Frank Leypoldt1, Romana Höftberger2, Maarten J Titulaer3, Thaís Armangue4, Nuria Gresa-Arribas4, Holger Jahn5, Kevin Rostásy6, Wolfgang Schlumberger7, Thomas Meyer8, Klaus-Peter Wandinger9, Myrna R Rosenfeld4, Francesc Graus4, Josep Dalmau10. 1. 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. 2. 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. 3. Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands. 4. August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Service of Neurology, Hospital Clínic, University of Barcelona, Barcelona, Spain. 5. Department of Psychiatry, University Medical Center Hamburg Eppendorf, Hamburg, Germany. 6. 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. 7. Institute for Experimental Immunology, Euroimmun AG, Lübeck, Germany. 8. Department of Microbiology, University Medical Hamburg Eppendorf, Hamburg, Germany. 9. Institute of Clinical Chemistry, Neuroimmunology Unit, Department of Neurology, University Medical Center Schleswig-Holstein Campus Lübeck, Lübeck, Germany. 10. 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.
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.
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-NMDARencephalitis 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-NMDARencephalitis 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-NMDARencephalitis was determined by immunohistochemistry. MAIN OUTCOMES AND MEASURES: Percentage of patients with anti-NMDARencephalitis and elevated CXCL13 in CSF. RESULTS: Compared with control individuals, 70% of patients with early-stage anti-NMDARencephalitis 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-NMDARencephalitis 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-NMDARencephalitis.
Authors: Ethan G Hughes; Xiaoyu Peng; Amy J Gleichman; Meizan Lai; Lei Zhou; Ryan Tsou; Thomas D Parsons; David R Lynch; Josep Dalmau; Rita J Balice-Gordon Journal: J Neurosci Date: 2010-04-28 Impact factor: 6.167
Authors: Mohsen Khademi; Ingrid Kockum; Magnus L Andersson; Ellen Iacobaeus; Lou Brundin; Finn Sellebjerg; Jan Hillert; Fredrik Piehl; Tomas Olsson Journal: Mult Scler Date: 2010-12-06 Impact factor: 6.312
Authors: Kavitha Narayan; Donna Dail; Libin Li; Diego Cadavid; Sheela Amrute; Patricia Fitzgerald-Bocarsly; Andrew R Pachner Journal: Ann Neurol Date: 2005-06 Impact factor: 10.422
Authors: Makbule Senel; Tobias A Rupprecht; Hayrettin Tumani; Hans W Pfister; Albert C Ludolph; Johannes Brettschneider Journal: J Neurol Neurosurg Psychiatry Date: 2009-12-03 Impact factor: 10.154
Authors: David G Baker; Tyson A Woods; Niranjan B Butchi; Timothy M Morgan; R Travis Taylor; Piyanate Sunyakumthorn; Piyali Mukherjee; Kirk J Lubick; Sonja M Best; Karin E Peterson Journal: J Gen Virol Date: 2012-11-07 Impact factor: 3.891
Authors: Ralf J Ludwig; Karen Vanhoorelbeke; Frank Leypoldt; Ziya Kaya; Katja Bieber; Sandra M McLachlan; Lars Komorowski; Jie Luo; Otavio Cabral-Marques; Christoph M Hammers; Jon M Lindstrom; Peter Lamprecht; Andrea Fischer; Gabriela Riemekasten; Claudia Tersteeg; Peter Sondermann; Basil Rapoport; Klaus-Peter Wandinger; Christian Probst; Asmaa El Beidaq; Enno Schmidt; Alan Verkman; Rudolf A Manz; Falk Nimmerjahn Journal: Front Immunol Date: 2017-05-31 Impact factor: 7.561
Authors: Maximilian Gahr; Florian Lauda; Moritz E Wigand; Bernhard J Connemann; Angela Rosenbohm; Hayrettin Tumani; Markus Reindl; Zeljko Uzelac; Jan Lewerenz Journal: BMJ Case Rep Date: 2015-04-26