Prospective Quantification of CSF Biomarkers in Antibody-Mediated Encephalitis

Neurology. 2021 May 18;96(20):e2546-e2557. doi: 10.1212/WNL.0000000000011937. Epub 2021 Apr 1.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / cerebrospinal fluid*
  • Autoantibodies / immunology
  • Autoimmune Diseases of the Nervous System / cerebrospinal fluid
  • Autoimmune Diseases of the Nervous System / immunology
  • Biomarkers / cerebrospinal fluid
  • Case-Control Studies
  • Child
  • Child, Preschool
  • Chitinase-3-Like Protein 1 / cerebrospinal fluid*
  • Encephalitis / cerebrospinal fluid
  • Encephalitis / immunology
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / immunology
  • Male
  • Membrane Proteins / immunology
  • Middle Aged
  • Nerve Tissue Proteins / immunology
  • Neurocalcin / cerebrospinal fluid*
  • Neurofilament Proteins / cerebrospinal fluid*
  • Neurogranin / cerebrospinal fluid
  • Synaptosomal-Associated Protein 25 / cerebrospinal fluid
  • Young Adult
  • tau Proteins / cerebrospinal fluid*

Substances

  • Autoantibodies
  • Biomarkers
  • CHI3L1 protein, human
  • CNTNAP2 protein, human
  • Chitinase-3-Like Protein 1
  • Intracellular Signaling Peptides and Proteins
  • LGI1 protein, human
  • MAPT protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Neurocalcin
  • Neurofilament Proteins
  • SNAP25 protein, human
  • Synaptosomal-Associated Protein 25
  • VSNL1 protein, human
  • neurofilament protein L
  • tau Proteins
  • Neurogranin