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Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines.

Magnesium (Mg) competes with calcium in normal synaptic transmission, inhibiting neurotransmitter release. As a drug, it is usually given as a treatment for eclampsia and pre-eclampsia. Two eclamptic pregnant women treated with Mg developed a pseudo-coma state immediately after emergency Caesarian Section. The clinical presentation was flaccid quadriparesis, areflexia, an absence of absent respiratory effort and vestibular-ocular reflexes, but with preserved pupillary responses. Decremental responses on repetitive nerve stimulation were found in both women. Recovery was obtained after cessation of the Mg. The persistence of pupillary reflexes in the absence of reflexes involving striated muscles was an important clinical clue, indicating neuromuscular junction dysfunction.

Epilepsy is characterized by unpredictable attacks. Hence, people with epilepsy (PWE) may develop anxious anticipation of upcoming seizures. Seizure phobia is an anxiety disorder wherein seizure anticipatory situations trigger fear, accompanied by avoidance behaviors. Research on seizure phobia among PWE is scarce. Therefore, we aimed to describe the diagnosis of seizure phobia and its association with demographic, psychiatric and neurological variables.This is a cross-sectional study of adult PWE in a tertiary epilepsy outpatient clinic. Data were collected from semi-structured interviews, demographic questionnaires and medical records. Patients with and without seizure phobia were compared in terms of sociodemographic, psychiatric, and neurological variables. A logistic regression analysis was performed to identify variables that predicted seizure phobia.Among 69 PWE included in the study, 19 (27.5%) were diagnosed with seizure phobia. In comparison with PWE without seizure phobia, PWE with seizure phobia were predominantly female (84.2% vs 44.2%, p = 0.005), and had more comorbid anxiety disorders (84.2% vs 34.9%, p = 0.01), past major depressive episode (MDE) (63.2% vs 20.9%, p = 0.003), and post-traumatic stress disorder (26.3% vs 7%, p = 0.05). There was a significant association between seizure phobia and comorbid psychogenic non-epileptic seizures (36.8% vs 11.6%, p = 0.034). However, no significant association was found with epilepsy-related variables. A multivariate logistic regression model indicated anxiety and a past MDE as predictive factors for seizure phobia (RSeizure phobia is a distinct psychiatric entity among PWE. Further research is required to understand its etiology, risk factors, and potential interventions for these patients.

Alterations in the default mode network (DMN) are known to associated with aging and with neurological and psychiatric diseases. We assessed age-dependent changes in interactions within the DMN and between the DMN with other brain areas, and correlations of these interactions with a battery of neuropsychological tests to formulate a macroscopic model of ageing.Using a novel multivariate analysis method, enabling determination of directed pathways, on resting-state functional MRI data from fifty young and thirty-one old healthy individuals, we identified directed intra- and inter-DMN directed pathways that differed between the groups and used their correlations with neuropsychological tests to infer their behavioral meaning.Pathways connecting the DMN with visual and limbic regions in old subjects engaged at BOLD low frequency and involved the dorsal PCC. In young subjects, they were at high frequency and involved the ventral PCC. Pathways combining the sensorimotor (SM) and the DMN, were efferent in young subjects (DMNSM). Most inter-DMN pathways in the old subjects, correlated with reduced speed and working memory and, were DMN efferent (DMN>).We suggest a macroscopic model of aging centered in the DMN. It suggests that the reduced sensorimotor efferent, probably brought about from reduced physical activity, and the increased need to control such activities by the mPFC, causes a higher dependency on external versus internal cues. This results in a shift from ventral to dorsal PCC of inter-DMN pathways. Consequently, the model combines physical activity with ageing.

Background: Binge eating disorder) BED) is the most common eating disorder in the United-States. Chronic, orally administered topiramate has shown BED treatment efficacy, but with two major limitations: frequent and severe side effects and slow time to action. SipNose is a novel-non-invasive-intranasal (IN) direct nose-to-brain (DNTB) drug delivery platform that delivers drugs to the central nervous system (CNS) consistently and fast. Herein, we study SipNose-topiramate combination product, as an acute "as needed"(PRN) solution for BED management. Methods: First, we evaluate the innovative SipNose-topiramate's pharmacokinetics (PK) and safety. The second part aimed to demonstrate SipNose-topiramate's PRN-treatment efficacy in reducing the number of binge-eating episodes in 12-BED patients (2-weeks of baseline monitoring [BL], 8-weeks of treatment [TX], 2-weeks of follow up [FU]). In this part 251 treatments were used by the 12 BED patients participated in the study. Results: The PK profile showed peak plasma levels at 90 minutes post-administration, and a t1/2 > 24hr, and demonstrated consistent topiramate delivery with no AE. In the second part, mean weekly binge events (WBE) and binge event days per week (DPW) showed a significant reduction from baseline to treatment period that was maintained in follow up period. Efficacy was corroborated by improved patient illness severity scales. There were no adverse events during all administered treatments. Patients were exposed to less drug when compared with accepted oral dosing. Conclusions: This study introduces the novel SipNose-topiramate drug-device combination as a safe, effective, and controlled method for BED management. Its findings represent a breakthrough approach to BED management both as an intranasal and "as needed" therapy for reducing binge eating episodes with a large-scale reduction in patient drug exposure and thus side effects and with improved patient quality of life. Further studies are needed with larger patient populations to establish SipNose-topiramate as a mainstream treatment for BED. Trial registration: Registration number and date of registration of the clinical studies reported in this article are as follows: 0157-18-HMO, August 15th 2018 and 6814-20-SMC, December 2nd 2020.

