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Reply to: N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness

  • Matthew S. Kayser
    Correspondence
    Address correspondence to Matthew S. Kayser, M.D., Ph.D., Translational Research Laboratory, Perelman School of Medicine at the University of Pennsylvania, 125 South 31st Street, Suite 2200, Philadelphia, PA 19104.
    Affiliations
    Departments of Psychiatry, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania

    Neuroscience, and Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania
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  • Josep Dalmau
    Affiliations
    Neurology, Perelman School of Medicine at The University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Neurology, Hospital Clinic, Barcelona, Spain
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      We appreciate the letter of Zandi et al. It raises important points related to the specificity of laboratory techniques used for N-methyl-D-aspartate receptor (NMDAR) antibody determination. However, Zandi et al. indicate they “seldom have problems with nonspecific binding of serum, which is more common with fixed cells as used in many laboratories.” In fact, their data show the opposite: In their own study, 23.2% of the patients had nonspecific binding of serum and were classified as “unlikely autoimmune encephalitis” (
      • Zandi M.S.
      • Paterson R.W.
      • Ellul M.A.
      • Jacobson L.
      • Al-Diwani A.
      • Jones J.L.
      • et al.
      Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes.
      ). That is, 23.2% of the patients with evidence of serum-positive NMDAR antibodies did not have anti-NMDAR encephalitis or autoimmune diseases (e.g., leukodystrophy, atypical motor neuron disease, central nervous system vasculitis, brain tumor). This figure is substantially higher than figures reported by other investigators (
      • Dahm L.
      • Ott C.
      • Steiner J.
      • Stepniak B.
      • Teegen B.
      • Saschenbrecker S.
      • et al.
      Seroprevalence of autoantibodies against brain antigens in health and disease.
      ). Zandi et al. indicate that the clinical relevance of the antibodies can be demonstrated through coupling of antibody removal and clinical improvement. To support this statement, they cite a study in which 9 of 18 patients with serum-positive NMDAR antibodies and acute psychosis were treated with immunotherapy; 8 of 9 patients showed improvement (
      • Zandi M.S.
      • Deakin J.B.
      • Morris K.
      • Buckley C.
      • Jacobson L.
      • Scoriels L.
      • et al.
      Immunotherapy for patients with acute psychosis and serum N-methyl D-aspartate receptor (NMDAR) antibodies: A description of a treated case series.
      ). This patient selection, the significance of the findings without control subjects, and whether the improvement was related to specific antibody removal or nonspecific change of underlying inflammatory mechanisms are unclear. The fact that the test of Zandi et al. produces a substantial percentage of nonspecific serum binding is not without consequence (
      • Armangue T.
      • Santamaria J.
      • Dalmau J.
      When a serum test overrides the clinical assessment.
      ). Zandi et al. point out that the field needs 1) to determine the most sensitive and specific methods of antibody testing and 2) controlled treatment trials with patients at the borderline of psychiatry and neurology. The first of these needs has already been addressed by several investigators (
      • Gresa-Arribas N.
      • Titulaer M.J.
      • Torrents A.
      • Aguilar E.
      • McCracken L.
      • Leypoldt F.
      • et al.
      Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study.
      ,
      • Ramberger M.
      • Peschl P.
      • Schanda K.
      • Irschick R.
      • Hoftberger R.
      • Deisenhammer F.
      • et al.
      Comparison of diagnostic accuracy of microscopy and flow cytometry in evaluating N-methyl-D-aspartate receptor antibodies in serum using a live cell-based assay.
      ) using assays with higher specificity and sensitivity (not cited by Zandi et al.). The second requirement can be addressed only by using these highly specific tests in serum and cerebrospinal fluid; this requires spinal taps, which continue to be difficult to obtain in patients with psychosis.
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      References

        • Zandi M.S.
        • Paterson R.W.
        • Ellul M.A.
        • Jacobson L.
        • Al-Diwani A.
        • Jones J.L.
        • et al.
        Clinical relevance of serum antibodies to extracellular N-methyl-d-aspartate receptor epitopes.
        J Neurol Neurosurg Psychiatry. 2015; 86: 708-713
        • Dahm L.
        • Ott C.
        • Steiner J.
        • Stepniak B.
        • Teegen B.
        • Saschenbrecker S.
        • et al.
        Seroprevalence of autoantibodies against brain antigens in health and disease.
        Ann Neurol. 2014; 76: 82-94
        • Zandi M.S.
        • Deakin J.B.
        • Morris K.
        • Buckley C.
        • Jacobson L.
        • Scoriels L.
        • et al.
        Immunotherapy for patients with acute psychosis and serum N-methyl D-aspartate receptor (NMDAR) antibodies: A description of a treated case series.
        Schizophr Res. 2014; 160: 193-195
        • Armangue T.
        • Santamaria J.
        • Dalmau J.
        When a serum test overrides the clinical assessment.
        Neurology. 2015; 84: 1379-1381
        • Gresa-Arribas N.
        • Titulaer M.J.
        • Torrents A.
        • Aguilar E.
        • McCracken L.
        • Leypoldt F.
        • et al.
        Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study.
        Lancet Neurol. 2014; 13: 167-177
        • Ramberger M.
        • Peschl P.
        • Schanda K.
        • Irschick R.
        • Hoftberger R.
        • Deisenhammer F.
        • et al.
        Comparison of diagnostic accuracy of microscopy and flow cytometry in evaluating N-methyl-D-aspartate receptor antibodies in serum using a live cell-based assay.
        PLoS One. 2015; 10: e0122037

      Linked Article

      • N-Methyl-D-Aspartate Receptor Autoantibodies in Psychiatric Illness
        Biological PsychiatryVol. 79Issue 9
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          We would like to respond to the comments made in a recent editorial (1) concerning the article by Pathmanandavel et al. (2). We agree the technique for detection of N-methyl-D-aspartate receptor (NMDAR) autoantibodies is critical and that cerebrospinal fluid is a useful material for identifying patients with classic “anti-NMDAR” encephalitis. However, the cell-based assays that Kayser (1) refers to can be done either with live cells or with permeabilized/fixed human embryonic kidney cells expressing NMDAR subunits (NR1 with or without NR2B).
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