Abstracts

Rationale: Clinical and experimental data strongly support that inflammation contributes to unprovoked seizures and cognitive comorbidities in epilepsy. The complement system plays a critical role in regulating immune and inflammatory responses both peripherally and in the brain. However, the extent to which complement activation in the blood is associated with inflammation, seizure burden, and cognitive decline in people with epilepsy is not well understood. To further investigate the association between peripheral blood inflammation and epilepsy pathophysiology, we measured the levels of complement proteins along with multiple cytokines in serum from people with drug-resistant epilepsy (DRE). In parallel, these molecules were compared to the epilepsy duration and neurophysiological scores for cognitive ability of each patient.

Methods: Serum samples were collected from patients with refractory epilepsy (RE) and healthy controls with informed consent under approved IRB protocols (n = 45 for each group) and obtained from the Indiana University Health ECRO Biorepository. Multiplex enzyme-linked immunosorbent assays (ELISA) were used to measure the levels 12 complement pathway signaling molecules and 27 cytokines. The students’ t-test was used to compare RE and healthy groups. Pearson correlation coefficient analysis was used to determine associations between levels of complement proteins and cytokines to epilepsy duration and cognitive scores for the full-scale intelligence quotient (FSIQ) assessed with the Wechsler Abbreviated Scale of Intelligence test.

Results:
We found that serum levels of complement proteins C1q, C3, C3b, C4, C4b, C5, MBL (Mannose-binding lectin), Factor B, and Factor H were significantly decreased in the RE group compared to the healthy group. In addition, we found significant increases in the serum levels of the inflammatory molecules eotaxin, IL-17, CCL2, and CCL5 in the RE group compared to the healthy group. A significant linear correlation between lower FSIQ and higher levels of TNF-α (p = 0.03), IL-9 (p = 0.01), and CXCL10 (p = 0.02) scores was observed in people with RE, suggesting that high blood inflammation may be a biomarker for cognitive decline. The levels of serum complement proteins did not correlate with either epilepsy duration or FSIQ scores.









Conclusions: Decreased levels of circulating complement proteins in epilepsy cases indicate a deficiency in complement activation. The increases in circulating eotaxin, IL-17, CCL2, and CCL5 suggest an enhanced peripheral inflammatory response in epilepsy. Taken together, this evidence suggests that people with epilepsy may be at higher risk for inflammation in the blood due to a lack of appropriate complement regulatory protection. While future research is needed to determine if inflammation in the blood is a cause or a consequence of seizures, our findings suggest that these immune molecules may serve as biomarkers of cognitive impairments in epilepsy.

Funding:
NS096234




Children’s Brain Diseases Foundation