Acta Neuropathologica

, 118:737 | Cite as

Evidence for antibody-mediated pathogenesis in anti-NMDAR encephalitis associated with ovarian teratoma

  • Erdem TüzünEmail author
  • Lei Zhou
  • Joachim M. Baehring
  • Serguei Bannykh
  • Myrna R. Rosenfeld
  • Josep Dalmau
Original Paper


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.


Paraneoplastic Limbic encephalitis NMDA Antibodies Teratoma 



This work was supported in part by RO1CA89054, RO1CA107192 (JD).

Supplementary material

401_2009_582_MOESM1_ESM.jpg (374 kb)
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)


  1. 1.
    Bernal F, Graus F, Pifarre A, Saiz A, Benyahia B, Ribalta T (2002) Immunohistochemical analysis of anti-Hu-associated paraneoplastic encephalomyelitis. Acta Neuropathol 103:509–515CrossRefPubMedGoogle Scholar
  2. 2.
    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 67:146–149CrossRefPubMedGoogle Scholar
  3. 3.
    Cattoretti G, Pileri S, Parravicini C et al (1993) Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol 171:83–98CrossRefPubMedGoogle Scholar
  4. 4.
    Dalmau J, Gleichman AJ, Hughes EG et al (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098CrossRefPubMedGoogle Scholar
  5. 5.
    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 122:27–39CrossRefPubMedGoogle Scholar
  6. 6.
    Dalmau J, Tuzun E, Wu HY et al (2007) Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36CrossRefPubMedGoogle Scholar
  7. 7.
    Florance NR, Davis RL, Lam C et al (2009) Anti-NMDA receptor encephalitis in children and adolescents. Ann Neurol. doi: 10.1002/ana.21756
  8. 8.
    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 322:1844–1851PubMedGoogle Scholar
  9. 9.
    Iizuka T, Sakai F, Ide T et al (2008) Anti-NMDAR encephalitis in Japan: long-term outcome without tumor removal. Neurology 70:504–511CrossRefPubMedGoogle Scholar
  10. 10.
    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 3:291–296CrossRefPubMedGoogle Scholar
  11. 11.
    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 35:694–697CrossRefPubMedGoogle Scholar
  12. 12.
    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 159:230–237CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Erdem Tüzün
    • 1
    Email author
  • Lei Zhou
    • 1
  • Joachim M. Baehring
    • 2
  • Serguei Bannykh
    • 2
  • Myrna R. Rosenfeld
    • 1
  • Josep Dalmau
    • 1
  1. 1.Division of Neuro-Oncology, Department of NeurologyHospital of the University of Pennsylvania, University of PennsylvaniaPhiladelphiaUSA
  2. 2.Yale University School of MedicineNew HavenUSA

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