Treatment-resistant Epilepsy Research Articles

Clinical Perspectives of Managing Epilepsy Across Different Patient Populations with a Focus on Brivaracetam: A Cross-sectional Study among Indian Physicians

Objective: To evaluate clinicians' preferences, prescribing patterns, and clinical experiences with brivaracetam compared to other antiepileptic drugs, particularly levetiracetam, in the management of epilepsy across different patient populations. Methodology: This cross-sectional study used a 24-item multi-response questionnaire to gather expert opinion across different Indian settings regarding their perspectives on epilepsy and brivaracetam. Data analysis employed descriptive statistics, with results reported as frequencies and percentages. Results: The survey included 360 participants. Clinicians showed a strong preference for brivaracetam as the first-line antiepileptic drug in patients with newly diagnosed epilepsy, with 72% favoring it for younger patients and 74% for elderly. This preference was particularly notable for managing partial-onset seizures, as cited by 71% of clinicians. Additionally, 65% reported that partial-onset seizures were the primary reason for switching to brivaracetam from other antiepileptics. Behavioral and psychiatric adverse effects were cited by 60% of clinicians as the main reasons for transitioning from levetiracetam to brivaracetam. Moreover, 47% reported that 10-20% of patients experiencing behavioral changes on levetiracetam were switched to brivaracetam, with 49% noting improved efficacy and behavioral outcomes in 20-30% of these cases. The minimal psychiatric and behavioral side effects of brivaracetam were noted as its main advantage by 41% of clinicians in managing partial-onset seizures. Furthermore, 70% of clinicians preferred brivaracetam for treatment-resistant epilepsy, and approximately half of them preferred it for pediatric partial seizures. Conclusion: This study highlighted brivaracetam as a preferred antiepileptic drug in clinical practice, especially for managing partial-onset seizures. It serves as an effective alternative for patients experiencing adverse effects with levetiracetam.

Real-world epilepsy monitoring with ultra long-term subcutaneous EEG: a 15-month prospective study.

Novel subcutaneous electroencephalography (sqEEG) systems enable prolonged, near-continuous cerebral monitoring in real-world conditions. Nevertheless, the feasibility, acceptability and overall clinical utility of these systems remains unclear. We report on the longest observational study using ultra long-term sqEEG to date. We conducted a 15-month prospective, observational study including ten adult people with treatment-resistant epilepsy. After device implantation, patients were asked to record sqEEG, to use an electronic seizure diary and to complete acceptability and usability questionnaires. sqEEG seizures were annotated visually, aided by automated detection. Seizure clustering was assessed via Fano Factor analysis and seizure periodicity at multiple timescales was investigated through circular statistics. Over a median duration of 438 days, ten patients recorded a median 18.8 hours/day, totalling 71,984 hours of real-world sqEEG data. Adherence and acceptability remained high throughout the study. While 754 sqEEG seizures were recorded across patients, over half (52%) of these were not reported in the patient diary. Of the 140 (27%) diary reports not associated with an identifiable sqEEG seizure, the majority (68%) were reported as seizures with preserved awareness. The sqEEG to diary F1 agreement score was highly variable, ranging from 0.06 to 0.97. Patient-specific patterns of seizure clustering and seizure periodicity were observed at multiple (circadian and multidien) timescales. We demonstrate feasibility and high acceptability of ultra long-term (months-years) sqEEG monitoring. These systems help provide real-world, more objective seizure counting compared to patient diaries. It is possible to monitor individual temporal fluctuations of seizure occurrence, including seizure cycles. [I do not have a X/Twitter handle]People with epilepsy may suffer from severe injuries or sudden death due to uncontrolled seizures. Many seizures remain unnoticed by people and unreported to doctors, despite these potentially catastrophic consequences. There is an urgent need to detect seizures more objectively. Our study used a novel device placed under the skin to monitor brainwave activity continuously, at home, for many months, in people with treatment-resistant epilepsy. By monitoring epilepsy from home, we detected many seizures unreported by patients, and we also found predictable patterns (cycles) of seizure occurrence over time. In the future, this type of monitoring could revolutionize epilepsy care, by improving safety, treatment management and reducing uncertainty in patients' daily lives.

