Search

Anterior thalamic deep brain stimulation is an effective therapeutic option for patients with drug-refractory focal epilepsy who are poor surgical candidates. Although the precise mechanism of action of thalamic neurostimulation is unknown, studies demonstrating increased efficacy over time have raised the possibility that therapeutic benefits are mediated by stimulation-related long-term neuroplastic changes. Adverse effects related to hardware malfunction have been previously described, and most commonly include local infection, sensory disturbances, and migration of leads. However, the withdrawal effect of sudden deep brain stimulation malfunction on seizure control is unclear. We present the case of a 21-year-old patient with intractable focal epilepsy who developed status epilepticus concurrently with unexpected deep brain stimulator battery failure, 21 months post implantation. This case demonstrates an unfamiliar possible adverse effect of anterior thalamic stimulation withdrawal and emphasizes the importance of stimulator hardware assessment in patients presenting with seizure worsening.

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.

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.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.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).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.

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.

Objective 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. Methods 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. Results 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. Conclusions In DLB visual event-related oscillations are characterized by a decrease in theta and lack of inhibition in alpha bands. Significance 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.

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 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 (

OBJECTIVEExperiential phenomena (EP), such as illusions and complex hallucinations, are vivid experiences created in one’s mind. They can occur spontaneously as epileptic auras or can be elicited by electrical brain stimulation (EBS) in patients undergoing presurgical evaluation for drug-resistant epilepsy. Previous work suggests that EP arise from activation of different nodes within interconnected neural networks mainly in the temporal lobes. Yet, the anatomical extent of these neural networks has not been described and the question of lateralization of EP has not been fully addressed. To this end, an extended number of brain regions in which electrical stimulation elicited EP were studied to test whether there is a lateralization propensity to EP phenomena.METHODSA total of 19 drug-resistant focal epilepsy patients who underwent EBS as part of invasive presurgical evaluation and who experienced EP during the stimulation were included. Spatial dispersion of visual and auditory illusions and complex hallucinations in each hemisphere was determined by calculation of Euclidean distances between electrodes and their centroid in common space, based on (x, y, z) Cartesian coordinates of electrode locations.RESULTSIn total, 5857 stimulation epochs were analyzed; 917 stimulations elicited responses, out of which 130 elicited EP. Complex visual hallucinations were found to be widely dispersed in the right hemisphere, while they were tightly clustered in the occipital lobe of the left hemisphere. Visual illusions were elicited mostly in the occipital lobes bilaterally. Auditory illusions and hallucinations were evoked symmetrically in the temporal lobes.CONCLUSIONSThese findings suggest that complex visual hallucinations arise from wider spread in the right compared to the left hemisphere, possibly mirroring the asymmetry in the white matter organization of the two hemispheres. These results offer some insights into lateralized differences in functional organization and connectivity that may be important for functional mapping and planning of surgical resections in patients with epilepsy.

Resolving approach-avoidance conflicts relies on encoding motivation outcomes and learning from past experiences. Accumulating evidence points to the role of the Medial Temporal Lobe (MTL) and Medial Prefrontal Cortex (mPFC) in these processes, but their differential contributions have not been convincingly deciphered in humans. We detect 310 neurons from mPFC and MTL from patients with epilepsy undergoing intracranial recordings and participating in a goal-conflict task where rewards and punishments could be controlled or not. mPFC neurons are more selective to punishments than rewards when controlled. However, only MTL firing following punishment is linked to a lower probability for subsequent approach behavior. mPFC response to punishment precedes a similar MTL response and affects subsequent behavior via an interaction with MTL firing. We thus propose a model where approach-avoidance conflict resolution in humans depends on outcome value tagging in mPFC neurons influencing encoding of such value in MTL to affect subsequent choice., Optimizing approach-avoidance behavior calls for neural encoding of related motivation outcomes. Here, the authors show that behavioral choice under conflict relies on differential neuronal firing patterns after punishment, in which mPFC neurons decode the outcome’s value and MTL neurons follow by reducing subsequent approach.

