Faculty Bibliography

Objective: Evaluate ability of inhaled alprazolam to rapidly suppress photosensitivity in a double blind placebo- controlled crossover proof of concept study. Background: Alprazolam formulated as an inhaled preparation (Staccato Alprazolam) could represent a rapidly effective rescue medication for epilepsy patients. Time to effect can be assessed in patients with photosensitive epilepsy, in whom epileptiform activity can be elicited at will. Design/Methods: Patients >= 18 y.o with photosensitive epilepsy at 3 sites were tested on a baseline day, and then received in randomized order either inhaled placebo (on 2 days) or .5, 1 or 2 mg inhaled alprazolam delivered using a hand-held Staccato device. Study days were separated by at least 1 week. Presence (and degree) of photosensitivity was measured predose, then at 2 min, 10 min, 30 min, 1, 2, 4 and 6 hours post-dose. Plasma concentration of study drug was measured at each time point. Sedation was assessed at each time point using the 100-mm linear visual analogue scale (VAS). Results: Five patients were enrolled and completed all treatment arms. All doses decreased the mean standardized photosensitivity range (SPR), with maximal or near-maximal effect occurring by 2 minutes post dose. Higher doses produced effects on SPR out to 4 hours. Sedation was dose related, but separated from SPR effects at later timepoints. Treatment was well tolerated with no serious adverse events. Conclusions: Results from this study suggest that inhaled alprazolam strongly suppresses epileptiform activity within 2 minutes. Duration of effect was dose related, as was sedation. This data supports the possibility that inhaled Alprazolam might have utility in stopping a seizure within 2 minutes of use

Objective: Evaluate efficacy associated with LGS. of CBD added to antiepileptic drug (AED) therapy for the treatment of seizures Background: Multiple data streams suggest that CBD may be an effective antiepileptic treatment; however, class 1 evidence supporting its use is lacking. Here we present the first controlled trial of CBD in LGS. Design/Methods: Eligible patients were 2-55 years old and had a clinical diagnosis of LGS, >=2 drop seizures each week during baseline, and documented failures on >=1 AED. Patients were randomized (1:1) to receive 20 mg/kg/day CBD (oral solution) or matched placebo, for 14 weeks (2-week titration; 12-week dose maintenance). The primary efficacy endpoint was percentage change from baseline in drop seizure frequency (tonic, atonic, and tonic-clonic) over the entire 14-week treatment period for patients on CBD vs placebo. Results: 171 patients were randomized (86 CBD; 85 placebo); 14 CBD and 1 placebo patient withdrew early. Demographic and baseline characteristics were evenly distributed between groups; mean age was 15 years (34% of patients >18 years) and median drop seizure frequency was 74/month. Patients had previously taken a median of 6 AEDs, and were taking a median of 3 concomitant AEDs throughout the trial. CBD resulted in a significantly greater median percent reduction in monthly drop seizure frequency, versus placebo (44% vs. 22%; p=0.0135). The treatment difference was established during the first 4 weeks of the maintenance period. 86% of CBD and 69% of placebo patients had adverse events (AEs); the most common were diarrhea, somnolence, pyrexia, decreased appetite, and vomiting. Treatment-related serious AEs were reported in 9 CBD patients and 1 placebo patient. There was 1 death (CBD), considered unrelated to treatment. Conclusions: Results from this trial suggest that CBD add-on therapy for the treatment of drop seizures associated with LGS may be efficacious and generally well-tolerated

OBJECTIVE: To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified. METHODS: Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus. RESULTS: Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0-17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16-0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64-2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence). RECOMMENDATIONS: Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.

OBJECTIVE: Presently, there is no simple method at initial presentation for identifying a patient's likelihood of progressing to surgery and a favorable outcome. The Epilepsy Surgery Grading Scale (ESGS) is a three-tier empirically derived mathematical scale with five categories: magnetic resonance imaging (MRI), electroencephalography (EEG), concordance (between MRI and EEG), semiology, and IQ designed to stratify patients with drug-resistant focal epilepsy based on their likelihood of proceeding to resective epilepsy surgery and achieving seizure freedom. METHODS: In this cross-sectional study, we abstracted data from the charts of all patients admitted to the New York University Langone Medical Center (NYULMC) for presurgical evaluation or presented in surgical multidisciplinary conference (MDC) at the NYU Comprehensive Epilepsy Center (CEC) from 1/1/2007 to 7/31/2008 with focal epilepsy, who met minimal criteria for treatment resistance. We classified patients into ESGS Grade 1 (most favorable), Grade 2 (intermediate), and Grade 3 (least favorable candidates). Three cohorts were evaluated: all patients, patients presented in MDC, and patients who had resective surgery. The primary outcome measure was proceeding to surgery and seizure freedom. RESULTS: Four hundred seven patients met eligibility criteria; 200 (49.1%) were presented in MDC and 113 (27.8%) underwent surgery. A significant difference was observed between Grades 1 and 3, Grades 1 and 2, and Grades 2 and 3 for all presurgical patients, and those presented in MDC, with Grade 1 patients having the highest likelihood of both having surgery and becoming seizure-free. There was no difference between Grades 1 and 2 among patients who had resective surgery. SIGNIFICANCE: These results demonstrate that by systematically using basic information available during initial assessment, patients with drug-resistant epilepsy may be successfully stratified into clinically meaningful groups with varied prognosis. The ESGS may improve communication, facilitate decision making and early referral to a CEC, and allow patients and physicians to better manage expectations.

