Current challenges in focal epilepsy treatment: An Italian Delphi consensus.

BACKGROUND: Epilepsy, a globally prevalent neurological condition, presents distinct challenges in management, particularly for focal-onset types. This study aimed at addressing the current challenges and perspectives in focal epilepsy management, with focus on the Italian reality. METHODS: Using the Delphi methodology, this research collected and analyzed the level of consensus of a panel of Italian epilepsy experts on key aspects of focal epilepsy care. Areas of focus included patient flow, treatment pathways, controlled versus uncontrolled epilepsy, follow-up protocols, and the relevance of patient-reported outcomes (PROs). This method allowed for a comprehensive assessment of consensus and divergences in clinical opinions and practices. RESULTS: The study achieved consensus on 23 out of 26 statements, with three items failing to reach a consensus. There was strong agreement on the importance of timely intervention, individualized treatment plans, regular follow-ups at Epilepsy Centers, and the role of PROs in clinical practice. In cases of uncontrolled focal epilepsy, there was a clear inclination to pursue alternative treatment options following the failure of two previous therapies. Divergent views were evident on the inclusion of epilepsy surgery in treatment for uncontrolled epilepsy and the routine necessity of EEG evaluations in follow-ups. Other key findings included concerns about the lack of pediatric-specific research limiting current therapeutic options in this patient population, insufficient attention to the transition from pediatric to adult care, and need for improved communication. The results highlighted the complexities in managing epilepsy, with broad consensus on patient care aspects, yet notable divergences in specific treatment and management approaches. CONCLUSION: The study offered valuable insights into the current state and complexities of managing focal-onset epilepsy. It highlighted many deficiencies in the therapeutic pathway of focal-onset epilepsy in the Italian reality, while it also underscored the importance of patient-centric care, the necessity of early and appropriate intervention, and individualized treatment approaches. The findings also called for continued research, policy development, and healthcare system improvements to enhance epilepsy management, highlighting the ongoing need for tailored healthcare solutions in this evolving field.

Use, experience and perspectives of high-density EEG among Italian epilepsy centers: a national survey.

INTRODUCTION: High-density EEG (hdEEG) is a validated tool in presurgical evaluation of people with epilepsy. The aim of this national survey is to estimate diffusion and knowledge of hdEEG to develop a network among Italian epilepsy centers. METHODS: A survey of 16 items (and 15 additional items) was distributed nationwide by email to all members of the Italian League Against Epilepsy and the Italian Society of Clinical Neurophysiology. The data obtained were analyzed using descriptive statistics. RESULTS: A total of 104 respondents were collected from 85 centers, 82% from the Centre-North of Italy; 27% of the respondents had a hdEEG. The main applications were for epileptogenic focus characterization in the pre-surgical evaluation (35%), biomarker research (35%) and scientific activity (30%). The greatest obstacles to hdEEG were economic resources (35%), acquisition of dedicated personnel (30%) and finding expertise (17%). Dissemination was limited by difficulties in finding expertise and dedicated personnel (74%) more than buying devices (9%); 43% of the respondents have already published hdEEG data, and 91% of centers were available to participate in multicenter hdEEG studies, helping in both pre-processing and analysis. Eighty-nine percent of respondents would be interested in referring patients to centers with established experience for clinical and research purposes. CONCLUSIONS: In Italy, hdEEG is mainly used in third-level epilepsy centers for research and clinical purposes. HdEEG diffusion is limited not only by costs but also by lack of trained personnel. Italian centers demonstrated a high interest in educational initiatives on hdEEG as well as in clinical and research collaborations.

Adjunctive brivaracetam and sustained seizure frequency reduction in very active focal epilepsy.

