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Autoimmune/Paraneoplastic Encephalitis Antibody Biomarkers: Frequency, Age, and Sex Associations

  • Amy Kunchok
    Affiliations
    Mellen Center, Neurological Institute, Cleveland Clinic, Cleveland, OH

    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Andrew McKeon
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Anastasia Zekeridou
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Eoin P. Flanagan
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Divyanshu Dubey
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Vanda A. Lennon
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Immunology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Christopher J. Klein
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • John R. Mills
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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  • Sean J. Pittock
    Correspondence
    Correspondence: Address to Sean J. Pittock, MD, Department of Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.
    Affiliations
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN

    Department of Neurology, Mayo Clinic, Rochester, MN

    Center for Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, Rochester, MN
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Open AccessPublished:December 23, 2021DOI:https://doi.org/10.1016/j.mayocp.2021.07.023

      Abstract

      Objective

      To determine the frequency of detection and the age and sex associations of autoimmune/paraneoplastic encephalitis antibody biomarkers (AE-Abs).

      Methods

      There were 42,032 patients tested in the Mayo Clinic Neuroimmunology Laboratory between January 2018 and December 2019 for AE-Abs in serum or cerebrospinal fluid (CSF), including NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, CASPR2-IgG, LGI1-IgG, GAD65-IgG, CRMP5-IgG, amphiphysin-IgG, PCA1/2/Tr-IgGs, ANNA1/2/3-IgGs, GFAP-IgG, mGluR1-IgG, DPPX-IgG, and MOG-IgG1. Results were examined to determine frequency of antibody positivity. Age and sex associations were examined by multivariable logistic regression.

      Results

      Adult serum analysis (22,472 patients; 56% female) revealed that 814 (3.6%) were positive: NMDA-R-IgG (24.6%) > GAD65-IgG (21.5%) > LGI1-IgG (20.5%) > others. Of children (5649; 50% female), 251 (4.4%) were positive: NMDA-R-IgG (53.1%) > MOG-IgG1 (32%) > GAD65-IgG (7.1%) > others. Adult CSF analysis (18,745 patients; 54% female) revealed that 796 (4.2%) were positive: NMDA-R-IgG (39.7%) > GAD65-IgG (28.5%) > LGI1-IgG (11.4%) > others. Of children (5136; 50% female), 282 (5.5%) were positive: NMDA-R-IgG (88.1%) > GAD65-IgG (8.7%) > others. Age younger than 20 years was associated with NMDA-R-IgG and MOG-IgG1 (odds ratio [OR], 8.11 and 7.84, respectively; P<.001). Age older than 65 years was associated with GABAB-R-IgG, LGI1-IgG, CASPR2-IgG, and ANNA1-IgG (OR, 7.33, 14.98, 3.67, and 14.53; P<.001). Women accounted for 60% of NMDA-R-IgG (CSF) and 78% of GAD65-IgG (CSF and serum) cohorts (OR, 1.32 [P=.002] and 2.23 [P<.001], respectively). Men accounted for 62% of the LGI1-IgG cohort (OR, 1.87; P<.001). Age and sex interacted for NMDA-R-IgG, particularly in female patients younger than 20 years (OR, 7.72; P<.001).

      Conclusion

      The most frequent AE-Abs detected were NMDA-R-IgG, GAD65-IgG, LGI1-IgG, and MOG-IgG1. Age and sex associations may suggest paraneoplastic, or aging influences on neurologic autoimmunity.

      Abbreviations and Acronyms:

