Seizure Onset Research Articles

Patients carrying pathogenic SCN8A variants with loss‐ and gain‐of‐function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy

AbstractObjectivePhenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using both supervised and unsupervised machine learning (ML) approaches, we previously found statistical support for two and three subgroups associated with loss‐ and gain‐ of‐ function vari‐ants, respectively. Here, we test the hypothesis that the unsupervised subgroups (U1–U3) are distinguished by differential contributions of developmental and epileptic components.MethodsWe predicted that patients in the U1 and U2 subgroups would differ in timing of developmental delay and seizure onset, with earlier and concurrent onset of both features for the U3 subgroup. Standard statistical procedures were used to test these predictions, as well as to investigate clinically relevant associations among all five subgroups.ResultsTwo‐population proportion and Kruskal–Wallis tests supported the hypothesis of a reversed order of developmental delay and seizure onset for patients in U1 and U2, and nearly synchronous developmental delay/seizure onset for the U3 (termed DEE) subgroup. Association testing identified subgroup variation in treatment response, frequency of initial seizure type, and comorbidities, as well as different median ages of developmental delay onset for all five subgroups.SignificanceUnsupervised ML approaches discern differential developmental and epileptic components among patients with SCN8A‐related epilepsy. Patients in U1 (termed developmental encephalopathy) typically gain seizure control yet rarely experience improvements in development, whereas those in U2 (termed epileptic encephalopathy) have fewer if any developmental impairments despite difficulty in achieving seizure control. This understanding improves prognosis and clinical management and provides a framework to discover mechanisms underlying variability in clinical outcome of patients with SCN8A‐related disorders.

Short-term effectiveness and side effects of ketogenic diet for drug-resistant epilepsy in children with genetic epilepsy syndromes.

Drug-resistant epilepsy (DRE) impacts a significant portion, one-third, of individuals diagnosed with epilepsy. In such cases, exploring non-pharmacological interventions are crucial, with the ketogenic diet (KD) standing out as a valuable option. KD, a high-fat and low-carb dietary approach with roots dating back to the 1920s for managing DRE, triggers the formation of ketone bodies and modifies biochemistry to aid in seizure control. Recent studies have increasingly supported the efficacy of KD in addressing DRE, showcasing positive outcomes. Furthermore, while more research is needed, limited data suggests that KD May also be beneficial for specific genetic epilepsy syndromes (GESs). This study aimed to assess the short-term efficacy of KD among pediatric patients diagnosed with GESs. This is a multi-center retrospective analysis of pediatric patients with GESs diagnosed using next-generation sequencing. The enrolled patients followed the keto-clinic protocol, and the KD efficacy was evaluated at 3, 6, and 12-month intervals based on seizure control and compliance. The collection instrument included demographic, baseline, and prognostic data. The collected data was coded and analyzed promptly. We enrolled a cohort of 77 patients with a mean current age of 7.94 ± 3.83 years. The mean age of seizure onset was 15.5 months. Notably, patients experienced seizures at a younger age tended to have less positive response to diet. Overall, 55 patients responded favorably to the diet (71.4%) while 22 patients (28.6%) showed no improvement. Patients with genetic etiology showed a significantly more favorable responses to the dietary intervention. Patients with Lennox-Gastaut syndrome showed the most significant improvement (14/15) followed by patients with Dravet syndrome (6/8), and West syndrome (3/4). The number of used anti-seizure medications also played a significant role in determining their response to the diet. While some patients experienced mild adverse events, the most common being constipation, these occurrences were not serious enough to necessitate discontinuation of the diet. The study revealed a high improvement rate in seizure control, especially among younger patients and those with later seizure onset. The success of dietary treatment hinges greatly on early intervention and the patient's age. Certain genetic mutations responded favorably to the KD, while efficacy varied among various genetic profiles.

Clinical efficacy and safety of perampanel monotherapy as primary anti-seizure medication in the treatment of pediatric epilepsy: A single-center, prospective, observational study.

