A scalable platform for acquisition of high-fidelity human intracranial EEG with minimal clinical burden.

Human neuroscience research has been significantly advanced by neuroelectrophysiological studies from people with refractory epilepsy-the only routine clinical intervention that acquires multi-day, multi-electrode human intracranial electroencephalography (iEEG). While a sampling rate below 2 kHz is sufficient for manual iEEG review by epileptologists, computational methods and research studies may benefit from higher resolution, which requires significant technical development. At adult and pediatric Stanford hospitals, research ports of commercial clinical acquisition systems were configured to collect 10 kHz iEEG of up to 256 electrodes simultaneously with the clinical data. The research digital stream was designed to be acquired post-digitization, resulting in no loss in clinical signal quality. This novel framework implements a near-invisible research platform to facilitate the secure, routine collection of high-resolution iEEG that minimizes research hardware footprint and clinical workflow interference. The addition of a pocket-sized router in the patient room enabled an encrypted tunnel to securely transmit research-quality iEEG across hospital networks to a research computer within the hospital server room, where data was coded, de-identified, and uploaded to cloud storage. Every eligible patient undergoing iEEG clinical evaluation at both hospitals since September 2017 has been recruited; participant recruitment is ongoing. Over 350+ terabytes (representing 1000+ days) of neuroelectrophysiology were recorded across 200+ participants of diverse demographics. To our knowledge, this is the first report of such a research integration within a hospital setting. It is a promising approach to promoting equitable participant enrollment and building comprehensive data repositories with consistent, high-fidelity specifications towards new discoveries in human neuroscience.

Feasibility, Safety, and Performance of Full-Head Subscalp EEG Using Minimally Invasive Electrode Implantation.

BACKGROUND AND OBJECTIVES: Current practice in clinical neurophysiology is limited to short recordings with conventional EEG (days) that fail to capture a range of brain (dys)functions at longer timescales (months). The future ability to optimally manage chronic brain disorders, such as epilepsy, hinges upon finding methods to monitor electrical brain activity in daily life. We developed a device for full-head subscalp EEG (Epios) and tested here the feasibility to safely insert the electrode leads beneath the scalp by a minimally invasive technique (primary outcome). As secondary outcome, we verified the noninferiority of subscalp EEG in measuring physiologic brain oscillations and pathologic discharges compared with scalp EEG, the established standard of care. METHODS: Eight participants with pharmacoresistant epilepsy undergoing intracranial EEG received in the same surgery subscalp electrodes tunneled between the scalp and the skull with custom-made tools. Postoperative safety was monitored on an inpatient ward for up to 9 days. Sleep-wake, ictal, and interictal EEG signals from subscalp, scalp, and intracranial electrodes were compared quantitatively using windowed multitaper transforms and spectral coherence. Noninferiority was tested for pairs of neighboring subscalp and scalp electrodes with a Bland-Altman analysis for measurement bias and calculation of the interclass correlation coefficient (ICC). RESULTS: As primary outcome, up to 28 subscalp electrodes could be safely placed over the entire head through 1-cm scalp incisions in a ∼1-hour procedure. Five of 10 observed perioperative adverse events were linked to the investigational procedure, but none were serious, and all resolved. As a secondary outcome, subscalp electrodes advantageously recorded EEG percutaneously without requiring any maintenance and were noninferior to scalp electrodes for measuring (1) variably strong, stage-specific brain oscillations (alpha in wake, delta, sigma, and beta in sleep) and (2) interictal spikes peak-potentials and ictal signals coherent with seizure propagation in different brain regions (ICC >0.8 and absence of bias). DISCUSSION: Recording full-head subscalp EEG for localization and monitoring purposes is feasible up to 9 days in humans using minimally invasive techniques and noninferior to the current standard of care. A longer prospective ambulatory study of the full system will be necessary to establish the safety and utility of this innovative approach. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov/study/NCT04796597.

Seizure, Motor, and Cognitive Outcomes After Epilepsy Surgery for Patients With Sturge-Weber Syndrome: Results From a Multicenter Study.

