One-year seizure freedom and quality of life in patients with drug-resistant epilepsy receiving adjunctive vagus nerve stimulation in Japan.

OBJECTIVE: Amount of seizure-free days is a critical determinant of quality of life (QoL) in patients with drug-resistant epilepsy (DRE). The fractions of patients experiencing prolonged periods of seizure freedom with adjunctive vagus nerve stimulation (VNS) have yet to be assessed on a large scale. METHODS: Retrospective analysis of patients in the Japanese VNS prospective observational registry who experienced at least 1 year of seizure freedom from all seizures, focal seizures, or tonic-clonic seizures (TCS), as well as patient-reported change in QoL in these groups. RESULTS: The study included 362 patients with DRE, 147 were female (40.6%), and the median age at VNS implant was 23.0 years (range: 1.0-73.0). A total of 225 patients reported focal seizures and 184 patients reported TCS. After 36 months of adjunctive VNS, the cumulative proportion of patients experiencing at least 1 year of complete seizure freedom was 11% (38/356) with an average duration of seizure freedom of 19.4 months. In patients with focal seizures, 25% (n = 57/225) experienced at least 1 year of freedom from focal seizures with an average duration of 24.8 months. Higher cumulative rates of freedom from TCS were observed: 55% (n = 101/184) experienced at least 1 year without TCS with an average duration of TCS-free periods of 28.9 months. 82.1% of patients with 12-month complete seizure freedom reported markedly improved or improved QoL compared with 51.9% of patients who were not seizure-free. QoL changes in patients with 12-month seizure freedom from TCS and focal seizures were similar: 61.8% and 63% of respective patients reported either markedly improved or improved QoL at 36 months. SIGNIFICANCE: Complete seizure freedom is rare in patients treated with VNS; however, this analysis found approximately half of patients who experienced TCS prior to VNS experienced prolonged periods of freedom from TCS with adjunctive VNS. PLAIN LANGUAGE SUMMARY: We studied patients in Japan with epilepsy that is difficult to treat. To understand if adding vagus nerve stimulation (VNS) helps such patients, we looked at which patients stopped having all seizures or stopped having a specific seizure type (such as tonic-clonic seizures or focal seizures), and how long these periods lasted. With VNS treatment, about 2 out of 4 patients with tonic-clonic seizures and 1 out of 4 patients with focal seizures had more time without these seizure types. Without seizures, patients felt better about their daily lives. Even patients who still had seizures felt better about their daily lives after 3 years of VNS treatment. TRIAL REGISTRATION: The clinical trial registry number is UMIN000014728.

Association of SCN1A Polymorphisms rs3812718 and rs2298771 with Epilepsy.

Background/Objectives: Epilepsy is a brain disease with both environmental and genetic inputs. Ion channel dysfunction seems to be of great significance for abnormal neuronal behavior during epileptic seizures. Within neurons, the voltage-gated sodium channels are crucial proteins contributing to the initiation and propagation of action potentials. The voltage-gated sodium channel α subunit 1 (SCN1A) gene encodes for the α subunit of a voltage-gated ion channel. The aim of the study was to investigate the relation of two common SCN1A variants, i.e., rs3812718 and rs2298771, with distinct epileptic phenotypes in a South-Eastern European population. Methods: DNA was extracted from 214 unrelated participants with focal onset, focal to bilateral tonic-clonic, or generalized onset epileptic seizures and genotyped using real-time PCR (LightSNiP assays) followed by melting curve analysis. Statistical analysis of the results was performed using IBM SPSS Statistics software (version 29.0 for Windows). Results: Genotype frequency distribution analysis indicated an association for the A-allele-containing genotypes of both rs3812718 and rs2298771 polymorphisms of SCN1A with generalized onset seizures and focal to bilateral tonic-clonic seizures versus focal onset seizures. Conclusions: Consequently, the study provides evidence that supports a potential association of the investigated SCN1A polymorphisms with distinct seizure subtype susceptibility in South-Eastern Europeans.

