A spike is a spike: On the universality of spike features in four epilepsy models.

OBJECTIVE: Frequency properties of the EEG characteristics of different seizure types including absence seizures have been described for various rodent models of epilepsy. However, little attention has been paid to the frequency properties of individual spike-wave complexes (SWCs), the constituting elements characterizing the different generalized seizure types. Knowledge of their properties is not only important for understanding the mechanisms underlying seizure generation but also for the identification of epileptiform activity in various seizure types. Here, we compared the frequency properties of SWCs in different epilepsy models. METHODS: A software package was designed and used for the extraction and frequency analysis of SWCs from long-term EEG of four spontaneously seizing, chronic epilepsy models: a post-status epilepticus model of temporal lobe epilepsy, a lateral fluid percussion injury model of post-traumatic epilepsy, and two genetic models of absence epilepsy-GAERS and rats of the WAG/Rij strain. The SWCs within the generalized seizures were separated into fast (three-phasic spike) and slow (mostly containing the wave) components. Eight animals from each model were used (32 recordings, 104 510 SWCs in total). A limitation of our study is that the recordings were hardware-filtered (high-pass), which could affect the frequency composition of the EEG. RESULTS: We found that the three-phasic spike component was similar in all animal models both in time and frequency domains, their amplitude spectra showed a single expressed peak at 18-20 Hz. The slow component showed a much larger variability across the rat models. SIGNIFICANCE: Despite differences in the morphology of the epileptiform activity in different models, the frequency composition of the spike component of single SWCs is identical and does not depend on the particular epilepsy model. This fact may be used for the development of universal algorithms for seizure detection applicable to different rat models of epilepsy. PLAIN LANGUAGE SUMMARY: There is a large variety between people with epilepsy regarding the clinical manifestations and the electroencephalographic (EEG) phenomena accompanying the epileptic seizures. Here, we show that one of the EEG signs of epilepsy, an epileptic spike, is universal, since it has the same shape and frequency characteristics in different animal models of generalized epilepsies, despite differences in recording sites and location.

WONOEP appraisal: The role of glial cells in focal malformations associated with early onset epilepsies.

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.

Valproic acid-induced teratogenicity is driven by senescence and prevented by Rapamycin in human spinal cord and animal models.

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.

Plasma biomarkers in chronic single moderate-severe traumatic brain injury.

Blood biomarkers are an emerging diagnostic and prognostic tool that reflect a range of neuropathological processes following traumatic brain injury (TBI). Their effectiveness in identifying long-term neuropathological processes after TBI is unclear. Studying biomarkers in the chronic phase is vital because elevated levels in TBI might result from distinct neuropathological mechanisms during acute and chronic phases. Here, we examine plasma biomarkers in the chronic period following TBI and their association with amyloid and tau PET, white matter microarchitecture, brain age and cognition. We recruited participants ≥40 years of age who had suffered a single moderate-severe TBI ≥10 years previously between January 2018 and March 2021. We measured plasma biomarkers using single molecule array technology [ubiquitin C-terminal hydrolase L1 (UCH-L1), neurofilament light (NfL), tau, glial fibrillary acidic protein (GFAP) and phosphorylated tau (P-tau181)]; PET tracers to measure amyloid-ß (18F-NAV4694) and tau neurofibrillary tangles (18F-MK6240); MRI to assess white matter microstructure and brain age; and the Rey Auditory Verbal Learning Test to measure verbal-episodic memory. A total of 90 post-TBI participants (73% male; mean = 58.2 years) were recruited on average 22 years (range = 10-33 years) post-injury, and 32 non-TBI control participants (66% male; mean = 57.9 years) were recruited. Plasma UCH-L1 levels were 67% higher {exp(b) = 1.67, P = 0.018, adjusted P = 0.044, 95% confidence interval (CI) [10% to 155%], area under the curve = 0.616} and P-tau181 were 27% higher {exp(b) = 1.24, P = 0.011, adjusted P = 0.044, 95% CI [5% to 46%], area under the curve = 0.632} in TBI participants compared with controls. Amyloid and tau PET were not elevated in TBI participants. Higher concentrations of plasma P-tau181, UCH-L1, GFAP and NfL were significantly associated with worse white matter microstructure but not brain age in TBI participants. For TBI participants, poorer verbal-episodic memory was associated with higher concentration of P-tau181 {short delay: b = -2.17, SE = 1.06, P = 0.043, 95% CI [-4.28, -0.07]; long delay: bP-tau = -2.56, SE = 1.08, P = 0.020, 95% CI [-4.71, -0.41]}, tau {immediate memory: bTau = -6.22, SE = 2.47, P = 0.014, 95% CI [-11.14, -1.30]} and UCH-L1 {immediate memory: bUCH-L1 = -2.14, SE = 1.07, P = 0.048, 95% CI [-4.26, -0.01]}, but was not associated with functional outcome. Elevated plasma markers related to neuronal damage and accumulation of phosphorylated tau suggest the presence of ongoing neuropathology in the chronic phase following a single moderate-severe TBI. Plasma biomarkers were associated with measures of microstructural brain disruption on MRI and disordered cognition, further highlighting their utility as potential objective tools to monitor evolving neuropathology post-TBI.