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.

Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01-3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02-1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001-0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08-0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5-0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.

Patients with juvenile myoclonic epilepsy (JME) are especially prone to having antiseizure medications (ASMs) withdrawal seizures (WS).To clarify whether WS in JME patients are caused by a high tendency of non-adherence from seizure-free patients or by a constitutive increased sensitivity to drug withdrawal.Epilepsy patients followed in a tertiary epilepsy clinic between 2010 and 2013 were included in the study. WS prevalence was compared between drug-responsive and drug-resistant JME patients and patients with other types of epilepsy.The study included 23 JME patients (16 drug-responsive and 7 drug-resistant) and 138 patients with other epilepsies (74 drug-responsive and 64 drug-resistant). JME patients were younger and included more women than non-JME patients. Significantly more WS were seen in JME than in non-JME patients (P = 0.01) and in the drug-resistant fraction of JME patients in comparison to drug-resistant non-JME patients (P = 0.02). On logistic regression, the type of epilepsy, but not the patient's sex, was found to significantly predict WS. No significant difference was found in the prevalence of WS between drug-responsive and drug-resistant JME patients. The main ASM discontinued in JME was valproic acid (VPA), especially in women.Our findings suggest a higher sensitivity of JME patients to withdrawal of medications. It is important to educate JME patients about treatment adherence and to explain to their physicians how to carefully reduce or replace ASMs to mitigate the morbidity and mortality related to ASM withdrawal.

Background Psychogenic nonepileptic seizures (PNES) represent one of the most sizable treatment challenges in neuropsychiatry. Although the underlying mechanism is far from being understood, several interventions have been suggested. However, patients with comorbid psychiatric diagnoses and epilepsy are excluded from most intervention studies. Objective To To present a within-group posttreatment vs pretreatment study representing the retrospective clinical results of an integrative psychotherapy model. Methods: We present the clinical results of 22 patients with PNES diagnosed in an epilepsy center and treated in our neuropsychiatry clinic using an integrative rehabilitative psychotherapy. Therapy included presenting the diagnosis, psychoeducation, seizure reduction behavioral techniques, and coping with past and present stressors. Insomuch as integrative biopsychosocial psychotherapy is based on an individualized treatment protocol for each patient, treatment was individualized and case specific. Results By the end of treatment, 36% of patients had become seizure free and a further 54% achieved a major seizure reduction (reduction of more than 70%). Seventy-two percent of patients kept at least 70% seizure reduction at follow-up. Global Assessment of Functioning scores improved from a mean of 43.09 to a mean of 72.81 at the end of treatment and 69.72 at follow-up. In addition, we present 3 case descriptions that emphasize the individualized nature of psychotherapeutic decisions. Conclusions Our results support the feasibility and effectiveness of biopsychosocial based integrative psychotherapy for PNES and set principles for future treatment and prospective clinical trials in the field of individualized psychotherapy.

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.

Therapeutic monoclonal antibodies (mAbs) have emerged as the fastest growing drug class. As such, mAbs are increasingly being co-prescribed with other drugs, including antiseizure medications (ASMs). Although mAbs do not share direct targets or mechanisms of disposition with small-molecule drugs (SMDs), combining therapeutics of both types can increase the risk of adverse effects and treatment failure. The primary goal of this literature review was identifying mAb-ASM combinations requiring the attention of professionals who are treating patients with epilepsy. Systematic PubMed and Embase searches (1980-2021) were performed for terms relating to mAbs, ASMs, drug interactions, and their combinations. Additional information was obtained from documents from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Evidence was critically appraised - key issues calling for clinicians' consideration and important knowledge gaps were identified, and practice recommendations were developed by a group of pharmacists and epileptologists. The majority of interactions were attributed to the indirect effects of cytokine-modulating antibodies on drug metabolism. Conversely, strong inhibitors or inducers of drug-metabolizing enzymes or drug transporters could potentially interact with the cytotoxic payload of antibody-drug conjugates, and ASMs could alter mAb biodistribution. In addition, mAbs could potentiate adverse ASM effects. Unfortunately, few studies involved ASMs, requiring the formulation of class-based recommendations. Based on the current literature, most mAb-ASM interactions do not warrant special precautions. However, specific combinations should preferably be avoided, whereas others require monitoring and potentially adjustment of the ASM doses. Reduced drug efficacy or adverse effects could manifest days to weeks after mAb treatment onset or discontinuation, complicating the implication of drug interactions in potentially deleterious outcomes. Prescribers who treat patients with epilepsy should be familiar with mAb pharmacology to better anticipate potential mAb-ASM interactions and avoid toxicity, loss of seizure control, or impaired efficacy of mAb treatment.

