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Show Bilateral Optic Neuropathy Associated With the Tumor Necrosis Factor-Alpha Inhibitor Golimumab Jessica R. Chang, MD, Neil R. Miller, MD Abstract: A 62-year-old man developed bilateral blurred vision associated with bilateral optic disc swelling shortly after receiving his third dose of the tumor necrosis factor- alpha (TNF-a) inhibitor golimumab, that he took for psoriatic arthritis. An extensive assessment including magnetic reso-nance imaging, lumbar puncture, and serologies was nega-tive. He was treated with systemic corticosteroids and the golimumab was stopped, after which his vision improved and his disc swelling resolved. We postulate that the bilateral, simultaneous anterior optic neuropathies in this patient were due to golimumab, representing a rare but well-documented serious adverse event associated with TNF-a inhibitors. Journal of Neuro-Ophthalmology 2014;34:336-339 doi: 10.1097/WNO.0000000000000137 © 2014 by North American Neuro-Ophthalmology Society Biologic drugs targeting tumor necrosis factor-alpha (TNF-a) are used to treat inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondy-litis, inflammatory bowel disease, and even uveitis. Golimu-mab, 1 of 5 currently available TNF-a inhibitors, was approved by the Food and Drug Administration in 2009. Adverse effects associated with this class of medication include increased risk of infection, congestive heart failure, lymphoma, demyelinating disease, and optic neuropathy, often described as "optic neuritis." Population-based data suggest an annual incidence rate for optic neuritis between 1.5 and 5 per 100,000 persons in the United States (1-3). A cohort study recently calculated the incidence of optic neuritis among new users of anti-TNF agents with no known previous demyelinating condition as 5-10 per 100,000 persons, not significantly different from the rate of optic neuritis in new nonbiologic disease-modifying antirheumatologic drug users (4). There have been at least 37 cases of reasonably well-documented optic neuropathy associated with TNF-a inhibitors described in the literature. The most commonly reported are infliximab, followed by etanercept and adalimumab; there are no well-documented cases involving golimumab, although there are 5 possible cases in the National Registry of Drug-Induced Ocular Side Effects, but without sufficient confirming data (4). We report a patient who developed bilateral anterior optic neuropathies shortly after beginning golimumab and whose visual function improved with steroid treatment and cessation of the medication. CASE REPORT A 62-year-old man was referred to the emergency room of the Johns Hopkins Hospital by an optometrist for blurry vision and "swollen" optic discs. The patient reported 3 days of haziness in the inferior visual field of each eye, which he initially noted early in the morning. He had mild headache on presentation, but no eye pain, no pain with eye movement, and no other neurologic symptoms. His ocular history was notable for amblyopia in the left eye, and his medical history was significant for prostate cancer for which he had recently undergone surgery, and psoriatic arthritis for which he pre-viously had been on methotrexate. He had a history of snoring but had never been assessed for obstructive sleep apnea (OSA). One year ago, he had begun taking golimumab, which he had stopped after 1 dose (50 mg) to undergo treatment for prostate cancer. He had then restarted the drug 2 months ago at the same dose, last taken 3 days before presentation, coincident with the beginning of his visual symptoms. Although he used tadalafil at times, he had not used any for at least 1 month. The patient's visual acuity was 20/20, right eye and 20/50, left eye. There was no relative afferent pupillary defect, and color vision was intact bilaterally. Visual field defects were Department of Ophthalmology (JRC, NRM), the Johns Hopkins University School of Medicine, Baltimore, Maryland. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Neil R. Miller, MD, Department of Ophthalmology, the Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287; E-mail: nrmiller@jhmi.edu 336 Chang and Miller: J Neuro-Ophthalmol 2014; 34: 336-339 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. present on automated perimetry (Fig. 1), and ophthalmos-copy revealed bilateral optic disc swelling with peripapillary hemorrhages but no exudates (Fig. 2). The patient was admitted to hospital and underwent magnetic resonance imaging (MRI), magnetic resonance venography, lumbar puncture, and bone scan, as well as a complete blood count, basic metabolic panel, erythrocyte sedimentation rate, and assays for C-reactive protein, Lyme antibody, rapid plasma reagin, and antinuclear antibody. All of these studies gave negative or normal results, except for MRI findings of a pituitary macroadenoma. However, there was no evidence of compression of the anterior visual pathways. Results of the Berlin questionnaire revealed a positive score in Category 1 and 3, indicating a high risk of OSA. The patient returned 5 days later with headache and worsening vision of 20/50, right eye and 20/400, left eye, with impaired color vision in each eye. His pupils were more sluggish than previously recorded. The fundus appearance was unchanged. He was readmitted to hospital and treated with 1 g of intravenous methylprednisolone for 3 days. Further testing included IgG, IgA, and IgM assays; thyroid stimulating hormone level; serum protein electro-phoresis; assays for anti-double-stranded DNA, anti-Smith antibodies, anti-Ro, and anti-La antibodies; vitamin B12 level; prostate specific antigen, computed tomography of the chest; and full-body positron emission tomography. Again the workup was unrevealing. After 1 day of treatment with methylprednisolone, the patient's visual acuity was improved to 20/30, right eye and 20/150, left eye, with improvement in color vision. He was discharged on predni-sone starting at 60 mg