Seizure Response Research Articles

Endocannabinoid involvement in beneficial effects of caloric restriction in a rodent model of comorbid depression and epilepsy

Clinically, patients with depression are at a heightened risk for developing epilepsy, and vice versa, suggesting shared mechanisms for this bidirectional comorbidity. Unfortunately, comorbid depression and epilepsy is associated with worsened quality of life and treatment refractoriness, highlighting the need for novel treatment targets and nonpharmacologic supplements to existing therapies. The present study used the Swim-Low Active rat, a well-validated model of depression and epilepsy comorbidity that was selectively bred based on forced swim test behavior, to assess the safety and efficacy of caloric restriction in treating this comorbidity. The study also investigated the role of endocannabinoids in the effects of caloric restriction on the behavioral endpoints and to determine whether there were any sex differences in these effects.Male rats restricted to approximately 80 % of their daily food intake for an acute 24-h period showed elevated struggling behavior in the Porsolt (Forced) Swim Test and increased latency to pilocarpine-induced seizure; this same caloric restriction yielded a significant increase in hippocampal anandamide levels compared to ad lib rats. These effects were not seen in female rats, although female rats did show anticonvulsant effects of chronic caloric restriction. Administration of 1 mg/kg SR141716 alongside an acute caloric restriction in male rats blocked the antidepressant-like effects of caloric restriction but did not affect seizure responses. Combined, these results suggest caloric restriction may be both safe and modestly effective in benefitting depression- and epilepsy-related behaviors in male SwLo rats, and that the endocannabinoid system may be a promising target for treating this comorbidity.

NCMP-10. EFFECT OF EXTENT OF RESECTION ON GLIOMA SEIZURE OUTCOMES BASED ON MOLECULAR GROUPS

Abstract INTRODUCTION Increased extent of resection (EOR) is a known predictor of seizure freedom in glioma patients. However, it is unknown how tumor genomic alterations affect EOR-induced seizure control. OBJECTIVE To evaluate the genotype-specific impact of EOR on post-operative seizure control METHODS Records of 553 glioma patients who underwent tumor resection from 2012-2023 were reviewed. All patient tumors were analyzed with next generation sequencing and FISH analysis. The unsupervised machine learning algorithm non-negative matrix factorization (NMF) was used to cluster the genomic data. Clinical variables including extent of resection of contrast enhancing tumor and non-enhancing tumor, temozolomide therapy, and radiation therapy were analyzed using Cox Proportional Hazards models. RESULTS NMF clustering of tumor sequencing data revealed four molecular groups: Group 1 (n=56): CDKN2a loss, EGFR copy number gain or mutation, TERT promoter (TERTp) mutation, and MGMT methylated; Group 2 (n=27): IDH mutation, TP53 mutation, and MGMT methylated; Group 3 (n=60): TP53 mutation, TERTp mutation and MGMT methylated; Group 4 (n=244): MGMT unmethylated. Thresholds in the post-operative residual non-enhancing tumor volume (NETV) were identified which marked the most difference in seizure control. For patients in Group 1, the NETV threshold that led to improved epilepsy outcomes was <94.7 cc (p=0.047), whereas the threshold for Group 4 was <89.1 cc (p=0.016). When analysis was conducted for Group 2, the threshold of 10.2 cc failed to reach significance (p=0.1). Interestingly, the threshold analysis for Group 3 found that having a NETV of > 10.1 cc showed improved seizure outcomes (p=0.016). A multivariable cox proportional hazard analysis found that twelve-month seizure freedom was predictive of better OS in group 1 (HR 0.02, p=0.05) and group 4 (HR 0.21, p=1.63e-9). CONCLUSION Our study reveals clinically distinct molecular groups of glioma that display different seizure responses. This data suggests a tumor-specific approach to aggressiveness of extent of resection in order to achieve optimal seizure control.

