How do we treat autoimmune encephalitis?

At present, there are no prospective clinical trials, but only good retrospective therapeutic data on anti-NMDAR encephalitis. Therefore, the therapy of the autoimmune types of encephalitides is oriented on the therapy established for anti-NMDAR encephalitis (Figure). When rapid-onset immunotherapy is given, the prognosis is not only principally good for anti-NMDAR encephalitis, but also for other encephalitides with antibodies against neuronal surface proteins. That is why any delays in treatment initiation should be minimized.

The following principles apply: The therapy of paraneoplastic and non-paraneoplastic autoimmune encephalitides in which antibodies against intracellular and membrane-based neuronal antigens are demonstrated should consist of a combination of

  1. Adequate cancer therapy (surgery, radiation chemotherapy), provided a tumor can be detected
  2. Immunotherapy and
  3. Symptomatic therapy.

According to experts’ opinion, the following immunosuppressant dosage and interval regimens are mostly used:

First-line therapy:

  • Plasmapheresis/immunoadsorption (5-10 cycles)
  • Intravenous immunoglobulins (2 g/kg body weight for 5 days)
  • Intravenous methylprednisolone pulse therapy (1 g/day for 5 days)

Second-line therapy:

  • Rituximab (1000 mg i.v. twice at 14-day intervals, repeat after 6 months as needed) → innumerable experts meanwhile give rituximab as first-line therapy, underpinned by its comparatively favorable side effect profile and its relatively selective action on the depletion of B cells
  • Cyclophosphamide for 6-12 months at a dose of 750-1000 mg/m² body surface area i.v. every 4 weeks with dose escalation as a function of leukocyte nadir
  • Azathioprine (100-250 mg/day)
  • MTX (7.5-25 mg/week), folic acid rescue

Some specialists recommend a second-line therapy (including a combination of enhancement therapy drugs, e.g. rituximab together with cyclophosphamide) after as early as 10-14 days of no response (Dalmau 2011). In therapy-refractory patients, more recent observations suggest a positive effect of bortezomib, the proteasome inhibitor used to deplete mainly mature plasma cells (Scheibe et al.).

References

  1. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10(1):63–74.
  2. Scheibe F, Prüss H, Mengel AM, Kohler S, Nümann A, Köhnlein M, Ruprecht K, Alexander T, Hiepe F, Meisel A. Bortezomib for treatment of therapy-refractory anti-NMDA receptor encephalitis. Neurology. 2017 Jan 24;88(4):366-370.

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Der Forschungsverbund CONNECT‐GENERATE – als Teil des bestehenden GENERATE‐Netzwerks – wird seit 2019 durch das Bundesministerium für Bildung und Forschung (BMBF) gefördert. Nun ist der Forschungsverbund auch Teil des Forschungsnetzwerks Research for Rare geworden, dessen Ziel es ist, durch Grundlagen‐ und Therapieforschung die Diagnostik seltener Erkrankungen zu beschleunigen und den Betroffenen zügig eine adäquate Behandlung zu ermöglichen. CONNECT-GENERATE wird in den aktuellen Research for Rare - Newsletter vorgestellt. Mit gegenwärtig über 100 Zentren im GENERATE‐Netzwerk, arbeiten wir an der Umsetzung unserer gemeinsamen klinisch‐wissenschaftlichen Ziele und freuen uns sehr, Teil dieser wertvollen Initiative zu sein!

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Berlin, Germany

13th GENERATE e.V. - network meeting 2020 in Berlin as part of the 93th Congress of the German Society of Neurology 4.-7. November in Berlin. This year there will also be a 90min symposium entitled: "GENERATE 2020: Controversies in the Diagnosis and Therapy of Autoimmune Encephalitides" on Friday, November 6th, 2020, 3.00 pm to 4.30 pm in the "Helsinki" room.

References

Peer M, Prüss H, Ben-Dayan I, Paul F, Arzy S, Finke C.
Lancet Psychiatry. 2017 Oct;4(10):768-774. doi: 10.1016/S2215-0366(17)30330-9. Epub 2017 Sep 4.
PMID: 28882707
Link: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(17)30330-9/fulltext

Heine J, Prüss H, Kopp UA, Wegner F, Then Bergh F, Münte T, Wandinger KP, Paul F, Bartsch T, Finke C.
J Neurol Neurosurg Psychiatry. 2018 Nov;89(11):1191-1199. doi: 10.1136/jnnp-2017-317780. Epub 2018 Jun 9.
PMID: 29886429
Link: https://jnnp.bmj.com/content/89/11/1191

Autoantibody-mediated encephalitis - differential diagnosis in patients with impaired consciousness of unclear origin

Wandinger, Klaus-Peter; Leypoldt, Frank; Junker, Ralf
Dtsch Arztebl Int 2018; 115(40): 666-73; DOI: 10.3238/arztebl.2018.0666
Link: https://www.aerzteblatt.de/archiv/201062/Autoantikoerper-vermittelte-Enzephalitiden

Dalmau J, Graus F.
N Engl J Med. 2018 Mar 1;378(9):840-851. doi: 10.1056/NEJMra1708712. Review. No abstract available.
PMID: 29490181
Link: https://www.nejm.org/doi/full/10.1056/NEJMra1708712

Mueller SH, Färber A, Prüss H, Melzer N, Golombeck KS, Kümpfel T, Thaler F, Elisak M, Lewerenz J, Kaufmann M, Sühs KW, Ringelstein M, Kellinghaus C, Bien CG, Kraft A, Zettl UK, Ehrlich S, Handreka R, Rostásy K, Then Bergh F, Faiss JH, Lieb W, Franke A, Kuhlenbäumer G, Wandinger KP, LeypoldtF; German Network for Research on Autoimmune Encephalitis (GENERATE).
Ann Neurol. 2018 Apr;83(4):863-869. doi: 10.1002/ana.25216.
Link: https://onlinelibrary.wiley.com/doi/abs/10.1002/ana.25216

Malviya M, Barman S, Golombeck KS, Planagumà J, Mannara F, Strutz-Seebohm N, Wrzos C, Demir F, Baksmeier C, Steckel J, Falk KK, Gross CC, Kovac S, Bönte K, Johnen A, Wandinger KP, Martín-García E, Becker AJ, Elger CE, Klöcker N, Wiendl H, Meuth SG, Hartung HP, Seebohm G, Leypoldt F, Maldonado R, Stadelmann C, Dalmau J, Melzer N, Goebels N.
Ann Clin Transl Neurol. 2017 Oct 3;4(11):768-783. doi: 10.1002/acn3.444. eCollection 2017 Nov.
PMID: 29159189
Link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5682115/