Skip to main content

Advertisement

SpringerLink
Log in

NMDA-receptor encephalitis in Denmark from 2009 to 2019: a national cohort study

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

To describe the national Danish N-methyl-d-aspartate receptor encephalitis (NMDARE) cohort.

Methods

All NMDAR immunoglobulin G (IgG) positive cases in Denmark from 2009 to 2019 were included. Medical information was assessed retrospectively for clinical phenotype, workup, treatment and outcome.

Results

Seventy-seven patients were NMDAR IgG positive in serum/CSF. Fifty-five fulfilled the criteria of NMDARE, 18 did not and 4 had missing data. Incidence was 0.17/100,000 persons per year in 2018, and incidence rates increased since 2009. Of the 55 NMDARE patients (median age 27; 60% female), 9 had post-herpes simplex (HSE) NMDARE and 7 had a tumor (four teratomas). MRI was normal in 51% of patients. Brain FDG PET was performed in 17 patients, and was abnormal in 47% of patients with a normal MRI. First-line therapy was administered to 91%, and 24% required second-line therapy. Maintenance therapy during recovery was given 84% of patients, with no effect on relapse-risk. ICU admission occurred in 29%. Poor outcome (mRS > 2) was reported in 27% and dependent on age and etiology. Patients > 45 years had a poorer outcome (71% vs 8%, p < 0.0001), more frequently post-HSE NMDARE (47% vs 3%, p < 0.0001) and underlying malignancies (18% vs 0%).

Conclusion

The incidence of NMDARE in Denmark is currently 0.17/100,000 persons per year, and has increased since 2009. NMDARE patients in Denmark display a higher median age, lower female:male ratio, a less frequent tumor association and need for ICU admission. Maintenance therapy did not reduce relapse rate. Poor outcome was seen with higher age, likely related to underlying etiology.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability statement

Anonymized patient data, the statistical analysis plan and supplementary data not published within this article will be made available for purposes of replicating results by request from any qualified investigator.

References

  1. Dalmau J et al (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7(12):1091–1098. https://doi.org/10.1016/s1474-4422(08)70224-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Dalmau J et al (2019) An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models. Lancet Neurol 18(11):1045–1057. https://doi.org/10.1016/S1474-4422(19)30244-3

    Article  CAS  PubMed  Google Scholar 

  3. Titulaer MJ et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 12(2):157–165. https://doi.org/10.1016/s1474-4422(12)70310-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bien CG et al (2012) Immunopathology of autoantibody-associated encephalitides: clues for pathogenesis. Brain 135(Pt 5):1622–1638. https://doi.org/10.1093/brain/aws082

    Article  PubMed  Google Scholar 

  5. Abboud H et al (2021) Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management. J Neurol Neurosurg Psychiatry 92(7):757–768. https://doi.org/10.1136/jnnp-2020-325300

    Article  PubMed  Google Scholar 

  6. Dalmau J, Graus F (2018) Antibody-mediated encephalitis. N Engl J Med 378(9):840–851. https://doi.org/10.1056/NEJMra1708712

    Article  PubMed  Google Scholar 

  7. McKeon G et al (2020) The patient experience of recovery following anti-NMDA receptor encephalitis: a qualitative content analysis. J Neuropsychiatry Clin Neurosci. https://doi.org/10.1176/appi.neuropsych.20030049

    Article  PubMed  Google Scholar 

  8. McKeon GL et al (2018) Cognitive outcomes following anti-N-methyl-d-aspartate receptor encephalitis: a systematic review. J Clin Exp Neuropsychol 40(3):234–252. https://doi.org/10.1080/13803395.2017.1329408

    Article  PubMed  Google Scholar 

  9. Finke C et al (2012) Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 83(2):195–198. https://doi.org/10.1136/jnnp-2011-300411

    Article  PubMed  Google Scholar 

  10. Graus F et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15(4):391–404. https://doi.org/10.1016/S1474-4422(15)00401-9

    Article  PubMed  PubMed Central  Google Scholar 

  11. Zandi MS et al (2015) Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes. J Neurol Neurosurg Psychiatry 86(7):708–713. https://doi.org/10.1136/jnnp-2014-308736

    Article  PubMed  Google Scholar 

  12. Gresa-Arribas N et al (2014) Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 13(2):167–177. https://doi.org/10.1016/s1474-4422(13)70282-5