BACKGROUND AND OBJECTIVES: Surgery is widely performed for refractory epilepsy in patients with Sturge-Weber syndrome (SWS), but reports on its effectiveness are limited. This study aimed to analyze seizure, motor, and cognitive outcomes of surgery in these patients and to identify factors associated with the outcomes. METHODS: This was a multicenter retrospective observational study using data from patients with SWS and refractory epilepsy who underwent epilepsy surgery between 2000 and 2020 at 16 centers throughout China. Longitudinal postoperative seizures were classified by Engel class, and Engel class I was regarded as seizure-free outcome. Functional (motor and cognitive) outcomes were evaluated using the SWS neurologic score, and improved or unchanged scores between baseline and follow-up were considered to have stable outcomes. Outcomes were analyzed using Kaplan-Meier analyses. Multivariate Cox regression was used to identify factors associated with outcomes. RESULTS: A total of 214 patients with a median age of 2.0 (interquartile range 1.2-4.6) years underwent surgery (focal resection, FR [n = 87]; hemisphere surgery, HS [n = 127]) and completed a median of 3.5 (1.7-5.0) years of follow-up. The overall estimated probability for being seizure-free postoperatively at 1, 2, and 5 years was 86.9% (95% CI 82.5-91.6), 81.4% (95% CI 76.1-87.1), and 70.7% (95% CI 63.3-79.0), respectively. The overall estimated probability of being motor stable at the same time post operatively was 65.4% (95% CI 58.4-71.2), 80.2% (95% CI 73.8-85.0), and 85.7% (95% CI 79.5-90.1), respectively. The overall probability for being cognition stable at 1, 2, and 5 years was 80.8% (95% CI 74.8-85.5), 85.1% (95% CI 79.3-89.2), and 89.5% (95% CI 83.8-93.2), respectively. Both FR and HS were effective at ensuring seizure control. For different HS techniques, modified hemispherotomy had comparable outcomes but improved safety compared with anatomical hemispherectomy. Regarding FR, partial resection (adjusted hazard ratio [aHR] 11.50, 95% CI 4.44-29.76), acute postoperative seizure (APOS, within 30 days of surgery; aHR 10.33, 95% CI 3.94-27.12), and generalized seizure (aHR 3.09, 95% CI 1.37-6.94) were associated with seizure persistence. For HS, seizure persistence was associated with APOS (aHR 27.61, 9.92-76.89), generalized seizure (aHR 7.95, 2.74-23.05), seizure frequency ≥30 times/month (aHR 4.76, 1.27-17.87), and surgical age ≥2 years (aHR 3.78, 1.51-9.47); motor stability was associated with severe motor defects (aHR 5.23, 2.27-12.05) and postoperative seizure-free status (aHR 3.09, 1.49-6.45); and cognition stability was associated with postoperative seizure-free status (aHR 2.84, 1.39-5.78) and surgical age <2 years (aHR 1.76, 1.13-2.75). DISCUSSION: FR is a valid option for refractory epilepsy in patients with SWS and has similar outcomes to those of HS, with less morbidity associated with refractory epilepsy. Early surgical treatment (under the age of 2 years) leads to better outcomes after HS, but there is insufficient evidence that surgical age affects FR outcomes. These findings warrant future prospective multicenter cohorts with international cooperation and prolonged follow-up in better exploring more precise outcomes and developing prognostic predictive models. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in children with SWS and refractory seizures, surgical resection-focal, hemispherectomy, or modified hemispherotomy-leads to improved outcomes.

Intracortical mechanisms of single pulse electrical stimulation (SPES) evoked excitations and inhibitions in humans.

Cortico-cortical evoked potentials (CCEPs) elicited by single-pulse electric stimulation (SPES) are widely used to assess effective connectivity between cortical areas and are also implemented in the presurgical evaluation of epileptic patients. Nevertheless, the cortical generators underlying the various components of CCEPs in humans have not yet been elucidated. Our aim was to describe the laminar pattern arising under SPES evoked CCEP components (P1, N1, P2, N2, P3) and to evaluate the similarities between N2 and the downstate of sleep slow waves. We used intra-cortical laminar microelectrodes (LMEs) to record CCEPs evoked by 10 mA bipolar 0.5 Hz electric pulses in seven patients with medically intractable epilepsy implanted with subdural grids. Based on the laminar profile of CCEPs, the latency of components is not layer-dependent, however their rate of appearance varies across cortical depth and stimulation distance, while the seizure onset zone does not seem to affect the emergence of components. Early neural excitation primarily engages middle and deep layers, propagating to the superficial layers, followed by mainly superficial inhibition, concluding in a sleep slow wave-like inhibition and excitation sequence.

Electroencephalogram synchronization measure as a predictive biomarker of Vagus nerve stimulation response in refractory epilepsy: A retrospective study.