The effectiveness and safety of bevacizumab in improving the efficacy of antiseizure medication in treating refractory epilepsy induced by stereotactic radiosurgery in meningiomas

Background: Refractory epilepsy (RE) increases rapidly after stereotactic radiosurgery (SRS), but the reports on RE treatment are rare, with various methods and efficacy. In recent years, bevacizumab (BEV) has been widely used as it is effective in eliminating intracranial oedema and reducing radioactive damage. The aim of this study was to evaluate the application of additional BEV to RE after SRS in the real world. Methods: Seizure freedom and seizure response were defined as 100% and > 50% reduction in seizure frequency at baseline and 6-, 9- and 12-month follow-ups. The sustained seizure-free (SSF), sustained seizure response (SSR) was used to assess the effectiveness of BEV. The number of anti-seizure medications (ASM), seizure severity (NH3), and epilepsy quality of life rating scale (QOLIE-31) scores were compared before and 12 months after treatment. Results: Forty-one patients were included from January 2020 to December 2022. During the 1-year follow-up, 5 patients (12.2%) achieved SSF lasting 12 months, and 4.9% and 7.3% enjoyed SSF more than 6 months and 9 months, respectively. Twelve patients (29.3%) achieved SSR lasting for 12 months, and 19.5% and 24.4% of the study cohort achieved SSR more than 6 months and 9 months, respectively. Patients’ ASM, NH3, and QOLIE-31 scores significantly improved 12 months after treatment, and the adverse reactions were controllable. Conclusion: This study is the first to explore and report the additional use of BEV in the treatment of RE after SRS in meningiomas. BEV was effective and safe in the treatment of SRS-induced RE.

Cenobamate as an Early Adjunctive Treatment in Drug-Resistant Focal-Onset Seizures: An Observational Cohort Study.

Cenobamate (CNB) is a new antiseizure medication (ASM) to treat drug-resistant, focal-onset seizures. Data on its use in early therapy lines are not yet available, and clinicians frequently consider CNB to be a later ASM drug choice. We investigated the efficacy and safety of CNB as an early adjunctive treatment in drug-resistant, focal-onset seizures. The study population were patients with drug-resistant, focal-onset seizures who were initiated with CNB after they did not respond to two or three lifetime ASMs, including all prior and concomitant ASMs. These patients were matched (1:2) by sex, age, and seizure frequency to controls who were initiated with any ASM other than CNB. All participants participated in the Mainz Epilepsy Registry. We evaluated the retention rate after 12 months of CNB and after each new adjunctive ASM in the control group. In addition, seizure freedom and the response rate (reduction of seizure frequency by ≥ 50% from baseline) after 12 months were estimated. We included 231 patients aged 44.4 ± 15.8 years. Of these, 33.3% (n = 77) were on CNB, 19.0% (n = 44) on valproate (VPA), 17.3% (n = 40) on lacosamide (LCS), 16.4% (n = 38) on levetiracetam (LEV), and 13.9% (n = 32) on topiramate (TPM). The highest retention rate after 12 months since the beginning of the early adjunctive therapy was observed on CNB (92.0%), compared with LCS (80.0%), LEV (73.3%), VPA (68.2%), or TPM (62.5%) (p < 0.05). Seizure freedom and response rate were also the best on CNB (19.5% and 71.4%, respectively) compared with other ASMs (8.3% and 52.5%, respectively; p < 0.05). No significant differences in adverse events between CNB and other ASMs were observed. Our study provides evidence that CNB is an effective ASM with a good safety profile in the early therapy lines of drug-resistant, focal-onset seizures. This data should support medical decision making in the management of patients with refractory epilepsy. NCT05267405.