The impact of COVID-19 on people with epilepsy: Global results from the coronavirus and epilepsy study.

OBJECTIVE: To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS: Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS: Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE: While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY: We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

Pathophysiology, blood biomarkers, and functional deficits after intimate partner violence-related brain injury: Insights from emergency department patients and a new rat model.

Intimate partner violence is a serious, but underappreciated, issue that predominantly affects women and often results in concussion (i.e., mild traumatic brain injury). However, concussion in intimate partner violence is unique because it often involves a concomitant strangulation which may exacerbate or alter the physiology and clinical presentation of the brain injury. Therefore, here we conducted human and rodent studies to provide insight into knowledge gaps related to the detection, pathophysiology, and functional consequences of intimate partner violence-related brain injury. We conducted the first study to analyze blood biomarkers and symptoms of brain injury in intimate partner violence patients presenting to an emergency department within 72 h of concussion. Intimate partner violence concussion patients, some of whom had also experienced a concomitant strangulation, had elevated serum neurofilament light and worse brain injury symptoms compared to healthy control, orthopedic trauma, and non-intimate partner violence concussion groups. We also developed the first rat model of non-fatal strangulation and examined the consequences of strangulation and concussion in isolation and in combination on pathophysiology, blood biomarkers, and behavior at 2 h and 1wk post-injury. Rats exposed to combined strangulation and concussion had exacerbated motor and cognitive deficits, neuroinflammation, and serum glial fibrillary acidic protein levels compared with either injury in isolation. Taken together, these rodent findings demonstrate that a concomitant strangulation modifies and exacerbates concussion pathophysiology, biomarkers, and functional consequences. Overall, these findings provide novel insights into intimate partner violence-related brain injury and provides a foundation for future translational studies.

WONOEP appraisal: Genetic insights into early onset epilepsies.

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed.

Paternal exposure to antiseizure medications and offspring outcomes: a systematic review.

BACKGROUND: Concerns have recently been raised about risks to the fetus resulting from paternal exposure to antiseizure medications (ASMs). To address these concerns, we conducted a systematic review of the literature to assess neurodevelopmental and anatomical outcomes in offspring born to fathers taking ASMs at the time of conception. METHODS: Electronic searches of MEDLINE, PsycINFO, and Embase were conducted to identify human studies published in English that reported on outcomes, comprising neurodevelopmental disorders, major congenital malformations, small-for-gestational age or low birth weight, in offspring of fathers taking ASMs at conception. Quality analysis of included studies was undertaken using the Newcastle-Ottawa Scale. A narrative synthesis was used to report study findings. RESULTS: Of 923 studies identified by the search and screened by title and abstract, 26 underwent full-text review and 10 met eligibility criteria. There was limited evidence available, but there appeared to be no clear evidence for an adverse impact of paternal ASM use on offspring outcomes. Few isolated adverse findings were not replicated by other investigations. Several methodological limitations prevented meta-analysis, including failure by most studies to report outcomes separately for each individual ASM, heterogeneity in measurement and outcome reporting, and small numbers of monotherapy exposures. CONCLUSIONS: Although there were limited data available, this systematic review provides reassuring evidence that paternal exposure to ASMs at conception is unlikely to pose any major risk of adverse outcomes for the offspring. Further research is needed to examine the relationship between preconception ASM use in males and offspring outcomes at birth and postnatally.

