Epilepsia最新文献

The interaction between basic science epilepsy researchers and clinical epileptologists is a longstanding issue. Efforts to provide opportunities for a dialogue between preclinical and clinical epilepsy professionals are crucial to reduce the knowledge gap between them and improve the translational success of neurobiology-based research. The International League Against Epilepsy (ILAE) Research and Innovation Task Force circulated a survey to investigate the need for an update on new clinical epilepsy concepts within the basic science community. The 336 respondents included basic scientists (BS), preclinical scientists (PCSs), and/or clinical scientists (CSs). The majority of the 237 BSs/PCSs were engaged in preclinical studies in translational epilepsy research and declared translational research as a priority research interest. Fewer respondents from low-middle-income countries than from upper-middle or high-income countries (40.7% vs 65%) considered translational research a critical aspect of their research. A broad understanding of both clinical and neurobiological aspects of epilepsy was declared by 48% of BSs/PCSs; 96% of CSs declared a superficial knowledge of neurobiology of epilepsy. Most BSs/PCSs were aware that epilepsy is a complex condition that should be investigated with the help of clinical epileptologists, even though concerns were expressed on the relationship with clinicians. A focused training program on emerging clinical epileptological aspects tailored for BSs/PCSs was recommended by 81% of the participants; the majority of respondents preferred either 1- or 2-week in-presence tutoring or continuous online training coordinated by ILAE at the regional/national level. The survey also underscored the value of educational programs on neurobiology of epilepsy targeting CSs and low-middle-income countries (LMIC) investigators.

General anesthesia (GA) earlier than recommended (as first- or second-line treatment) was recently described to improve status epilepticus (SE) outcome. We aimed to assess the impact of early GA on outcome in matched groups. Data from a multicenter, prospective cohort of 1179 SE episodes in 1049 adults were retrospectively analyzed. Incident SE episodes were categorized as “early anesthesia” (eGA; GA as first- or second-line treatment) or “non-early anesthesia” (neGA; GA after second-line treatment or not at all). Using propensity score matching, eGA episodes were paired 1:4 with neGA episodes. We assessed survival, functional outcomes at discharge (good: modified Rankin Scale = 0–2 or no worsening), SE cessation rate, SE duration, and hospital stay. Among 1049 SE episodes, 55 (5.2%) received eGA, and 994 constituted the neGA group; 220 represented the matched controls. Patients receiving eGA were younger (median = 63, interquartile range [IQR] = 56–76 vs. median = 70, IQR = 54–80 years, p = .004), had deeper consciousness impairment (80% vs. 40% stuporous/comatose, p < .001), and had more severe SE forms (89% vs. 54% generalized convulsive SE/nonconvulsive SE in coma, p < .001). Mortality, functional outcome, SE cessation rate, and duration of SE and hospital stay were similar between the eGA group and matched controls. We conclude that early anesthesia for SE treatment did not influence prognosis.

Objective: Neuronal cell death and neuroinflammation are characteristic features of epilepsy, but it remains unclear whether neuronal cell death as such is causative for the development of epileptic seizures. To test this hypothesis, we established a novel mouse line permitting inducible ablation of pyramidal neurons by inserting simian diphtheria toxin (DT) receptor (DTR) cDNA into the Ccl17 locus. The chemokine CCL17 is expressed in pyramidal CA1 neurons in adult mice controlling microglial quiescence.

Methods: Seizure activity in CCL17-DTR mice was analyzed by electroencephalographic recordings following treatment with DT for 3 consecutive days. Neuroinflammation and neuronal cell death were evaluated by (immuno)histochemistry. Pharmacological inhibition of TNFR1 signaling was achieved by treatment with XPro1595, a dominant-negative inhibitor of soluble tumor necrosis factor.