Combined generalized and focal epilepsy with reflex features in Adaptor protein complex 4-associated hereditary spastic paraplegias: A cohort observational study

BackgroundPatients with genetic deficiency of the adaptor protein complex 4 (AP-4) exhibit earlyonset developmental delay, spastic diplegia, intellectual disability, speech impairment. The phenotype overlaps with other hereditary spastic paraplegias and cerebral palsies. Febrile seizures are common at onset. Epilepsy has been described in more than half of cases, arising in early infancy often with status epilepticus, but no typical seizure semiology or electroencephalographic features have been identified thus far. PurposeWe aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency. MethodsObservational cohort study on patients with bi-allelic pathogenic variants in AP-4 subunits and epilepsy. We focused on the seizure semiology, electroencephalographic characteristics and response to antiseizure medications. ResultsPatients harboured pathogenic variants in AP4S1 (n = 5) or AP4M1 (n = 1). The phenotype included spastic paraparesis, intellectual disability, speech/language impairment, microcephaly, and MRI evidence of hypoplasia of the corpus callosum. In 66 % of the patients, febrile seizures preceded the onset of epilepsy, which spanned from infancy to adolescence (range=14 months-13 years). Absences (66 %) and focal motor seizures (50 %) were common. No patient met the criteria for drug-resistance. Peculiar electroencephalographic features arose after the epilepsy onset and persisted at long-term follow-up: bilateral and asynchronous focal discharges combined with independent diffuse spike-wave-discharges (100 %) and reflex abnormalities (66 %). ConclusionIn AP-4 complex disease, epilepsy could arise beyond early infancy, until adolescence, with variable combination of generalized and focal seizures. The prognosis was favourable. We observed a common electroencephalographic signature - combined focal/generalized and reflex abnormalities - which may constitute a biomarker of AP-4 deficiency with epilepsy, applicable to inform genetic testing and disentangle the differential diagnosis.

Factors associated with seizure response in adults with epilepsy on a modified Atkins diet

PurposeThis study investigated factors associated with improved seizure control in adults with epilepsy following a modified Atkins diet (MAD). MethodsFollow-up data collected from participants enrolled in a prospective study between March 2016 and November 2023 was analyzed. Demographic and clinical differences between diet responders and non-responders were evaluated. MAD response was defined as ≥ 50 % reduction in seizure frequency from baseline. ResultsMAD use led to clinical response in 48 % of study participants with 2–3 month follow-up and in 56 % of study participants with 6 month follow-up. No significant differences were found for gender, age at diet initiation, age at epilepsy diagnosis, or for number of current or past medications tried. However, a significant relationship emerged between epilepsy type and diet response at 6 months with a response of 100 % seen in adults with generalized epilepsy and a response of only 42 % in adults with focal epilepsy (p = 0.004). Those who responded to the diet showed non-significant increases in many of the measured lipid biomarkers. Levels of apolipoprotein-B and small low-density lipoprotein particles showed significant increases from baseline after 3 months in responders compared to non-responders (p = 0.004 and 0.049, respectively). ConclusionsThese findings support the continued use of MAD particularly for seizure management in adults with generalized epilepsy and highlight potential mechanisms of clinical response involving lipoprotein and energy metabolism.

Maintenance of response to ketogenic diet therapy for drug-resistant epilepsy post diet discontinuation: A multi-centre case note review

PurposeThere is limited research on the proportion of individuals with epilepsy who maintain response to ketogenic diet therapy (KDT) after discontinuing treatment. We aimed to determine the proportion of individuals who did / did not maintain response post KDT and explore factors that may influence the likelihood of maintaining response. MethodsRetrospective data were collected from 97 individuals from 9 KDT centres. Individuals had achieved ≥50 % seizure reduction on KDT for at least 12 months, with seizure frequency data available at 3 months+ post diet. Outcome 1 was: recurrence of seizures or increase in seizure frequency post diet; outcome 2: recurrence of seizures, increase in seizure frequency or an additional anti-seizure treatment started post diet. Results61/97 (62.9 %) individuals maintained response at latest follow-up (mean 2.5[2.0] years since stopping KDT). Approximately one third maintained response without further anti-seizure treatments. One quarter of individuals had an increase in frequency or recurrence of seizures within 6 months (95 %CI 4, 12) for outcome 1 and within 3 months (3, 6) for outcome 2.Individuals who did not achieve seizure freedom on diet were significantly more likely to have an increase in seizures or to require additional anti-seizure treatments post diet compared to those who were seizure-free on diet (hazard ratio 4.02, 95 %CI (1.46, 11.16) p < 0.01). ConclusionOur findings should help guide clinical teams with the information they provide patients and their families regarding likelihood of long-term seizure response to KDT. Realistic costings for KDT services may need to be considered.