Re-PROGRAM: The evaluation of a brief intervention program for patients with functional seizures in an outpatient hospital setting.

OBJECTIVE: Functional seizures (FS) account for 20%-25% of referrals to specialist epilepsy clinics. They are associated with major disability, increased mortality, and frequent and costly health care use. Current guidelines emphasize the importance of implementing clinical pathways to coordinate and deliver effective treatment, but there are few targeted evidence-based interventions that reliably improve patient outcomes, and treatment resources are limited. We conducted a retrospective evaluation of Re-PROGRAM, a novel, brief intervention for functional seizure patients, to assess its feasibility in an outpatient setting. METHODS: Twenty-nine patients with FS undertook Re-PROGRAM between August 2020 and January 2022 at the Alfred Hospital Functional Seizures Clinic, Melbourne, Australia. The intervention comprised five 60-90-min consecutive weekly appointments via telehealth, where psychologists engaged patients in a structured program of seizure management skills, lifestyle modification, and behavioral activation strategies. Following the intervention, patient feedback was collected in routine clinical follow-up as well as with a 24-item self-report pre-/postintervention comparison questionnaire. RESULTS: All 29 patients who enrolled in Re-PROGRAM completed the scheduled sessions. Of those who returned the postintervention questionnaire (n = 16), 15 reported a reduction in seizure frequency. Four patients were lost to follow-up. Of the remaining nine, eight reported seizure frequency reduction during clinical follow-up. Qualitative analysis of the feedback revealed the majority of patients reported reduced seizure duration, intensity, and bothersomeness, and patients felt improvements in their sense of control over seizures, confidence to use seizure control strategies, assertive communication, problem solving, coping skills, relationships with others, and their day-to-day functioning. SIGNIFICANCE: This retrospective evaluation demonstrates the feasibility and acceptability of Re-PROGRAM as a brief intervention for individuals diagnosed with FS delivered in a clinical outpatient setting and warrants further investigation in larger scale, randomized controlled studies.

Fluoxetine accelerates epileptogenesis and magnifies disease severity in a rat model of acquired epilepsy.

OBJECTIVE: Many people with epilepsy experience comorbid anxiety and depression, and antidepressants remain a primary treatment for this. Emerging evidence suggests that these agents may modulate epileptogenesis to influence disease severity. Here, we assessed how treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine impacts epileptogenic, behavioral, and pathological sequelae following status epilepticus. METHODS: Male Wistar rats received kainic acid to induce status epilepticus (SE) or vehicle (sham). Animals then received either fluoxetine (10 mg/kg/day) or vehicle for 8 weeks via subcutaneous osmotic pump. Video-electroencephalography was recorded continuously until behavioral testing at day 56, including assessments of anxiety- and depression-like behavior and spatial cognition. Postmortem immunocytochemistry studies examined mossy fiber sprouting. RESULTS: Fluoxetine treatment significantly accelerated epileptogenesis following SE, reducing the average period to the first spontaneous seizure (from 32 days [vehicle] to 6 days [fluoxetine], p < .01). Also, fluoxetine exposure magnified the severity of the resultant epilepsy, increasing seizure frequency compared to vehicle (p < .01). Exposure to fluoxetine was associated with improved anxiety- and depression-like behaviors but significantly worsened cognition. Mossy fiber sprouting was more pronounced in fluoxetine-treated rats compared to vehicle (p < .0001). SIGNIFICANCE: Our studies demonstrate that, using a model exhibiting spontaneous seizures, epileptogenesis is accelerated and magnified by fluoxetine, an effect that may be related to more severe pathological neuroplasticity. The differential influence of fluoxetine on behavior indicates that different circuitry and mechanisms are responsible for these comorbidities. These findings suggest that caution should be exercised when prescribing SSRI antidepressants to people at risk of developing epilepsy.

Do germline genetic variants influence surgical outcomes in drug-resistant epilepsy?

