Author Affiliations: Departments of Ophthalmology and Visual Science (Drs Afshar, Fernandes, Patel, Ksiazek, Sheth, and Hariprasad) and Neurology (Dr Reder), Pritzker School of Medicine, University of Chicago, Chicago, and Division of Ophthalmology, NorthShore University HealthSystem, Glenview (Dr Sheth), Illinois.
Fingolimod is the first oral drug approved by the US Food and Drug Administration for multiple sclerosis (MS). It is a sphingosine-1-phosphate–receptor modulator that prevents lymphocyte egress from lymph nodes and enhances astrocyte function.1,2 In this retrospective case series, 4 eyes from 3 patients developed cystoid macular edema (CME) after initiating fingolimod therapy. The study was approved by the University of Chicago Institutional Review Board.
A 52-year-old man with primary progressive MS had progressively blurred vision in the left eye for 3 weeks. He was not diabetic. The patient started treatment with oral fingolimod, 0.5 mg/d, 4 weeks prior for MS refractory to mycophenolate mofetil and intravenous steroids. Best-corrected visual acuity was 20/20 OD and 20/40 OS, from 20/20 OD and 20/25 OS 2 months prior. Retinal examination showed new CME in the left eye. One week prior to starting fingolimod, at the request of his 1 neurologist, the patient had spectral-domain optical coherence tomography (SD-OCT) of the optic nerves and maculas (Figure 1A), which were normal in each eye. Findings on SD-OCT 4 weeks after starting fingolimod treatment confirmed CME in the left eye with central foveal thickness of 573 μm (Figure 1B). The neurologist continued fingolimod therapy owing to improvement in the patient's MS, so the patient began treatment with topical nepafenac 3 times daily and difluprednate twice daily in the left eye. Four weeks later, visual acuity was 20/20 OD and 20/30 OS. Dilated examination showed retinal pigment epithelial changes but no CME in the left eye. Findings on SD-OCT showed resolution of CME with central foveal thickness of 301 μm (Figure 1C).
Figure 1. Case 1. Spectral-domain optical coherence tomographic images of the left eye 1 week prior to starting fingolimod (A), 4 weeks after starting fingolimod (B), and 8 weeks after starting fingolimod, after 4 weeks of topical nepafenac and difluprednate (C). I indicates inferior; N, nasal; S, superior; and T, temporal.
A 60-year-old woman with relapsing-remitting MS had progressively blurred vision in each eye for 2 weeks. She had optic neuritis in the right eye 15 years prior and diabetes without retinopathy. Her glycated hemoglobin level was 6.1% of total hemoglobin (to convert to proportion of total hemoglobin, multiply by 0.01) 1 month prior. The patient started treatment with oral fingolimod, 0.5 mg/d, 1 month prior for MS refractory to azathioprine sodium, interferon beta-1b, and natalizumab. At the request of her neurologist, she had an eye examination and SD-OCT of her optic nerves and maculas 2 weeks prior to starting fingolimod treatment; they were normal in each eye (Figure 2A and D). Visual symptoms began 10 days after starting the drug. Best-corrected visual acuity was 20/60 OD and 20/40 OS, from 20/25 OU prior to starting the drug. Dilated examination showed CME in each eye, with central foveal thickness of 477 μm OD (Figure 2B) and 389 μm OS (Figure 2E) on SD-OCT. Fundus photographs and fluorescein angiography confirmed CME in each eye (Figure 3). The neurologist discontinued fingolimod treatment. Four weeks later, visual acuity was 20/30 OU. Dilated examination findings were normal in each eye and central foveal thickness was 210 μm OD (Figure 2C) and 212 μm OS (Figure 2F) on SD-OCT.
Figure 2. Case 2. Spectral-domain optical coherence tomographic images of the right eye 2 weeks prior to starting fingolimod (A), 4 weeks after starting fingolimod (B), and 4 weeks after discontinuing fingolimod (C), and spectral-domain optical coherence tomographic images of the left eye 2 weeks prior to starting fingolimod (D), 4 weeks after starting fingolimod (E), and 4 weeks after discontinuing fingolimod (F). I indicates inferior; N, nasal; S, superior; and T, temporal.
Figure 3. Case 2. Fundus photographs (A) and fluorescein angiograms (B) of the right and left eyes 4 weeks after starting fingolimod.
A 57-year-old man with relapsing-remitting MS had blurred vision in the left eye for 1 week. Four weeks prior, he started treatment with oral fingolimod, 0.5 mg/d, for progressive MS refractory to interferon beta-1b, intramuscular interferon beta-1a, and glatiramer acetate. At the request of his neurologist, 5 days prior to initiating fingolimod treatment, he had an eye examination and time-domain OCT of his optic nerves and maculas (Figure 4A), which were normal in each eye. One month after starting fingolimod, visual acuity was 20/20 OD and 20/30 OS, from 20/20 OU prior. Dilated examination showed CME in the left eye (the right eye was normal). Time-domain OCT confirmed CME in the left eye with central foveal thickness of 452 μm and an incidental new epiretinal membrane (Figure 4B). The neurologist stopped fingolimod treatment and the patient began treatment with topical bromfenac twice daily in the left eye. One month after discontinuing fingolimod treatment, visual acuity was 20/25 OS. This visit was at a different office, where SD-OCT showed epiretinal membrane and central foveal thickness of 341 μm in the left eye (Figure 4C). Three months after discontinuing fingolimod treatment, visual acuity was 20/25 OS and the blurred vision had resolved. Findings on SD-OCT showed epiretinal membrane and central foveal thickness of 348 μm in the left eye (Figure 4D).