There are currently no established biomarkers for predicting the therapeutic effectiveness of Vagus Nerve Stimulation (VNS). Given that neural desynchronization is a pivotal mechanism underlying VNS action, EEG synchronization measures could potentially serve as predictive biomarkers of VNS response. Notably, an increased brain synchronization in delta band has been observed during sleep-potentially due to an activation of thalamocortical circuitry, and interictal epileptiform discharges are more frequently observed during sleep. Therefore, investigation of EEG synchronization metrics during sleep could provide a valuable insight into the excitatory-inhibitory balance in a pro-epileptogenic state, that could be pathological in patients exhibiting a poor response to VNS. A 19-channel-standard EEG system was used to collect data from 38 individuals with Drug-Resistant Epilepsy (DRE) who were candidates for VNS implantation. An EEG synchronization metric-the Weighted Phase Lag Index (wPLI)-was extracted before VNS implantation and compared between sleep and wakefulness, and between responders (R) and non-responders (NR). In the delta band, a higher wPLI was found during wakefulness compared to sleep in NR only. However, in this band, no synchronization difference in any state was found between R and NR. During sleep and within the alpha band, a negative correlation was found between wPLI and the percentage of seizure reduction after VNS implantation. Overall, our results suggest that patients exhibiting a poor VNS efficacy may present a more pathological thalamocortical circuitry before VNS implantation. EEG synchronization measures could provide interesting insights into the prerequisites for responding to VNS, in order to avoid unnecessary implantations in patients showing a poor therapeutic efficacy.

[Neuropsychological profile of Mexican paediatric patients with pharmacoresistant focal epilepsy]. / Perfil neuropsicológico de pacientes pediátricos mexicanos con epilepsia focal farmacorresistente.

INTRODUCTION: At least 20% of paediatric patients with epilepsy present resistance to multiple anti-crisis drugs in trials, which has a negative impact on their neuropsychological state, quality of life and prognosis; it is therefore necessary to document their neuropsychological profile in order to improve the clinical approach to them. AIMS: To describe the neuropsychological profile (cognitive, academic, behavioural, emotional, adaptive, sleep disturbances and quality of life) of paediatric patients with drug-resistant focal epilepsy in the frontal, temporal and occipital lobes, and to compare performance between patients with frontal and temporal foci, and to assess the link between the duration of the condition, the frequency of seizures and the amount of anti-crisis drugs and the neuropsychological profile. PATIENTS AND METHODS: The neuropsychological profile of 19 paediatric patients with a diagnosis of pharmacoresistant epilepsy with a mean age of 10.89 years was evaluated. RESULTS: 57.9% of the 19 patients were men. 63.2% presented frontal focus; 26.3% presented temporal focus; and 10.5% presented occipital focus. Deficiencies in attention, comprehension, verbal memory, working memory and processing speed, in addition to adaptive difficulties were observed. When the patients with frontal and temporal focus were compared, the former were found to present greater deficits in planning, while the patients with temporal focus presented more severe symptoms of anxiety. Patients with a longer disease duration were found to present greater impairment to their intelligence quotient and adaptive behavioural skills. CONCLUSIONS: Pharmacoresistant epilepsy in paediatric patients affects intelligence quotient and adaptive skills, as well as attention, memory and executive functions, and neuropsychological intervention programmes must therefore be implemented to improve these patients' quality of life.

TITLE: Perfil neuropsicológico de pacientes pediátricos mexicanos con epilepsia focal farmacorresistente.Introducción. Al menos el 20% de los pacientes pediátricos con epilepsia muestra resistencia a los ensayos de múltiples fármacos anticrisis, que impactan negativamente en su estado neuropsicológico, calidad de vida y pronóstico; por tal motivo, es necesario documentar ampliamente su perfil neuropsicológico para mejorar su abordaje clínico. Objetivos. Describir el perfil neuropsicológico (cognitivo, académico, conductual, emocional, adaptativo, alteraciones del sueño y calidad de vida) de pacientes pediátricos con epilepsia focal farmacorresistente de los lóbulos frontal, temporal y occipital, así como comparar el desempeño entre los pacientes con foco frontal y temporal, y evaluar la asociación entre la duración del padecimiento, la frecuencia de las crisis y la cantidad de fármacos anticrisis con el perfil neuropsicológico. Pacientes y métodos. Se evaluó el perfil neuropsicológico de 19 pacientes pediátricos con diagnóstico de epilepsia farmacorresistente, con una edad promedio de 10,89 años. Resultados. De los 19 pacientes, el 57,9% fueron hombres. El 63,2% presentó foco frontal; el 26,3%, temporal; y el 10,5%, occipital. Se encontraron deficiencias en atención, comprensión, memoria verbal, memoria de trabajo y velocidad de procesamiento, además de dificultades adaptativas. Al comparar a los pacientes con foco frontal y temporal, se encontró que los primeros presentaron mayores deficiencias en planificación, mientras que los pacientes con foco temporal presentaron mayores síntomas de ansiedad. Con respecto a la duración de la enfermedad, se encontró que los pacientes con mayor duración del padecimiento presentaron mayor afectación en el cociente intelectual y en las habilidades en la conducta adaptativa. Conclusiones. La epilepsia farmacorresistente en pacientes pediátricos afecta el cociente intelectual y las habilidades adaptativas, así como a la atención, la memoria y las funciones ejecutivas, por lo que es necesaria la implementación de programas de intervención neuropsicológica para mejorar la calidad de vida de estos pacientes.