OBJECTIVEPreoperative localization of seizure onset zones (SOZs) is an evolving field in the treatment of refractory epilepsy. Both magnetic source imaging (MSI), and the more recent EEG-correlated functional MRI (EEG-fMRI), have shown applicability in assisting surgical planning. The purpose of this study was to evaluate the capability of each method and their combination in localizing the seizure onset lobe (SL).METHODSThe study included 14 patients who underwent both MSI and EEG-fMRI before undergoing implantation of intracranial EEG (icEEG) as part of the presurgical planning of the resection of an epileptogenic zone (EZ) during the years 2012–2018. The estimated location of the SL by each method was compared with the location determined by icEEG. Identification rates of the SL were compared between the different methods.RESULTSMSI and EEG-fMRI showed similar identification rates of SL locations in relation to icEEG results (88% ± 31% and 73% ± 42%, respectively; p = 0.281). The additive use of the coverage lobes of both methods correctly identified 100% of the SL, significantly higher than EEG-fMRI alone (p = 0.039) and nonsignificantly higher than MSI (p = 0.180). False-identification rates of the additive coverage lobes were significantly higher than MSI (p = 0.026) and EEG-fMRI (p = 0.027). The intersecting lobes of both methods showed the lowest false identification rate (13% ± 6%, p = 0.01).CONCLUSIONSBoth MSI and EEG-fMRI can assist in the presurgical evaluation of patients with refractory epilepsy. The additive use of both tests confers a high identification rate in finding the SL. This combination can help in focusing implantation of icEEG electrodes targeting the SOZ.

International audience; 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.

Background and ObjectivesTo explore the clinical characteristics and HLA associations of patients with anti–leucine-rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in Israel. Anti-LGI1E is the most commonly diagnosed antibody-associated encephalitic syndrome in adults. Recent studies of various populations reveal significant associations with specific HLA genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.MethodsSeventeen consecutive patients with anti-LGI1E diagnosed at Tel Aviv Medical Center between the years 2011 and 2018 were included. HLA typing was performed using next-generation sequencing at the tissue typing laboratory of Sheba Medical Center and compared with data from the Ezer Mizion Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age at onset in the 7th decade, as previously reported. The most common presenting symptom was seizures. Notably, paroxysmal dizziness spells were significantly more common than previously reported (35%), whereas faciobrachial dystonic seizures were found only in 23%. HLA analysis revealed overrepresentation of DRB1*07:01 (OR: 3.18, CI: 20.9p< 1.e-5) and DRB1*04:02 (OR: 3.8, CI: 20.1p< 1.e-5), as well as of the DQ allele DQB1*02:02 (OR: 2.8, CI: 14.2p< 0.0001) as previously reported. A novel overrepresentation observed among our patients was of the DQB1*03:02 allele (OR: 2.3, CI: 6.9p< 0.008). In addition, we found DR-DQ associations, among patients with anti-LGI1E, that showed complete or near-complete linkage disequilibrium (LD). By applying LD analysis to an unprecedentedly large control cohort, we were able to show that although in the general population, DQB*03:02 is not fully associated with DRB1*04:02, in the patient population, both alleles are always coupled, suggesting the DRB1*04:02 association to be primary to disease predisposition. In silico predictions performed for the overrepresented DQ alleles reveal them to be strong binders of LGI1-derived peptides, similarly to overrepresented DR alleles. These predictions suggest a possible correlation between peptide binding sites of paired DR-DQ alleles.DiscussionOur cohort presents distinct immune characteristics with substantially higher overrepresentation of DRB1*04:02 and slightly lower overrepresentation of DQB1*07:01 compared with previous reports implying differences between different populations. DQ-DR interactions found in our cohort may shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying a possible relevance of certain DQ alleles and DR-DQ interactions.

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.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.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-VHDecreased 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.

ObjectiveExploring the clinical characteristics and HLA associations of patients with anti-leucine–rich glioma-inactivated 1 encephalitis (LGI1E) from a large single center in IsraelBackgroundAnti-LGI1E is one of the most commonly diagnosed antibody-associated encephalitic syndromes in adults. Recent studies of various populations reveal significant associations with specific Human Leukocyte Antigen (HLA) genes. We examined the clinical characteristics and HLA associations of a cohort of Israeli patients.Design/MethodsSeventeen consecutive anti-LGI1E patients diagnosed at Tel Aviv Sourasky Medical Center between the years 2011-2018 were included. HLA typing was performed using NGS methodology at the tissue typing laboratory of Sheba Medical Center and compared to data from the "Ezer Mizion" Bone Marrow Donor Registry, containing over 1,000,000 samples.ResultsOur cohort displayed a male predominance and median age of onset in the 7th decade, as previously reported. All patients responded to immunotherapy, though residual damage was not uncommon (23% with MRS >1). HLA analysis revealed overexpression of DRB1*07:01 (OR 13, CI 0.6 p < 1.e-10) and DRB1*04:02 (OR 12, CI-0.6 p < 1.e-10), as previously reported, as well as of the DQ alleles DQB1*02:02 (OR 12, CI 0.6 p < 1.e-10), DQB1*03:03 (OR 27, CI 0.9 p < 1.e-10), previously attributed to linkage disequilibrium (LD) with the mentioned DR alleles. An additional allele overexpressed among our patients was the DQB1*03:02 allele (OR 12, CI 0.6 p < 1.e-10), which appeared in complete LD with DRB1*04:02. Linkage disequilibrium analysis performed on patients and controls suggests these DR-DQ associations are unique to anti-LGI1E patients. In silico predictions performed for the overexpressed DQ alleles reveal them to be strong binders of LGI1 derived peptides, and suggest a correlation between peptide binding sites of paired DR-DQ alleles.ConclusionsOur findings shed additional light on the complex role of immunogenetics in the pathogenesis of anti-LGI1E, implying the possible relevance of certain DQ alleles as well as DR-DQ interactions.

