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February 27, 2012

Fingolimod-associated macular edema
Incidence, detection, and management

February 28, 2012 issue
78 (9) 672-680


Fingolimod (FTY-720), a sphingosine-1-phosphate receptor modulator, is the first US Food and Drug Administration (FDA)–approved oral agent for the treatment of relapsing forms of multiple sclerosis (MS). Two recent phase III clinical studies (TRANSFORMS [Trial Assessing Injectable Interferon vs FTY720 Oral in RRMS] and FREEDOMS [FTY720 Research Evaluating Effects of Daily Oral Therapy in MS]) demonstrated a significant reduction in the annualized relapse rate in patients with relapsing-remitting MS, compared to once weekly interferon β-1a and placebo. Macular edema was a prominent adverse event reported in these and prior studies of fingolimod. Thirteen of 2,564 (0.5%) patients treated with fingolimod in FREEDOMS and TRANSFORMS developed macular edema. Fingolimod-associated macular edema (FAME) appears to be dose-dependent (observed in only 2 patients taking the FDA-approved 0.5 mg dose) and typically resolves upon cessation of therapy. Although a relatively common condition in ophthalmology, most neurologists have not encountered macular edema in clinical practice. The purpose of this review is to educate the neurologist on the etiology, clinical manifestations, diagnostic modalities, and treatment approaches in patients with FAME. We also discuss the use of fingolimod in patients with uveitis and diabetes mellitus, highlight the guidelines for surveillance ophthalmic examination, and outline the key distinguishing features between FAME and optic neuritis.