Cenobamate: real-world data from a retrospective multicenter study

BackgroundClinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs.MethodsWe conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs.Results116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged.ConclusionsCNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.

Level-Headed: Correlating Antiseizure Medication Drug Concentrations With Adverse Effects and Seizure Response.

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Cannabidiol-enriched oil for adult patients with drug-resistant epilepsy: Prospective clinical and electrophysiological study.

Cannabidiol-enriched oil (CBDO) is being used increasingly to improve seizure control in adult patients with drug-resistant epilepsy (DRE), despite the lack of large-scale studies supporting its efficacy in this patient population. We aimed to assess the effects of add-on CBDO on seizure frequency as well as on gait, cognitive, affective, and sleep-quality metrics, and to explore the electrophysiological changes in responder and non-responder DRE patients treated with add-on CBDO. We prospectively recruited adult DRE patients who were treated with add-on CBDO. Patients were evaluated prior to treatment and following 4 weeks of a maintenance daily dose of ≈260 mg CBD and ≈12 mg Δ9-tetrahydrocannabinol (THC). The outcome measures included seizure response to CBDO (defined as ≥50% decrease in seizures compared to pre-CBDO baseline), gait testing, Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS), and sleep-quality questionnaire assessments. Patients underwent electroencephalography (EEG) recording during rest as well as event-related potentials (ERPs) during visual Go/NoGo task while sitting and while walking. Nineteen patients were recruited, of which 16 finished pre- and post-CBDO assessments. Seven patients (43.75%) were responders demonstrating an average reduction of 82.4% in seizures, and nine patients (56.25%) were non-responders with an average seizure increase of 30.1%. No differences in demographics and clinical parameters were found between responders and non-responders at baseline. However, responders demonstrated better performance in the dual-task walking post-treatment (p = .015), and correlation between increase in MoCA and seizure reduction (r = .810, p = .027). Post-CBDO P300 amplitude was lower during No/Go-sitting in non-responders (p = .028) and during No/Go-walking in responders (p = .068). CBDO treatment can reduce seizures in a subset of patients with DRE, but could aggravate seizure control in a minority of patients; yet we found no specific baseline clinical or electrophysiological characteristics that are associated with response to CBDO. However, changes in ERPs in response to treatment could be a promising direction to better identify patients who could benefit from CBDO treatment.

Monopolar stereoelectroencephalography-guided radiofrequency thermocoagulation.

Stereoelectroencephalography (SEEG)-guided radiofrequency thermocoagulation (RFTC) has the advantage of producing a lesion in the epileptogenic zone (EZ) at the end of SEEG. The majority of published SEEG-guided RFTCs have been bipolar and usually performed between contiguous contacts of the same electrode. In the present study, the authors evaluate the safety, efficacy, and benefits of monopolar RFTC at the end of SEEG. This study included a series of 31 consecutive patients who had undergone RFTC at the end of SEEG for drug-resistant focal epilepsy in the period of January 2013-December 2019. Post-RFTC seizure control was assessed after 2 months and at the last follow-up visit. Twenty-one patients underwent resective epilepsy surgery after the SEEG-guided RFTC, and the postoperative seizure outcome among these patients was compared with the post-RFTC seizure outcome. Four hundred forty-six monopolar RFTCs were done in the 31 patients. Monopolar RFTCs were performed in all cortical areas, including the insular cortex in 11 patients (56 insular RFTCs). There were 31 noncontiguous lesions (7.0%) because of vascular constraints. The volume of one monopolar RFTC, as measured on T2-weighted MRI immediately after the procedure, was between 44 and 56 mm3 (mean 50 mm3). The 2-month post-RFTC seizure outcomes were as follows: seizure freedom in 13 patients (41.9%), ≥ 50% reduced seizure frequency in 11 (35.5%), and no significant change in 7 (22.6%). Seizure outcome at the last follow-up visit (mean 18 months, range 2-54 months) showed seizure freedom in 2 patients (6.5%) and ≥ 50% reduced seizure frequency in 20 patients (64.5%). Seizure freedom after monopolar RFTC was not significantly associated with the number or location of coagulated contacts. Seizure response after monopolar RFTC had a high positive predictive value (93.8%) but a low negative predictive value (40%) for seizure outcome after subsequent resective surgery. In this series, the only complication (3.2%) was a limited intraventricular hematoma following RFTC performed in the hippocampal head, with spontaneous resolution and no sequelae. The use of monopolar SEEG-guided RFTC provides more freedom in terms of choosing the SEEG contacts for thermocoagulation and a larger thermolesion volume. Monopolar thermocoagulation seems particularly beneficial in cases with an insular EZ, in which vascular constraints could be partially avoided by making noncontiguous lesions within the EZ.