OBJECTIVE: We retrospectively explored patients with drug-resistant epilepsy (DRE) who previously underwent presurgical evaluation to identify correlations between surgical outcomes and pathogenic variants in epilepsy genes. METHODS: Through an international collaboration, we evaluated adult DRE patients who were screened for surgical candidacy. Patients with pathogenic (P) or likely pathogenic (LP) germline variants in genes relevant to their epilepsy were included, regardless of whether the genetic diagnosis was made before or after the presurgical evaluation. Patients were divided into two groups: resective surgery (RS) and non-resective surgery candidates (NRSC), with the latter group further divided into: palliative surgery (vagus nerve stimulation, deep brain stimulation, responsive neurostimulation or corpus callosotomy) and no surgery. We compared surgical candidacy evaluations and postsurgical outcomes in patients with different genetic abnormalities. RESULTS: We identified 142 patients with P/LP variants. After presurgical evaluation, 36 patients underwent RS, while 106 patients were NRSC. Patients with variants in ion channel and synaptic transmission genes were more common in the NRSC group (48 %), compared with the RS group (14 %) (p<0.001). Most patients in the RS group had tuberous sclerosis complex. Almost half (17/36, 47 %) in the RS group had Engel class I or II outcomes. Patients with channelopathies were less likely to undergo a surgical procedure than patients with mTORopathies, but when deemed suitable for resection had better surgical outcomes (71 % versus 41 % with Engel I/II). Within the NRSC group, 40 underwent palliative surgery, with 26/40 (65 %) having ≥50 % seizure reduction after mean follow-up of 11 years. Favourable palliative surgery outcomes were observed across a diverse range of genetic epilepsies. SIGNIFICANCE: Genomic findings, including a channelopathy diagnosis, should not preclude presurgical evaluation or epilepsy surgery, and appropriately selected cases may have good surgical outcomes. Prospective registries of patients with monogenic epilepsies who undergo epilepsy surgery can provide additional insights on outcomes.

Engagement in online cognitive testing with the Cogstate brief battery among a multinational cohort of people with focal epilepsy.

OBJECTIVE: The Human Epilepsy Project (HEP) is a large multinational cohort study of people with newly diagnosed and treated focal epilepsy. HEP utilized the Cogstate Brief Battery (CBB) as a self-directed online assessment to examine cognitive outcomes in study participants. The CBB has previously been validated in healthy individuals and people with various brain disorders, but its use in adults participating in HEP has not been assessed. In this study, we describe how the CBB was used in the HEP cohort and assess factors associated with test completion among study participants. METHODS: Enrollment data for HEP included 408 participants with comprehensive enrollment records, of whom 249 completed CBB assessments. HEP enrolled cognitively normal-range participants between the ages of 12 and 60 from June 29, 2012, to November 7, 2017, with newly diagnosed focal epilepsy and within 4 months of initial treatment. Baseline participant characteristics were analyzed, including demographics, pre-treatment seizure histories, MRI abnormalities, and the presence of any learning difficulties while in school, including formal learning disability diagnoses, repeated grades, and remediation. HEP participant characteristics for those who completed CBB testing were compared to those who did not using multiple logistic regression. RESULTS: The analysis of HEP participants who completed CBB testing showed that, after controlling for other factors, male participants were more likely to engage in testing (OR 2.14, 95 % CI 1.29 to 3.5, p < 0.01), Black subjects were less likely (OR 0.45, 95 % CI 0.22 to 0.9, p = 0.02), primary English speakers were more likely (OR 3.1, 95 % CI 1.21 to 7.96, p = 0.02), and those with a history of learning challenges were less likely (OR 0.69, 95 % CI 0.49 to 0.97, p = 0.03). There were no significant associations between completing CBB testing and age, employment (employed or student vs not), education (higher education vs not), diagnostic delay, pre-diagnostic seizure burden, or initial seizure semiology (motor vs non-motor). SIGNIFICANCE: The findings from this study highlight factors associated with the application of remote and unsupervised assessments of cognition in a prospective cohort of adults with focal epilepsy. These factors can be considered when interpreting performance on the CBB in HEP, as well as assisting the design of future studies that use similar approaches.

Characterizing Gut Microbiota in Older Chinese Adults with Cognitive Impairment: A Cross-Sectional Study.