Vagus Nerve Stimulation for Neurologic Recovery

Neural plasticity, a potential mode of managing various neurologic diseases, can be modulated via bursts of neurotransmitter release, including norepinephrine and acetylcholine. One method to do so is by electrically stimulating the vagus nerve while performing a specific task. Vagus nerve stimulation (VNS) has proven to be a viable intervention for conditions, including treatment-resistant epilepsy, depression, and, more recently, motor recovery after ischemic stroke. This article aims to explain the neurobiologic mechanism of VNS-induced cortical plasticity. It highlights both animal and human studies of VNS therapy, with a primary focus on recovery after stroke, traumatic brain injury, and spinal cord injury recovery. Furthermore, we discuss the long-term effects of VNS therapy, suggest potential solutions to overcome challenges encountered in previous studies, and elaborate on future directions in the field.

Advances in VNS efficiency and mechanisms of action on cognitive functions.

This systematic review aims to comprehensively analyze the efficacy and underlying mechanisms of vagus nerve stimulation (VNS) in enhancing cognitive functions and its therapeutic potential for various cognitive impairments. The review focuses on the impact of VNS on emotional processing, executive functions, learning, memory, and its clinical applications in conditions such as epilepsy, depression, Alzheimer's disease, and other neurological disorders. A systematic search of electronic databases (PubMed, Scopus, Web of Science) was conducted using the keywords "vagus nerve stimulation," "cognitive enhancement," "emotional processing," "executive function," "learning and memory," "epilepsy," "depression," "Alzheimer's disease," "neurological disorders," "attention-deficit/hyperactivity disorder," "sleep disorders," and "long COVID." The inclusion criteria encompassed controlled trials, longitudinal studies, and meta-analyses published in English between 2000 and July 2024. A comprehensive review of 100 articles highlighted the cognitive effects of Vagus Nerve Stimulation (VNS). Studies show that VNS, especially through transcutaneous auricular VNS (taVNS), enhances emotional recognition, particularly for facial expressions, and improves selective attention under high cognitive demands. Additionally, VNS enhances learning and memory, including associative memory and spatial working memory tasks. In clinical applications, VNS exhibits promising benefits for improving cognitive functions in treatment-resistant epilepsy, depression, and Alzheimer's disease. VNS represents a promising therapeutic approach for enhancing cognitive function across diverse patient populations. The reviewed evidence highlights its efficacy in modulating cognitive domains in healthy individuals and improving cognition in neurological conditions. However, the comparative effectiveness of different VNS modalities and the differential effects of online versus offline VNS on cognitive psychology require further investigation. Future research should focus on optimizing VNS protocols and elucidating specific cognitive domains that benefit most from VNS interventions. This ongoing exploration is essential for maximizing the therapeutic potential of VNS in clinical practice.

Presurgical Use of Cenobamate for Adult and Pediatric Patients Referred for Epilepsy Surgery: Expert Panel Recommendations.

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

Long-term efficacy and safety of cannabidiol in patients with tuberous sclerosis complex: 3-year results from the cannabidiol expanded access program.

The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC. Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12-week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks. Thirty-four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8-31.2), and patients were receiving a median of 3 (range, 1-7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25-28 mg/kg/d for 36 weeks and then 20-50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%-81%, 51%-87%, and 44%-87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%-71%, 14%-58%, and 0%-25% for convulsive seizures; 52%-75%, 35%-60%, and 7%-32% for focal seizures; and 46%-79%, 26%-65%, and 0%-13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment-related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths. Long-term add-on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports. In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%-79% of patients had at least 50% reduction and 26%-65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment-related side effects. These results show that long-term CBD treatment was associated with fewer seizures and mild/moderate side effects.

