Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis

Background: We describe a 75-year-old woman who experienced vision loss in her left eye due to biopsy-proven giant cell arteritis (GCA). She subsequently developed pachymeningitis causing refractory headaches and bilateral optic neuropathy and maculopathy. Methods: Case report with literature review. Results: Eighteen months after the initial diagnosis of GCA, imaging studies in our patient demonstrated pachymeningeal enhancement, and meningeal biopsy confirmed lymphoplasmacytic tissue infiltrates with low frequencies of IgG4+ plasma cells. Laboratory investigation revealed the presence of 3 antiretinal antibodies and antimyeloperoxidase antibodies, consistent with autoimmune retinopathy. Treatment with B-cell-depleting anti-CD20 antibodies suppressed meningeal inflammation and prevented further vision loss. Conclusions: This case illustrates that bilateral vision loss and chronic headaches in patients with GCA may result from retina-directed autoimmunity and pachymeningitis.

Original Contribution Refractory Giant Cell Arteritis Complicated by Vision Loss From Optic Atrophy and Maculopathy Associated With Pachymeningitis Jorge A. Uribe, MD, Ishita Aggarwal, MD, Juthamat Witthayaweerasak, MD, Y. Joyce Liao, MD, PhD, Gerald J. Berry, MD, Umesh K. Sab, MD, Cornelia M. Weyand, MD, PhD Background: We describe a 75-year-old woman who experienced vision loss in her left eye due to biopsy-proven giant cell arteritis (GCA). She subsequently developed pachymeningitis causing refractory headaches and bilateral optic neuropathy and maculopathy. Methods: Case report with literature review. Results: Eighteen months after the initial diagnosis of GCA, imaging studies in our patient demonstrated pachymeningeal enhancement, and meningeal biopsy confirmed lymphoplasmacytic tissue infiltrates with low frequencies of IgG4+ plasma cells. Laboratory investigation revealed the presence of 3 antiretinal antibodies and antimyeloperoxidase antibodies, consistent with autoimmune retinopathy. Treatment with B-cell-depleting anti-CD20 antibodies suppressed meningeal inflammation and prevented further vision loss. Conclusions: This case illustrates that bilateral vision loss and chronic headaches in patients with GCA may result from retina-directed autoimmunity and pachymeningitis. Journal of Neuro-Ophthalmology 2018;38:17-23 doi: 10.1097/WNO.0000000000000566 © 2017 by North American Neuro-Ophthalmology Society G iant cell arteritis (GCA) is a granulomatous inflammation of medium and large arteries, which typically Departments of Rheumatology (JAU, IA, CMW), Ophthalmology (JW, YJL), and Pathology (GJB), Stanford University School of Medicine, Stanford, California; and Department of Rheumatology (US), Sequoia Hospital, Redwood City, California. C. M. Weyand is supported by the NIH and the Governor Discovery Fund. J. Witthayaweerasak was supported by the grant from Prince of Songkla University, Songkhla, Thailand. Y. J. Liao was supported by the NANOS Pilot Grant. The authors report no conflicts of interest. Address correspondence to Cornelia M. Weyand, MD, PhD, Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CCSR Building Room 2225, Mail Code 5166, 269 Campus Drive West, Stanford, CA 94305‐5166; E-mail: [e-mail] Uribe et al: J Neuro-Ophthalmol 2018; 38: 17-23 leads to critical arterial stenosis, causing tissue ischemia (1). The classic ophthalmic manifestation is anterior ischemic optic neuropathy and, less commonly, posterior ischemic optic neuropathy or ocular ischemic syndrome (2-4). Vascular stenosis/occlusion results from immune-mediated tissue injury to the arterial wall, initiated and sustained by highly activated T cells and macrophages (5). No direct involvement of B cells and autoantibodies in the vascular lesions has been identified. Giant cell arteritis has a stringent tissue tropism for medium and large arteries, and extravascular inflammatory lesions are considered to be distinctly unusual. We report a patient with biopsy-proven GCA who developed refractory headaches, bilateral optic neuropathy, and bilateral maculopathy while on systemic corticosteroids. She also had multiple autoantibodies against retinal antigens and myeloperoxidase. Based on the neuro-ophthalmologic findings and a meningeal biopsy, the patient was eventually