Background: Cognitive impairment is a clinical manifestation that occurs in the course of dementia like Alzheimer's disease. The association between cognitive impairment and gut microbiota is unclear. Objective: We aimed to identify gut microbiota characteristics and key gut microbiota biomarkers associated with cognitive impairment in a relatively large cohort of older adults in China. Methods: A total of 229 adults aged ≥60 years from Shenzhen, China were recruited into this cross-sectional study. Participants were divided into cognitive impairment (CI) and no cognitive impairment (NCI) groups according to the results of the Mini-Mental State Examination. Diversity analysis and network analysis were used to characterize the gut microbiota between the two groups. The linear discriminant analysis effect size method and machine learning approaches were sequentially performed to identify gut microbiota biomarkers. The relationship between biomarkers and lifestyle factors was explored using Transformation-based redundancy analysis (tb-RDA). Results: A total of 74 CI participants and 131 NCI participants were included in the analysis. The CI group demonstrated lower α-diversity compared to the NCI group (Shannon: 2.798 versus 3.152, p < 0.001). The density of the gut microbiota interaction network was lower in the CI group (0.074) compared to the NCI group (0.081). Megamonas, Blautia, Pseudomonas, Stenotrophomonas, and Veillonella were key biomarkers for CI. The tb-RDA revealed that increased fruit intake and exercise contribute to a higher abundance of Megamonas, Blautia, and Veillonella. Conclusions: We identified a significantly reduced abundance of certain beneficial gut microbiota in older Chinese adults with cognitive impairment.

Huperzine A suppresses absence seizures in the genetic absence epilepsy rat from Strasbourg (GAERS) model of genetic generalized epilepsy with absence seizures.

OBJECTIVE: We evaluated huperzine A treatment in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) model of genetic generalized epilepsy (GGE) with absence seizures. METHODS: Adult male GAERS (N = 15) were implanted with EEG recording electrodes 10 days before receiving study drug. Each animal received the following six treatments as a single, intraperitoneal dose, 7 days apart (in random order): huperzine A (0.3, 1.0, or 3.0 mg/kg), two periods of vehicle (0.9% NaCl), or ethosuximide (100 mg/kg) as a positive control. Electroencephalograms (EEGs) were acquired for 24 h before and after each treatment and analyzed for seizure activity during the 90-min period immediately post-treatment, including 30-min intervals at 30, 60, and 90 min. Additional analyses evaluated seizure activity over the 24-h post-treatment period using 60-min intervals at 6, 12, and 24 h. The cumulative 24-h periods before and after each administered treatment were also compared. RESULTS: Two-way ANOVA showed a treatment difference [F(91,182) = 3.592, p < 0.0001] on the number of seizures over the first 90-min post-treatment (primary outcome); Tukey's post hoc analyses showed that, compared to vehicle, huperzine A (3.0 mg/kg) significantly reduced seizures in the 30-min (p = 0.02) and 60-min (p = 0.001) intervals, and ethosuximide significantly reduced seizures at all measured time intervals except the 1-h blocks at 12 and 24 h. Huperzine A 3.0 mg/kg and ethosuximide significantly reduced seizures during the cumulative 24-h post-treatment period relative to pretreatment baseline. While huperzine A 3.0 mg/kg did not differ significantly from ethosuximide at any time point, the study was not designed to evaluate non-inferiority. The only adverse event after huperzine A or ethosuximide was mild, dose-dependent sedation. SIGNIFICANCE: Huperzine A potently suppressed absence-like seizures in GAERS, albeit with a shorter duration of action relative to ethosuximide, showing promise for clinical efficacy in GGE. PLAIN LANGUAGE SUMMARY: This study looked at how huperzine A affects seizures in rats with similar abnormal brain activity as seen in humans with absence epilepsy. Rats received different treatments, placebo (i.e., saline solution), huperzine A, and ethosuximide. Ethosuximide is considered a gold standard treatment for absence epilepsy. We recorded brain activity to measure seizures before and after each treatment. We found that huperzine A (3.0 mg/kg) reduced seizures soon after treatment, like ethosuximide. Both treatments appeared safe, causing only mild sleepiness. The study shows that huperzine A could be a good new treatment for a type of absence epilepsy.

Baseline characteristics and predictors for early implantation of vagus nerve stimulation therapy in people with drug-resistant epilepsy: Observations from an international prospective outcomes registry (CORE-VNS).