Results: Neuronal cell death was detectable 7 days (d7) after the first DT injection in heterozygous CCL17-DTR mice. Spontaneous epileptic seizures were observed in the vast majority of mice, often with an initial peak at d6-9, followed by a period of reduced activity and a gradual increase during the 1-month observation period. Microglial reactivity was overt from d5 after DT administration not only in the CA1 region but also in the CA2/CA3 area, shortly followed by astrogliosis. Reactive microgliosis and astrogliosis persisted until d30 and, together with neuronal loss and stratum radiatum shrinkage, reflected important features of human hippocampal sclerosis. Granule cell dispersion was detectable only 3 months after DT treatment. Application of XPro1595 significantly reduced chronic seizure burden without affecting the development of hippocampal sclerosis.

Significance: In conclusion, our data demonstrate that sterile pyramidal neuronal death is sufficient to cause epilepsy in the absence of other pathological processes. The CCL17-DTR mouse line may thus be a valuable model for further mechanistic studies on epilepsy and assessment of antiseizure medication.

Objective: Benzodiazepine rescue medications are established as therapy for acute termination of seizure clusters. A post-hoc analysis of a clinical trial of seizure cluster treatment with diazepam nasal spray found a potential longer-term impact over a year of treatment. In this retrospective analysis, we tested the hypothesis that benzodiazepine-treated seizure clusters are associated with prolonged time to the next seizure cluster compared with untreated seizure clusters in a patient-reported real-world database.

Methods: We analyzed data on self-reported seizures and benzodiazepine rescue medication administration in the Seizure Tracker™ database between 2007 and 2022. Kaplan-Meier analysis was used to compare treated vs untreated seizure clusters with respect to time to start of the next seizure cluster or immediate-use medication administration. Mixed-effects analysis was used to compare the number of seizures per cluster for treated and untreated seizure clusters. Robustness of findings was evaluated across three operational seizure-cluster definitions: ≥2 seizures in 4 hours as primary analysis and in 6 and 24 hours as sensitivity analyses.

Results: A total of 10 889 benzodiazepine immediate-use medication administrations (n = 220 patients) met inclusion criteria. Benzodiazepine rescue administrations were followed by longer time to the next seizure cluster or rescue administration, compared with untreated seizure clusters, corresponding to a median of 4.9 days following treated seizure clusters and a median of 0.8 days following untreated seizure clusters. This prolongation was driven by a minority of patients (accounting for 45.9% of seizure clusters in the sample) and patients were more likely to be women. The number of seizures per cluster was lower when treatment was administered earlier in the seizure cluster.

Significance: These retrospective real-world data suggest that the effect of benzodiazepines on termination of seizure clusters may be more pronounced when administration occurs earlier after onset, and support a hypothesis of a possible longer-term effect of benzodiazepines beyond immediate-use acute seizure termination.

Objective: The human brain undergoes an activity-dependent organization during late gestation, making it very sensitive to all effects on the spontaneous neuronal activity. Pregnant mothers with epilepsy are treated with antiepileptic drugs (AEDs) that may reach the fetus and cause altered cortical network activity after birth. However, it is not known whether these functional effects of intrauterine AED exposure persist later in childhood.

Methods: We studied cortical activity networks computed from electroencephalographic recordings during sleep of 25, 6-year-old children with in utero exposure to AEDs and 21 without exposure. The frequency-specific networks were determined for N1 and N2 sleep states, and the study groups were compared for sleep-state-specific changes and dynamic differences between sleep states. Finally, we correlated these difference networks with the children's neurophysiological performance at 6 years.

Results: We found brain-wide changes in the cortical activity networks and their sleep-state dynamics in the children with intrauterine AED exposure. Moreover, the strength of cortical network connectivity was significantly associated with multiple domains of neurocognitive performance, in particular, verbal comprehension, processing speed, and IQ. Our findings together suggest that fetal AED exposure causes very long-lasting changes in the cortical networks with significant links to early school-age cognitive performance.

