© 2014 Direct One Communications, Inc. All rights reserved. 1 New Insights into the Basic Mechanisms, Diagnosis, and Staging of Epilepsy Nicole Odom, MD Columbia University Medical Center Comprehensive Epilepsy Center, New York–Presbyterian Medical Center, New York, New York A REPORT FROM THE 67 TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)

© 2014 Direct One Communications, Inc. All rights reserved NINDS Benchmarks for Epilepsy Research National Institute of Neurological Disorders and Stroke (NINDS)

© 2014 Direct One Communications, Inc. All rights reserved. 3 “No seizures, no side effects, and the prevention of epilepsy” are the primary goals of epileptologists.” These goals are important because they raise awareness of priorities across the epilepsy community. Benchmark III—improving treatment options for controlling seizures and epilepsy-related conditions without side effects—is the impetus driving research in the three areas discussed in the remainder of this presentation NINDS Benchmarks for Epilepsy Research National Institute of Neurological Disorders and Stroke (NINDS)

© 2014 Direct One Communications, Inc. All rights reserved. 4 Staging and Translational Aspects of Animal Models of Epilepsy The concept of staging epilepsy is a hypothetical construct stemming from its similarities to cancer research. Epilepsy syndromes, similar to different types of cancer, have significant heterogeneity yet often possess common signaling pathways and capacity for disease modification. One advantage of this model is that it may allow for a more accurate assessment of whether the disease has been altered. Based on a presentation by Frances Jensen, MD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 5 Staging and Translational Aspects of Animal Models of Epilepsy To successfully stage epilepsy, certain essential elements need to be clearly defined and harmonized, such as common data elements and biomarkers. Biomarkers rely on indirect histopathology associated with common data elements. Common data elements must therefore be synchronized and calibrated. A recent example of translational research aligning common data elements and biomarkers is the identification of MRI imaging of glutamate (GluCEST). Cai K et al. Nat Med. 2012;18:302

© 2014 Direct One Communications, Inc. All rights reserved. 6 Staging and Translational Aspects of Animal Models of Epilepsy The staging of epilepsy should encompass pre- epilepsy to drug-resistant epilepsy. Secondary staging, including comorbidities, also may prove useful. Based on a presentation by Frances Jensen, MD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 7 Clinical Issues and Seizure Severity The severity of seizures differs dramatically between individuals. Some remain seizure free on low doses of one drug, while others have weekly seizures despite surgery, vagal nerve stimulation, or multiple medications. Two cases may present with a single similar complex partial seizure, but what factors are responsible for the differences between the two patients? Staging seizures by way of improved identification of seizure severity and disease course will allow providers to make better management decisions. Based on a presentation by R. Edward Hogan, MD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 8 Clinical Issues and Seizure Severity Current tools to measure seizure severity are suboptimal: » Therapeutic drug levels needed to achieve seizure freedom » Amount of interictal discharges on EEG » Progession of MRI lesion For these reasons, improved diagnostic tools, including those with longitudinal capabilities, are necessary: » “Dry electrode” system and long-term intracranial EEG are examples of ways in which patients may be monitored on EEG for a longer time, thereby enhancing sensitivity of seizure detection. » Quantitative structural MRI studies, based on volumetry, voxel- based morphometry, cortical thickness mapping, and structural covariance analysis have shown extensive and progressive loss of cortical gray matter in temporal and extratemporal regions. Based on a presentation by R. Edward Hogan, MD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 9 Staging of Seizures According to Current Classification Systems Staging of epilepsy helps the physician make management decisions for the individual patient. Staging also may help the patient to understand his or her condition. Staging incorporates severity, extent, and prognosis. Staging should evolve over time as knowledge about epilepsy advances. To date, very few studies have tried to use staging as a means for gaining information or making a prediction. Based on a presentation by Elinor Ben-Menachem, MD, PhD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 10 Investigating a Staging System Proposed staging system: FEDS » (F) size and/or extent of primary focus or foci » (E) pathologic EEG and extent of interictal pathology » (D) patient status as being truly drug-resistant or able to have successful epilepsy surgery » (S) history of status epilepticus Advantages include: » Ability to estimate prognosis » Plan the appropriate treatment » Identify clinical trials and contribute to a common terminology for evaluating and comparing results of clinical trials and different treatment approaches Based on a presentation by Elinor Ben-Menachem, MD, PhD, at AES 2013

© 2014 Direct One Communications, Inc. All rights reserved. 11 Conclusion As new and exciting advances in the field of epilepsy emerge, innovative ways of organizing this information also must evolve. The staging of epilepsy may help us to improve treatment options for epilepsy-related conditions while minimizing the side effects of therapy.