OBJECTIVE: This study aimed to explore the effectiveness of brivaracetam (BRV) according to baseline seizure frequency and past treatment history in subjects with focal epilepsy who were included in the Brivaracetam Add-On First Italian Network Study (BRIVAFIRST). METHODS: BRIVAFIRST was a 12-month retrospective, multicenter study including adults prescribed adjunctive BRV. Study outcomes included sustained seizure response (SSR), sustained seizure freedom (SSF), and the rates of treatment discontinuation and adverse events (AEs). Baseline seizure frequency was stratified as <5, 5-20, and >20 seizures per month, and the number of prior antiseizure medications (ASMs) as <5 and ≥6. RESULTS: A total of 994 participants were included. During the 1-year study period, SSR was reached by 45.8%, 39.3%, and 22.6% of subjects with a baseline frequency of <5, 5-20, and >20 seizures per month (p < .001); the corresponding figures for the SSF were 23.4%, 9.8%, and 2.8% (p < .001). SSR was reached by 51.2% and 26.5% participants with a history of 1-5 and ≥6 ASMs (p < .001); the corresponding rates of SSF were 24.7% and 4.5% (p < .001). Treatment discontinuation due to lack of efficacy was more common in participants with >20 seizures compared to those with <5 seizures per month (25.8% vs. 9.3%, p < .001), and in participants with history of ≥6 prior ASMs compared to those with history of 1-5 ASMs (19.6% vs. 12.2%, p = .002). There were no differences in the rates of BRV withdrawal due to AEs and the rates of AEs across the groups of participants defined according to the number of seizures at baseline and the number of prior ASMs. SIGNIFICANCE: The baseline seizure frequency and the number of previous ASMs were predictors of sustained seizure frequency reduction with adjunctive BRV in subjects with focal epilepsy.

Sustained seizure freedom with adjunctive brivaracetam in patients with focal onset seizures.

The maintenance of seizure control over time is a clinical priority in patients with epilepsy. The aim of this study was to assess the sustained seizure frequency reduction with adjunctive brivaracetam (BRV) in real-world practice. Patients with focal epilepsy prescribed add-on BRV were identified. Study outcomes included sustained seizure freedom and sustained seizure response, defined as a 100% and a ≥50% reduction in baseline seizure frequency that continued without interruption and without BRV withdrawal through the 12-month follow-up. Nine hundred ninety-four patients with a median age of 45 (interquartile range = 32-56) years were included. During the 1-year study period, sustained seizure freedom was achieved by 142 (14.3%) patients, of whom 72 (50.7%) were seizure-free from Day 1 of BRV treatment. Sustained seizure freedom was maintained for ≥6, ≥9, and 12 months by 14.3%, 11.9%, and 7.2% of patients from the study cohort. Sustained seizure response was reached by 383 (38.5%) patients; 236 of 383 (61.6%) achieved sustained ≥50% reduction in seizure frequency by Day 1, 94 of 383 (24.5%) by Month 4, and 53 of 383 (13.8%) by Month 7 up to Month 12. Adjunctive BRV was associated with sustained seizure frequency reduction from the first day of treatment in a subset of patients with uncontrolled focal epilepsy.

Levetiracetam Modulates EEG Microstates in Temporal Lobe Epilepsy.

To determine the effects of Levetiracetam (LEV) therapy using EEG microstates analysis in a population of newly diagnosed Temporal Lobe Epilepsy (TLE) patients. We hypothesized that the impact of LEV therapy on the electrical activity of the brain can be globally explored using EEG microstates. Twenty-seven patients with TLE were examined. We performed resting-state microstate EEG analysis and compared microstate metrics between the EEG performed at baseline (EEGpre) and after 3 months of LEV therapy (EEGpost). The microstates A, B, C and D emerged as the most stable. LEV induced a reduction of microstate B and D mean duration and occurrence per second (p < 0.01). Additionally, LEV treatment increased the directional predominance of microstate A to C and microstate B to D (p = 0.01). LEV treatment induces a modulation of resting-state EEG microstates in newly diagnosed TLE patients. Microstates analysis has the potential to identify a neurophysiological indicator of LEV therapeutic activity. This study of EEG microstates in people with epilepsy opens an interesting path to identify potential LEV activity biomarkers that may involve increased neuronal inhibition of the epileptic network.

Unmet needs and perspectives in management of drug resistant focal epilepsy: An Italian study.

This study aimed to evaluate the consensus level between a representative group of Italian neurologists and people with Drug-Resistant Epilepsy (DRE) regarding a series of statements about different aspects involved in the management of epilepsy to identify the unmet needs of the People with Epilepsy (PwE) and the future perspectives for the management of this disease. This observational study was conducted using a classic Delphi technique. A 19-statement questionnaire was administered anonymously through an online platform to a panel of expert clinicians and a panel of PwE, analyzing three main topics of interest: drug resistance, access to care, and PwE's experience. The consensus was achieved on 8 of the 19 statements administered to the panel of medical experts and on 4 of the 14 submitted to the panel of PwE, particularly on the definition of DRE and its consequences on treatment, Quality of Life (QoL), and autonomy of PwE. Most of the items, however, did not reach a consensus and highlighted the lack of a shared univocal view on some topics, such as accessibility to care throughout the country and the role of emerging tools such as telemedicine, narrative medicine, and digital devices. In many cases, the two panels expressed different views on the statements. The results outlined many fields of possible intervention, such as the need for educational initiatives targeted at physicians and PwE - for example, regarding telemedicine, digital devices, and narrative medicine - as well as the spread of better knowledge about epilepsy among the general population, in order to reduce epilepsy stigma. Institutions, moreover, could take a cue from this survey to develop facilities aimed at enhancing PwE's autonomy and promoting more equal access to care throughout the country.