Significance: AED treatment of pregnant mothers is indicated for maternal health reasons; however, the long-term neurodevelopmental effects on the offspring are poorly understood. Our present study shows that in utero exposure to AEDs causes persisting changes in the cortical activity networks, which can be measured with electroencephalography at 6 years of age. Moreover, these network changes correlate to the child's neurocognitive performance at the same age. These findings together suggest a pathway for how fetal drug exposures may cause persisting and neurocognitively meaningful changes in cortical connectivity patterns.

Objective: Few studies have evaluated the efficacy of antiseizure medications (ASMs) according to the etiology of neonatal acute provoked seizures. We aimed to investigate the response to ASMs in term/near term neonates with acute arterial ischemic stroke (AIS), as well as the type of seizure at presentation and the monitoring approach.

Methods: We retrospectively evaluated neonates from 15 European level IV neonatal intensive care units who presented with seizures due to AIS and were monitored by continuous electroencephalography (cEEG) and/or amplitude-integrated EEG (aEEG) in whom actual recordings, timing, doses, and response to ASMs were available for review.

Results: One hundred seven neonates were referred, and 88 were included. Of those, 56 met the criteria for evaluating the treatment response. The mean time to treatment was 7.9 h (SD = 16.4), and the most frequently administered first-line ASM was phenobarbital (PB; 74/88, 84.1%). Seizures were controlled within 24 h from onset of symptoms in 64.3% (36/56) of neonates. Phenytoin (PHT) was effective in almost all neonates in whom it was trialed (24/25, 96.0%), whereas PB was effective in only 22.0% of patients (11/50). Infants treated with PB or PHT as first-line treatment (53/56, 94.6%) showed a higher response rate with PHT (6/6, 100.0%) than with PB (11/47, 23.4%). Monitoring approach and seizure types were evaluated in 88 infants. Forty-six of 88 (52.3%) were monitored with cEEG and 47.7% (42/88) with aEEG, with or without intermittent cEEG. The mean monitoring duration was 65.8 h (SD = 39.21). In 83 of 88 (94.3%) infants, the type of seizure suspected clinically prior to monitoring was confirmed afterward. Unilateral focal clonic seizures were seen in 71 of 88 infants (80.7%), whereas 11 of 88 (12.5%) presented with ictal apneas.

Significance: Our findings provide evidence in a large, homogenous cohort that PHT is more effective than PB in treating neonatal acute symptomatic seizures due to AIS.

Objectives: The Phase 3 Study 338 (NCT02834793) assessed long-term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox-Gastaut syndrome (LGS).

Methods: Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18-week double-blind, randomized, placebo-controlled Core Study and ≥52-week open-label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure-freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures.

Results: Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs -.7%, respectively, p = .001) or all countable motor seizures (44.0% vs -.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment-emergent adverse events occurred in 85.3% of perampanel-treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo-treated patients.

Significance: This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long-term efficacy and safety of perampanel in the LGS population.

This case report shows the importance of multimodal evaluation to formulate a proper diagnosis of negative motor seizures (NMSs). Only few reports in literature document NMSs with video-electroencephalographic (EEG) and electromyographic coregistration. A multimodal evaluation is crucial to exclude common mimics and propose correct therapy. We describe a case of a 62-year-old man with drug-resistant focal epilepsy and NMSs, evaluated with video-EEG recording with polygraphy, magnetoencephalography (MEG), and brain magnetic resonance imaging (MRI). Video-EEG monitoring showed 182 focal NMSs, with preserved awareness and comprehension. The patient reported complex paresthesia of the left hand followed by left facial grimace, left arm flaccid paralysis, and bradycardia. EEG showed ictal discharges in the right frontocentral region associated with sudden electromyographical silence in left limb muscles consistent with loss of tonic contraction from distal to proximal muscles of the arm. MEG localized the epileptic zone in the right opercular region, consistent with MRI evidence of type II cortical dysplasia in the right inferior frontal gyrus. Multimodal evaluation is essential to document the temporal relationship between ictal discharges, clinical onset of limb paresis, and electrophysiologic evidence of loss of tonic muscular contraction. It allows definition of the specific cortical area involved in NMSs, offering new insight into physiological brain functioning.