Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor

Hara, Makoto; Martínez‐Hernández, Eugenia; Ariño, Helena; Armangué, Thaís; Spatola, Marianna; Petit‐Pedrol, Mar; Sáiz, Albert; Rosenfeld, Myrna R.; Graus, Francesc; Dalmau, Josep

doi:10.1212/wnl.0000000000005329

Cited by 120 publications

(119 citation statements)

References 42 publications

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“…NMDAR1-abs serum prevalence has been observed in about ~10% of the healthy population, and in those with various diseases, including stroke. (9,10,20) Similar to our study results, mainly IgM and IgA antibodies were observed. (10) The swift blood sampling in our study and the similar proportion of seropositive patients in healthy individuals suggests that antibodies were preexistent before the stroke and thus not a consequence of the acute event.…”

Section: Discussionsupporting

confidence: 91%

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Sperber

Gebert

Broersen

et al. 2020

Preprint

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Objective:We aimed to investigate whether serum anti-N-Methyl-D-Aspartate-receptor GluN1 antibodies (NMDAR1-abs) are associated with worse cognitive function over three years after first ischemic stroke. Methods: Data were used from the PROSpective Cohort with Incident Stroke-Berlin (PROSCIS-B;NCT01363856). NMDAR1-abs (IgM/IgA/IgG) were measured with cell-based assays from serum obtained within seven days after first-ever stroke. Seropositivity was defined as titers ≥1:10, low titers as ≤1:100 and high titers as >1:100. We assessed cognitive status annually up to three years after stroke with the Telephone Interview for Cognitive Status -modified (TICS-m) and used crude and adjusted linear mixed models to estimate the impact of NMDAR1-abs exposure on TICS-m over time. Results: Data on NMDAR1-abs (median day of sampling=4[IQR=2-5]) were available in 583 of 621 PROSCIS-B patients (39% female; median NIHSS=2[IQR=1-4]; median MMSE=28[IQR:26-30]; median mRS=2[IQR=1-3]) of whom 76(13%) were seropositive (IgM:n=48/IgA:n=43/IgG:n=2). TICS-m over time was not different in NMDAR1-abs seropositive compared to seronegative patients (βCrude=0.38[95%CI=-1.00 to 1.76]; adjusted βModel3=0.30[95%CI=-1.14 to 1.73]). In subgroups, TICS-m over time was not different in patients with low titers (βCrude=1.53[95%CI=-0.06 to 3.11]; adjusted βModel3=1.42[95%CI=-0.23 to 3.08]), however, in patients with high titers TICS-m was lower in the crude model (β=-2.54[95%CI=-4.99 to -0.08]), with a similar effect size after confounder adjustment (βModel3=-2.30[95%CI=-4.82 to 0.21]). All groups were compared to seronegative patients, respectively. All rights reserved. No reuse allowed without permission.(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Section: Discussionsupporting

confidence: 91%

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Sperber

Gebert

Broersen

et al. 2020

Preprint

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“…These antibodies were also found in a small proportion of healthy controls (0.4–6.3%) in all but one of the studies that included a control group [10-12], further complicating interpretation of the results. Additionally, one study that screened for IgA and IgM antibodies was negative [27]. Finally, a few other studies that either screened for antibodies against the NR1a/NR2b receptor subunit [10, 31], NR2a/NR2b subunit [32], or non-specifically for both NR1 and NR2 subunits [33-36], have found seropositivity in a small percentage of patients.…”

Section: Resultsmentioning

confidence: 99%

“…This arguable exception notwithstanding, overall none of these methodological issues appear to independently explain the inconsistent findings. With this in mind, perhaps one of the biggest issues relates to the subjective nature of the interpretation of antibody testing [27], rather than to the particular antibody detection method used. It has been suggested that relying on any single method of detecting antibodies in serum may increase the risk of false-positive and false-negative results [27].…”

Section: Discussionmentioning

confidence: 99%

“…With this in mind, perhaps one of the biggest issues relates to the subjective nature of the interpretation of antibody testing [27], rather than to the particular antibody detection method used. It has been suggested that relying on any single method of detecting antibodies in serum may increase the risk of false-positive and false-negative results [27]. Notably, while three studies that included multiple antibody detection methods were entirely negative [19, 26, 27], one study that included both live and fixed CBAs found seropositivity using both assays, but the authors do highlight that the choice of CBA influenced the results [14].…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that relying on any single method of detecting antibodies in serum may increase the risk of false-positive and false-negative results [27]. Notably, while three studies that included multiple antibody detection methods were entirely negative [19, 26, 27], one study that included both live and fixed CBAs found seropositivity using both assays, but the authors do highlight that the choice of CBA influenced the results [14]. While the selection and interpretation of antibody detection methods may be an ongoing point of debate, the inclusion of a control group can help make sense of findings and assist in safeguarding against the misinterpretation of false-positive results.…”

Section: Discussionmentioning

confidence: 99%

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Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders

