Bilateral Orbital Fat Hyperintensity in Early Glial Fibrillary Acidic Protein Astrocytopathy

Abstract

Objectives

Glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory autoimmune disease of the CNS that targets astrocytes. Although optic disc edema is a frequently reported ocular manifestation in GFAP astrocytopathy, it has not been well-characterized as orbital fat hyperintensity. Here, we report a rare case in which GFAP astrocytopathy initially presented with orbital fat hyperintensity.

Methods

A 26-year-old woman presenting with headache, fever, and bilateral ocular pain was evaluated using neurologic examination, CSF examination, autoantibody testing, and multimodal MRI including orbital conditions.

Results

Orbital MRI revealed hyperintensity in the bilateral orbital fat tissue on short tau inversion recovery sequences without optic nerve involvement, whereas intracranial MRI was initially unremarkable. CSF examination showed increase in lymphocytes and was positive for anti-GFAP antibodies. Subsequent MRI revealed characteristic lesions in the thalamic and perivascular area. High-dose corticosteroid therapy led to rapid clinical improvement and resolution of orbital and intracranial MRI lesions.

Discussion

This case demonstrates that orbital fat hyperintensity may be an early manifestation of GFAP astrocytopathy, preceding intracranial lesions. Recognition of this orbital MRI finding facilitates earlier diagnosis and treatment, potentially leading to improved prognosis.

Introduction

Glial fibrillary acidic protein (GFAP) astrocytopathy is an inflammatory autoimmune disease of the CNS that targets astrocytes. First reported in 2016, this disease is characterized by GFAP-specific IgG autoantibodies in CSF.¹ Clinical manifestations include meningitis-like symptoms, impaired consciousness, autonomic dysfunction, and motor deficits.^1-4 Ocular manifestations are also characteristic, with frequent optic disc edema^1,2,4,5 and occasional optic neuritis.^4,6,7 Corticosteroid therapy is generally effective.^1,2,4,5

Brain and spinal cord MRI typically reveal hyperintensity on T2-weighted images and fluid-attenuated inversion recovery (FLAIR), along with linear perivascular radial enhancement.^1-5,8,9 Abnormalities of the optic nerve and optic sheath have been reported on orbital MRI,^7,8 but orbital fat hyperintensity has not been well characterized.

We here report a case of GFAP astrocytopathy presenting orbital fat hyperintensity in which orbital MRI provided an important diagnostic clue.

Case Report

A 26-year-old woman in good health developed a headache. Two days later, she developed a fever of 38.0°C, worsening headache, pain in both eyes, and vomiting. Despite no visual impairment, visual field defects, or diplopia, symptoms persisted, and she was admitted to the neurology department 12 days after onset.

On admission, her height was 155.7 cm, weight was 40.7 kg, and body temperature was 38.0°C. She was alert and well-oriented, with mild tenderness in both temporal regions and pain in lateral gaze. Her cranial nerve, motor, and sensory function were normal, and meningeal irritation signs were absent.

Blood tests showed normal cell counts, and levels of C-reactive protein, IgG4, angiotensin-converting enzyme, sIL-2R, and IFN-γ, as well as thyroid function, were within normal ranges. CSF examination showed normal pressure at 16 cmH₂O, but elevated cell count (186/mm³; mononuclear cells 100%), elevated protein (104 mg/dL), and decreased glucose (32 mg/dL; blood glucose: 98 mg/dL). Quantitative CSF herpes simplex virus DNA testing, CSF cultures, the FilmArray Meningitis/Encephalitis panel (BioFire Diagnostics), as well as serum autoantibodies, including anti-aquaporin 4 antibody (live cell-based assay), antinuclear antibodies, anti–SS-A antibodies, cytoplasmic antineutrophil cytoplasmic autoantibodies, myeloperoxidase antineutrophil cytoplasmic autoantibodies, and onconeuronal antibodies, were all negative. Serum anti-myelin oligodendrocyte glycoprotein (MOG) antibody could not be tested. CSF tests were also negative for anti-MOG antibody (live cell-based assay) and anti–N-methyl-d-aspartate receptor antibodies.

