Epilepsia最新文献

Objective: Deep brain stimulation, particularly low-frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug-resistant epilepsy (DRE) and for generalized epilepsy, both of which pose significant treatment challenges. LFS diffusely suppresses seizures in the cortex when applied to fiber tracts like the corpus callosum (CC). Nevertheless, the specific processes responsible for suppressing epileptic activity in the cortex induced by LFS remain unclear. This study investigates the mechanisms underlying the antiepileptic effect in the cortex of LFS of the CC in coronal rodent brain slices.

Methods: An in vitro 4-aminopyridine (4-AP) seizure model of cortical seizures was generated. LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in artificial cerebrospinal fluid, 4-AP, and in the presence of various specific and nonspecific γ-aminobutyric acid type B (GABA_B) and slow afterhyperpolarization (sAHP) antagonists.

Results: LFS significantly suppressed seizure activity in the cortex, with an optimal frequency of 5 Hz (76.5%). Tissue excitability during LFS reduces across a wide range of interstimulus intervals, with a maximum reduction at 200 ms. Notably, the tissue excitability remains depressed at 1000 ms. LFS, in the presence of GABA_B antagonists, had diminished seizure reduction (<15%) and failed to reduce tissue excitability in the 50-400-ms range. Tissue excitability measured with paired pulses in the 600-1000-ms range was depressed in the presence of GABA_B antagonists, suggesting a different antiepileptic mechanism was active. Upon administering sAHP antagonists, seizure reduction was once again diminished (<15%). Upon administration of both sAHP and GABA_B antagonists, LFS failed to provide any meaningful seizure reduction (<5%).

Significance: LFS of the CC provides an antiepileptic effect in the cortex with well-understood mechanisms and could be an alternative to surgical intervention for patients suffering from DRE.

Time is critical in executing acute seizure treatment, and efforts to minimize operational delays with medication preparation confer potential logistical and practical advantages. Multiple studies have demonstrated the safety and tolerability of intravenous (IV) undiluted levetiracetam (LEV) in adults; however, published pediatric data are limited. This study aims to evaluate the safety and tolerability of IV undiluted LEV in pediatrics. This was a retrospective, dual-center, observational cohort study evaluating concentration-related adverse drug events with IV undiluted (100 mg/mL) LEV in pediatrics over a 3-year 3-month timespan. A total of 60 undiluted administrations in 52 patients were included in the study. The median age was 4 years; 58.3% of patients were younger than 5 years of age. All doses were administered via a peripheral IV line. The most common IV anatomic site and peripheral IV gauge (G) was the antecubital (66.6%) and 22G catheter (63.3%). There were no documented concentration-related adverse drug events. Regardless of IV anatomic site, IV gauge, and administered dose there were no documented concentration-related adverse effects with IV undiluted LEV in a pediatric population. IV undiluted LEV may be considered safe and tolerable in pediatrics. Prospective pediatric studies should assess the safety and tolerability of IV undiluted LEV.

Here we critique recent arguments proposing to distinguish ictal from non-ictal generalized periodic discharges (GPDs) based on etiology and stimulation response, arguing that these are unreliable. We advocate for an empirical approach to GPDs: describe objectively, interpret through medication trials, and base further treatment on response. We call for evidence-based approaches considering meaningful clinical outcomes.

Objective: Despite growing interest in the potential use of exogenous ketones for the treatment of epilepsy, their impact on seizures and the gut microbiome and mycobiome remain unclear.

Methods: Here, we examined the effects of both oral gavage and subcutaneous (SC) injection of a ketone ester (KE) in spontaneously epileptic Kcna1-null (KO) mice that model seminal aspects of human temporal lobe epilepsy. Electroencephalographic recordings and biochemical analyses were performed in KE-treated KO mice. Fecal microbial and fungal communities were profiled to determine whether the antiseizure activity of KE involves changes in the gut microbiome.