Effectiveness of add-on acetazolamide in children with drug-resistant CHD2-related epilepsy and in a zebrafish CHD2 model.

CHD2-related epilepsy is characterized by early-onset photosensitive myoclonic epilepsy with developmental delay and a high rate of pharmacoresistance. We sought to evaluate the efficacy of acetazolamide (ACZ) in CHD2-related epilepsy, due to ACZ's unexpected efficacy in our first patient harboring a pathogenic CHD2 variant. We collected patients from different Eastern European countries with drug-resistant CHD2-related epilepsy who were then treated with ACZ. Patients underwent video EEG before and during ACZ treatment. In a zebrafish model of CHD2-related epilepsy, ictal-like events were recorded 5 days post-fertilization after overnight ACZ exposure. Developmental delay preceded the onset of seizures in 10 of the 12 patients. Four had ataxia, and 6 exhibited autistic features. Seizures, primarily myoclonic, began at an average age of 3.4 years and were photosensitive in all 12 patients. Add-on ACZ treatment controlled photosensitive seizures in all patients: 6 became seizure-free, and in the remaining 6, seizure frequency decreased by over 75%. Four patients transitioned to ACZ monotherapy. The median follow-up was 13 months. In the zebrafish model, ACZ exposure reduced ictal-like events by 72%. ACZ, a well-tolerated and cost-effective medication, could be a good option for CHD2-related epilepsy, predominantly manifesting with myoclonic seizures and photosensitivity. PLAIN LANGUAGE SUMMARY: Epilepsy associated with CHD2 mutations is often pharmacoresistant and associated with developmental delay and eventually ataxia. There are several generalized seizure types, including generalized tonic-clonic seizures, but the most characteristic are jerks triggered by light stimulation. We collected 12 patients who received acetazolamide, a drug usually given as a diuretic and registered as a mild antiseizure medication. All jerks triggered by light disappeared while the frequency of spontaneous seizures decreased by over 75%. Further studies are needed to confirm this promising finding and identify the mechanism by which an old compound seems to have such a specific antiseizure effect.

Characterizing white matter connectome abnormalities in patients with temporal lobe epilepsy using threshold-free network-based statistics.

INTRODUCTION: Emerging evidence illustrates that temporal lobe epilepsy (TLE) involves network disruptions represented by hyperexcitability and other seizure-related neural plasticity. However, these associations are not well-characterized. Our study characterizes the whole brain white matter connectome abnormalities in TLE patients compared to healthy controls (HCs) from the prospective Epilepsy Connectome Project study. Furthermore, we assessed whether aberrant white matter connections are differentially related to cognitive impairment and a history of focal-to-bilateral tonic-clonic (FBTC) seizures. METHODS: Multi-shell connectome MRI data were preprocessed using the DESIGNER guidelines. The IIT Destrieux gray matter atlas was used to derive the 162 × 162 structural connectivity matrices (SCMs) using MRTrix3. ComBat data harmonization was applied to harmonize the SCMs from pre- and post-scanner upgrade acquisitions. Threshold-free network-based statistics were used for statistical analysis of the harmonized SCMs. Cognitive impairment status and FBTC seizure status were then correlated with these findings. RESULTS: We employed connectome measurements from 142 subjects, including 92 patients with TLE (36 males, mean age = 40.1 ± 11.7 years) and 50 HCs (25 males, mean age = 32.6 ± 10.2 years). Our analysis revealed overall significant decreases in cross-sectional area (CSA) of the white matter tract in TLE group compared to controls, indicating decreased white matter tract integrity and connectivity abnormalities in addition to apparent differences in graph theoretic measures of connectivity and network-based statistics. Focal and generalized cognitive impaired TLE patients showcased higher trend-level abnormalities in the white matter connectome via decreased CSA than those with no cognitive impairment. Patients with a positive FBTC seizure history also showed trend-level findings of association via decreased CSA. CONCLUSIONS: Widespread global aberrant white matter connectome changes were observed in TLE patients and characterized by seizure history and cognitive impairment, laying a foundation for future studies to expand on and validate the novel biomarkers and further elucidate TLE's impact on brain plasticity.

