 39.2 months, 53.7% of the patients had died (age- and gender-adjusted mortality rate of 5.2/100 000). Mortality stabilized 2 years after diagnosis. Analysis of the cohort from 2008-2013 confirmed stabilization of survival after 2-3 years and the high mortality 2 years after discharge. When correcting for acute symptomatic causes, the in-hospital mortality was 16.7% and 46.7% at follow-up (crude mortality rate of nonhypoxic and nonacute symptomatic SE = 3.5/100 000). An exploratory multivariate analysis of pooled patients with SE from 2008 to 2014 revealed mRS ≥ 2 at discharge as a prognostic factor for long-term mortality. SIGNIFICANCE: In this cohort, the overall mortality of first-time nonhypoxic SE was >50%. Mortality of SE after discharge was substantially higher than in-house mortality and stabilized after 2 years. The degree of disability as indicated by mRS at discharge was associated with long-term mortality after discharge.

CAMTA1 is a novel tumour suppressor regulated by miR-9/9* in glioblastoma stem cells.

Cancer stem cells or cancer initiating cells are believed to contribute to cancer recurrence after therapy. MicroRNAs (miRNAs) are short RNA molecules with fundamental roles in gene regulation. The role of miRNAs in cancer stem cells is only poorly understood. Here, we report miRNA expression profiles of glioblastoma stem cell-containing CD133(+) cell populations. We find that miR-9, miR-9(*) (referred to as miR-9/9(*)), miR-17 and miR-106b are highly abundant in CD133(+) cells. Furthermore, inhibition of miR-9/9(*) or miR-17 leads to reduced neurosphere formation and stimulates cell differentiation. Calmodulin-binding transcription activator 1 (CAMTA1) is a putative transcription factor, which induces the expression of the anti-proliferative cardiac hormone natriuretic peptide A (NPPA). We identify CAMTA1 as an miR-9/9(*) and miR-17 target. CAMTA1 expression leads to reduced neurosphere formation and tumour growth in nude mice, suggesting that CAMTA1 can function as tumour suppressor. Consistently, CAMTA1 and NPPA expression correlate with patient survival. Our findings could provide a basis for novel strategies of glioblastoma therapy.

Predictors of Seizure Recurrence in Women With Idiopathic Generalized Epilepsy Who Switch From Valproate to Another Medication.

BACKGROUND AND OBJECTIVES: To investigate the predictors of seizure recurrence in women of childbearing age with idiopathic generalized epilepsy (IGE) who switched from valproate (VPA) to alternative antiseizure medications (ASMs) and compare the effectiveness of levetiracetam (LEV) and lamotrigine (LTG) as VPA alternatives after switch. METHODS: This multicenter retrospective study included women of childbearing age diagnosed with IGE from 16 epilepsy centers. Study outcomes included worsening or recurrence of generalized tonic-clonic seizure (GTCS) at 12 months and 24 months after the switch from VPA to an alternative ASM. The comparative effectiveness of LEV and LTG as alternative ASM following VPA discontinuation was assessed through inverse probability treatment-weighted (IPTW) Cox regression analysis. RESULTS: We included 426 women with IGE, with a median (interquartile range) age at VPA switch of 24 (19-30) years and a median VPA dosage of 750 (500-1,000) mg/d. The most common reason for VPA switch was teratogenicity concern in 249 women (58.6%), and the most common ASM used in place of VPA was LEV in 197 (46.2%) cases, followed by LTG in 140 (32.9%). GTCS worsening/recurrence occurred in 105 (24.6%) and 139 (32.6%) women at 12 and 24 months, respectively. Catamenial worsening of seizures, higher VPA dosage during switch, multiple seizure types, and shorter duration of GTCS freedom before switch were independent predictors of GTCS recurrence or worsening at 12 months according to mixed multivariable logistic regression analysis. After internal-external validation through 16 independent cohorts, the model showed an area under the curve of 0.71 (95% CI 0.64-0.77). In the subgroup of 337 women who switched to LEV or LTG, IPTW Cox regression analysis showed that LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG (adjusted hazard ratio 0.59, 95% CI 0.40-0.87, p = 0.008) during the 24-month follow-up. DISCUSSION: Our findings can have practical implications for optimizing counselling and treatment choices in women of childbearing age with IGE and may help clinicians in making informed treatment decisions in this special population of patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with IGE switching from VPA, LEV was associated with a reduced risk of GTCS worsening or recurrence compared with LTG.