OBJECTIVE: To assess the diagnostic accuracy and prognostic value of functional MRI (fMRI) in determining lateralization and predicting postsurgical language and memory outcomes. METHODS: An 11-member panel evaluated and rated available evidence according to the 2004 American Academy of Neurology process. At least 2 panelists reviewed the full text of 172 articles and selected 37 for data extraction. Case reports, reports with <15 cases, meta-analyses, and editorials were excluded. RESULTS AND RECOMMENDATIONS: The use of fMRI may be considered an option for lateralizing language functions in place of intracarotid amobarbital procedure (IAP) in patients with medial temporal lobe epilepsy (MTLE; Level C), temporal epilepsy in general (Level C), or extratemporal epilepsy (Level C). For patients with temporal neocortical epilepsy or temporal tumors, the evidence is insufficient (Level U). fMRI may be considered to predict postsurgical language deficits after anterior temporal lobe resection (Level C). The use of fMRI may be considered for lateralizing memory functions in place of IAP in patients with MTLE (Level C) but is of unclear utility in other epilepsy types (Level U). fMRI of verbal memory or language encoding should be considered for predicting verbal memory outcome (Level B). fMRI using nonverbal memory encoding may be considered for predicting visuospatial memory outcomes (Level C). Presurgical fMRI could be an adequate alternative to IAP memory testing for predicting verbal memory outcome (Level C). Clinicians should carefully advise patients of the risks and benefits of fMRI vs IAP during discussions concerning choice of specific modality in each case.

This companion paper to the introduction of the International League Against Epilepsy (ILAE) 2017 classification of seizure types provides guidance on how to employ the classification. Illustration of the classification is enacted by tables, a glossary of relevant terms, mapping of old to new terms, suggested abbreviations, and examples. Basic and extended versions of the classification are available, depending on the desired degree of detail. Key signs and symptoms of seizures (semiology) are used as a basis for categories of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can further be optionally characterized by whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it a focal impaired awareness seizure. Focal seizures are further optionally characterized by motor onset signs and symptoms: atonic, automatisms, clonic, epileptic spasms, or hyperkinetic, myoclonic, or tonic activity. Nonmotor-onset seizures can manifest as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which might then progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic. Generalized seizures engage bilateral networks from onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic, or tonic-clonic. Nonmotor (absence) seizures are typical or atypical, or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown onset may have features that can still be classified as motor, nonmotor, tonic-clonic, epileptic spasms, or behavior arrest. This "users' manual" for the ILAE 2017 seizure classification will assist the adoption of the new system.

The International League Against Epilepsy (ILAE) Classification of the Epilepsies has been updated to reflect our gain in understanding of the epilepsies and their underlying mechanisms following the major scientific advances that have taken place since the last ratified classification in 1989. As a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking, yet robust and translatable to all areas of the globe. Its primary purpose is for diagnosis of patients, but it is also critical for epilepsy research, development of antiepileptic therapies, and communication around the world. The new classification originates from a draft document submitted for public comments in 2013, which was revised to incorporate extensive feedback from the international epilepsy community over several rounds of consultation. It presents three levels, starting with seizure type, where it assumes that the patient is having epileptic seizures as defined by the new 2017 ILAE Seizure Classification. After diagnosis of the seizure type, the next step is diagnosis of epilepsy type, including focal epilepsy, generalized epilepsy, combined generalized, and focal epilepsy, and also an unknown epilepsy group. The third level is that of epilepsy syndrome, where a specific syndromic diagnosis can be made. The new classification incorporates etiology along each stage, emphasizing the need to consider etiology at each step of diagnosis, as it often carries significant treatment implications. Etiology is broken into six subgroups, selected because of their potential therapeutic consequences. New terminology is introduced such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limited and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the 21st century.

The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of such a revision is to recognize that some seizure types can have either a focal or generalized onset, to allow classification when the onset is unobserved, to include some missing seizure types, and to adopt more transparent names. Because current knowledge is insufficient to form a scientifically based classification, the 2017 Classification is operational (practical) and based on the 1981 Classification, extended in 2010. Changes include the following: (1) "partial" becomes "focal"; (2) awareness is used as a classifier of focal seizures; (3) the terms dyscognitive, simple partial, complex partial, psychic, and secondarily generalized are eliminated; (4) new focal seizure types include automatisms, behavior arrest, hyperkinetic, autonomic, cognitive, and emotional; (5) atonic, clonic, epileptic spasms, myoclonic, and tonic seizures can be of either focal or generalized onset; (6) focal to bilateral tonic-clonic seizure replaces secondarily generalized seizure; (7) new generalized seizure types are absence with eyelid myoclonia, myoclonic absence, myoclonic-atonic, myoclonic-tonic-clonic; and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change, but allows greater flexibility and transparency in naming seizure types.

Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2.3, 95% CI 1.7-3.2, p=9.1 x 10(-8); familial non acquired focal epilepsy 3.6, 2.7-4.9, p=1.1 x 10(17)). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5.8 x 10(-8)) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection I between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future.

The ILAE Task Force on Classification presents a road map for the development of an updated, relevant classification of the epilepsies. Our objective is to explain the process to date and the plan moving forward as well as to invite further discussion about the newly proposed terms and concepts. Here, we present our response to feedback about the 2010 Organization of the Epilepsies and clarify the reintroduction of the word "classification" to map out a framework for epilepsy diagnosis. We introduce some new concepts and suggest four diagnostic levels: seizure type, epilepsy category, epilepsy syndrome, and epilepsy with (specific) etiology to denote specific levels of diagnosis. We expand the etiological categories to six, focusing on those with treatment implications. Finally, we discuss the changes in terminology originally suggested and modifications in response to comments from the epilepsy community. We welcome feedback and discussion from the global epilepsy community, particularly for the new suggested terms, so that we can cement a classification that both reflects current thinking and scientific understanding and provides a dynamic, evolving framework.