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Intracerebroventricular (ICV) administration is increasingly being explored as a means for delivering antiseizure and antiepileptic therapies to epileptic brain tissue. This route bypasses the blood–brain barrier, thus enabling the delivery of therapeutics that are restricted from the brain, while reducing the risk of systemic adverse reactions. Nevertheless, projections from studies in patients with other diseases suggest that efficacy of some ICV‐delivered therapeutics may be limited when the epileptogenic tissue or network circuits are localized more than a few millimeters away from the ventricles. In this article, we present the characteristics of the cerebrospinal fluid as a drug administration site, the brain barriers, and their relevance to treating focal and generalized epilepsies. We refer to ICV delivery of advanced therapies for treating neurodevelopmental disorders with epilepsy. We describe properties of therapeutic compounds, from small molecules to RNA‐based therapeutics, proteins, and viral vectors, which can make them either fitting or poor candidates for ICV administration in epilepsy. We additionally provide an overview of preclinical studies and clinical trials involving the ICV route of delivery. Finally, we compare ICV delivery with other routes of administration that bypass the cerebral circulation. This review aims to provide information that will hopefully help investigators select candidate patients and therapeutics for ICV therapies, and to highlight advantages and challenges inherent to this approach. [ABSTRACT FROM AUTHOR]

Objective: Levetiracetam (LEV) is an antiseizure medication that is mainly excreted by the kidneys. Due to its low teratogenic risk, LEV is frequently prescribed for women with epilepsy (WWE). Physiological changes during gestation affect the pharmacokinetic characteristics of LEV. The goal of our study was to characterize the changes in LEV clearance during pregnancy and the postpartum period, to better plan an LEV dosing paradigm for pregnant women. Methods: This retrospective observational study incorporated a cohort of women who were followed up at the epilepsy in pregnancy clinic at Tel Aviv Sourasky Medical Center during the years 2020–2023. Individualized target concentrations of LEV and an empirical postpartum taper were used for seizure control and to reduce toxicity likelihood. Patient visits took place every 1–2 months and included a review of medication dosage, trough LEV blood levels, week of gestation and LEV dose at the time of level measurement, and seizure diaries. Total LEV concentration/dose was calculated based on LEV levels and dose as an estimation of LEV clearance. Results: A total of 263 samples were collected from 38 pregnant patients. We observed a decrease in LEV concentration/dose (C/D) as the pregnancy progressed, followed by an abrupt postpartum increase. Compared to the 3rd trimester, the most significant C/D decrease was observed at the 1st trimester (slope =.85), with no significant change in the 2nd trimester (slope =.11). A significant increase in C/D occurred postpartum (slope = 5.23). LEV dose was gradually increased by 75% during pregnancy compared to preconception. Average serum levels (μg/mL) decreased during pregnancy. During the postpartum period, serum levels increased, whereas the LEV dose was decreased by 24%, compared to the 3rd trimester. Significance: LEV serum level monitoring is essential for WWE prior to and during pregnancy as well as postpartum. Our data contribute to determining a rational treatment and dosing paradigm for LEV use during both pregnancy and the postpartum period. [ABSTRACT FROM AUTHOR]

Vagus nerve stimulation (VNS) is widely used to treat drug-resistant epilepsy and depression. While the precise mechanisms mediating its long-term therapeutic effects are not fully resolved, they likely involve locus coeruleus (LC) stimulation via the nucleus of the solitary tract, which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Noninvasive transcutaneous VNS (tVNS) uses electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent to which tVNS mimics VNS remains unclear. Here, we investigated the short-term effects of tVNS in healthy human male volunteers (n = 24), using high-density EEG and pupillometry during visual fixation at rest. We compared short (3.4 s) trials of tVNS to sham electrical stimulation at the earlobe (far from the vagus nerve branch) to control for somatosensory stimulation. Although tVNS and sham stimulation did not differ in subjective intensity ratings, tVNS led to robust pupil dilation (peaking 4-5 s after trial onset) that was significantly higher than following sham stimulation. We further quantified, using parallel factor analysis, how tVNS modulates idle occipital alpha (8-13Hz) activity identified in each participant. We found greater attenuation of alpha oscillations by tVNS than by sham stimulation. This demonstrates that tVNS reliably induces pupillary and EEG markers of arousal beyond the effects of somatosensory stimulation, thus supporting the hypothesis that tVNS elevates noradrenaline and other arousal-promoting neuromodulatory signaling, and mimics invasive VNS. [ABSTRACT FROM AUTHOR]