De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females.

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.

The management of epilepsy in clinical practice: Do the timing and severity of the disease influence the priorities of patients and the caring physicians? Data from the EPINEEDS study.

OBJECTIVE: The objective of this study was to assess the priorities of patients with epilepsy and their caring physicians with reference to the timing and severity of the disease. METHODS: This is a national survey in which patients with epilepsy followed in 21 Italian epilepsy centers, and their caring physicians were asked to fill anonymous questionnaires to collect data on different aspects of the disease and their needs and priorities in its management. The collected information included demographics, clinical profile and diagnosis, treatment and outcome of epilepsy. The questions were designed to understand the expectations of the patients and their caring physicians and verify the degree of concordance between patient and doctor. The study population was divided in six prognostic categories: (1) Newly diagnosed epilepsy; (2) Absence of seizures for at least 2 years; (3) Absence of seizures for at least 1 year or occasional seizures; (4) Nondrug-resistant recurrent seizures; (5) drug-resistant seizures; (6) surgical candidate. RESULTS: Of the 787 patients enrolled, 432 were women and 355 men aged 15 to 88 years (median 41 years). Disease duration ranged from 6 months to 75 years. The sample included 53 patients with newly diagnosed epilepsy, 283 without seizures for at least 2 years, 162 seizure-free for at least 1 year or with occasional seizures, 123 with nondrug-resistant recurrent seizures, 128 with drug-resistant seizures, and 38 surgical candidates. Significant differences were found between patients and physicians in terms of priorities and needs with reference to the management of the disease. While physicians tend to prioritize the information on the diagnosis and treatment of epilepsy depending on timing and severity, patients focus on the search of the cause, the side effects of drugs, and the effects of any new treatment on the control of seizures regardless of the prognostic category. In addition, physicians tend to undervalue the communication of specific information, like the risk of sudden unexpected death in epilepsy (SUDEP) or the existence of lay associations, which might be of special interest for selected categories of patients. SIGNIFICANCE: Differences between patients with epilepsy and their caring physicians in terms of needs and priorities and suboptimal communication call for the implementation of programs aimed at addressing the factors deemed most relevant by patients and caregivers for the management of the disease.

Appropriate use of generic and branded antiseizure medications in epilepsy: Updated recommendations from the Italian League Against Epilepsy (LICE).

Generic drugs are increasingly used to treat many diseases including epilepsy. The growing importance of generic antiseizure medications (ASMs) has led the ASMs commission of the Italian League Against Epilepsy (LICE) to review current evidence in the literature about efficacy and safety of these products. Recommendations from other scientific organizations have also been considered to provide an update of the LICE position about their utilization (List of Recommendations). Compared with the previous literature review, randomized controlled trials assessing bioequivalence among branded drugs and generics are currently available. Although some contrasting results have been reported, brand-to-generic switching was effective and tolerable in real-life settings, with similar adverse event ratios. Based on these findings, LICE concluded that, conforming to the rigorous regulation of USA and EU markets, generic ASMs are not inferior to the respective branded, providing a cost advantage for patients starting or replacing monotherapy or add-on, and for those with incomplete seizure control. Branded-to-generic (and vice versa) switching is not recommended (although applicable) during seizure remission, as well as the generic-to-other generic switching. Other recommendations focus on the appropriateness of therapeutic drug monitoring (TDM) when switching is required, paying attention to avoiding the erroneous switch between modified and immediate-release formulations during dispensation. Finally, to support patients' compliance, they should be assured of generics' safety and efficacy and carefully informed with practical advice, particularly when the switching is associated with aspect modifications (e.g. color and shape changes) of the pill or the packaging.

Digital narrative medicine for the personalization of epilepsy care pathways.

