Therapeutic drug monitoring in pregnancy: Levetiracetam.

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.

Cannabidiol-enriched oil for adult patients with drug-resistant epilepsy: Prospective clinical and electrophysiological study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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). SIGNIFICANCE: 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.

Grading system for assessing the confidence in the epileptogenic zone reported in published studies: A Delphi consensus study.

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.

Intracerebroventricular administration for delivery of antiseizure therapeutics: Challenges and opportunities.

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.

Anesthesia-induced loss of consciousness disrupts auditory responses beyond primary cortex.

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.

Paroxysmal Slow-Wave Events Are Uncommon in Parkinson's Disease.

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.

Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations.

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.SIGNIFICANCE STATEMENT Current noninvasive 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 (3.4 s) tVNS pulses in naive 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 that tVNS mimics VNS. Therefore, tVNS can be used as a tool for studying how endogenous subcortical neuromodulatory signaling affects human cognition, including perception, attention, memory, and decision-making; and also for developing novel clinical applications.

Using nirmatrelvir/ritonavir in patients with epilepsy: An update from the Israeli chapter of the International League Against Epilepsy.

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.

Minimum standards for inpatient long-term video-electroencephalographic monitoring: A clinical practice guideline of the International League Against Epilepsy and International Federation of Clinical Neurophysiology.

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.

Rapid titration of VNS therapy reduces time-to-response in epilepsy.

BACKGROUND: 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. OBJECTIVE: This study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Bilateral epileptic networks in congenital and acquired corpus callosum defects: EEG-fMRI study.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. SIGNIFICANCE: 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.

Adopting MR-guided stereotactic laser ablations for epileptic lesions: initial clinical experience and lessons learned.

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.

Atypical duration of epileptic and psychogenic nonepileptic events.

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 ±â€¯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 ±â€¯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 ±â€¯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.

Treating Epilepsy Patients with Investigational Anti-COVID-19 Drugs: Recommendations by the Israeli Chapter of the ILAE.

BACKGROUND: 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.

Clinical correlates and electroencephalographic features of FIRDA in a tertiary center.

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.

Dual array EEG-fMRI: An approach for motion artifact suppression in EEG recorded simultaneously with fMRI.

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 3T 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.

Safety in the epilepsy monitoring unit: A retrospective study of 524 consecutive admissions.

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.

Epileptic scalp ripples are associated with corticothalamic BOLD changes.

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.

A Speech Neuroprosthesis in the Frontal Lobe and Hippocampus: Decoding High-Frequency Activity into Phonemes.

BACKGROUND AND OBJECTIVES: Loss of speech due to injury or disease is devastating. Here, we report a novel speech neuroprosthesis that artificially articulates building blocks of speech based on high-frequency activity in brain areas never harnessed for a neuroprosthesis before: anterior cingulate and orbitofrontal cortices, and hippocampus. METHODS: A 37-year-old male neurosurgical epilepsy patient with intact speech, implanted with depth electrodes for clinical reasons only, silently controlled the neuroprosthesis almost immediately and in a natural way to voluntarily produce 2 vowel sounds. RESULTS: During the first set of trials, the participant made the neuroprosthesis produce the different vowel sounds artificially with 85% accuracy. In the following trials, performance improved consistently, which may be attributed to neuroplasticity. We show that a neuroprosthesis trained on overt speech data may be controlled silently. CONCLUSION: This may open the way for a novel strategy of neuroprosthesis implantation at earlier disease stages (eg, amyotrophic lateral sclerosis), while speech is intact, for improved training that still allows silent control at later stages. The results demonstrate clinical feasibility of direct decoding of high-frequency activity that includes spiking activity in the aforementioned areas for silent production of phonemes that may serve as a part of a neuroprosthesis for replacing lost speech control pathways.

Electroencephalography/functional magnetic resonance imaging responses help predict surgical outcome in focal epilepsy.

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 co-registered 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.