Optic Disc Edema in Glial Fibrillary Acidic Protein Autoantibody-Positive Meningoencephalitis

Glial fibrillary acidic protein (GFAP) autoantibody-positive meningoencephalitis is a newly described entity characterized by a corticosteroid-responsive meningoencephalomyelitis. Some patients with GFAP autoantibody-positive meningoencephalitis have been found to have optic disc edema, which has previously not been well characterized. We performed a retrospective, observational case series of Mayo Clinic patients found to have GFAP-IgG and optic disc edema from January 1, 2000, to December 31, 2016. We identified 40 patients with GFAP-IgG seropositivity by tissue-based immunofluorescence and cell-based assay. Patients were screened for the following inclusion criteria: 1) serum, cerebrospinal fluid, or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining with confirmation of IgG reactive with specific GFAPα isoform by cell-based assay; 2) meningoencephalitis or encephalitis; and 3) optic disc edema. We excluded those with coexisting aquaporin-4-IgG or insufficient clinical information. Ten patients had optic disc edema and met inclusion criteria. The median age was 39.5 years and 60% were men. Visual acuity was unaffected and disc edema was bilateral in all cases. Mild vitreous cell was noted in 3 patients. The optic disc edema resolved with corticosteroid treatment but resulted in mild optic atrophy in 2 patients. The median lumbar puncture opening pressure was 144 mm H2O (range, 84-298 mm H2O). Brain MRI revealed radial perivascular enhancement in all except 1 patient. Fluorescein angiography was available for 1 patient with optic disc edema, which showed leakage from the venules. Patients with GFAP autoantibody-positive meningoencephalitis can have optic disc edema that can mimic papilledema. The cause of the optic disc edema remains uncertain, but most patients did not have raised intracranial pressure.

Original Contribution Optic Disc Edema in Glial Fibrillary Acidic Protein Autoantibody-Positive Meningoencephalitis John J. Chen, MD, PhD, Allen J. Aksamit, MD, Andrew McKeon, MB, BCh, Sean J. Pittock, MD, Brian G. Weinshenker, MD, Jacqueline A. Leavitt, MD, Padraig P. Morris, MB, BCh, Eoin P. Flanagan, MB, BCh Background: Glial fibrillary acidic protein (GFAP) autoantibody- positive meningoencephalitis is a newly described entity characterized by a corticosteroid-responsive meningoencephalomyelitis. Some patients with GFAP autoantibody-positive meningoencephalitis have been found to have optic disc edema, which has previously not been well characterized. Methods: We performed a retrospective, observational case series of Mayo Clinic patients found to have GFAP-IgG and optic disc edema from January 1, 2000, to December 31, 2016. We identified 40 patients with GFAP-IgG seropositivity by tissue-based immunofluorescence and cell-based assay. Patients were screened for the following inclusion criteria: 1) serum, cerebrospinal fluid, or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining with confirmation of IgG reactive with specific GFAPa isoform by cell-based assay; 2) meningoencephalitis or encephalitis; and 3) optic disc edema. We excluded those with coexisting aquaporin-4-IgG or insufficient clinical information. Results: Ten patients had optic disc edema and met inclusion criteria. The median age was 39.5 years and 60% were men. Visual acuity was unaffected and disc edema was bilateral in all cases. Mild vitreous cell was noted in 3 patients. The optic disc edema resolved with corticosteroid treatment but resulted in mild optic atrophy in 2 patients. The median lumbar puncture opening pressure was 144 mm H2O (range, 84-298 mm H2O). Brain MRI revealed radial perivascular enhancement in all except 1 patient. Fluorescein angiography was available for 1 patient Departments of Ophthalmology (JJC, JAL), Neurology (AJA, AM, SJP, BGW, EPF), Laboratory Medicine and Pathology (AM, SJP, EPF), and Neuroradiology (PPM), Mayo Clinic, Rochester, Minnesota. Supported in part by an unrestricted grant to the Department