daily and tapered over the next 6 weeks. Visual acuity 14 months later was 20/25, right eye and 20/400, left eye. The patient's color vision was intact in the right eye, but he was unable to identify figures on any of the FIG. 1. At presentation, automated visual fields show inferior altitudinal defects in each eye. FIG. 2. Bilateral optic disc edema is present on initial examination. Chang and Miller: J Neuro-Ophthalmol 2014; 34: 336-339 337 Original Contribution Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. color plates with this his left eye. Visual fields remained unchanged, although his optic disc swelling and peripapil-lary hemorrhages resolved, leaving bilateral optic disc pallor. The patient has not yet undergone polysomnography nor is he being treated for OSA. DISCUSSION Our patient developed bilateral anterior optic neuropathies temporally related to the use of the TNF-a inhibitor golimumab. Alternative diagnoses such as compressive, infec-tious, and infiltrative optic neuropathies were eliminated based on laboratory testing, neuroimaging, and clinical history. Although it is conceivable that this patient's optic neuropathies were ischemic in origin, possibly related to use of an erectile dysfunction drug, he had not used the medi-cation for at least 1 month and had no vascular risk factors. Specifically, he had no hyperlipidemia or anemia and no history of tobacco use. He did endorse snoring, and his Berlin questionnaire (5) score indicated high risk for OSA. We believe that a bilateral optic neuropathy related to golimumab is more likely than a simultaneous non-arteritic anterior ischemic optic neuropathy related to OSA. It often is difficult to pinpoint causality in cases of possible adverse drug reactions. Scales such as those derived by Naranjo et al (6) attempt to quantify this probability, but the issue of alternative diagnosis likelihood ultimately relies on clinical judgment. Given the evidence against alter-native diagnoses and considering the published reports of similar cases with other TNF-a inhibitors, we believe this patient most likely had an optic neuropathy related to golimumab therapy. Using the PubMed database, we identified 37 cases of optic neuropathy associated with TNF-a inhibitors (7-32) (see Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A109). There were 23 females (60%), and the average age was 41.6 years (range, 8-76 years). Among these 37 patients, 9 had simultaneous bilat-eral involvement, 1 had sequential bilateral involvement 6 weeks apart, 23 had unilateral involvement, and 4 were unspecified (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A110). Of the simulta-neous bilateral cases, 1 was retrobulbar, 1 was unspecified, and the remaining 7 had disc swelling (2 with associated hemorrhages). Of the unilateral cases, 7 (30%) had variable degrees of disc swelling, with 2 noted to have disc hemor-rhages, 12 were retrobulbar, and 4 were not specified as to being anterior vs retrobulbar. Twenty-nine patients (78%) had MRI results reported, and of these, 23 (79%) had white-matter lesions consistent with demyelinating plaques. For comparison, 40% of the patients in the Optic Neuritis Treatment Trial (ONTT) had normal MRI findings (33), although technology has improved significantly and the first cases of optic neuritis associated with TNF-a inhibitors were published 10 years after the ONTT was completed. Many reports describe the optic neuropathy associated with TNF-a inhibitors as an optic neuritis, rather than a toxic optic neuropathy, but it is unclear if demyelination is neces-sarily involved as a mechanism, as the term optic neuritis implies. In the ONTT, optic neuritis was retrobulbar in 65% of patients, and pain was present in 92% (34). In the cases of optic neuropathy with TNF-a inhibitors, 13/27 patients (48%) had a retrobulbar optic neuropathy and 13/ 19 patients (68%) had pain (1/4 bilateral cases and 12/15 unilateral cases) (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A110). Visual field defects at baseline in the ONTT were found to be variable, with central or cecocentral scotomas making up 8.3% (35), whereas in toxic optic neuropathies, a central or cecocen-tral scotoma is by far the dominant pattern (36). Among the 24 cases of TNF-a inhibitors in which visual field defects have been reported, 10/24 (42%) were central or cecocentral (see Supplemental Digital Content, Table E2, http://links.lww.com/WNO/A110). It remains unclear if these case reports represent a spectrum of toxic optic neu-ropathies or combine some cases of toxic optic neuropathy and others of idiopathic optic neuritis. In reported cases of TNF-a associated optic neuropathy, the duration of therapy before onset of visual symptoms ranged from 0 to 23 months (mean: 7.8 months). Visual symptoms began immediately or as long as 60 days after the last dose (average = 22 days from the 20 cases in which this information was reported). Steroid therapy was used in 29 cases, and all but 7 of these patients had at least partial recovery. Interferon-beta and intravenous immunoglobulin were given as first-line therapy in 1 patient in whom there was partial recovery, interferon-beta alone in another patient with complete recovery, and no treatment was given in 5 patients, 2 of whom experienced complete recovery, and 3, partial recovery. The TNF-a inhibitor was stopped in 25 cases, continued in 3 cases, and not reported in the remainder. Of the 3 cases in which the drug was continued, 2 received steroid therapy, but in all 3 cases, visual symptoms persisted or worsened. It is unclear from published case reports if the specific agent, cumulative dose, or duration of therapy influences the clinical presentation, that is, anterior or retrobulbar, unilateral or bilateral. Our patient received 1 dose of golimumab, 1 year before presentation and then restarted therapy 2 months before presentation, with visual symptoms starting on the day of his third dose. 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