Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Abstract

Objectives: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/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin 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, while 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 cases from cognitively normal individuals (AUC=0.99; 95%CI: 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 modified Rankin 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 modified Rankin Scores 12-months following hospital discharge.Conclusions:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, 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.

Case Report: Anti-flotillin 1/2 Autoantibody-Associated Atypical Dementia

“…A hypothetical mechanism is delineated suggesting how anti-flotillin 1/2 autoantibodies might cause autoimmune processes on the one hand in step one, and on the other hand in step two, neuroaxonal degeneration marked by a high phosphorylated tau protein. This case supports existing evidence about a possible secondary neurodegeneration in autoimmune CNS inflammation ( 15 , 16 , 24 ). On the other hand it is conceivable, but less likely that a neurodegenerative disorder is triggered by an autoimmune process.…”

“…According to Banks et al (5), markers of axonal degeneration may be elevated in autoimmune encephalitis with cognitive dysfunction (15,16); resembling autoimmune dementia they do not preclude the assumption of an autoimmune dementia. However, no genetic tests were conducted to exclude FTD mutations like C9 or 72 mutations.…”

“…Her slight clinical improvement supports the autoimmune origin of her dementia according to the guidelines on autoimmune dementia ( 4 ) and argues against a worsening neurodegenerative dementia such as FTD although markers of axonal neurodegeneration have been detected. According to Banks et al ( 5 ), markers of axonal degeneration may be elevated in autoimmune encephalitis with cognitive dysfunction ( 15 , 16 ); resembling autoimmune dementia they do not preclude the assumption of an autoimmune dementia. However, no genetic tests were conducted to exclude FTD mutations like C9 or 72 mutations.…”

CSF-Neurofilament Light Chain Levels in NMDAR and LGI1 Encephalitis: A National Cohort Study

“…This is in line with not only previous findings in other inflammatory diseases, but also a smaller study in AE ( 22 , 24 , 31 ). Five previous smaller studies on NfL as a biomarker in AE have been published ( 31 – 36 ).…”

Current Nosology of Neural Autoantibody-Associated Dementia

“…Other studies proved IgLON5 disease and the co-occurrence of axonal brain damage ( Hansen et al, 2020a ; Landa et al, 2020 ). However, not just IgLON5 antibodies are known to result in neuroaxonal degeneration, as shown in a study of patients characterized by LGI1, CASPR2 or NMDAR antibodies and encephalitis ( Day et al, 2021 ). However, there has been no prospective study to date examining autoimmune dementia and neurodegeneration.…”