Impaired excitability of fast-spiking neurons in a novel mouse model of KCNC1 epileptic encephalopathy.

The recurrent pathogenic variant KCNC1-p.Ala421Val (A421V) is a cause of developmental and epileptic encephalopathy characterized by moderate-to-severe developmental delay/intellectual disability, and infantile-onset treatment-resistant epilepsy with multiple seizure types including myoclonic seizures. Yet, the mechanistic basis of disease is unclear. KCNC1 encodes Kv3.1, a voltage-gated potassium channel subunit that is highly and selectively expressed in neurons capable of generating action potentials at high frequency, including parvalbumin-positive fast-spiking GABAergic inhibitory interneurons in cerebral cortex (PV-INs) known to be important for cognitive function and plasticity as well as control of network excitation to prevent seizures. In this study, we generate a novel transgenic mouse model with conditional expression of the Ala421Val pathogenic missense variant (Kcnc1-A421V/+ mice) to explore the physiological mechanisms of KCNC1 developmental and epileptic encephalopathy. Our results indicate that global heterozygous expression of the A421V variant leads to epilepsy and premature lethality. We observe decreased PV-IN cell surface expression of Kv3.1 via immunohistochemistry, decreased voltage-gated potassium current density in PV-INs using outside-out nucleated macropatch recordings in brain slice, and profound impairments in the intrinsic excitability of cerebral cortex PV-INs but not excitatory neurons in current-clamp electrophysiology. In vivo two-photon calcium imaging revealed hypersynchronous discharges correlated with brief paroxysmal movements, subsequently shown to be myoclonic seizures on electroencephalography. We found alterations in PV-IN-mediated inhibitory neurotransmission in young adult but not juvenile Kcnc1-A421V/+ mice relative to wild-type controls. Together, these results establish the impact of the recurrent Kv3.1-A421V variant on neuronal excitability and synaptic physiology across development to drive network dysfunction underlying KCNC1 epileptic encephalopathy.

Pediatric Epilepsy Genetic Testing Results and Long-term Seizure Freedom.

Objective: To determine whether there is a correlation of genetic diagnosis/result with long-term seizure freedom in pediatric epilepsy patients. Methods: This was a prospective and retrospective cohort study of children with epilepsy referred for genetic testing at a single center. The primary outcomes were presence and type of genetic diagnosis (pathogenic, benign, or variant of uncertain significance) and patient epilepsy status (seizure free, treatment failure, uncertain). Epilepsy gene panels were the primary method of genetic testing. Results: The prospective cohort had 22 patients followed for >11 years and for whom genetic testing was then performed; the retrospective cohort had 78 patients with previous genetic testing followed for >8 years. In the prospective cohort, one patient each of the seizure free or treatment failure groups had a pathogenic genetic variant; mean Combined Annotation Dependent Depletion (CADD) scores 22 and 24, respectively (P = .62). In the retrospective cohort, there was no difference in the number of variants (P = .97), the variant interpretations (P = .29 ClinVar, P = .39 lab interpretation) or mean CADD scores (P = .29) between the seizure-free, treatment failure, and uncertain epilepsy patients. Whole exome and genome sequencing identified pathogenic variants in 70% of patients with treatment failure but were not performed in seizure-free patients. Significance: Our findings show no correlation of the presence or type of epilepsy gene panel result with long-term seizure freedom in pediatric patients. The yield and specificity of pathogenic variants may be higher using whole exome and whole genome sequencing in patients with treatment-resistant epilepsy. Whole exome and whole genome sequencing, or more targeted understanding of specific variants, may be needed to improve the utility of pediatric epilepsy genetic testing.

Interictal psychosis of epilepsy: What is the role of the neurologist?

