Comparative Effectiveness of Epilepsy Surgery Versus Additional Anti-Seizure Medications for Lennox-Gastaut Syndrome: Study Protocol for a Multicenter, Mixed-Methods Study

Sandi Lam^1,2*Marc Rosenman^3,4Tracy Dixon-Salazar⁵Kelly G Knupp⁶Liu Lin Thio⁷Taylor J Abel^8,9William P Welch^10,11Laurel Reed^12,13Stephanie C Randle^14,15Rebecca Garcia-Sosa^16,17Jason S Hauptman¹⁸Carolyn C Foster^3,4Elizabeth R Alpern^19,4Lu Zhang^1,2Nicole Villalba^1,2Maura Carroll¹Anup D Patel²⁰

• ¹Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, United States
• ²Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
• ³Mary Ann & J. Millburn Smith Child Health Outcomes, Research, and Evaluation Center (SCHORE), Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, United States
• ⁴Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States
• ⁵Lennox-Gastaut Syndrome (LGS) Foundation, San Diego, CA, United States
• ⁶Department of Pediatrics, Division of Neurology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, United States
• ⁷Department of Neurology, School of Medicine, Washington University, St. Louis, United States
• ⁸Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ⁹Division of Pediatric Neurosurgery, University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh, United States
• ¹⁰Division of Neurology and Child Development Unit, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ¹¹Division of Child Neurology, University of Pittsburgh Medical Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States
• ¹²Division of Pediatric Neurology, Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, United States
• ¹³Pediatric Neurology Department, C.S. Mott Children’s Hospital, Ann Arbor, United States
• ¹⁴Division of Pediatric Neurology, Department of Neurology, University of Washington, Seattle, United States
• ¹⁵Division of Pediatric Neurology and Epilepsy, Department of Pediatrics, Seattle Children's Hospital, Seattle, United States
• ¹⁶Division of Neurology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, United States
• ¹⁷Division of Pediatric Neurology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, United States
• ¹⁸Division of Neurological Surgery, Phoenix Children's Hospital, Phoenix, United States
• ¹⁹Division of Pediatric Emergency Medicine, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States
• ²⁰Division of Neurology, Nationwide Children's Hospital, Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, United States

Introduction: Lennox-Gastaut Syndrome (LGS) is a severe developmental epileptic encephalopathy without a known cure. Management of symptoms requires substantial care. Treatment options include anti-seizure medications, dietary therapy, and epilepsy surgery. Two main treatment pathways for patients with LGS with drug resistant epilepsy are additional anti-seizure medications or epilepsy surgery, which have been reported to be effective in reduction of seizure burden and improving quality of life. No studies have directly compared the outcomes of using epilepsy surgery versus using additional anti-seizure medications for the treatment of LGS.Methods: This study is a multicenter, mixed-methods comparative effectiveness study of LGS patients who have undergone epilepsy surgery or have received an LGS-approved medication for treatment resistant seizures. Aim 1 will analyze the effect of surgical therapies and additional medication on two clinical outcomes: (1a) seizure-related healthcare utilization, and (1b) expressive communication, behavior, and parent-reported quality of life. Based on electronic health record review and coding validation as part of Aim 1a, we will develop computable phenotypes for LGS. The phenotypes will inform the analyses in Aim 1a and Aim 2. Aim 2 will describe the real-world utilization of these treatments across multiple healthcare institutions in the United States. Data will be collected from electronic health records, data marts in the National Patient-Centered Clinical Research Network (PCORnet®) format, caregiver surveys, and focus groups.Discussion: This study of LGS will provide currently unavailable evidence concerning the real-world comparative effectiveness of epilepsy surgeries and additional anti-seizure medications. The outcomes are those that families identify as important: emergency medical care for seizures and patients' functional outcomes. The results of this study may help guide decisions regarding the treatment of LGS and development of computable phenotypes for this rare disease. This study using PCORnet® data will also lay the groundwork for future large-scale studies on LGS and other rare epilepsies.Clinical trial registration: ClinicalTrials.gov, NCT05374824.