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Clinical Observation

Fingolimod Therapy and Macular Hemorrhage

Bhatti, M. Tariq MD; Freedman, S. Mitchell MD; Mahmoud, Tamer H. MD, PhD

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Journal of Neuro-Ophthalmology: December 2013 - Volume 33 - Issue 4 - p 370-372
doi: 10.1097/WNO.0b013e31829b42e1
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Abstract

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.

CASE REPORT

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.

FIG. 1
FIG. 1:
A. Left fundus shows macular hemorrhage encroaching on the fovea (arrowhead) with adjacent inferior yellowish hard exudate (arrow). B. Horizontal scan through the fovea using spectral domain optical coherence tomography demonstrates a hyperdense opacity (arrow 1) extending the full thickness of the retina disrupting the external limiting membrane (arrow 2) and the inner segment/outer segment junction (arrow 3). C. Fluorescein angiogram during arteriovenous transit phase shows blocked fluorescence by the macular hemorrhage and adjacent hyperfluorescence corresponding to hard exudate.

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.

FIG. 2
FIG. 2:
Imaging findings 1 month after stopping fingolimod.A. There is resolution of the macular hemorrhage with residual hard exudate in the left eye. B. There is faint residual hyperdense opacity on spectral domain optical coherence tomography with recovery of the external lining membrane and inner segment/outer segment junction. C. Marked improvement in the appearance of the fluorescein angiogram.

DISCUSSION

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.

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© 2013 by North American Neuro-Ophthalmology Society