Case of the Month

Edited by Robert N. Johnson, MD

Case History

A 65-year-old woman presented for evaluation for two weeks of decreased vision in both eyes.

On examination visual acuity was 20/32 in both eyes. Her pupils were equal round and reactive with no afferent pupillary defect.  The intraocular pressure and anterior segment examination in both eyes were unremarkable. Fundus examination demonstrated bilateral shallow small yellow pockets of subretinal fluid within the fovea and scattered around the arcades (Figures 1A and B) which was more apparent on fundus autofluorescence (FAF) than on clinical examination (Figures 2A and B). Ocular coherence tomography (OCT) demonstrated multiple pockets of subretinal fluid (Figures 3A-D). Fluorescein angiography (FA) showed no leakage in either eye (Figures 4A and B).

Differential Diagnosis

Central serous chorioretinopathy, multiple myeloma, MEK inhibitor-associated retinopathy, Exudative polymorphous vitelliform maculopathy, Paraneoplastic vitelliform retinopathy, melanoma associated retinopathy.

Additional History and Diagnosis

Upon further questioning she had a history of cutaneous melanoma of her toe which had been resected five years ago. Four years later on routine surveillance she was found to have metastases in both her lungs and liver. She was started on Binimetinib and Encorafenib shortly before her visual symptoms began.

She was diagnosed with MEK-inhibitor associated retinopathy and her retinal findings were observed. She was initially continued on MEK-inhibitor therapy. Four months later the areas of subretinal fluid were seen to improve. The medications were unfortunately ineffective at controlling her metastases so she has since been switched to Ipilimumab and Nivolumab. Since cessation of the MEK inhibitors she has had further improvement in her level of subretinal fluid.

Discussion

Mitogen-activated protein kinase kinase (MEK) inhibitors are medications that selectively inhibit the mitogen-activated protein kinase cascade. This cascade is an intracellular signaling pathway involved in the regulation of tumor cell proliferation which is overactive in certain cancers, particularly melanoma. Common MEK inhibitors include binimetinib, trametinib, and cobimetinib.¹ While these treatments are more targeted than traditional chemotherapy, they are accompanied by unique ocular toxicities.²

One of the first case reports of MEK inhibitor associated retinopathy (MEKAR) was published in 2013 and demonstrated similar findings to our case.³ Later, a retrospective case series of 25 patients showed that the median time from initiation to subretinal fluid detection was 14 days. Median time to resolution of subretinal fluid was 32 days. In all 25 cases the fluid was self-limiting and did not require discontinuation of the drug.⁴ Another prospective observational study of 62 patients similarly confirmed findings of dose and time dependent self-limiting serous detachments notable only on OCT.⁵

The mechanism for these findings remains unknown. Within the retina, animal studies have shown that the MEK pathway regulates tight junctions between retinal pigment epithelial (RPE) cells thus suggesting that the MEK inhibitors are toxic to the RPE and result in disruption of the blood-retinal barrier.^6,7 A variety of adnexal, anterior segment, uveitic, glaucomatous, and cataractous changes have also been reported.⁸

Clinical findings are best detected and followed on OCT. There are four morphologies which have been described: “dome” (such as our patient), “caterpillar”, “wavy”, or “splitting”. The most common was noted to be dome shaped. FA typically reveals no abnormalities. We found the subretinal fluid collections to be more visible on FAF, though previous reports state that there is no difference.⁴ One case report noted subretinal granular deposits within the macula.⁹

Management is directed toward close observation of the fluid collections as they tend not to cause eye damage. MEKAR and central serous retinopathy may present with similar findings and it is important to distinguish between the two conditions as the management differs. Typically, MEK patients have multifocal fluid which displays no gravitational dependency (no gutter), normal choroidal thickness, no pigment epithelial detachments, and an undisturbed RPE upon resolution.⁴

References

1. Grimaldi AM, Simeone E, Festino L, et al. MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors. Am J Clin Dermatol. 2017;18(6): 745-754.
2. Liu CY, Francis JH, Brodie SE, et al. Retinal toxicities of cancer therapy drugs: biologics, small molecule inhibitors, and chemotherapies. Retina. 2014: 34(7): 1261-80.
3. Shoenberger SD and Kim SJ. Bilateral Multifocal Central Serous-Like Chorioretinopathy due to MEK Inhibition for Metastatic Cutaneous Melanoma. Case Rep Ophthal Med. 2013; 2013: 673796.
4. Francis JH, Habib LA, Abramson DH, et al. Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences From Central Serous Chorioretinopathy. Ophthal. 2017; 124(12): 1788-1798.
5. Urner-Bloch U, Urner M, Jaberg-Bentele, et al. MEK inhibitor-associated retinopathy (MEKAR) in metastatic melanoma: Long-term ophthalmic effects. Eur J Cancer. 2016; 65: 130-138.
6. Jiang Q, Cao C, Lu S, et al. MEK/ERK pathway mediates UVB-induced AQP1 downregulation and water permeability impairment in human retinal pigment epithelial cells. Int J Mol Med. 2009; 23(6): 771–777.
7.  Huang W, Yang AH, Matsumoto D, et al. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion. J Ocu Pharmacol Ther. 2009; 25(6): 519-530.
8. Mendez-Martinez S, Calvo P, Ruiz-Moreno O, et al. Ocular Adverse Events Associated with MEK Inhibitors. Retina. 2019 Aug; 39 (8): 1435-1450.
9. Tyagi P and Santiago C. New features in MEK retinopathy. BMC Ophthalmol. 2018;18(Suppl 1): 221.