“NMDA receptor spectrum disorder” in the differential diagnosis of demyelinating disorders of the CNS: optic neuritis and myelitis



The aim of this study was to investigate the frequency of anti-N-methyl-D-aspartate receptor (anti-NMDAR) antibody positivity in patients presenting with transverse myelitis (TM) and/or optic neuritis (ON), to describe their neurologic and radiological characteristics, and to compare these characteristics with those reported in previous studies.

Material and methods

This study included 179 patients (ON: 96, TM: 74, ON and TM: 9) who visited Isfahan Multiple Sclerosis Center from January 2017 to September 2019, for approximately 32 months. The respective neurological examinations were performed. Demographic data of the patients, as well as findings from radiological and serological investigations were obtained.


Frequencies of anti-NMDAR seropositivity in patients with TM, ON, and concurrent TM and ON were approximately 3.4%, 1.4%, and 11.1%, respectively. None exhibited any psychiatric symptoms.


Based on the frequency of seropositivity for anti-NMDAR antibody in our patients, positivity for this antibody appears to be more frequent than previously anticipated in patients presenting with these conditions. We recommend that the anti-NMDAR antibody presence in CSF/serum be checked and considered in addition to the routine examinations performed upon confronting demyelinating conditions such as TM and ON. We suggest considering the term “NMDAR spectrum disorder” to more clearly distinguish the potentially overlapping conditions with different etiologies in patients with CNS disorders.

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

Fig. 1


  1. 1.

    Solimena M, Folli F, Denis-Donini S, Comi GC, Pozza G, De Camilli P, Vicari AM (1988) Autoantibodies to glutamic acid decarboxylase in a patient with stiff-man syndrome, epilepsy, and type I diabetes mellitus. N Engl J Med 318(16):1012–1020

    CAS  Article  Google Scholar 

  2. 2.

    Clapham DE (2007) Calcium signaling. Cell 131(6):1047–1058

    CAS  Article  Google Scholar 

  3. 3.

    Li F, Tsien JZ (2009) Memory and the NMDA receptors. N Engl J Med 361(3):302–303

    CAS  Article  Google Scholar 

  4. 4.

    Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14(6):383–400

    CAS  Article  Google Scholar 

  5. 5.

    Rosenfeld MR, Dalmau J (2011) Anti–NMDA-receptor encephalitis and other synaptic autoimmune disorders. Curr Treat Options Neurol 13(3):324–332

    Article  Google Scholar 

  6. 6.

    Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A et al (2007) Paraneoplastic anti–N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 61(1):25–36

    CAS  Article  Google Scholar 

  7. 7.

    Schermann H, Ponomareva IV, Maltsev VG, Yakushev KB, Sherman MA (2019) Clinical variants of limbic encephalitis. SAGE Open Med Case Rep 7:2050313X19846042

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Graus F, Saiz A, Dalmau J (2010) Antibodies and neuronal autoimmune disorders of the CNS. J Neurol 257(4):509–517

    CAS  Article  Google Scholar 

  9. 9.

    Cobo-Calvo Á, Gracia CI, Quiñones SM, Torro CM, Saiz A, Dalmau J, Martínez-Yélamos S (2014) Optic neuritis in the setting of NMDA receptor encephalitis. J Neuroophthalmol 34(3):316–319

    Article  Google Scholar 

  10. 10.

    Takei K, Sato M, Nakamura M, Shimizu H (2015) Longitudinally extensive transverse myelitis with anti-NMDA receptor antibodies during a systemic lupus erythematosus flare-up. Case Reports 2015:bcr2015212112

    Google Scholar 

  11. 11.

    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(12):1091–1098

    CAS  Article  Google Scholar 

  12. 12.

    Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T et al (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15(4):391–404

    Article  Google Scholar 

  13. 13.

    Liu CY, Zhu J, Zheng XY, Ma C, Wang X (2017) Anti-N-methyl-D-aspartate receptor encephalitis: a severe, potentially reversible autoimmune encephalitis. Mediat Inflamm 2017:1–14

    Google Scholar 

  14. 14.

    Yoshimura B, Takaki M (2017) Anti-NMDA receptor antibody positivity and presentations without seizure, involuntary movement, hypoventilation, or tumor: a systematic review of the literature. J Neuropsychiatry Clin Neurosci 29(3):267–274

    Article  Google Scholar 

  15. 15.

    Beasley SJ, Greer JMJC, Neuroimmunology E (2015) Autoantibodies and their potential roles in diseases of the nervous system. 6(4):370–386

  16. 16.

    Káradóttir R, Cavelier P, Bergersen LH, Attwell D (2005) NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438(7071):1162–1166

    Article  Google Scholar 

  17. 17.

    Titulaer MJ, Höftberger R, Iizuka T, Leypoldt F, McCracken L, Cellucci T et al (2014) Overlapping demyelinating syndromes and anti–N-methyl-D-aspartate receptor encephalitis. Ann Neurol 75(3):411–428

    CAS  Article  Google Scholar 

  18. 18.

    Ramberger M, Bsteh G, Schanda K, Höftberger R, Rostásy K, Baumann M, Aboulenein-Djamshidian F, Lutterotti A, Deisenhammer F, Berger T, Reindl M (2015) NMDA receptor antibodies: a rare association in inflammatory demyelinating diseases. Neurology-Neuroimmunol Neuroinflamm 2(5):e141

    Article  Google Scholar 

  19. 19.