Results: We found that exogenous KE administration by SC injection was more effective than oral gavage in terms of rendering antiseizure effects while generating similar degrees of ketonemia. However, reductions in mean daily seizure counts were accompanied by overall alterations in the fecal bacterial microbiome. Either oral or SC injection imposed a greater impact on the microbiome in male than female mice. In males, oral KE decreased Bacteroidota phylum and genera of Ligilactobacillus and Muribaculaceae, whereas SC injection decreased Bacteroides, Lactobacillus, and Lachnospiraceae. The fecal mycobiome was affected by KE injection to a greater degree than by oral gavage, and more in females than in males, as reflected by an increase in Ascomycota and Saccharomyces. Correlation analysis between microbiome and seizure counts revealed that in mice receiving KE injection, the seizure count was positively correlated with an amplicon sequencing variant of Lactobacillus (Spearman rho = .64, p = .03) and tended toward a negative correlation with Saccharomyces (Spearman rho = -.57, p = .057).

Significance: Our findings demonstrate that exogenous ketone administration alone can induce antiseizure effects equally via different routes of administration, and that they induce differential shifts in both the bacterial microbiome and mycobiome.

Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy. However, there is a lack of reliable predictors of VNS response in clinical use. The identification of factors predictive of VNS response is important for patient selection and stratification as well as tailored stimulation programming. We conducted a narrative review of the existing literature on prognostic markers for VNS response using clinical, demographic, biochemical, and modality-specific information such as from electroencephalography (EEG), magnetoencephalography, and magnetic resonance imaging (MRI). No individual marker demonstrated sufficient predictive power for individual patients, although several have been suggested, with some promising initial findings. Combining markers from underresearched modalities such as T1-weighted MRI morphometrics and EEG may provide better strategies for treatment optimization.

Objective: Little is known about the incidence of late onset epilepsy (LOE) across different racial/ethnic groups in the USA, particularly in the Hispanic population. Stroke, a strong predictor of LOE, is more common in non-Hispanic Blacks (NHBs) and Hispanics than in non-Hispanic Whites (NHWs). We assessed the incidence of LOE across racial/ethnic groups and examined whether the associations of stroke with LOE risk differ by race/ethnicity.

Methods: The Northern Manhattan Study is a population-based longitudinal study of older adults enrolled between 1993 and 2001. Participants free of history of stroke or epilepsy at baseline (n = 3419) were followed prospectively for incidence of LOE. We estimated LOE incidence per 1000 person-years in each racial/ethnic group. We used Cox proportional hazards regression to assess the association of race/ethnicity with LOE and multiplicative interactions of race/ethnicity with incident stroke in relation to LOE, adjusting for demographics and comorbid diagnoses.

Results: During 51 176 person-years of follow-up, 183 individuals developed LOE. Incidence of LOE was significantly higher in NHBs (6.2 per 1000 person-years) than in NHWs (3.3 per 1000 person-years, p = .004). There was no significant difference in LOE incidence between NHWs (3.3 per 1000 person-years) and Hispanics (2.6 per 1000 person-years, p = .875). However, following incident stroke, the risk of LOE differed across racial/ethnic groups. Incident stroke was associated with 2.55 times the risk of LOE among NHWs (95% confidence interval [CI] = .88-7.35), 8.53 times the risk of LOE among Hispanics (95% CI = 5.36-13.57, p = .04 for stronger association than that in NHWs), and 6.46 times the risk of LOE among NHBs (95% CI = 3.79-11.01, p = .12 for stronger association than that in NHWs).

Significance: We found a stronger association of incident stroke with LOE risk in Hispanics and NHBs than in NHWs, offering some insight into the racial/ethnic disparities of LOE incidence.

Objective: Pathological amyloid-β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1-42 and p181-tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug-resistant temporal lobe epilepsy (TLE).

Methods: In this cross-sectional study, we enrolled individuals with drug-resistant TLE who were 25-55 years old. Each participant underwent ¹⁸F-flutemetamol PET, determination of CSF Aβ1-42, p181-tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET.

