Introduction
Use of Rho-associated protein kinase inhibitor eye drops (ROCK) for corneal endothelial dysfunction or damage other than glaucoma has been reported owing to its property of promoting cell adhesion and proliferation and inhibiting the apoptosis of primate corneal endothelial cells in culture.[1] Simultaneously, various ocular side effects of these agents have been reported, common being conjunctival hyperemia, visually insignificant corneal verticillata, reticular epithelial edema (REE), or corneal honeycombing. Watering of the eyes, corneal staining, and blurred or reduced vision are other side effects being less observed or reported.[2,3,4,5]
With this case series, we aim to report REE with netarsudil (0.02%) therapy in four cases with different clinical scenarios.
Case Reports
The retrospective analysis of cases was done in accordance with the institutional ethical standards of the Helsinki Declaration of 1975, as revised in 2000.
Case 1
Details of case history and examination before starting netarsudil are as per Table 1.
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Table 1: Details of cases: History, examination, and treatment before netarsudil therapy
The patient was advised of right eye (RE) netarsudil 0.02% eye drop once at night time (HS) to maximize intraocular pressure (IOP) control medically in addition to other topical antiglaucoma agents (TAGAs). REE developed across the entire cornea after a week of netarsudil treatment, which cleared after cessation of netarsudil within a week. IOP was 18 mmHg on noncontact tonometer (NCT) with the rest of TAGA with subsidence of anterior chamber inflammation. Visual acuity (V/A) remained the same posttreatment (counting finger near the face) due to preexisting glaucomatous optic nerve damage (CD 0.9) [Figure 1a-c].
Figure 1: (a-l): Slit-lamp images for corneal status. Case 1: (a-c), case 2: (d-f), case 3: (g-i), and case 4: ((j-l)). First row before REE manifestation prenetarsudil, middle row with netarsudil-induced REE (fluorescein stain pattern of REE as inset pictures for case 2: (e and case 3: h) and bottom row post REE clearance on cessation of netarsudil for all cases, respectively (except 1l, case 4)
Case 2
Details of case history and examination before starting netarsudil are as per Table 1.
Netarsudil 0.02% HS (off-label) was added for partial donor decompensation and better IOP control in addition to TAGA. REE developed across the entire donor cornea with 10 days of netarsudil therapy with diffuse mild bulbar conjunctival hyperemia, which cleared within a week of cessation of netarsudil. Stromal clarity improved partially but advanced cataract prevented V/A improvement with normal IOP [Figure 1d-f].
Case 3
Details of case history and examination before starting netarsudil are as per Table 1.
The patient was given netarsudil 0.02% HS (off-label) at 4 weeks post-Descemet's stripping endothelial keratoplasty (DSEK) to prevent graft failure due to slow recovery of donor and recipient stromal edema in the presence of well-adherent donor lamella. The patient presented with REE (central 6–7 mm zone) after 17 days of netarsudil therapy with diffuse mild bulbar conjunctival hyperemia and mild ocular pain for 1 day, all of which resolved by 10 days with cessation of netarsudil. V/A improved to 6/36 with partial clearance of stromal edema (CF 3-m prenetarsudil, CF 1 m with REE) at 10 weeks post-DSEK with normal IOP [Figure 1g-i].
Case 4
Details of case history and examination before starting netarsudil are as per Table 1.
The patient was started on netarsudil 0.02% HS (off-label) for the prevention of potential graft failure post endothelial rejection (2 months back, topical and systemic immunosuppression was given for rejection) and for IOP control in addition to TAGA. REE developed adjacent to the graft host junction within 14 days of netarsudil therapy, sparing the visual axis. With no active complaints, netarsudil was continued for stromal edema and IOP control medically (19 mmHg on NCT). RE V/A was 6/36 (patchy capsular opacification) with partial stromal edema clearance compared to CF 4-m prenetarsudil therapy [Figure 1j-l].
All cases were on topical sodium chloride 5% eye drops QID for stromal edema before netarsudil addition apart from other treatments required for inflammation control, postcataract extraction, and postcorneal transplant (CT) in an individual case as per Table 1. Final visual rehabilitation is awaited with cataract extraction in two patients and posterior segment pathology management if required in diabetic DSEK patients.
Discussion
ROCK inhibitor eye drops benefit glaucoma cases mainly by increasing aqueous outflow and reducing aqueous production, decreasing episcleral venous pressure, and by providing optic nerve head neuroprotection.[2,5] Accelerated corneal endothelial wound healing resulting in corneal endothelial monolayer regeneration with a high endothelial cell density has been studied in animal models with topical application.[1] Since its approval for the treatment of glaucoma or ocular hypertension, netarsudil 0.02% eye drops (off-label) also has been utilized for refractory corneal edema post cataract surgery as well in CT patients.[5,6,7]
In the present study, netarsudil was used for corneal edema post-CT (with postpenetrating keratoplasty (PK) glaucoma in two out of three cases) and postcataract extraction (with raised IOP) in all the cases. The possibility of preexisting corneal endothelial dysfunction/damage exists due to the type of transplant surgery (one re-PK with rejection episode, one large therapeutic CT, both with peripheral anterior synechia (PAS) and posterior synechia (PS)) and existing comorbidities (one diabetic patient with DSEK for chronic corneal edema, one phacomorphic glaucoma). The presence of compromised endothelial function and inflammation was similar to the study by Wisely et al.[8]
This case series is among the very few published in the literature which describes different clinical manifestations of REE such as diffuse REE, centrally located REE, and REE observed across graft host junction sparing central area.[6,7,9] This study highlights the possibility of REE manifestation in partially decompensated corneas as early as a week postnetarsudil therapy in different clinical scenarios. REE was observed as early as 17 days in the DSEK graft and 10 days in the PK graft compared to 1 month and 2 weeks, respectively, as reported by Chen et al. and Davies.[6,9] Furthermore, REE cleared after the cessation of netarsudil as early as within a week in two cases and by 10 days in one case as observed in other studies.[2,6,7,8] However, complete stromal edema clearance in the presence of preexisting corneal edema was not seen in CT patients.[6,9,10] Mild conjunctival hyperemia (two patients) and mild ocular pain (one patient) were observed in the present study, which resolved on discontinuation of netarsudil similarly as reported in other studies.[2,5]
Although REE and stromal thickness changes are clearly evident with slit-lamp examination only, the study has the limitation of reporting them clinically without capturing and/or quantifying thickness on imaging modalities, for example, Anterior Segment Optical Coherence Tomography (ASOCT) (retrospective analysis limiting comparison of pre- and postnetarsudil corneal status). Furthermore, preetarsudil endothelial evaluation on specular imaging was not possible (hazy media). However, this case series aids clinical information regarding netarsudil use and its effects observed for partial endothelial dysfunction (off-label) due to different clinical conditions with or without raised IOP, which may help to strengthen existing knowledge on the same. Different manifestations of REE and its clearance along with the slit-lamp images aid in academic value regarding the same as well.
Conclusion
The present case series observed REE as the most common ocular side effect, which is transient and reversible on cessation of the netarsudil. All patients showed partial corneal stromal edema clearance clinically either due to better IOP control or improved residual endothelial function or both with control of inflammation. However, large-scale studies are required to evaluate REE and stromal edema with endothelial changes with ROCK inhibitor therapy in decompensated corneas and inflamed eyes with or without raised IOP.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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