Effect of Antiseizure Medication on the Salience Network in Patients with Epilepsy with Generalized Tonic-Clonic Seizures Alone.

This study aimed to investigate the effects of antiepileptic drugs on salience network regions in patients with epilepsy with generalized tonic-clonic seizures alone (EGTCSa). A retrospective observational case-control study was performed on 40 patients diagnosed with epilepsy with EGTCSa and 40 healthy age-matched controls. In LORETA, a voxel-by-voxel analysis between regions from the salience network was performed for both hemispheres, specifically between the anterior cingulate (BA 32 and BA 24) and the sublobar insula (BA 13). Subsequently, a Wilcoxon rank-sum test (the Mann-Whitney U test) was conducted for the equality of medians in the transformation matrix. A comparison was then made between each region of interest as defined by the salience network and the controls. Marked differences were found in the brain regions assessed in patients with EGTCSa treated with valproic acid and carbamazepine compared to the control group; few differences in patients treated with levetiracetam; and no difference was found in the group without treatment compared with those in the control group. These results suggest that ASMs can influence cognitive processes, which provide novel insights toward understanding the neural mechanisms underlying the effects of ASMs administration.

Inhibition of TRPC3 channels suppresses seizure susceptibility in the genetically-epilepsy prone rats.

Transient receptor potential canonical 3 (TRPC3) channels are important in regulating Ca2+ homeostasis and have been implicated in the pathophysiology of chemically induced seizures. Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) has been linked to increased voltage-gated Ca2+ channel currents in the inferior colliculus neurons, which can affect intraneuronal Ca2+ homeostasis. However, whether TRPC3 channels also contribute to inherited seizure susceptibility in GEPR-3s is unclear. This study investigated the effects of JW-65, a potent and selective inhibitor of TRPC3 channels, on acoustically evoked seizure susceptibility in adult male and female GEPR-3s. These seizures consisted of wild running seizures (WRSs) that evolved into generalized tonic-clonic seizures (GTCSs). The results showed that acute administration of low doses of JW-65 significantly decreased by 55-89% the occurrence of WRSs and GTCSs and the seizure severity in both male and female GEPR-3s. This antiseizure effect was accompanied by increased seizure latency and decreased seizure duration. Additionally, female GEPR-3s were more responsive to JW-65's antiseizure effects than males. Moreover, JW-65 treatment for five consecutive days completely suppressed acoustically evoked seizures in male and female GEPR-3s. These findings suggest that inhibiting TRPC3 channels could be a promising antiseizure strategy targeting Ca2+ signaling mechanisms in inherited generalized tonic-clonic epilepsy.

Perampanel as monotherapy or first adjunctive therapy in pediatric and adult patients with epilepsy: the first United States-based phase IV open-label ELEVATE study.

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4 years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, perampanel was initiated at 2 mg/day and up-titrated to 4 mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12 mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8 weeks and 32 (59.3%) patients completed the study. Retention rate at 12 months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy.

Brain activation and connection across resting and motor-task states in patients with generalized tonic-clonic seizures.

AIMS: Motor abnormalities have been identified as one common symptom in patients with generalized tonic-clonic seizures (GTCS) inspiring us to explore the disease in a motor execution condition, which might provide novel insight into the pathomechanism. METHODS: Resting-state and motor-task fMRI data were collected from 50 patients with GTCS, including 18 patients newly diagnosed without antiepileptic drugs (ND_GTCS) and 32 patients receiving antiepileptic drugs (AEDs_GTCS). Motor activation and its association with head motion and cerebral gradients were assessed. Whole-brain network connectivity across resting and motor states was further calculated and compared between groups. RESULTS: All patients showed over-activation in the postcentral gyrus and the ND_GTCS showed decreased activation in putamen. Specifically, activation maps of ND_GTCS showed an abnormal correlation with head motion and cerebral gradient. Moreover, we detected altered functional network connectivity in patients within states and across resting and motor states by using repeated-measures analysis of variance. Patients did not show abnormal connectivity in the resting state, while distributed abnormal connectivity in the motor-task state. Decreased across-state network connectivity was also found in all patients. CONCLUSION: Convergent findings suggested the over-response of activation and connection of the brain to motor execution in GTCS, providing new clues to uncover motor susceptibility underlying the disease.

