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Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis
Gregory S Day1, Melanie Y Yarbrough2, Peter Körtvelyessy2
1From the Department of Neurology (G.S.D., A.S.L.-C., N.R.G.-R.), Mayo Clinic, Jacksonville, FL; Departments of Pathology and Immunology (M.Y.Y., E.M.H., J.H.L.) and Neurology (R.C.B., R.L.H., E.M.H., J.H.L., J.C.M., A.F.) and The Charles F. and Joanne Knight Alzheimer Disease Research Center (R.L.H., J.C.M., A.F.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (P.M.D.K.), University of Magdeburg; Department of Neurology and Experimental Neurology (P.M.D.K., H.P.) Charité, Universitätmedizin Berlin, Germany; Department of Medicine (M.J.F.), Cumming School of Medicine, University of Calgary; Department of Medicine (W.M., D.F.T.-W., J.H.), Division of Neurology, University of Toronto, Canada; and NYU Langone Comprehensive Epilepsy Center (C.S.), NYU Langone Health, New York, NY. day.gregory@mayo.edu.
Objective:
To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals.
Methods:
Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients.
Results:
Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge.
Conclusions:
CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.
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