Background: The ability to maintain adequate motor-cognitive performance under increasing task demands depends on the regulation and coordination of neural resources. Studies have shown that such resources diminish with aging and disease. EEG spectral analysis is a method that has the potential to provide insight into neural alterations affecting motor-cognitive performance. The aim of this study was to assess changes in spectral analysis during dual-task walking in aging and disease Methods: 10 young adults, ten older adults, and ten patients with Parkinson's disease (PD) completed an auditory oddball task while standing and while walking on a treadmill. Spectral power within four frequency bandwidths, delta (< 4 Hz), theta (4–8 Hz), alpha (8–12 Hz), and beta (12–30 Hz), was calculated using Event-Related Spectral Perturbation (ERSP) analyses and compared between single task and dual task and between groups. Results: Differences in ERSP were found in all groups between the single and dual-task conditions. In response to dual-task walking, beta increased in all groups (p < 0.026), delta decreased in young adults (p = 0.03) and patients with PD (0.015) while theta increased in young adults (p = 0.028) but decreased in older adults (p = 0.02) and patients with PD (p = 0.015). Differences were seen between the young, the older adults, and the patients with PD. Conclusions: These findings are the first to show changes in the power of different frequency bands during dual-task walking with aging and disease. These specific brain modulations may reflect deficits in readiness and allocation of attention that may be responsible for the deficits in dual-task performance. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to explore the diagnostic value, clinical correlates and electroencephalographic features of FIRDA (Frontal intermittent rhythmic delta activity). Materials and methods: We retrospectively reviewed reports from EEG studies done in adults at our tertiary center between January 2015 and May 2018. For cases demonstrating FIRDA, medical files were reviewed and each case was given a diagnostic category. EEG recordings were reviewed and electrophysiologic data were extracted including FIRDA characteristics (frequency, location, duration, and symmetry). Then, a statistical analysis was done to evaluate the relationship between the diagnostic categories and EEG variables. Results: Ninety‐four cases of FIRDA were found, with a frequency of 1.6% among inpatients. EEG recordings were available for review in 84 cases. FIRDA was asymmetric in 43 of these cases (49%), usually more prominent on the left (36/43, 84%). The diagnostic category groups included epilepsy (n = 39, 41%), other central nervous system (CNS) disease (n = 33, 35%), and systemic illness (n = 22, 23%). A significant difference in FIRDA location was found, as patients with epilepsy or other CNS disease, had a significantly higher probability for the delta activity to involve the temporal areas (frontotemporal location in 27/64 in these groups compared with 3/20 in the systemic illness group, P‐value = .033). Conclusions: This study provides insights to the diagnosis underlying FIRDA, especially the high rate of epilepsy patients, and calls for further neurologic investigation of cases in which FIRDA involves the temporal areas since most of these cases were due to epilepsy or other CNS disease and not a systemic illness. [ABSTRACT FROM AUTHOR]

Highlights • Prolonged P300 latency during walking is pronounced in aging and Parkinson's disease (PD). • Prolonged P300 latency is correlated with reduced cognitive and motor function. • Reduced P300 amplitude during walking is found only in patients with PD. Abstract Objective To investigate EEG changes during an auditory odd-ball task while walking (dual-task) in young adults, older adults, and patients with Parkinson's disease. Methods 11 young adults, 10 older adults, and 10 patients with Parkinson's disease (PD) performed an auditory oddball task during standing and walking on a treadmill, while wearing a wireless EEG cap. The amplitude and latency of P300 were compared between groups and within conditions using linear mix model analysis. Gait was evaluated using wearable sensors and cognition was assessed using the Color Trail Test. Results P300 latency became longer during walking in all groups (p = 0.005). During walking, older adults (p = 0.005) and patients with PD (p = 0.001) showed prolonged P300 latency compared to young adults. Significant task by group interaction was found in P300 amplitude (p = 0.008). Patients with PD demonstrated reduced P300 amplitude during walking compared to standing (p = 0.023). Among all subjects, better motor and cognitive performance correlated with shorter P300 latency (r = 0.457, p = 0.014 and r = 0.431, p = 0.040, respectively). Conclusions These findings provide direct evidence of the physiological recruitment of attentional networks during walking and their impact by ageing and disease. Significance This study is the first to report on changes in P300 latency and amplitude during dual-task oddball walking in older adults and patients with PD. [ABSTRACT FROM AUTHOR]

The yield of monitoring patients at an epilepsy monitoring unit (EMU) depends on the recording of paroxysmal events in a timely fashion, however, increasing the risk of safety adverse events (AEs). We aimed to retrospectively study the frequency and risk factors for AE occurrences in all consecutive admissions to an adult EMU in a tertiary medical center. We also compared our findings with published data from other centers. Between January 2011 and June 2014, there were 524 consecutive admissions to the adult EMU at the Tel Aviv Sourasky Medical Center. Adverse events were recorded in 47 (9.0%) admissions. The most common AE was 4-hour seizure cluster (58.7% of AEs) and, in decreasing frequency, AEs related to antiepileptic drugs (AEDs, 11.1%), falls and traumatic injuries (9.5%), intravenous line complications (9.5%), electrode-related (4.8%), status epilepticus (SE, 3.2%), and cardiac (1.6%) and psychiatric (1.6%) complications. There were significantly more AEs among patients with a younger age at disease onset ( p = 0.005), a history of temporal lobe epilepsy ( p = 0.046), a history of focal seizures with altered consciousness ( p = 0.008), a history of SE ( p = 0.022), use of a vagal nerve stimulator ( p = 0.039), and intellectual disability ( p = 0.016) and when the indication for EMU monitoring was noninvasive or invasive presurgical evaluation ( p = 0.001). Adverse events occurred more frequently when patients had more events in the EMU ( p = 0.001) and among those administered carbamazepine ( p = 0.037), levetiracetam ( p = 0.004), clobazam ( p = 0.008), and sulthiame ( p = 0.016). Patients with a history of psychogenic nonepileptic seizures (PNESs) had significantly fewer AEs ( p = 0.013). Adverse events were not associated with the age, gender, duration of hospitalization or monitoring, AED withdrawal and renewal, seizure frequency by history, presence of major psychiatric comorbidities, abnormal neurological exam, or the presence of a lesion as on brain magnetic resonance imaging. In conclusion, this study reveals that AEs are not unusual in the EMU and that seizure clustering is the most common among them. Adverse events occur more frequently in patients with more severe epilepsy and intellectual disability and in patients undergoing presurgical evaluations and less frequently in patients with PNESs. [ABSTRACT FROM AUTHOR]