Optimized microburst VNS elicits fMRI responses beyond thalamic-specific response from standard VNS.

In parallel to standard vagus nerve stimulation (VNS), microburst stimulation delivery has been developed. We evaluated the fMRI-related signal changes associated with standard and optimized microburst stimulation in a proof-of-concept study (NCT03446664). Twenty-nine drug-resistant epilepsy patients were prospectively implanted with VNS. Three 3T fMRI scans were collected 2 weeks postimplantation. The maximum tolerated VNS intensity was determined prior to each scan starting at 0.125 mA with 0.125 mA increments. FMRI scans were block-design with alternating 30 sec stimulation [ON] and 30 sec no stimulation [OFF]: Scan 1 utilized standard VNS and Scan 3 optimized microburst parameters to determine target settings. Semi-automated on-site fMRI data processing utilized ON-OFF block modeling to determine VNS-related fMRI activation per stimulation setting. Anatomical thalamic mask was used to derive highest mean thalamic t-value for determination of microburst stimulation parameters. Paired t-tests corrected at P < 0.05 examined differences in fMRI responses to each stimulation type. Standard and microburst stimulation intensities at Scans 1 and 3 were similar (P = 0.16). Thalamic fMRI responses were obtained in 28 participants (19 with focal; 9 with generalized seizures). Group activation maps showed standard VNS elicited thalamic activation while optimized microburst VNS showed widespread activation patterns including thalamus. Comparison of stimulation types revealed significantly greater cerebellar, midbrain, and parietal fMRI signal changes in microburst compared to standard VNS. These differences were not associated with seizure responses. While standard and optimized microburst VNS elicited thalamic activation, microburst also engaged other brain regions. Relationship between these fMRI activation patterns and clinical response warrants further investigation. The study was registered with clinicaltrials.gov (NCT03446664).

Utilization of APE2 and RITE2 scores in autoimmune encephalitis patients with seizures

PurposeImmune-mediated seizures are rare but are increasingly recognized as an etiology of seizures resistant to anti-seizure medications (ASMs). Antibody Prevalence in Epilepsy 2 (APE2) and Response to Immunotherapy in Epilepsy 2 (RITE2) scores were developed recently to identify patients who may be seropositive for serum central nervous system (CNS) specific antibodies (Ab) and may benefit from immunotherapy (Dubey et al. 2018). The goal of this study was to apply APE2 and RITE2 scores to an independent cohort of patients with seizures secondary to autoimmune encephalitis (AE) and to further verify the sensitivity and specificity of the scores. Principal resultsWe conducted a retrospective study at Stanford University Hospital between 2008 and 2021 and included patients who had acute seizures and AE using diagnostic criteria from Graus (n = 34 definite AE, 10 probable AE, and 12 possible AE) (Graus et al. 2016). Patients were excluded if they did not have a serum Ab panel investigated or had alternate diagnoses (n = 55). APE2 and RITE2 scores were calculated based on clinical and diagnostic data (n = 56). Serum Ab were positive in 73 % of patients, in which 63 % cases carried CNS specific Ab. An APE2 score ≥ 4 had a sensitivity of 97 % and specificity of 14 % to predict a positive serum CNS specific Ab. A RITE2 score ≥ 7 had a sensitivity of 93 % and specificity of 60 % to predict seizure responsiveness to immunotherapy. ConclusionAPE2 and RITE2 scores had high sensitivities but low specificities to predict seropositivity and seizure responsiveness to immunotherapy in patients with autoimmune encephalitis with seizures.