Background: Inflammation is a hallmark of epileptogenic brain tissue. Previously, we have shown that inflammation in epilepsy can be delineated using systemically-injected fluorescent and magnetite- laden nanoparticles. Suggested mechanisms included distribution of free nanoparticles across a compromised blood-brain barrier or their transfer by monocytes that infiltrate the epileptic brain. Objective: In the current study, we evaluated monocytes as vehicles that deliver nanoparticles into the epileptic brain. We also assessed the effect of epilepsy on the systemic distribution of nanoparticleloaded monocytes. Methods: The in vitro uptake of 300-nm nanoparticles labeled with magnetite and BODIPY (for optical imaging) was evaluated using rat monocytes and fluorescence detection. For in vivo studies we used the rat lithium-pilocarpine model of temporal lobe epilepsy. In vivo nanoparticle distribution was evaluated using immunohistochemistry. Results: 89% of nanoparticle loading into rat monocytes was accomplished within 8 hours, enabling overnight nanoparticle loading ex vivo. The dose-normalized distribution of nanoparticle-loaded monocytes into the hippocampal CA1 and dentate gyrus of rats with spontaneous seizures was 176-fold and 380-fold higher compared to the free nanoparticles (p Conclusion: Nanoparticle-loaded monocytes are attracted to epileptogenic brain tissue and may be used for labeling or targeting it, while significantly reducing the systemic dose of potentially toxic compounds. The effect of seizures on monocyte biodistribution should be further explored to better understand the systemic effects of epilepsy.

Psychogenic nonepileptic seizures (PNES) are of the most elusive phenomena in epileptology. Patients with PNES present episodes resembling epileptic seizures in their semiology yet lacking the underlying epileptic brain activity. These episodes are assumed to be related to psychological distress from past trauma, yet the underlying mechanism of this manifestation is still unknown. Using resting-state functional magnetic resonance imaging (fMRI), we investigated functional connectivity changes within and between large-scale brain networks in 9 patients with PNES, compared with a group of 13 age- and gender-matched healthy controls. Functional magnetic resonance imaging analyses identified functional connectivity disturbances between the medial temporal lobe (MTL) and the sensorimotor cortex and between the MTL and ventral attention networks in patients with PNES. Within network connectivity reduction was found within the visual network. Our findings suggest that PNES relate to changes in connectivity in between areas that are involved in memory processing and motor activity and attention control. These results may shed new light on the way by which traumatic memories may relate to PNES.

Background Stroke prevention is an important socio-economic aim. Epilepsy and antiepileptic drugs (AEDs), roughly divided into enzyme-inducers and non-enzyme-inducers, have been associated with increased risk of stroke. Methods A retrospective review of patients admitted with a diagnosis of anytime stroke and taking at least one AED was performed. A subgroup of subjects admitted for acute strokes was separately studied. Potential interactions between AEDs and other consumed medications were identified using MicroMedex and Lexi-Interact. Results The study included 827 patients, 59% of them using 5–10 medications. Two thirds of the patients received at least one enzyme-inducer AED, with phenytoin being the most commonly used AED (38% of the patients). Among the subgroup of 82 patients admitted for stroke, 61% were prescribed AEDs after the stroke. More patients had large vessel and embolic strokes among these than among the patients that had strokes while on AEDs. Statins, antiplatelet drugs, antidiabetics and calcium channel blockers (CCBs) were the most frequently used non-AED drugs, by 56, 55, 30 and 28%, respectively. The most common combinations between AEDs and non-AED medications bearing risk for potential major interactions were those of AEDs with statins, warfarin, calcium channel blockers and anti-depressants. Conclusions A change in the AEDs prescription practice in stroke patients should be implemented, to avoid interactions with major groups of other medications prescribed to these patients.

