Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Abstract

<h3>Objective</h3> 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. <h3>Methods</h3> 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 <i>LGI1</i>/<i>CASPR2</i> (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. <h3>Results</h3> 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, &gt;0.99). Younger age (ρ = −0.56; <i>p</i> = 0.01), lower VILIP-1 (ρ = −0.60; <i>p</i> &lt; 0.01) and SNAP-25 (ρ = −0.54; <i>p</i> = 0.01), and higher log₁₀(YKL-40/SNAP-25) (ρ = 0.48; <i>p</i> = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; <i>p</i> = 0.02) and neurogranin (ρ = 0.55; <i>p</i> = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. <h3>Conclusions</h3> 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.