Vision Loss Associated With Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Vision Loss Associated With Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy Michael M. Han, MD, Catherine R. Sheils, MD, Robert W. Crow, MD A utoimmune Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy is an autoimmune meningoencephalitis characterized by Immunoglobulin G (IgG) autoantibodies against GFAP in cerebrospinal fluid (CSF) (1–3). Brain, meningeal, and spinal cord involvement is common, whereas optic neuritis and ocular movement disorders have been infrequently described (4). Visual acuity is typically preserved despite presentation with optic nerve edema (4). We discuss a patient who presented months into the disease with bilateral optic neuritis and rapid vision loss that reversed with immunosuppression. A 35-year-old Indian woman presented with 3 months of intractable headaches, subjective fevers, myalgias, weight loss, and 90-minute episodes of confusion and nonfluent speech. Her initial workup at an outside hospital included brain MRI, which demonstrated bilateral symmetric linear striations in the pericallosal deep white matter on FLAIR. Lumbar puncture demonstrated lymphocytic pleocytosis, elevated protein, and normal glucose. Serum studies showed positive purified protein derivative skin test and QuantiFERON Gold, although chest X-rays were unremarkable and serial sputum cultures were negative. She was discharged with intravenous acyclovir for presumed viral meningitis. Despite treatment, she reported increasing episodes of inattention and confusion, and developed square wave jerks, postural tremor of her upper extremities, and diffuse hyperreflexia. Additional brain and spine MRI revealed new T2 hyperintense spinal cord edema from T1-T8. She was started on rifampin-isoniazidpyrazinamide-ethambutol in addition to dexamethasone for suspected tuberculosis meningoencephalitis. Despite treatment, she developed progressive blurred vision of the left eye, accompanied by sharp retro-orbital pain worse with ocular movements. The patient was again admitted to the hospital and ophthalmology was consulted. Initially, her visual acuity was 20/25 and 20/30, with intraocular pressures of 21 and 17, in the right and left eyes, respectively. There was no Department of Medicine (MMH), University of California Irvine Medical Center, Orange, California; and Gavin Herbert Eye Institute (CRS, RWC), University of California, Irvine, California. The authors acknowledge departmental support from a Research to Prevent Blindness unrestricted grant. The authors report no conflicts of interest. Address correspondence to Catherine R. Sheils, MD, Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, 850 Health Sciences Road, Irvine, CA 92697; E-mail: [e-mail] Han et al: J Neuro-Ophthalmol 2022; 42: e485-e487 relative afferent pupillary defect (rAPD). Color vision testing with Ishihara plates was 11/13 in the right and 10/13 in the left. Ocular motility, external, and anterior segment examinations were normal. Dilated fundus examination demonstrated grade IV optic disc edema without vitritis or retinal lesions (Fig. 1A). Fluorescein angiography demonstrated bilateral optic nerve hyperfluorescence (Fig. 1B). Optical coherence tomography (OCT) demonstrated severe bilateral optic nerve edema and left subretinal fluid (Fig. 1C, D). Repeated MRI brain revealed radial perivascular T1 hyperintensities (Fig. 2A), and a new 1.4-cm left periventricular enhancing lesion (Fig. 2B). MRI orbits demonstrated diffuse bilateral optic nerve enhancement (Fig. 2C). MRI spine showed worsening T2 hyperintensities now involving C7-T10 (Fig. 2D). Repeat lumbar puncture demonstrated an opening pressure of 13 mm Hg and again showed lymphocytic pleocytosis. Targeted CSF studies revealed normal angiotensin converting enzyme and adenosine deaminase, and negative results for Venereal Disease Research Laboratory test (VDRL), Neuromyelitis OpticaAquaporin 4 IgG, Myelin Oligodendrocyte Glycoprotein-1 IgG, and Herpes Simplex Virus 1 and 2 polymerase chain reaction. Serum Bartonella IgG was negative. Cerebrospinal fluid flow cytometry was negative for lymphoproliferative disorder. Whole body imaging revealed no underlying neoplasms. The patient underwent a brain biopsy of the periventricular lesion. Pathology demonstrated prominent angiocentric and transmural lymphocytic inflammation, markedly abnormal white matter with reduction of axonal density, absence of myelin, and reactive gliosis. Special stains demonstrated no microorganisms or viral inclusions. Serial bedside examinations revealed a progressive decline in vision. By Day 4, she described transient visual obscurations, developed a brisk, 2+ rAPD in the left eye, and decreased vision in the left eye from 20/30 to 20/800. Dilated fundus exams remained stable. An interdisciplinary team including neurology, neuroimmunology, infectious disease, rheumatology and ophthalmology favored an autoimmune process