OBJECTIVE: Vagus nerve stimulation (VNS) Therapy is routinely indicated for people with drug-resistant epilepsy (DRE). We analyzed the baseline characteristics of individuals receiving the recently released VNS models and identified factors associated with early or late implantation. METHODS: The Comprehensive Outcomes Registry of subjects with Epilepsy (CORE-VNS), a prospective observational study evaluating the clinical and psychosocial outcomes of VNS Therapy®, is following participants for up to 60 months after VNS implantation. In this analysis, we used Cox proportional hazards model to identify baseline characteristics associated with the time from diagnosis to first implantation. RESULTS: Of the 819 enrolled, 792 (96.7%) participants implanted with a VNS device were evaluated. 529 (64.6%) underwent the first implantation and 263 (32.1%) a re-implantation. Participants' median age at first implant was 24 years; 492 (62.1%) were ≥18 years old and 166 (20.3%) were < 12 years old. The average number of failed ASMs prior to VNS implantation was 7.1, and 145 (17.7%) had undergone previous epilepsy-related surgery. Epilepsy was classified as focal in 47.7% of participants, generalized in 16.1% and combined focal and generalized in 34.2%. Many of the participants (40.9%) had epilepsy of unknown etiology. The median time from diagnosis to first implantation was 10.33 years and was significantly shorter in participants with combined focal and generalized epilepsy compared to those with focal epilepsy alone, and in participants with genetic and immune epilepsy compared to those with unknown etiologies. SIGNIFICANCE: In people with DRE, VNS Therapy is provided after multiple failures of ASMs and after failure of epilepsy surgery in one in six individuals. Time from diagnosis to first implantation is associated with epilepsy type and etiology, likely reflecting variable treatment pathways. Clearer guidelines on when and how non-drug therapies should be deployed in people with DRE related to different epilepsy factors are needed. PLAIN LANGUAGE SUMMARY: Neuromodulation can be a very helpful treatment in people who have seizures that do not respond to medications. The most widely utilized neuromodulation therapy is vagus nerve stimulation (VNS). We present data from a large, global study to show that people use an average of seven anti-seizure medications before attempting VNS Therapy and that it takes about 10 years for people to get their first VNS implant. We advocate for clearer treatment guidelines on how and when to consider VNS Therapy in people with seizures that are resistant to medication.

Elevated plasma neurofilament light and glial fibrillary acidic protein in epilepsy versus nonepileptic seizures and nonepileptic disorders.

OBJECTIVE: Research suggests that recurrent seizures may lead to neuronal injury. Neurofilament light chain protein (NfL) and glial fibrillary acidic protein (GFAP) levels increase in cerebrospinal fluid and blood in response to neuroaxonal damage, and they have been hypothesized as potential biomarkers for epilepsy. We examined plasma NfL and GFAP levels and their diagnostic utility in differentiating patients with epilepsy from those with psychogenic nonepileptic seizures (PNES) and other nonepileptic disorders. METHODS: We recruited consecutive adults admitted for video-electroencephalographic monitoring and formal neuropsychiatric assessment. NfL and GFAP levels were quantified and compared between different patient groups and an age-matched reference cohort (n = 1926) and correlated with clinical variables in patients with epilepsy. RESULTS: A total of 138 patients were included, of whom 104 were diagnosed with epilepsy, 22 with PNES, and 12 with other conditions. Plasma NfL and GFAP levels were elevated in patients with epilepsy compared to PNES, adjusted for age and sex (NfL p = .04, GFAP p = .04). A high proportion of patients with epilepsy (20%) had NfL levels above the 95th age-matched percentile compared to the reference cohort (5%). NfL levels above the 95th percentile of the reference cohort had a 95% positive predictive value for epilepsy. Patients with epilepsy who had NfL levels above the 95th percentile were younger than those with lower levels (37.5 vs. 43.8 years, p = .03). SIGNIFICANCE: An elevated NfL or GFAP level in an individual patient may support an underlying epilepsy diagnosis, particularly in younger adults, and cautions against a diagnosis of PNES alone. Further examination of the association between NfL and GFAP levels and specific epilepsy subtypes or seizure characteristics may provide valuable insights into disease heterogeneity and contribute to the refinement of diagnosis, understanding pathophysiological mechanisms, and formulating treatment approaches.

The Australian Traumatic Brain Injury Initiative: Systematic Review of Clinical Factors Associated with Outcomes in People with Moderate-Severe Traumatic Brain Injury.