Objective Interictal high frequency oscillations (HFOs) in the 40-200 Hz range have been identified in scalp electroencephalography (EEG) recordings of patients with focal epilepsy. HFOs usually co-occur with interictal epileptiform discharges (IEDs), and are specific and accurate markers for the epileptic focus, but the brain regions involved when HFOs are generated are unknown. We investigated this question with combined EEG-functional magnetic resonance imaging ( fMRI), measuring the blood oxygenation level-dependent (BOLD) signal, and examined HFOs in the gamma (40-80 Hz) and ripple (80-200 Hz) bands. Methods Twenty-eight consecutive patients with focal epilepsy who underwent HFO and EEG- fMRI studies were selected; six were excluded because of negative EEG- fMRI. The remaining 22 patients were divided into two equal groups (11 patients each) based on the frequency of co-occurrence of gamma or ripples with IEDs: low versus high gamma (LG/HG) and low versus high ripples (LR/HR). Results No significant changes were found in the BOLD characteristics between the LG and HG groups. As a group, HR had a larger IED concordant BOLD cluster than the LR group, despite similar IED rates. In addition, the HR group had significantly more thalamic BOLD changes than the LR group (11/11 vs. 2/11). In HR, 5 of 11 patients had thalamic activation only, 4 of 11 had thalamic deactivation only, and 2 of 11 had activation and deactivation in different thalamic regions. In the LR group, 2 of 11 had thalamic activation. The lateralization of thalamic BOLD responses was concordant with the lateralization of cortical ripples in 12 of 13 patients. Significance Scalp IEDs, when frequently accompanied by HFOs in the ripple but not in the gamma band, are associated with larger cortical metabolic responses and with thalamic involvement lateralized to the side of cortical ripples. We propose that a high rate of epileptic ripples is associated with a more active pathologic cortical-thalamocortical network. [ABSTRACT FROM AUTHOR]

Purpose Simultaneous electroencephalography/functional magnetic resonance imaging ( EEG/fMRI) recording can noninvasively map in the whole brain the hemodynamic response following an interictal epileptic discharge. EEG/fMRI is gaining interest as a presurgical evaluation tool. This study aims to determine how hemodynamic responses related to epileptic activity can help predict surgical outcome in patients considered for epilepsy surgery. Methods Thirty-five consecutive patients with focal epilepsy who had significant hemodynamic responses and eventually surgical resection, were studied. The statistical map of hemodynamic responses were generated and coregistered to postoperative anatomic imaging. Patients were classified into four groups defined by the relative relationship between the location of the maximum hemodynamic response and the resection: group 1, fully concordant; group 2, partially concordant; group 3, partially discordant; and group 4, fully discordant. These findings were correlated with surgical outcome with at least 12-month follow-up. Key Findings Ten patients in group 1 had the maximum t value (t-max) inside the resection; nine in group 2 had the t-max outside but close to the resection and the cluster with t-max overlapped the resection; five in group 3 had the t-max remote from resection, but with another less significant cluster in the resection; and 11 in group 4 had no response in the resection. The degree of concordance correlated largely with surgical outcome: a good surgical outcome (Engel's class I) was found in 7 of 10 patients of group 1, 4 of 9 of group 2, 3 of 5 of group 3, and only 1 of 11 of group 4. These results indicate that the partially concordant and partially discordant groups are best considered as inconclusive. In contrast, in the fully concordant and fully discordant groups, the sensitivity, specificity, positive predictive value, and negative predictive value were high, 87.5%, 76.9%, 70%, and 90.9%, respectively. Significance This study demonstrates that hemodynamic responses related to epileptic activity can help delineate the epileptogenic region. Full concordance between maximum response and surgical resection is indicative of seizure freedom, whereas a resection leaving the maximum response intact is likely to lead to a poor outcome. EEG/fMRI is noninvasive but is limited to patients in whom interictal epileptic discharges can be recorded during the 60-90 min scan. [ABSTRACT FROM AUTHOR]

Functional neuroimaging studies of epilepsy patients often show, at the time of epileptic activity, deactivation in default mode network (DMN) regions, which is hypothesized to reflect altered consciousness. We aimed to study the metabolic and electrophysiological correlates of these changes in the DMN regions. We studied six epilepsy patients that underwent scalp EEG-fMRI and later stereotaxic intracerebral EEG (SEEG) sampling regions of DMN (posterior cingulate cortex, Pre-cuneus, inferior parietal lobule, medial prefrontal cortex and dorsolateral frontal cortex) as well as non-DMN regions. SEEG recordings were subject to frequency analyses comparing sections with interictal epileptic discharges (IED) to IED-free baselines in the IED-generating region, DMN and non-DMN regions. EEG-fMRI and SEEG were obtained at rest. During IEDs, EEG-fMRI demonstrated deactivation in various DMN nodes in 5 of 6 patients, most frequently the pre-cuneus and inferior parietal lobule, and less frequently the other DMN nodes. SEEG analyses demonstrated decrease in gamma power (50–150 Hz), and increase in the power of lower frequencies (<30 Hz) at times of IEDs, in at least one DMN node in all patients. These changes were not apparent in the non-DMN regions. We demonstrate that, at the time of IEDs, DMN regions decrease their metabolic demand and undergo an EEG change consisting of decreased gamma and increased lower frequencies. These findings, specific to DMN regions, confirm in a pathological condition a direct relationship between DMN BOLD activity and EEG activity. They indicate that epileptic activity affects the DMN, and therefore may momentarily reduce the consciousness level and cognitive reserve. [ABSTRACT FROM AUTHOR]

Purpose: To assess the extent of brain involvement during focal epileptic activity, we studied patterns of cortical and subcortical metabolic changes coinciding with interictal epileptic discharges (IEDs) using group analysis of simultaneous electroencephalography and functional magnetic resonance imaging (EEG-fMRI) scans in patients with focal epilepsy. Methods: We selected patients with temporal lobe epilepsy (TLE, n = 32), frontal lobe epilepsy (FLE, n = 14), and posterior quadrant epilepsy (PQE, n = 20) from our 3 Tesla EEG-fMRI database. We applied group analysis upon the blood oxygen-level dependent (BOLD) response associated with focal IEDs. Key Findings: Patients with TLE and FLE showed activations and deactivations, whereas in PQE only deactivations occurred. In TLE and FLE, the largest activation was in the mid-cingulate gyri bilaterally. In FLE, activations were also found in the ipsilateral frontal operculum, thalamus, and internal capsule, and in the contralateral cerebellum, whereas in TLE, we found additional activations in the ipsilateral mesial and neocortical temporal regions, insula, and cerebellar cortex. All three groups showed deactivations in default mode network regions, the most widespread being in the TLE group, and less in PQE and FLE. Significance: These results indicate that different epileptic syndromes result in unique and widespread networks related to focal IEDs. Default mode regions are deactivated in response to focal discharges in all three groups with syndrome specific pattern. We conclude that focal IEDs are associated with specific networks of widespread metabolic changes that may cause more substantial disturbance to brain function than might be appreciated from the focal nature of the scalp EEG discharges. [ABSTRACT FROM AUTHOR]