To assess the efficacy and safety of perampanel (PER) as primary monotherapy in patients aged 4-18 years old with epilepsy. A single-center, prospective, observational study was conducted from October 2021 to October 2023, to evaluate PER monotherapy's efficacy and safety as initial therapy for pediatric epilepsy. Changes in seizure frequency, safety, and retention rate were observed at 3, 6, 9, and 12 months after initiating PER primary monotherapy. A total of 124 children aged 4-15 years (mean age = 8.25 ± 2.50 years) were included in the Analysis Sets. The retention rates at 3, 6, 9, and 12 months were 88.71% (110/124), 84.68% (105/124), 78.26% (90/115), and 71.58% (68/95), respectively. Seizure freedom rates at 3, 6, 9, and 12 months were 85.45%, 79.09%, 76.24%, and 75.31%, respectively. The responder rates (≥50% but <100%) at the same endpoints were 9.09%, 14.55%, 12.87%, and 7.41%, respectively. Seizure freedom rate of PER was independent of age at PER initiation, seizure onset age, gender, baseline frequency, seizure types, and family history of epilepsy (p > 0.05) but associated with duration of treatment (p = 0.001) and maintenance dose (p = 0.022). Additionally, 124 patients were included in the safety analysis set. The overall adverse event rate was 38.71% (48/124), with irritability (19 cases, 15.32%) and dizziness (18 cases, 14.52%) being the most common adverse effects. One patient discontinued PER monotherapy within 1 month due to unbearable itching of the skin. PER monotherapy as the primary anti-seizure medication (ASM) for pediatric epilepsy demonstrates high efficacy and safety in real-world clinical treatment. Patients who respond well to this drug and adhere to long-term treatment can achieve favorable seizure control. Furthermore, patients achieving seizure freedom with a relatively lower dose can opt for the same dose as the maintenance dose. This study provided the efficacy and safety of PER monotherapy as the primary ASM for Chinese pediatric epilepsy. In total, 124 patients took part. The seizure freedom rates were over 70% at different observation points (OPs), along with a retention rate of 71.58% at the 12-month OP. Most of adverse effects observed were mild to moderate.

Unveiling the disease progression in developmental and epileptic encephalopathies: Insights from EEG and neuropsychology.

Developmental and epileptic encephalopathies (DEEs) are neurological disorders characterized by developmental impairment and epilepsy. Our study aims to assess disease progression by comparing clinical findings, electroencephalography (EEG), and neuropsychological data from seizure onset to the last follow-up evaluation. We retrospectively reviewed patients with genetic DEEs who were followed-up at the epilepsy unit of Bambino Gesù Children's Hospital, Rome. We collected information regarding gender, family history, genetic variant, age at onset and at last follow-up, neurological examination, type of seizure, drug resistance, occurrence of status epilepticus, and movement and cognitive and behavioral disorders. We compared EEG background activity, epileptiform abnormalities, and cognitive functions between seizure onset and the last follow-up evaluation using the McNemar-Bowker test (α = 5%). A total of 160 patients (94 female) were included. Genetic analysis revealed a spectrum of pathogenic variants, with SCN1A being the most prevalent (25%). The median age at seizure onset and at the last follow-up was 0.37 (interquartile range [IQR]: 0.09-0.75) and 8.54 years (IQR: 4.32-14.55), respectively. We documented a statistically significant difference in EEG background activity (p = .017) and cognitive impairment (p = .01) from seizure onset to the last follow-up evaluation. No significant differences were detected for epileptiform abnormalities (p = .2). In addition, high prevalence rates were observed for drug resistance (81.9%), movement disorders (60.6%), behavioral and autism spectrum disorders (45%), neurological deficits (31.3%), and occurrence of status epilepticus (23.1%). Our study provides evidence that a clinical progression may appear in genetic DEEs, manifesting as development or worsening of cognitive impairment and disruption of EEG background activity. These results highlight the challenging clinical course and the importance of early intervention and personalized care in the management of patients with DEEs.

A rare case report on neurocysticercosis – A parasitic disease

Neurocysticercosis is commonly known as cysticercosis, which is the most common parasitic disease of the human nervous system caused by the parasitic tapeworm The development of lesions in the brain and leptomeninges and the consequent onset of symptoms associated with NCC is mainly due to the host immune-inflammatory response. The absolute diagnostic criteria include histological conformation of parasites, evidence of subretinal cysts, and demonstration of the scolex within a cyst. It is treated by a course of steroids or immunosuppressants; for intravascular cysts, endoscopic surgery is the procedure of choice as it is minimally invasive.We present a case of 8-year-old female patient who was admitted to the Neurology ward with the chief complaints of loss of consciousness, involuntary movements, headache, fever, and onset of seizures associated with vomiting. She had a seizure episode at the age of 2 years associated with fever, but no treatment was done. She was not on any past medication and was hemodynamically stable. Her lab investigations of magnetic resonance imaging show infective granuloma in the left parietal lobe with mass effect as described above, suggesting neurocysticercosiswhich should be carefully observed at an early stage. We summarized the case report of neurocysticercosis, its diagnosis, and treatment plan.