      AE-Ab (autoimmune/paraneoplastic encephalitis antibody), AMPA-R (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), ANNA1 (antineuronal nuclear antibody type 1 (also known as anti-Hu)), ANNA2 (antineuronal nuclear antibody type 2 (also known as anti-Ri)), ANNA3 (antineuronal nuclear antibody type 3), CASPR2 (contactin-associated protein–like 2), CBA (cell-based assay), CRMP5 (collapsin response mediator protein), CSF (cerebrospinal fluid), DPPX (dipeptidyl peptidase–like protein 6), GABAA-R (γ-aminobutyric acid (A) receptor), GABAB-R (γ-aminobutyric acid (B) receptor), GAD65 (glutamic acid decarboxylase (65-kD isoform)), GFAP (glial fibrillary acidic protein), KLHL11 (kelch-like-11), LGI1 (leucine-rich, glioma inactivated 1), mGlur1 (metabotropic glutamate receptor (type 1)), mGlur5 (metabotropic glutamate receptor (type 5)), MOG (myelin oligodendrocyte glycoprotein), NMDA-R (N-methyl-d-aspartate receptor), OR (odds ratio), PCA1 (Purkinje cell cytoplasmic antibody type 1 (also known as anti-Yo)), PCA2 (Purkinje cell cytoplasmic antibody type 2), PCA-Tr (Purkinje cell cytoplasmic antibody type Tr)
      Autoimmune/paraneoplastic encephalitis/encephalopathy (AE), although uncommon, is an increasingly recognized condition with several antibody (IgG) biomarkers (AE-Abs) that have transformed diagnosis. These include N-methyl-d-aspartate receptor (NMDA-R-IgG); α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R-IgG); leucine-rich, glioma-inactivated 1 (LGI1-IgG); contactin-associated protein–like 2 (CASPR2-IgG); γ-aminobutyric acid receptors A and B (GABAA-R-IgG, GABAB-R-IgG); myelin oligodendrocyte glycoprotein (MOG-IgG1); glutamic acid decarboxylase 65 (GAD65-IgG); glial fibrillary acidic protein (GFAP-IgG); antineuronal nuclear autoantibody types 1, 2, and 3 (ANNA1-IgG [Hu], ANNA2-IgG [Ri], ANNA3-IgG); Purkinje cell cytoplasmic antibody types 1, 2, and Tr (PCA1-IgG [Yo], PCA2-IgG, PCA-Tr-IgG); amphiphysin-IgG; dipeptidyl peptidase–like protein 6 (DPPX-IgG); metabotropic glutamate receptor 1 (mGluR1-IgG); and collapsin response mediator protein 5 (CRMP5-IgG).
      • Dalmau J.
      • Gleichman A.J.
      • Hughes E.G.
      • et al.
      Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies.
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody–associated encephalitis.
      • Van Sonderen A.
      • Petit-Pedrol M.
      • Dalmau J.
      • Titulaer M.J.
      The value of LGI1, Caspr2 and voltage-gated potassium channel antibodies in encephalitis.
      • Walikonis J.E.
      • Lennon V.A.
      Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus.
      • Fang B.
      • McKeon A.
      • Hinson S.R.
      • et al.
      Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis.
      • O’Connor K.
      • Waters P.
      • Komorowski L.
      • et al.
      GABAA receptor autoimmunity.
      • Hoftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      Use of large neuroimmunology laboratory data can provide a unique big-picture perspective in examining these rare diseases, which are often difficult to study because of small sample sizes.
      • Murdoch T.B.
      • Detsky A.S.
      The inevitable application of big data to health care.
      It can provide an overview of the distribution of antibody detection, coexistence of antibodies, and demographic associations that may provide inference to pathophysiologic processes and clinical associations.
      In this study, we investigated the frequency of detection and age and sex associations of AE-Abs from our large serologic database established from patients evaluated for autoimmune encephalopathy.

      Methods

      Study Data Collection

      This retrospective study was approved by the Mayo Clinic Review Board (study number 08-00647). Age and sex data were collected in the course of clinical testing with consent waiver.
      All patients’ samples (serum and cerebrospinal fluid [CSF]) submitted to the Mayo Clinic Neuroimmunology Laboratory during a 2-year period (January 2018 to December 2019) for the “autoimmune encephalopathy” serologic evaluation were included. This autoimmune encephalopathy evaluation includes both autoimmune and paraneoplastic autoantibodies (NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, CASPR2-IgG, LGI1-IgG, GAD65-IgG, CRMP5-IgG, amphiphysin-IgG, PCA1/2/Tr-IgGs, ANNA1/2/3-IgGs, GFAP-IgG, mGluR1-IgG, DPPX-IgG).
      In addition, MOG-IgG1 serologic evaluations during this time frame were included but restricted to patients in whom MOG-IgG1 was concurrently requested with AE evaluation in serum or CSF within ± 90 days of MOG-IgG1 serum testing. Certain AE-Abs not validated for clinical use in our laboratory at the time of study (all relatively rare in our experience) were not tested. These included Ma1/Ma2-IgG, GABAA-R-IgG, mGluR5-IgG, and KLHL11-IgG. Patients whose specimens were designated for other autoimmune phenotype evaluations (dementia, paraneoplastic, myelopathy, central demyelination syndromes, movement disorders, myasthenia gravis) were excluded.
      The minimum data set required samples to have complete data for specimen type, patient name/identifier, date of birth, and collection date. Results were required for GAD65-IgG by immunoprecipitation assay; and for NMDA-R-IgG, AMPA-R-IgG, GABAB-R-IgG, CASPR2-IgG, and LGI1-IgG by transfected cell-based assays (CBAs).

      Detection of AE-Abs

      Clinically validated assays (Clinical Laboratory Improvement Amendments certified and approved by New York State) were used to test for IgGs: indirect immunofluorescence on rodent tissues (ANNA1, 2, 3; PCA1, 2, Tr; amphiphysin; CRMP5; NMDA-R; AMPA-R; GABAB-R; GFAP; mGluR1; DPPX); CBAs employing fixed human embryonic kidney 293 cells transfected with expression plasmids encoding NMDA-R, AMPA-R, GABAB-R, CASPR2, LGI1, mGluR1, DPPX (Euroimmun),
      • Probst C.
      • Saschenbrecker S.
      • Stoecker W.
      • Komorowski L.
      Anti-neuronal autoantibodies: current diagnostic challenges.
      or GFAP-α
      • Fang B.
      • McKeon A.
      • Hinson S.R.
      • et al.
      Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis.
      (in-house CBA); CBA using live transfected cells measured by flow cytometric assay (MOG)
      • Waters P.J.
      • Komorowski L.
      • Woodhall M.
      • et al.
      A multicenter comparison of MOG-IgG cell-based assays.
      ; immunoprecipitation assay (GAD65)
      • Walikonis J.E.
      • Lennon V.A.
      Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus.
      ; and Western blot for confirmation (CRMP5; amphiphysin; PCA1, 2, Tr; ANNA1, 2, 3).
      Only CSF was tested for GFAP-IgG (higher specificity for meningoencephalitis in CSF).
      • Fang B.
      • McKeon A.
      • Hinson S.R.
      • et al.
      Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis.
      Only serum was tested for MOG-IgG1.
      • Waters P.J.
      • Komorowski L.
      • Woodhall M.
      • et al.
      A multicenter comparison of MOG-IgG cell-based assays.
      Either or both specimens were tested for other AE-Abs. Positivity was confirmed by testing at least twice. Serum GAD65-IgG values of 20 nmol/L or higher and CSF GAD65-IgG values of 0.06 nmol/L or higher were considered positive in the context of neurologic autoimmunity (lower values lack specificity).
      • Pittock S.J.
      • Yoshikawa H.
      • Ahlskog J.E.
      • et al.
      Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
      At the time of this study, the CASPR2-IgG CBA screening dilution was 1:10. This has subsequently been changed to a screening dilution of 1:100 per the manufacturer’s guidelines.