Summary: Two-dimensional temporal clustering analysis (2D-TCA) is a relatively new functional MRI (fMRI) based technique that breaks blood oxygen level dependent activity into separate components based on timing and has shown potential for localizing epileptic activity independently of electroencephalography (EEG). 2D-TCA has only been applied to detect epileptic activity in a few studies and its limits in detecting activity of various forms (i.e. activation size, amplitude, and frequency) have not been investigated. This study evaluated 2D-TCA''s ability to detect various forms of both simulated epileptic activity and EEG-fMRI activity detected in patients. When applied to simulated data, 2D-TCA consistently detected activity in 6min runs containing 5 spikes/run, 10 spikes/run, and one 5s long event with hemodynamic response function amplitudes of at least 1.5%, 1.25%, and 1% above baseline respectively. When applied to patient data, while detection of interictal spikes was inconsistent, 2D-TCA consistently produced results similar to those obtained by EEG-fMRI when at least 2 prolonged interictal events (a few seconds each) occurred during the run. However, even for such cases it was determined that 2D-TCA can only be used to validate localization by other means or to create hypotheses as to where activity may occur, as it also detects changes not caused by epileptic activity. [Copyright &y& Elsevier]

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

Objective: This study was undertaken to develop a standardized grading system based on expert consensus for evaluating the level of confidence in the localization of the epileptogenic zone (EZ) as reported in published studies, to harmonize and facilitate systematic reviews in the field of epilepsy surgery. Methods: We conducted a Delphi study involving 22 experts from 18 countries, who were asked to rate their level of confidence in the localization of the EZ for various theoretical clinical scenarios, using different scales. Information provided in these scenarios included one or several of the following data: magnetic resonance imaging (MRI) findings, invasive electroencephalography summary, and postoperative seizure outcome. Results: The first explorative phase showed an overall interrater agreement of.347, pointing to large heterogeneity among experts' assessments, with only 17% of the 42 proposed scenarios associated with a substantial level of agreement. A majority showed preferences for the simpler scale and single‐item scenarios. The successive Delphi voting phases resulted in a majority consensus across experts, with more than two thirds of respondents agreeing on the rating of each of the tested single‐item scenarios. High or very high levels of confidence were ascribed to patients with either an Engel class I or class IA postoperative seizure outcome, a well‐delineated EZ according to all available invasive EEG (iEEG) data, or a well‐delineated focal epileptogenic lesion on MRI. MRI signs of hippocampal sclerosis or atrophy were associated with a moderate level of confidence, whereas a low level was ascribed to other MRI findings, a poorly delineated EZ according to iEEG data, or an Engel class II–IV postoperative seizure outcome. Significance: The proposed grading system, based on an expert consensus, provides a simple framework to rate the level of confidence in the EZ reported in published studies in a structured and harmonized way, offering an opportunity to facilitate and increase the quality of systematic reviews and guidelines in the field of epilepsy surgery. [ABSTRACT FROM AUTHOR]

We aimed to estimate the frequency of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) with atypical duration in our epilepsy monitoring unit (EMU), in order to raise awareness of atypical durations of both types of events. We retrospectively reviewed all consecutive video-electroencephalogram (vEEG) recordings in our medical center's EMU from January 2013 to December 2017 and identified patients with seizures with atypical duration. Short PNES were defined as those lasting fewer than 2 min and long ES as those lasting for more than 5 min. The files of 830 adult (age > 16 years) patients were reviewed, of whom 26 patients (3.1%, mean age: 33.3 ± 9.8 years, 12 females) were diagnosed as having an unusual seizure duration. Among 432 patients with ES during monitoring, fourteen patients [3.2% (95% confidence interval (CI): 1.5%–5.0%), mean age: 33.0 ± 12.2, 5 females [had long ES durations (exceeding 5 min). In 64% of patients with long ES, the events were provoked by antiepileptic drug (AED) withdrawal during vEEG, 62% had focal lesion on brain imaging, and 64% had a frontotemporal or a temporal seizure focus. Among 223 patients diagnosed with PNES, 12 patients [5.4% (95% CI: 2.2%–8.6%), mean age: 33.6 ± 6.6, 7 females] had short PNES durations (less than 2 min) and demonstrated motor (9/12, 75%), altered responsiveness (6/12, 50%), and vocalization (5/12, 42%) as the most prominent clinical features. The data from our case files highlight two main considerations in the diagnosis of paroxysmal events: prolonged event can be due to ES, while short events can be psychogenic. • Atypical long epileptic or short psychogenic nonepileptic event may cause diagnostic challenge. • Video-EEG is the gold standard method to differentiate between epileptic and psychogenic events. • Raising awareness of atypical durations of both types of events is of paramount importance. • One must be aware that prolonged event may be epileptic seizure, while short one may be psychogenic. [ABSTRACT FROM AUTHOR]

Presented herein are recommendations for use of nirmatrelvir/ritonavir in patients with epilepsy, as issued by the Steering Committee of the Israeli chapter of the International League Against Epilepsy. The recommendations suggest that patients on moderate‐to‐strong enzyme‐inducing antiseizure medications (ASMs) and everolimus should not be treated with nirmatrelvir/ritonavir; rectal diazepam may be used as an alternative to buccal midazolam; doses of ASMs that are cytochrome P450 (CYP3A4) substrates might be adjusted; and patients treated with combinations of nirmatrelvir/ritonavir and ASMs that are CYP3A4 substrates or lamotrigine should be monitored for drug efficacy and adverse drug reactions. [ABSTRACT FROM AUTHOR]