Preoptic area controls sleep-related seizure onset in a genetic epilepsy mouse model.

In genetic and refractory epileptic patients, seizure activity exhibits sleep-related modulation/regulation and sleep and seizure are intermingled. In this study, by using one het Gabrg2 Q390X KI mice as a genetic epilepsy model and optogenetic method in vivo , we found that subcortical POA neurons were active within epileptic network from the het Gabrg2 Q390X KI mice and the POA activity preceded epileptic (poly)spike-wave discharges(SWD/PSDs) in the het Gabrg2 Q390X KI mice. Meanwhile, as expected, the manipulating of the POA activity relatively altered NREM sleep and wake periods in both wt and the het Gabrg2 Q390X KI mice. Most importantly, the short activation of epileptic cortical neurons alone did not effectively trigger seizure activity in the het Gabrg2 Q390X KI mice. In contrast, compared to the wt mice, combined the POA nucleus activation and short activation of the epileptic cortical neurons effectively triggered or suppressed epileptic activity in the het Gabrg2 Q390X KI mice, indicating that the POA activity can control the brain state to trigger seizure incidence in the het Gabrg2 Q390X KI mice in vivo. In addition, the suppression of POA nucleus activity decreased myoclonic jerks in the Gabrg2 Q390X KI mice. Overall, this study discloses an operational mechanism for sleep-dependent seizure incidence in the genetic epilepsy model with the implications for refractory epilepsy. This operational mechanism also underlies myoclonic jerk generation, further with translational implications in seizure treatment for genetic/refractory epileptic patients and with contribution to memory/cognitive deficits in epileptic patients.

Evaluation of Risk Factors, Clinical Spectrum and Management of New Onset Seizure

A seizure is a brief deviation from the brain's regular electrical activity that alters awareness and behavior. Seizures are brief burst so fun controllable movement that can affect either a piece of the body (partial) or the full body (generalized) and are frequently followed by a loss of awareness and control over bowel or bladder function. Epilepsy is distinguished by recurring seizures. Epilepsy is a neurological disorder marked by sudden recurrent episodes of sensory disturbance, loss of consciousness, associated with abnormal electrical activity in the brain. The goal of the study is to find out risk factors and prescribing pattern of antiseizure drugs in different types of seizure disorder. An educational observational study was carried out among 42 samples in the In-patient Department of General Medicine, ESI MC- PGIMSR, and Rajajinagar. The data was collected using self-designed data collection form. All information’s were processed and analyzed by using Microsoft excel. It was observed that a majority of the subjects involved in the study was prescribed with Levetiracetam (69.81%). A high prevalence of New onset seizure with risk factor of CVS causes (36.92%) and Alcohol withdrawal (20%) was observed. In CVS cause, stroke was prominent. From this study, generalized tonic clonic seizure was most commonly observed type of seizure and Levetiracetam was most frequently prescribed drug to them. Majority of patients were given mono therapy to achieve seizure control.

Brain perfusion SPECT in the presurgical evaluation of epilepsy: is additional ictal SPECT required in case of high-confidence lateralization of the seizure onset zone by interictal SPECT and vice versa?

BackgroundIctal brain perfusion SPECT provides higher sensitivity for the identification of the epileptic seizure onset zone (SOZ) than interictal SPECT. However, ictal SPECT is demanding due to the unpredictable waiting period for the next seizure to allow for ictal tracer injection. Thus, starting with an interictal scan and skipping the ictal scan if the interictal scan provides a SOZ candidate with high confidence could be an efficient approach. The current study estimated the rate of high-confidence SOZ candidates and the false lateralization rate among them for interictal and ictal SPECT.Methods177 patients (48% females, median age 38y, interquartile range 27–48y) with ictal and interictal SPECT acquired with 99mTc-HMPAO (n = 141) or -ECD (n = 36) were included retrospectively. The vast majority of the patients was suspected to have temporal lobe epilepsy. Visual interpretation of the SPECT data was performed independently by 3 readers in 3 settings: “interictal only” (interictal SPECT and statistical hypoperfusion map), “ictal only” (ictal SPECT and hyperperfusion map), and “full” setting (side-by-side interpretation of ictal and interictal SPECT including statistical maps and SISCOM analysis). The readers lateralized the SOZ (right, left, none) and characterized their confidence using a 5-score. A case was considered "lateralizing with high confidence” if all readers lateralized to the same hemisphere with at least 4 of 5 confidence points. Lateralization of the SOZ in the “full” setting was used as reference standard.ResultsThe proportion of “lateralizing with high confidence” cases was 4.5/31.6/38.4% in the “interictal only”/“ictal only”/“full” setting. One (12.5%) of the 8 cases that were “lateralizing with high confidence” in the “interictal only” setting lateralized to the wrong hemisphere. Among the 56 cases that were “lateralizing with high confidence” in the “ictal only” setting, 54 (96.4%) were also lateralizing in the “full” setting, all to the same hemisphere.ConclusionsStarting brain perfusion SPECT in the presurgical evaluation of epilepsy with an interictal scan to skip the ictal scan in case of a high-confidence interictal SOZ candidate is not a useful approach. In contrast, starting with an ictal scan to skip the interictal scan in case of a high-confidence ictal SOZ candidate can be recommended.

