Skip to main content
Log in

Anti-N-methyl-D-aspartate receptor encephalitis: a prospective study focused on cerebrospinal fluid and clinical symptoms

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

Abstract

Background and objective

To analyze the relationship between brain MRI, clinical symptoms, and cerebrospinal fluid (CSF) and to provide a reference for early diagnosis of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Materials and Methods

A total of 62 patients with anti-NMDAR encephalitis in Zhengzhou, China (2016–2018) were observed and registered prospectively. First, we analyzed the characteristics of clinical symptoms. Second, according to the disease duration, patients were divided into two groups, and then we analyzed the CSF features. In addition, they were divided into two groups according to the brain MRI, and then the CSF features were analyzed. Finally, the characteristics of cerebrospinal fluid in patients with seizure as the initial symptom were analyzed.

Results

Seizure presents as the initial symptom in 14 patients (22.5%), including 11 males (78.57%). The proportion and concentration of CSF total protein abnormalities in the early stage group were significantly higher than those in the middle and late group (P < 0.05). The total protein concentration in the abnormal brain MRI group was significantly higher than that in the normal MRI group (P < 0.05).

Conclusion

Anti-NMDAR encephalitis should be suspected, when male patients complain of seizure as an initial symptom and have simultaneously had headaches or fever prior to onset. The sensitivity of anti-NMDAR antibody is higher in CSF than in serum. Total CSF protein is more prone to elevation in the middle and late stages of anti-NMDAR encephalitis. Brain MRI abnormalities with anti-NMDAR encephalitis are related to the total protein concentration of CSF, which may be related to the disease duration.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, Dessain SK, Rosenfeld MR, Balice-Gordon R, Lynch DR (2008) Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 7:1091–1098. https://doi.org/10.1016/S1474-4422(08)70224-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Armangue T, Titulaer MJ, Málaga I, Bataller L, Gabilondo I, Graus F, Dalmau J, Spanish Anti-N-methyl-D-Aspartate Receptor (NMDAR) Encephalitis Work Group (2013) Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients. J Pediatr 162:850–856. https://doi.org/10.1016/j.jpeds

    Article  CAS  PubMed  Google Scholar 

  3. Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Höftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Prüss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostásy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404. https://doi.org/10.1016/S1474-4422(15)00401-9

    Article  PubMed  PubMed Central  Google Scholar 

  4. Titulaer MJ, McCracken L, Gabilondo I et al (2013) Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis:an observational cohort study. Lancet Neurol 12:157–165. https://doi.org/10.1016/S1474-4422(12)70310-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang R, Guan HZ, Ren H, Wang W, Hong Z, Zhou D (2015) CSF findings in patients with anti-N-metIlyl-D-aspartate receptor-encephalitis. Seizure 29:137–142. https://doi.org/10.1016/j.seizure.2015.04.005

    Article  CAS  PubMed  Google Scholar 

  6. Deng B, Chen XJ, Li X et al (2016) Analysis of the cerebrospinal fluid abnormalities and their correlation with disease course in patients with anti-N-methyl-D-aspartate receptor encephalitis. Chin J Clin Neurosci 24:528–534

    Google Scholar 

  7. Gastaldi M, Zardini E, Leante R et al (2017) Cerebrospinal fluid analysis and the determination of oligoclonal bands. Neurol Sci 38:217–224. https://doi.org/10.1007/s10072-017-3034-2

    Article  PubMed  Google Scholar 

  8. Malter MP, Elger CE, Surges R (2013) Diagnostic value of CSF findings in antibody associated limbic and anti-NMDAR-encephalitis. Seizure 22:136–140. https://doi.org/10.1016/j.seizure.2012.12.013

    Article  PubMed  Google Scholar 

  9. Reiber H (1998) Cerebrospinal fluid--physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases. Mult Scler 4:99–107. https://doi.org/10.1177/135245859800400302

    Article  CAS  PubMed  Google Scholar 

  10. Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Öhman S, Racke MK, Sharief M, Sindic CJM, Sellebjerg F, Tourtellotte WW (2005) Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 62:865–870. https://doi.org/10.1001/archneur.62.6.865

    Article  PubMed  Google Scholar 

  11. Zuliani L, Zoccarato M, Gastaldi M et al (2017) Diagnostics of autoimmune encephalitis associated with antibodies against neuronal surface antigens. Neurol Sci 38:225–229. https://doi.org/10.1007/s10072-017-3032-4

