Enlarged and Enhancing Optic Nerves in Advanced Glial Fibrillary Acidic Protein Meningoencephalomyelitis

A 36-year-old woman presented with intermittent fever, nausea and vomiting, generalized polyarthralgias, and bilateral optic disc swelling. She had a history of difficult-to-control myasthenia gravis since the age of 18 years. Lumbar puncture demonstrated a normal opening pressure; cerebrospinal fluid (CSF) was remarkable for high protein, low glucose, and a mononuclear pleocytosis. Although initial MRI of the brain was normal, a repeat study 8 weeks later revealed enlarged and enhancing bilateral intraorbital and intracranial optic nerves. After a nondiagnostic brain biopsy, a CSF sample tested positive for antibodies to glial fibrillary acidic protein (GFAP). Findings in this case indicate that optic nerve swelling encountered in GFAP meningoencephalomyelitis is more likely due to optic nerve inflammation rather than elevated intracranial pressure.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD Enlarged and Enhancing Optic Nerves in Advanced Glial Fibrillary Acidic Protein Meningoencephalomyelitis Daniel White, MBBS, MRCP, Susan P. Mollan, FRCOphth, Satheesh Ramalingam, MRCP, FRCR, Santhoosh Nagaraju, FRCPath, Tom Hayton, MRCP, PhD, Saiju Jacob, FRCP, DPhil, MD Abstract: A 36-year-old woman presented with intermittent fever, nausea and vomiting, generalized polyarthralgias, and bilateral optic disc swelling. She had a history of difficult-tocontrol myasthenia gravis since the age of 18 years. Lumbar puncture demonstrated a normal opening pressure; cerebrospinal fluid (CSF) was remarkable for high protein, low glucose, and a mononuclear pleocytosis. Although initial MRI of the brain was normal, a repeat study 8 weeks later revealed enlarged and enhancing bilateral intraorbital and intracranial optic nerves. After a nondiagnostic brain biopsy, a CSF sample tested positive for antibodies to glial fibrillary acidic protein (GFAP). Findings in this case indicate that optic nerve swelling encountered in GFAP meningoencephalomyelitis is more likely due to optic nerve inflammation rather than elevated intracranial pressure. Journal of Neuro-Ophthalmology 2019;39:411-415 doi: 10.1097/WNO.0000000000000842 © 2019 by North American Neuro-Ophthalmology Society Drs. White, Hayton, and Jacob: A 36-year-old woman presented with recurrent fever, nausea and vomiting, and generalized polyarthralgias. She reported headache, mild photophobia, and Department of Neurology (DW, TH, SJ), University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Birmingham Neuro-Ophthalmology Unit (SPM), Ophthalmology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; Department of Neuroradiology (SR), University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; and Department of Neuropathology (SN), University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom. The authors report no conflicts of interest. Address correspondence to Susan P. Mollan, FRCOphth, Birmingham Neuro-Ophthalmology Unit, Ophthalmology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, United Kingdom; E-mail: [e-mail] White et al: J Neuro-Ophthalmol 2019; 39: 411-415 retro-orbital pain. She had experienced double vision since the age of 18 and had been diagnosed as having myasthenia gravis (MG) based on the clinical findings and strongly positive acetylcholine receptor-binding antibodies (radioimmunoassay-194 nmol/L, normal range 0-5) 5 years after the onset of diplopia. Her ocular history was otherwise notable for dry eyes, myopia, and laser-assisted in situ keratomileusis. The medical history consisted of polycystic ovary disease and hypothyroidism, and surgical history included a thymectomy. She did not drink alcohol or smoke cigarettes. Her immediate family history included parents with type 2 diabetes mellitus, hypertension, and dyslipidemia. The myasthenia gravis symptoms had been challenging to control, with intolerable side effects to azathioprine and methotrexate. Initially, mycophenolate was ineffective, so she was enrolled in a double-blind placebo-controlled trial of the terminal complement inhibitor, eculizumab. She required intravenous immunoglobulin (IVIg) as rescue therapy initially and began open-label use of eculizumab 9 months after this. She subsequently developed alopecia areata, followed by nummular dermatitis, and then alopecia totalis. The decision was made to temporarily cease immunosuppressive therapies. However, another flare of the myasthenia gravis prompted reinitiation of IVIg and eculizumab 3 weeks before her ultimate presentation. Medications on admission included oral pyridostigmine 60 mg 4 times daily, prednisolone 7 mg daily, mycophenolate 1.5 g twice daily, eculizumab twice weekly, levothyroxine 100 mg daily, alendronic acid weekly, and artificial tears as needed. On neurological examination, there was no neck stiffness or photophobia. Regarding the myasthenia gravis, there was no ptosis, or shortness of breath; she demonstrated normal strength. There were brisk reflexes in the arms and legs and Hoffman's sign bilaterally with flexor plantar responses. The sensory examination was normal. 