MEK retinopathy usually presents acutely within the first week of the first dose. The retinal features described in MEK retinopathy include central serous retinopathy, serous retinal detachment, cystoid macular edema, intra-retinal fluid and cysts and thin choroid. Most of these features are identified on optical coherence tomography scans [6,7,8,9,10]. The retinopathy is typically bilateral and symmetrical [5,6,7,8,9]. In cases where only one eye is affected, other diagnoses should be considered [5]. Symptoms of MEK retinopathy can vary from being asymptomatic to blurred vision, altered color perception, shadows, light sensitivity, metamorphopsia and glare. Cases are often mild, short-lived, self-limiting, and do not interfere with activities of daily living [8, 11,12,13]. Central retinal thickness and volume showed dose-dependent increases after the start of treatment, followed by a marked decrease despite continued treatment [8]. The retinopathy partially recovers, but can still be detected many months later [12]. Retinal thinning and retinal atrophy have been observed after long-term treatment [14] Cessation of life-extending treatment with MEK inhibitors is not indicated when SRF is present [12].
MEK pathway and its activation by the fibroblast growth factor receptor (FGFR) plays prominent role in the maintenance, survival and repair of RPE. Inhibition of this pathway leads to degeneration of RPE cells. The pathophysiology of MEK retinopathy is due to acute RPE toxicity which results in RPE hyperpermeability and breakdown of the retinal–blood barrier [15,16,17].
The treatment of MEK retinopathy is based on Common Terminology Criteria for Adverse Events (CTCAE) criteria, widely used for AE reporting in oncology studies, include a 4-category grading scheme for retinopathy according to symptom severity [18]. Asymptomatic patients and mild retinopathy with vision better than 6/12 do not require interruption of dosing as mild symptoms and OCT abnormalities frequently resolve within days after continued dosing. This suggests that many patients with MEK retinopathy develop tachyphylaxis to continued MEK inhibitor therapy. For significant visual symptoms or vision below 6/12, patients should be instructed to interrupt dosing with MEK inhibitor therapy. When symptoms resolve, patients may be rechallenged at the same dose of MEK inhibitor therapy with close monitoring following re-initiation of treatment. For toxicities with severe visual impairment or interruption of daily activities, MEK inhibitor treatment should be discontinued and when symptoms and OCT findings resolve, patients may be rechallenged at a lower dose [5, 18].
Our case showed bilateral, symmetrical changes within the retina in the form of cystoid edema, intra-retinal fluid and sub-retinal fluid signifying abnormal RPE permeability. Two new features were identified as thickening of ellipsoid zone and characteristically distributed subretinal granular deposits. The thickening of the ellipsoid zone could be due to swelling of the photoreceptors secondary to RPE toxicity and dysfunction affecting the photoreceptor nutrition. The subretinal granular deposits overlying a normal appearing RPE showed increased autofluorescence suggested abnormal lipofuscin clearance due to RPE dysfunction. Although the intra-retinal and sub-retinal fluid reduced, the ellipsoid layer changes and the granular changes persisted signifying ongoing RPE dysfunction despite reduced dosage even though the patient became asymptomatic. We were unable to perform fundus fluorescein angiography and electrodiagnostic tests which could have potentially shed more light on the structural and functional changes in retina.
In this case report we identified two new features of MEK retinopathy not previously described in literature. Introduction of molecularly targeted therapy have revolutionized the cancer treatment and increased the survival rate. Most of these agents are associated with ocular toxicities. These agents are relatively new and recently approved by NICE for clinical use in cancer treatment. Awareness of ocular symptoms, side-effect profile of drugs, monitoring regime and liaison between oncologist and eye care professional with ocular imaging is key to early diagnosis and management of ocular adverse events.