of Ophthalmology by Research to Prevent Blindness, Inc, New York, NY; the Mayo Clinic Center for Individualized Medicine; Department of Laboratory Medicine and Pathology; and the Center of MS and Autoimmune Neurology. Dr. A. McKeon is a named inventor on a patent application filed by the Mayo Foundation relating to the GFAP antibody. The remaining authors report no conflicts of interest. Address correspondence to John J. Chen, MD, PhD, Departments of Ophthalmology and Neurology, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905; E-mail: [e-mail] 276 with optic disc edema, which showed leakage from the venules. Conclusions: Patients with GFAP autoantibody-positive meningoencephalitis can have optic disc edema that can mimic papilledema. The cause of the optic disc edema remains uncertain, but most patients did not have raised intracranial pressure. Journal of Neuro-Ophthalmology 2018;38:276-284 doi: 10.1097/WNO.0000000000000593 © 2017 by North American Neuro-Ophthalmology Society G lial fibrillary acidic protein (GFAP) autoantibody-positive meningoencephalomyelitis is a newly described entity that is typically characterized by a corticosteroid-responsive meningoencephalomyelitis or limited form thereof, accompanied by GFAP-IgG (1,2). Brain MRI often shows perivascular radial enhancement, and imaging of the spine can show longitudinally extensive myelitic lesions (1). Although many of these cases mimic a vasculitic process, cerebral catheter angiography has been normal. Aquaporin-4 and N-methyl-D-aspartate receptor antibodies have been reported to coexist with GFAP-IgG in a third of cases and occasionally, it occurs as a paraneoplastic phenomenon (usually teratoma) (1). Some patients with GFAP autoantibody-positive meningoencephalomyelitis have been reported to have bilateral optic disc edema (1,2), which is often asymptomatic and was first recognized in this clinical phenotype of encephalomyelitis before discovery of GFAP-IgG (3). The pathogenesis of autoimmune GFAP autoantibody-positive meningoencephalomyelitis and the cause of the optic disc edema are still unknown. We report the ophthalmic details in GFAP-IgG-positive patients seen at the Mayo Clinic to better define the optic disc edema seen in this disease. METHODS This study was approved by the Mayo Clinic Institutional Review Board. Forty GFAP-IgG-seropositive Mayo Clinic patients were identified through our Neuroimmunology Chen et al: J Neuro-Ophthalmol 2018; 38: 276-284 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Laboratory from January 1, 2000, to December 31, 2016 (1,2). For this study, our inclusion criteria were: A) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining with confirmation of IgG reactive with specific GFAPa isoform by cell-based assay (1,2); B) meningoencephalitis or encephalitis; and C) optic disc edema. Fifteen did not have meningoencephalomyelitis or encephalitis and were excluded (14 positive in serum and CSF unavailable and 1 positive in serum but negative in CSF). Eleven patients with GFAP autoantibody-positive meningoencephalitis did not have optic disc edema, although 7 did not have an ophthalmology examination at presentation. We also excluded those with coexisting aquaporin-4-IgG (1 patient) or insufficient clinical information (3 patients). The medical records of patients were reviewed for the characteristics of optic disc edema, visual acuity, visual fields, optical coherence tomography, fluorescein angiography, MRI findings, lumbar puncture opening pressures, and CSF parameters. Eight of the included patients were reported in previous series on GFAP-IgG (1,2) but did not include detailed information on the ophthalmological findings, which was the focus of this report. RESULTS Ten patients were included. GFAP-IgG was detected in CSF, 2 (serum unavailable, 1; serum negative, 1); serum, 3 (CSF unavailable for testing in all 3); or both, 5. The demographics and clinical findings of these patients are shown in Table 1. The median age was 39.5 years (range, 19-74 years) and 60% were men. All patients had