411 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Infrared images of the right (RE) and left (LE) eyes show bilateral optic disc swelling. Both images show Paton lines next to the disc and also radial folds extending toward the fovea (more prominent in the left eye). Dr. Mollan: Visual acuities were 6/5 in both eyes. Color vision, as tested with the Ishihara plates, was normal for both eyes. There was no afferent pupillary defect. There was a longstanding left hypertropia, with overaction of the right superior oblique. Vertical and horizontal saccades were normal. Humphrey visual field testing revealed enlarged blind spots bilaterally. Dilated fundus examination was remarkable for bilateral optic nerve head swelling as demonstrated on infrared imaging (Fig. 1). There were no additional cranial neuropathies. Drs. White, Hayton, and Jacob: The patient was febrile to 38.5°C. She had no rash or oral ulcerations. Serological testing, including inflammatory markers and three sets of blood cultures, was unremarkable. Blood tests for inflammation included normal C-reactive protein and an erythrocyte sedimentation rate that was within the normal range. Complement C3 and C4, antibodies to aquaporin 4, myelin oligodendrocyte glycoprotein, antinuclear antibodies, cardiolipin antibodies, double-stranded DNA, rheumatoid factor, antineutro- phil cytoplasmic antibodies, myeloperoxidase, and proteinase 3 were all negative. HIV and the quantiferon gold test were negative. Opening pressure on lumbar puncture (LP), as measured in the left lateral decubitus position, was 23 cm of water, with elevated protein (0.93 g/dL). There was low cerebrospinal fluid (CSF) glucose compared with serum (43%). There were 100/mL white blood cells, and oligoclonal bands in the CSF only, Polymerase chain reaction for viral and bacterial DNA, cryptococcus, mycoplasma, tuberculosis, Neisseria meningitidis, and Streptococcus pneumonia were negative. Two subsequent LPs continued to document normal intracranial pressure (ICP). The patient was treated initially with broad-spectrum intravenous antibiotics, antituberculosis therapy, and antifungal medications. Subsequently, she was managed with corticosteroids, cyclophosphamide, mycophenolate, IVIg, plasma exchange, and rituximab. She temporarily improved, only to later experience progressive decline with quadriplegia and bilateral blindness. She became ventilator dependent and ultimately succumbed to her illness. FIG. 2. Admission orbital MRI, reported as normal. A. T2-weighted coronal image obtained before contrast administration demonstrates normal caliber intracranial portions of the optic nerves. B. T1-weighted coronal image acquired after gadolinium administrations demonstrates no pathologic enhancement of the intracranial portion of the prechiasmal and chiasmal optic nerves. 412 White et al: J Neuro-Ophthalmol 2019; 39: 411-415 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 3. Cervical and lumbar spinal cord inflammation is demonstrated on fluorine-18-fluorodeoxyglucose-positron emission tomography (FDG-PET) and MRI. A. FDG-PET image showing increased activity in the cervical spinal cord (arrow). B. FDG-PET image showing a further longitudinal segment of high uptake in the lumbar spinal cord (arrows). C. MRI T2-weighted coronal image post‐gadolinium injection, demonstrating longitudinal cervical spinal cord enhancement (arrows). D. MRI T2-weighted sagittal image demonstrating longitudinal increased signal in the spinal cord (arrows). Dr. Ramalingam: Initial contrast‐enhanced orbital MRI was unremarkable (Fig. 2). Computed tomography of the thorax, abdomen, and pelvis was also normal. Fluorodeoxyglucose (FDG)- positron-emission tomography (PET) showed no evidence of primary malignancy. However, there was striking uptake in the cervical and lumbar spinal cord, suggesting an inflammatory process. Coronal T2-weighted MRI showed diffuse hyperintensity in the upper cervical cord, representing a longitudinally extensive transverse myelitis. This corresponded to the diffuse area of increased uptake on the FDG-PET (Fig. 3). Eight weeks into the admission, the MRI was repeated as she had experienced seizures. Her vision significantly deteriorated. There was bilateral optic nerve enlargement with enhancement (Fig. 4). Likewise, the postcontrast MRI sequences demonstrated bilateral, symmetric and linear contrast enhancement in a radial distribution throughout the white matter of both cerebral hemispheres (Figs. 4 and 5). There was evident leptomeningeal enhancement (Fig. 5). In the absence of a unifying diagnosis, brain biopsy was pursued. Dr. Nagaraju: Histopathology of a fragment of the cerebral cortex and leptomeninges was reported. There was an infiltrate of mature lymphocytes and a