      Statistical Analyses

      Detection frequencies in CSF and serum of adults and children were compared by Fisher exact test for count data. Age and sex associations with AE-Abs were evaluated when power was sufficient for analysis (>50 seropositive patients). Serum- and CSF-positive cohorts were combined except for NMDA-R-IgG (analyzed only for CSF, which is more specific for AE).
      • Gresa-Arribas N.
      • Titulaer M.J.
      • Torrents A.
      • et al.
      Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study [erratum appears in Lancet Neurol. 2014;13(2):135].
      The comparison seronegative cohort (results combined for serum and CSF) was restricted to patients whose serum and CSF specimens were both negative (to exclude comparison to a patient who was negative in only 1 specimen type, thus excluding possible false negatives). A subgroup analysis restricted to patients with AE-Ab paired testing of serum and CSF tested within 180 days was performed to determine the frequency of CSF and serum detection in both samples or in either sample.
      Multivariable logistic regression was used to determine the odds ratio (OR), 95% CI, and P value for age group and sex associations for individual AE-Ab detection. To evaluate the interaction between age and sex, the interaction term age group∗sex was used; those with significant interactions are described separately, and the specific sex effect is reported for each age group. All tests were 2 sided; P values less than .05 were considered significant, and reported P values are unadjusted for multiple comparisons. The statistical software R version 3.5.1 was used (R Foundation for Statistical Computing).

      Data Sharing

      Data of individual participants after deidentification can be made available on reasonable request and institutional approval.

      Results

      Study Cohort

      There were 42,032 patients (28,121 tested in serum and 23,881 tested in CSF) who underwent AE evaluation (includes 18 AE-Abs) during a 2-year period (January 2018 to December 2019).

      NMDA-R-IgG, GAD65-IgG, and LGI1-IgG Are the Most Frequently Detected AE-Abs in Serum of Adults