    Salter MG, Fern R (2005) NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature 438(7071):1167–1171

    CAS  Article  Google Scholar 

  20. 20.

    Dambinova SA, Khounteev GA, Izykenova GA, Zavolokov IG, Ilyukhina AY, Skoromets AA (2003) Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem 49(10):1752–1762

    CAS  Article  Google Scholar 

  21. 21.

    Izykenova G, Granstrem O, Gappoeva M, Dambinova S (2001) Autoantibodies to NMDA receptor in chronic cerebral ischemia. J Stroke Cerebrovasc Dis 10:195

    Google Scholar 

  22. 22.

    Bokesch PM, Izykenova GA, Justice JB, Easley KA, Dambinova SA (2006) NMDA receptor antibodies predict adverse neurological outcome after cardiac surgery in high-risk patients. Stroke 37(6):1432–1436

    CAS  Article  Google Scholar 

  23. 23.

    Kolls BJ, Meyer RL (2013) N-methyl-D-aspartate receptors strongly regulate postsynaptic activity levels during optic nerve regeneration. J Neurosci Res 91(10):1263–1279

    CAS  Article  Google Scholar 

  24. 24.

    Li C, Xiao L, Liu X, Yang W, Shen W, Hu C, Yang G, He C (2013) A functional role of NMDA receptor in regulating the differentiation of oligodendrocyte precursor cells and remyelination. Glia 61(5):732–749

    Article  Google Scholar 

  25. 25.

    Hacohen Y, Absoud M, Hemingway C, Jacobson L, Lin JP, Pike M et al (2014) NMDA receptor antibodies associated with distinct white matter syndromes. Neurology-Neuroimmunol Neuroinflamm 1(1):e2

    Article  Google Scholar 

  26. 26.

    Yang HK, Kim JH, Park YH, Park KS, Kim JS, Hwang JM (2017) Anti-NMDA-receptor optic neuritis in a patient with a history of encephalitis. Can J Ophthalmol 52(6):e216–e218

    Article  Google Scholar 

  27. 27.

    Ishikawa N, Tajima G, Hyodo S, Takahashi Y, Kobayashi M (2007) Detection of autoantibodies against NMDA-type glutamate receptor in a patient with recurrent optic neuritis and transient cerebral lesions. Neuropediatrics 38(05):257–260

    CAS  Article  Google Scholar 

  28. 28.

    Johnston J, Ali K, Pearson OR, Rickards C, Vincent A (2010) POI14 multiple sclerosis: a potential association with anti-N-methyl-d-aspartate receptor encephalitis. J Neurol Neurosurg Psychiatry 81(11):e56–e56

    Article  Google Scholar 

  29. 29.

    Lekoubou A, Viaccoz A, Didelot A, Anastasi A, Marignier R, Ducray F, Rogemond V, Honnorat J (2012) Anti-N-methyl-D-aspartate receptor encephalitis with acute disseminated encephalomyelitis-like MRI features. Eur J Neurol 19(2):e16–e17

    CAS  Article  Google Scholar 

  30. 30.

    Pennington C, Livingstone S, Santosh C, Razvi S (2012) N-methyl D-aspartate receptor antibody encephalitis associated with myelitis. J Neurol Sci 317(1–2):151–153

    Article  Google Scholar 

  31. 31.

    Takeda A, Shimada H, Tamura A, Yasui M, Yamamoto KI, Itoh K et al (2014) A case of anti-N-methyl-D-aspartate receptor encephalitis with multiple sclerosis-like demyelinated lesions. Multiple Scler Relat Disord 3(3):391–397

    Article  Google Scholar 

  32. 32.

    Kruer MC, Koch TK, Bourdette DN, Chabas D, Waubant E, Mueller S, Moscarello MA, Dalmau J, Woltjer RL, Adamus G (2010) NMDA receptor encephalitis mimicking seronegative neuromyelitis optica. Neurology 74(18):1473–1475

    CAS  Article  Google Scholar 

  33. 33.

    Outteryck O, Baille G, Hodel J, Giroux M, Lacour A, Honnorat J, Zéphir H, Vermersch P (2013) Extensive myelitis associated with anti-NMDA receptor antibodies. BMC Neurol 13(1):211

    Article  Google Scholar 

Download references

Author information




The main idea of the study was presented by Prof. Masoud Etemadifar. Ali Aghababaee and Fatemeh Hashemi performed the literature search and gathered the previously published data, Mohammad Hasan Khayati and Reza Khorvash assisted with the data collection and analysis, and Hosein Nouri and Amir Parsa Abhari prepared the manuscript, with the supervision of Prof. Etemadifar and critical revisions from Fatemeh Sabeti, Mazdak Ganjalikhani-Hakemi, and Mehri Salari, throughout the whole process of the study.

Corresponding author

Correspondence to Hosein Nouri.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval


Additional information

Publisher’s note

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

Electronic supplementary material


(PDF 601 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Etemadifar, M., Abhari, A.P., Sabeti, F. et al. “NMDA receptor spectrum disorder” in the differential diagnosis of demyelinating disorders of the CNS: optic neuritis and myelitis. Neurol Sci (2020). https://doi.org/10.1007/s10072-020-04518-y

Download citation


  • NMDA receptor
  • Optic neuritis
  • Transverse myelitis
  • NMDAR spectrum disorder