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Background and Objectives: To compare long-term seizure control in patients with long-term VNS (vagal nerve stimulator) stimulation (VNS-on) with those who discontinued VNS after >3 years (VNS-off)., Methods: Patients with refractory epilepsy with VNS therapy for >3 years (and follow-up for >2 years after VNS discontinuation for VNS-off patients) were included. Patients with brain surgery <3 years after VNS were excluded. We compared the percentage of patients with ≥50% seizure reduction (50% responder rate) and change in seizure frequency within and between groups in follow-up., Results: Thirty-three VNS-on and 16 VNS-off patients were evaluated. VNS-on patients underwent stimulation for 9.7 years (mean). VNS-off patients had VNS treatment for 6.5 years (mean), discontinued treatment, then had additional 8.0 years (mean) follow-up. 50% responder rates were similar between groups (VNS-on: 54.5% vs VNS-off at last-on: 37.5%, p = 0.26; vs VNS-off at the last follow-up: 62.5%, p = 0.60). VNS-on patients had a significant reduction in seizure frequency at the last follow-up compared with baseline (median [Mdn] = -4.5 seizures/month, interquartile range [IQR] = 14.0, 56% reduction, p = 0.013). VNS-off patients also showed significant seizure reduction while still continuing VNS therapy (Mdn = -1.0 seizures/month, IQR = 13.0, 35% reduction, p = 0.020) and, after discontinuing therapy, at the last follow-up compared with baseline (Mdn = -3.2, IQR = 11.0, 52% reduction, p = 0.020). The 2 groups were comparable in seizure frequency change both at the last-on visit (absolute change, p = 0.62; relative change, p = 0.50) at the last follow-up (absolute change, p = 0.67; relative change, p = 0.76)., Discussion: Patients who discontinued VNS therapy and those who continued therapy had similar response during active treatment and similar long-term outcomes, suggesting that factors such as the natural disease course and/or medication treatment strongly affect long-term outcomes., Competing Interests: K.N. Devlin (knd52@drexel.edu) has served as a consultant for Neurologic Solutions, Inc., and Diagnostic Driving, Inc., and currently receives research grants from NIH (R01HD096066, P30MH092177); H. Yuan (hsiangkuo.yuan@jefferson.edu) has received funding from NIH (R44NS115460); institutional support for serving as an investigator from Teva, Abbvie, Thermaquil; consultant fees from Salvia, Pfizer, Cerenovus; and royalties from Cambridge University Press and MedLink; C.T. Skidmore (christopher.skidmore@jefferson.edu) has received lecture honoraria from Natus and research support through Neuropace and Jazz Pharmaceuticals; C. Wu (chengyuan.wu@jefferson.edu) is a paid consultant for Medtronic, Boston Scientific, Abbott, Neuropace, Nevro, BrainLab, and NeuroOne; and serves on the Advisory Board for ZetaSurgical; M. Sperling (michael.sperling@jefferson.edu) has received compensation for speaking at CME programs from Medscape, Projects for Knowledge, International Medical Press, and Darnitsa. He has consulted for Medtronic, Neurelis, and Johnson & Johnson. He has received research support from Medtronic; Neurelis; SK Life Science; Takeda; Xenon; Cavion; Cerevel; UCB Pharma; Janssen; Equilibre; and Engage Pharmaceuticals. He has received royalties from Oxford University Press and Cambridge University Press; M. Nei (maromi.nei@jefferson.edu) receives honoraria from MedLink Neurology and has research support through UCB Pharma and Eisai. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Background and Objectives: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases., Methods: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z -score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors., Results: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers ( p > 0.05)., Discussion: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Purpose: To evaluate the radiographic diagnostic criteria and propose standardised radiographic criteria for Lisfranc injuries., Methods: A systematic review of the PubMed and Embase databases was performed according to the PRISMA guidelines. The various radiographic criteria for the diagnosis of Lisfranc injuries were extracted. Descriptive statistics were presented for all continuous (as mean ± standard deviation) and categorical variables (as frequencies by percentages)., Results: The literature search included 29 studies that totalled 1115 Lisfranc injuries. The risk of bias ranged from "Low" to "Moderate" risk according to the ROBINS-I tool. The overall recommendations according to the GRADE assessment ranged from "Very Low" to "High". 1 st metatarsal to 2 nd metatarsal diastasis was the most common of the 12 various radiographic diagnostic criteria observed, as was employed in 18 studies. This was followed by 2 nd cuneiform to 2 nd metatarsal subluxation, as was employed in 11 studies., Conclusion: The radiographic diagnostic criteria of Lisfranc injuries were heterogeneous. The proposition for homogenous radiographic diagnostic criteria is that the following features must be observed for the diagnosis of Lisfranc injuries: 1 st metatarsal to 2 nd metatarsal diastasis of ≥ 2 mm on anteroposterior view or 2 nd cuneiform to 2 nd metatarsal subluxation on anteroposterior or oblique views. Further advanced imaging by CT or MRI may be required in patients with normal radiographs but with continued suspicion for Lisfranc injuries., Level of Evidence: 4, systematic review., (© 2023. The Author(s).)