Our goal was to measure the absolute differential abundance of key drug transporters in human epileptogenic brain tissue and to compare them between patients and at various distances from the epileptogenic zone within the same patient. Transporter protein abundance was quantified in brain tissue homogenates from patients who underwent epilepsy surgery, using targeted proteomics, and correlations with clinical and tissue characteristics were assessed. Fourteen brain samples (including four epileptogenic hippocampal samples) were collected from nine patients. Among the quantifiable drug transporters, the abundance (median, range) ranked: breast cancer resistance protein (ABCG2/BCRP; 0.55, 0.01–3.26 pmol/g tissue) > P-glycoprotein (ABCB1/MDR1; 0.30, 0.02–1.15 pmol/g tissue) > equilibrative nucleoside transporter 1 (SLC29A1/ENT1; 0.06, 0.001–0.35 pmol/g tissue). The ABCB1/ABCG2 ratio (mean 0.27, range 0.08–0.47) was comparable with literature values from nonepileptogenic brain tissue (mean 0.5–0.8). Transporter abundance was lower in the hippocampi than in the less epileptogenic neocortex of the same patients. ABCG2/BCRP and ABCB1/MDR1 expression strongly correlated with that of glucose transporter 1 (SLC2A1/GLUT1) (r = 0.97, p < 0.001; r = 0.90, p < 0.01, respectively). Low transporter abundance was found in patients with overt vascular pathology, whereas the highest abundance was seen in a sample with normally appearing blood vessels. In conclusion, drug transporter abundance highly varies across patients and between epileptogenic and less epileptogenic brain tissue of the same patient. The strong correlation in abundance of ABCB1/MDR1, ABCG2/BCRP, and SLC2A1/GLUT1 suggests variation in the content of the functional vasculature within the tissue samples. The epileptogenic tissue can be depleted of key drug transport mechanisms, warranting consideration when selecting treatments for patients with drug-resistant epilepsy.

A 17-year-old elite triathlete presented with recurrent loss of consciousness events. Implantable loop recorder (ILR) documented sinus node asystoles of up to 21 seconds. She underwent cardiac neuromodulation ablation. After ablation, a generalized tonic-clonic seizure (GTCS) occurred, without concomitant asystole on the ILR. Temporal lobe seizures were diagnosed and supported by interictal epileptic activity on electroencephalogram. We assumed that the syncope episodes were ictal asystole (IA) and that the IA terminated the epileptic seizures early after their onset. The cardiac ablation prevented IA, enabling spread of seizure activity and development of GTCS. To the best of our knowledge, this is the first case of IA treated with cardiac ablation, allowing avoidance of cardiac pacing. This case raises the awareness to epileptic seizures as a cause of asystole in athletes, with an elusive and atypical presentation.

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.

Purpose Resection of the hippocampus can cause verbal memory decline, especially in the pediatric population. Thus, preservation of the hippocampus can be crucial for the quality of life of children with intractable temporal lobe epilepsy (TLE) who are candidates for epilepsy surgery. We investigated techniques that determine whether the hippocampus is part of the epileptogenic zone and the outcomes of pediatric surgery aimed to spare the hippocampus. Methods We accessed data of children with normal hippocampus on MRI, who underwent surgery for medically refractory TLE. To identify epileptogenic areas, electrocorticography was performed in patients with space occupying lesions adjacent to the hippocampus, and long term invasive monitoring in patients with nonlesional TLE. Postoperative seizure control was classified according to Engel I-IV; Class I indicates seizure-free. Results Eleven females and 11 males met study inclusion criteria; the mean age at surgery was 11.3 years. Cortical and hippocampal electrocorticography was performed in 15 patients and long term invasive hippocampal monitoring in seven. The hippocampus was preserved in 16 patients (73%) while hippocampectomy was performed in 6 (27%). At the end of a mean follow-up of 3.5 years, 94% (15/16) of the patients who did not undergo hippocampectomy were classified as Engel I, compared to 50% (3/6) who underwent hippocampectomy. Conclusion Sparing the hippocampus in temporal lobe epilepsy surgery is possible with excellent seizure outcome, while using the proper intraoperative technique.

Purpose The aim of the study was to identify trends in utilization of antiepileptic drugs (AEDs) over time in a nation-wide population in Israel. Methods Data on AED utilization (for all indications) for the period 2010–2014 were obtained from pharmaceutical companies that distribute AEDs in Israel. Prevalence of AED utilization was reported as defined daily doses (DDD)/1000 inhabitants/day. Results The utilization of most AEDs included in our analysis remained stable over the study period. The greatest increases in utilization of drugs established in Israel were observed for lamotrigine (33%), oxcarbazepine (31%), and primidone (18%). Decreases in use were recorded for carbamazepine (18%) and phenobarbital (15%). Use of older AEDs appeared to be relatively high, compared with the use of newer AEDs. Conclusions During the study period of 2010–2014, conventional AEDs remained a main treatment choice in Israel, in certain cases in contrast to current recommendations and guidelines, for reasons yet to be revealed in further research.

Correct localization of epileptic foci can improve surgical outcome in patients with drug-resistant seizures. Our aim was to demonstrate that systemically injected nanoparticles identify activated immune cells, which have been reported to accumulate in epileptogenic brain tissue. Fluorescent and magnetite-labeled nanoparticles were injected intravenously to rats with lithium-pilocarpine-induced chronic epilepsy. Cerebral uptake was studied ex vivo by confocal microscopy and MRI. Cellular uptake and biological effects were characterized in vitro in murine monocytes and microglia cell lines. Microscopy confirmed that the nanoparticles selectively accumulate within myeloid cells in the hippocampus, in association with inflammation. The nanoparticle signal was also detectable by MRI. The in vitro studies demonstrate rapid nanoparticle uptake and good cellular tolerability. We show that nanoparticles can target myeloid cells in epileptogenic brain tissue. This system can contribute to pre-surgical and intra-surgical localization of epileptic foci, and assist in detecting immune system involvement in epilepsy.