AGR – 2 The Multi-Dimensional Role of Neuropsychology in Diagnostically Complex Epilepsy Patients: Refining the Surgical Plan and Post-Operative Expectations

Abstract Objective We present a case highlighting the importance of neuropsychological involvement at all phases of a pre-surgical epilepsy work-up, including clinical interview, neuropsychological evaluation, Wada testing, extra-operative electrical stimulation mapping (ESM), and psychoeducation. Method A 24-year-old, right-handed, Caucasian female presented with non-lesional, intractable left-hemisphere localization-related epilepsy characterized by frequent experiences of déjà vu and autonomic sensations. Results Neuropsychological evaluation revealed weaknesses in processing speed and verbal memory implicating left hippocampal involvement. Wada testing suggested minimal contralateral memory support, indicating poor candidacy for resective surgery. The patient underwent prolonged sEEG monitoring to refine a plan for device implantation (i.e., responsive neurostimulation; RNS). No typical events were captured during extended study. Episodic somatosensory changes were captured, which had no electrographic correlate and were presumed to be non-epileptic. ESM evoked the patient’s classic semiology, elucidating nuanced information about her seizure onset zone and network. Barriers to extended monitoring and consistent, reliable engagement during ESM included depression, anxiety, and trauma; considerable neuropsychologist-led emotional support was required. Typical seizure semiology was elicited during stimulation of entorhinal cortices, posterior and anterior hippocampi, amygdala, cingulate and insula. RNS placement included a depth electrode targeting the medial structures (via a posterior approach) with a sub-temporal strip. Conclusions Involvement of neocortical and mesial temporal structures, coupled with a clear neuropsychiatric component, were believed to be poly-etiological factors to the patient’s presentation. Neuropsychological input at all phases of pre-surgical assessment was instrumental in systematically identifying and addressing her complex needs. Psychotherapeutic intervention was suggested to be equally as important to clinical, long-term patient outcome.

Acquired motor speech disorders in childhood epilepsy.

To evaluate a group of children with epilepsy and motor speech regression, with the aim of characterizing their speech disorders, electrographic features, and outcomes. Children referred to a tertiary developmental epilepsy clinic with epilepsy and motor speech regression were identified retrospectively. A clinical history was taken, and longitudinal speech and cognitive data were recorded. Speech samples were scored for severity and speech features. Seizure frequency and epileptiform discharges in the interictal electroencephalogram were analysed. Eighteen children (10 female) were evaluated, including seven with Landau-Kleffner syndrome and six with Rasmussen syndrome. Speech regression occurred at a mean age of 5 years (SD = 2 years 6 months), which was concurrent with seizure onset or peak seizure burden in eight children. Speech features included dysarthria (n = 13), phonological errors (n = 7), and dyspraxia (n = 6). Electrographic abnormalities occurred most frequently in the left centrotemporal and right frontal regions. Among children who were followed up, intelligibility of speech was affected in 13 at baseline and seven at follow-up (p = 0.03). Expressive language standardized scores increased from a mean (SD) of 50.0 (11.3) to 91.4 (27.8) in children with Landau-Kleffner syndrome (mean change = 41.4, 95% confidence interval [CI] 0.04-82.8, p = 0.0498) and decreased from 75.2 (15.3) to 59.0 (9.8) in children with Rasmussen syndrome (mean change -16.2, 95% CI -9.0 to -23.4, p = 0.002) over the follow-up. Motor speech disorders in epilepsy were severe, multifarious, and often fluctuated with seizure burden. Symptoms typically improved, especially in children with Landau-Kleffner syndrome, but rarely fully resolved.