Identifying epileptogenic abnormality by decomposing intracranial EEG and MEG power spectra.

BACKGROUND: Accurate identification of abnormal electroencephalographic (EEG) activity is pivotal for diagnosing and treating epilepsy. Recent studies indicate that decomposing brain activity into periodic (oscillatory) and aperiodic (trend across all frequencies) components can illuminate the drivers of spectral activity changes. NEW METHODS: We analysed intracranial EEG (iEEG) data from 234 subjects, creating a normative map. This map was compared to a cohort of 63 patients with refractory focal epilepsy under consideration for neurosurgery. The normative map was computed using three approaches: (i) relative complete band power, (ii) relative band power with the aperiodic component removed, and (iii) the aperiodic exponent. Abnormalities were calculated for each approach in the patient cohort. We evaluated the spatial profiles, assessed their ability to localize abnormalities, and replicated the findings using magnetoencephalography (MEG). RESULTS: Normative maps of relative complete band power and relative periodic band power exhibited similar spatial profiles, while the aperiodic normative map revealed higher exponent values in the temporal lobe. Abnormalities estimated through complete band power effectively distinguished between good and bad outcome patients. Combining periodic and aperiodic abnormalities enhanced performance, like the complete band power approach. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: Sparing cerebral tissue with abnormalities in both periodic and aperiodic activity may result in poor surgical outcomes. Both periodic and aperiodic components do not carry sufficient information in isolation. The relative complete band power solution proved to be the most reliable method for this purpose. Future studies could investigate how cerebral location or pathology influences periodic or aperiodic abnormalities.

Super-selective injection of propofol into the intracranial arteries enables Patient's self-evaluation of expected neurological deficit.

INTRODUCTION: It is hard to realize the extent of the expected postoperative neurological deficit for patients themselves. The provision of appropriate information can contribute not only to examining surgical indications but also to filling the gap between patient and expert expectations. We hypothesized that propofol infusion into the intracranial arteries (ssWada) could induce focal neurological symptoms with preserved wakefulness, enabling the patients to evaluate the postsurgical risk subjectively. METHODS: Presurgical evaluation using ssWada was performed in 28 patients with drug-resistant epilepsy. Based on anatomical knowledge, propofol was super-selectively infused into the intracranial arteries including the M1, M2, and M3 segments of the middle cerebral artery (MCA), A2 segment of the anterior cerebral artery, and P2 segment of the posterior cerebral artery to evaluate the neurological and cognitive symptoms. We retrospectively analyzed a total of 107 infusion trials, including their target vessels, and elicited symptoms of motor weakness, sensory disturbance, language, unilateral hemispatial neglect (UHN), and hemianopsia. We evaluated preserved wakefulness which enabled subjective evaluations of the symptoms and comparison of the subjective experience to the objective findings, besides adverse effects during the procedure. RESULTS: Preserved wakefulness was found in 97.2% of all trials. Changes in neurological symptoms were positively evaluated for motor weakness in 51.4%, sensory disturbance in 5.6%, language in 48.6%, UHN in 22.4%, and hemianopsia in 32.7%. Six trials elicited seizures. Multivariate analysis showed significant correlations between symptom and infusion site of language and left side, language and MCA branches, motor weakness and A2 or M2 superior division, and hemianopsia and P2. Transient adverse effect was observed in 8 cases with 12 infusion trials (11.2 %). CONCLUSION: The ssWada could elicit focal neurological symptoms with preserved wakefulness. The methodology enables specific evaluation of risk for cortical resection and subjective evaluation of the expected outcome by the patients.

Postoperative Neurologic Outcome in Patients Undergoing Resective Surgery for Parietal Lobe Epilepsy: A Systematic Review.