Psychotic disorders are more frequent in people with epilepsy than the general population. They constitute one of the most serious psychiatric comorbidities which require an immediate psychopharmacologic intervention. Yet, access to psychiatrists is often limited or not available and the neurologists taking care of these patients are called-upon to start treatment with antipsychotic medication. The purpose of this manuscript is to provide clinicians with pragmatic psychopharmacologic strategies to treat interictal psychotic disorders in patients with epilepsy. We review the case of a 45 years-old man with a 35-year history of treatment-resistant focal epilepsy of bitemporal origin who developed a de-novo psychotic episode that began with insomnia, mood lability and agitation and evolved into paranoid delusions, auditory hallucinations and a thought disorder. The patient was diagnosed with an interictal psychotic episode and was treated with aripiprazole which resulted in significant improvement after reaching a 20 mg /day dose and allowed for the patient to be discharged home. In summary, interictal psychotic episodes of epilepsy are relatively frequent in patients with epilepsy and require of an early psychopharmacologic treatment to facilitate their remission or stabilization until mental health professionals can take over their long-term care. Compared to primary psychotic disorders, interictal psychotic episodes respond better and at lower doses of antipsychotic drugs.

Demonstration of Group-Level and Individual-Level Efficacy Using Time-to-Event Designs for Clinical Trials of Antiseizure Medications.

Participants with treatment-resistant epilepsy who are randomized to add-on placebo and remain in a trial for the typical 3 to 5-month maintenance period may be at increased risk of adverse outcomes. A novel trial design has been suggested, time to prerandomization monthly seizure count (T-PSC), which would limit participants' time on ineffective therapy. We reanalyzed 11 completed trials to determine whether the primary efficacy conclusions at T-PSC matched each of the original, longer trials. A total of 11 double-blind, placebo-controlled trials of levetiracetam, brivaracetam, lacosamide, topiramate, and lamotrigine for either focal-onset or generalized-onset epilepsy were selected. We evaluated the group-level and individual-level efficacy of treatments including the median percent reduction (MPR) in seizure frequency and 50% responder rate (50RR) at T-PSC, time to second seizure, and time to first seizure compared with the full-length trial. The primary efficacy conclusions of 10 of the 11 trials would have been the same with a T-PSC design compared with the traditional design (the exception of lamotrigine had a very high initial placebo response). As a proportion of the full-length effect size, 90% of the MPR and 85% of the 50RR were seen at T-PSC (95% CI 73%-113% and 65%-110%, respectively). Using the T-PSC design, the time on blinded treatment was at least 312 participant-years shorter (40% of total duration) and 142,000 seizures occurred during this time (60% of total seizures). By contrast, the time to first or second seizure designs reproduced group-level effect size, but the primary efficacy conclusions of each trial and individual-level efficacy correspondence were fair to poor. These results support the use of this trial design for new epilepsy medication trials because this reanalysis of 11 randomized controlled trials demonstrated that observation until T-PSC was sufficient to demonstrate efficacy while potentially improving participant safety by reducing the time of exposure to placebo and inadequate treatment. Despite analysis of 11 trials including 3,619 participants, we did not observe a significant reduction in the group-level effect size, which is directly related to statistical power. The next step is to evaluate whether T-PSC is sufficient to evaluate safety as measured by adverse events.

Mapping Functional Connectivity Signatures of Pharmacoresistant Focal Cortical Dysplasia-Related Epilepsy.

