Cytokine and Chemokine Expression in CSF May Differentiate Viral and Autoimmune NMDAR Encephalitis in Children

Abstract

Childhood encephalitis is a potentially devastating condition with significant morbidity and mortality. Researchers currently lack biomarkers for differentiating infectious encephalitis from those with autoimmune causes which may delay adequate treatment. The authors studied the possibility of using cerebrospinal fluid cytokine and chemokine levels for this purpose. Children admitted to hospital care fulfilling criteria for encephalitis were prospectively included. Children who underwent lumbar puncture but were not classified as central nervous system infections served as controls. Cytokine and chemokine levels in the cerebrospinal fluid obtained upon initial presentation were analyzed using Luminex technology. In children with infectious encephalitis (n = 13), the cerebrospinal fluid displayed markedly elevated mean levels of IL6, IL7, and IL13 as compared to N-methyl-D-aspartate receptor (NMDAR) encephalitis (n = 4) and controls (n = 13). The expression of IL6 appeared to precede that of IL13. Analysis of selected cerebrospinal fluid cytokines may thus allow differential diagnosis of infectious and NMDAR encephalitis already at the initial lumbar puncture and enable immediate therapy.

Keywords

pediatric immunomodulation central nervous system childhood

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References

Fowler

Stodberg

Eriksson

Wickstrom

. Long-term outcomes of acute encephalitis in childhood. Pediatrics. 2010;126(4):e828–835.

Kolski

Ford-Jones

Richardson

. Etiology of acute childhood encephalitis at The Hospital for Sick Children, Toronto, 1994-1995. Clin Infect Dis. 1998;26(2):398–409.

Fowler

Stodberg

Eriksson

Wickstrom

. Childhood encephalitis in Sweden: etiology, clinical presentation and outcome. Eur J Paediatr Neurol. 2008;12(6):484–490.

Irani

Bera

Waters

. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133(pt 6):1655–1667.

Armangue

Titulaer

Malaga

. Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr. 2013;162(4):850–856.

Wang

Lei

. Cerebrospinal fluid cytokines in enterovirus 71 brain stem encephalitis and echovirus meningitis infections of varying severity. Clin Microbiol Infect. 2007;13(7):677–682.

Hasegawa

Matsushige

Inoue

Shirabe

Fukano

Ichiyama

. Serum and cerebrospinal fluid cytokine profile of patients with 2009 pandemic H1N1 influenza virus-associated encephalopathy. Cytokine. 2011;54(2):167–172.

Ichiyama

Ito

Kubota

Yamazaki

Nakamura

Furukawa

. Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection. Brain Dev. 2009;31(10):731–738.

Sato

Hosoya

Honzumi

. Cytokine and cellular inflammatory sequence in enteroviral meningitis. Pediatrics. 2003;112(5):1103–1107.

10.

Wickstrom

Fowler

Cooray

Karlsson-Parra

Grillner

. Viral triggering of anti-NMDA receptor encephalitis in a child—an important cause for disease relapse. Eur J Paediatr Neurol. 2014;18(4):543–546.

11.

Bien

Vincent

Barnett

. Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain. 2012;135(pt 5):1622–1638.

12.

Pruss

Finke

Holtje

. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72(6):902–911.

13.

Leypoldt

Titulaer

Aguilar

. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology. 2013;81(18):1637–1639.

14.

Hacohen

Deiva

Pettingill

. N-methyl-D-aspartate receptor antibodies in post-herpes simplex virus encephalitis neurological relapse. Move Disord. 2014;29(1):90–96.

15.

Leypoldt

Hoftberger

Titulaer

. Investigations on CXCL13 in anti-N-methyl-D-aspartate receptor encephalitis: a potential biomarker of treatment response. JAMA Neurol. 2015;72(2):180–186.

16.

Wright

Hacohen

Jacobson

. N-methyl-D-aspartate receptor antibody-mediated neurological disease: results of a UK-based surveillance study in children. Arch Dis Child. 2015;100(6):521–526.

17.

Thompson

Kneen

Riordan

Kelly

Pollard

. Encephalitis in children. Arch Dis Child. 2012;97(2):150–161.

18.

Titulaer

McCracken

Gabilondo

. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12(2):157–165.