      Among 22,472 adults (56% female) undergoing serum analysis, 814 (3.6%) were seropositive for AE-Abs. Most common were NMDA-R-IgG (193 [24.6%]), GAD65-IgG (169 [21.5%]), and LGI1-IgG (161 [20.5%]; Figure 1A; Table 1). Multiple (≥2) AE-Abs were identified in serum of 28 (3.4% of seropositive adults); LGI1-IgG and CASPR2-IgG were the most common coexisting autoantibodies (8 [28.6%]), followed by ANNA1-IgG and CRMP5-IgG (5 [17.9%]; Table 2).
      Figure thumbnail gr1
      Figure 1Frequency of autoimmune/paraneoplastic encephalitis antibody (AE-Ab) biomarkers. Pie graph demonstrating the proportional distribution of AE-Abs in adult serum (A), pediatric serum (B), adult cerebrospinal fluid (C), and pediatric cerebrospinal fluid (D).
      Table 1Baseline Characteristics and Frequency of AE-Abs Biomarkers in Serum of Adults and Children (Single Antibody Detected)
      AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; IQR, interquartile range.
      ,
      Values are reported as number (%) unless otherwise indicated.
      Adults (n=786)
      Two additional patients with GABAA-R-IgG antibodies were identified in research testing (not part of routine clinical testing) during this study period, 1 with coexistent high-titer serum GAD65-IgG.
      Children (n=241)Total (N=1027)P value
      Age (y)
       Median56.09.046.0
       IQR38.0-68.05.0-13.019.0-64.0
      Female sex474 (60.3)134 (55.6)608 (59.2).20
      Fisher exact test for count data with simulated P value (based on 2000 replicates).
      NMDA-R-IgG193 (24.6)128 (53.1)321 (31.3)<.001
      Fisher exact test for count data.
      GAD65-IgG (>20 nmol/L)169 (21.5)17 (7.1)186 (18.1)<.001
      Fisher exact test for count data.
      LGI1-IgG161 (20.5)5 (2.1)166 (16.2)<.001
      Fisher exact test for count data.
      CASPR2-IgG78 (9.9)8 (3.3)86 (8.4)<.001
      Fisher exact test for count data.
      GABAB-R-IgG57 (7.3)3 (1.2)60 (5.8)<.001
      Fisher exact test for count data.
      MOG-IgG157 (7.3)77 (32.0)134 (13.0)<.001
      Fisher exact test for count data.
      ANNA1-IgG26 (3.3)2 (0.8)28 (2.7).04
      Fisher exact test for count data.
      AMPA-R-IgG13 (1.7)1 (0.4)14 (1.4).21
      Fisher exact test for count data.
      PCA1-IgG12 (1.5)0 (0.0)12 (1.2).08
      Fisher exact test for count data.
      CRMP5-IgG4 (0.5)0 (0.0)4 (0.4).58
      Fisher exact test for count data.
      ANNA2-IgG4 (0.5)0 (0.0)4 (0.4).58
      Fisher exact test for count data.
      DPPX-IgG3 (0.4)0 (0.0)3 (0.3)>.99
      Fisher exact test for count data.
      Amphiphysin-IgG2 (0.3)0 (0.0)2 (0.2)>.99
      Fisher exact test for count data.
      PCA2-IgG2 (0.3)0 (0.0)2 (0.2)>.99
      Fisher exact test for count data.
      PCA-Tr-IgG2 (0.3)0 (0.0)2 (0.2)>.99
      Fisher exact test for count data.
      mGluR1-IgG2 (0.3)0 (0.0)2 (0.2)>.99
      Fisher exact test for count data.
      ANNA3-IgG1 (0.1)0 (0.0)1 (0.1)>.99
      Fisher exact test for count data.
      Note: There were an additional 28 adults and 10 children with ≥1 coexisting AE-Abs in serum included in the total of AE-Ab biomarkers reported positive in serum.
      a AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; IQR, interquartile range.
      b Values are reported as number (%) unless otherwise indicated.
      c Two additional patients with GABAA-R-IgG antibodies were identified in research testing (not part of routine clinical testing) during this study period, 1 with coexistent high-titer serum GAD65-IgG.
      d Fisher exact test for count data with simulated P value (based on 2000 replicates).
      e Fisher exact test for count data.
      Table 2Patients With Multiple AE-Ab Biomarkers Detected in the Same Sample Type
      AE-Ab biomarkersCSF
      AdultsChildren
      NMDA-R-IgGGFAP-IgG190
      NMDA-R-IgGAMPA-R-IgG81
      ANNA1-IgGCRMP5-IgG30
      NMDA-R-IgGANNA1-IgG20
      NMDA-R-IgGmGluR1-IgG10
      NMDA-R-IgGGABAB-R-IgG10
      PCA2-IgGCRMP5-IgG10
      PCA1-IgGGFAP-IgG10
      NMDA-R-IgGLGI1-IgG10
      NMDA-R-IgGGAD65-IgG21
      GFAP-IgGGAD65-IgG20
      NMDA-R-IgGCASPR2-IgG01
      CRMP5-IgGGAD65-IgG01
      CRMP5-IgGAMPA-R-IgG01
      GAD65-IgGANNA1-IgG10
      425
      AE-Ab biomarkersSerum
      AdultsChildren
      CASPR2-IgGLGI1-IgG85
      ANNA1-IgGCRMP5-IgG50
      NMDA-R-IgGCASPR2-IgG20
      ANNA1-IgGGABAB-R-IgG20
      NMDA-R-IgGAMPA-R-IgGCASPR2-IgG10
      GAD65-IgGANNA1-IgG10
      GAD65-IgGGABAB-R-IgG10
      GAD65-IgGAMPA-R-IgG10
      ANNA1-IgGNMDA-R-IgG10
      ANNA1-IgGAMPA-R-IgG10
      CRMP5-IgGGABAB-R-IgG10
      CASPR2-IgGGABAB-R-IgG10
      NMDA-R-IgGAMPA-R-IgG11
      GABAB-R-IgGAMPA-R-IgG10
      NMDA-R-IgGGABAB-R-IgG01
      CRMP5-IgGGAD65-IgGAMPA-R-IgG01
      AMPA-R-IgGGABAB-R-IgGMOG-IgG1GAD65-IgG01
      MOG-IgG1NMDA-R-IgG01
      MOG-IgG1LGI1-IgG10
      2810
      AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid.

      NMDA-R-IgG Is the Most Frequently Detected AE-Ab in Serum of Children

      Among 5649 children (50% female) undergoing serum analysis, 251 (4.4%) were seropositive for AE-Abs. Most common were NMDA-R-IgG (128 [53.1%]), MOG-IgG1 (77 [32%]), and GAD65-IgG (17 [7.1%]; Figure 1B; Table 1). Multiple (≥2) coexistent AE-Abs were identified in 10 patients (4% of all seropositive children) and are reported separately. LGI1-IgG and CASPR2-IgG were the most common coexisting AE-Abs (5 [50%]; Table 2).