    Article  PubMed  Google Scholar 

  12. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R (2011) Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 10:63–74. https://doi.org/10.1016/S1474-4422(10)70253-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Viaccoz A, Desestret V, Ducray F et al (2014) Clinical specificities of adult male patients with NMDA receptor antibodies encephalitis. Neurology 82:556–563. https://doi.org/10.1093/cid/cir1038

    Article  CAS  PubMed  Google Scholar 

  14. Woolley CS, McEwen BS (1994) Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor dependent mechanism. J Neurosci 14:7680–7687

    Article  CAS  Google Scholar 

  15. Lynch JJ 3rd, Shek EW, Castagne V, Mittelstadt SW (2010) The proconvulsant effects of leptin on glutamate receptor mediated seizures in mice. Brain Res Bull 82:99–103. https://doi.org/10.1016/j.brainresbull.2010.02.003

    Article  CAS  PubMed  Google Scholar 

  16. Pennell PB (2009) Hormonal aspects of epilepsy. Neurol Clin 27:941–965. https://doi.org/10.1016/j.ncl.2009.08.005

    Article  PubMed  PubMed Central  Google Scholar 

  17. Kalkbrenner KA, Standley CA (2003) Estrogen modulation of NMDA-induced seizures in ovariectomized and non-ovariectomized rats. Brain Res 964:244–249. https://doi.org/10.1016/s0006-8993(02)04065-9

    Article  CAS  PubMed  Google Scholar 

  18. Wang Y, Xueqiang H, Xueping Z et al (2013) The clinical significance of cerebrospinal fluid oligoclonal bands for multiple sclerosis. Chin J Neuroimmunol 20:153–155

    CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  20. Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, Kästner A, Skalej M, Jordan W, Schiltz K, Klingbeil C, Wandinger KP, Bogerts B, Stoecker W (2013) Increased prevalence of diverse N -methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry 70:1–8. https://doi.org/10.1001/2013.jamapsychiatry.86

    Article  Google Scholar 

  21. Zerche M, Weissenborn K, Ott C, Dere E, Asif AR, Worthmann H, Hassouna I, Rentzsch K, Tryc AB, Dahm L, Steiner J, Binder L, Wiltfang J, Sirén AL, Stöcker W, Ehrenreich H (2015) Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke 46:1180–1186. https://doi.org/10.1161/STROKEAHA.114.008323

    Article  CAS  PubMed  Google Scholar 

  22. Busse S, Busse M, Brix B, Probst C, Genz A, Bogerts B, Stoecker W, Steiner J (2014) Seroprevalence of N-methyl-D-aspartate glutamate receptor (NMDA-R) autoantibodies in aging subjects without neuropsychiatric disorders and in dementia patients. Eur Arch Psychiatry Clin Neurosci 264:545–550. https://doi.org/10.1007/s00406-014-0493-9

    Article  PubMed  Google Scholar 

  23. Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, Hammer C, Borowski K, Begemann M, Lemke S, Rentzsch K, Probst C, Martens H, Wienands J, Spalletta G, Weissenborn K, Stöcker W, Ehrenreich H (2014) Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol 76:82–94. https://doi.org/10.1002/ana.24189

    Article  CAS  PubMed  Google Scholar 

  24. Titulaer MJ, Hoftberger R, Iizuka T et al (2014) Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis. Ann Neurol 75:411–428. https://doi.org/10.1002/ana.24117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dalmau J, Rosenfeld MR (2008) Paraneoplastic syndromes of the CNS. Lancet Neurol 7:327–340. https://doi.org/10.1016/S1474-4422(08)70060-7

    Article  PubMed  PubMed Central  Google Scholar 

  26. Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, Baehring JM, Shimazaki H, Koide R, King D, Mason W, Sansing LH, Dichter MA, Rosenfeld MR, Lynch DR (2007) Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61:25–36. https://doi.org/10.1002/ana.21050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank the patients for their collaboration.

Funding

This study was supported by the grant from the National Natural Science Foundation of China (81371438) and the National Natural Science Foundation of China (81771397).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Yajun Lian or Zhengrong Mao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The Ethics Committee of the First Affiliated Hospital of Zhengzhou University approved this study (number: KY-2015-51).

Informed consent

All subjects gave their informed consent prior to their inclusion in the study.

Additional information

Publisher’s note

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

Electronic supplementary material

ESM 1

(XLSX 20 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, S., Li, H., Lian, Y. et al. Anti-N-methyl-D-aspartate receptor encephalitis: a prospective study focused on cerebrospinal fluid and clinical symptoms. Neurol Sci 41, 3255–3263 (2020). https://doi.org/10.1007/s10072-020-04451-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-020-04451-0

Keywords

Navigation