BACKGROUND AND OBJECTIVES: Parietal lobe epilepsy (PLE) surgery can be an effective treatment for selected patients with intractable epilepsy but can be associated with the risk of serious neurologic deficits. We performed a systematic review of the literature to obtain a comprehensive summary of the frequency and types of new postoperative neurologic deficits in patients undergoing PLE resective surgery. METHODS: We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials for articles published between January 1, 1990, and April 28, 2022. We included studies that reported postoperative neurologic outcome following PLE resective surgery confined to the parietal lobe. We required that studies included ≥5 patients. The data collected included demographic information and specific details of postoperative neurologic deficits. When available, individual patient data were collected. We used the Risk of Bias in Nonrandomized Studies of Interventions tool to assess the risk of bias and Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of the evidence. RESULTS: Of the 3,461 articles screened, 33 studies met the inclusion criteria. A total of 370 patients were included. One hundred patients (27.0%) had a new deficit noted postoperatively. Approximately half of the patients with deficits experienced only transient deficits. Motor deficits were the most commonly identified deficit. The rates of motor deficits noted after PLE surgery were 5.7%, 3.2%, and 2.2% for transient, long-term, and duration not specified, respectively. Sensory and visual field deficits were also commonly reported. Gerstmann syndrome was noted postoperatively in 4.9% of patients and was almost always transient. Individual patient data added information on parietal lobe subregion postoperative neurologic outcome. DISCUSSION: Our systematic review provides a comprehensive summary of the frequency and types of neurologic deficits associated with PLE surgery. A significant percentage of postoperative deficits are transient. In addition to the expected sensory and visual deficits, PLE surgery is associated with a notable risk of motor deficits. The available literature has important deficiencies. Our study highlights gaps in the literature and provides recommendations for future directions. TRIAL REGISTRATION INFORMATION: This systematic review was registered on PROSPERO (CRD42022313108, May 26, 2022).

Ketogenic Diet in the Treatment of Epilepsy.

Epilepsy is one of the most disabling neurological diseases. Despite proper pharmacotherapy and the availability of 2nd and 3rd generation antiepileptic drugs, deep brain stimulation, and surgery, up to 30-40% of epilepsy patients remain drug-resistant. Consequences of this phenomenon include not only decreased a quality of life, and cognitive, behavioral, and personal disorders, but also an increased risk of death, i.e., in the mechanism of sudden unexpected death in epilepsy patients (SUDEP). The main goals of epilepsy treatment include three basic issues: achieving the best possible seizure control, avoiding the undesired effects of treatment, and maintaining/improving the quality of patients' lives. Therefore, numerous attempts are made to offer alternative treatments for drug-resistant seizures, an example of which is the ketogenic diet. It is a long-known but rarely used dietary therapy for intractable seizures. One of the reasons for this is the unpalatability of the classic ketogenic diet, which reduces patient compliance and adherence rates. However, its antiseizure effects are often considered to be worth the effort. Until recently, the diet was considered the last-resort treatment. Currently, it is believed that a ketogenic diet should be used much earlier in patients with well-defined indications. In correctly qualified patients, seizure activity may be reduced by over 90% or even abolished for long periods after the diet is stopped. A ketogenic diet can be used in all age groups, although most of the available literature addresses pediatric epilepsy. In this article, we focus on the mechanisms of action, effectiveness, and adverse effects of different variants of the ketogenic diet, including its classic version, a medium-chain triglyceride diet, a modified Atkins diet, and a low glycemic index treatment.

Long-term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial.

A post hoc analysis of data from Asian patients included in the study BIA-2093-304 was conducted to evaluate the long-term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12-week maintenance period. Patients completing Part I could enter two open-label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400-1600 mg QD). Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL-related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL-related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy.

The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the ß-hydroxybutyrate (ßHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-ßHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the ßHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the ßHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

Synaptic vesicle protein 2A mitigates parthanatos via apoptosis-inducing factor in a rat model of pharmacoresistant epilepsy.