• The study directly compares auditory and visual event-related oscillations in dementia with Lewy bodies. • Early sensory and later cognitive processing activity in theta band is impaired in the visual, but not in the auditory task. • Visual event-related oscillations are characterized by a decrease in theta and lack of inhibition in alpha bands. Aside from the cognitive impairment, patients with dementia with Lewy bodies (DLB) have a high frequency of visual hallucinations and a number of other vision-related symptoms, whereas auditory hallucinations are less frequent. To better understand the differential dysfunction of the visual network in DLB, we compared auditory and visual event-related potentials and oscillations in patients with DLB. Event-related potentials elicited by visual and auditory oddball tasks were recorded in 23 patients with DLB and 22 healthy controls and analyzed in time and time-frequency domain. DLB patients had decreased theta band activity related to both early sensory and later cognitive processing in the visual, but not in the auditory task. Patients had lower delta and higher alpha and beta bands power related to later cognitive processing in both auditory and visual tasks. In DLB visual event-related oscillations are characterized by a decrease in theta and lack of inhibition in alpha bands. Decreased theta and a lack of inhibition in alpha band power might be an oscillatory underpinning of some classical DLB symptoms such as fluctuations in attention and high-level visual disturbances and a potential marker of dysfunction of the visual system in DLB. [ABSTRACT FROM AUTHOR]

Neural oscillations and signal complexity have been widely studied in neurodegenerative diseases, whereas aperiodic activity has not been explored yet in those disorders. Here, we assessed whether the study of aperiodic activity brings new insights relating to disease as compared to the conventional spectral and complexity analyses. Eyes-closed resting-state electroencephalography (EEG) was recorded in 21 patients with dementia with Lewy bodies (DLB), 28 patients with Parkinson's disease (PD), 27 patients with mild cognitive impairment (MCI) and 22 age-matched healthy controls. Spectral power was differentiated into its oscillatory and aperiodic components using the Irregularly Resampled Auto-Spectral Analysis. Signal complexity was explored using the Lempel–Ziv algorithm (LZC). We found that DLB patients showed steeper slopes of the aperiodic power component with large effect sizes compared to the controls and MCI and with a moderate effect size compared to PD. PD patients showed steeper slopes with a moderate effect size compared to controls and MCI. Oscillatory power and LZC differentiated only between DLB and other study groups and were not sensitive enough to detect differences between PD, MCI, and controls. In conclusion, both DLB and PD are characterized by alterations in aperiodic dynamics, which are more sensitive in detecting disease-related neural changes than the traditional spectral and complexity analyses. Our findings suggest that steeper aperiodic slopes may serve as a marker of network dysfunction in DLB and PD features. [ABSTRACT FROM AUTHOR]

Background: Juvenile myoclonic epilepsy (JME) is characterized by generalized seizures. Nearly 30% of JME patients are drug‐resistant (DR‐JME), indicating a widespread cortical dysfunction. Walking is an important function that necessitates orchestrated coordination of frontocentral cortical regions. However, gait alterations in JME have been scarcely investigated. Our aim was to assess changes in gait and motor‐evoked responses in DR‐JME patients. Methods: Twenty‐nine subjects (11 JME drug‐responder, 8 DR‐JME, and 10 healthy controls) underwent a gait analyses during usual walking and dual‐task walking. Later, subjects underwent 64‐channel EEG recordings while performing a simple motor task. We calculated the motor‐evoked current source densities (CSD) at a priori chosen cortical regions. Gait and CSD measures were compared between groups and tasks using mixed model analysis. Results: DR‐JME patients demonstrated an altered gait pattern that included slower gait speed (p =.018), reduced cadence (p =.003), and smaller arm‐swing amplitude (p =.011). The DR‐JME group showed higher motor‐evoked CSD in the postcentral gyri compared to responders (p =.049) and both JME groups showed higher CSD in the superior frontal gyri compared to healthy controls (p <.011). Moreover, higher CSD in the superior frontal gyri correlated with worse performance in dual‐task walking (r > |–0.494|, p <.008). Conclusions: These alterations in gait and motor‐evoked responses in DRE‐JME patients reflect a more severe dysfunction of motor‐cognitive neural processing in frontocentral regions, leading to poorer gait performance. Further studies are needed to investigate the predictive value of altered gait and cortical motor processing as biomarkers for poor response to treatment in JME and other epilepsy syndromes. [ABSTRACT FROM AUTHOR]

