Skip to main content

Advertisement

SpringerLink
Log in

Back to the future: encephalitis lethargica as an autoimmune disorder?

  • Review Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

More than 100 years after its emergence, the exact pathophysiological mechanisms underlying encephalitis lethargica (EL) are still elusive and awaiting convincing and complete elucidation. This article summarizes arguments proposed over time to support or refute the hypothesis of EL as an autoimmune neuropsychiatric disorder triggered by an infectious process. It also provides a critical evaluation of modern cases labeled as EL and a comprehensive differential diagnosis of autoimmune neurological conditions that could mimic EL. The evidence supporting the autoimmune nature of historical EL is sparse and not entirely convincing. It is possible that autoimmune mechanisms were involved in the pathogenesis of this disease as an idiosyncratic response to a yet unidentified infectious agent in genetically predisposed individuals. Although there has been an increase in the incidence of presumed autoimmune encephalomyelitis since the peak of EL pandemics, most evidence does not support an underlying autoimmune mechanism. There are significant differences between historical and recent EL cases in terms of clinical symptomatology, epidemiology, and neuropathological features, suggesting that they are different entities with only superficial similarity. The term “encephalitis lethargica,” still frequently used in the medical literature, should not be used for cases occurring at present in the sporadic form. Historical EL should be kept apart from recent EL, as they differ in important aspects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. von Economo C (1917) Encephalitis lethargica. Wien Klin Wochenschr 30:581–585

    Google Scholar 

  2. Brigo F, Martini M, Lorusso L, Study Group on the History of Neurology of the Italian Neurological Society (2021) “You are older, although you do not know that”: time, consciousness, and memory in “A kind of Alaska” by Harold Pinter (1930-2008). Eur Neurol 84:486–489

    Article  PubMed  Google Scholar 

  3. Brigo F, Lorusso L, Martini M (2022) L’eredità socio-culturale dell’encefalite letargica e la sua rappresentazione nella cultura popolare e di massa. Conf Cephalal et Neurol 32(1):e2022004

    Google Scholar 

  4. Cruchet R, Moutier F, Calmette A (1917) Quarante cas d’encéphalo-myélite subaiguë. Bulletins et Mémoires de la Société médicale des Hôpitaux série 41:614–616

    Google Scholar 

  5. Vilensky JA (2011) Encephalitis lethargica during and after the epidemic. Oxford University Press

    Google Scholar 

  6. Foley P (2018) Encephalitis lethargica - the mind and brain virus. Springer Nature

    Book  Google Scholar 

  7. Stern F (1928) Die epidemische Encephalitis. Julius Springer, Berlin

    Book  Google Scholar 

  8. von Economo C (1929) Die encephalitis lethargica, ihre Nachkrankheiten und ihre Bechandlung. Urban and Swarzenberg, Vienna

    Google Scholar 

  9. Tilney F, Howe HS (1920) Epidemic encephalitis (encephalitis lethargica). Paul B. Hoeber, New York

    Google Scholar 

  10. Kyrieleis W (1931) Die Augenveränderungen bei den entzündlichen Erkrankungen des Zentralnervensystems. In: Schieck F, Bruckner A (eds) Kurzes Handbuch der Ophthalmologie. Sechster Band: Auge und Nervensystem. Julius Springer, Berlin, pp 669–799

    Google Scholar 

  11. Vilensky JA, Foley P, Gilman S (2007) Children and encephalitis lethargica: a historical review. Pediatr Neurol 37(2):79–84

    Article  PubMed  Google Scholar 

  12. Spatz H (1930) Ergebnis der anatomischen Untersuchung von 70 Fällen von Encephalitis epidemica. Zentralblatt für die gesamte Neurologie und Psychiatrie 56:435–437

    Google Scholar 

  13. van Bogaert L (1958) Encéphalite léthargique type A (Maladie d’Economo). In: Scholz W, Lubarsch O, Henke F, RössIe R (eds) Nervensystem. Zweiter Teil: Erkrankungen des zentralen Nervensystems II; Bandteil A (Handbuch der speziellen pathologischen Anatomie und Histologie), Band 13. Springer, Berlin, Göttingen, Heidelberg, pp 313–361

    Chapter  Google Scholar 

  14. Klarfeld (1920) Histopathologie der Encephalitis choreatica. Allgemeine Zeitschrift für Psychiatrie und psychisch-gerichtliche Medizin 76:812–816

    Google Scholar 

  15. Scholz W (1922) Über herdförmige, protoplasmatische Gliawucherung von syncytialem Charakter. Mit einem Ausblick auf ihre Bedeutung für den Verlauf des pathologisch-anatomischen Prozesses bei der Encephalitis epidemica. Zeitschrift für die gesamte Neurologie und Psychiatrie 79:114–179

    Article  Google Scholar 

  16. Lutters B, Foley P, Koehler PJ (2018) The centennial lesson of encephalitis lethargica. Neurology 90(12):563–567

    Article  PubMed  Google Scholar 

  17. Blackburn KM, Wang C (2020) Post-infectious neurological disorders. Ther Adv Neurol Disord 13:1756286420952901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dop D, Marcu IR, Padureanu R, Niculescu CE, Padureanu V (2021) Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Review). Exp Ther Med 21(1):94

