Abstract Details

Title CSF Metagenomics and Host Transcriptomics of Cryptogenic New-onset Refractory Status Epilepticus

Topic Autoimmune Neurology

Presentation(s) C14 - Neuroinfectious Disease Diagnostics (2:41 PM-2:48 PM)
P1 - Poster Session 1 (12:00 PM-1:00 PM)

Poster/Presentation
Number 011

Background

NORSE is a severe neurological disorder with high rates of morbidity and mortality. While certain commonly tested viruses (i.e. herpes simplex virus 1) and antibodies (i.e. NMDA, GAD65, VGKC) may trigger NORSE, >50% of cases remain cryptogenic. A better understanding of the host immune response in cryptogenic NORSE (cNORSE) may provide insight into dysregulated pathways that could inform more targeted treatment approaches.

Objective

To investigate cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) and host transcriptomics of cryptogenic New-onset refractory status epilepticus (NORSE).

Design/Methods Bulk RNA sequencing for unbiased pathogen detection and host response was performed on the CSF of 38 patients with cNORSE. Differential gene expression analysis was performed comparing a subset of pediatric cNORSE patients (n=9) to a cohort of pediatric NMDA-receptor encephalitis (n=14) and viral encephalitis (n=8). Ingenuity Pathway Analysis assessed for dysregulated pathways.

Results

cNORSE and pediatric cNORSE cohorts were a median age of 34.0 and 14.1 and 39% and 22% male, respectively. 25/38 (66%) met criteria for febrile infection-related epilepsy syndrome (FIRES). NMDA-receptor and viral encephalitis cohorts were a median age of 14.0 and 8.1 and 43% and 22% male, respectively. There were no viral infections identified on mNGS in the cNORSE cohort. There were no significant differences in gene expression signatures between pediatric cNORSE and NMDA-receptor encephalitis. 2,471 genes were differentially expressed between pediatric cNORSE and viral encephalitis (p<0.01, LogFC >|1|). Significant upregulated pathways correlated with epileptogenesis including glutaminergic receptor signaling, endocannabinoid neuronal synapse, and reelin signaling in neurons.

Conclusions This is the first study to perform CSF mNGS for unbiased pathogen detection on a large cohort of cNORSE patients and to explore the underlying host response in pediatric cNORSE patients using CSF host transcriptomics. We demonstrate upregulation of key epileptogenic pathways. Further investigations of these pathways and repeat analyses with larger sample sizes are currently underway.

Authors/Disclosures
Mary Karalius, MD (UCSF) PRESENTER	Dr. Karalius has nothing to disclose.
Aurelie Hanin, PhD (Yale University School of Medicine)	Dr. Hanin has nothing to disclose.
Aaron Bodansky	No disclosure on file
Martineau Louine, MD (UCSF)	Dr. Louine has nothing to disclose.
Shiyin Wang (UCSF)	No disclosure on file
Kelsey Zorn	No disclosure on file
Asritha Tubati (University of California, San Francisco)	No disclosure on file
Sukhman Sidhu (University of California San Francisco)	No disclosure on file
Samuel Pleasure, MD, PhD (UCSF)	Dr. Pleasure has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. The institution of Dr. Pleasure has received research support from NINDS, NIMH, NIDA, National MS Society, Brain Research Foundation, John Merck Fund, Whitehall Foundation, Lupus Research Association, Juvenile Diabetes Research Foundation.
Lawrence J. Hirsch, MD, FAAN (Yale University Comprehensive Epilepsy Center)	Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ceribell. Dr. Hirsch has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for marinus. The institution of Dr. Hirsch has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Accure. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Natus. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurelis. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Rafa Laboratories, Ltd. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Rapport Therapeutics. Dr. Hirsch has received publishing royalties from a publication relating to health care. Dr. Hirsch has received publishing royalties from a publication relating to health care. Dr. Hirsch has received personal compensation in the range of $5,000-$9,999 for serving as a Speaker with Neuropace. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a Speaker with Natus. Dr. Hirsch has received personal compensation in the range of $500-$4,999 for serving as a speaker with UCB.
Michael R. Wilson, MD, FAAN (University of California San Francisco)	Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Delve Bio. Dr. Wilson has stock in Delve Bio. The institution of Dr. Wilson has received research support from Genentech / Roche. The institution of Dr. Wilson has received research support from NIH. The institution of Dr. Wilson has received research support from UCSF Weill Institute for Neurosciences. The institution of Dr. Wilson has received research support from Novartis. The institution of Dr. Wilson has received research support from National Multiple Sclerosis Society. The institution of Dr. Wilson has received research support from Fanconi Anemia Research Foundation. The institution of Dr. Wilson has received research support from Department of Defense. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received intellectual property interests from a discovery or technology relating to health care. Dr. Wilson has received personal compensation in the range of $10,000-$49,999 for serving as a Expert Witness with US Dept of Justice.