AIMS: Synaptic vesicle protein 2A (SV2A) is a unique therapeutic target for pharmacoresistant epilepsy (PRE). As seizure-induced neuronal programmed death, parthanatos was rarely reported in PRE. Apoptosis-inducing factor (AIF), which has been implicated in parthanatos, shares a common cytoprotective function with SV2A. We aimed to investigate whether parthanatos participates in PRE and is mitigated by SV2A via AIF. METHODS: An intraperitoneal injection of lithium chloride-pilocarpine was used to establish an epileptic rat model, and phenytoin and phenobarbital sodium were utilized to select PRE and pharmacosensitive rats. The expression of SV2A was manipulated via lentivirus delivery into the hippocampus. Video surveillance was used to assess epileptic ethology. Biochemical tests were employed to test hippocampal tissues following a successful SV2A infection. Molecular dynamic calculations were used to simulate the interaction between SV2A and AIF. RESULTS: Parthanatos core index, PARP1, PAR, nuclear AIF and MIF, γ-H2AX, and TUNEL staining were all increased in PRE. SV2A is bound to AIF to form a stable complex, successfully inhibiting AIF and MIF nuclear translocation and parthanatos and consequently mitigating spontaneous recurrent seizures in PRE. Moreover, parthanatos deteriorated after the SV2A reduction. SIGNIFICANCE: SV2A protected hippocampal neurons and mitigated epileptic seizures by inhibiting parthanatos via binding to AIF in PRE.

Surgical outcomes in children with drug-resistant epilepsy and hippocampal sclerosis.

BACKGROUND: Hippocampal sclerosis (HS) is a common surgical substrate in adult epilepsy surgery cohorts but variably reported in various pediatric cohorts. OBJECTIVE: We aimed to study the epilepsy phenotype, radiological and pathological variability, seizure and neurocognitive outcomes in children with drug-resistant epilepsy and hippocampal sclerosis (HS) with or without additional subtle signal changes in anterior temporal lobe who underwent surgery. METHODS: This retrospective study enrolled children with drug-resistant focal epilepsy and hippocampal sclerosis with or without additional subtle T2-Fluid Attenuated Inversion Recovery (FLAR)/Proton Density (PD) signal changes in anterior temporal lobe who underwent anterior temporal lobectomy with amygdalohippocampectomy. Their clinical, EEG, neuropsychological, radiological and pathological data were reviewed and summarized. RESULTS: Thirty-six eligible patients were identified. The mean age at seizure onset was 3.7 years; 25% had daily seizures at time of surgery. Isolated HS was noted in 22 (61.1%) cases and additional subtle signal changes in ipsilateral temporal lobe in 14 (38.9%) cases. Compared to the normative population, the group mean performance in intellectual functioning and most auditory and visual memory tasks were significantly lower than the normative sample. The mean age at surgery was 12.3 years; 22 patients (61.1%) had left hemispheric surgeries. ILAE class 1 outcomes was seen in 28 (77.8%) patients after a mean follow up duration of 2.3 years. Hippocampal sclerosis was noted pathologically in 32 (88.9%) cases; type 2 (54.5%) was predominant subtype where further classification was possible. Additional pathological abnormalities were seen in 11 cases (30.6%); these had had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis (63.6% vs 84%, p=0.21). Significant reliable changes were observed across auditory and visual memory tasks at an individual level post surgery. CONCLUSIONS: Favourable seizure outcomes were seen in most children with isolated radiological hippocampal sclerosis. Patients with additional pathological abnormalities had similar rates of seizure freedom as compared to children with isolated hippocampal sclerosis/gliosis.

Single-Cell Transcriptomic Analyses of Brain Parenchyma in Patients With New-Onset Refractory Status Epilepticus (NORSE).

BACKGROUND AND OBJECTIVES: New-onset refractory status epilepticus (NORSE) occurs in previously healthy children or adults, often followed by refractory epilepsy and poor outcomes. The mechanisms that transform a normal brain into an epileptic one capable of seizing for prolonged periods despite treatment remain unclear. Nonetheless, several pieces of evidence suggest that immune dysregulation could contribute to hyperexcitability and modulate NORSE sequelae. METHODS: We used single-nucleus RNA sequencing to delineate the composition and phenotypic states of the CNS of 4 patients with NORSE, to better understand the relationship between hyperexcitability and immune disturbances. We compared them with 4 patients with chronic temporal lobe epilepsy (TLE) and 2 controls with no known neurologic disorder. RESULTS: Patients with NORSE and TLE exhibited a significantly higher proportion of excitatory neurons compared with controls, with no discernible difference in inhibitory GABAergic neurons. When examining the ratio between excitatory neurons and GABAergic neurons for each patient individually, we observed a higher ratio in patients with acute NORSE or TLE compared with controls. Furthermore, a negative correlation was found between the ratio of excitatory to GABAergic neurons and the proportion of GABAergic neurons. The ratio between excitatory neurons and GABAergic neurons correlated with the proportion of resident or infiltrating macrophages, suggesting the influence of microglial reactivity on neuronal excitability. Both patients with NORSE and TLE exhibited increased expression of genes associated with microglia activation, phagocytic activity, and NLRP3 inflammasome activation. However, patients with NORSE had decreased expression of genes related to the downregulation of the inflammatory response, potentially explaining the severity of their presentation. Microglial activation in patients with NORSE also correlated with astrocyte reactivity, possibly leading to higher degrees of demyelination. DISCUSSION: Our study sheds light on the complex cellular dynamics in NORSE, revealing the potential roles of microglia, infiltrating macrophages, and astrocytes in hyperexcitability and demyelination, offering potential avenues for future research targeting the identified pathways.