To determine common network alterations in focal cortical dysplasia pharmacoresistant epilepsy (FCD-PRE) using functional connectivity analysis of resting-state functional magnetic resonance imaging (rsfMRI). This is a retrospective imaging cohort from Children's National Hospital (Washington, DC, USA) from January, 2011 to January, 2022. Patients with 3-T MRI-confirmed FCD-PRE underwent rsfMRI as part of routine clinical care. Patients were included if they were age 5-22 years at the time of the scan, and had a minimum of 18 months of follow-up. Healthy, typically-developing controls were included from Children's National Hospital (n = 16) and matched from Human Connectome Project-Development public dataset (n = 100). A total of 42 FCD-PRE patients (20 M:22 F, aged 14.2 ± 4.1 years) and 116 healthy controls (56 M:60 F, aged 13.7 ± 3.3 years) with rsfMRI were included. Seed-based functional connectivity maps were generated for each FCD, and each seed was used to generate a patient-specific z-scored connectivity map on 116 controls. FCD-PRE patients had mutual altered connectivity in regions of dorsal attention, default mode, and control networks. Functional connectivity was diminished within the FCD dominant functional network, as well as in homotopic regions. Cluster specific connectivity patterns varied by pathological subtype. Higher FCD connectivity to the limbic network was associated with increased odds of Engel I outcome. This study demonstrates diminished functional connectivity patterns in FCD-PRE, which may represent a neuromarker for the disease, independent of FCD location, involving the dorsal attention, default mode, and control functional networks. Higher connectivity to the limbic network is associated with a seizure-free outcome. Future multicenter, prospective studies are needed to allow for much earlier detection of signatures of treatment-resistant epilepsy. ANN NEUROL 2024.

Increasing serum HMGB1 as a potential biomarker of treatment-resistant epilepsy in children: A case series and literature review

Epilepsy still causes the most burden compared to any other neurological diseases in children. Recent studies point to a connection between inflammation and epilepsy, particularly in epileptogenic epilepsy development, and the long-term effects of seizures. This pilot study describes the increasing serum High Mobility Group Box 1 (HMGB1) in two children with treatment-resistant epilepsy and how this marker could be considered a promising biomarker for treatment-resistant epilepsy in children. Case 1: A four-year-eight-month-old boy was presented with treatment-resistant epilepsy, communicating hydrocephalus on the ventriculoperitoneal shunt, cerebral palsy and global developmental delay. The seizure form was involuntary jerky head twisting and body shivering three times a day. Despite three antiepileptic medications (valproic acid, phenobarbital, and levetiracetam) given in maximal dose, the seizures were not well-controlled, three up to four times per week. The serum HMGB1 level was 5.93 ng/ml. Case 2: A four-year-three-month-old boy was presented with treatment-resistant epilepsy, cerebral palsy, global developmental delay, and sensorineural hearing loss. His first seizure started as status epilepticus. Symptoms progressed to generalized tonic seizures, with eyes bulging upward, occurring more than five times a day. The patient still suffers seizures daily for one minute despite the maximal dosage of valproic acid and levetiracetam therapy. The serum HMGB1 level was 5.342 ng/ml. Serum HMGB1 could be considered a potential biomarker for treatment-resistant epilepsy in children. Further diagnostic studies with adequate sample sizes are needed to support the proposed aetiology for developing targeted treatment options.

An observational time-series study on the behavioral effects of adjunctive artisanal cannabidiol use by adults with treatment resistant epilepsies

BackgroundFor approximately 30% of people with epilepsy, seizures are not well-controlled by anti-seizure medication (ASM). This condition, called treatment resistant epilepsy (TRE), is associated with increased morbidity and mortality, and substantially impacts the quality of life of both the individual and their family. Non-responsiveness to ASMs leads many people with TRE to seek alternative therapies, such as cannabinoid-based medication, particularly cannabidiol (CBD), with or without medical or professional advice. This is due in part to widespread reporting in the media about the benefits of CBD for seizures in some forms of epilepsy.MethodsAdults with TRE, opting to add CBD to their existing treatment regime, completed this prospective, observational, longitudinal, quasi-experimental, time-series study. We hypothesized that adjunctive CBD use would positively impact participants’ quality of life and psychological well-being in comparison to a baseline period without CBD use. Participants were followed for a period of approximately six months – for approximately one month of baseline prior to the initiation of CBD use and approximately five months after the initiation of CBD use. Participants provided urine samples and completed behavioral questionnaires that assessed quality of life, anxiety/depression, and adverse events during baseline and at two times during CBD use.ResultsComplete case analyses (n = 10) showed a statistically significant improvement in quality of life, a statistically significant decrease in anxiety symptoms, and a statistically significant decrease in the experience of adverse events over time (p < 0.05). Improvements noted in the experience of depression symptoms did not reach statistical significance. Urinalysis revealed the majority of participants had no CBD/metabolites in their system at the beginning of the study, and confirmed the presence of CBD/metabolites in participants’ urine after CBD was added to their treatment regime. Analysis of missing data using multiple imputation supported the findings of the complete case analysis.InterpretationFor a small group of individuals with TRE of varying etiologies, adjunctive use of artisanal CBD was associated with improvements in the behavioral and psychological symptoms of TRE, as well as improved medication tolerability.

