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Original Investigation
November 2016

Autoimmune Glial Fibrillary Acidic Protein AstrocytopathyA Novel Meningoencephalomyelitis

Author Affiliations
  • 1Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
  • 2Department of Neurology, Mayo Clinic, Rochester, Minnesota
  • 3Department of Immunology, Mayo Clinic, Rochester, Minnesota
JAMA Neurol. 2016;73(11):1297-1307. doi:10.1001/jamaneurol.2016.2549
Key Points

Question  Can a serologic biomarker aid the diagnosis of autoimmune meningoencephalomyelitis?

Findings  A novel astrocyte-specific IgG autoantibody discovered in the cerebrospinal fluid and serum of 103 patients undergoing testing for potential autoimmune neurologic disorders in a high-volume service laboratory was found in review of medical records to be associated with a disabling and relapsing corticosteroid-responsive meningoencephalitis, with or without myelitis. Glial fibrillary acidic protein (GFAP) was identified as the antigen, and one-third of cases were paraneoplastic.

Meaning  As a disease biomarker, GFAP-specific IgG unifies a spectrum of treatable autoimmune meningoencephalomyelitis, a new class of autoimmune astrocytopathy that is presumably mediated by GFAP peptide–specific cytotoxic CD8+ T cells.

Abstract

Importance  A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis.

Objective  To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes.

Design, Setting, and Participants  Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood).

Main Outcomes and Measures  Frequency and definition of novel autoantibody, the autoantigen’s immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness.

Results  Of 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression.

Conclusions and Relevance  Glial fibrillary acidic protein–specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide–specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.

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