Objective Although simultaneous recording of EEG and MRI has gained increasing popularity in recent years, the extent of its clinical use remains limited by various technical challenges. Motion interference is one of the major challenges in EEG-fMRI. Here we present an approach which reduces its impact with the aid of an MR compatible dual-array EEG (daEEG) in which the EEG itself is used both as a brain signal recorder and a motion sensor. Methods We implemented two arrays of EEG electrodes organized into two sets of nearly orthogonally intersecting wire bundles. The EEG was recorded using referential amplifiers inside a 3 T MR-scanner. Virtual bipolar measurements were taken both along bundles (creating a small wire loop and therefore minimizing artifact) and across bundles (creating a large wire loop and therefore maximizing artifact). Independent component analysis (ICA) was applied. The resulting ICA components were classified into brain signal and noise using three criteria: 1) degree of two-dimensional spatial correlation between ICA coefficients along bundles and across bundles; 2) amplitude along bundles vs. across bundles; 3) correlation with ECG. The components which passed the criteria set were transformed back to the channel space. Motion artifact suppression and the ability to detect interictal epileptic spikes following daEEG and Optimal Basis Set (OBS) procedures were compared in 10 patients with epilepsy. Results The SNR achieved by daEEG was 11.05 ± 3.10 and by OBS was 8.25 ± 1.01 ( p < 0.00001). In 9 of 10 patients, more spikes were detected after daEEG than after OBS ( p < 0.05). Significance daEEG improves signal quality in EEG-fMRI recordings, expanding its clinical and research potential. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is currently considered to be a multisystem neurodegenerative disease that involves cognitive alterations. EEG slowing has been associated with cognitive decline in various neurological diseases, such as PD, Alzheimer's disease (AD), and epilepsy, indicating cortical involvement. A novel method revealed that this EEG slowing is composed of paroxysmal slow-wave events (PSWE) in AD and epilepsy, but in PD it has not been tested yet. Therefore, this study aimed to examine the presence of PSWE in PD as a biomarker for cortical involvement. Methods: 31 PD patients, 28 healthy controls, and 18 juvenile myoclonic epilepsy (JME) patients (served as positive control), underwent four minutes of resting-state EEG. Spectral analyses were performed to identify PSWEs in nine brain regions. Mixed-model analysis was used to compare between groups and brain regions. The correlation between PSWEs and PD duration was examined using Spearman's test. Results: No significant differences in the number of PSWEs were observed between PD patients and controls (p > 0.478) in all brain regions. In contrast, JME patients showed a higher number of PSWEs than healthy controls in specific brain regions (p < 0.023). Specifically in the PD group, we found that a higher number of PSWEs correlated with longer disease duration. Conclusions: This study is the first to examine the temporal characteristics of EEG slowing in PD by measuring the occurrence of PSWEs. Our findings indicate that PD patients who are cognitively intact do not have electrographic manifestations of cortical involvement. However, the correlation between PSWEs and disease duration may support future studies of repeated EEG recordings along the disease course to detect early signs of cortical involvement in PD. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share pathological and clinical similarities while differing in the timing and severity of motor cognitive and visual impairment. Previous EEG studies found abnormal neural oscillations in PD, mild cognitive impairment (MCI) and Alzheimer's disease, however, the electrophysiological signature of clinical symptoms is still unclear. We assessed the specificity of event-related oscillations in distinguishing between cognitive, motor and visual involvement in patients with neurodegenerative conditions. Methods: EEG was recorded during a visual oddball task in 30 PD, 28 DLB, 30 MCI patients and 32 age-matched healthy controls. Target and non-target event-related power were examined in the time–frequency domain using complex Morlet wavelet convolution and compared within and between the study groups. Results: MCI (z = − 1.8, p = 0.04, Cohen's d = − 0.5) and DLB (z = − 3.1, p < 0.001, d = − 1.0) patients showed decreased delta-band target event-related synchronization compared to participants with normal cognition. PD (z = 1.6, p = 0.05, d = 0.5) and DLB (z = 2.7, p < 0.01, d = 0.9) patients showed decreased beta suppression compared to MCI patients and controls. DLB patients with visual hallucinations (VH) showed decreased early-alpha suppression (z = 2.08, p = 0.019, d = 3.19, AUC = 1.0 ± 0.0) compared to DLB-VH−. Conclusions: Decreased event-related delta-band synchronization, reflecting a decline in information processing ability, was characteristic of cognitive impairment due to any cause. Decreased event-related beta suppression, reflecting impaired execution of motor action, was specific to PD and DLB. Decreased event-related early-alpha suppression was characteristic of the presence of VH in DLB. These findings show that specific oscillations may reflect specific clinical symptoms, being a marker of network dysfunction. [ABSTRACT FROM AUTHOR]

• This clinical practice guideline identified standards with recommendations summarized in Table S1. • Limited high-level evidence addressing standards for LTVEM exist, and further research is needed. • Selected topics for utility of LTVEM exist, although comprehensive criteria addressing minimum standards for performance are needed. • Clinicians, hospital administrators, and insurers benefit from establishing standards for inpatient video-EEG monitoring applied to patient management. The objective of this clinical practice guideline is to provide recommendations on the indications and minimum standards for inpatient long-term video-electroencephalographic monitoring (LTVEM). The Working Group of the International League Against Epilepsy and the International Federation of Clinical Neurophysiology develop guidelines aligned with the Epilepsy Guidelines Task Force. We reviewed published evidence using The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. We found limited high-level evidence aimed at specific aspects of diagnosis for LTVEM performed to evaluate patients with seizures and nonepileptic events (see Table S1). For classification of evidence, we used the Clinical Practice Guideline Process Manual of the American Academy of Neurology. We formulated recommendations for the indications, technical requirements, and essential practice elements of LTVEM to derive minimum standards used in the evaluation of patients with suspected epilepsy using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation). Further research is needed to obtain evidence about long-term outcome effects of LTVEM and establish its clinical utility. [ABSTRACT FROM AUTHOR]

Summary: The objective of this clinical practice guideline is to provide recommendations on the indications and minimum standards for inpatient long‐term video‐electroencephalographic monitoring (LTVEM). The Working Group of the International League Against Epilepsy and the International Federation of Clinical Neurophysiology develop guidelines aligned with the Epilepsy Guidelines Task Force. We reviewed published evidence using the PRISMA (Preferred Reporting Items for Systematic Review and Meta‐Analysis) statement. We found limited high‐level evidence aimed at specific aspects of diagnosis for LTVEM performed to evaluate patients with seizures and nonepileptic events. For classification of evidence, we used the Clinical Practice Guideline Process Manual of the American Academy of Neurology. We formulated recommendations for the indications, technical requirements, and essential practice elements of LTVEM to derive minimum standards used in the evaluation of patients with suspected epilepsy using GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Further research is needed to obtain evidence about long‐term outcome effects of LTVEM and to establish its clinical utility. [ABSTRACT FROM AUTHOR]