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

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 (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.

International audience; 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.

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. 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. 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. 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.

Sleep in all species is universally defined as a reversible, homeostatically-regulated state of a reduced behavioral responsiveness, with a high arousal threshold in response to external sensory stimulation1. However, it remains unclear whether sleep mainly gates motor output or affects responses along sensory pathways, and whether sleep primarily modulates specific aspects of the sensory response such as feedforward vs. feedback signaling2–7. Here, we simultaneously recorded polysomnography, iEEG, microwire LFPs, and neuronal spiking activity during wakefulness and sleep in 13 epilepsy patients implanted with clinical depth electrodes, while presenting auditory stimuli (e.g. click-trains, words, music). The results revealed robust spiking and induced LFP high-gamma (80-200Hz) power responses during both NREM and REM sleep across the lateral temporal lobe. The magnitude of the responses was only moderately attenuated in sleep, most notably for late responses beyond the early auditory cortex. Nonetheless, sleep responses maintained their tight locking with soundwave envelopes and their information content was only minimally affected. In contrast, a decrease in LFP alpha-beta (10-30Hz) power responses was prevalent in wakefulness but significantly disrupted in sleep. Entrainment to 40 Hz click-trains was comparable across REM sleep and wakefulness, but reduced in NREM sleep. In conclusion, our results establish the presence of extensive and robust auditory responses during sleep while LFP alpha-beta power decrease, likely reflecting top-down processes8–10, is deficient. More broadly, our findings suggest that feedback signalling is key to conscious sensory processing11–13.

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 (NTS), which receives afferent vagal inputs. In rats, VNS elevates LC firing and forebrain noradrenaline levels, whereas LC lesions suppress VNS therapeutic efficacy. Non-invasive transcutaneous VNS (tVNS) employs electrical stimulation that targets the auricular branch of the vagus nerve at the cymba conchae of the ear. However, the extent that 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 (3.4s) 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 4-5s 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.Significance statementCurrent non-invasive brain stimulation techniques are mostly confined to modulating cortical activity, as is typical with transcranial magnetic or transcranial direct/alternating-current electrical stimulation. Transcutaneous vagus nerve stimulation (tVNS) has been proposed to stimulate subcortical arousal-promoting nuclei, though previous studies yielded inconsistent results. Here we show that short (3.4s) tVNS pulses in naïve healthy male volunteers induced transient pupil dilation and attenuation of occipital alpha oscillations. These markers of brain arousal are in line with the established effects of invasive VNS on locus coeruleus-noradrenaline signaling, and support the notion that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying the means by which endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

The coronavirus disease-2019 (COVID-19) and its management in patients with epilepsy can be complex. Prescribers should consider potential effects of investigational anti-COVID-19 drugs on seizures, immunomodulation by anti-seizure medications (ASMs), changes in ASM pharmacokinetics, and the potential for drug-drug interactions (DDIs). The goal of the Board of the Israeli League Against Epilepsy (the Israeli Chapter of the International League Against Epilepsy, ILAE) was to summarize the main principles of the pharmacological treatment of COVID-19 in patients with epilepsy. This guide was based on current literature, drug labels, and drug interaction resources. We summarized the available data related to the potential implications of anti-COVID-19 co-medication in patients treated with ASMs. Our recommendations refer to drug selection, dosing, and patient monitoring. Given the limited availability of data, some recommendations are based on general pharmacokinetic or pharmacodynamic principles and might apply to additional future drug combinations as novel treatments emerge. They do not replace evidence-based guidelines, should those become available. Awareness to drug characteristics that increase the risk of interactions can help adjust anti-COVID-19 and ASM treatment for patients with epilepsy.

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.

Objectives 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. Materials & methods 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. Results 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. Conclusions 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.