because of negative infectious workup and biopsy results suggestive of central nervous system (CNS) vasculitis. She was started on high-dose intravenous methylprednisolone and plasma exchange. Her retro-orbital pain improved and after 5 days of treatment, her vision returned to 20/20 bilaterally with improved rAPD in the left eye. Repeat OCT demonstrated improved subretinal fluid of the left eye, but new subretinal fluid in the right, potentially from steroid-induced retinal pigment epithelium dysfunction. e485 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. Fundus photos of the right and left eyes (A) demonstrate severe optic disc edema with obscuration of the retinal vessels. Fluorescein angiography reveals bilateral optic nerve hyperfluorescence, and absence of vascular leakage, staining, or pooling (B). Optical coherence tomography demonstrates severe optic disc edema (C, D) and noncontiguous subretinal fluid in the left eye (C). The Mayo Clinic autoimmune encephalopathy panel returned positive for GFAP autoantibodies with a titer of 1:32. The patient underwent cyclophosphamide induction followed by mycophenolate therapy and gradual prednisone taper. Four months later, her visual acuity remained 20/20 in both eyes, OCT showed optic nerve atrophy and resolved subretinal fluid, and her visual fields had normalized. Autoimmune GFAP Astrocytopathy was first described in 2016 and is diagnosed with positive GFAP autoantibody in the CSF, which distinguishes this disorder from infectious meningoencephalitis and other idiopathic inflammatory CNS disorders such as multiple sclerosis, vasculitis, and neurosarcoidosis (4). GFAP astrocytopathy is most frequently associated with meningitis or encephalitis (54.5%) and myelitis (10.5%), but less commonly with optic neuritis (4.5%) (3). The striking disc edema may mimic papilledema; however, patients have normal intracranial e486 pressure on lumbar puncture and may have retro-orbital pain, loss of color vision, and development of an rAPD (4,5). The pathophysiology may be from an inflammatory vasculopathy with breakdown of the retinal–blood barrier and release of GFAP found in retinal astrocytes and Muller cells, or a primary disorder of astrocytes with similar consequences (5). GFAP antibody is not known to induce pathological changes itself; rather the presence of GFAP antibodies is a biomarker for the immune neuroinflammation (3). The histopathology in this case demonstrated astrocyte destruction and prominent perivascular inflammatory infiltrate suggestive of angiitis. MRI brain characteristically demonstrates T1 postgadolinium linear radial enhancement in a perivascular pattern, as seen in our patient (4). Furthermore, MRI orbits demonstrated florid optic nerve and chiasm enhancement suggestive of diffuse optic neuritis. Nearly a third of patients are found to have Han et al: J Neuro-Ophthalmol 2022; 42: e485-e487 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 2. MRI brain demonstrates T1 postgadolinium radial enhancement (A) and an enhancing T2 FLAIR periventricular lesion (B) on axial views. MRI orbits demonstrates T1 postgadolinium bilateral optic nerve enhancement on axial view. MRI orbits demonstrates T1 postgadolinium bilateral optic nerve enhancement on axial view (C). MRI spine demonstrates multilevel T1 postgadolinium perivascular spinal cord enhancement on sagittal view (D). an underlying neoplasm diagnosed within 2 years of symptom onset (4). GFAP astrocytopathy is responsive to immunosuppression, with more than 70% of cases responding to steroids, intravenous immunoglobulin, and plasma exchange (2,3). To the authors’ knowledge, subretinal fluid has not previously been described, but is seen in uveitic conditions with optic nerve and retinal involvement including lupus choroidopathy and Vogt–Koyanagi–Harada disease. The improvement in subretinal fluid while receiving increased steroid doses makes steroid-induced central serous chorioretinopathy unlikely. Patients with GFAP astrocytopathy typically have preserved vision in spite of optic nerve edema, but in our case our patient suffered from visual deterioration and development of an rAPD. However, the patient’s markedly reduced visual acuity resolved with immunosuppression, potentially indicating a good visual prognosis in other similarly affected patients. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. R. Sheils and R. W. Crow; b. Acquisition of data: M. M. Han, C. R. Sheils, and R. W. Crow; c. Analysis and interpretation of data: M. M. Han, C. R. Sheils, and Han et al: J Neuro-Ophthalmol 2022; 42: e485-e487 R. W. Crow. Category 2: a. Drafting the manuscript: M. M. Han and C. R. Sheils; b. Revising it for intellectual content: C. R. Sheils and R. W. Crow. Category 3: a. Final approval of the completed manuscript: M. M. Han, C. R. Sheils, and R. W. Crow. REFERENCES 1. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, Lennon VA. 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