meningoencephalitis or encephalitis and 3 also had myelitis. At initial presentation, the optic disc edema was bilateral and symmetric in all patients (Figs. 1A, 2A). Optical coherence tomography showed a thickened retinal nerve fiber layer without any retinal outer layer abnormalities (Fig. 2C). Visual acuity was preserved, and patients were asymptomatic except for 3 patients with transient visual obscurations. On automated perimetry, 2 patients had mild arcuate visual field defects, 1 patient had nonspecific depression, and 1 patient had enlarged blind spots (Figs. 1C, 2E and Table 1). The opening pressure on lumbar puncture was normal in all patients except for 2 who had mildly elevated pressures of 265 and 298 mm H2O; the median lumbar puncture opening pressure was 144 mm H2O (range, 84-298 mm H2O). All patients had elevated cells and protein in the CSF (Table 1). Fluorescein angiography was available in 1 patient with optic disc edema, which showed leakage from the retinal venules (Fig. 2B). Mild vitritis was noted in this patient and 2 others. The majority of the patients (90%) had the characteristic radial perivascular enhancement on MRI that can be seen in autoimmune GFAP autoantibody-positive meningoencephalitis (Figs. 1B, 2D and Table 1). The optic disc edema and MRI abnormalities resolved with high-dose intravenous Chen et al: J Neuro-Ophthalmol 2018; 38: 276-284 corticosteroid treatment followed by a prolonged oral course. Patient 9 was treated briefly with acetazolamide. Mild optic disc pallor, ganglion cell layer thinning, and persistent arcuate visual field defects were noted in 2 patients after resolution of the disc edema (Fig. 1D, E and Table 1). DISCUSSION GFAP autoantibody-positive meningoencephalitis is a recently described entity characterized by a steroidresponsive meningoencephalomyelitis accompanied by GFAP-IgG (1,2). The clinical presentation of this disorder is quite broad and can range from subacute to chronic encephalitis with or without accompanying meningitis or myelitis. Patients may have characteristic radial perivascular enhancement on MRI, although other enhancement patterns have been encountered (leptomeningeal), and most have an inflammatory CSF. We described 10 patients with bilateral optic disc edema from GFAP autoantibody- positive meningoencephalitis who all had an inflammatory CSF, and 9 of 10 had radial perivascular enhancement on MRI. Most patients were visually asymptomatic, despite the optic disc edema. Two patients had mild optic nerve pallor and arcuate visual field defects after treatment and resolution of the disc edema. The cause of the optic disc edema remains uncertain. Although it was typically asymptomatic and mimicked papilledema, the opening pressure was normal in the majority of the patients. Only 2 patients in our cohort had a mildly elevated opening pressure, indicating that raised intracranial pressure is unlikely the primary cause of the optic disc edema in the majority of cases. It is possible that elevated CSF protein could have played a role in the elevated intracranial pressure in 2 of our patients. Most patients were evaluated before initiation of therapy, and therefore, steroids did not influence the lumbar puncture opening pressure measurements. GFAP is found in the retina, especially within the end foot of Müller cells and astrocytes and could be targeted in GFAP autoantibody-positive meningoencephalitis, leading to a breakdown of the retina-blood barrier that contributes to optic disc edema (4). Knockout GFAP experiments in mice have shown locally impaired blood-brain barrier function (5). Fluorescein angiography in 1 patient showed prominent venular leakage. This suggests that the underlying pathogenesis of GFAP autoantibody-positive meningoencephalitis may be a venulitis or at least primarily involves venous inflammation. The characteristic radial perivascular enhancement on MRI also supports a venular process. These findings suggest that the optic disc edema may be a papillitis from an inflammatory vasculopathy as opposed to papilledema from