Retrospective Multicenter Cohort Study on Safety and Electroencephalographic Response to Lacosamide for Neonatal Seizures

BackgroundThere is growing evidence supporting the safety and effectiveness of lacosamide in older children. However, minimal data are available for neonates. We aimed to determine the incidence of adverse events associated with lacosamide use and explore the electroencephalographic seizure response to lacosamide in neonates. MethodsA retrospective cohort study was conducted using data from seven pediatric hospitals from January 2009 to February 2020. For safety outcomes, neonates were followed for ≤30 days from index date. Electroencephalographic response of lacosamide was evaluated based on electroencephalographic reports for ≤3 days. ResultsAmong 47 neonates, 98% received the first lacosamide dose in the intensive care units. During the median follow-up of 12 days, 19% of neonates died, and the crude incidence rate per 1000 patient-days (95% confidence interval) of the adverse events by diagnostic categories ranged from 2.8 (0.3, 10.2) for blood or lymphatic system disorders and nervous system disorders to 10.5 (4.2, 21.6) for cardiac disorders. Electroencephalographic seizures were observed in 31 of 34 patients with available electroencephalographic data on the index date. There was seizure improvement in 29% of neonates on day 1 and also in 29% of neonates on day 2. On day 3, there was no change in 50% of neonates and unknown change in 50% of neonates. ConclusionsThe results are reassuring regarding the safety of lacosamide in neonates. Although some neonates had fewer seizures after lacosamide administration, the lack of a comparator arm and reliance on qualitative statements in electroencephalographic reports limit the preliminary efficacy results.

MyD88-mediated signaling is critical for the generation of seizure responses and cognitive impairment in a model of anti-N-methyl-D-aspartate receptor encephalitis.

We previously demonstrated that interleukin-1 receptor-mediated immune activation contributes to seizure severity and memory loss in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. In the present study, we assessed the role of the myeloid differentiation primary response gene 88 (MyD88), an adaptor protein in Toll-like receptor signaling, in the key phenotypic characteristics of anti-NMDAR encephalitis. Monoclonal anti-NMDAR antibodies or control antibodies were infused into the lateral ventricle of MyD88 knockout mice (MyD88-/-) and control C56BL/6J mice (wild type [WT]) via osmotic minipumps for 2 weeks. Seizure responses were measured by electroencephalography. Upon completion of the infusion, the motor, anxiety, and memory functions of the mice were assessed. Astrocytic (glial fibrillary acidic protein [GFAP]) and microglial (ionized calcium-binding adaptor molecule 1 [Iba-1]) activation and transcriptional activation for the principal inflammatory mediators involved in seizures were determined using immunohistochemistry and quantitative real-time polymerase chain reaction, respectively. As shown before, 80% of WT mice infused with anti-NMDAR antibodies (n = 10) developed seizures (median = 11, interquartile range [IQR] = 3-25 in 2 weeks). In contrast, only three of 14 MyD88-/- mice (21.4%) had seizures (0, IQR = 0-.25, p = .01). The WT mice treated with antibodies also developed memory loss in the novel object recognition test, whereas such memory deficits were not apparent in MyD88-/- mice treated with anti-NMDAR antibodies (p = .03) or control antibodies (p = .04). Furthermore, in contrast to the WT mice exposed to anti-NMDAR antibodies, the MyD88-/- mice had a significantly lower induction of chemokine (C-C motif) ligand 2 (CCL2) in the hippocampus (p = .0001, Sidak tests). There were no significant changes in the expression of GFAP and Iba-1 in the MyD88-/- mice treated with anti-NMDAR or control antibodies. These findings suggest that MyD88-mediated signaling contributes to the seizure and memory phenotype in anti-NMDAR encephalitis and that CCL2 activation may participate in the expression of these features. The removal of MyD88 inflammation may be protective and therapeutically relevant.