Bilateral Todd's paralysis in a patient with left fronto-opercular epilepsy.

Postictal paresis ("Todd's paralysis") is commonly observed as a unilateral, transient motor weakness, lasting minutes to hours, after focal or focal to bilateral tonic-clonic seizures, contralateral to the epileptogenic zone. Bilateral postictal paresis is exceedingly rare and could be misinterpreted, especially if the preceding convulsive phase was not witnessed. An 18-year-old right-handed male patient with refractory focal epilepsy with seizure onset at age 3 years, was admitted for presurgical video-EEG monitoring. His seizures were predominantly nocturnal, consisting of a laryngeal somatosensory aura, occasionally evolving to bilateral tonic or tonic-clonic seizures with occasional asymmetrical limb extension during the tonic phase (right arm extension). Postictally, consciousness recovery was fast, if ever lost. At that stage, we documented severe dysarthria and bilateral symmetrical arm paresis lasting several minutes. The ictal pattern and interictal epileptiform activity were projected on the fronto-central midline. Brain MRI was highly suggestive of a bottom-of-sulcus dysplasia with underlying transmantle sign on the left premotor, fronto-opercular region and an FDG-PET-CT showed a concordant left fronto-operculo-insular hypometabolism. A complete lesionectomy was performed, with the additional guidance of intraoperative electrocorticography, resulting in sustained seizure freedom. Anatomo-pathology confirmed a type 2b focal cortical dysplasia. We speculate that, in our patient, a left fronto-opercular ictal onset with an early spread to both primary motor cortices and relative sparing of consciousness networks allowed the emergence of a clinically detectable postictal bilateral paresis.

Pharmacology of Adenosine A1 Receptor Agonist in a Humanized Esterase Mouse Seizure Model Following Soman Intoxication

Recently a novel genetically modified mouse strain with serum carboxylesterase knocked-out and the human acetylcholinesterase gene knocked-in (KIKO) was created to simulate human responses to nerve agent (NA) exposure and its standard medical treatment. A1 adenosine receptor (A1AR) agonist N-bicyclo-(2.2.1)-hept-2-yl-5'-chloro-5'-deoxyadenosine (ENBA) alone is a potent anticonvulsant and neuroprotectant (A/N) in both rat and KIKO mouse soman (GD) seizure models. In this study we utilized the KIKO mouse to evaluate further the basic pharmacologic A/N effects of ENBA as an adjunct to standard NA medical treatments (i.e., atropine sulfate, pralidoxime chloride [2-PAM], and midazolam). Male mice, implanted with cortical electroencephalographic (EEG) electrodes, were pretreated with asoxime (HI-6) and exposed to an epileptogenic dose of GD (33 µg/kg, s.c.) or saline (sham exposure) and then treated 15 min after seizure onset with ENBA at 15 mg/kg, i.p. (a minimum efficacy dose in suppressing NA-induced seizure) alone or as an adjunct to standard medical treatments. We collected EEG activity, seizure suppression outcomes, daily body temperature and weight, heart rate, toxic signs, neuropathology, and lethality data for up to 14 days. Without ENBA, death from NA exposure was 45%, while with ENBA, either alone or in combination with midazolam, the survival improved to 80% and 90%, respectively. Additionally, seizure was suppressed quickly and permanently, toxic signs, hypothermia, and bradycardia recovered by 48 h, and no neuropathology was evident. Our findings confirmed that ENBA is a potent A/N adjunct for delayed medical treatments of NA exposure.

Candesartan restores blood-brain barrier dysfunction, mitigates aberrant gene expression, and extends lifespan in a knockin mouse model of epileptogenesis.

Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes play a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability. CND treatment also partially reversed or 'normalized' disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-β signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust effectiveness of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy.

SEEG4D: a tool for 4D visualization of stereoelectroencephalography data.