MRI revealed mild hyperintensity in the bilateral orbital fat tissue on short tau inversion recovery (STIR) sequences (Figure 1, A and B). No abnormalities were noted in the optic nerves, brain parenchyma, or spinal cord. CT of the chest and abdomen showed no evidence of malignancy.

Figure 1. Orbital and Brain MRI.

Orbital MRI at admission (A and B) showed hyperintensity in bilateral orbital fat tissue on STIR images. One week after admission, high intensity lesions on FLAIR sequences were observed in the left thalamus and periventricular regions in gadolinium-enhanced brain MRI (C and D). MRI showed a linear radial enhancement pattern in the periventricular area (E and F). These lesions showed trend toward improvement 3 weeks after admission (G and H), and after 9 months, no hyperintensity was observed (I and J). FLAIR = fluid-attenuated inversion recovery; STIR = short tau inversion recovery.

Ophthalmologic examination revealed normal visual acuity in both eyes, intraocular pressure of 14 mm Hg (right) and 16 mm Hg (left), and critical fusion frequencies of 49.0 Hz (right) and 46.0 Hz (left). Pupillary light reflexes were normal, and relative afferent pupillary defects were negative. No abnormalities were noted in the anterior segment examination and visual field. Fundus examination revealed bilateral optic disc edema and dilation and tortuosity of the right retinal vein (Figure 2, A and B). Optical coherence tomography (OCT) showed elevated retinal nerve fiber layer thickness (Figure 2C).

Figure 2. Ophthalmologic Examination.

Fundus examination and OCT of the right eye at admission (A–C) and 9 months after discharge (D and E). At admission, fundus examination revealed optic disc edema, dilation and tortuosity of right retinal vein (A, arrowheads). OCT showed elevated retinal nerve fiber layer thickness (B and C). These abnormalities showed improvement at 9 months after discharge (D and E). OCT = Optical Coherence Tomography.

At the time of admission, the results of autoantibodies test were unknown, and a presumptive diagnosis of meningitis complicated by orbital fat hyperintensity was made, and treatment was initiated. Initial treatment consisted of IV acyclovir 10 mg/kg body weight every 8 hours, but urinary retention emerged the day after admission. A gadolinium-enhanced brain MRI performed 1 week after admission revealed new hyperintense lesions in the left thalamus and perivascular area on FLAIR sequences (Figure 1, C and D), and gadolinium-enhanced MRI showed a linear radial enhancement pattern in the periventricular area (Figure 1, E and F). Follow-up CSF testing showed no improvement, and acyclovir was discontinued 1 week after admission. Assuming immunoreactive meningitis, the patient received 2 courses of IV methylprednisolone therapy (each course consisting of 1,000 mg daily for 3 days), followed by oral prednisolone 40 mg/d as maintenance therapy. Her symptoms of headache, fever, pain in both eyes, and vomiting improved gradually after starting corticosteroid therapy. MRI scan 3 weeks after admission showed a trend toward improvement in the hyperintense lesions in the orbital fat tissue, left thalamus, and perivascular regions (Figure 1, G and H). Four weeks after admission, her symptoms subsided, and she was discharged.

After discharge, CSF testing was positive for anti-GFAP antibodies assessed by cell-based and tissue-based assays with previously reported methods,³ leading to a diagnosis of GFAP astrocytopathy (Figure 3). She was free from recurrence of neurologic symptoms, and the prednisolone dose was gradually reduced to 3 mg/d while maintaining disease stability. An ophthalmologic examination 9 months after discharge showed improvement of optic disc edema and the dilation and tortuosity of the right retinal vein (Figure 2, D and E). In addition, MRI revealed no hyperintensity of the orbital fat tissue (Figure 1, I and J).

Figure 3. GFAP Antibody Test on Tissue-Based Assay and Cell-Based Assay.