Oligoepilepsy and lifelong seizure susceptibility in epilepsy with generalized tonic-clonic seizures alone: Experience at an adult tertiary center.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is the least studied syndrome within the idiopathic generalized epilepsy (IGE) spectrum. We characterize a large cohort of adult patients with GTCA to understand natural history and drug responsiveness. METHODS: In this retrospective single-center study using our epilepsy electronic record, we evaluated clinical characteristics, seizure outcomes, anti-seizure medication (ASM) response including seizure recurrence after ASM withdrawal, and sex differences in a cohort of GTCA patients aged ≥17 years. RESULTS: Within a cohort of 434 IGE patients, 87 patients (20 %) with GTCA were included. The mean age was 34.9 years (range 17-73 years). Forty-six patients (52.8 %) were females. Seventy-two patients (82.8 %) were seizure-free and 15 (17.2 %) had active epilepsy over the previous 12 months. Thirty-four patients (39.1 %) had ≤5 lifetime seizures, aligning with a prior definition of 'oligoepilepsy'. Sixty-five patients (74.7 %) were treated with monotherapy, 19 (21.8 %) were treated with polytherapy, and three were not taking any ASM. Levetiracetam (37.9 %) was the most commonly prescribed ASM, followed by lamotrigine (32.1 %) and valproate (31 %). Seventeen patients (19.5 %) attempted to withdraw their ASM. The rate of seizure recurrence after ASM withdrawal was 88.2 % (15/17), including two patients who relapsed more than 20 years after ASM discontinuation. Females had more seizures in their lifetime and had trialed more ASM compared to males. SIGNIFICANCE: GTCA has a relatively good prognosis, with most patients becoming seizure-free on monotherapy. The high rate of seizure recurrence after ASM withdrawal supports lifetime seizure susceptibility. We found potential sex differences in seizure outcomes and ASM response, although further research is needed to validate this finding.

Clearance for Driving in Genetic Generalized Epilepsy.

A key aspect of management of genetic generalized epilepsy involves assessing seizure control and deciding suitability for driving motor vehicles. We surveyed child neurologists and pediatric epileptologists on key questions that practitioners should ask prior to providing clearance for driving. The results showed a wide variability of practice among responders. We propose a likely appropriate process necessary to determine seizure control.

[Incidence of sudden death in epilepsy (SUDEP): update and limitations]. / Inzidenz des plötzlichen Epilepsietodes (SUDEP): Update und Limitationen.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is in most cases probably due to a fatal complication of tonic-clonic seizures and plays a significant role in the premature mortality of individuals with epilepsy. The reported risks of SUDEP vary considerably depending on the study population, so that an up-dated systematic review of SUDEP incidence including most recent studies is required to improve the estimated SUDEP risk and the counseling of individuals with epilepsy. OBJECTIVE: To provide an overview of the current research landscape concerning SUDEP incidence across different patient populations and discuss potential conclusions and existing limitations. MATERIAL AND METHODS: A systematic literature review on SUDEP incidence was conducted in MEDLINE and EMBASE, supplemented by a manual search in June 2023. Out of a total of 3324 publications, 50 were reviewed for this study. RESULTS: The analyzed studies showed significant heterogeneity concerning cohorts, study design and data sources. Studies conducted without specific criteria and relying on comprehensive registers indicated an incidence of 0.78-1.2 per 1000 patient-years. Research providing incidences across various age groups predominantly show an increase with age, peaking in middle age. DISCUSSION: Due to varying methods of data collection and incidence calculation, comparing between studies is challenging. The association with age might be due to an underrepresentation of children, adolescents and patients over 60 years. CONCLUSION: Considering all age groups and types of epilepsy it is estimated that about 1 in 1000 individuals with epilepsy dies of SUDEP annually. With an assumed epilepsy prevalence of 0.6% in Germany, this could lead to more than one SUDEP case daily. Standardization of research methods is essential to gain more profound insights.