      NMDA-R-IgG Is the Most Frequently Detected AE-Ab in CSF of Adults

      Among 18,745 adults (54% female) undergoing CSF analysis, 796 (4.2%) were positive for AE-Abs (Figure 1C; Table 3). Most common were NMDA-R-IgG (299 [39.7%]), GAD65-IgG (215 [28.5%]), and LGI1-IgG (86 [11.4%]). Multiple (≥2) coexistent AE-Abs were identified in 42 (5.3% of CSF-positive adults), most commonly with NMDA-R-IgG (34 [81%]). Of those with coexisting antibodies, NMDA-R-IgG and GFAP-IgG coexisted most often (19 [45.2%]), followed by AMPA-R-IgG (8 [19%]; Table 2).
      Table 3Baseline Characteristics and Frequency of AE-Ab Biomarkers in CSF of Adults and Children (Single Antibody Detected)
      AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; IQR, interquartile range.
      ,
      Values are reported as number (%) unless otherwise indicated.
      Adults (n=754)Children (n=277)Total (N=1031)P value
      Age (y)
       Median52.511.034.0
       IQR31.0-66.05.0-15.016.0-61.0
      Female sex451 (59.8)172 (62.1)623 (60.4).40
      Fisher exact test for count data with simulated P value (based on 2000 replicates).
      NMDA-R-IgG299 (39.7)244 (88.1)543 (52.7)<.001
      Fisher exact test for count data.
      GAD65-IgG215 (28.5)24 (8.7)239 (23.2)<.001
      Fisher exact test for count data.
      LGI1-IgG86 (11.4)2 (0.7)88 (9.4)<.001
      Fisher exact test for count data.
      GABAB-R-IgG34 (5.1)0 (0.0)34 (3.6)<.001
      Fisher exact test for count data.
      ANNA1-IgG33 (4.4)2 (0.7)35 (3.4)<.003
      Fisher exact test for count data.
      GFAP-IgG28 (4.2)5 (1.8)33 (3.5).16
      Fisher exact test for count data.
      PCA1-IgG16 (2.4)0 (0.0)16 (1.7).009
      Fisher exact test for count data.
      AMPA-R-IgG13 (1.9)0 (0.0)13 (1.4).03
      Fisher exact test for count data.
      CASPR2-IgG6 (0.9)0 (0.0)6 (0.6).35
      Fisher exact test for count data.
      Amphiphysin-IgG5 (0.7)0 (0.0)5 (0.5).33
      Fisher exact test for count data.
      PCA2-IgG5 (0.7)0 (0.0)5 (0.5).33
      Fisher exact test for count data.
      CRMP5-IgG5 (0.7)0 (0.0)5 (0.5).33
      Fisher exact test for count data.
      ANNA2-IgG5 (0.7)0 (0.0)5 (0.5).33
      Fisher exact test for count data.
      DPPX-IgG3 (0.4)0 (0.0)3 (0.3).57
      Fisher exact test for count data.
      mGluR1-IgG1 (0.1)0 (0.0)1 (0.1)>.99
      Fisher exact test for count data.
      PCA-Tr-IgG0 (0.0)0 (0.0)0 (0.0)
      ANNA3-IgG0 (0.0)0 (0.0)0 (0.0)
      Note: There were an additional 42 adults and 5 children with ≥1 coexisting AE-Abs in CSF included in the total of AE-Ab biomarkers reported positive in CSF.
      a AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; IQR, interquartile range.
      b Values are reported as number (%) unless otherwise indicated.
      c Fisher exact test for count data with simulated P value (based on 2000 replicates).
      d Fisher exact test for count data.

      NMDA-R-IgG Is the Most Frequently Detected AE-Ab in CSF of Children

      Among 5136 children (50% female) undergoing CSF analysis, 282 (5.5%) were positive for AE-Abs (Figure 1D; Table 3). Most common were NMDA-R-IgG (244 [88.1%]) and GAD65-IgG (24 [8.7%]). Multiple (≥2) unique coexistent AE-Abs were identified in 5 patients (1.8%; Table 2).

      Serum and CSF Compartment Positivity

      Among a subgroup restricted to 9468 patients with serum and CSF testing within 180 days, we observed that for patients positive for NMDA-R-IgG, CSF was the only compartment that was positive in 38.2% of patients. The CSF and serum were both positive in 48.5%; NMDA-R-IgG was detected in serum only in 13.3%. For GAD65-IgG-positive patients, serum and CSF were both positive in 84%, serum was positive alone in 2%. For CASPR2-IgG, serum was the only compartment in which it was positive in 91.7% of patients with a low correlation between CSF and serum. LGI1-IgG was detected in both serum and CSF in 60% and in only serum in 36% of patients (Supplemental Table, available online at http://www.mayoclinicproceedings.org).