Among neurological conditions, epilepsy is the disorder best suited to a narrative approach. In epilepsy, the disease, i.e., the condition from the clinical and therapeutic point of view, the illness, the personal experience and impact of the condition, and the sickness, the representations, and social imaginary of epilepsy, are strongly interdependent. Within this context, the Italian League Against Epilepsy (LICE) has launched a multiyear narrative program in Italy resulting in the foundation of a specific Study Group on Narrative Medicine in Epileptology. The Epimena Study is part of this program and involves the "Epilepsy Center, Department of Human Neurosciences, Sapienza University of Rome and Umberto 1° Hospital". The study consists of a pilot project whose aim is to assess the usefulness and feasibility of integrating narrative medicine methodologies into routine clinical practice through a digital platform. The carrying out of the study is based on the acquisition of narrative elements of the patient that the referring doctor uses, integrating them with clinical data, to share and customize the diagnostic-therapeutic pathway of patients. The Epimena Study preliminary results look encouraging. Over 12 months, 57% of the invited patients (37 out of a total of 65) decided to formalize their registration in the digital diary, and 46% responded to one or more narrative prompt generating the story of their experience. Every patient story was then analyzed according to a methodology (Illness Digital StoryMap - IDS) that made it possible to detect the existential impact of the disease and the perception of care. Patients' overall judgment on the project was positive. Through it, they were able to better focus on themselves, bringing out and communicating information to the physician that otherwise would not have been taken into consideration. The majority of patients involved believe that the methodology should be included in the regular clinical practice or in any case would like to continue using it. The data collected confirmed that the time spent on story sharing contributed objectively to a clinical practice of greater quality and effectiveness.

The management of epilepsy in clinical practice: Do the needs manifested by the patients correspond to the priorities of the caring physicians? Findings from the EPINEEDS Study.

PURPOSE: The purpose of this study was to assess the priorities of patients with epilepsy and caring physicians and the correspondence between these priorities. METHODS: In this multicenter cross-sectional study, patients with epilepsy attending 21 Italian epilepsy centers and their caring physicians filled anonymously questionnaires on the needs and priorities in the management of the disease. Included were questions on patients' demographics, diagnosis, treatment, and outcome of epilepsy. The concordance between patients and their physicians was assessed on various aspects of the diagnosis and care of the disease. Patients' satisfaction with communication, services, and patient-doctor relationship was also assessed. RESULTS: Included were 432 women and 355 men aged 15 to 88 years (median: 41 years). Disease duration ranged from 6 months to 75 years. A structural/metabolic etiology predominated (52.7%), followed by a (presumed) genetic etiology (33.0%). Seizure remission was present in 56.5% of cases. Comorbidities requiring chronic treatment were present in 27.5%, and comorbidities affecting self-sufficiency in 9.5%. Psychiatric comorbidity was present in 35.0%. Patients' priorities included discovery of the cause (89.1%), use of right drug (98.7%), use of a drug without chronic side effects (94.0%), and a life without restrictions (90.4%). Physicians' priorities included choice of right drug (83.5%) and use of drugs without chronic side effects (86.8%). Priorities varied with patients' age, sex, education, and occupation. Patient-doctor relationships were at least good in most cases. The information imparted was considered unsatisfactory by 21-44% of cases on seizure circumstances and complications, side effects of drugs, limitations of daily activities, and management of physiologic or pathologic conditions. Patients declared overall satisfaction, except for appointments (21.5%) and emergencies (30.8%). CONCLUSION: Patients and physicians' priorities in the management of epilepsy overlap only in part. Patients are satisfied with their caring physicians and less satisfied with communication and management of routine and emergency problems.

Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy.

Since the publication of the Italian League Against Epilepsy guidelines for the treatment of status epilepticus in 2006, advances in the field have ushered in improvements in the therapeutic arsenal. The present position paper provides neurologists, epileptologists, neurointensive care specialists, and emergency physicians with updated recommendations for the treatment of adult patients with status epilepticus. The aim is to standardize treatment recommendations in the care of this patient population.

Electroencephalography during SARS-CoV-2 outbreak: practical recommendations from the task force of the Italian Society of Neurophysiology (SINC), the Italian League Against Epilepsy (LICE), and the Italian Association of Neurophysiology Technologists (AITN).