Figure 4. Case 3. Time-domain optical coherence tomographic images of the left eye 5 days prior to starting fingolimod (A) and 4 weeks after starting fingolimod (B), and spectral-domain optical coherence tomographic images of the left eye 4 weeks after discontinuing fingolimod (C) and 3 months after discontinuing fingolimod (D). I indicates inferior; N, nasal; S, superior; and T, temporal.
This first case series reporting CME associated with fingolimod in patients with MS includes the first case of bilateral fingolimod-associated CME. There are 2 case reports documenting fingolimod-associated CME.3,4 Saab et al3 described a patient receiving 5 mg/d of fingolimod after a renal allograft. Turaka and Bryan4 described a patient with MS who developed CME 3 months after starting treatment with fingolimod, 0.5 mg/d. All patients in our series developed CME within 1 month of starting treatment with fingolimod, 0.5 mg/d.
The phase 3 TRANSFORMS1 (n = 1123) and FREEDOMS2 (n = 946) studies investigating fingolimod for MS showed CME in 6 and 7 patients, respectively. In the TRANSFORMS study, 4 of the 6 patients were taking 1.25 mg/d and 2 were taking 0.5 mg/d. All 7 patients in the FREEDOMS study were taking 1.25 mg/d. Only a dosage of 0.5 mg/d is approved by the US Food and Drug Administration for MS. A limitation of these studies was the use of time-domain OCT, which is less sensitive than SD-OCT at illuminating subtle macular pathology. Owing to CME in these trials, many neurologists request eye examinations and OCT prior to starting fingolimod treatment.
Treatment of fingolimod-associated CME with a newer-generation nonsteroidal anti-inflammatory drug and a steroid may hasten resolution of CME. In the 2 patients treated with topical nonsteroidal anti-inflammatory drugs, CME resolved within 4 weeks; this is in contrast to the TRANSFORMS and FREEDOMS studies, in which CME took up to 6 months to resolve without treatment. In case 1, suppression of CME by a retina specialist allowed the patient to continue treatment with fingolimod.
The patient with bilateral fingolimod-associated CME was diabetic. Although she had no retinopathy, diabetic microvascular changes likely increased susceptibility to developing CME. Owing to its mechanism of action, fingolimod may increase vascular permeability and cause breakdown of the blood-retinal barrier.5
With increasing use of fingolimod for MS, reports of associated CME will likely increase. The 0.5% incidence in the TRANSFORMS and FREEDOMS studies in patients taking 0.5 mg/d is likely an underrepresentation of this adverse effect. The patients in this study were not consecutively screened; they were isolated referrals from a neurologist during a 4-month span. A study screening all patients starting fingolimod at 1 institution would more accurately depict the prevalence of fingolimod-associated CME and warrants further investigation.
Correspondence: Dr Hariprasad, Department of Ophthalmology and Visual Science, Pritzker School of Medicine, University of Chicago, 5841 S Maryland Ave, MC 2114, Chicago, IL 60637 (email@example.com).
Author Contributions: Dr Hariprasad had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
Conflict of Interest Disclosures: Dr Reder has been a consultant for Abbott Laboratories, Astra Merck, Athena Neurosciences, Avanir, Aventis, Bayer Pharma AG, Berlex Laboratories, Biogen and Biogen/Idec, BioMS Medical, Boehringer Ingelheim Pharmaceuticals, Caremark Rx, Centocor, Cephalon, Connectics/Connective Therapeutics, CroMedica Global, Elan Pharmaceuticals, Eli Lilly & Co, Ezose Sciences, Genentech, Genzyme Corp, GlaxoSmithKline, Hoechst Marion Roussel Canada Research, Hoffman-LaRoche, Idec, Immunex, Johnson & Johnson, Kalobios, Neurocrine Biosciences, Novartis, Parke-Davis, Pfizer, Pharmacia & Upjohn, Protein Design Labs, Quantum Biotechnologies, Quintiles, Serono, Sention, Shering AG, SmithKline Beecham, Berlipharm, Takeda Pharmaceuticals, Teva-Marion, and Triton Biosciences. Dr Hariprasad has been a consultant for Alcon, Allergan, Genentech, Bayer, OD-OS, Optos, and Regeneron.
Afshar AR, Fernandes JK, Patel RD, Ksiazek SM, Sheth VS, Reder AT, Hariprasad SM. Cystoid Macular Edema Associated With Fingolimod Use for Multiple Sclerosis. JAMA Ophthalmol. 2013;131(1):103-107. doi:10.1001/jamaophthalmol.2013.570