Focal electroclinical features in generalized tonic-clonic seizures: Decision flowchart for a diagnostic challenge.

OBJECTIVE: Bilateral tonic-clonic seizures with focal semiology or focal interictal electroencephalography (EEG) can occur in both focal and generalized epilepsy types, leading to diagnostic errors and inappropriate therapy. We investigated the prevalence and prognostic values of focal features in patients with idiopathic generalized epilepsy (IGE), and we propose a decision flowchart to distinguish between focal and generalized epilepsy in patients with bilateral tonic-clonic seizures and focal EEG or semiology. METHODS: We retrospectively analyzed video-EEG recordings of 101 bilateral tonic-clonic seizures from 60 patients (18 with IGE, 42 with focal epilepsy). Diagnosis and therapeutic response were extracted after ≥1-year follow-up. The decision flowchart was based on previous observations and assessed concordance between interictal and ictal EEG. RESULTS: Focal semiology in IGE was observed in 75% of seizures and 77.8% of patients, most often corresponding to forced head version (66.7%). In patients with multiple seizures, direction of head version was consistent across seizures. Focal interictal epileptiform discharges (IEDs) were observed in 61.1% of patients with IGE, whereas focal ictal EEG onset only occurred in 13% of seizures and 16.7% of patients. However, later during the seizures, a reproducible pattern of 7-Hz lateralized ictal rhythm was observed in 56% of seizures, associated with contralateral head version. We did not find correlation between presence of focal features and therapeutic response in IGE patients. Our decision flowchart distinguished between focal and generalized epilepsy in patients with bilateral tonic-clonic seizures and focal features with an accuracy of 96.6%. SIGNIFICANCE: Focal semiology associated with bilateral tonic-clonic seizures and focal IEDs are common features in patients with IGE, but focal ictal EEG onset is rare. None of these focal findings appears to influence therapeutic response. By assessing the concordance between interictal and ictal EEG findings, one can accurately distinguish between focal and generalized epilepsies.

Association between retinal thickness and disease characteristics in adult epilepsy: A cross-sectional OCT evaluation.

OBJECTIVE: Thinning of the peripapillary retinal nerve fiber layer (p-RNFL), as measured by optical coherence tomography (OCT), was recently introduced as a promising marker for cerebral neuronal loss in people with epilepsy (PwE). However, its clinical implication remains to be elucidated. We thus aimed to (1) systematically characterize the extent of the retinal neuroaxonal loss in a broad spectrum of unselected PwE and (2) to evaluate the main clinical determinants. METHODS: In this prospective study, a spectral-domain OCT evaluation was performed on 98 well-characterized PwE and 85 healthy controls (HCs) (18-55 years of age). All inner retinal layers and the total macula volume were assessed. Group comparisons and linear regression analyses with stepwise backward selection were performed to identify relevant clinical and demographic modulators of the retinal neuroaxonal integrity. RESULTS: PwE (age: 33.7 ± 10.6 years; 58.2% female) revealed a significant neuroaxonal loss across all assessed retinal layers (global pRNFL, P = 0.001, Δ = 4.24 µm; macular RNFL, P < 0.001, Δ = 0.05 mm3 ; ganglion cell inner plexiform layer, P < 0.001, Δ = 0.11 mm3 ; inner nuclear layer, INL, P = 0.03, Δ = 0.02 mm3 ) as well as significantly reduced total macula volumes (TMV, P < 0.001, Δ = 0.18 mm3 ) compared to HCs (age: 31.2 ± 9.0 years; 57.6% female). The extent of retinal neuroaxonal loss was associated with the occurrence and frequency of tonic-clonic seizures and the number of antiseizure medications, and was most pronounced in male patients. SIGNIFICANCE: PwE presented an extensive retinal neuroaxonal loss, affecting not only the peripapillary but also macular structures. The noninvasive and economic measurement via OCT bears the potential to establish as a practical tool to inform patient management, as the extent of the retinal neuroaxonal loss reflects aspects of disease severity and sex-specific vulnerability. PLAIN LANGUAGE SUMMARY: The retina is an extension of the brain and closely connected to it. Thus, cerebral alterations like atrophy reflect also on the retinal level. This is advantageous, as the retina is easily accessible and measureable with help of the optical coherence tomography. Here we report that adults with epilepsy have a significantly thinner retina than healthy persons. Especially people with many big seizures and a lot of medications have a thinner retina. We propose that measurement of the retina can be useful as a marker of disease severity and to inform patient management.

