Article published by The Scientist
Doctors treat epilepsy with anticonvulsants to control seizures, but some patients do not respond to these first-line therapies. For patients with drug-refractory epilepsy (DRE), whose seizures persist after treatment with two or more anticonvulsants, clinicians must surgically remove part of the brain tissue to cure the disease.
When first-line medicines fall short, scientists examine the molecular mechanisms of a disease to understand why and to develop alternatives. At Duke-NUS Medical School and KK Women’s and Children’s Hospital, clinicians and researchers teamed up to investigate how inappropriate proinflammatory mechanisms contribute to DRE pathogenesis. This work builds on evidence from animal models and resected brains of human patients that associated inflammation with epilepsy. Derrick Chan, a clinician scientist at KK Women’s and Children’s Hospital believes this research is an extension of his clinical work. “[T]his direction became really important, because we were looking for a less invasive way to try to help all the children with drug resistant epilepsy,” he said.
Chan and his team partnered with the immunology research group of fellow physician scientist, Salvatore Albani. In a study published in Nature Neuroscience, Chan and Albani described their efforts to understand the immunologic factors that contribute to DRE pathology. They examined the holistic involvement of the immune system in epileptic tissue that clinicians surgically removed from patients. The researchers used a single-cell sequencing technique called cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), which gathers information on RNA and surface proteins in single cells They uncovered a proinflammatory microenvironment in DRE lesions that resembles brain autoimmune diseases, such as multiple sclerosis (MS).
The researchers identified cell types and their functions in DRE lesions at single-cell resolution and differentiated resident brain and neurovascular cells from infiltrating immune cells. They found that the DRE microenvironment includes activated microglia and other proinflammatory immune cells, and they captured cellular interactions with additional molecular analyses. “We had not expected these interactions between microglia and other immune cells, and then how these microglia become kind of a pivot to attract all of the immune cells by starting this proinflammatory milieu inside the brain,” explained Pavanish Kumar, the first author of the study.