    Article  CAS  PubMed  Google Scholar 

  19. Dale RC, Church AJ, Surtees RA, Lees AJ, Adcock JE, Harding B, Neville BG, Giovannoni G (2004) Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity. Brain 127(Pt 1):21–33

    Article  PubMed  Google Scholar 

  20. Church AJ, Cardoso F, Dale RC, Lees AJ, Thompson EJ, Giovannoni G (2002) Anti-basal ganglia antibodies in acute and persistent Sydenham’s chorea. Neurology 59(2):227–231

    Article  CAS  PubMed  Google Scholar 

  21. Vincent A (2004) Encephalitis lethargica: part of a spectrum of post-streptococcal autoimmune diseases? Brain 127(Pt 1):2–3

    Article  PubMed  Google Scholar 

  22. Singer HS, Hong JJ, Yoon DY, Williams PN (2005) Serum autoantibodies do not differentiate PANDAS and Tourette syndrome from controls. Neurology 65(11):1701–1707

    Article  CAS  PubMed  Google Scholar 

  23. Rosenow EC (1922) Experimental studies on the etiology of encephalitis. JAMA 79:443–448

    Article  Google Scholar 

  24. Rosenow EC (1924) Streptococci in relation to etiology of epidemic encephalitis. Experimental results in eighty-one cases. J Infect Dis 34:329–389

    Article  Google Scholar 

  25. Claassen DO, Boes CJ (2009) Rosenow’s rabbits and postencephalitic parkinsonism. Neurology 73(15):1240–1241

    Article  PubMed  Google Scholar 

  26. Dale RC, Merheb V, Pillai S, Wang D, Cantrill L, Murphy TK, Ben-Pazi H, Varadkar S, Aumann TD, Horne MK, Church AJ, Fath T, Brilot F (2012) Antibodies to surface dopamine-2 receptor in autoimmune movement and psychiatric disorders. Brain 135(Pt 11):3453–3468

    Article  PubMed  Google Scholar 

  27. Dale RC, Irani SR, Brilot F, Pillai S, Webster R, Gill D, Lang B, Vincent A (2009) N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol 66(5):704–709

    Article  CAS  PubMed  Google Scholar 

  28. Armangue T, Olivé-Cirera G, Martínez-Hernandez E, Rodes M, Peris-Sempere V, Guasp M, Ruiz R, Palou E, González A, Marcos MÁ, Erro ME (2023) Neurologic complications in herpes simplex encephalitis: clinical, immunological and genetic studies. Brain:awad238. https://doi.org/10.1093/brain/awad238

  29. Vogrig A, Muñiz-Castrillo S, Desestret V, Joubert B, Honnorat J (2020) Pathophysiology of paraneoplastic and autoimmune encephalitis: genes, infections, and checkpoint inhibitors. Ther Adv Neurol Disord 13:1756286420932797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Howard RS, Lees AJ (1987) Encephalitis lethargica. A report of four recent cases. Brain 110(Pt 1):19–33

    Article  PubMed  Google Scholar 

  31. Damato V, Balint B, Kienzler AK, Irani SR (2018) The clinical features, underlying immunology, and treatment of autoantibody-mediated movement disorders. Mov Disord 33(9):1376–1389

    Article  PubMed  PubMed Central  Google Scholar 

  32. Muñoz-Lopetegi A, Graus F, Dalmau J, Santamaria J (2020) Sleep disorders in autoimmune encephalitis. Lancet Neurol 19(12):1010–1022

    Article  PubMed  Google Scholar 

  33. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15(4):391–404

    Article  PubMed  PubMed Central  Google Scholar 

  34. Di Vito A, Donato A, Bria J, Donato F, Donato G (2023) Encephalitis lethargica. What is still wrong? Int J Immunopathol Pharmacol 37:3946320231154997

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurology, Hospital of Merano (SABES-ASDAA), Merano-Meran, Italy

    Francesco Brigo

  2. Lehrkrankenhaus der Paracelsus Medizinischen Privatuniversität, Salzburg, Austria

    Francesco Brigo

  3. Clinical Neurology, Santa Maria Della Misericordia University Hospital, Azienda Sanitaria Universitaria Friuli Centrale (ASU FC), Udine, Italy

    Alberto Vogrig

  4. Department of Medicine (DAME), University of Udine, Udine, Italy

    Alberto Vogrig

Authors
  1. Francesco Brigo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alberto Vogrig
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Francesco Brigo conceived and wrote the article; Alberto Vogrig revised it critically for important intellectual content.

Corresponding author

Correspondence to Francesco Brigo.

Ethics declarations

Ethical approval

Not required.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brigo, ., Vogrig, A. Back to the future: encephalitis lethargica as an autoimmune disorder?. Neurol Sci 45, 93–99 (2024). https://doi.org/10.1007/s10072-023-07053-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-023-07053-8

Keywords

Search

Navigation