Efficacy, tolerability and safety of add-on third-generation antiseizure medications in treating focal seizures worldwide: a network meta-analysis of randomised, placebo-controlled trials

Adjunctive newer antiseizure medications (ASMs) are being used in patients with treatment-resistant focal-onset seizures (FOS). An updated network meta-analysis (NMA) was necessary to compile evidence in this critical area. We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus from their inception until 17 January 2024, evaluating the efficacy, tolerability, and safety of rufinamide (RUF), brivaracetam (BRV), cenobamate (CNB), eslicarbazepine (ESL), lacosamide (LCM), retigabine (RTG), and perampanel (PER) as adjunctive treatments for FOS. Efficacy outcomes included seizure response and seizure freedom. Tolerability was assessed by discontinuation due to adverse events (AEs). Safety outcomes were evaluated based on the number of patients experiencing at least one AE and serious adverse events (SAEs). This review is registered with PROSPERO (CRD42023485130). A total of 29 studies involving 11,750 participants were included. For seizure response, all ASMs were significantly superior to placebo, with RTG ranking highest, followed by CNB. Considering dosage, CNB 400mg/d was top-ranked, followed by RTG 1200mg/d. For seizure freedom, BRV was highest-ranked, followed by CNB, with BRV 100mg/d leading, followed by CNB 400mg/d. Regarding tolerability, LCM 600mg/d had the lowest ranking, followed by CNB 400mg/d. For the safety outcome of AEs, ESL 1200mg/d was ranked lowest, followed by CNB 400mg/d. Regarding SAEs, LCM 400mg/d was ranked lowest, followed by RTG 1200mg/d. ASMs at different dosages have varying efficacy and tolerability profiles. We have provided hierarchical rankings of ASMs for efficacy and safety outcomes. Our findings offer the most comprehensive evidence available to inform patients, families, physicians, guideline developers, and policymakers about the choice of ASMs in patients with treatment-resistant FOS. None.

Efficacy and safety of corticosteroids and ACTH in epileptic syndromes beyond Infantile Epileptic Spasms Syndrome (IESS): A systematic review and meta-analysis.

We conducted a systematic review investigating the efficacy and tolerability of adrenocorticotropic hormone (ACTH) and corticosteroids in children with epilepsies other than infantile epileptic spasm syndrome (IESS) that are resistant to anti-seizure medication (ASM). We included retrospective and prospective studies reporting on more than five patients and with clear case definitions and descriptions of treatment and outcome measures. We searched multiple databases and registries, and we assessed the risk of bias in the selected studies using a questionnaire based on published templates. Results were summarized with meta-analyses that pooled logit-transformed proportions or rates. Subgroup analyses and univariable and multivariable meta-regressions were performed to examine the influence of covariates. We included 38 studies (2 controlled and 5 uncontrolled prospective; 31 retrospective) involving 1152 patients. Meta-analysis of aggregate data for the primary outcomes of seizure response and reduction of electroencephalography (EEG) spikes at the end of treatment yielded pooled proportions (PPs) of 0.60 (95% confidence interval [CI] 0.52-0.67) and 0.56 (95% CI 0.43-0.68). The relapse rate was high (PP 0.33, 95% CI 0.27-0.40). Group analyses and meta-regression showed a small benefit of ACTH and no difference between all other corticosteroids, a slightly better effect in electric status epilepticus in slow sleep (ESES) and a weaker effect in patients with cognitive impairment and "symptomatic" etiology. Obesity and Cushing's syndrome were the most common adverse effects, occurring more frequently in trials addressing continuous ACTH (PP 0.73, 95% CI 0.48-0.89) or corticosteroids (PP 0.72, 95% CI 0.54-0.85) than intermittent intravenous or oral corticosteroid administration (PP 0.05, 95% CI 0.02-0.10). The validity of these results is limited by the high risk of bias in most included studies and large heterogeneity among study results. This report was registered under International Prospective Register of Systematic Reviews (PROSPERO) number CRD42022313846. We received no financial support.