Distinctive Clinico-electrographic and Radiological Profile of Childhood and Adolescent Seizures.

AIM: Electroencephalogram (EEG) is specific, but not sensitive, for the diagnosis of epilepsy. This study aimed to correlate the clinico-electrographic and radiological features of seizure disorders in children attending a tertiary care centre in northern India. METHODS: Children aged between one to 18 years with seizure episodes were included. Clinical details, including historical as well as physical findings, were evaluated along with EEG and neuroimaging (Magnetic resonance imaging). Details were noted on pre-designed proforma. Variables were analysed by using appropriate statistical methods. RESULTS: A total of 110 children with seizures were enrolled in the study. Male to female ratio was 1.6: 1, and the mean age of the study children was 8 years. The majority of the children were symptomatic for more than one year. The most common seizure type was Generalised Tonic Clonic Seizure (GTCS), and Hypoxic-ischemic Encephalopathy (HIE) sequelae was the most commonly attributed etiology, followed by neurocysticercosis. EEG and neuroimaging findings were found to correlate well with seizure semiology from history. The incidence of febrile seizures was 10% in this study, with nearly three-fourths of them being simple febrile seizures. CONCLUSION: Microcephaly and developmental delay were the most distinctive clinical correlates in children with seizures. There was a fair agreement between the types of seizures described in history and depicted on EEG with Cohen's kappa of 0.4. Also, there was a significant association between the type of seizures on EEG and the duration of symptoms.

Lafora Disease: A Case Report and Evolving Treatment Advancements.

Lafora disease is a rare genetic disorder characterized by a disruption in glycogen metabolism. It manifests as progressive myoclonus epilepsy and cognitive decline during adolescence. Pathognomonic is the presence of abnormal glycogen aggregates that, over time, produce large inclusions (Lafora bodies) in various tissues. This study aims to describe the clinical and histopathological aspects of a novel Lafora disease patient, and to provide an update on the therapeutical advancements for this disorder. A 20-year-old Libyan boy presented with generalized tonic-clonic seizures, sporadic muscular jerks, eyelid spasms, and mental impairment. Electroencephalography showed multiple discharges across both brain hemispheres. Brain magnetic resonance imaging was unremarkable. Muscle biopsy showed increased lipid content and a very mild increase of intermyofibrillar glycogen, without the polyglucosan accumulation typically observed in Lafora bodies. Despite undergoing three lines of antiepileptic treatment, the patient's condition showed minimal to no improvement. We identified the homozygous variant c.137G>A, p.(Cys46Tyr), in the EPM2B/NHLRC1 gene, confirming the diagnosis of Lafora disease. To our knowledge, the presence of lipid aggregates without Lafora bodies is atypical. Lafora disease should be considered during the differential diagnosis of progressive, myoclonic, and refractory epilepsies in both children and young adults, especially when accompanied by cognitive decline. Although there are no effective therapies yet, the development of promising new strategies prompts the need for an early and accurate diagnosis.

Greater female than male resilience to mortality and morbidity in the Scn8a mouse model of pediatric epilepsy.

