Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response

JAMA Neurol. 2015 Feb;72(2):180-6. doi: 10.1001/jamaneurol.2014.2956.

Abstract

Importance: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe but treatable autoimmune encephalitis affecting mainly young adults and children. The lack of suitable biomarkers of disease activity makes treatment decisions and identification of relapses challenging.

Objective: To determine the levels of the B-cell-attracting C-X-C motif chemokine 13 (CXCL13) in serum samples and cerebrospinal fluid (CSF) of patients with anti-NMDAR encephalitis and whether they can be used as biomarkers of treatment response and outcome.

Design, settings, and participants: Retrospective cohort study of 167 patients consecutively diagnosed as having anti-NMDAR encephalitis between May 1, 2008, and January 31, 2013. Concentration of CXCL13 was determined with enzyme-linked immunosorbent assay in all available patients' samples (272 CSF and 55 serum samples). Samples from 25 patients with noninflammatory neurological disorders and 9 with neuroborreliosis served as controls. Expression of CXCL13 in the brain biopsy of a patient with anti-NMDAR encephalitis was determined by immunohistochemistry.

Main outcomes and measures: Percentage of patients with anti-NMDAR encephalitis and elevated CXCL13 in CSF.

Results: Compared with control individuals, 70% of patients with early-stage anti-NMDAR encephalitis had increased CXCL13 in CSF (>7 pg/mL; P < .001) but none in serum samples (>1047 pg/mL; P > .99). High concentration of CSF CXCL13 was associated with the presence of prodromal fever or headache (P = .01), limited response to therapy (P = .003), clinical relapses (P = .03), and intrathecal NMDAR-antibody synthesis (P < .001). Among patients with monophasic disease assessed 2 to 6 months after starting treatment, 10 of 15 with limited treatment response vs 0 of 13 with favorable response had increased CSF CXCL13 (specificity, 100%; 95% CI, 75-100 and sensitivity, 67%; 95% CI, 38-88; P = .02). Six of 12 patients had elevated CSF CXCL13 at relapse including 3 with previously normal levels. In brain, abundant mononuclear cells in perivascular infiltrates and scattered intraparenchymal microglia expressed CXCL13.

Conclusions and relevance: Seventy percent of patients with early-stage anti-NMDAR encephalitis had increased CSF CXCL13 concentration that correlated with intrathecal NMDAR-antibody synthesis. Prolonged or secondary elevation of CXCL13 was associated with limited response to treatment and relapses. CXCL13 is a potentially useful biomarker of treatment response and outcome in anti-NMDAR encephalitis.

Publication types

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

MeSH terms

  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / blood
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / cerebrospinal fluid*
  • Anti-N-Methyl-D-Aspartate Receptor Encephalitis / immunology
  • Biomarkers / blood
  • Biomarkers / cerebrospinal fluid*
  • Chemokine CXCL13 / blood
  • Chemokine CXCL13 / cerebrospinal fluid*
  • Humans
  • Lyme Neuroborreliosis / blood
  • Lyme Neuroborreliosis / cerebrospinal fluid
  • Prodromal Symptoms
  • Recurrence
  • Treatment Outcome*

Substances

  • Biomarkers
  • CXCL13 protein, human
  • Chemokine CXCL13