EEG Ictal Power Dynamics, Function-Structure Associations, and Epilepsy Surgical Outcomes.

BACKGROUND AND OBJECTIVES: Postoperative seizure control in drug-resistant temporal lobe epilepsy (TLE) remains variable, and the causes for this variability are not well understood. One contributing factor could be the extensive spread of synchronized ictal activity across networks. Our study used novel quantifiable assessments from intracranial EEG (iEEG) to test this hypothesis and investigated how the spread of seizures is determined by underlying structural network topological properties. METHODS: We evaluated iEEG data from 157 seizures in 27 patients with TLE: 100 seizures from 17 patients with postoperative seizure control (Engel score I) vs 57 seizures from 10 patients with unfavorable surgical outcomes (Engel score II-IV). We introduced a quantifiable method to measure seizure power dynamics within anatomical regions, refining existing seizure imaging frameworks and minimizing reliance on subjective human decision-making. Time-frequency power representations were obtained in 6 frequency bands ranging from theta to gamma. Ictal power spectrums were normalized against a baseline clip taken at least 6 hours away from ictal events. Electrodes' time-frequency power spectrums were then mapped onto individual T1-weighted MRIs and grouped based on a standard brain atlas. We compared spatiotemporal dynamics for seizures between groups with favorable and unfavorable surgical outcomes. This comparison included examining the range of activated brain regions and the spreading rate of ictal activities. We then evaluated whether regional iEEG power values were a function of fractional anisotropy (FA) from diffusion tensor imaging across regions over time. RESULTS: Seizures from patients with unfavorable outcomes exhibited significantly higher maximum activation sizes in various frequency bands. Notably, we provided quantifiable evidence that in seizures associated with unfavorable surgical outcomes, the spread of beta-band power across brain regions is significantly faster, detectable as early as the first second after seizure onset. There was a significant correlation between beta power during seizures and FA in the corresponding areas, particularly in the unfavorable outcome group. Our findings further suggest that integrating structural and functional features could improve the prediction of epilepsy surgical outcomes. DISCUSSION: Our findings suggest that ictal iEEG power dynamics and the structural-functional relationship are mechanistic factors associated with surgical outcomes in TLE.

Memory and language risk assessment with Wada test in patients candidates for epilepsy surgery. / Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.

AIM: To determine post-surgical cognitive risk and associated factors according to lesion location in a sample of patients evaluated for epilepsy surgery with Wada test at the Fundacion Instituto Neurologico de Colombia. MATERIALS AND METHODS: An observational, retrospective, analytical study was completed in patients with drug-resistant temporal lobe epilepsy candidates for epilepsy surgery treated from 2001 to 2021, who completed the Wada test as part of the pre-surgical evaluation. A descriptive analysis of sociodemographic, clinical, imaging and neuropsychological variables was completed; a multivariate logistic regression was performed analyzing factors associated with resection risk in patients with left lesions. RESULTS A total of 369 patients were included, 54.74% of the cases were women, with a median age of seizure onset of 11 years. 92.66% of the cases had lesional epilepsy and 68.56% were secondary to hippocampal sclerosis. Left hemisphere was the most frequently affected (65.68%) being dominant for memory and language in most of the patients with a proportion of 42.82% and 81.3%, respectively. The median functional adequacy was 43.75 (IQR 0-75) and the functional reserve was 75 (IQR 25 -93.75). In 104 patients, the Wada test determined a resection risk. In patients with a left lesion, it was found that functional reserve (PRadjusted 0.99, CI 95% 0.9997-0.9998) and having a right hemispheric dominance for memory (PRadjusted 0.92, CI 95% 0.547-0.999) were protective factors for post-surgical resection risk. CONCLUSION: Wada test is a useful tool for surgical decision-making in patients with drug-resistant temporal lobe epilepsy. When considering cognitive risk, components such as memory dominance and functional reserve should be considered as protective factors for postsurgical cognitive function preservation in patients with left lesions.