      Age Associations With AE-Ab Detection

      Multivariable analyses identified that younger age (<20 years) was associated with NMDA-R-IgG and MOG-IgG1 detection (OR, 8.11 and 7.84, respectively [P<.001]; Figure 2A; Table 4). Older age (>65 years) was associated with GABAB-R-IgG, LGI1-IgG, CASPR2-IgG, and ANNA1-IgG (OR, 7.33, 14.98, 3.67, and 14.53, respectively [P<.001]; Figure 2A; Table 5).
      Figure thumbnail gr2a
      Figure 2Age and sex characteristics of autoimmune/paraneoplastic encephalitis (AE) biomarkers. A, Density plot demonstrating the distribution of AE-Ab biomarkers by the continuous variable of age. B, Forest plot of female sex association with AE-Ab biomarker detection. OR, odds ratio.
      Figure thumbnail gr2b
      Figure 2Age and sex characteristics of autoimmune/paraneoplastic encephalitis (AE) biomarkers. A, Density plot demonstrating the distribution of AE-Ab biomarkers by the continuous variable of age. B, Forest plot of female sex association with AE-Ab biomarker detection. OR, odds ratio.
      Table 4Multivariable Logistic Regression of Young Age and Sex Associations for Each Autoimmune Encephalopathy AE-Ab Biomarker Compared With a Reference Group Older Than 65 Years
      PredictorsNMDA-R-IgG (CSF)MOG-IgG1 (serum)GAD65-IgG (CSF and serum)
      ORCIPORCIPORCIP
      Female sex1.321.11-1.58.0020.750.52-1.08.132.231.75-2.84<.001
      Age
       >65 yearsReference
       0-20 years8.115.83-11.27<.0017.842.43-25.35.0010.550.37-0.81.02
       21-40 years6.424.52-9.13<.0014.331.29-14.48.0172.121.53-2.93<.001
       40-65 years1.461.00-2.14.0501.740.51-5.98.381.651.23-2.22.001
      AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; OR, odds ratio.
      Boldface P values represent statistical significance.
      Table 5Multivariable Logistic Regression of Older Age and Sex Associations for Each Autoimmune Encephalopathy AE-Ab Biomarker Compared With a Reference Group 20 Years of Age and Younger
      PredictorsGABAB-R-IgG (CSF and serum)LGI1-IgG (CSF and serum)CASPR2-IgG (CSF and serum)ANNA1-IgG (CSF and serum)
      ORCIPORCIPORCIPORCIP
      Female sex1.160.74-1.84.520.530.40-0.71<.0010.920.61-1.40.7051.740.95-3.17.07
      Age
       0-20 yearsReference
       21-40 years2.720.86-8.60.092.771.16-6.58.0212.170.96-4.94.0641.890.27-13.43.53
       40-65 years6.582.58-16.83<.0018.714.37-17.38<.0013.021.53-5.96.0019.772.29-41.71.002
       >65 years7.332.83-18.95<.00114.987.56-29.65<.0013.671.85-7.30<.00114.533.42-61.71<.001
      AE, autoimmune/paraneoplastic encephalitis; CSF, cerebrospinal fluid; OR, odds ratio.
      Boldface P values represent statistical significance.
      Note: LGI1-IgG detection is associated with male sex (OR, 1.87; P<.001) using the reference of female sex.

      Sex Associations With AE-Ab Detection

      Women accounted for 60% of the NMDA-R-IgG CSF-positive cohort and 73% of the GAD65-IgG cohort. In the multivariable analysis cohort, female sex was associated with NMDA-R-IgG detection in the whole cohort (OR, 1.32 [P=.002]) and GAD65-IgG (OR, 2.23 [P<.001]; Figure 2B; Table 4). Men accounted for 62% of the LGI1-IgG cohort, and male sex was associated with LGI1-IgG detection in the whole cohort tested (OR, 1.87 [P<.001], reference female sex; OR, 0.53 [P<.001], reference male sex; Figure 2B).
      The interaction between age and sex was used to investigate whether sex modified the risk of detection of any of the 7 well-powered autoantibody biomarkers within a specific age group. NMDA-R-IgG was the only AE-Ab demonstrating significant interaction between sex and age (P<.001). Further stratification demonstrated that the greatest risk for female patients was in the age group younger than 20 years (OR, 7.72; 95% CI, 5.14-11.61; P <.001) compared with the reference group (male >65 years; Supplemental Figure, available online at http://www.mayoclinicproceedings.org).