Tissue-based immunofluorescence assay using frozen rat brain sagittal sections (A–D). Immunoreactivity of CSF IgG from the patient was observed in astrocytes (red arrows) within the cerebral cortex (A), hippocampal dentate gyrus (B), periventricular region (C), and in Bergmann glia (white arrows) of the cerebellum (D). Nuclei are stained with Hoechst 33342 (bisbenzimide dye) (blue). Cell-based assay of GFAPα-transfected HEK293 cells (F–I). HEK293 cells stably expressing green fluorescent protein (GFP)-tagged GFAPα are shown (F and I). Glial fibrillary acidic protein (GFAP) IgG was detected in the CSF from a patient with autoimmune GFAP astrocytopathy (E), but not in CSF from a patient with meningoencephalitis of unknown etiology (H). Colocalization of patient IgG and GFAPα appears yellow in the merged images (G). Nuclei are stained with Hoechst 33342 (bisbenzimide dye) (blue).

Discussion

Ocular symptoms are characteristic of GFAP astrocytopathy. Optic disc edema occurs in 30%–50% of cases,^1,2,4 and papilledema may occur without increased intracranial pressure.⁴ A study on visual system involvement found abnormalities in 25% of patients. Among those undergoing fundoscopy, optic disc edema was observed in 50%, and 61% of affected patients were asymptomatic.⁶ These results indicate that optic disc edema may occur more frequently than symptomatic visual disturbance. In our case, fundus examination and OCT detected optic disc edema despite absent visual impairment, with subsequent improvement paralleling clinical recovery. This observation is consistent with previous reports.

MRI in GFAP astrocytopathy typically shows widespread lesions including the cerebrum, brainstem, spinal cord, and optic nerve.^8,9 Orbital MRI has shown optic neuritis (bilateral 2%, unilateral 1%) and gadolinium enhancement of the optic nerve sheath and anterior optic nerve.^8,9 GFAP is expressed in the endfeet of retinal Müller cells and astrocytes, and optic disc edema may result from blood-retinal barrier disruption and venous inflammation caused by retinal cell injury.^10,11 This hypothesis may explain the MRI findings of the optic nerve and optic disc edema without increased intracranial pressure. Orbital fat hyperintensity may reflect local inflammatory extension, potentially increasing intraorbital pressure and contributing to ocular pain and disc edema. Differential diagnoses of orbital fat hyperintensity include infectious diseases, thyroid-associated orbitopathy, idiopathic orbital inflammatory disease, ANCA-associated vasculitis, sarcoidosis, and IgG4-related disease, all of which should be carefully excluded.¹²

In our patient, orbital MRI provided the first objective abnormality before intracranial lesions became apparent. Although the orbital fat hyperintensity was mild, its early detection on STIR sequences highlights the potential value of this finding as an early imaging abnormality in GFAP astrocytopathy. This case highlights 2 important clinical features of GFAP astrocytopathy. First, ocular pain, abnormal fundus findings, and orbital MRI abnormalities may precede typical intracranial lesions. Second, recognizing atypical orbital MRI changes may prompt earlier CSF evaluation and initiation of treatment, thereby potentially preventing disease progression in GFAP astrocytopathy. The hyperintensity of the orbital fat tissue observed in this case was only detectable on STIR sequences. This finding indicates the necessity of performing orbital MRI with STIR sequences when optic disc edema is identified. Although further case accumulation is required, orbital fat hyperintensity, when accompanied by compatible clinical features and CSF findings, may raise suspicion of GFAP astrocytopathy, facilitating earlier diagnosis when intracranial lesions are not yet evident. Although visual evoked potentials test was not performed, the clinical and radiologic findings were sufficient to establish the diagnosis.

In conclusion, orbital fat hyperintensity may represent an early manifestation of GFAP astrocytopathy. Awareness of such atypical ocular symptoms and orbital MRI findings may help clinicians consider GFAP astrocytopathy earlier in the diagnostic process, particularly when orbital inflammation is present despite initially unremarkable brain imaging.

Author Contributions

Y. Ito: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. K. Ohyama: drafting/revision of the manuscript for content, including medical writing for content; study concept or design. A. Kimura: analysis or interpretation of data. K. Yamashita: drafting/revision of the manuscript for content, including medical writing for content. M. Nakayabu: drafting/revision of the manuscript for content, including medical writing for content. Y. Fukami: drafting/revision of the manuscript for content, including medical writing for content. T. Shimohata: drafting/revision of the manuscript for content, including medical writing for content. M. Katsuno: drafting/revision of the manuscript for content, including medical writing for content.

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant dislclosures. Go to Neurology.org/NN for full disclosures.