TITLE: Evaluación de la memoria y el lenguaje mediante el test de Wada en pacientes candidatos a cirugía de epilepsia.Objetivo. Determinar el riesgo cognitivo posquirúrgico y factores asociados según la localización de la lesión en una muestra de pacientes evaluados para cirugía de epilepsia con el test de Wada en la Fundación Instituto Neurológico de Colombia. Materiales y métodos. Se realizó un estudio observacional, retrospectivo y analítico en pacientes con epilepsia farmacorresistente del lóbulo temporal candidatos a cirugía de epilepsia tratados entre 2001 y 2021, que completaron el test de Wada como parte de la evaluación prequirúrgica. Se realizó un análisis descriptivo de variables sociodemográficas, clínicas, imagenológicas y neuropsicológicas. Se realizó una regresión logística multivariada analizando factores asociados al riesgo de resección en pacientes con lesiones izquierdas. Resultados. Se incluyó a 369 pacientes, el 54,74% de los casos fueron mujeres, con una mediana de edad de inicio de las convulsiones de 11 años. El 92,66% de los casos presentó epilepsia lesional; de éstos, el 68,56% fue secundario a esclerosis hipocampal. El hemisferio izquierdo fue el más frecuentemente afectado (65,68%), y éste fue dominante para la memoria y el lenguaje en la mayoría de los pacientes, con una proporción del 42,82 y el 81,3%, respectivamente. La mediana de adecuación funcional fue de 43,75 (rango intercuartílico: 0-75) y la reserva funcional de 75 (rango intercuartílico: 25-93,75). En 104 pacientes, el test de Wada determinó un riesgo de resección. En pacientes con lesiones izquierdas se encontró que la reserva funcional (razón de prevalencia ajustada: 0,99; intervalo de confianza al 95%: 0,9997-0,9998) y tener dominancia del hemisferio derecho para la memoria (razón de prevalencia ajustada: 0,92; intervalo de confianza al 95%: 0,547-0,999) fueron factores asociados para determinar el riesgo de resección posquirúrgico en el test de Wada. Conclusión. El test de Wada es una herramienta útil para la toma de decisiones quirúrgicas en pacientes con epilepsia del lóbulo temporal farmacorresistente. Componentes como la dominancia de la memoria y la reserva funcional en el test de Wada deben considerarse como factores que se deben tener en cuenta en la predicción de la preservación de la función cognitiva posquirúrgica en pacientes con lesiones izquierdas.

Novel Surgical Approaches in Childhood Epilepsy: Laser, Brain Stimulation, and Focused Ultrasound.

Pediatric epilepsy has a worldwide prevalence of approximately 1% (Berg et al., Handb Clin Neurol 111:391-398, 2013) and is associated with not only lower quality of life but also long-term deficits in executive function, significant psychosocial stressors, poor cognitive outcomes, and developmental delays (Schraegle and Titus, Epilepsy Behav 62:20-26, 2016; Puka and Smith, Epilepsia 56:873-881, 2015). With approximately one-third of patients resistant to medical control, surgical intervention can offer a cure or palliation to decrease the disease burden and improve neurological development. Despite its potential, epilepsy surgery is drastically underutilized. Even today only 1% of the millions of epilepsy patients are referred annually for neurosurgical evaluation, and the average delay between diagnosis of Drug Resistant Epilepsy (DRE) and surgical intervention is approximately 20 years in adults and 5 years in children (Solli et al., Epilepsia 61:1352-1364, 2020). It is still estimated that only one-third of surgical candidates undergo operative intervention (Pestana Knight et al., Epilepsia 56:375, 2015). In contrast to the stable to declining rates of adult epilepsy surgery (Englot et al., Neurology 78:1200-1206, 2012; Neligan et al., Epilepsia 54:e62-e65, 2013), rates of pediatric surgery are rising (Pestana Knight et al., Epilepsia 56:375, 2015). Innovations in surgical approaches to epilepsy not only minimize potential complications but also expand the definition of a surgical candidate. In this chapter, three alternatives to classical resection are presented. First, laser ablation provides a minimally invasive approach to focal lesions. Next, both central and peripheral nervous system stimulation can interrupt seizure networks without creating permanent lesions. Lastly, focused ultrasound is discussed as a potential new avenue not only for ablation but also modulation of small, deep foci within seizure networks. A better understanding of the potential surgical options can guide patients and providers to explore all treatment avenues.