diagnosed with hypertrophic pachymeningitis (HP) and autoimmune retinopathy (AIR) (also known as autoimmunerelated retinopathy and optic neuropathy [ARRON]). Potential pathophysiologic mechanisms of this unusual clinical course are discussed. CASE REPORT A 75-year-old woman experienced transient vision loss in her left eye accompanied by new onset temporal tenderness and jaw pain 3 years previously. At that time, visual function was normal, erythrocyte sedimentation rate (ESR) was elevated (45-96 mm/hour), C-reactive protein (CRP) level was normal, and temporal artery biopsy was diagnostic of GCA (Fig. 1). The patient was started on prednisone 50 mg daily. Computed tomographic angiography yielded no evidence of aortitis or large vessel vasculitis. 17 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Nine months later, while on prednisone 25 mg per day, the patient developed binocular horizontal diplopia due to a right sixth nerve palsy. Erythrocyte sedimentation rate was 51 mm/hour and CRP level was 1.3 mg/dL (normal , 0.9 mg/dL). Her diplopia resolved with high-dose corticosteroid treatment. With persistent elevation of her ESR, the patient was started on methotrexate. Eighteen months after initial presentation, while on prednisone 15 mg per day and methotrexate 15 mg weekly, the patient developed subacute, painless, progressive vision loss accompanied by photophobia. Visual acuity was 20/40 in the right eye and 20/25 in the left eye. Automated perimetry revealed bilateral visual field constriction and patchy field loss involving all quadrants (mean deviation: right eye: 221.5 dB and left eye 28.34 dB) (Fig. 2A). On optical coherence tomography (OCT), the mean retinal nerve fiber layer (RNFL) thickness was normal (right eye: 86 mm and left eye: 87 mm (Fig. 3A) as was macular total retinal thickness (right eye: 254 mm and left eye: 253 mm) (Fig. 3B). Full-field electroretinogram and pattern-reversal visual evoked potential recordings were abnormal. After dark adaptation, rod responses to dim flash were of normal amplitudes in the right eye but only 90%-95% of the minimum in the left eye. The combined rod-cone responses to a strong flash had amplitudes approximately 90% of the minimum in the right eye and two-thirds of the minimum in the left eye. Oscillatory potentials were present, but lower in the left eye than the right. After light adaptation, the single-flash cone responses had normal amplitudes in the right eye, but less than 60% of normal minimum values in the left eye. The 30 Hz flicker responses revealed implicit times that were delayed in the left eye. With small (15 minute) checks, the visual evoked potential showed broad peaks with low amplitudes and delayed P100 peak latencies bilaterally (right eye: 153 milliseconds and left eye: 143 milliseconds). Brain MRI showed diffuse pachymeningeal enhancement without optic nerve involvement (Fig. 4A, B). On lumbar puncture, the opening pressure was 10 cm H2O, and cerebrospinal fluid showed 2 white blood cells/mL, 82 red blood cells/ mL, protein level of 39 mg/dL (normal , 45 mg/dL), glucose level of 53 mg/dL, negative Gram stain and cultures, and negative cytology. Three antiretinal autoantibodies (28-kDa, 30-kDa [carbonic anhydrase II], and 70-kDa) were positive on immunoblotting (Ocular Immunology Laboratory, Oregon Health Sciences University). Anti-optic nerve antibodies were negative. Laboratory testing also was positive for antimyeloperoxidase antibody of 2.4 units (normal , 0.4 units) and elevated IgG4 levels of 194 mg/dL (normal , 150 mg/ dL) with negative antinuclear antibody (ANA), anti-PR3, rheumatoid factor, serum protein immune-fixation electrophoresis, angiotensin-converting enzyme (ACE), HIV, rapid plasma reagin (RPR), and fluorescent treponemal antibody absorption (FTA-Abs). Computed tomography of the chest, abdomen, and pelvis was normal. The patient declined a meningeal biopsy and was empirically treated with high-dose oral FIG. 1. Temporal artery biopsy showing typical findings of Giant cell arteritis. A. There is transmural fibroinflammatory features of giant cell arteritis, with marked intimal proliferation and severe luminal narrowing (hematoxylin & eosin, ·50). B. CD138 immunostaining reveals plasma cells in the intimal and medial layers of the vessel wall (·60). C and F. IgG4 immunostaining at low and high powers, respectively, showing sparse number of IgG4+ plasma cells (C, ·60; F, ·200). D and E. CD3 and CD4 immunostaining, respectively, reveal dense CD4+ T cells infiltrating all layers of the vessel wall (D, ·100; E, ·60). 