Faculty Bibliography

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. The classification is illustrated by tables, a glossary of relevant terms, a table mapping old to new terms, recommended 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 categorization of seizures that are focal or generalized from onset or with unknown onset. Any focal seizure can be further optionally characterized with respect to whether awareness is retained or impaired. Impaired awareness during any segment of the seizure renders it classified as a focal impaired awareness seizure. Focal seizures can be further optionally characterized by the first motor signs and symptoms as atonic, automatisms, clonic, epileptic spasms, hyperkinetic, myoclonic or tonic activity. Nonmotor onset seizures can be manifested as autonomic, behavior arrest, cognitive, emotional, or sensory dysfunction. The earliest prominent manifestation defines the seizure type, which can then further progress to other signs and symptoms. Focal seizures can become bilateral tonic-clonic seizures. Generalized seizures include an early involvement of bilateral networks from the onset. Generalized motor seizure characteristics comprise atonic, clonic, epileptic spasms, myoclonic, myoclonic-atonic, myoclonic-tonic-clonic, tonic or tonic-clonic manifestations. Nonmotor (absence) seizures are typical or atypical or seizures that present prominent myoclonic activity or eyelid myoclonia. Seizures of unknown origin 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 can assist the acceptance of the new system.

The International League Against Epilepsy (ILAE) presents a revised operational classification of seizure types. The purpose of this revision is to recognize that some seizure types can have either a focal or generalized onset, to enable a classification when the onset is unobserved, to include some missing seizure types and to implement a more transparent and understandable nomenclature. Because current knowledge is insufficient to form a scientifically based classification, the 2017 classification is operational (practical) and based on the 1981 classification with the amendments from 2010. The changes include the following: (1) "partial" becomes "focal"; (2) awareness (disturbance of consciousness) is used as a classification criterion 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) epileptic spasms as well as atonic, clonic, myoclonic and tonic seizures can have a focal or generalized onset, (6) focal (seizure with progression) to (a) 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 seizures and (8) seizures of unknown onset may have features that can still be classified. The new classification does not represent a fundamental change but enables greater flexibility and transparency in naming seizure types.

The International League Against Epilepsy (ILAE) classification of the epilepsies has been updated to reflect the 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 the clinical diagnosis of patients but it is also critical for epilepsy research, development of antiepileptic treatment and communication around the world. The new classification is based on 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 consists of three levels starting with seizure type, where it is assumed that the epileptic seizures of the patient are defined by the new 2017 ILAE seizure classification. After diagnosis of the seizure type, the next step is the diagnosis of the epilepsy type, which includes focal epilepsy, generalized epilepsy, combined generalized and focal epilepsy and also an unclassified epilepsy group. At the third level the disease is assigned to a specific epilepsy syndrome. The new classification incorporates etiology at each stage, emphasizing the need to consider etiology at each step of the diagnosis, as it often carries significant treatment implications. The various etiologies can be assigned to six subgroups, defined with respect to the potential therapeutic consequences. New terminology is introduced, such as developmental and epileptic encephalopathy. The term benign is replaced by the terms self-limiting and pharmacoresponsive, to be used where appropriate. It is hoped that this new framework will assist in improving epilepsy care and research in the twenty-first century.

Common data elements (CDEs) are becoming more common as more areas of preclinical research have generated CDEs. Herein we provide an overview of the progress to date in generating CDEs for preclinical epilepsy research. Currently there are CDEs that have been developed for Physiology (in vivo), Behavior, Pharmacology, and Electroencephalography (EEG). Together the CDEs and methodologic considerations associated with these CDEs are laid out in consecutive manuscripts published in Epilepsia Open, each describing CDEs for their respective topic area. In addition to the overview of progress for the 4 subjects, core characteristics (Core CDEs) are described and explained. Data collection using a case report form (CRF) is described, and considerations that are involved in using the CDEs and CRFs are discussed.

OBJECTIVE:To determine how early lamotrigine clearance (LTG-CL/F) increases during early pregnancy in women with epilepsy and to quantify the relationship of LTG-CL/F to estradiol concentrations and gestational week. METHODS:This was a multicenter, observational study of pregnant women with epilepsy on lamotrigine and no interacting concomitant medications, employing frequent blood sampling prior to and early in pregnancy. A population mixed-effects modeling approach was used to describe the relationship between LTG-CL/F and gestational week and between LTG-CL/F and estradiol. Akaike information criterion (AIC) compared goodness of fit between final models and a generalized estimating equation to compare differences between low and high percentage LTG-CL/F change groups (p < 0.05). RESULTS:Twenty-five pregnancies (22 participants) were available. Increases in LTG-CL/F were present at 5 weeks gestational age. Both estradiol and gestational week were highly correlated with LTG-CL/F changes; LTG-CL/F increased at the rate of 0.115l/h for every gestational week and 0.844l/h for every 1ng/ml of estradiol, with women in the high LTG-CL/F percentage change group changing at a faster rate (p < 0.001). Models using gestational week performed better than models using estradiol. INTERPRETATION/CONCLUSIONS:Gestational week was a better predictor of changes in LTG-CL/F than estradiol concentration and may reflect additional factors, although neither was robust enough to use clinically due to substantial interpatient variability. Changes in LTG-CL/F begin as early as the 5th gestational week, often before women know they are pregnant, emphasizing the importance of planning and early detection of pregnancy and consideration of early implementation of therapeutic drug monitoring. Ann Neurol 2018;84:556-563.

Objective: To update the 2004 American Academy of Neurology (AAN) guideline for treating new-onset focal or generalized epilepsy (GE) with second- and third-generation antiepileptic drugs (AEDs). Methods: The 2004 AAN criteria was used to systematically review literature (January 2003 to November 2015), classify pertinent studies according to the therapeutic rating scheme, and link recommendations to evidence strength. Results: Several second-generation AEDs are effective for new-onset focal epilepsy. Data are lacking on efficacy in new-onset generalized tonic-clonic seizures, juvenile myoclonic epilepsy, or juvenile absence epilepsy, and on efficacy of third-generation AEDs in new-onset epilepsy. Recommendations: Lamotrigine (LTG) should (Level B) and levetiracetam (LEV) and zonisamide (ZNS) may (Level C) be considered in decreasing seizure frequency in adults with new-onset focal epilepsy. LTG should (Level B) and gabapentin (GBP) may (Level C) be considered in decreasing seizure frequency in patients ≥60 years with new-onset focal epilepsy. Unless there are compelling adverse-effect-related concerns, ethosuximide (ETS) or valproic acid (VPA) should be considered before LTG to decrease seizure frequency in treating absence seizures in childhood absence epilepsy (Level B). No high-quality studies suggest clobazam, eslicarbazepine, ezogabine, felbamate, GBP, lacosamide, LEV, LTG, oxcarbazepine, perampanel, pregabalin, rufinamide, tiagabine, topiramate, vigabatrin, or ZNS is effective in treating new-onset epilepsy because no high-quality studies exist in adults of various ages. A recent FDA strategy allows extrapolation of efficacy across populations; therefore, for focal epilepsy, eslicarbazepine and lacosamide (oral only for pediatric use) as add-on or monotherapy in persons ≥4 years old and perampanel as monotherapy received FDA approval.