      Discussion

      In this large clinical laboratory cohort study, age and sex were determinants of the frequency of AE-Ab detection. For patients younger than 60 years, NMDA-R-IgG was the most commonly detected AE-Ab biomarker in both CSF and serum; whereas in patients older than 60 years, LGI1-IgG was most common. Female sex was associated with NMDA-R-IgG and GAD65-IgG; male sex was associated with LGI1-IgG.
      Among children, the frequency of NMDA-R-IgG evaluated in CSF was 9-fold greater than that of other AE-Abs. GAD65-IgG was second most common (8.7%). In serum, MOG-IgG1 was positive in 32% and GAD65-IgG in 7.1% of all seropositives. This finding underscores the importance of MOG-IgG1 as an AE-Ab biomarker in children
      • Armangue T.
      • Olivé-Cirera G.
      • Martínez-Hernandez E.
      • et al.
      Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study [erratum appears in Lancet Neurol. 2020;19(4):e4].
      ,
      • Kunchok A.
      • Flanagan E.P.
      • Krecke K.N.
      • et al.
      MOG-IgG1 and co-existence of neuronal autoantibodies.
      and supports testing for NMDA-R-IgG (in CSF), MOG-IgG1 (in serum), and GAD65-IgG (in CSF and serum) in children being evaluated for autoimmune encephalopathy.
      Among adults, NMDA-R-IgG was the most commonly detected AE-Ab in both CSF (39.7%) and serum (24.6%), similar to findings of other cohort studies.
      • Hayden Z.
      • Bóné B.
      • Orsi G.
      • et al.
      Clinical characteristics and outcome of neuronal surface antibody-mediated autoimmune encephalitis patients in a national cohort.
      NMDA-R-IgG is recognized to affect patients of young median age, with a minority older than 45 years (4.5% of a cohort positive for NMDA-R-IgG [n=661]).
      • Titulaer M.J.
      • McCracken L.
      • Gabilondo I.
      • et al.
      Late-onset anti-NMDA receptor encephalitis.
      ,
      • Bien C.G.
      • Bien C.I.
      • Dogan Onugoren M.
      • et al.
      Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome [erratum appears in J Neurol. 2020;267(7):2115-2116; J Neurol. 2021;268(8):3056-3057].
      Pathophysiologic differences have been postulated in the 2 age groups, with more ovarian teratomas and post herpes simplex–encephalitis NMDA-R-IgG--encephalitis being documented in younger patients and carcinomas in patients older than 45 years.
      • Titulaer M.J.
      • McCracken L.
      • Gabilondo I.
      • et al.
      Late-onset anti-NMDA receptor encephalitis.
      ,
      • Armangue T.
      • Moris G.
      • Cantarín-Extremera V.
      • et al.
      Autoimmune post–herpes simplex encephalitis of adults and teenagers.
      In adults, GAD65-IgG and LGI1-IgG were also detected commonly (respectively, 21.5% and 20.5% in serum and 28.5% and 11.4% in CSF). In patients older than 60 years, LGI1-IgG was the most commonly detected AE-Ab in serum or CSF, correlating with findings of LGI1-IgG in 31% of a cohort of elderly patients evaluated for antibodies against cell surface antigens
      • Escudero D.
      • Guasp M.
      • Ariño H.
      • et al.
      Antibody-associated CNS syndromes without signs of inflammation in the elderly.
      and older median age reported in LGI1-IgG encephalitis cohorts.
      • Irani S.R.
      • Alexander S.
      • Waters P.
      • et al.
      Antibodies to Kv1 potassium channel–complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia.
      Older age has been found to be associated with central nervous system involvement (including encephalopathy) compared with peripheral involvement in LGI1-IgG encephalitis cohorts.
      • Gadoth A.
      • Pittock S.J.
      • Dubey D.
      • et al.
      Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients.
      In younger patients, the lower risk of detecting GABAB-R-IgG, CASPR2-IgG, and ANNA1-IgG probably represents paraneoplastic associations of these antibodies in older patients.
      • Hoftberger R.
      • Titulaer M.J.
      • Sabater L.
      • et al.
      Encephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients.
      ,
      • Vernino S.
      • Eggenberger E.R.
      • Rogers L.R.
      • Lennon V.A.
      Paraneoplastic neurological autoimmunity associated with ANNA-1 autoantibody and thymoma.
      ,
      • van Sonderen A.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      The clinical spectrum of Caspr2 antibody–associated disease.
      Across all age groups, female sex was associated with NMDA-R-IgG and GAD65-IgG. GAD65-IgG has long been recognized to be associated with autoimmune neurologic disorders predominantly affecting women.
      • Pittock S.J.
      • Yoshikawa H.
      • Ahlskog J.E.
      • et al.
      Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.
      Sex and age interacted in the detection of NMDA-R-IgG, with the greatest association seen in female patients aged 0 to 20 years. This may represent the known association of young girls with NMDA-R-IgG and ovarian teratoma.
      • Dalmau J.
      • Armangué T.
      • Planagumà J.
      • et al.
      An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models.
      In contrast to the strong female sex association observed for many autoimmune conditions, such as AQP4-IgG neuromyelitis optica spectrum disorder,
      • Kunchok A.
      • Flanagan E.P.
      • Snyder M.
      • et al.
      Coexisting systemic and organ-specific autoimmunity in MOG-IgG1–associated disorders versus AQP4-IgG+ NMOSD.
      systemic lupus erythematous, and rheumatoid arthritis, male sex was associated with LGI1-IgG detection. The pathophysiologic mechanism for the greater detection frequency of LGI1-IgG in older men is unclear but may represent a hormonal effect. There is no known sex-specific malignant neoplasm associated with LGI1-IgG.
      Several patients demonstrated coexisting antibodies in the same sample. The most common of these were LGI1-IgG and CASPR2-IgG tested in serum of adults. Similarly, although LGI1-IgG and CASPR2-IgG are uncommon in children, when present they coexisted in half of patients tested in serum.
      • Dubey D.
      • Pittock S.J.
      • Kelly C.R.
      • et al.
      Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.
      This coexistence of serum antibodies to LGI1 and CASPR2, both extracellular antigens of the voltage-gated potassium channel complex, may represent a common immunologic trigger or predisposition.
      • Binks S.N.M.
      • Klein C.J.
      • Waters P.
      • Pittock S.J.
      • Irani S.R.
      LGI1, CASPR2 and related antibodies: a molecular evolution of the phenotypes.
      Among adults tested in CSF with coexistent antibodies, NMDA-R-IgG was the most common antibody to coexist with other antibodies (81%). When NMDA-R-IgG coexisted with neural antibodies, it was most commonly detected with GFAP-IgG and AMPA-R-IgG. GFAP-IgG has previously been reported by our coauthors as well as by other centers to coexist with NMDA-R-IgG (22% of Mayo Clinic GFAP-IgG cohort).
