Biomarkers of neuroaxonal and astrocytic pathology in autoimmune encephalitis

Autoimmune encephalitis (AE) is an immune mediated central nervous system disorder that results in significant symptoms and disability including cognitive dysfunction. Biomarkers of neuro-axonal (neurofilament light, NfL) and astrocytic (glial fibrillary acidic protein, GFAP) pathology in autoimmune encephalitis (AE) are altered in the cerebrospinal fluid and serum in AE. However, their relationship to disease phase and outcomes, particularly cognition, is not well established. Understanding their association with the AE disease course may enhance monitoring and prognostication.

In this cross-sectional observational study patients with acute and chronic (>3 months post treatment) AE recruited through the Australian Autoimmune Encephalitis Consortium underwent serum NfL and GFAP analysis and were compared to a control cohort using linear mixed modelling. Participants with chronic AE underwent a comprehensive cognitive assessment and were stratified by level of cognitive dysfunction. Correlations between NfL or GFAP and cognitive dysfunction, modified Rankin Scale [mRS] or Clinical Assessment Scale in Autoimmune Encephalitis [CASE] scores were analysed with regression modelling.

The acute AE cohort (n = 15) had higher NfL (Z score: 2.18 [1.39, 2.98]) and GFAP (212.35 pg/ml [148.09, 304.50) compared with the chronic cohort (n = 51; 0.88 [0.46, 1.29], p < 0.01; 118.97 pg/ml [100.88, 140.30], p = 0.02) and control cohort (n = 28; 0.66 [0.12, 1.21], p < 0.001; 111.35 pg/ml [82.81, 149.75], p = 0.03). Poorer discharge mRS correlated with elevated NfL (OR 3.77 [1.21, 11.70]) and GFAP (OR 47.92 [2.35, 978.68]). Higher GFAP was associated with moderate-severe cognitive dysfunction (150.61 pg/ml [115.94, 195.64] vs 108.43 pg/ml [90.68, 129.65]), p = 0.04) and correlated with poorer follow-up mRS (OR 2.28 [1.27, 4.10]) and CASE (ß = 1.04 [0.34, 1.73]) scores.

Overall, acute AE is characterized by elevated markers of neuronal and astrocytic pathology. Low levels of sNfL in chronic AE, regardless of current function, suggest that ongoing neuroaxonal injury is unlikely. However, elevated sGFAP in AE patients with ongoing sequalae, most notably cognitive dysfunction, suggest there may be ongoing changes that contribute to the chronic AE disease course.