ANTI-NMDA-RECEPTOR ENCEPHALITIS

Transcription

1 ANTI-NMDA-RECEPTOR ENCEPHALITIS Joint Program for European Medical Studies Nantes, 17th October 2014 Felix Gassert - Universität Ulm, Germany Sara Mahmoud Université d'angers, France Sindy Sim Université de Nantes, France Borbàla Szepes University of Szeged, Hungary César Terán Zea Universidad Espíritu Santo, Ecuador Tutor: Dr. Franck Letournel

2 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion MCQ at the end!

3 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

4 INTRODUCTION neuropsychiatric immune-mediated disease NMDA receptor involved: NR-1 subunit often paraneoplastic treatable diagnosis: CSF sample +++

5 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

6 NMDA RECEPTOR ligand gated cation channel selective agonist N-methyl-D-aspartate and glutamate 1 Ca 2+ and Na + into the cell and K + out of the cell ubiquitously expressed in the brain requirement for activation: glutamate + co-agonist (glycine or d-serine)

7 SUBTYPE COMPOSITION

8 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

9 CLINICAL FEATURES psychiatric neurological others anxiety (initial acute) behavioral changes, psychosis dementia short-term memory deficit seizures decreased consciousness autonomic instability hypoventilation

10 PARACLINIC & DIAGNOSIS MRI often normal but possible fluid attenuation (T2) diagnosis by CSF samples At symptoms presentation After recovery

11 PARANEOPLASTICITY paraneoplatic syndrome: tumors contain nervous tissue (express the NMDA receptor +++) ovarian teratomas +++ women older than 18 testis teratomas non-paraneoplastic syndrome: auto-immune children ø tumor other immunology triggers (cf.physiopathlogy) paraneoplastic anti-nmdar encephalitis auto-immune anti-nmdar encephalitis

12 CHILDREN similar clinical features BUT: mostly non-paraneoplastic syndrome psychosis less obvious autonomic manifestations less severe anti-nmdar encephalitis suspected with: acute behavioral changes seizures dystonia or diskinesia

13 EXPERIMENTAL APPROACH Antibodies in CSF or serum react with extra cellular epitope of NR1 subunit

14 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

15 PHYSIOPATHOLOGICAL BACKGROUND what is anti-nmda receptor encephalitis indeed on a molecular and cellular level? receptor loss by autoantibodies which? how? what way? what type? NMDA-R internalization NR-1 subunit targeting IgG

16 IMMUNOLOGICAL TRIGGER antibodies attack a physiologically present receptor abberant self-non-self differentiation the disease can occur as a paraneoplastic syndrome an existing tumor expresses NMDA-receptors ectopic receptor expression leads to the breakdown of immunological tolerance unknown cause

17 SOURCE OF ANTIBODIES circumventricular organs pathologically broken barrier leaky BBB intrathecal synthesis local plasma cells regions sensitive to systematical changes

18 IgGs bind NR-1 NMDA-R subunit appearance of IgG antibodies internalisation in endocytotic vesicle receptor cross-linkage N M D A A M P A N M D A A M P A N M D A post synaptic site

19 WHAT DO THESE CHANGES MEAN IN FUNCTIONALITY? change in receptor distribution reduced receptor number altered synaptic transmission and plasticity insufficient glutamate signaling decrease in mepsc LTP/LTD alterations manifests as psychosis, memory deficit LTD: long-term depression LTP: long-term potentiation mepsc: miniature excitatory end-plate current

20 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

21 TREATMENT slow response tumor resection immunotherapy Alemtuzumab based on clinical symptoms, not on Ab titers

22 Introduction NMDA Receptor Clinical features Physiopathology Treatment Conclusion

23 CONCLUSION Prompt diagnosis better outcome and treatment: Slow recovery Routine medical assessments

24 MCQ Which of the following statements is/are true? A) The NMDAR consists out of two subunits, both binding glycine B) Paraneoplastic syndrome is mostly observed in people younger than 18 C) ANRE is an autoimmune-mediated neuropsychiatric disease D) NMDA-R internalisation is triggered by IgM antibodies, resulting in irreversible receptor loss and cell death E) Alemtuzumab is used as a first-line treatment in ANRE