Hyperfunction of post-synaptic density protein 95 promotes seizure response in early-stage aβ pathology

Accumulation of amyloid-beta (Aβ) can lead to the formation of aggregates that contribute to neurodegeneration in Alzheimer’s disease (AD). Despite globally reduced neural activity during AD onset, recent studies have suggested that Aβ induces hyperexcitability and seizure-like activity during the early stages of the disease that ultimately exacerbate cognitive decline. However, the underlying mechanism is unknown. Here, we reveal an Aβ-induced elevation of postsynaptic density protein 95 (PSD-95) in cultured neurons in vitro and in an in vivo AD model using APP/PS1 mice at 8 weeks of age. Elevation of PSD-95 occurs as a result of reduced ubiquitination caused by Akt-dependent phosphorylation of E3 ubiquitin ligase murine-double-minute 2 (Mdm2). The elevation of PSD-95 is consistent with the facilitation of excitatory synapses and the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors induced by Aβ. Inhibition of PSD-95 corrects these Aβ-induced synaptic defects and reduces seizure activity in APP/PS1 mice. Our results demonstrate a mechanism underlying elevated seizure activity during early-stage Aβ pathology and suggest that PSD-95 could be an early biomarker and novel therapeutic target for AD.

A prospective, observational, multicentre study to evaluate the efficacy of brivaracetam as adjuvant therapy for epilepsy: The Bravo study.

Epilepsy is a persistent tendency to experience epileptic seizures and can lead to various neurobiological disorders, with an elevated risk of premature mortality. This study evaluates the efficacy of brivaracetam adjuvant therapy in patients with epilepsy. A prospective observational multicentre study that was conducted in Pakistan from March to September 2022, by using a non-probability convenience sampling technique. The population consisted of 543 individuals with a diagnosis of epilepsy for whom adjunctive brivaracetam (Brivera; manufactured by Helix Pharma Pvt Ltd., Sindh, Pakistan) was recommended by the treating physician. The research sample was drawn from various private neurology clinics of Karachi, Lahore, Rawalpindi, Islamabad and Peshawar. Data originating from routine patient visits, and assessments at three study time points, were recorded in the study case report form. Across 18 clinical sites, 543 individuals participated, with a mean age of 32.9 years. The most prescribed dosages were 50 mg BD, followed by 100 mg BD. Notably, brivaracetam combined with divalproex sodium was the most prevalent treatment, followed by brivaracetam with levetiracetam. At both the 14th and 90th day assessments, a significant reduction in seizure frequency was observed, with 63.1% of individuals showing a favourable response by day 90. Treatment-naive individuals exhibited higher rates of seizure freedom and response compared with treatment-resistant individuals. The study demonstrates the effectiveness of brivaracetam combination therapy in epilepsy management, with notable reductions in seizure frequency and favourable clinical responses observed, particularly in treatment-naive individuals.

Comparing Methods of Seizure Response Monitoring During Electroconvulsive Therapy: Comparer les méthodes de surveillance des interventions en cas de crise durant la thérapie par électrochocs.

Electroconvulsive therapy (ECT) is used to treat several mental illnesses. Seizure duration is used to determine if the administered stimulus was adequate. Duration is estimated by electroencephalogram (EEG) interpretation and/or observed motor response (OMR). Neither method is considered the gold standard. This study investigated the relationship between the 2 methods. The hypothesis was that both EEG and OMR would be significantly positively correlated. Previous researchers have suggested that the 2 methods resulted in different estimates. A case series was conducted using recorded estimates obtained prospectively from 102 ECTs on adult psychiatric inpatients. A strong positive association was not observed in this study, correlation coefficient 0.510 (p < 0.001). This study suggests that the 2 methods differ, and further research is needed to determine the best indicator of adequate treatment.