BACKGROUND: During COVID-19 lockdown, non-urgent medical procedures were suspended. Grade of urgency of electroencephalography (EEG) may vary according to the clinical indication, setting, and status of infection of SARS-CoV-2 virus. "Italian Society of Clinical Neurophysiology" (SINC), "Italian League Against Epilepsy" (LICE), and the "Italian Association of Neurophysiology Technologists" (AITN) aimed to provide clinical and technical recommendation for EEG indications and recording standards in this pandemic era. METHODS: Presidents of SINC, LICE, and AITN endorsed three members per each society to formulate recommendations: classification of the degree of urgency of EEG clinical indications, management and behavior of physicians and neurophysiology technologists, hygiene and personal protection standards, and use of technical equipment. RESULTS: Scientific societies endorsed a paper conveying the recommendation for EEG execution in accordance with clinical urgency, setting (inpatients/outpatients), status of SARS-CoV-2 virus infection (positive, negative and uncertain), and phase of governmental restrictions (phase 1 and 2). Briefly, in phase 1, EEG was recommended only for those acute/subacute neurological symptoms where EEG is necessary for diagnosis, prognosis, or therapy. Outpatient examinations should be avoided in phase 1, while they should be recommended in urgent cases in phase 2 when they could prevent an emergency room access. Reduction of staff contacts must be encouraged through rescheduling job shifts. The use of disposable electrodes and dedicated EEG devices for COVID-19-positive patients are recommended. CONCLUSIONS: During the different phases of COVID-19 pandemic, the EEG should be reserved for patients really benefiting from its execution in terms of diagnosis, treatment, prognosis, and avoidance of emergency room access.

Electroencephalography at the time of Covid-19 pandemic in Italy.

OBJECTIVE: During the Covid-19 pandemic, government restrictions limited health care to urgent needs. Neurophysiology centers had to suddenly reschedule their activities, with a lack of specific recommendations about electroencephalography (EEG) execution. During the pandemic phase 1, we launched an online survey to understand the flaws and strengths of the EEG management in Italy at the time of Covid-19 pandemic. METHODS: A 45-item online survey (published from April 16 to 30, 2020), endorsed by the Italian Society of Clinical Neurophysiology (SINC), the Italian League Against epilepsy (LICE), and the Italian Association of Neurophysiology technologists (AITN), collected EEG management data (EEG's number and type, indications, personnel and patients safety, devices' sanification) during the Covid-19 pandemic. RESULTS: We received responses from 206 centers. The number of EEGs performed was reduced by 76 ± 20%, and several types of specific EEG (video-EEG, ambulatory-EEG, LTM, polysomnography) were reduced at a minimum. Half of the centers performed inpatient EEGs only for urgencies. Repetitive seizures, encephalitis, and non-convulsive status epilepticus were the most common indications. Covid-19-positive patients received less EEG than negative ones (p < 0.0001). EEG requests came mainly not only from neurologists (n = 176) but also from general practitioners (n = 40), emergentists (n = 79), intensivists (n = 72), and other specialists (n = 53). Those centers which continued performing outpatient EEG examinations were instructed to perform the EEG after a Covid-19-related symptom screening for patients and using personal protective equipment (PPE) through all the procedure. Inpatient EEGs were performed using FFP2/FFP3 masks by neurophysiology technologists in only 50% of cases. Patients executed hyperventilation only for real clinical needs, but often (56%) with a mask. CONCLUSIONS: Italian neurophysiology centers strongly adhered to government restrictions of lockdown. Some issues emerged, ranging from the evaluation of a proper indication for EEG, technical procedures of EEG recording, and protection of neurophysiology technicians.

Validated outcome of treatment changes according to International League Against Epilepsy criteria in adults with drug-resistant focal epilepsy.

OBJECTIVE: Although many studies have attempted to describe treatment outcomes in patients with drug-resistant epilepsy, results are often limited by the adoption of nonhomogeneous criteria and different definitions of seizure freedom. We sought to evaluate treatment outcomes with a newly administered antiepileptic drug (AED) in a large population of adults with drug-resistant focal epilepsy according to the International League Against Epilepsy (ILAE) outcome criteria. METHODS: This is a multicenter, observational, prospective study of 1053 patients with focal epilepsy diagnosed as drug-resistant by the investigators. Patients were assessed at baseline and 6, 12, and 18 months, for up to a maximum of 34 months after introducing another AED into their treatment regimen. Drug resistance status and treatment outcomes were rated according to ILAE criteria by the investigators and by at least two independent members of an external expert panel (EP). RESULTS: A seizure-free outcome after a newly administered AED according to ILAE criteria ranged from 11.8% after two failed drugs to 2.6% for more than six failures. Significantly fewer patients were rated by the EP as having a "treatment failure" as compared to the judgment of the investigator (46.7% vs 62.9%, P < 0.001), because many more patients were rated as "undetermined outcome" (45.6% vs 27.7%, P < 0.001); 19.3% of the recruited patients were not considered drug-resistant by the EP. SIGNIFICANCE: This study validates the use of ILAE treatment outcome criteria in a real-life setting, providing validated estimates of seizure freedom in patients with drug-resistant focal epilepsy in relation to the number of previously failed AEDs. Fewer than one in 10 patients achieved seizure freedom on a newly introduced AED over the study period. Pseudo drug resistance could be identified in one of five cases.