Surveys among women with epilepsy (WWE) show that they receive their essential pregnancy-related information from many sources, including the internet. Our aim was to assess the types of websites provided by searching Google for the use of four antiepileptic drugs (AEDs) during pregnancy and lactation. The search was performed on 40 computers used by health-care professionals, on 40 computers used by nonhealth-care professionals, and on 5 computers used by WWE in Israel and on 8 computers used by nonhealth-care professionals in the U.S. On each computer, a Google search was conducted for term combinations that included one AED name (“carbamazepine”,“valproic acid”, “lamotrigine”, “levetiracetam”, or “Keppra”) and “Pregnancy”, “Lactation”, or “Breastfeeding”. The top three and top ten websites retrieved in every search were mapped (a total of 45 and 150 websites, respectively, from each computer). Across all searches in English, on both U.S. and Israeli computers, the majority of websites listed among the first three and first ten results were those of independent health portals. The representation of the Epilepsy Foundation website was 10% or less, and only a few results were obtained from the NIH's general public-oriented MedlinePlus. In Hebrew, results included almost exclusively Israeli or Hebrew-translated websites. As in English, results from public-oriented, professionally-written websites in Hebrew accounted for less than 50% of entries. Overall, the availability of readable and high-quality information on AEDs used by pregnant and breastfeeding women is limited. Guiding patients towards accurate web resources can help them navigate among the huge amount of available online information.

Purpose As pharmacists play an important role in managing antiepileptic drug (AED) therapy, they should be aware of different aspects of the treatment. Our aim was to evaluate pharmacists' knowledge of the pharmacological treatment of epilepsy, and their recommendations under hypothetical situations, through a written questionnaire. Methods The questionnaire included 22 questions divided into three sections: demographic data (eight questions), knowledge of specific aspects of AED therapy (true/false; four questions), and actions taken in theoretical situations involving AED therapy (multiple choice; ten questions). The questionnaire was distributed to pharmacists practicing in Israel and working in pharmacies and/or participating in professional meetings and continued education programs. Results One hundred and twenty one pharmacists completed the questionnaire (response rate 19%). The mean overall score was 48±15% correct answers. Most pharmacists were aware of the need to continue AED treatment during pregnancy, the risk of generic switches, and the need to call the physician for loss of seizure control (92%, 89% and 81% of responders, respectively). Twelve percent identified correctly all three situations in which the clinicians should be contacted urgently, and 27% did not identify any of them. The total score was related to the academic degree (PharmD vs. other) and to the duration since training completion. Conclusion Pharmacists were knowledgeable regarding some aspects of care of people with epilepsy. However, our study, as in previous studies among health care professionals, identified some gaps in knowledge. These findings indicate the need for better education of pharmacists regarding epilepsy and its treatment.

Objective: The antiepileptic drug valproate has been shown to affect the expression of carriers for essential compounds and drugs in extracerebral tissues. The aim of the current study was to evaluate in vivo the effect of valproate treatment on the cerebral expression of carriers and selected genes of the blood-brain barrier (BBB) in the rat. Methods: Male Wistar rats were treated daily for seven days by intraperitoneal injections of valproate (75 mg/kg/day, 150 mg/kg/day, or 300 mg/kg/day) or the vehicle. mRNA was isolated from the cerebral cortex and the hippocampus. Transcript levels of 37 genes were measured using a customized gene expression assay. Quantitative histone acetylation was evaluated by western blotting. Glucose6-phosphate (G6P) tissue levels were used as a surrogate of cerebral glucose concentrations. Results: Valproate treatment was associated with significant reduction (up to 22%; P

Folate is involved in metabolic processes and it has been implicated in both aggravation and amelioration of seizures. The aim of the current work was to study the effect of chronic temporal lobe epilepsy (TLE) on the plasma and brain concentrations of folate and on its uptake carriers in the brain - the reduced folate carrier (RFC), folate receptor α (FRα) and proton coupled folate transporter (PCFT). We utilized the rat lithium pilocarpine model for TLE. Approximately two months following status epilepticus, rats with spontaneous recurrent seizures (SRS) were sacrificed for brain and plasma folate concentration analyses and folate uptake carrier expression studies. RT-PCR and western blot analyses were utilized for quantification of folate carriers' mRNAs and proteins, respectively. The distribution of folate carriers in the brain was studied using immunohistochemistry. In the SRS rats we found lower plasma concentrations (10 ± 0.9 in control vs. 6.6 ± 1.6 ng/ml in SRS, P 0.05), but preserved cortical and increased hippocampal levels of folate (0.5 ± 0.1 in control vs. 0.9 ± 0.2 ng/mg in SRS, P = 0.055). Hippocampus - to - plasma ratio of folate concentration was 3-fold higher in the SRS group, compared with the controls (0.13 ± 0.03 vs. 0.04 ± 0.02, respectively; P 0.01). mRNA and protein levels of the folate uptake carriers did not differ between SRS rats and controls. However, immunofluorescent staining quantification revealed that the emission intensity of both RFC and FRα was elevated 8-fold and 4-fold, respectively, in hippocampal CA1 neurons of SRS rats, compared to controls (P 0.01). PCFT was unquantifiable. If corroborated by complementary research in humans, the findings of this study may be utilized clinically for supplemental therapy planning, in imaging the epileptic focus, and for drug delivery into the epileptic brain. Further studies are required for better elucidating the clinical and mechanistic significance of altered folate balances in the epileptic brain.