Background: The performance on a visual Go/NoGo (VGNG) task during walking has been used to evaluate the effect of gait on response inhibition in young and older adults; however, no work has yet included Parkinson's disease (PD) patients for whom such changes may be even more enhanced. Objective: In this study, we aimed to explore the effect of gait on automatic and cognitive inhibitory control phases in PD patients and the associated changes in neural activity and compared them with young and older adults. Methods: 30 PD patients, 30 older adults, and 11 young adults performed a visual Go/NoGo task in a sitting position and during walking on a treadmill while their EEG activity and gait were recorded. Brain electrical activity was evaluated by the amplitude, latency, and scalp distribution of N2 and P300 event related potentials. Mix model analysis was used to examine group and condition effects on task performance and brain activity. Results: The VGNG accuracy rates in PD patients during walking were lower than in young and older adults (F = 5.619, p = 0.006). For all groups, N2 latency during walking was significantly longer than during sitting (p = 0.013). In addition, P300 latency was significantly longer in PD patients (p < 0.001) and older adults (p = 0.032) during walking compared to sitting and during 'NoGo' trials compared with 'Go' trials. Moreover, the young adults showed the smallest number of electrodes for which a significant differential activation between sit to walk was observed, while PD patients showed the largest with N2 being more strongly manifested in bilateral parietal electrodes during walking and in frontocentral electrodes while seated. Conclusion: The results show that response inhibition during walking is impaired in older subjects and PD patients and that increased cognitive load during dual-task walking relates to significant change in scalp electrical activity, mainly in parietal and frontocentral channels. [ABSTRACT FROM AUTHOR]

Introduction: In idiopathic generalized epilepsy (IGE), a normal electroencephalogram between generalized spike and wave (GSW) discharges is believed to reflect normal brain function. However, some studies indicate that even excluding GSWrelated errors, IGE patients perform poorly on sustained attention task, the deficit being worse as a function of disease duration. We hypothesized that at least in a subset of structures which are normally involved in sustained attention, restingstate functional connectivity (FC) is different in IGE patients compared to controls and that some of the changes are related to disease duration. Method: Seeds were selected based on a sustained attention study in controls. Resting-state functional magnetic resonance imaging (fMRI) data was obtained from 14 IGE patients and 14 matched controls. After physiological noise removal, the mean time-series of each seed was used as a regressor in a general linear model to detect regions that showed correlation with the seed. In patients, duration factor was defined based on epilepsy duration. Between-group differences weighted by the duration factor were evaluated with mixed-effects model. Correlation was then evaluated in IGE patients between the FC, averaged over each significant cluster, and the duration factor. Results: Eight of 18 seeds showed significant difference in FC across groups. However, only for seeds in the medial superior frontal and precentral gyri and in the medial prefrontal area, average FC taken over significant clusters showed high correlation with the duration factor. These 3 seeds showed changes in FC respectively with the premotor and superior frontal gyrus, the dorsal premotor, and the supplementary motor area plus precentral gyrus. Conclusion: Alterations of FC in IGE patients are not limited to the frontal areas. However, as indicated by specificity analysis, patients with long history of disease show changes in FC mainly within the frontal areas. [ABSTRACT FROM AUTHOR]

Objective: MR-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive technique for ablating brain lesions under real-time MRI feedback and control of the ablation process. The Medtronic Visualase system was recently approved for use in Europe and Israel. We report our initial technical experience using the system in the first 16 cases in which the system was used to ablate focal epileptogenic lesions. Methods: We included all consecutive patients with intractable epilepsy who underwent MRgLITT procedures between 2018 and 2020. We reviewed medical charts and imaging studies of patients. Post-ablation MRIs were used to calculate ablation volumes. Results: Seventeen MRgLITT procedures were performed in 16 patients. One cooling catheter/laser fiber assemblies were placed per patient. Indications for surgery were intractable epilepsy due to TLE (n = 7), suspected low-grade glioma (n = 4), radiological cortical dysplasia (n = 1), hypothalamic hamartoma (n = 1), and MR-negative foci (n = 3). Ablations were made using 30 to 70% of the maximal energy of the Visualase system. We used serial ablations as needed along the tract of the catheter by pulling back the optic fiber; the length of the lesion ranged between 7.4 and 38.1 mm. Ablation volume ranged between 0.27 and 6.78 mm3. Immediate post-ablation MRI demonstrated good ablation of the epileptic lesion in 16/17 cases. In one case with mesial temporal sclerosis, no ablation was performed due to suboptimal position of the catheter. That patient was successfully reoperated at a later date. Mean follow-up was 14.9 months (± 11.6 months). Eleven patients had follow-up longer than 12 months. Good seizure control (Engel I, A) was achieved in 7/11 patients (63%) and 1/11 (9%) had significant improvement in seizure frequency (Angle IIIa). Three patients (27%) did not experience improvement in their seizure frequency (Engel IV, B), and one of these patients died during the follow-up period from sudden unexpected death of epilepsy (SUDEP). No immediate or delayed neurological complications were documented in any of the cases during the follow-up period. Conclusions: MRgLITT is a promising technique and can be used safely as an alternative to open resection in both lesional and non-lesional intractable epilepsy cases. In our local series, the success rate of epilepsy surgery was comparable to recent publications. [ABSTRACT FROM AUTHOR]

Despite its ubiquitous use in medicine, and extensive knowledge of its molecular and cellular effects, how anesthesia induces loss of consciousness (LOC) and affects sensory processing remains poorly understood. Specifically, it is unclear whether anesthesia primarily disrupts thalamocortical relay or intercortical signaling. Here we recorded intracranial electroencephalogram (iEEG), local field potentials (LFPs), and single-unit activity in patients during wakefulness and light anesthesia. Propofol infusion was gradually increased while auditory stimuli were presented and patients responded to a target stimulus until they became unresponsive. We found widespread iEEG responses in association cortices during wakefulness, which were attenuated and restricted to auditory regions upon LOC. Neuronal spiking and LFP responses in primary auditory cortex (PAC) persisted after LOC, while responses in higher-order auditory regions were variable, with neuronal spiking largely attenuated. Gamma power induced by word stimuli increased after LOC while its frequency profile slowed, thus differing from local spiking activity. In summary, anesthesia-induced LOC disrupts auditory processing in association cortices while relatively sparing responses in PAC, opening new avenues for future research into mechanisms of LOC and the design of anesthetic monitoring devices. [ABSTRACT FROM AUTHOR]