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Cunha-Vaz JG, Shakib M, Ashton N. Studies on the permeability of the blood-retinal barrier: I: on the existence, development, and site of a blood-retinal barrier. Br J Ophthalmol 1966; 50: 441– 453.
Hudspeth AJ, Yee AG. The intercellular junctional complexes of retinal pigment epithelia. Invest Ophthalmol 1973; 12: 354– 365.
Miller SS, Steinberg RH. Active transport of ions across frog retinal pigment epithelium. Exp Eye Res 1977; 25: 235– 248.
Complications of cataract surgery. In: Lens and Cataract. San Francisco: American Academy of Ophthalmology; 2008: 193– 194.
Moroi SE, Gottfredsdottir MS, Schteingart MT, et al. Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology 1999; 106: 1024– 1029.
Kaiser-Kupfer MI, Lippman ME. Tamoxifen retinopathy. Cancer Treat Rep 1978; 62: 315– 320.
Liazos E, Broadbent DM, Beare N, Kumar N. Spontaneous resolution of diabetic macular oedema after discontinuation of thiazolidinediones. Diabet Med 2008; 25: 860– 862.
Kinyoun J, Barton F, Fisher M, Hubbard L, Aiello L, Ferris F. Detection of diabetic macular edema: ophthalmoscopy versus photography–Early Treatment Diabetic Retinopathy Study Report Number 5: the ETDRS Research Group. Ophthalmology 1989; 96: 746– 750; discussion 750–751.
Jaffe GJ, Caprioli J. Optical coherence tomography to detect and manage retinal disease and glaucoma. Am J Ophthalmol 2004; 137: 156– 169.
Wojtkowski M, Srinivasan V, Fujimoto JG, et al. Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 2005; 112: 1734– 1746.
Chan A, Duker JS, Ko TH, Fujimoto JG, Schuman JS. Normal macular thickness measurements in healthy eyes using Stratus optical coherence tomography. Arch Ophthalmol 2006; 124: 193– 198.
Brown JC, Solomon SD, Bressler SB, Schachat AP, DiBernardo C, Bressler NM. Detection of diabetic foveal edema: contact lens biomicroscopy compared with optical coherence tomography. Arch Ophthalmol 2004; 122: 330– 335.
Antcliff RJ, Stanford MR, Chauhan DS, et al. Comparison between optical coherence tomography and fundus fluorescein angiography for the detection of cystoid macular edema in patients with uveitis. Ophthalmology 2000; 107: 593– 599.
Ali F. A review of diabetic macular edema. Available at: Accessed June 5, 2011.
Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985; 103: 1796– 1806.
Mandala S, Hajdu R, Bergstrom J, et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002; 296: 346– 349.
Mehling M, Brinkmann V, Antel J, et al. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. Neurology 2008; 71: 1261– 1267.
Garcia JG, Liu F, Verin AD, et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 2001; 108: 689– 701.
Lee MJ, Thangada S, Claffey KP, et al. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 1999; 99: 301– 312.
Tauseef M, Kini V, Knezevic N, et al. Activation of sphingosine kinase-1 reverses the increase in lung vascular permeability through sphingosine-1-phosphate receptor signaling in endothelial cells. Circ Res 2008; 103: 1164– 1172.
McVerry BJ, Peng X, Hassoun PM, Sammani S, Simon BA, Garcia JG. Sphingosine 1-phosphate reduces vascular leak in murine and canine models of acute lung injury. Am J Respir Crit Care Med 2004; 170: 987– 993.
Peng X, Hassoun PM, Sammani S, et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am J Respir Crit Care Med 2004; 169: 1245– 1251.
Sanna MG, Wang SK, Gonzalez-Cabrera PJ, et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nat Chem Biol 2006; 2: 434– 441.
Wang L, Dudek SM. Regulation of vascular permeability by sphingosine 1-phosphate. Microvasc Res 2009; 77: 39– 45.
Dudek SM, Jacobson JR, Chiang ET, et al. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase. J Biol Chem 2004; 279: 24692– 24700.
Lee JF, Zeng Q, Ozaki H, et al. Dual roles of tight junction-associated protein, zonula occludens-1, in sphingosine 1-phosphate-mediated endothelial chemotaxis and barrier integrity. J Biol Chem 2006; 281: 29190– 29200.
Paik JH, Skoura A, Chae SS, et al. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev 2004; 18: 2392– 2403.
de Oliveira F. Pericytes in diabetic retinopathy. Br J Ophthalmol 1966; 50: 134– 143.
Cohen JA, Barkhof F, Comi G, et al. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N Engl J Med 2010; 362: 402– 415.
Kappos L, Radue EW, O'Connor P, et al. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 2010; 362: 387– 401.
Salvadori M, Budde K, Charpentier B, et al. FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia. Am J Transplant 2006; 6: 2912– 2921.
Zarbin M, Reder A, Collins W, et al. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis (MS) (suppl 4:P03.208). Presented at the American Academy of Neurology annual meeting. Honolulu, HI, 2011.
Biousse V, Trichet C, Bloch-Michel E, Roullet E. Multiple sclerosis associated with uveitis in two large clinic-based series. Neurology 1999; 52: 179– 181.
Malinowski SM, Pulido JS, Folk JC. Long-term visual outcome and complications associated with pars planitis. Ophthalmology 1993; 100: 818– 824.
Gilenya full prescribing information. Available at: Accessed May 14, 2011.
Abou Zeid N, Bhatti MT. Acute inflammatory demyelinating optic neuritis: evidence-based visual and neurological considerations. Neurologist 2008; 14: 207– 223.
Beck RW, Cleary PA, Anderson MM, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis: The Optic Neuritis Study Group. N Engl J Med 1992; 326: 581– 588.
Kappos L, Antel J, Comi G, et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med 2006; 355: 1124– 1140.
Tedesco-Silva H, Pescovitz MD, Cibrik D, et al. Randomized controlled trial of FTY720 versus MMF in de novo renal transplantation. Transplantation 2006; 82: 1689– 1697.

Information & Authors


Published In

Volume 78Number 9February 28, 2012
Pages: 672-680
PubMed: 22371414

Publication History

Received: June 7, 2011
Accepted: September 23, 2011
Published online: February 27, 2012
Published in print: February 28, 2012


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Dr. Jain reports no disclosures. Dr. Bhatti has received consultancy fees, speaker fees, or honoraria from Pfizer Inc, EMD Serono, Inc., Novartis, and Bayer Schering Pharma.


Affiliations & Disclosures

Nieraj Jain, MD
From the Departments of Ophthalmology (N.J., M.T.B.) and Medicine (Division of Neurology) (M.T.B.), Duke Eye Center and Duke University Medical Center, Durham, NC.
M. Tariq Bhatti, MD
From the Departments of Ophthalmology (N.J., M.T.B.) and Medicine (Division of Neurology) (M.T.B.), Duke Eye Center and Duke University Medical Center, Durham, NC.


Study funding: Funded in part by a departmental grant from Research to Prevent Blindness, Inc.
Correspondence & reprint requests to Dr. Bhatti: [email protected]

Author Contributions

Dr. Jain: drafting/revising manuscript for content. Dr. Bhatti: conception of review, drafting/revising manuscript for content, study supervision.

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