The aim of the Australian Traumatic Brain Injury Initiative (AUS-TBI) is to design a data dictionary to inform data collection and facilitate prediction of outcomes for moderate-severe traumatic brain injury (TBI) across Australia. The process has engaged diverse stakeholders across six areas: social, health, clinical, biological, acute interventions, and long-term outcomes. Here, we report the results of the clinical review. Standardized searches were implemented across databases to April 2022. English-language reports of studies evaluating an association between a clinical factor and any clinical outcome in at least 100 patients with moderate-severe TBI were included. Abstracts, and full-text records, were independently screened by at least two reviewers in Covidence. The findings were assessed through a consensus process to determine inclusion in the AUS-TBI data resource. The searches retrieved 22,441 records, of which 1137 were screened at full text and 313 papers were included. The clinical outcomes identified were predominantly measures of survival and disability. The clinical predictors most frequently associated with these outcomes were the Glasgow Coma Scale, pupil reactivity, and blood pressure measures. Following discussion with an expert consensus group, 15 were recommended for inclusion in the data dictionary. This review identified numerous studies evaluating associations between clinical factors and outcomes in patients with moderate-severe TBI. A small number of factors were reported consistently, however, how and when these factors were assessed varied. The findings of this review and the subsequent consensus process have informed the development of an evidence-informed data dictionary for moderate-severe TBI in Australia.

Inflammasomes at the crossroads of traumatic brain injury and post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) is one of the most debilitating consequences of traumatic brain injury (TBI) and is one of the most drug-resistant forms of epilepsy. Novel therapeutic treatment options are an urgent unmet clinical need. The current focus in healthcare has been shifting to disease prevention, rather than treatment, though, not much progress has been made due to a limited understanding of the disease pathogenesis. Neuroinflammation has been implicated in the pathophysiology of traumatic brain injury and may impact neurological sequelae following TBI including functional behavior and post-traumatic epilepsy development. Inflammasome signaling is one of the major components of the neuroinflammatory response, which is increasingly being explored for its contribution to the epileptogenic mechanisms and a novel therapeutic target against epilepsy. This review discusses the role of inflammasomes as a possible connecting link between TBI and PTE with a particular focus on clinical and preclinical evidence of therapeutic inflammasome targeting and its downstream effector molecules for their contribution to epileptogenesis. Finally, we also discuss emerging evidence indicating the potential of evaluating inflammasome proteins in biofluids and the brain by non-invasive neuroimaging, as potential biomarkers for predicting PTE development.

CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study.

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

"What are your seizures telling you?": A therapeutic tool for functional seizures.

BACKGROUND: Understanding illness representations is considered important for improving health outcomes, yet how people with functional seizures reflect on the possible psychological function of their seizures has not been studied. METHODS: A semi-structured interview comprising open and closed questions was administered to 99 participants with a documented diagnosis of functional seizures. One item, 'What do you think your functional seizure symptoms are telling you?" sought to explore how individuals reflect on the possible function of their seizures. Qualitative analysis using NVivo comprised thematic content analysis of responses to the question, and pattern analysis, to determine association with diagnosis acceptance, and openness to a possible psychological aetiology. RESULTS: Most patients (88 %) readily interpreted their seizures in response to this question. We identified one major theme, with the majority of participants interpreting seizure symptoms as an enforced hiatus. Two minor themes were identified: personal growth and contempt. Subthemes were identified within both the enforced hiatus (stop, slow down, relax) and personal growth (self-care, self-development, acceptance) themes. Individuals who did not accept the diagnosis of functional seizures referenced seizures with contempt towards the self or answered, 'don't know'. Respondents who did not know also tended to reject a psychological basis for their seizures in contrast to those who discussed themes of enforced hiatus, personal growth, and contempt. CONCLUSIONS: Responses provide valuable insight into how individuals reflect on their condition in a non-acute setting. Themes can serve as a foundation for future therapeutic discussions and patient-centred communication strategies to build a mutual understanding of the potential function of physical symptoms regardless of whether a psychological basis for them is accepted or not. What is already known on this topic: Outcomes for functional seizures are generally poor and often attributed to patients rejecting psychiatric care or not accepting the diagnosis. WHAT THIS STUDY ADDS: This study is the first to explore patient conceptualisations of the possible function of their functional seizures as a therapeutic tool for understanding the condition. How this study might affect research, practice, or policy: Findings may provide a basis for improved clinician-patient relationships, treatment engagement, and more targeted interventions for people with functional seizures.