few CD68+ macrophages in the leptomeninges and perivascular spaces. Most of the lymphocytes were T-cells with a slightly higher number of CD4+ cells in the meninges and perivascular spaces FIG. 4. New bilateral optic nerve thickening and enhancement on repeat MRI 8 weeks after admission. A. Axial contrastenhanced T1-weighted MR image with fat saturation shows bilateral diffuse enhancement of the intraorbital segment optic nerve, bilateral optic nerve head protrusion, and flattening of the globes. B. Coronal contrast-enhanced T1-weighted images show bilateral enhancement of the intracranial optic nerve segment, which in (C) demonstrates the enhancement extending to the prechiasmatic optic nerves. In addition to this, (B and C) show bilateral, symmetrical and linear contrast enhancement in a radial distribution throughout the white matter of both cerebral hemispheres. White et al: J Neuro-Ophthalmol 2019; 39: 411-415 413 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. Linear periventricular radial enhancement on brain MRI. A. T2-weighted coronal image prior to gadolinium injection demonstrates normal parenchyma for comparison. B and C. Axial contrast-enhanced T1-weighted images show a bilateral radial pattern of linear perivascular enhancement throughout the cerebral white matter; this is present perpendicular to the walls of lateral ventricles of both cerebral hemispheres. There was mild leptomeningeal enhancement. and CD8+ cells in the brain parenchyma. There were a smaller number of reactive CD20+ B-cells. There were no granulomas, and Ziehl-Neelsen stain was negative for acid-fast bacilli. The appearance was consistent with a nonspecific meningoencephalitis (Fig. 6). Dr. Jacob: A CSF sample was sent for glial fibrillary acidic protein (GFAP) autoantibody testing; this returned as positive (1:512). Final Diagnosis GFAP meningoencephalomyelitis. Drs. Mollan and Jacob: Autoimmune GFAP astrocytopathy is a recently proposed neurologic syndrome characterized by meningitis, encephalitis, and/or myelitis associated with immunoglobulin G (IgG) antibodies to GFAP (1). Our patient had many similarities to the predominant phenotype described in the initial series. First, she was a young adult with a prodromal flu-like illness. Second, the patient had a coexisting autoimmune disorder (myasthenia gravis). Third, she exhibited typical MRI findings of classic diffuse linear periventricular signal. Fourth, there were longitudinally extensive spinal cord lesions. Finally, brain biopsy demonstrated a nonspecific meningoencephalitis. Ocular involvement in GFAP meningoencephalitis consists of bilateral disc swelling (1,2). Our patient was found FIG. 6. Histopathology of the cerebral cortex and leptomeninges. A. Haematoxylin and eosin (H&E) stain at low power shows perivascular inflammatory cells. B. H&E low power and (C) H&E high power images demonstrate the perivascular inflammatory cells, consisting of lymphocytes and macrophages. Immunochemistry for (D) CD20; (E) CD8; and (F) CD68 did not indicate a specific diagnosis. 414 White et al: J Neuro-Ophthalmol 2019; 39: 411-415 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study to have diffuse bilateral enlargement and enhancement of the optic nerves, which is a novel observation. This supports a mechanism of optic disc swelling from inflammatory papillitis, as proposed by Chen et al (3), rather than papilledema secondary to elevated ICP. Despite intensive immunosuppression, the patient ultimately suffered widespread neurologic decline. Yang et al (4) also expressed a subgroup of those positive for GFAP-IgG with aggressive disease and a poor response to immunosuppression. Atypical for this condition, the patient's visual acuity declined to no light perception in both eyes. Usually, vision is preserved even when optic nerve swelling is present. It remains to be seen whether visually asymptomatic patients exhibit less prominent radiographic findings, with enhancement limited to the optic nerve sheath. Future studies will be helpful to define the spectrum of optic nerve involvement in GFAP meningoencephalitis. White et al: J Neuro-Ophthalmol 2019; 39: 411-415 ACKNOWLEDGMENTS The authors thank Dr. Andrew McKeon, Mayo clinic, for performing the GFAP assay in this case. REFERENCES 1. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, Lennon VA. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA Neurol. 2016;73:1297-1307. 2. 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. 3. Chen JJ, Aksamit AJ, McKeon A, Pittock SJ, Weinshenker BG, Leavitt JA, Morris PP, Flanagan EP. Optic disc edema in glial fibrillary acidic protein autoantibody-positive meningoencephalitis. J Neuroophthalmol. 2018;38:276-281. 4. Yang X, Liang J, Huang Q, Xu H, Gao C, Long Y, Xiao X. Treatment of autoimmune glial fibrillary acidic protein astrocytopathy: follow-up in 7 cases. Neuroimmunomodulation. 2017;24:113-119. 415 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.