Long-term Effectiveness of Cannabidiol (CBD) Against Focal-onset Seizures in Treatment-resistant Epilepsies (TRE): Experience from the Expanded Access Program (EAP) (S29.005)

Long-term Effectiveness of Cannabidiol (CBD) Against Focal-onset Seizures in Treatment-resistant Epilepsies (TRE): Experience from the Expanded Access Program (EAP) (S29.005)

Real-world Safety and Effectiveness of Cannabidiol (CBD) in Adults with Treatment-resistant Epilepsies (TREs): Long-term Results from the United States Expanded Access Program (EAP) (P8-1.002)

Real-world Safety and Effectiveness of Cannabidiol (CBD) in Adults with Treatment-resistant Epilepsies (TREs): Long-term Results from the United States Expanded Access Program (EAP) (P8-1.002)

Use of cannabidiol in the treatment of drug-refractory epilepsy in children and young adults: A systematic review.

Epilepsy poses a significant challenge in pediatric and adolescent populations, impacting not only seizures but also psychological and cognitive comorbidities, leading to higher mortality rates than the general population. Drug-refractory epilepsy, resistant to conventional treatments, affects a range of 7-20% of pediatric patients. The search for alternative therapies has led to exploring the therapeutic potential of Cannabis sativa L. compounds, particularly cannabidiol (CBD). Examine the use of CBD for treating drug-refractory epilepsy in children and young adults, summarizing existing evidence on its efficacy. A systematic review, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, assessed studies from 2018 to 2023, focusing on CBD's efficacy and safety for treatment-resistant epilepsy in pediatric and juvenile populations. The search spanned seven databases, and the studies underwent rigorous screening and data extraction. Out of 6351 identified articles, eight were selected for review. The included studies reported positive outcomes, with CBD leading to a reduction in seizure frequency ranging from 50% to complete seizure freedom. Adverse effects were mostly mild and reversible, including drowsiness, diarrhea, and loss of appetite. The CBD emerges as a promising tool for refractory epilepsy in pediatric patients, showing efficacy in reducing seizure frequency and improving overall quality of life. Despite mild and reversible adverse effects, CBD's benefits outweigh the risks. However, more research on long-term effects is needed to fully understand its implications.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders

BackgroundSCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia.MethodsIn this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing.ResultsClinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Three novel and three reported variants were observed in SCN8A. Electrophysiological analysis in transfected cells revealed a loss-of-function variant in Patient 4.ConclusionsThis work expands the clinical and genotypic spectrum of SCN8A-related disorders and provides electrophysiological results on a novel loss-of-function SCN8A variant.

The longitudinal effects of cannabidiol on brain temperature in patients with treatment-resistant epilepsy