Neuropsychological profile and drug treatment response in Idiopathic Generalized Epilepsy.

PURPOSE: The endophenotype of Idiopathic Generalized Epilepsies (IGE) comprises distinct neuropsychological deficits compared to normal controls. It is unknown if the severity of features of the endophenotype correlates with resistance to anti-seizure medication. Therefore, we here studied the association of neuropsychological profiles with treatment response. METHODS: We evaluated 106 Danish patients aged ≥18 and diagnosed with IGE using a neuropsychological test battery comprising tests for executive dysfunction, visual attention, episodic memory, and verbal comprehension. Tests were complemented by the Purdue Pegboard test. Patients with suspected ongoing psychogenic non-epileptic seizures were excluded. RESULTS: At testing, 72 patients were seizure free, and 34 patients had recent seizures despite anti-seizure medication. As compared to age corrected Danish normative values, IGE patients showed significant impairments in semantic fluency and performed significantly worse in the Purdue Pegboard test. The vocabulary subtest of the WAIS-IV suggested lower verbal comprehension in IGE patients. We found no signs of memory impairment. Comparisons between results of the test battery, drug resistance, and the different IGE subsyndromes revealed consistent null-associations in various predefined and exploratory univariate and multivariate analyses. CONCLUSION: We here found and confirmed the distinct neuropsychological profile comprising impaired executive functions, reduced psychomotor speed, and normal memory previously described in juvenile myoclonic epilepsy. This profile was, however, not restricted to juvenile myoclonic epilepsy but equally affected all IGE patients. The neuropsychological deficits were not significantly associated with drug treatment outcome.

Levetiracetam vs Lamotrigine as First-Line Antiseizure Medication in Female Patients With Idiopathic Generalized Epilepsy.

Importance: After the recent limitations to prescribing valproate, many studies have highlighted the challenging management of female patients of reproductive age with idiopathic generalized epilepsy (IGE). However, no study, to the authors' knowledge, has addressed the comparative effectiveness of alternative antiseizure medications (ASMs) in these patients. Objective: To compare the effectiveness and safety of levetiracetam and lamotrigine as initial monotherapy in female patients of childbearing age with IGE. Design, Setting, and Participants: This was a multicenter, retrospective, comparative effectiveness cohort study analyzing data from patients followed up from 1994 to 2022. Patients were recruited from 22 primary, secondary, and tertiary adult and child epilepsy centers from 4 countries. Eligible patients were female individuals of childbearing age, diagnosed with IGE according to International League Against Epilepsy (2022) criteria and who initiated levetiracetam or lamotrigine as initial monotherapy. Patients were excluded due to insufficient follow-up after ASM prescription. Exposures: Levetiracetam or lamotrigine as initial monotherapy. Main Outcomes and Measures: Inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazards regression was performed to compare treatment failure (TF) among patients who received levetiracetam or lamotrigine as initial monotherapy. Results: A total of 543 patients were included in the study, with a median (IQR) age at ASM prescription of 17 (15-21) years and a median (IQR) follow-up of 60 (24-108) months. Of the study population, 312 patients (57.5%) were prescribed levetiracetam, and 231 (42.5%) were prescribed lamotrigine. An IPTW-adjusted Cox model showed that levetiracetam was associated with a reduced risk of treatment failure after adjustment for all baseline variables (IPTW-adjusted hazard ratio [HR], 0.77; 95% CI, 0.59-0.99; P = .04). However, after stratification according to different IGE syndromes, the higher effectiveness of levetiracetam was confirmed only in patients with juvenile myoclonic epilepsy (JME; IPTW-adjusted HR, 0.47; 95% CI, 0.32-0.68; P < .001), whereas no significant differences were found in other syndromes. Patients treated with levetiracetam experienced adverse effects more frequently compared with those treated with lamotrigine (88 of 312 [28.2%] vs 42 of 231 [18.1%]), whereas the 2 ASMs had similar retention rates during follow-up (IPTW-adjusted HR, 0.91; 95% CI, 0.65-1.23; P = .60). Conclusions and Relevance: Results of this comparative effectiveness research study suggest the use of levetiracetam as initial alternative monotherapy in female patients with JME. Further studies are needed to identify the most effective ASM alternative in other IGE syndromes.

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.

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.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

CERT1 mutations perturb human development by disrupting sphingolipid homeostasis.

Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.