Fingolimod (Gilenya; Novartis Pharma AG, Stein, Switzerland), a structural analog of sphingosine-1-phosphate (S1P), is a S1P receptor (S1PR) agonist that irreversibly binds to 4 of the 5 S1P (1,3–5), known subtypes of S1PR. Its primary mechanism of action for the treatment of multiple sclerosis (MS) is believed to be its effect on the immune system through the sequestration of circulating lymphocytes into lymphatic tissue (1). S1P and S1PR have also been shown to be important in the regulation and maintenance of vascular integrity by contributing to the intercellular adhesion of endothelial cells (2). Macular edema may develop in a small percentage (0.4%) of patients treated with fingolimod (3). However, we are not aware of any reported cases of macular hemorrhage in the setting of fingolimod therapy.
A 54-year-old Caucasian woman reported a 3-day history of seeing a gray opaque spot in the central visual field of her left eye. She had no eye or head pain nor visual complaints regarding her right eye. Her medical history was only notable for relapsing-remitting MS diagnosed 14 years previously. She had no history of hypertension, diabetes mellitus, rheumatological disease, or hematological disease. The patient had experienced only 2 MS exacerbations since diagnosis while being treated with interferon β-1b, but she was switched to 0.5 mg/day of fingolimod 11 months before her visual complaints because of injection fatigue. Four months after starting fingolimod, her ophthalmologic examination was stable. Her ocular history was notable for narrow angles, for which she underwent laser peripheral iridectomy, refractive surgery in both eyes, and mild amblyopia in the left eye.
When we initially evaluated the patient, visual acuity was 20/20 in the right eye and 20/80 in the left eye. Color vision and pupillary testing were normal. Slit-lamp examination revealed mild corneal scarring bilaterally from previous refractive surgery, and the intraocular pressure was 13 mm Hg in each eye. Funduscopic examination of the right eye was unremarkable. In the left eye, there was a retinal hemorrhage involving the fovea with adjacent hard exudate (Fig. 1A). Spectral domain optical coherence tomography (SD-OCT) showed a hyperdense opacity encroaching on the center of the fovea and extending from the inner retina to involve the outer retinal layers (Fig. 1B). Intravenous fluorescein angiography of the right eye was normal, but in the left eye, there was fluorescein blockage from the hemorrhage with adjacent hyperfluorescence corresponding to the hard exudate (Fig. 1C). After discussion with her neurologist, the fingolimod was immediately discontinued. The patient was found to have normal blood pressure with no clinical or laboratory evidence of diabetes mellitus.
After consulting her neurologist, fingolimod was discontinued. One month later, visual acuity was 20/40 in the left eye. Funduscopy showed complete resolution of the macular hemorrhage with small amounts of residual hard exudates (Fig. 2A). SD-OCT revealed near complete resolution of the hyperdense opacity in the macula (Fig. 2B), and intravenous fluorescein angiography of the left eye showed resolution of the blocked fluorescence and faint hard exudate hyperfluorescence (Fig. 2C). Three months after cessation of fingolimod, visual acuity improved further returning to a baseline level of 20/30, and SD-OCT was normal.
Unlike the brain in which there is a single blood–brain barrier, the eye has 2 blood–ocular barriers: anterior (blood–aqueous) and posterior (blood–retinal). The blood–retinal barrier can be further divided into inner (intraretinal vasculature) and outer (retinal pigment epithelium) barriers (4). Disruption of the blood–retinal barrier from a wide variety of ocular and systemic pathologies can result in the accumulation of fluid within the retina.
In patients treated with fingolimod, reports of macular edema (3), branch retinal vein occlusion (5), arterial vasospasm (6), hemorrhagic encephalitis (7), and posterior reversible encephalopathy syndrome (8) have suggested a connection between fingolimod and an alteration in retinal and cerebral vasculature. Substantial evidence has confirmed a vital role of S1P and S1PR in endothelial cell-to-cell and cell-to-matrix adhesions. Coupled to G-protein receptors, S1P signals a complex chain of events to the cytoskeleton system to regulate and maintain vascular impermeability between endothelial cells by way of tight junctions, adherens junctions, and focal adhesions (2). In animal models, disruption of this system with the application of S1P antagonists results in pulmonary edema (9). Although the precise pathomechanism of fingolimod-associated macular edema is not known, it is believed to be the result of the dysfunction of the S1PR in regulating retinal vascular integrity. A subset of MS patients particularly appear to be sensitive to fingolimod and development of macular edema, including those with uveitis. Therefore, inflammation may be a contributing factor. Recently, a small percentage of untreated MS patients were found to have microcystic macular edema suggesting underlying retinal inflammation or blood–retinal barrier disruption as part of the MS disease process (10).
Two aspects of our patient's clinical course deserve comment. First, the macular hemorrhage occurred in only 1 eye. Of interest is that almost 75% of fingolimod-associated macular edema cases in 2 phase III MS clinical trials were unilateral (11). Second, although our patient developed a macular hemorrhage after 11 months of fingolimod therapy, approximately 25% of patients with fingolimod-associated macular edema presented 6 months after initiating treatment (11). After discontinuation of fingolimod, 85% of patients had complete resolution of their macular edema as occurred with our patient's macular hemorrhage.
It is difficult to state with absolute certainty that the macular hemorrhage in our patient was related to fingolimod therapy. However, we believe this to be the case, given the temporal relationship of the clinical findings, the initiation and discontinuation of the medication, and the known effect of fingolimod on vascular integrity. We were unable to identify any systemic or ocular abnormality to account for the hemorrhage. We caution clinicians that patients receiving fingolimod require careful funduscopic examination if they note a change in vision while on treatment.
1. Cohen JA, Chun J. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann Neurol. 2011;69:759–777.
2. McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1-phosphate. J Cell Biochem. 2004;92:1075–1085.
3. Jain N, Bhatti MT. Fingolimod-associated macular edema: incidence, detection, and management. Neurology. 2012;78:672–680.
4. Cunha-Vaz JG. The blood-retinal barriers system. Basic concepts and clinical evaluation. Exp Eye Res. 2004;78:715–721.
5. Gallego-Pinazo R, Espana-Gregori E, Casanova B, Pardo-Lopez D, Diaz-Llopis M. Branch retinal vein occlusion during fingolimod treatment in a patient with multiple sclerosis. J Neuroophthalmol. 2011;31:292–293.
6. Schwarz A, Korporal M, Hosch W, Max R, Wildemann B. Critical vasospasm during fingolimod (FTY720) treatment in a patient with multiple sclerosis. Neurology. 2010;74:2022–2024.
7. Leypoldt F, Munchau A, Moeller F, Bester M, Gerloff C, Heesen C. Hemorrhaging focal encephalitis under fingolimod (FTY720) treatment: a case report. Neurology. 2009;72:1022–1024.
8. Kappos L, Antel J, Comi G, et al.. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N Engl J Med. 2006;355:1124–1140.
9. 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.
10. Gelfand JM, Nolan R, Schwartz DM, Graves J, Green AJ. Microcystic macular oedema in multiple sclerosis is associated with disease severity. Brain. 2012;135:1786–1793.
11. Zarbin M, Reder AT, Collins W, Francis G, Zhang X, Kappos L, Cohen L. Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Presented at the 2011 Annual American Academy of Ophthalmology Meeting, Orlando, Florida.