Reader Response: Clinical Significance of Anti-NMDAR Concurrent With Glial or Neuronal Surface Antibodies

We welcome the study by Martinez-Hernandez et al.1 reporting antibody coexistence in anti-n-methyl-d-aspartate receptor (NMDA-R) encephalitis. The authors confirmed coexistence of aquaporin-4-IgG or myelin oligodendrocyte glycoprotein (MOG)-IgG as predictors of co-occurrence of anti-NMDA-R encephalitis and autoimmune CNS demyelination. By contrast, it was concluded that coexisting GFAP-IgG is “clinicoradiologically nonspecific.”1 The diagnosis of autoimmune GFAP astrocytopathy—AGA, a clinical-radiological-serological entity, characterized by an inflammatory steroid-responsive meningoencephalomyelitis—requires adherence to a 2-step CSF evaluation2–5 (figure): (1) detection—by optimized rodent tissue-based immunohistochemistry—of an astrocytic filamentous-appearing pattern of IgG staining of all of midbrain (meningeal, subpial, and periventricular), cerebellar white—but not gray—matter, hippocampal, and cortical brain regions, and myenteric plexus and (2) positivity by GFAPα isoform-transfected HEK293 CBA (figure). Serum testing is insensitive and generates nonspecific results, as occasionally does CSF if both tissue and cell-based assays steps are not followed. Two patients with coexisting GFAP-IgG reported by Martinez-Hernandez et al.1 had meningeal enhancement on MRI, but the authors attribute this to anti-NMDA-R encephalitis alone, although the question of these 2 IgGs coexisting was not addressed systematically. Deviations from published methods may explain the paucity of cases found by Martinez-Hernandez et al.—10 of 846 anti-NMDA-R encephalitis patients total, 1.2%.2 Since test “go-live” in June 2019, we have detected GFAP-IgG coexisting in 6% of NMDA-R-IgG positive CSF specimens. Martinez-Hernandez et al. reported universal nondetection of coexisting GFAP-IgG by immunohistochemistry.2 The authors did not state whether fixation and permeabilization were optimized for detection of IgGs reactive with cytoplasmic proteins, such as GFAP. Furthermore, the authors used a “live” GFAP-specific cell-based assay (CBA) to identify 10 patients with coexisting GFAP-IgG, yet the intracellular location of GFAP should preclude detection in live cells. Additional details pertaining to the GFAP isoform expressed, and the specimen types tested—CSF or serum—were lacking. All of these factors can impact the sensitivity and specificity of GFAP-IgG testing and frequency of coexistence with NMDA-R-IgG.2,6 To address the question of neurologic phenotype further, we reviewed data for 248 unique patients in whom CSF GFAP-IgG was detected and confirmed by our 2-step laboratory protocol2,6 over the course of 4.5 years (January 1, 2015–June 30, 2019). Median GFAP-IgG endpoint titer was 1:64 (range 4–512; normal, <2). Twenty-three (9%) had coexisting CSF NMDA-R-IgG detected, 11 with clinical information available. Six of 11 patients also had NMDA-R-IgG detected at high titer on tissue-based assay (median, 1:32 [range, 4–128; normal, <2], figure), confirmed by GluN1-specific CBA. Of those 6, 5 had typical anti-NMDA-R encephalitis clinical phenotype, 4 of whom had anti-NMDA-R encephalitis-typical (normal) MRI brain imaging, and 1had radial periventricular enhancement (AGA-typical). The 6th patient had an inflammatory encephalomyelitis clinically and radiologically (AGA-typical) but accompanied by orofacial dyskinesias (anti-NMDA-R encephalitis-typical). The remaining 5 patients had NMDA-R-IgG detected (robustly) by GluN1-specific CBA only. Four of 5 patients were AGA-typical radiologically and clinically—with headache and meningism prominent—and 1 was anti-NMDA-R encephalitis typical. Although the pathophysiology of AGA remains to be elucidated, GFAP-IgG is a biomarker of a treatable inflammatory CNS disorder, when appropriately evaluated for. Rigorous CSF evaluation permits clear AGA diagnosis, identification of clinically pertinent coexisting IgGs, avoidance of unnecessary brain biopsies, and facilitation of early treatment.

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