Huperzine A (HupA) is a naturally occurring compound found in the firmoss Huperzia serrata. While HupA is a potent acetylcholinesterase inhibitor, its full pharmacologic profile is incompletely described. Since previous works suggested a capacity for HupA to prophylax against seizures, we tested the HupA antiepileptic potential in pentylenetetrazole (PTZ) rat epilepsy model and explored its mechanism of action by spectral EEG analysis and by paired-pulse transcranial magnetic stimulation (ppTMS), a measure of GABA-mediated intracortical inhibition. We tested whether HupA suppresses seizures in the rat PTZ acute seizure model, and quantified latency to first myoclonus and to generalized tonic-clonic seizure, and spike frequency on EEG. Additionally, we measured power in the EEG gamma frequency band which is associated with GABAergic cortical interneuron activation. Then, as a step toward further examining the HupA antiepileptic mechanism of action, we tested long-interval intracortical inhibition (LICI) using ppTMS coupled with electromyography to assess whether HupA augments GABA-mediated paired-pulse inhibition of the motor evoked potential. We also tested whether the HupA effect on paired-pulse inhibition was central or peripheral by comparison of outcomes following administration of HupA or the peripheral acetylcholinesterase inhibitor pyridostigmine. We also tested whether the HupA effect was dependent on central muscarinic or GABAA receptors by co-administration of HupA and atropine or PTZ, respectively. In tests of antiepileptic potential, HupA suppressed seizures and epileptic spikes on EEG. Spectral EEG analysis also revealed enhanced gamma frequency band power with HupA treatment. By ppTMS we found that HupA increases intracortical inhibition and blocks PTZ-induced cortical excitation. Atropine co-administration with HupA did not alter HupA-induced intracortical inhibition suggesting independent of muscarinic acetylcholine receptors mechanism in this model. Last, pyridostigmine did not affect the ppTMS-measured cortical inhibition suggesting that HupA-induced effect is centrally-mediated. Our data support antiepileptic HupA applications, and suggest that such activity may be via enhancement of GABAergic intracortical inhibition.

Objective: Cathodal transcranial direct current stimulation (tDCS) is a focal neuromodulation technique that suppresses cortical excitability by low-amplitude constant electrical current, and may have an antiepileptic effect. Yet, tDCS has not been tested in status epilepticus (SE). Furthermore, a combined tDCS and pharmacotherapy antiseizure approach is unexplored. We therefore examined in the rat pentylenetetrazol (PTZ) SE model whether cathodal tDCS (1) suppresses seizures, (2) augments lorazepam (LZP) efficacy, and (3) enhances GABAergic cortical inhibition. Methods: Experiment 1 aimed to identify an effective cathodal tDCS intensity. Rats received intraperitoneal PTZ followed by tDCS (sham, cathodal 1 mA, or cathodal 0.1 mA; for 20 min), and then a second PTZ challenge. In Experiment 2, two additional animal groups received a subtherapeutic LZP dose after PTZ, and then verum or sham tDCS. Clinical and electroencephalography (EEG) epileptic activity were compared between all groups. In Experiment 3, we measured GABA-mediated paired-pulse inhibition of the motor evoked potential by paired-pulse transcranial magnetic stimulation (ppTMS) in rats that received PTZ or saline, and either verum or sham tDCS. Results: Cathodal 1 mA tDCS (1) reduced EEG spike bursts, and suppressed clinical seizures after the second PTZ challenge, (2) in combination with LZP was more effective in seizure suppression and improved the clinical seizure outcomes compared to either tDCS or LZP alone, and (3) prevented the loss of ppTMS motor cortex inhibition that accompanied PTZ injection. Interpretation: These results suggest that cathodal 1 mA tDCS alone and in combination with LZP can suppress seizures by augmenting GABAergic cortical inhibition.