18 Uribe et al: J Neuro-Ophthalmol 2018; 38: 17-23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. A. Automated perimetry performed at the onset of pachymeningitis demonstrates bilateral visual field loss. B. Improved visual field loss is seen 3 years later. prednisone. Her vision improved gradually, and prednisone was gradually tapered off. Approximately 2 years after the diagnosis of pachymeningitis, while on prednisone 5 mg per day, she developed severe headaches. Her visual acuity was 20/ 30 in the right eye and 20/25 in the left eye. Visual fields had improved (Fig. 2B), but her OCT results had worsened. The mean RNFL thickness was 56 mm in the right eye and 75 mm in the left eye (Fig. 3C), and total retinal thickness was 232 mm in the right eye and 238 mm in the left eye (Fig. 3D). Repeat brain MRI demonstrated increased pachymeningeal thickening and enhancement (Fig. 4C, D). Two years after the onset of pachymeningitis, the patient agreed to a meningeal biopsy, which showed diffuse fibrous thickening with focal storiform arrangement, moderate lymphoplasmacytic infiltrates, particularly in the inner dural aspects with perivascular infiltrates in a perivenular distribution (Fig. 5). There was no arteritis, granulomatous inflammation, neoplastic infiltrates, and obliterative phlebitis. Plasma cells were present within the inflammatory infiltrate but were ,10 plasma cells per high-power field. The IgG4+:IgG+ plasma cell ratio was considerably less than 0.4 by immunostaining (6) and consistent with HP, but not IgG4 disease. The previous temporal artery sections were retrospectively reviewed and immunostained, and the IgG4: IgG plasma cell ratio was 10%, with only scattered IgG4+ plasma cells in the vessel wall infiltrates, consistent with previous pathologic diagnoses of GCA (Fig. 1C, F). Our diagnoses were 1) GCA complicated by HP and 2) AIR (7) (also known as autoimmune-related retinopathy and optic neuropathy [ARRON]) (8). Methotrexate was discontinued because of elevated liver enzymes necessitating a change to anti-CD20 therapy (rituximab, 375 mg/m2). Uribe et al: J Neuro-Ophthalmol 2018; 38: 17-23 After 4 treatment cycles, the patient had marked improvement of her headaches, and her and anti-myeloperoxidase (MPO) antibody levels normalized. There was no further vision loss or other adverse events over the ensuing 12 months, and her prednisone dose was decreased to 5 mg daily. Follow-up brain MRI showed improved but persistent, mild pachymeningeal enhancement. DISCUSSION Hypertrophic pachymeningitis has been reported in patients with GCA, but this is a rare complication (9-14) that typically occurs early in the disease course. Joelson et al (11) noted that the middle meningeal artery, a branch of the external carotid artery, supplies the dural vessels and hypothesized that HP in GCA may be related to secondary changes in dural vessels or embolic disease. In general, a diagnosis of pachymeningitis prompts a workup for lymphoproliferative disorders, infectious diseases, and autoimmune syndromes, such as systemic lupus erythematosus, rheumatoid arthritis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, tuberculosis, syphilis, Lyme disease, neurocysticercosis, Epstein-Barr virus infection, fungal infection, and IgG4-related disease (9,15). Autoantibody measurements in patients with GCA serve to rule out an alternative diagnosis. The presence of antimyeloperoxidase antibodies and 3 antiretinal antibodies in our patient led us to consider the coexistence of 2 diagnoses. Among the autoimmune syndromes manifesting with pachymeningitis, IgG4-related disease is high on the differential diagnosis (16,17). Yet, review of our patient's temporal artery and meningeal biopsies did not support this diagnosis. 