    Article  CAS  PubMed  Google Scholar 

  13. Hara M et al (2018) Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor. Neurology 90(16):e1386–e1394. https://doi.org/10.1212/WNL.0000000000005329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ruiz-García R et al (2021) Limitations of a commercial assay as diagnostic test of autoimmune encephalitis. Front Immunol 12:691536. https://doi.org/10.3389/fimmu.2021.691536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vitaliani R et al (2005) Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 58(4):594–604. https://doi.org/10.1002/ana.20614

    Article  PubMed  PubMed Central  Google Scholar 

  16. de Montmollin E et al (2017) Anti-N-methyl-d-aspartate receptor encephalitis in adult patients requiring intensive care. Am J Respir Crit Care Med 195(4):491–499. https://doi.org/10.1164/rccm.201603-0507OC

    Article  PubMed  Google Scholar 

  17. Zekeridou A et al (2015) Treatment and outcome of children and adolescents with N-methyl-d-aspartate receptor encephalitis. J Neurol 262(8):1859–1866. https://doi.org/10.1007/s00415-015-7781-9

    Article  CAS  PubMed  Google Scholar 

  18. Titulaer MJ et al (2014) Overlapping demyelinating syndromes and anti-N-methyl-d-aspartate receptor encephalitis. Ann Neurol 75(3):411–428. https://doi.org/10.1002/ana.24117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Martinez-Hernandez E et al (2020) Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies. Neurology 94(22):e2302–e2310. https://doi.org/10.1212/wnl.0000000000009239

    Article  CAS  PubMed  Google Scholar 

  20. Armangue T et al (2014) Herpes simplex virus encephalitis is a trigger of brain autoimmunity. Ann Neurol 75(2):317–323. https://doi.org/10.1002/ana.24083

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pruss H et al (2012) N-Methyl-d-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol 72(6):902–911. https://doi.org/10.1002/ana.23689

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Armangue T et al (2018) Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis. Lancet Neurol 17(9):760–772. https://doi.org/10.1016/S1474-4422(18)30244-8

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nosadini M et al (2017) Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases. Dev Med Child Neurol 59(8):796–805. https://doi.org/10.1111/dmcn.13448

    Article  PubMed  Google Scholar 

  24. Titulaer MJ et al (2013) Late-onset anti-NMDA receptor encephalitis. Neurology 81(12):1058–1063. https://doi.org/10.1212/WNL.0b013e3182a4a49c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Abboud H et al (2021) Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management. J Neurol Neurosurg Psychiatry. https://doi.org/10.1136/jnnp-2020-325302

    Article  PubMed  Google Scholar 

  26. Ho ACC et al (2017) High sensitivity and specificity in proposed clinical diagnostic criteria for anti-N-methyl-d-aspartate receptor encephalitis. Dev Med Child Neurol 59(12):1256–1260. https://doi.org/10.1111/dmcn.13579

    Article  PubMed  Google Scholar 

  27. Irani SR et al (2010) N-Methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 133(Pt 6):1655–1667. https://doi.org/10.1093/brain/awq113

    Article  PubMed  PubMed Central  Google Scholar 

  28. Viaccoz A et al (2014) Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 82(7):556–563. https://doi.org/10.1212/WNL.0000000000000126

    Article  CAS  PubMed  Google Scholar 

  29. Florance NR et al (2009) Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 66(1):11–18. https://doi.org/10.1002/ana.21756

    Article  PubMed  PubMed Central  Google Scholar 

  30. Jørgensen LK et al (2017) Incidence and mortality of herpes simplex encephalitis in Denmark: a nationwide registry-based cohort study. J Infect 74(1):42–49. https://doi.org/10.1016/j.jinf.2016.09.004

    Article  PubMed  Google Scholar 

  31. Erickson TA et al (2020) Infectious and autoimmune causes of encephalitis in children. Pediatrics. https://doi.org/10.1542/peds.2019-2543

    Article  PubMed  Google Scholar 

  32. Gable MS et al (2012) The frequency of autoimmune N-methyl-d-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis 54(7):899–904. https://doi.org/10.1093/cid/cir1038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Dubey D et al (2018) Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis. Ann Neurol 83(1):166–177. https://doi.org/10.1002/ana.25131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Guasp M et al (2020) Clinical features of seronegative, but CSF antibody-positive, anti-NMDA receptor encephalitis. Neurol Neuroimmunol Neuroinflamm. https://doi.org/10.1212/NXI.0000000000000659

