Fingolimod was the first oral agent approved by the Food and Drug Administration (FDA) for the treatment of RRMS. Active metabolites of fingolimod bind to the sphinogosine-1-phosphate (S1P) receptor on lymphocytes resulting in internalization and degradation of the receptor. This action prevents lymphocytes from leaving secondary lymphoid organs, thus reducing the number of circulating lymphocytes available to participate in central nervous system autoimmune demyelination. In addition to modulating lymphocytes, the S1P receptor is responsible for regulating vascular permeability via interaction with the cytoskeleton and intracellular junctions. Disruption of the endothelial barrier in the retina may be implicated in the development of ME with use of fingolimod [1].
Data from clinical trials compiled by the FDA demonstrate the incidence of FAME to be 0.4% at the 0.5 mg dose with most cases occurring within 3–4 months of initiating treatment. The FDA recommends baseline ophthalmologic examination with repeated studies at 3–4 months. Should ME develop, resolution typically occurs after cessation of fingolimod [1].
For patients who develop fingolimod-associated ME, resolution typically occurs within 6 months following cessation of fingolimod, with 84% of patients in the pooled safety cohort having complete resolution [1, 2]. FAME was first realized not in ophthalmology or neurology patient populations but in renal transplant recipients who were treated with fingolimod as an immunosuppression agent during trials. Specifically, fingolimod at 2.5 mg/day or 5.0 mg/day, caused macular edema in 1.3% and 2.2% of patients, respectively [3]. Two trials, the TRANSFORMS and FREEDOMS trials subsequently utilized routine ophthalmic evaluation for fingolimod associated macular edema thereafter. The importance of these two studies with regard to FAME was that they found 0.2% incidence at a then lower FDA approval dosage of 0.5 mg/day. There are extensions of these trials ongoing on ophthalmic monitoring continues in both trials. Fingolimod discontinuation resulted in resolution of FAME and thus the studies mandated that should FAME develop the drug was to be discontinued. This has been incorporated into many clinical practices but leaves a problem for patients with severe demyelinating disease who have suboptimal response to other treatments. In these two trials, topical NSAIDs were occasionally prescribed by neurologists/ophthalmologists. There is minimal high level evidence to study this given that the incidence of FAME is low [4].
Possible treatment options for ME include nonsteroidal anti-inflammatory drugs, corticosteroids, vascular endothelial growth factor antagonists, laser photocoagulation, and vitreoretinal surgery. However, only a few cases report successful treatment of ME in the setting of continued fingolimod use. Such cases describe use of topical or injected corticosteroids, which are associated with serious adverse effects, such as delayed healing, infection, elevated intraocular pressure, and cataracts [5,6,7,8]. In one case fingolimod was continued while FAME was persistent and not specifically treated [9].
Nepefanac topical application may result in the following adverse reactions: hypertension (≤ 4%), headache (≤ 4%), Nausea (≤ 4%), vomiting (≤ 4%), Decreased visual acuity (≤ 10%), increased intraocular pressure (≤ 10%), conjunctival edema (≤ 5%), corneal edema (≤ 5%), eye pain (≤ 5%), eye pruritus (≤ 5%), lacrimation (≤ 5%), ocular hyperemia (≤ 5%), photophobia (≤ 5%), vitreous detachment (≤ 5%), xerophthalmia (≤ 5%), Sinusitis (≤ 4%). Nepafenac carries the following contra-indications which should be discussed with the patient prior to administration: hypersensitivity should the patient have NSAID allergy documented [10, 11].
This report describes a case of FAME successfully treated with nonsteroidal anti-inflammatory drops without discontinuation of fingolimod. The patient’s ME resolved with ongoing treatment without evidence of side effects. This provides class IV evidence for safe management of FAME with nonsteroidal anti-inflammatory eye drops without discontinuation of fingolimod.