Colijn

Ismail

2019

Neuropsychobiology

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Schizophrenia is a phenotypically heterogeneous and poorly understood disorder. While its etiology is likely multifactorial, immune system dysfunction has increasingly been implicated in its development. As hallucinations and delusions occur frequently and prominently in autoimmune encephalitis (AE), numerous studies have sought to determine whether a small subset of individuals diagnosed with schizophrenia possess anti-neuronal antibodies implicated in AE. Exploring this possibility is of clinical relevance, as identifying individuals with AE who have been misdiagnosed as having a primary psychotic disorder may allow for the implementation of appropriate immune-related therapies as early as possible in the course of the illness, in order to optimize outcomes, reduce illness chronicity, and minimize adverse events. This qualitative review serves to provide an overview of the existing literature on this topic, as well as to update previously published reviews. Although there is some evidence to suggest that in rare cases AE may be misdiagnosed as a primary psychotic disorder, particularly early in the course of the illness, numerous methodological differences between studies likely account for the highly variable findings, and interpretation of the results is particularly limited by a paucity of cerebrospinal fluid data. Moreover, the prevalence of misdiagnosis in chronic and treatment-resistant populations remains understudied. This is particularly problematic, as treatment resistance may represent an enriched population with respect to the presence of anti-neuronal antibodies, and given that such patients have few evidence-based treatment options available to them beyond clozapine.

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Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis

et al. 2020

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IMPORTANCE Recognizing the presenting and immunopathological features of Kelch-like protein-11 immunoglobulin G seropositive (KLHL11 IgG+) patients may aid in early diagnosis and management.OBJECTIVE To describe expanding neurologic phenotype, cancer associations, outcomes, and immunopathologic features of KLHL11 encephalitis. DESIGN, SETTING, AND PARTICIPANTSThis retrospective tertiary care center study, conducted from October 15, 1998, to November 1, 2019, prospectively identified 31 KLHL11 IgG+ cases in the neuroimmunology laboratory. Eight were identified by retrospective testing of patients with rhomboencephalitis (confirmed by tissue-based-immunofluorescence and transfected-cell-based assays). MAIN OUTCOMES AND MEASURESOutcome variables included modified Rankin score and gait aid use.RESULTS All 39 KLHL11 IgG+ patients were men (median age, 46 years; range, 28-73 years). Initial clinical presentations were ataxia (n = 32; 82%), diplopia (n = 22; 56%), vertigo (n = 21; 54%), hearing loss (n = 15; 39%), tinnitus (n = 14; 36%), dysarthria (n = 11; 28%), and seizures (n = 9; 23%). Atypical neurologic presentations included neuropsychiatric dysfunction, myeloneuropathy, and cervical amyotrophy. Hearing loss or tinnitus preceded other neurologic deficits by 1 to 8 months in 10 patients (26%). Among patients screened for malignancy (n = 36), testicular germ-cell tumors (n = 23; 64%) or testicular microlithiasis and fibrosis concerning for regressed germ cell tumor (n = 7; 19%) were found in 83% of the patients (n = 30). In 2 patients, lymph node biopsy diagnosed metastatic lung adenocarcinoma in one and chronic lymphocytic leukemia in the other. Initial brain magnetic resonance imaging revealed T2 hyperintensities in the temporal lobe (n = 12), cerebellum (n = 9), brainstem (n = 3), or diencephalon (n = 3). Among KLHL11 IgG+ patients who underwent HLA class I and class II genotyping (n = 10), most were found to have HLA-DQB1*02:01 (n = 7; 70%) and HLA-DRB1*03:01 (n = 6; 60%) associations. A biopsied gadolinium-enhancing temporal lobe lesion demonstrated T cell-predominant inflammation and nonnecrotizing granulomas. Cerebellar biopsy (patient with chronic ataxia) and 2 autopsied brains demonstrated Purkinje neuronal loss and Bergmann gliosis, supporting early active inflammation and later extensive neuronal loss. Compared with nonautoimmune control peripheral blood mononuclear cells, cluster of differentiation (CD) 8+ and CD4+ T cells were significantly activated when patient peripheral blood mononuclear cells were cultured with KLHL11 protein. Most patients (58%) benefitted from immunotherapy and/or cancer treatment (neurological disability stabilized [n = 10] or improved [n = 9]). Kaplan-Meier curve demonstrated significantly higher probability of wheelchair dependence among patients without detectable testicular cancer. Long-term outcomes in KLHL11-IgG+ patients were similar to Ma2 encephalitis. IgG is a biomarker of testicular germ-cell tumor and paraneoplastic neurologic syndrome, often refractory to treatm...

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Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor

Abstract: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.

Cited by 120 publications

References 42 publications

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Serum anti-NMDA-receptor antibodies and cognitive function after ischemic stroke (PROSCIS-B)

Clinically Relevant Anti-Neuronal Cell Surface Antibodies in Schizophrenia Spectrum Disorders

Expanded Clinical Phenotype, Oncological Associations, and Immunopathologic Insights of Paraneoplastic Kelch-like Protein-11 Encephalitis

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