Abstract EEG-fMRI allows the localization of the hemodynamic correlates of neural activity and has been shown to be useful as a diagnostic tool in pre-surgical evaluation of refractory epilepsy. However, EEG recordings may be highly contaminated by artifacts induced by movements inside the magnetic field thus rendering the scan difficult for interpretation. Existing methods for motion correction require additional equipment or hardware modification. We introduce a simple method for motion artifact detection, the conductive gel bridge sensor (CGBS), easily applicable using the standard setup. We report examples of CGBS use in two patients with epilepsy and demonstrate the method's ability to successfully differentiate between epochs of brain activity and those of movement. [ABSTRACT FROM AUTHOR]

• Conservative titration of VNS can lead to delayed onset of clinical benefit. • Faster VNS titration correlates with faster onset of clinical response. • Faster titration was not associated with greater adverse events in children. Common titration strategies for vagus nerve stimulation (VNS) prioritize monitoring of tolerability during small increases in stimulation intensity over several months. Prioritization of tolerability is partially based on how quickly side effects can be perceived and reported by patients, and the delayed onset of clinical benefits from VNS. However, many practices assess the clinical benefit of VNS at one year after implantation, and excessive caution during the titration phase can significantly delay target dosing or prevent a patient from reaching a therapeutic dose entirely. This study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. To assess differences between more aggressive titration strategies and more conservative ones, we analyzed the relationship between time-to-dose and time-to-response using a weighted Cox regression. The target dose was empirically defined as 1.625 mA output current delivered at 250 microsecond pulse widths at 20 Hz. Patient-level outcomes and dosing data were segregated into fast (<3 months), medium (3–6 months), and slow (>6 months) cohorts based on their titration speed. The statistical model revealed a significant relationship between titration speed and onset of clinical response, defined as a 50% reduction from baseline in seizure frequency. Frequency of adverse events reported between each cohort trended toward higher rates of adverse events in adults who were titrated quickly; however, the pediatric population appeared to be more tolerant of titration at any speed. This analysis indicates that faster titration yields faster onset of clinical benefit and is especially practical in the pediatric population, though attempts to accelerate adult titration may still be warranted. [ABSTRACT FROM AUTHOR]

Abstract: We had reported that immune cells from relapsing remitting multiple sclerosis (RR-MS) patients secrete low levels of BDNF and that there is a defective regulation of its secretion via DC40. We now studied the effect of interferon-β (IFN-β1) on the secretion and regulation of BDNF from immune cells in patients with RR-MS. The PBMCs of IFN-β1a treated RR-MS patients secreted higher BDNF levels vs. untreated patients. Anti CD40 mAb stimulation of PBMCs of IFN-β1a treated patients upregulated the BDNF levels. There was no significant effect of CD40 stimulation on PBMCs of untreated patients. CD40+ expression on CD14+ cells was higher in IFN-β treated patients vs. untreated patients. In vitro treatment with IFN-β1a of PBMCs from healthy controls and untreated patients led to a significant increase in CD40 expression on CD14+ cells in both groups. The addition of IFN-β1a to CD40 stimulated PBMCs of untreated patients restored the up regulatory effect of CD40 stimulation on BDNF levels. Therefore, reduced BDNF secretion from PBMCs and defective regulation effect of CD40 stimulation on BDNF levels in untreated RR-MS are reversible by therapy with IFN-β1a. [Copyright &y& Elsevier]

• Electroencephalography-correlated functional magnetic resonance imaging is valid in assessing epileptic focus for patients with callosal defects. • Epileptic networks are widespread and bilateral with agenesis of corpus callosum. • Epileptic networks are bilateral in resistant post anterior callosotomy patients. • The anterior commissure's diameter is larger in ACC and post-callosotomy patients. Electroencephalography-correlated functional magnetic resonance imaging (EEG-fMRI) allows imaging of brain-wide epileptic networks, and demonstrates that focal interictal epileptic activity is sometimes accompanied by bilateral functional activations. The corpus callosum (CC) facilitates bilateral spread of epileptic activity and at times targeted surgically for drug-resistant epilepsy (DRE). We hypothesized that focal epileptic networks are more unilateral in patients lacking intact CC. We included focal DRE patients who underwent pre-surgical EEG-fMRI and had CC agenesis (group A, n = 5), patients who previously underwent anterior callosotomy as treatment for drop attacks and continued having seizures (group B, n = 6), and control group of patients with focal epilepsy and intact CC (group C, n = 9). Blood-oxygenation-level-dependent (BOLD) signal maps were generated for interictal epileptic discharges. To quantify bi-hemispheric distribution of epileptic networks, laterality indices were compared between groups. Anatomical and diffusion-weighted imaging demonstrated white matter pathways. 96% of studies demonstrated bilateral activations. Laterality indices were similar in groups A and C, whereas group B demonstrated a more bilateral network than group C (p = 0.028). Diffusion-weighted and anatomical imaging showed aberrant white matter pathways and larger anterior commissure in groups A and B. 68% of studies showed maximal activation cluster concordant with the presumed epileptic focus, 28% showed non-maximal activation at presumed focus. Focal epileptic activity is associated with bilateral functional activations despite lack of intact CC, and is associated with stronger contralateral activation in patients after anterior callosotomy compared to controls. These findings disprove our initial hypothesis, and combined with white matter structural imaging, may indicate that the CC is not a sole route of propagation of epileptic activity, which might spread via anterior commissure. Our study demonstrates the utility of EEG-fMRI in assessing epileptic networks and potentially aiding in tailoring surgical treatments in DRE patients with callosal anomalies, and in callosal surgeries. [ABSTRACT FROM AUTHOR]