19 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Optical coherence tomography at the onset of pachymeningitis shows normal retinal nerve fiber layer (RNFL) thickness (A) and good macular total retinal thickness (B). Two years later, there is diminished RNFL (C) and macular total retinal thickness (D). ILM, internal limiting membrane; OD, right eye; OS, left eye; RPE, retinal pigment epithelium; TEMP, temporal; SUP, superior; NAS, nasal; INF, inferior. The temporal artery tissue lacked the band-like or storiform collagenous fibrosis and venous sclerosis indicative of IgG4related disease. Staining for IgG4+ plasma cells failed to demonstrate a sufficient number of IgG4+ cells (typically .10-30 cells/high-power field) or a IgG4+:IgG+ plasma cell ratio (typically .40%) to establish a tissue diagnosis of IgG4related disease. Elevated serum IgG4 levels are not unusual in the setting of polyclonal B-cell stimulation, and IgG4+ immunostaining is often nonspecific, unless the density of IgG4 20 + plasma cells exceeds predefined frequencies (6,18,19). There was no evidence of lacrimal gland involvement or of orbital myositis, which present in 81% and 25%, respectively, in patients with IgG4-related orbital disease (20). Clinically, patients with cranial HP present with headaches, cranial nerve palsies, and cerebellar ataxia. Interestingly, HP also has been associated with bilateral optic neuropathy, in the setting of granulomatosis with polyangiitis (21-23), pANCA-associated vasculitis (24), and neuromyelitis optica Uribe et al: J Neuro-Ophthalmol 2018; 38: 17-23 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. Brain MRI performed one and a half years after initial presentation of giant cell arteritis and at the onset of headache and bilateral vision loss demonstrates pachymeningeal enhancement (arrows) on postcontrast axial (A) and coronal (B) T1 scans. Two years later with worsening headache, there is increased pachymeningeal enhancement on postcontrast axial (C) and coronal (D) T1 images. (25). We did consider the possibility of the patient having ANCA-associated vasculitis, given the patient's low-titer antiMPO antibody. However, the patient's course and the clinical and diagnostic findings were not consistent with ANCAassociated vasculitis, as she had no evidence of inflammatory disease of the ears, lungs, kidneys, larynx, or skin. Given the central role of T-cell immunity in GCA, it is rare that affected patients would produce autoantibodies. However, our patient had a distinct spectrum of autoantibodies, including those reactive with retinal antigens. The presence of these autoantibodies coupled with the electrophysiologic abnormalities raised the possibility of AIR and FIG. 5. Meningeal biopsy shows prominent inflammation. A. There is thickened dural tissue with dense collagenous fibrosis and clusters of chronic inflammatory cells (hematoxylin & eosin, ·100). B. On higher magnification view, there are perivenular infiltrates composed predominantly of lymphocytes and occasional plasma cells without vascular mural injury (hematoxylin & eosin, ·400). C. IgG4 immunostaining revealed rare IgG4+ cells (·200). Uribe et al: J Neuro-Ophthalmol 2018; 38: 17-23 21 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution optic neuropathy, which is a rare condition that can be associated with autoimmune diseases (7). A recent consensus statement on AIR describes essential diagnostic criteria as: no apparent cause responsible for vision loss, electrophysiology abnormalities, presence of serum antiretinal antibodies, absence of fundus lesions or retinal degeneration to explain vision loss, and absence of overt intraocular inflammation (7). This consensus statement did not include discussion on optic neuropathy. Another proposed name for autoimmune retinopathy is autoimmune-related retinopathy and optic neuropathy (ARRON), which is described as vision loss associated with abnormal retinal electrophysiology and antiretinal and anti-optic nerve antibodies without evidence of malignancy (8). An overall inflammatory phenomenon may have given rise to both HP and progressive maculopathy and optic neuropathy. The possibility remains that the patient had more than 1 unrelated immune-mediated disease including a biopsy-positive temporal arteritis, which initially responded well to standard therapy and a subsequent pachymeningitis and autoimmune-mediated vision loss due to AIR/ARRON years later as the steroid doses were reduced. Giant cell arteritis now is recognized as a chronic autoimmune condition, requiring long-term immunosuppressive therapy (26). 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