raised intracranial pressure (1). In addition, the fluorescein angiogram had a similar appearance to frosted branch angiitis, which is caused by 277 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Visual Symptoms Duration of Disease Before Eye Examination Chen et al: J Neuro-Ophthalmol 2018; 38: 276-284 Patient Age Sex 1 2 51 52 M None M None 1 mo 3 mo 3* 37 3 mo 4† 29 5 21 6 42 M Transient visual obscurations F Transient visual obscurations M Transient visual obscurations M None 7 74 F 8 9 51 19 F F 10 36 Treatment Before Eye Examination Visual Acuity Disc at Follow-up CSF CSF White Protein Cells (mg/ (/mL)§ dL)║ Full OU None Normal Normal Both Serum Yes Yes 138 181 67 90 173 205 Yes 134 185 112 Both Yes 298 71 192 1 mo Mild pallor OU Mild pallor OU No f/u Serum Previous intermittent 20/20 OU prednisone None 20/20 OU Superior arcuate defects OU Arcuate defects OU None CSF No 86 26 64 3 mo Prednisone Full OU Normal Both Yes 140 148 168 None 1 mo None No f/u CSF Yes 176 41 70 None None 6 mo 1 mo Normal Normal Serum Both Yes Yes 84 265 48 48 73 73 M None 3 mo None Acetazolamide 500 mg bid Intermittent prednisone Nonspecific depression None Full OD; enlarged blind spot OS None Normal Both Yes 148 58 79 3 mo None 20/20 OU Previous intermittent 20/20 OD, 20/ prednisone 25 OS None 20/20 OU Visual Fields GFAP Serology MRI Radial ICP (Serum, Perivascular (mm CSF, Both) Enhancement H2O)‡ 20/20 OD, 20/ 25 OS 20/30 OU 20/20 OU 20/20 OU 20/15 OU CSF, cerebrospinal fluid; f/u, follow-up; GFAP, glial fibrillary acidic protein; ICP, intracranial pressure; mm H2O, millimeters of water; OD, right eye; OS, left eye; OU, both eyes. *Patient in Figure 1. † Patient in Figure 2. ‡ Normal range, 100-200 mm H2O. § All lymphocytic predominant; normal range, 0-5/mL. ║ Normal range, 0-35 mg/dL. Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 278 TABLE 1. Characteristics of patients with optic disc edema and autoimmune GFAP astrocytopathy Original Contribution FIG. 1. A 37-year-old man with GFAP autoantibody-positive meningoencephalitis. A. At presentation, there is bilateral optic disc edema. B. Postcontrast axial T1 MRI demonstrates the characteristic radial enhancement. C. Automated visual fields show mild superior arcuate defects, which remained after the disc edema resolved. D. After corticosteroid treatment, there is resolution of the disc edema leaving mild bilateral optic disc pallor. E. Optical coherence tomography at follow-up shows mild symmetric thinning of the retinal nerve fiber and ganglion cell layers (Patient 3, Table 1). GFAP, glial fibrillary acidic protein. multiple etiologies including infection, inflammation, and neoplasm, where disc edema is the result of papillitis (6,7). Hassan et al (8) described a patient with a similar phenotype who presented with bilateral optic disc edema and Chen et al: J Neuro-Ophthalmol 2018; 38: 276-284 radial perivascular magnetic resonance enhancement, which was attributed to primary angiitis of the central nervous system because of inflammatory cells infiltrating the walls of small vessels evident on pathology specimens. Similar to 279 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A 29-year-old woman with GFAP autoantibody-positive meningoencephalitis. A. At initial evaluation, there is bilateral optic disc edema. B. Fluorescein angiography shows leakage of the retinal venules and optic discs. C. Optical coherence tomography at presentation shows the normal outer retina with a markedly elevated retinal nerve fiber layer thickness. D. Postcontrast axial T1 MRI reveals subtle radial enhancement. E. Automated visual fields show mild arcuate defects, which persisted after completion of corticosteroid treatment and resolution of the optic disc edema (Patient 4, Table 1). GFAP, glial fibrillary acidic protein. our patients, the lumbar puncture showed a normal opening pressure with lymphocytic predominant CSF. In retrospect, we suspect that this may have been a case of GFAP autoantibody-positive meningoencephalitis. Cases with pathology are needed to determine whether GFAP 280 