AIMS: Females and males of all ages are affected by epilepsy; however, unlike many clinical studies, most preclinical research has focused on males. Genetic variants in the voltage-gated sodium channel gene, SCN8A, are associated with a broad spectrum of neurological and epileptic syndromes. Here we investigate sex differences in the natural history of the Scn8a-N1768D knockin mouse model of pediatric epilepsy. METHODS: We utilize 24/7 video to monitor juveniles and adults of both sexes to investigate variability in seizure activity (e.g. onset and frequency), mortality and morbidity, response to cannabinoids, and mode of death. We also monitor sleep architecture using a noninvasive piezoelectric method in order to identify factors that influence seizure severity and outcome. RESULTS: Both sexes had nearly 100% penetrance in seizure onset and early mortality. However, adult heterozygous (D/+) females were more resilient as exhibited by the ability to tolerate more seizures over a longer lifespan. Homozygous (D/D) juveniles did not exhibit a sex difference in overall survival. Female estrus cycle was disrupted before seizure onset, while sleep was disrupted in both sexes in association with seizure onset. Females typically died while in convulsive status epilepticus; however, a high proportion of males died while not experiencing behavioral seizures. Only juvenile and adult males benefited from cannabinoid administration. CONCLUSIONS: These results support the hypothesis that factors associated with sexual differentiation play a role in the neurobiology of epilepsy and point to the importance of including both sexes in the design of studies to identify new epilepsy therapies.

Aberrant structural rich club organization in temporal lobe epilepsy with focal to bilateral tonic-clonic seizures.

OBJECTIVE: The purpose of this study was to assess the differences of topological characteristic and rich club organization between temporal lobe epilepsy (TLE) patients with focal seizure (FS) only and those with focal to bilateral tonic-clonic seizures (FBTCS). METHODS: We recruited 130 unilateral TLE patients, of which 57 patients with FS only and 73 patients with both FS and FBTCS, and 68 age- and gender-matched healthy controls (HC). Whole-brain networks were constructed based on diffusion weighted imaging data. Graph theory was applied to quantify the topological network metrics and rich club organization. Network-based statistic (NBS) analysis was administered to investigate the difference in edge-wise connectivity strength. The non-parametric permutation test was applied to evaluate the differences between groups. Benjamini-Hochberg FDR at the alpha of 5% was carried out for multiple comparations. RESULTS: In comparison with HC, both the FS and FBTCS group displayed a significant reduction in whole-brain connectivity strength and global efficiency. The FBTCS group showed lower connectivity strength both in the rich club and feeder connections compared to HC. The FS group had lower connectivity strength in the feeder and local connections compared to HC. NBS analysis revealed a wider range of decreased connectivity strength in the FBTCS group, involving 90% of the rich club regions, mainly affecting temporal-subcortical, frontal-parietal, and frontal-temporal lobe, the majority decreasing connections were between temporal lobe and stratum. While the decreased connectivity strength in the FS group were relatively local, involving 50% of rich club regions, mainly concentrated on the temporal-subcortical lobe. CONCLUSIONS: Network integration was reduced in TLE. TLE with FBTCS selectively disrupted the rich club regions, while TLE with FS only were more likely to affect the non-rich club regions, emphasizing the contribution of rich club organization to seizure generalization.

Altered amygdala volumes and microstructure in focal epilepsy patients with tonic-clonic seizures, ictal, and post-convulsive central apnea.