Results: Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4-24) years. Twenty-six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z-score = .90, 95% confidence interval [CI] = .60-1.20; contralateral: SUVR z-score = .92, 95% CI = .57-1.27; p < .001), which was higher when compared to SUVR z-scores in all the remaining regions (p < .001) and in the ipsilateral anterior cingulate (SUVR z-score = .27, 95% CI = .04-.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1-42 levels, and two (7%) had elevated p181-tau levels in CSF. Higher p181-tau levels correlated with poorer verbal fluency (R = -.427, p = .044).

Significance: Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug-resistant TLE. Additionally, abnormal CSF Aβ1-42 levels were observed in a significant proportion of patients, and p181-tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation.

Objective: To determine the optimal duration of electroencephalography (EEG) recording to detect epileptic spasms (ES) based on inpatient overnight video-EEG monitoring in patients with infantile epileptic spasms syndrome (IESS) at the 2-week follow-up.

Methods: Patients with IESS and overnight EEG monitoring between January 2020 and June 2022 were retrospectively reviewed. Time-to-ES, time-to-sleep and time-to-epileptic encephalopathy (EE) per the Burden of Amplitudes and Epileptiform Discharges (BASED 2021) score. BASED 2021 score were reported. ES and sleep detection sensitivity were calculated with respect to monitoring time. Etiology, treatment, and EEG features were assessed for strength of association with continued ES. Time-to-event analysis was performed with the first ES as the event of interest.

Results: Of 90 patients, 39 (43%) continued to have ES; 78.6% with EE continued to have ES, whereas only 27.4% without EE had ES (odds ratio [OR] 12.05). Structural etiologies were also associated with continued ES (OR 5.24). ES detection was 35.9%, 76.9%, and 84.6% at 1, 4, and 6 h, respectively, with corresponding negative likelihood ratios (NLRs) of .64, .23, and .15. ES detection reached >90% and >95% at 14 and 19 h, respectively. Sleep detection was 52.2%, 84.4%, and 95.6% at 1, 4, and 6 h, respectively, and captured in all patients by 11 h. EE was observed by 6 h for all associated patients.

Significance: Typical routine EEG durations (<1 h) were not sufficient to detect ES, EE, or sleep in patients with IESS at the 2-week follow-up. Four hour outpatient EEG will capture ES in 77% and sleep in 84% of the patients. EE, if present, was shortly after sleep onset. Additional monitoring of up to 19 h was needed to capture >95% of patients with ES. Although EE was strongly associated with continued ES, 27.4% of patients without EE demonstrated ES. This study will help guide adequate duration of EEG monitoring at the 2-week follow-up for patients with IESS.

Epilepsy represents a common neurological disorder in patients with developmental brain lesions, particularly in association with malformations of cortical development and low-grade glioneuronal tumors. In these diseases, genetic and molecular alterations in neurons are increasingly discovered that can trigger abnormalities in the neuronal network, leading to higher neuronal excitability levels. However, the mechanisms underlying epilepsy cannot rely solely on assessing the neuronal component. Growing evidence has revealed the high degree of complexity underlying epileptogenic processes, in which glial cells emerge as potential modulators of neuronal activity. Understanding the role of glial cells in developmental brain lesions such as malformations of cortical development and low-grade glioneuronal tumors is crucial due to the high degree of pharmacoresistance characteristic of these lesions. This has prompted research to investigate the role of glial and immune cells in epileptiform activity to find new therapeutic targets that could be used as combinatorial drug therapy. In a special session of the XVI Workshop of the Neurobiology of Epilepsy (WONOEP, Talloires, France, July 2022) organized by the Neurobiology Commission of the International League Against Epilepsy, we discussed the evidence exploring the genetic and molecular mechanisms of glial cells and immune response and their implications in the pathogenesis of neurodevelopmental pathologies associated with early life epilepsies.