Association of Epileptic and Nonepileptic Seizures and Changes in Circulating Plasma Proteins Linked to Neuroinflammation Gledhill J, Brand E, Pollard J, Clair RS, Wallach T, Crino P. Neurology. 2021;96(10):e1443-e1452. doi:10.1212/WNL.0000000000011552 Objective: To develop a diagnostic test that stratifies epileptic seizure (ES) from psychogenic nonepileptic seizure (PNES) by developing a multimodal algorithm that integrates plasma concentrations of selected immune response associated proteins and patient clinical risk factors for seizure. Methods: Daily blood samples were collected from patients evaluated in the epilepsy monitoring unit (EMU) within 24 hours after EEG confirmed ES or PNES and plasma was isolated. Levels of 51 candidate plasma proteins were quantified using an automated, multiplexed, sandwich ELISA and then integrated and analyzed using our diagnostic algorithm. Results: A 51 protein multiplexed ELISA panel was used to determine the plasma concentrations of ES patients, PNES patients, and healthy controls. A combination of protein concentrations, TRAIL, ICAM-1, MCP-2, and TNF-R1 provided a probability that a patient recently experienced a seizure with TRAIL and ICAM-1 higher in PNES than ES, and MCP-2 and TNF-R1 higher in ES than PNES. The diagnostic algorithm yielded an AUC of 0.94 ± 0.07, sensitivity of 82.6% (95% CI: 62.9-93.0), and specificity of 91.6% (95% CI: 74.2-97.7). Further, expanding the diagnostic algorithm to include previously identified PNES risk factors enhanced diagnostic performance with AUC of 0.97 ± 0.05, sensitivity of 91.3% (95% CI: 73.2-97.6), and specificity of 95.8% (95% CI: 79.8-99.3). Conclusions: These 4 plasma proteins could provide a rapid, cost-effective, and accurate blood-based diagnostic test to confirm recent ES or PNES. Classification of Evidence: This study provides Class III evidence that variable levels of 4 plasma proteins, when analyzed by a diagnostic algorithm, can distinguish PNES from ES with sensitivity of 82.6% and specificity of 91.6%.