    Article  PubMed  PubMed Central  Google Scholar 

  35. Probasco JC et al (2017) Abnormal brain metabolism on FDG-PET/CT is a common early finding in autoimmune encephalitis. Neurol Neuroimmunol Neuroinflamm 4(4):e352. https://doi.org/10.1212/nxi.0000000000000352

    Article  PubMed  PubMed Central  Google Scholar 

  36. Solnes LB et al (2017) Diagnostic value of (18)F-FDG PET/CT versus MRI in the setting of antibody-specific autoimmune encephalitis. J Nucl Med 58(8):1307–1313. https://doi.org/10.2967/jnumed.116.184333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yuan J et al (2016) Changing brain metabolism patterns in patients with ANMDARE: serial 18F-FDG PET/CT findings. Clin Nucl Med 41(5):366–370. https://doi.org/10.1097/RLU.0000000000001164

    Article  PubMed  Google Scholar 

  38. Ganesh A, Bartolini L, Wesley SF (2020) Worldwide survey of neurologists on approach to autoimmune encephalitis. Neurol Clin Pract 10(2):140–148. https://doi.org/10.1212/CPJ.0000000000000701

    Article  PubMed  PubMed Central  Google Scholar 

  39. McKeon GL et al (2016) Cognitive and social functioning deficits after anti-N-methyl-d-aspartate receptor encephalitis: an exploratory case series. J Int Neuropsychol Soc 22(8):828–838. https://doi.org/10.1017/s1355617716000679

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This research was conducted using the Danish National Biobank resource, supported by the Novo Nordisk Foundation. Authors acknowledge the Autoimmune Laboratory at the Dept. of Clinical Immunology, Odense University Hospital and the Autoimmune Laboratory at Statens Serum Institut, Denmark. In addition, all the involved hospitals who kindly provided clinical information on patients.

Funding

MSN received grant support by Odense University Hospital and the Faculty of Health Sciences, University of Southern Denmark. No award/grant number.

Author information

Authors and Affiliations

  1. Department of Neurology, Odense University Hospital, J.B. Winsløws Vej 4, 5000, Odense C, Denmark

    Mette Scheller Nissen & Morten Blaabjerg

  2. Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Mette Scheller Nissen, Anna Christine Nilsson, Matias Ryding & Morten Blaabjerg

  3. Brain Research-Inter Disciplinary Guided Excellence (BRIDGE), Odense, Denmark

    Mette Scheller Nissen, Matias Ryding & Morten Blaabjerg

  4. Department of Neurology, Telemark Hospital, Skien, Norway

    Maren Synnøve Ørvik

  5. Department of Clinical Immunology, Odense University Hospital, Odense, Denmark

    Anna Christine Nilsson

  6. Danish National Biobank, Statens Serum Institut, Copenhagen, Denmark

    Magnus Lydolph

  7. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Morten Blaabjerg

Authors
  1. Mette Scheller Nissen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maren Synnøve Ørvik
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anna Christine Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matias Ryding
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Magnus Lydolph
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Morten Blaabjerg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Design and conceptualization: MB and MSN. Acquisition of data: MSN, MSØ, MR, ACN, and ML. Analysis and interpretation of the data: MSN and MB. Drafting and revising the manuscript: MSN, MSØ, ACN, MR, ML, and MB.

Corresponding authors

Correspondence to Mette Scheller Nissen or Morten Blaabjerg.

Ethics declarations

Conflicts of interest

The authors declare that they have no conflict of interest.

Standard protocol approvals, registrations, and patient consents

Approval was obtained from the Danish Data Protection Agency and the Danish Medical Authorities (3–3013-3124/1), who granted a waiver for patient consent.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 28 KB)

Supplementary file2 (DOCX 13 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Nissen, M.S., Ørvik, M.S., Nilsson, A.C. et al. NMDA-receptor encephalitis in Denmark from 2009 to 2019: a national cohort study. J Neurol 269, 1618–1630 (2022). https://doi.org/10.1007/s00415-021-10738-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-021-10738-9

Keywords

Search

Navigation