Objective: Prolonged postictal generalized electroencephalographic suppression (PGES) is a potential biomarker for sudden unexpected death in epilepsy (SUDEP), which may be associated with dysfunctional autonomic responses and serotonin signaling. To better understand molecular mechanisms, PGES duration was correlated to 5HT1A and 5HT2A receptor protein expression and RNAseq from resected hippocampus and temporal cortex of temporal lobe epilepsy patients with seizures recorded in preoperative evaluation., Methods: Analyses included 36 cases (age = 14-64 years, age at epilepsy onset = 0-51 years, epilepsy duration = 2-53 years, PGES duration = 0-93 s), with 13 cases in all hippocampal analyses. 5HT1A and 5HT2A protein was evaluated by Western blot and histologically in hippocampus (n = 16) and temporal cortex (n = 9). We correlated PGES duration to our previous RNAseq dataset for serotonin receptor expression and signaling pathways, as well as weighted gene correlation network analysis (WGCNA) to identify correlated gene clusters., Results: In hippocampus, 5HT2A protein by Western blot positively correlated with PGES duration (p = .0024, R 2  = .52), but 5HT1A did not (p = .87, R 2  = .0020). In temporal cortex, 5HT1A and 5HT2A had lower expression and did not correlate with PGES duration. Histologically, PGES duration did not correlate with 5HT1A or 5HT2A expression in hippocampal CA4, dentate gyrus, or temporal cortex. RNAseq identified two serotonin receptors with expression that correlated with PGES duration in an exploratory analysis: HTR3B negatively correlated (p = .043, R 2  = .26) and HTR4 positively correlated (p = .049, R 2  = .25). WGCNA identified four modules correlated with PGES duration, including positive correlation with synaptic transcripts (p = .040, Pearson correlation r = .52), particularly potassium channels (KCNA4, KCNC4, KCNH1, KCNIP4, KCNJ3, KCNJ6, KCNK1). No modules were associated with serotonin receptor signaling., Significance: Higher hippocampal 5HT2A receptor protein and potassium channel transcripts may reflect underlying mechanisms contributing to or resulting from prolonged PGES. Future studies with larger cohorts should assess functional analyses and additional brain regions to elucidate mechanisms underlying PGES and SUDEP risk., (© 2022 International League Against Epilepsy.)

Sudden unexpected death in epilepsy (SUDEP) is a tragic and unexpected cause of death in patients with a known diagnosis of epilepsy. It occurs in up to 6.3 to 9.3/1,000 patients with drug-resistant epilepsy. The main three risk factors associated with SUDEP are the presence of generalized tonic-clonic seizures, the presence of a seizure in the past year, and an intellectual disability. There are several mechanisms that can result in SUDEP. The most likely sequence of events appears to be a convulsive seizure, overactivation of the autonomic nervous system, cardiorespiratory dysfunction, and death. While the risk of SUDEP is relatively high in patients with drug-resistant epilepsy, studies indicate that more than 50% of patients and caregivers are unaware of the diagnosis. Counseling about the diagnosis and preventative measures at the time of diagnosis is important. There are numerous interventions that may reduce the risk of SUDEP, including conservative measures such as nocturnal surveillance with a bed partner (where applicable) and automated devices. Optimizing seizure control with antiseizure medications and surgical interventions can result in a reduced risk of SUDEP., Competing Interests: None declared., (Thieme. All rights reserved.)

Getah virus (GETV) is a zoonotic arbovirus that can cause infection in many animals. It can cause pyrexia and reproductive losses in animals. The objective of the study was to explore the effects of GETV on male reproductive ability. Male mice were injected with 100 × TCID 50 /0.1 ml in a volume of 100-μL GETV in their hindquarter muscle, resulting in decreased semen quality and testicular histopathological changes, and the virus was detected in the testes. At 0.5 dpi (day post-infection), male mice showed decreased sperm density, motility, and decreased serum testosterone concentration, an increased sperm malformation rate, vacuoles in spermatogonial cells/spermatocytes in spermatogenic tubules, and the highest virus copies in testis. At 2 dpi, the sperm density and motility reached the lowest value of 3.99 × 10 6 /ml and 62.03%, and the malformation rate reached 43.67%. At 28 dpi, the sperm indexes of the experimental group gradually approached that of the control group, but there were still significant differences. Since then, histopathological changes have worsened, with the most severe histopathological changes at 7 dpi and gradual recovery. Up to 14 dpi, the virus was detected by qRT-PCR and immunohistochemistry, which showed that the virus was only present in the testicular interstitium. GETV infection can rapidly enter the testis of mice and reduce the semen quality of mice, which needs to be paid attention to in the prevention and control of GETV., Competing Interests: BZ was employed by Sichuan Techlex Food Co., Ltd. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Zhang, Xu, Jiang, Nei, Xu, Zhao, Deng, Sun, Zhou and Zhu.)