Epilepsy is a prevalent and serious neurological condition which impacts millions of people worldwide. Stereoelectroencephalography (sEEG) is used in cases of drug resistant epilepsy to aid in surgical resection planning due to its high spatial resolution and ability to visualize seizure onset zones. For accurate localization of the seizure focus, sEEG studies combine pre-implantation magnetic resonance imaging, post-implant computed tomography to visualize electrodes, and temporally recorded sEEG electrophysiological data. Many tools exist to assist in merging multimodal spatial information; however, few allow for an integrated spatiotemporal view of the electrical activity. In the current work, we present SEEG4D, an automated tool to merge spatial and temporal data into a complete, four-dimensional virtual reality (VR) object with temporal electrophysiology that enables the simultaneous viewing of anatomy and seizure activity for seizure localization and presurgical planning. We developed an automated, containerized pipeline to segment tissues and electrode contacts. Contacts are aligned with electrical activity and then animated based on relative power. SEEG4D generates models which can be loaded into VR platforms for viewing and planning with the surgical team. Automated contact segmentation locations are within 1 mm of trained raters and models generated show signal propagation along electrodes. Critically, spatial-temporal information communicated through our models in a VR space have potential to enhance sEEG pre-surgical planning.

Epilepsy surgery below the age of 5 years: Are we still in time to preserve developmental and intellectual functions?

The aim of this study is to describe the pre- and post-operative developmental and intellectual functions in a cohort of patients who underwent surgery for drug-resistant epilepsy (DRE) before the age of 5 years. We retrospectively reviewed the medical records and neurodevelopmental assessments of a cohort of 80 surgically treated pediatric patients with DRE. We included patients if they had at least one pre- and one post-surgical neuropsychological assessments; 27 met the inclusion criteria. We evaluated Developmental Quotient (DQ) and Intelligence Quotient (IQ) before and after surgery. We identified two groups based on psychological evaluation outcome: Group 1, with stable or improved developmental and intellectual functions, and Group 2, experiencing developmental and intellectual loss. The mean age at seizure onset was 1.2 ± 1.0 years, and the mean age at surgery was 2.9 ± 1.2 years. At the last follow-up (mean 4 years, SD ± 2), 19/27 (70%) patients were seizure- and drug-free; 18/27 patients (67%) fit in Group 1, and 9/27 (33%) fit in Group 2. The mean age at surgery was 2.6 years (SD ± 1.1; range 1.2-5.1) in Group 1 and 3.4 years in Group 2 (SD ± 1.1; range 1.6-5.0). Group 1 had a lower pre-operative DQ/IQ total score than Group 2 (median DQ/IQ respectively 82 vs 108, p = 0.05). Between pre- and post-assessments, we found that in Group 1, Performance scores improved (82.7 vs 102, p = 0.001), while in Group 2, the Total and Verbal scores worsened (respectively 108 vs 75, p = 0.008, and 100 vs 76, p = 0.021). Our study's results emphasize the positive impact of surgery before the age of 5 years on developmental and intellectual outcomes. Despite limitations such as a small sample size, lack of a control group, and diverse etiologies, our findings support the crucial role of early intervention in preserving or enhancing developmental and intellectual functions in young patients with DRE. This retrospective study, conducted at the Bambino Gesù Children Hospital in Italy, reports neuropsychological and developmental and/or cognitive data for children undergoing early epilepsy surgery (before the age of 5). It found that children with lower developmental or cognitive profiles gained the highest scores on post-operative neuropsychological evaluations. This study provides information on the potential benefits of early surgery in shortening the duration of epilepsy, preventing or arresting deterioration, and enhancing plasticity and recovery.

Ex-SPECTing success: Predictors of successful SPECT radiotracer injection during presurgical video-EEG admissions.

To determine predictors of successful ictal single photon emission computed tomography (SPECT) injections during Epilepsy Monitoring Unit (EMU) admissions for patients undergoing presurgical evaluation for drug-resistant focal epilepsy. In this retrospective study, consecutive EMU admissions were analyzed at a single center between 2019 and 2021. All seizures that occurred during the admission were reviewed. "Injectable seizures" occurred during hours when the radiotracer was available. EMU-level data were analyzed to identify factors predictive of an EMU admission with a successful SPECT injection (successful admission). Seizure-level data were analyzed to identify factors predictive of an injectable seizure receiving a SPECT injection during the ictal phase (successful injection). A multivariate generalized linear model was used to identify predictive variables. 125 EMU admissions involving 103 patients (median 37 years, IQR 27.0-45.5) were analyzed. 38.8% of seizures that were eligible for SPECT (n = 134) were successfully injected; this represented 17.4% of all seizures (n = 298) that occurred during admission. Unsuccessful admissions were most commonly due to a lack of seizures during EMU-SPECT (19.3%) or no injectable seizures (62.3%). Successful EMU-SPECT was associated with baseline seizure frequency >1 per week (95% CI 2.1-3.0, P < 0.001) and focal PET hypometabolism (95% CI 2.0-3.7, P < 0.001). On multivariate analysis, the only factor associated with successful injection was patients being able to indicate they were having a seizure to staff (95% CI 1.0-4.4, P = 0.038). Completing a successful ictal SPECT study remains challenging. A baseline seizure frequency of >1 per week, a PET hypometabolic focus, and a patient's ability to indicate seizure onset were identified as predictors of success. These findings may assist EMUs in optimizing their SPECT protocols, patient selection, and resource allocation.