      • Flanagan E.P.
      • Hinson S.R.
      • Lennon V.A.
      • et al.
      Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients.
      ,
      • Martinez-Hernandez E.
      • Guasp M.
      • García-Serra A.
      • et al.
      Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.
      AMPA-R-IgG has been identified to coexist in 6 patients in a large NMDA-R-IgG encephalitis cohort (n=646).
      • Martinez-Hernandez E.
      • Guasp M.
      • García-Serra A.
      • et al.
      Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.
      We and others have previously identified patients with coexisting NMDA-R-IgG (CSF) and MOG-IgG1 (serum).
      • Kunchok A.
      • Flanagan E.P.
      • Krecke K.N.
      • et al.
      MOG-IgG1 and co-existence of neuronal autoantibodies.
      ,
      • Titulaer M.J.
      • Höftberger R.
      • Iizuka T.
      • et al.
      Overlapping demyelinating syndromes and anti-N-methyl-D-aspartate receptor encephalitis.
      Several of these patients were tested during the time frame of this study; however, they are not represented in this study’s coexisting antibody table (Table 2) as they were positive in different sample types.
      The incorporation of more recently recognized AE-Abs increased the yield of detection, including MOG-IgG1, GFAP-IgG, DPPX-IgG, and mGluR1-IgG.
      • Hara M.
      • Ariño H.
      • Petit-Pedrol M.
      • et al.
      DPPX antibody–associated encephalitis.
      ,
      • Kunchok A.
      • Flanagan E.P.
      • Krecke K.N.
      • et al.
      MOG-IgG1 and co-existence of neuronal autoantibodies.
      ,
      • Flanagan E.P.
      • Hinson S.R.
      • Lennon V.A.
      • et al.
      Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients.
      ,
      • Lopez-Chiriboga A.S.
      • Komorowski L.
      • Kümpfel T.
      • et al.
      Metabotropic glutamate receptor type 1 autoimmunity.
      GFAP-IgG, DPPX-IgG, and mGluR1-IgG together accounted for 4% to 5% of CSF-positive patients. We anticipate that the seropositivity yield will continue to increase with the addition of other recently discovered AE-Ab biomarkers, such as GABAA-R-IgG, to the AE evaluation.
      • O’Connor K.
      • Waters P.
      • Komorowski L.
      • et al.
      GABAA receptor autoimmunity.
      Our evaluation of CSF and serum compartment positivity identified that more than one-third of patients with NMDA-R-IgG were detected only in CSF, similar to other cohorts that have identified 28% detected only in CSF, highlighting the importance of CSF testing for NMDA-R-IgG detection.
      • Bien C.G.
      • Bien C.I.
      • Dogan Onugoren M.
      • et al.
      Routine diagnostics for neural antibodies, clinical correlates, treatment and functional outcome [erratum appears in J Neurol. 2020;267(7):2115-2116; J Neurol. 2021;268(8):3056-3057].
      CASPR2-IgG was detected in serum alone in most cases. Several studies have previously reported a low sensitivity of CSF for CASPR2-IgG.
      • Gadoth A.
      • Pittock S.J.
      • Dubey D.
      • et al.
      Expanded phenotypes and outcomes among 256 LGI1/CASPR2-IgG–positive patients.
      ,
      • Van Sonderen A.
      • Thijs R.D.
      • Coenders E.C.
      • et al.
      Anti-LGI1 encephalitis.
      ,
      • Irani S.R.
      • Pettingill P.
      • Kleopa K.A.
      • et al.
      Morvan syndrome: clinical and serological observations in 29 cases.
      Therefore, we recommend that clinicians test both serum and CSF in patients undergoing evaluation for AE.
      The strengths of this study are the large size of this laboratory cohort evaluated for AE, which can provide big-picture insights into the frequency of AE-Abs and their demographic associations. A limitation of this study is that the frequency of detection of AE-Abs in patients selected for serologic evaluation cannot be interpreted as seroincidence. For example, the overall proportion of AE-Abs (4% to 6%) positive in the cohort of patients evaluated for AE may be underestimated because patients for whom other serologic evaluations were requested (such as paraneoplastic evaluation) were not included or physicians requested the AE evaluation in settings with low pretest probability of AE. The frequency of MOG-IgG1 in patients evaluated for AE may be underestimated as this test is currently a stand-alone test and is not part of the comprehensive AE evaluation. The titration for the CASPR2-IgG detection by CBA has changed to a higher titration, per the manufacturer’s guidelines, since the completion of this study. Therefore, it is possible that some detections of the CASPR2-IgG in the study period were of low titer positives and could include false positives.
      Despite these limitations, using large data from more than 40,000 patients evaluated for AE during the past 2 years provides insights into these rare conditions that are unable to be obtained from smaller study populations. For example, our colleagues conducted a sophisticated population-based study of Olmsted County.
      • Dubey D.
      • Pittock S.J.
      • Kelly C.R.
      • et al.
      Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.
      This study determined the incidence and prevalence of autoimmune encephalitis within the county and showed it to be increasing over time, similar to infectious encephalitis. However, examining rare diseases in small populations has limitations, and the authors also acknowledged this with the example that the prevalence of NMDA-R-IgG (commonly seen in autoimmune clinical practice) was similar to the very rare ANNA2-IgG, with 1 case each detected within the population. Hence, it is difficult for population-based studies to determine accurate prevalence and incidence for rare AE-Abs without studying a very large population.

      Conclusion

      This neuroimmunology laboratory cohort study provides a big-picture perspective of the distribution among samples that are positive for AE-Abs. This study also finds age and sex associations in patients evaluated for AE that can aid in clinical prognostication and provide inference to pathophysiologic processes.

      Acknowledgments

      We would like to acknowledge Mrs Mary Curtis, our neuroimmunology laboratory secretary, for her administrative support. We would like to acknowledge the neuroimmunology laboratory technicians who assisted with clinical testing. We would like to thank Ms Sarah Jenkins from the Mayo Clinic biostatistical department for her review of the manuscript draft.

      Supplemental Online Material

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