Online behavior of people visiting a scientific website on epilepsy.

We investigated the online behavior of Internet users consulting the website of the Italian Chapter of the International League Against Epilepsy (Lega Italiana Contro l'Epilessia [LICE]). We obtained the visualization statistics of the LICE website using AWStats (https://awstats.sourceforge.io/) and Google Trends (https://trends.google.com/trends/), and compared the statistics of years 2010, 2014, and 2017. The following variables were analyzed: number of unique visitors and visits, visit duration, the day of week and rush hours, most downloaded documents, most viewed pages, keyphrases and keywords used for online searches, origins of searches, and geographic trends of Google searches related to the LICE. The total numbers of unique visitors, visits and page views remained quite stable over time. Most visits (70 to 76.7%) lasted less than 30 s. The most frequent keyphrases and keywords used for online searches were related to clinical guidelines and driving license. Among the most frequently downloaded documents were general guides on epilepsy. The pages with the list of epilepsy centers endorsed by the LICE and those with the list of LICE guidelines were among those most frequently viewed, together with educational videos. Most users directly accessed the website without being referred from external links. No information on geographic origin of Google searches was available. The visualization statistics suggested two distinct populations of visitors. The first one is likely represented by physicians who seek specialist information on diagnosis and management of epilepsy, including guidelines. The second population is represented by lay people who seek accessible and easily comprehensible information to better understand epilepsy and know which centers are best for its management.

Management of epilepsy in brain tumors.

Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.

Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.

Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.

Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.

GAT-1, encoded by SLC6A1, is one of the major gamma-aminobutyric acid (GABA) transporters in the brain and is responsible for re-uptake of GABA from the synapse. In this study, targeted resequencing of 644 individuals with epileptic encephalopathies led to the identification of six SLC6A1 mutations in seven individuals, all of whom have epilepsy with myoclonic-atonic seizures (MAE). We describe two truncations and four missense alterations, all of which most likely lead to loss of function of GAT-1 and thus reduced GABA re-uptake from the synapse. These individuals share many of the electrophysiological properties of Gat1-deficient mice, including spontaneous spike-wave discharges. Overall, pathogenic mutations occurred in 6/160 individuals with MAE, accounting for ~4% of unsolved MAE cases.

Defining the phenotypic spectrum of SLC6A1 mutations.

OBJECTIVE: Pathogenic SLC6A1 variants were recently described in patients with myoclonic atonic epilepsy (MAE) and intellectual disability (ID). We set out to define the phenotypic spectrum in a larger cohort of SCL6A1-mutated patients. METHODS: We collected 24 SLC6A1 probands and 6 affected family members. Four previously published cases were included for further electroclinical description. In total, we reviewed the electroclinical data of 34 subjects. RESULTS: Cognitive development was impaired in 33/34 (97%) subjects; 28/34 had mild to moderate ID, with language impairment being the most common feature. Epilepsy was diagnosed in 31/34 cases with mean onset at 3.7 years. Cognitive assessment before epilepsy onset was available in 24/31 subjects and was normal in 25% (6/24), and consistent with mild ID in 46% (11/24) or moderate ID in 17% (4/24). Two patients had speech delay only, and 1 had severe ID. After epilepsy onset, cognition deteriorated in 46% (11/24) of cases. The most common seizure types were absence, myoclonic, and atonic seizures. Sixteen cases fulfilled the diagnostic criteria for MAE. Seven further patients had different forms of generalized epilepsy and 2 had focal epilepsy. Twenty of 31 patients became seizure-free, with valproic acid being the most effective drug. There was no clear-cut correlation between seizure control and cognitive outcome. Electroencephalography (EEG) findings were available in 27/31 patients showing irregular bursts of diffuse 2.5-3.5 Hz spikes/polyspikes-and-slow waves in 25/31. Two patients developed an EEG pattern resembling electrical status epilepticus during sleep. Ataxia was observed in 7/34 cases. We describe 7 truncating and 18 missense variants, including 4 recurrent variants (Gly232Val, Ala288Val, Val342Met, and Gly362Arg). SIGNIFICANCE: Most patients carrying pathogenic SLC6A1 variants have an MAE phenotype with language delay and mild/moderate ID before epilepsy onset. However, ID alone or associated with focal epilepsy can also be observed.