The Doctor Jekyll and Mr. Hyde Story of Topical Netarsudil

BY AUSTIN S. NAKATSUKA, MD

Topical netarsudil 0.02% (Rhopressa, Aerie Pharmaceuticals) is an FDA-approved rho-kinase (ROCK) inhibitor for reducing intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. ROCKs are enzymes with effector roles in the Rho pathway, a group of proteins that regulate cell structure, motility, and destruction. ROCKs are present in many tissue types, including the cornea, trabecular meshwork, and Schlemm’s canal. Clinically, ROCK inhibition has been utilized effectively in glaucoma and corneal pathology. Currently, the use of Rhopressa for corneal pathology is off-label. We present three short case presentations showing beneficial and adverse effects of topical netarsudil treatment.

Case Presentation 1

A 66-year-old aphakic patient with steroid-response glaucoma is referred for secondary intraocular lens (IOL) placement and possible corneal transplant for chronic corneal edema. We started him on netarsudil nightly. After one month, visual acuity improved from 20/60 to 20/40, corneal thickness decreased from 675 to 587 microns, and slit lamp examination revealed a clear cornea with minimal edema. We decided to defer corneal transplantation due to significant improvement.

Aphakia and a clear cornea with minimal residual corneal folds following treatment with topical netarsudil.

Case Presentation 2

A 63-year-old patient with severe primary open-angle glaucoma and a history of Descemet’s stripping endothelial keratoplasty (DSEK) is started on netarsudil/latanoprost (Rocklatan) nightly. The patient has a history of a failed trabeculectomy, two Ahmed glaucoma tube shunts, and micropulse diode treatment. Twelve days after starting Rocklatan, the patient is noted to have focal honeycomb subepithelial changes with corneal edema most prominently in the area of his corneal graft.

Focal honeycomb subepithelial corneal changes adjacent to an endothelial graft.

Case Presentation 3

A 78-year-old patient with moderate primary open-angle glaucoma is started on netarsudil nightly in both eyes. She had been on latanoprost monotherapy due to systemic effects of other drops. Although IOP decreased to low teens with the addition of netarsudil, the patient reported vision loss and BCVA decreased from 20/20 to 20/25- OU. We found marked corneal verticillata and decided to stop netarsudil. Shortly after, the verticillata resolved and visual acuity returned to baseline.

An eye with marked corneal verticillata or whorl-like keratopathy.

Case Presentation 4

A 60-year-old patient underwent Descemet’s membrane endothelial keratoplasty (DMEK) and started on netarsudil after 1 month to expedite corneal clearing and offset steroidrelated IOP spikes. A few days after we initiated treatment, the cornea cleared and IOP was controlled, but we noted mild honeycomb changes peripheral to the graft.

Slit lamp photo showing a clear DMEK graft with mild honeycomb supbepithelial corneal changes peripheral to the graft.

Slit lamp photo showing a clear DMEK graft with mild honeycomb supbepithelial corneal changes peripheral to the graft.

Discussion:

Topical netarsudil is a versatile treatment option for glaucoma and corneal pathology and may be even more beneficial in cases where a combination of these diseases exist in the same eye. Because of the ubiquitous nature of ROCKs in the human body, there is evidence to suggest that ROCK inhibition may affect the episcleral venous network, leading to an IOP-lowering effect downstream of the trabecular meshwork. This may mimic the IOP results of filtering surgeries such as trabeculectomy. In this author’s experience, netarsudil has been able to lower patients’ IOP to single digits even after the failure of multiple glaucoma drop classes, preventing larger glaucoma surgeries in highrisk patients.

This has also been the case for clearing corneal edema and preventing corneal transplants. Topical netarsudil has been successfully used off-label as an adjunct to Descemet’s stripping without endothelial keratoplasty where corneal clearing is achieved despite no corneal graft being placed. Nevertheless, the adverse effects of netarsudil can be debilitating. Besides frequent complaints of conjunctival hyperemia and discomfort, punctal stenosis has been reported as a reversible effect in a recent Ophthalmology publication (Reference 1). In this author’s experience, hyperemia is common, but patients are often willing to overlook cosmetic changes if they have significant improvements in IOP. However, visually significant verticillata and honeycomb edema can be difficult to predict, and the author has had to suspend treatment for these reasons on more than one occasion.

More studies are needed to determine the full capabilities of this unique ophthalmic medication. This treatment has yet to be studied in pregnant women or patients with congenital glaucoma, where systemic side effects from other medication classes can be prohibitive. Perhaps a different route of administration, including intracameral or intravitreal, may mitigate many of the adverse effects. Netarsudil has promising results in treating retinal pathology and may even have a role in optic nerve protection.

Dr. Nakatsuka specializes in glaucoma and anterior segment conditions. He completed a fellowship at Moran in glaucoma and advanced cataract and iris surgery, training extensively with the late Alan S. Crandall, MD. Before that, he completed a fellowship in cornea and refractive surgery at Moran.

REFERENCE

1. Meirick TM, Mudumbai RC, Zhang MM, Chen PP. (2022). Punctal Stenosis Associated with Topical Netarsudil Use. Ophthalmology, 129(7), 765–770. https://doi.org/10.1016/j.ophtha.2022.02.025.

FINANCIAL DISCLOSURE

Dr. Nakatsuka has no financial interest in any of the products mentioned in this article.