Clinical and Morphologic Characteristics of MEK Inhibitor-Associated Retinopathy: Differences from Central Serous Chorioretinopathy

Abstract

Purpose: To investigate the clinical and morphologic characteristics of serous retinal disturbances in patients taking mitogen-activated protein kinase kinase (MEK) inhibitors.

Participants: A total of 313 fluid foci in 50 eyes of 25 patients receiving MEK inhibitors for treatment of their metastatic cancer, who had evidence of serous retinal detachments confirmed by optical coherence tomography (OCT).

Design: Single-center, retrospective cohort study.

Methods: Clinical examination and OCT were used to evaluate MEK inhibitor-associated subretinal fluid. The morphology, distribution, and location of fluid foci were serially evaluated for each eye. Choroidal thickness was measured at each time point (baseline, fluid accumulation, and fluid resolution). Two independent observers performed all measurements. Statistical analysis was used to correlate interobserver findings and compare choroidal thickness and visual acuity at each time point.

Main outcome measures: Comparison of OCT characteristics of retinal abnormalities at baseline to fluid accumulation.

Results: The majority of patients had fluid foci that were bilateral (92%) and multifocal (77%) and at least 1 focus involving the fovea (83.3%). All fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. The 313 fluid foci were classified into 4 morphologies, as follows: 231 (73.8%) dome, 36 (11.5%) caterpillar, 31 (9.9%) wavy, and 15 (4.8%) splitting. Best-corrected visual acuity at fluid resolution was not statistically different from baseline; and no eye lost more than 2 Snellen lines from baseline at the time of fluid accumulation. There was no statistical difference in the choroidal thickness between the different time points (baseline, fluid accumulation, and fluid resolution). A strong positive interobserver correlation was obtained for choroidal thickness measurements (r = 0.97, P < 0.0001) and grading of foci morphology (r = 0.97, P < 0.0001).

Conclusion: The subretinal fluid foci associated with MEK inhibitors have unique clinical and morphologic characteristics, which can be distinguished from the findings of central serous chorioretinopathy. In this series, MEK inhibitors did not cause irreversible loss of vision or serious eye damage.

Figure 1

Schematic diagram of 50 eyes of 25 patients showing the location, size and configuration of each fluid focus: blue = dome, green = caterpillar, red = wavy, yellow = splitting. Number represents patient number and circle designates those patients with visual symptoms. Note the predominantly bilateral, multifocal involvement of the foci and relative symmetry between each eye. Subfoveal fluid foci are dome, if present, and splitting is comparatively widespread. A confluence of fluid foci occurs along the arcades.

Figure 2

Visual acuity changes at fluid accumulation and resolution. A) Waterfall plot demonstrating change in lines of Snellen visual acuity lines from baseline to fluid accumulation in 49 eyes. B) Waterfall plot demonstrating change in lines of Snellen visual acuity from baseline to fluid resolution in 35 eyes. No statistically significant difference was observed between baseline and at fluid resolution, with no greater change of more than two Snellen lines.

Figure 3

Examples of the four fluid configurations. Upper left: Domes appear as dome-shaped fluid accumulation between the IZ and RPE akin to the configuration that is observed in classic central serous chorioretinopathy. This larger dome focus displaces both the outer and inner retinal layers. Upper middle: Caterpillars appears as a straight or plateau, low-lying accumulation of fluid, which displaces a portion of the IZ (and outer retinal layers) inwards towards the vitreous. Upper right: Wavy refers to a linear collection of tiny dome-shaped fluid collections, which displace the IZ (and outer retinal layers) in an undulating, wave-like pattern. Lower: Splitting appears as a broad, low-lying accumulation of fluid between the RPE and IZ, the boundaries of which may extend beyond the OCT border.

Figure 4

A representative case demonstrating optical coherence tomography findings at baseline, fluid accumulation and its resolution. Left column = right eye, right column = left eye. (A) Baseline optical coherence tomography showing normal retinal, retinal pigment epithelium (RPE) and choroidal structures. Note the difficulty in fully distinguishing the interdigitation zone (IZ) from the RPE and ellipsoid zone (EZ). (B) One day following binimetinib, the IZ shows “splitting” from the underlying RPE. (C) Ten days following binimetinib, a fluid foci appears in both eyes in a dome configuration (concurrently multiple foci were present along the superior and inferior arcades– not shown). The IZ is elongated and both the IZ and EZ remain distinguishable and hyperreflectile. Note the absence of pigment epithelial detachments, intraretinal edema and hyperreflectile dots. (D) Forty-days following binimetinib, the retinal layers resume their normal appearance and remain so 2 months after drug (E). The choroidal thickness remains relatively constant through the fluid evolution.

Figure 5

Graphic representation of clinical and morphologic differences in MEKAR and CSC. MEKAR (right) and CSC (left). EZ= ellipsoid zone; IZ= interdigitation zone; RPE=retinal pigment epithelium; PED= pigment epithelial detachment.

Figure 6

Optical coherence tomography of central serous chorioretinopathy in a patient with metastatic melanoma. This 68-year-old man with metastatic melanoma was receiving systemic prednisone for management of colitis when he reported decreased vision and was found to have subretinal fluid. Upper: The optical coherence findings (lack of hyperreflectivity of IZ and EZ, intraretinal and choroid hyperreflectile dots, and disturbed RPE) are consistent with central serous chorioretinopathy. Lower: at fluid resolution and 20 month follow up, the IZ/EZ has not reconstituted, and the RPE remains disturbed as evidenced by pigmentary changes on fundus exam. Also note the relatively thick choroid.