25 THANK YOU VERY MUCH FOR YOUR ATTENTION! References: 1. Dalmau, J., Gleichman, A.J., Hughes, E.G., Rossi, J.E., Peng, X., Lai, M., Dessain, S.K., Rosenfeld, M.R., Balice-Gordon, R. & Lynch, D.R. (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol., 7, Dalmau J, Erdem Tüzün, Haiyan Wu, Jaime Masjuan, Jeffrey E. Rossi, Alfredo Voloschin, Joachim M. Baehring, Haruo Shimazaki, Reiji Koide, Dale King, Warren Mason, Lauren H. Sansing, Marc A. Dichter, Myrna R. Rosenfeld, and David R. Lynch.Ann Neurol January ; 61(1): Paraneoplastic Anti N-methyl-D-aspartate Receptor Encephalitis Associated with Ovarian Teratoma 3. Ethan G. Hughes, Xiaoyu Peng, Amy J. Gleichman, Meizan Lai, Lei Zhou, Ryan Tsou, Thomas D. Parsons,David R. Lynch, Josep Dalmau, and Rita J. Balice-Gordon (2010) J Neurosci. Apr 28, 2010; 30(17): Cellular and synaptic mechanisms of anti-nmda receptor encephalitis 4. Florance, N.R., Davis, R.L., Lam, C., Szperka, C., Zhou, L., Ahmad, S., Campen, C.J., Moss, H., Peter, N., Gleichman, A.J., Glaser, C.A., Lynch, D.R., Rosenfeld, M.R. & Dalmau, J. (2009) Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann. Neurol. 5. Graus F, Saiz A, Dalmau J. (2010) J Neurol (2010) 257: Antibodies and neuronal autoimmune disorders of the CNS. 6. Jichuan Zhanga, Ya Yanga, Hongbin Lia, Jun Caoa, Lin X (2005) Volume 1050, Issues 1 2, 19 July 2005, Pages Brain Research 7. Laube, U., Kiderlen, A.F. (1997) Detection of Pneumocystis carinii with DNA-binding bisbenzimide Hoechst. J. Eukaryot. Microbiol., 44, 35S 8. Lee C.-H., Lu W., Michel J., Goehring A., Du J., Song X., Gouaux E. (2014) NMDA receptor structures reveal subunit arrangement and pore architecture. Nature, Vol. 511, pp Liba, Z., Sebranova, V., Komarek, V., Sediva, A., & Sedlacek, P. (2013). Prevalence and treatment of anti-nmda receptor encephalitis. THE LANCET Neurology, 12 (5), Moscato E., Jain A., Peng X., Hughes E., Dalmau J., Balice-Gordon R. (2010) Mechanisms underlying autoimmune synaptic encephalitis leading to disorders of memory, behavior and cognition: insights from molecular, cellular and synaptic studies. European Journal of Neuroscience, Vol. 32, pp M. S. Gable,, S. Gavali, A. Radner, D. H. Tilley, B. Lee, L. Dyner, A. Collins, A. Dengel, J. Dalmau and C. A. Glaser (2009) Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. European Journal of Clinical Microbiology & Infectious Diseases 12. Paoletti P., Bellone C., Zhou Q. (2013) NMDA receptor subunit diversity: impact on receptorproperties, synaptic plasticity and disease. Nature Reviews Neuroscience, Vol. 14, pp Titulaer, M., McCracken, L., Gabilondo, I., Armangué, T., Glaser, C., Iizuka, T., et al. (2013). Treatment and prognosis factors for long-term outcome in patients with anti-nmda receptor encephalitis: an observational cohort study. THE LANCET Neurology, 12 (2),