Abstract
We report the immunopathological analysis of the brain and tumor of two patients who died of anti-NMDAR-associated encephalitis, and of the tumor of nine patients who recovered. Findings included prominent microgliosis and deposits of IgG with rare inflammatory infiltrates in the hippocampus, forebrain, basal ganglia, and spinal cord. Detection of cells expressing markers of cytotoxicity (TIA, granzyme B, perforin and Fas/Fas ligand) was extremely uncommon. All tumors showed NMDAR-expressing neurons and inflammatory infiltrates. All patients’ NMDAR antibodies were IgG1, IgG2, or IgG3. No complement deposits were observed in any of the central nervous system regions examined. Overall, these findings coupled with recently reported in vitro data showing that antibodies downregulate the levels of NMDA receptors suggest that the antibody immune-response is more relevant than cytotoxic T-cell mechanisms in the pathogenesis of anti-NMDAR-associated encephalitis.
References
Bernal F, Graus F, Pifarre A, Saiz A, Benyahia B, Ribalta T (2002) Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol 103:509–515
Blumenthal DT, Salzman KL, Digre KB, Jensen RL, Dunson WA, Dalmau J (2006) Early pathologic findings and long-term improvement in anti-Ma2-associated encephalitis. Neurology 67:146–149
Cattoretti G, Pileri S, Parravicini C et al (1993) Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol 171:83–98
Dalmau J, Gleichman AJ, Hughes EG et al (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098
Dalmau J, Gultekin SH, Voltz R et al (1999) Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain 122:27–39
Dalmau J, Tuzun E, Wu HY et al (2007) Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36
Florance NR, Davis RL, Lam C et al (2009) Anti-NMDA receptor encephalitis in children and adolescents. Ann Neurol. doi:10.1002/ana.21756
Furneaux HM, Rosenblum MK, Dalmau J et al (1990) Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med 322:1844–1851
Iizuka T, Sakai F, Ide T et al (2008) Anti-NMDAR encephalitis in Japan: long-term outcome without tumor removal. Neurology 70:504–511
Sansing LH, Tuzun E, Ko MW, Baccon J, Lynch DR, Dalmau J (2007) A patient with encephalitis associated with NMDA receptor antibodies. Nat Clin Pract Neurol 3:291–296
Stein-Wexler R, Wootton-Gorges SL, Greco CM, Brunberg JA (2005) Paraneoplastic limbic encephalitis in a teenage girl with an immature ovarian teratoma. Pediatr Radiol 35:694–697
Wirtz PW, Willcox N, van der Slik AR et al (2005) HLA and smoking in prediction and prognosis of small cell lung cancer in autoimmune Lambert-Eaton myasthenic syndrome. J Neuroimmunol 159:230–237
Acknowledgment
This work was supported in part by RO1CA89054, RO1CA107192 (JD).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
401_2009_582_MOESM1_ESM.jpg
Supplementary Figure 1. Inflammatory infiltrates in the control tumor sample. Panels a–f, control tumor sections immunolabeled for the presence of CD8+ cells (a), granzyme-b (b), perforin (c), Fas (d), Fas ligand (e) and TIA-1 (f). All panels original magnification ×400, avidin–biotin–peroxidase technique with mild hematoxylin counterstaining. All studies were performed with paraffin-embedded sections (JPG 374 kb)
Rights and permissions
About this article
Cite this article
Tüzün, E., Zhou, L., Baehring, J.M. et al. Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma. Acta Neuropathol 118, 737–743 (2009). https://doi.org/10.1007/s00401-009-0582-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-009-0582-4