The sixth sense: how much does interictal intracranial EEG add to determining the focality of epileptic networks?

Intracranial EEG is used for two main purposes: to determine (i) if epileptic networks are amenable to focal treatment and (ii) where to intervene. Currently, these questions are answered qualitatively and differently across centres. There is a need to quantify the focality of epileptic networks systematically, which may guide surgical decision-making, enable large-scale data analysis and facilitate multi-centre prospective clinical trials. We analysed interictal data from 101 patients with drug-resistant epilepsy who underwent pre-surgical evaluation with intracranial EEG at a single centre. We chose interictal data because of its potential to reduce the morbidity and cost associated with ictal recording. Sixty-five patients had unifocal seizure onset on intracranial EEG, and 36 were non-focal or multi-focal. We quantified the spatial dispersion of implanted electrodes and interictal intracranial EEG abnormalities for each patient. We compared these measures against the '5 Sense Score,' a pre-implant prediction of the likelihood of focal seizure onset, assessed the ability to predict unifocal seizure onset by combining these metrics and evaluated how predicted focality relates to subsequent treatment and outcomes. The spatial dispersion of intracranial EEG electrodes predicted network focality with similar performance to the 5-SENSE score [area under the receiver operating characteristic curve = 0.68 (95% confidence interval 0.57, 0.78)], indicating that electrode placement accurately reflected pre-implant information. A cross-validated model combining the 5-SENSE score and the spatial dispersion of interictal intracranial EEG abnormalities significantly improved this prediction [area under the receiver operating characteristic curve = 0.79 (95% confidence interval 0.70, 0.88); P < 0.05]. Predictions from this combined model differed between surgical- from device-treated patients with an area under the receiver operating characteristic curve of 0.81 (95% confidence interval 0.68, 0.85) and between patients with good and poor post-surgical outcome at 2 years with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval 0.56, 0.85). Spatial measures of interictal intracranial EEG abnormality significantly improved upon pre-implant predictions of network focality by area under the receiver operating characteristic curve and increased sensitivity in a single-centre study. Quantified focality predictions related to ultimate treatment strategy and surgical outcomes. While the 5-SENSE score weighed for specificity in their multi-centre validation to prevent unnecessary implantation, sensitivity improvement found in our single-centre study by including intracranial EEG may aid the decision on whom to perform the focal intervention. We present this study as an important step in building standardized, quantitative tools to guide epilepsy surgery.

ERK1/2 Regulates Epileptic Seizures by Modulating the DRP1-Mediated Mitochondrial Dynamic.

After seizures, the hyperactivation of extracellular signal-regulated kinases (ERK1/2) causes mitochondrial dysfunction. Through the guidance of dynamin-related protein 1 (DRP1), ERK1/2 plays a role in the pathogenesis of several illnesses. Herein, we speculate that ERK1/2 affects mitochondrial division and participates in the pathogenesis of epilepsy by regulating the activity of DRP1. LiCl-Pilocarpine was injected intraperitoneally to establish a rat model of status epilepticus (SE) for this study. Before SE induction, PD98059 and Mdivi-1 were injected intraperitoneally. The number of seizures and the latency period before the onset of the first seizure were then monitored. The analysis of Western blot was also used to measure the phosphorylated and total ERK1/2 and DRP1 protein expression levels in the rat hippocampus. In addition, immunohistochemistry revealed the distribution of ERK1/2 and DRP1 in neurons of hippocampal CA1 and CA3. Both PD98059 and Mdivi-1 reduced the susceptibility of rats to epileptic seizures, according to behavioral findings. By inhibiting ERK1/2 phosphorylation, the Western blot revealed that PD98059 indirectly reduced the phosphorylation of DRP1 at Ser616 (p-DRP1-Ser616). Eventually, the ERK1/2 and DRP1 were distributed in the cytoplasm of neurons by immunohistochemistry. Inhibition of ERK1/2 signaling pathways downregulates p-DRP1-Ser616 expression, which could inhibit DRP1-mediated excessive mitochondrial fission and then regulate the pathogenesis of epilepsy.