Neuroinflammation (NI) is a key pathophysiological contributor to treatment-resistant epilepsy (TRE) that remains challenging to observe in vivo. Magnetic resonance spectroscopic imaging and thermometry (MRSI-t) is an emerging technique that can be used to non-invasively map brain temperature, whereby brain temperature elevations serve as a surrogate for the cellular and biochemical processes associated with NI. In a previous multimodal imaging study of focal epilepsy patients, we observed MRSI-t-based brain temperature elevations ipsilateral to the seizure onset zone (SOZ) that were concordant with evidence of edema (Sharma et al., 2023). Despite its potential as tool, it is unclear if MRSI-t can monitor changes in brain temperature in response to treatment. We imaged 25 participants approximately 12-weeks apart. Eight patients with TRE were imaged before receiving highly-purified pharmaceutical grade cannabidiol (CBD; pre-CBD) and after 12-weeks of CBD (on-CBD) therapy. Seventeen healthy controls (HCs) were also imaged twice. Repeated measures t-tests computed changes in TRE patients’ seizure symptoms, mood, and brain temperature within their respective SOZs. Repeated measures ANOVAs tested Group*Time changes in imaging data. Participants with TRE had abnormally high peak brain temperatures within their SOZs that decreased after CBD initiation (p < 0.0001). Seizure severity scores also improved after CBD initiation (p < 0.001). These findings provide insights into the possible neural effects of CBD, and further demonstrate MRSI-t’s potential as a tool for delineating SOZ. Further investigations into MRSI-t as a longitudinal measure of therapy-induced changes in NI are warranted.

Potential contributions of the intrinsic retinal oscillations recording using non-invasive electroretinogram to bioelectronics.

Targeted electric signal use for disease diagnostics and treatment is emerging as a healthcare game-changer. Besides arrhythmias, treatment-resistant epilepsy and chronic pain, blindness, and perhaps soon vision loss, could be among the pathologies that benefit from bioelectronic medicine. The electroretinogram (ERG) technique has long demonstrated its role in diagnosing eye diseases and early stages of neurodegenerative diseases. Conspicuously, ERG applications are all based on light-induced responses. However, spontaneous, intrinsic activity also originates in retinal cells. It is a hallmark of degenerated retinas and its alterations accompany obesity and diabetes. To the extent that variables extracted from the resting activity of the retina measured by ERG allow the predictive diagnosis of risk factors for type 2 diabetes. Here, we provided a comparison of the baseline characteristics of intrinsic oscillatory activity recorded by ERGs in mice, rats, and humans, as well as in several rat strains, and explore whether zebrafish exhibit comparable activity. Their pattern was altered in neurodegenerative models including the cuprizone-induced demyelination model in mice as well as in the Royal College of Surgeons (RCS-/-) rats. We also discuss how the study of their properties may pave the way for future research directions and treatment approaches for retinopathies, among others.

Anti-seizure effects of JNJ-54175446 in the intra-amygdala kainic acid model of drug-resistant temporal lobe epilepsy in mice.

There remains a need for new drug targets for treatment-resistant temporal lobe epilepsy. The ATP-gated P2X7 receptor coordinates neuroinflammatory responses to tissue injury. Previous studies in mice reported that the P2X7 receptor antagonist JNJ-47965567 suppressed spontaneous seizures in the intraamygdala kainic acid model of epilepsy and reduced attendant gliosis in the hippocampus. The drug-resistance profile of this model is not fully characterised, however, and newer P2X7 receptor antagonists with superior pharmacokinetic profiles have recently entered clinical trials. Using telemetry-based continuous EEG recordings in mice, we demonstrate that spontaneous recurrent seizures in the intraamygdala kainic acid model are refractory to the common anti-seizure medicine levetiracetam. In contrast, once-daily dosing of JNJ-54175446 (30mg/kg, intraperitoneal) resulted in a significant reduction in spontaneous recurrent seizures which lasted several days after the end of drug administration. Using a combination of immunohistochemistry and ex vivo radiotracer assay, we find that JNJ-54175446-treated mice at the end of recordings display a reduction in astrogliosis and altered microglia process morphology within the ipsilateral CA3 subfield of the hippocampus, but no difference in P2X7 receptor surface expression. The present study extends the characterisation of the drug-resistance profile of the intraamygdala kainic acid model in mice and provides further evidence that targeting the P2X7 receptor may have therapeutic applications in the treatment of temporal lobe epilepsy.