Interactions of antiepileptic drugs (AEDs) with other substances may lead to adverse effects and treatment failure. To avoid such interactions, clinicians often rely on drug interaction compendia. Our objective was to compare the concordance for twenty-two AEDs among three drug interaction compendia (Micromedex, Lexi-Interact, and Clinical Pharmacology) and the US Food and Drug Administration-approved product labels. For each AED, the overall concordance among data sources regarding existence of interactions and their classification was poor, with less than twenty percent of interactions listed in all four sources. Concordance among the three drug compendia decreased with the fraction of the drug excreted unchanged and was greater for established inducers of hepatic drug-metabolizing enzymes than for the drugs that are not inducers (R-square=0.83, P0.01). For interactions classified as contraindications, major, and severe, concordance among the four data sources was, in most cases, less than 30%. Prescribers should be aware of the differences between drug interaction sources of information for both older AEDs and newer AEDs, in particular for those AEDs which are not involved in hepatic enzyme-mediated interactions.

We investigated the prevalence, onset, characteristics, and long-term course of epilepsy disease in children who underwent surgical intervention for diagnosed brain tumors.We reviewed the medical records of children with diagnosed brain tumors who underwent surgery during 2004-2014 at the Hadassah Medical Center. All patients with epilepsy were invited to a clinical visit that included a neurologic examination. The primary outcome measures were neurologic status according to the Glasgow outcome score (GOS) and postoperative seizure outcome according to the Engel system. We compared clinical characteristics according to the timing of epilepsy onset.The mean follow-up was 49 months. Of 128 patients included in the study, 44 (34%) had seizures; 23 (18%) developed epilepsy after surgery. Of the 30 patients with epilepsy who survived, 21 (70%) are in Engel class I and 13% Engel are in class II. Forty-five percent of the children are classified as GOS 5. Children who developed epilepsy after surgery were more likely to be in GOS 1-2 than were those who had seizures before surgery (P = 0.0173). Children with seizures were more likely to have cortical tumors and less likely to have tumors of the posterior fossa (P0.001). Children who underwent gross total resection were less likely to have epilepsy (P0.001).We show a high incidence of epilepsy in the late course of pediatric brain tumor disease. In the long term, seizure outcome was excellent. However, postsurgical onset of epilepsy was associated with a less favorable neurologic outcome.

Epilepsy is a neurological disease with variable etiology and clinical manifestation, affecting more than 50 million people worldwide. Although the ultimate precipitators of seizures are neurons, it is becoming evident that epileptic activity is associated with changes in the function of other cell types, including those consisting the blood-brain barrier (BBB) and regulating its permeability. The interrelationships between impaired BBB function and epilepsy are complex, as BBB dysfunction may both lead to seizures and be induced by epileptic activity. In this article, we review alterations in key BBB properties that have been found in patients with epilepsy and in animal models of the disease. We highlight emerging biomarkers for individualized treatment, implications for pharmacotherapy, and potential BBB-related targets for drug development.

The human leukocyte antigen (HLA) alleles B*15:02 and A*31:01 have been identified as predictive markers of adverse cutaneous effects of carbamazepine and phenytoin in Asian and North European populations, respectively. Our aim was to estimate the distribution of these alleles in Jewish and Arab populations in Israel. The HLA-B*15:02 and HLA-A*31:01 carrier rate was estimated based on data from the Hadassah Bone Marrow Registry. Data on Stevens-Johnson syndrome (SJS)- and toxic epidermal necrolysis (TEN)-related hospitalizations were obtained from the Israeli Ministry of Health (MOH) registries and from four Israeli medical centers. Of 83,705 Jewish and Arab-Muslim donors, 81 individuals of known origin carried the HLA-B*15:02. Among them, 66 were Jews of India-Cochin descent. Of the Cochin Jewish donors, 12.7% were B*15:02 carriers. HLA-A*31:01 carrier incidence among Arab and Jewish Israeli populations (3.5% and 2.2%, respectively) was within the range reported in other countries. We did not identify SJS- or TEN-related hospitalizations of Jews of Indian descent. Yet, this population should be considered at greater risk for antiepileptic drug-induced SJS and TEN. Until further data on actual risk are available, such patients should be typed for HLA-B before treatment with carbamazepine or phenytoin.

Objective: To analyze the clinical syndromes and inheritance patterns of multiplex families with epilepsy toward the ultimate aim of uncovering the underlying molecular genetic basis. Methods: Following the referral of families with 2 or more relatives with epilepsy, individuals were classified into epilepsy syndromes. Families were classified into syndromes where at least 2 family members had a specific diagnosis. Pedigrees were analyzed and molecular genetic studies were performed as appropriate. Results: A total of 211 families were ascertained over an 11-year period in Israel. A total of 169 were classified into broad familial epilepsy syndrome groups: 61 generalized, 22 focal, 24 febrile seizure syndromes, 33 special syndromes, and 29 mixed. A total of 42 families remained unclassified. Pathogenic variants were identified in 49/211 families (23%). The majority were found in established epilepsy genes (e.g., SCN1A , KCNQ2 , CSTB ), but in 11 families, this cohort contributed to the initial discovery (e.g., KCNT1 , PCDH19 , TBC1D24 ). We expand the phenotypic spectrum of established epilepsy genes by reporting a familial LAMC3 homozygous variant, where the predominant phenotype was epilepsy with myoclonic-atonic seizures, and a pathogenic SCN1A variant in a family where in 5 siblings the phenotype was broadly consistent with Dravet syndrome, a disorder that usually occurs sporadically. Conclusion: A total of 80% of families were successfully classified, with pathogenic variants identified in 23%. The successful characterization of familial electroclinical and inheritance patterns has highlighted the value of studying multiplex families and their contribution towards uncovering the genetic basis of the epilepsies.