Preliminary observation on clinical outcome and safety of surgery in early infants (

ObjectiveTo investigate the clinical outcomes and safety of surgery in infants (< 12 months of age) with drug-resistant epilepsy, clarify surgical indications, and select appropriate surgical methods. MethodsThis was a retrospective analysis of infants with drug-resistant epilepsy who underwent epilepsy surgery and were followed up for > 6 months at the Epilepsy Center of Shenzhen Children's Hospital. Clinical data included etiology, seizure type, surgical procedure, preoperative auxiliary examinations, pathological findings, and intraoperative and postoperative complications. Clinical outcomes were assessed based on postoperative seizure frequency, antiseizure medicines (ASMs) use, and neurocognitive development. Intraoperative blood loss, operative duration, postoperative complications, and duration of intensive care were evaluated to assess the safety of epilepsy surgery. Univariate and logistic analyses were performed to explore the factors influencing prognosis. ResultsEpilepsy surgery was performed on 44 infants with drug-resistant epilepsy, including 7 patients who underwent two operations. The age of seizure onset ranged from 1 day to 11 months (median: 1 month, interquartile range (IQR): 0.1–3.8), the disease course was 1–11 months (median: 4 months, IQR: 2–7), and the age at surgery was 6.9±3.6 months. Twenty-three patients underwent hemispherectomy (52.3%), and two underwent subtotal hemispherectomy. Five patients underwent multilobar disconnection, five underwent frontal lobotomy, and the remaining nine underwent focal resection. The surgical duration was 7.5±2 hours. Intraoperative blood loss ranged from 50–1800 ml (median: 275 ml, IQR: 200–500), with all patients receiving an intraoperative blood transfusion of 0.5–6 U (median: 1.5 U, IQR: 1.5–3). The intensive care unit stay was 1–4 days (median: 1 day, IQR: 1–2). The postoperative complication rate was 13.6% (6/44; two cases of hydrocephalus with intracranial infection, two isolated hydrocephalus, and two subdural hematomas). Excluding one child who died of severe lung infection approximately one year after surgery and one child lost to follow-up after surgery, all other cases were regularly followed up for 10 –49 months (median: 30 months, IQR: 16.5–36). After surgery, patients were treated with 0–3 ASMs (median: 1 ASM, IQR: 0–2); 27.9% (12/43) stopped taking ASMs and 51.2% (22/43) had reduced number of ASMs. Engel I was achieved in 76.7% (33/43) of the patients at the last follow-up. In 17 cases with complete developmental quotient follow-up data, the preoperative and postoperative developmental quotient means were 28.8±21 and 43.2±20.1, showing statistically significant differences (p<0.05) SignificanceEpilepsy surgery in infants under 12 months of age is safe and effective. Early preoperative evaluation is crucial for identifying structural lesions and suitable candidates for surgery among infants with drug-resistant epilepsy. The timeliness of surgery is essential for achieving favorable clinical outcomes.

The part and the whole: how single nodes contribute to large-scale phase-locking in functional EEG networks

ObjectiveThe application of signal analysis techniques to electroencephalographic (EEG) recordings from epilepsy patients shows that epilepsy involves not only altered neuronal synchronization but also the reorganization of functional EEG networks. This study aims to assess the large-scale phase-locking of such functional networks and how individual network nodes contribute to this collective dynamics. MethodsWe analyze the EEG recorded before, during and after seizures from sixteen patients with pharmacoresistant focal-onset epilepsy. The data is filtered to low (4–30 Hz) and high (80–150 Hz) frequencies. We define the multivariate phase-locking measure and the univariate phase-locking contribution measure. Surrogate signals are used to estimate baseline results expected under the null hypothesis that the EEG is a correlated linear stochastic process. ResultsOn average, nodes from inside and outside the seizure onset zone (SOZ) increase and decrease, respectively, the large-scale phase-locking. This difference becomes most evident in a joint analysis of low and high frequencies. ConclusionsNodes inside and outside the SOZ play opposite roles for the large-scale phase-locking in functional EEG network in epilepsy patients. SignificanceThe application of the phase-locking contribution measure to EEG recordings from epilepsy patients can potentially help in localizing the SOZ.