title: Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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
  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.
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain2Institute of Clinical Chemistry, Neuroimmunology Unit, Department of Neurology, University Medical Center Schleswi.
authors.forename: Frank
authors.initials: F
authors.lastname: Leypoldt
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain3Institute of Neurology, Medical University of Vienna, Vienna, Austria.
authors.forename: Romana
authors.initials: R
authors.lastname: Höftberger
authors.affiliation: Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Maarten J
authors.initials: MJ
authors.lastname: Titulaer
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Thaís
authors.initials: T
authors.lastname: Armangue
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Gresa-Arribas
authors.affiliation: Department of Psychiatry, University Medical Center Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Jahn
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain6Department of Pediatrics I, Division of Pediatric Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Kevin
authors.initials: K
authors.lastname: Rostásy
authors.affiliation: Institute for Experimental Immunology, Euroimmun AG, Lübeck, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schlumberger
authors.affiliation: Department of Microbiology, University Medical Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
authors.affiliation: Institute of Clinical Chemistry, Neuroimmunology Unit, Department of Neurology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Wandinger
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Myrna R
authors.initials: MR
authors.lastname: Rosenfeld
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Graus
authors.affiliation: August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain10Department of Neurology, University of Pennsylvania, Philadelphia11Catalan Institution for Research and Advanced.
authors.forename: Josep
authors.initials: J
authors.lastname: Dalmau
mesh_terms: D060426:Anti-N-Methyl-D-Aspartate Receptor Encephalitis / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid*; D054382:Chemokine CXCL13 / Q000097:blood / Q000134:cerebrospinal fluid*; D006801:Humans; D020852:Lyme Neuroborreliosis / Q000097:blood / Q000134:cerebrospinal fluid; D062706:Prodromal Symptoms; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13