Fingolimod has been approved for the treatment of multiple sclerosis (MS) and relapsing-remitting multiple sclerosis (RRMS) since 2010 (1). Active metabolites of fingolimod bind to the sphingosine-1-phosphate (S1P) receptor on lymphocytes, resulting in internalization and degradation of the receptor. This action prevents the egression of lymphocytes from lymphoid tissue into the circulation, thereby, sparing the central nervous system from attack by myelin-reactive lymphocytes (2).

The most common adverse events reported with fingolimod are nasopharyngitis, bradycardia, influenza, and headache. Macular edema (ME) is a rare complication of fingolimod. Two-phase 3 clinical trial studies have shown that fingolimod is associated with the development of ME (3, 4). Randomized controlled trials have demonstrated that macular edema is related to fingolimod. The current understanding of fingolimod-related macular edema is based primarily on case reports. However, the severity, visual symptoms, visual acuity, treatment, and prognosis of fingolimod-associated macular edema (FAME) remain unclear, especially in patients who wish to continue treatment with fingolimod. The purpose of this study was to explore the clinical features of FAME and provide evidence for its prevention, diagnosis, treatment, and prognosis by pooling and analyzing relevant case reports.

The incidence of FAME appeared to be dose-dependent, occurring in 0.4% of patients receiving 0.5 mg and 1% of patients receiving 1.25 mg (37). Our study found that FAME occurred mainly 3 m after the initiation of fingolimod, consistent with the phase III MS study and their extensions (14). However, a small proportion of patients develop late-onset ME (more than 12 months) (6, 15, 24, 30, 35), and blurred vision has also been reported as early as 24 h after initiation of the 0.5 mg dose (29). Patients with ME with diabetes or previous uveitis appear to develop it earlier. FAME cases can be unilateral or bilateral and can present with blurred vision, decreased vision, or no symptoms.

The diagnosis of FAME is based on OCT scanning and FFA to rule out any possible cause of ME. FAME is more likely to occur in patients with a history of diabetes, uveitis, or undergoing cataract surgery (38). Foveal thickening, foveal cysts, subretinal fluid, or dye leakage were seen on OCT scan and FFA in patients with FAME. In addition, ME associated with uveitis due to MS should also be excluded (39).

In addition to having a baseline eye exam before starting fingolimod, the FDA also recommends that patients have an eye exam 3 to 4 months after initiating the drug (35). However, the optimal frequency of follow-up periodic re-evaluation has not been determined, but some researchers recommend regular eye exams after 6 months and then annually (35). Patients who had fingolimod therapy, and who are also undergoing ophthalmic surgery, such as cataract surgery, may be at increased risk of developing ME and may benefit from increased monitoring or preventive treatment for ME (10, 15, 22, 34). Patients who have started fingolimod with a history of diabetes mellitus, uveitis, or concomitant medication associated with ME require closer monitoring.

Although the exact pathogenesis of FAME has not been determined, the likely mechanism is the disruption of the inner blood-retinal barrier. Sphingosine 1-phosphate (SIP) is a biologically active sphingolipid metabolite with five G protein-coupled receptors (S1PR 1-S1PR 5) (40). These receptors are found in nearly every cell type in the body, including lymphocytes, endothelial cells, neurons, and astrocytes. S1PR1 signaling is responsible for maintaining cell-to-cell and cell-to-matrix adhesion. Fingolimod downregulates S1P1R and antagonizes S1P2 R/S1P3R, thus, leading to downregulation of adhesion complexes and increased retinal vascular permeability, resulting in ME (41).

No consensus on best management has yet been established for FAME. Most patients with FAME resolve spontaneously after discontinuation of fingolimod. It should be noted that attempts to restart fingolimod resulted in recurrence of ME, which resolved after discontinuation. For patients requiring continued treatment, topical NSAIDs (e.g., nepafenac, bromfenac, and ketorelac), topical corticosteroids (e.g., prednisolone, and dexamethasone), and carbonic anhydrase inhibitors (e.g., acetazolamide) have been used to accelerate the resolution of FAME. More invasive interventions, such as subconjunctival or intravitreal administration of steroids (triamcinolone) or anti-vascular endothelial growth factor (e.g., ranibizumab and bevacizumab), may be required for refractory FAME (42). Some patients may not respond to topical anti-inflammatory therapy. Intravitreal corticosteroids may be an appropriate treatment option for patients with FAME who are refractory to topical anti-inflammatory therapy (34). However, caution must be exercised whenever steroids are used due to steroid-induced effects, such as ocular hypertension, glaucoma, and cataract formation (43). Patients should be informed of the risks and that they require ongoing monitoring. After the resolution of ME, a small proportion of patients had residual vision loss, which may be related to concurrent cataracts, uveitis, or optic neuritis. In addition, retinal damage is also a possible explanation (42). Determination of whether to discontinue fingolimod therapy should include an assessment of the individual patient's potential benefits and risks and their response to topical anti-inflammatory drugs.

In conclusion, ME is a known complication of fingolimod. FAME usually has a better prognosis with discontinuation or topical therapy. Eye exams are required before and after using fingolimod. Patients undergoing cataract surgery and with a history of diabetes and uveitis require closer monitoring.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

CW and SZ conceived of the presented idea. ZD, LS, WS, and CW analyzed and wrote the manuscript. SZ contributed to critical revision of the manuscript. All authors discussed the results and contributed to the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.