OBJECTIVES: Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death for patients with epilepsy; however, the pathophysiology remains unclear. Focal-to-bilateral tonic-clonic seizures (FBTCS) are a major risk factor, and centrally-mediated respiratory depression may increase the risk further. Here, we determined the volume and microstructure of the amygdala, a key structure that can trigger apnea in people with focal epilepsy, stratified by the presence or absence of FBTCS, ictal central apnea (ICA), and post-convulsive central apnea (PCCA). METHODS: Seventy-three patients with focal impaired awareness seizures without FBTC seizures (FBTCneg group) and 30 with FBTCS (FBTCpos group) recorded during video electroencephalography (VEEG) with respiratory monitoring were recruited prospectively during presurgical investigations. We acquired high-resolution T1-weighted anatomic and multi-shell diffusion images, and computed neurite orientation dispersion and density imaging (NODDI) metrics in all patients with epilepsy and 69 healthy controls. Amygdala volumetric and microstructure alterations were compared between three groups: healthy subjects, FBTCneg and FBTCpos groups. The FBTCpos group was further subdivided by the presence of ICA and PCCA, verified by VEEG. RESULTS: Bilateral amygdala volumes were significantly increased in the FBTCpos cohort compared to healthy controls and the FBTCneg group. Patients with recorded PCCA had the highest increase in bilateral amygdala volume of the FBTCpos cohort. Amygdala neurite density index (NDI) values were decreased significantly in both the FBTCneg and FBTCpos groups relative to healthy controls, with values in the FBTCpos group being the lowest of the two. The presence of PCCA was associated with significantly lower NDI values vs the non-apnea FBTCpos group (p = 0.004). SIGNIFICANCE: Individuals with FBTCpos and PCCA show significantly increased amygdala volumes and disrupted architecture bilaterally, with greater changes on the left side. The structural alterations reflected by NODDI and volume differences may be associated with inappropriate cardiorespiratory patterns mediated by the amygdala, particularly after FBTCS. Determination of amygdala volumetric and architectural changes may assist identification of individuals at risk.

Top of the Basilar Syndrome: A Case Report of a Healthy Young Woman and Literature Review.

Top of the basilar syndrome (TBS) is defined as the presence of multiple ischemic lesions on magnetic resonance image (MRI) including more than two territories supplied by branches of the distal portion of the basilar artery, causing symptoms such as dizziness, diplopia, ataxia, and acute cognitive decline that can lead to quadriplegia and death. Diagnosing TBS is challenging because it can mimic other conditions such as thalamic hemorrhages or vertebrobasilar ischemia, and requires advanced imaging. Although the prognosis for these patients is poor, rehabilitation is essential for their recovery. This case describes a healthy 28-year-old woman who presented with headache, vomiting, and tonic-clonic seizures sent to the hospital with a stroke diagnosis.

Efficacy and safety of perampanel monotherapy in Chinese patients with focal-onset seizures: A single-center, prospective, real-world observational study.

OBJECTIVE: Efficacy and safety of perampanel monotherapy for treating focal-onset seizures (FOS) has been barely studied in China. This observational study aimed to evaluate the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS. METHODS: This single-center, prospective, real-world observational study enrolled patients aged ≥4 years with FOS who visited the Epilepsy Out-Patient Clinic of Nanjing Brain Hospital affiliated to Nanjing Medical University from January 2020 to December 2021. All patients were treated with perampanel monotherapy. Seizure-freedom rates after 6 and 12 months of treatment were calculated. Adverse events (AEs) were recorded. RESULTS: Seventy patients with FOS were enrolled. The mean maintenance perampanel dose was 4.64 ± 1.55 mg/day. The 6- and 12-month retention rates of perampanel monotherapy were 78.6% (55/70) and 70.0% (49/70), respectively. The 6- and 12-month seizure-freedom rates were 69.84% (44/63) and 65.08% (41/63), respectively. Patients with focal to bilateral tonic-clonic seizures had significantly higher 6-month and numerically higher 12-month seizure freedom rates than patients with focal impaired awareness seizures (P = 0.046 and P = 0.204, respectively). Twenty-six (37.1%) patients experienced treatment-emergent AEs, and the most common AE was dizziness. Four (5.7%) patients withdrew from the study due to AEs. No new safety concern was observed. SIGNIFICANCE: This is the first prospective study on the efficacy and safety of perampanel monotherapy in treating Chinese patients with FOS, and perampanel monotherapy was effective and safe in treating Chinese patients aged ≥4 years with FOS up to 12 months. More multicenter, real-world studies with large sample sizes and longer follow-ups are needed to further evaluate the long-term efficacy and safety of perampanel monotherapy.