autoantibody-positive meningoencephalitis is primarily an astrocytic disorder or due to venous or arterial inflammation. Limitations of our study include its retrospective nature and a small sample size, including a very limited number of Chen et al: J Neuro-Ophthalmol 2018; 38: 276-284 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution fluorescein angiograms available to review. Although aquaporin-4-IgG may coexist with GFAP-IgG, we focused on isolated GFAP-IgG cases in this study, as overlapping clinical features would have been difficult to separate. The 3 patients with serum GFAP-IgG seropositivity alone did not have CSF available for testing, but all had the classic clinical phenotype of meningoencephalomyelitis. This is an important finding, as CSF testing of GFAP-IgG has been preferred, given its higher specificity for autoimmune central nervous system disease (1). Not all patients with GFAP autoantibody-positive meningoencephalitis underwent ophthalmic evaluation, and therefore, it is likely that optic disc edema in this condition is more common than reported here. In summary, the clinical characteristics of GFAP autoantibody-positive meningoencephalitis are still being elucidated. We recommend testing CSF GFAP autoantibodies in patients with unexplained meningoencephalitis, particularly if they have bilateral optic disc edema, accompanying myelitis or radial perivascular enhancement on MRI. The optic disc edema may be due to an inflammatory papillitis affecting the venules as opposed to elevated intracranial pressure. Prospective and pathologic studies will be required to better determine the pathophysiology and frequency of optic disc edema in GFAP autoantibody- positive meningoencephalitis. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. J. Chen and E. P. Flanagan; b. Acquisition of data: J. J. Chen and E. P. Flanagan; c. Analysis and interpretation of data: J. J. Chen, A. J. Aksamit, A. McKeon, and E. P. Flanagan. Category 2: a. Drafting the manuscript: J. J. Chen and E. P. Flanagan; b. Revising it for intellectual content: J. J. Chen, A. J. Aksamit, A. McKeon, S. J. Pittock, B. G. Weinshenker, J. A. Leavitt, P. P. Morris, and E. P. Flanagan. Category 3: a. Final approval of the completed manuscript: J. J. Chen, A. J. Aksamit, A. McKeon, S. J. Pittock, B. G. Weinshenker, J. A. Leavitt, P. P. Morris, and E. P. Flanagan. REFERENCES 1. Flanagan EP, Hinson SR, Lennon VA, Fang B, Aksamit AJ, Morris PP, Basal E, Honorat JA, Alfugham NB, Linnoila JJ, Weinshenker BG, Pittock SJ, McKeon A. Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: analysis of 102 patients. Ann Neurol. 2017;81:298-309. 2. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, Lennon VA. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. 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J Neuroophthalmol. 2003;23:127-131. Invited Commentary Glial Fibrillary Acidic Protein Antibody: Another Antibody in the Multiple Sclerosis Diagnostic Mix Meagan Seay, DO, Steven Galetta, MD C linical practice and research of inflammatory demyelinating diseases is a dynamic and evolving field, particularly since the start of the 21st century. Our Departments of Neurology (MS, SG) and Ophthalmology (SG), New York University School of Medicine, New York, New York. The authors report no conflicts of interest. Address correspondence to Steven Galetta, MD, 222 E. 41st Street, 14th Floor, New York, NY 10017; E-mail: [e-mail] Seay and Galetta: J Neuro-Ophthalmol 2018; 38: 276-284 understanding the disease course of multiple sclerosis (MS) and the impact of disease modifying treatments, along with the discovery of novel antibody biomarkers, have greatly transformed the practice of neuroimmunology. In 2017, updated criteria for the diagnosis of MS were released (1). One significant change was the inclusion of symptomatic supratentorial, infratentorial, or spinal cord lesions in satisfying criteria for dissemination in time or space. Two of 4 locations need to be involved to qualify 281 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.