ARISEN (Autoimmunity, Rasmussen’s, Inflammation & Status Epilepticus research Network)

Emory University, Atlanta GA

Investigators

Abstract

CLINICAL PROJECT 3: Project Summary The goal of this project is to identify diagnostic biomarkers to aid in early diagnosis of autoimmune encephalitis (AE), Rasmussen syndrome, and new onset refractory status epilepticus (NORSE). These are severe and poorly understood neuroinflammatory conditions with high rates of morbidity and mortality. Mortality is high, with residual neurological symptoms occurring in >80-90% of survivors. This is partly due to challenges in making a timely diagnosis and lack of understanding of the underlying mechanisms driving disease leading to delayed or inappropriate treatment. While differing clinical phenotypes eventually emerge over time, these syndromes can initially present with similar neurological symptoms including altered mental status, behavioral changes, and seizures, which can be particularly difficult to recognize in children. all three syndromes, the difficulty and uncertainty in diagnosis leads to delays in initiation of immunomodulatory treatments which can lead to worse outcomes. Treatment of these syndromes is also challenging, in part due to the lack of understanding of the underlying inflammatory processes driving disease. Our long-term goal is to improve the diagnosis and treatment of these diseases. The objective of this project is to explore the underlying immune mechanisms mediating AE, Rasmussen’s, and NORSE with the goal of identifying key immune pathways that may differentiate these diseases. Our central hypothesis is that while these diseases share some similar neuroinflammatory pathways, there are underlying differences in both the proteome and transcriptome and novel autoantibodies that contribute to disease. Our team, with expertise in cytokine analysis, CSF transcriptomics, and autoantibody discovery, is exceptionally well qualified to test our hypotheses with the following aims: Aim 1 will identify blood and CSF cytokine signatures that distinguish AE, Rasmussen syndrome, and NORSE. We will assess cytokine signatures from serum and CSF at the time of presentation to identify differences and overlaps in inflammatory pathways in AE, Rasmussen’s, and NORSE. Aim 2 will focus on identifying CSF host transcriptomic profiles that differentiate between AE, Rasmussen syndrome, and NORSE. Although immune dysregulation likely contributes to all three conditions, we hypothesize that the transcriptional profiles will differ given variable clinical phenotypes. We will use bulk-RNA sequencing of CSF to identify similarities and differences in the host immune response in these three diseases. Aim 3 will be to perform human proteome-wide antigen discovery on CSF from patients with seronegative AE, Rasmussen syndrome and NORSE to identify novel autoantibodies that can help better diagnose and sub-categorize patients. The impact of this project will be by leveraging cutting-edge laboratory technologies, we will improve early diagnosis and expand our understanding of the underlying inflammatory mechanisms driving AE, Rasmussen’s, and NORSE. Results of these studies will inform future studies on treatment response, patient outcomes, and novel targeted treatments.