Extracellular zinc can induce numerous acute and persistent physiological and toxic effects in neurons by acting at their plasma membrane or intracellularly following permeation or uptake into them. Zinc acutely and reversibly blocks T-type voltage-gated calcium current (I(CaT)), but the long-term effect of zinc on this current has not been studied. Because chemically induced status epilepticus (SE) results in the release of zinc into the extracellular space, as well as in a long-lasting increase in I(CaT) in CA1 pyramidal cells, we hypothesized that zinc may play a causative role in I(CaT) upregulation. We tested this hypothesis by monitoring for 18 days the effects of zinc and ibotenic acid (a neurotoxic agent serving as control for zinc), injected into the right lateral ventricle, on I(CaT) in rat CA1 pyramidal cells. Both zinc and ibotenic acid caused marked hippocampal lesions on the side of injection, but only minor damage to contralateral hippocampi. Zinc, but not ibotenic acid, caused upregulation of a nickel-sensitive I(CaT) in a subset of contralateral CA1 pyramidal cells, appearing 2 days after injection and lasting for about 2 weeks thereafter. In contrast, acute application of zinc to CA1 pyramidal cells promptly blocked I(CaT). These data indicate that extracellular zinc has a dual effect on I(CaT), blocking it acutely while causing its long-term upregulation. Through the latter effect, zinc may regulate the intrinsic excitability of principal neurons, particularly in pathological conditions associated with enhanced release of zinc, such as SE.

SUMMARY Purpose: Ictal video‐electroencephalography (EEG) is commonly used to establish ictal onset-zone location. Recently software development has enabled systematic studies of ictal magnetoencephalography (MEG). In this article, we evaluate the ability of ictal MEG signals tolocalize the seizure-onset zone. Methods: Twenty-six patients underwent ictal MEG and epilepsy surgery. Prediction of seizure-onset zone by ictal and interictal MEG was retrospectively compared with ictal-onset area found by intracranial EEG in 12 patients. The specificity and sensitivity of the prediction were calculated at hemisphere-lobe (HL) and at hemisphere-lobesurface (HLS) levels. Key Findings: The sensitivity of ictal MEG source localization was 0.958 on HL and 0.706 on HLS levels, and its specificity was 0.900 on HL and 0.731 on HLS levels. The interictal MEG dipole cluster, defined as >10 dipoles on one lobar surface, had sensitivity of 0.400 and specificity of 0.769. Ictal MEG was equally sensitive and specific on dorsolateral and nondorsolateral neocortical surfaces up to a depth of 4 cm from the scalp. Significance: Sources of ictal-onset MEG signals and interictal dipole clusters are essentially equally specific in estimation of the ictal-onset zone on lobar surface resolution, but ictal MEG is more sensitive. On the lobe resolution, ictal MEG estimates ictal-onset zone with high sensitivity

Postictal headache (PIH) is defined by the International Classification of Headache Disorders as "headache with features of tension-type headache or, in a patient with migraine, of migraine headache, which develops within 3 hours following a partial or generalized seizure and resolves within 72 hours after the seizure." PIHs are prevalent, moderate to severe in intensity, last many hours, and frequently have characteristics of migraine. Young adults with a history of interictal headaches are at increased risk of developing PIH. Young age at onset and long duration of epilepsy, drug-resistant seizures, generalized tonic-clonic seizures, and possibly an occipital epileptic focus are additional risk factors. Although PIH is estimated to have a significant impact on the quality of life of people with epilepsy, it is frequently undertreated. Simple analgesics may prove beneficial. Epilepsy and headache share common pathophysiological mechanisms, as suggested by clinical and investigational findings, although the exact processes underlying these conditions are still largely unknown.

Paroxysmal exercise-induced dyskinesia (PED) and epilepsy without intellectual disability have recently been recognized as manifestations of deficiency of the glucose transporter GLUT1, due to mutations in the gene SLC2A1. We describe a family with six definitely affected members in two generations. Two had PED, three had epilepsy, and one had both. A missense mutation in SLC2A1 (c.950A>C; p.N317T) was detected in five living affected members, but absent in three nonaffected first-degree members and in one subject believed to be a phenocopy. The clinical picture of mild epilepsy with onset in adolescence or early adulthood plus PED should raise a suspicion of GLUT1 deficiency.