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 Table of Contents  
Year : 2022  |  Volume : 2  |  Issue : 3  |  Page : 649-651

Netarsudil-associated reticular epithelial edema in a corneal ulcer

Department of Cornea and Refractive Services, Aravind Eye Hospital and Post-Graduate Institute of Ophthalmology, Coimbatore, Tamil Nadu, India

Date of Submission15-Sep-2021
Date of Acceptance24-Feb-2022
Date of Web Publication16-Jul-2022

Correspondence Address:
Dr. Arjun Velayudhan Nair
Department of Cornea and Refractive Services, Aravind Eye Hospital and Post-Graduate Institute of Ophthalmology, Coimbatore, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_2417_21

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Netarsudil is a novel Rho-kinase (ROCK) inhibitor approved for the reduction in intraocular pressure (IOP). Reticular epithelial edema (REE) is a side effect commonly noted in patients on netarsudil with pre-existing corneal edema. We report a case of netarsudil-associated REE in a corneal ulcer with secondary glaucoma. The patient had a recurrence of REE even after debridement, and the resolution was seen only after discontinuing the drug. Netarsudil-associated REE is a side effect previously reported in patients with corneal edema and decompensation. To the best of our knowledge, there are no previous case reports of REE in a corneal ulcer. ROCK inhibitors have additional anti-inflammatory and antifibrotic action, which can lead to delayed healing and scarring in corneal ulcers. In conclusion, ROCK inhibitors should be used judiciously in corneal ulcers.

Keywords: Acanthamoeba keratitis, corneal ulcer, netarsudil, reticular epithelial edema

How to cite this article:
Nair AV, Rosette D, Rajaraman R. Netarsudil-associated reticular epithelial edema in a corneal ulcer. Indian J Ophthalmol Case Rep 2022;2:649-51

How to cite this URL:
Nair AV, Rosette D, Rajaraman R. Netarsudil-associated reticular epithelial edema in a corneal ulcer. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 Aug 13];2:649-51. Available from: https://www.ijoreports.in/text.asp?2022/2/3/649/351139

Patients on Rock inhibitors who already have compromised corneas and edema are more likely to experience reticular epithelial edema (REE) as a side effect. Only a few cases of REE without decompensation have been documented. In this case report, we illustrate REE in a patient with corneal ulcer on Rock inhibitor for secondary glaucoma and no prior history of decompensation.

  Case Report Top

A 30-year-old-male patient presented with redness, pain, and watering in his right eye (RE) of 2 weeks duration. The patient after a therapeutic trial of topical moxifloxacin and voriconazole drops elsewhere was referred to a higher center as the ulcer was worsening. He presented with visual acuity of 1/60 in the RE and 6/6 in the left. On examination, there was circumcorneal congestion, a central 5 × 6.3 mm epithelial defect (ED), 6 × 6 mm circular corneal infiltrate with ill-defined margins, stromal edema, central thinning, endoexudates, and pigments on the back of the cornea. A hypopyon of 1 mm with cells and flare was present within the anterior chamber; the rest of the anterior segment could not be assessed due to hazy media. Intraocular pressure (IOP) in RE was 11 mmHg measured using a rebound tonometer. Corneal scraping revealed the presence of Acanthamoeba (AK) cysts in Gram's stain, and cysts were seen in vitro confocal microscopy [Figure 1]b. The patient was advised 0.04% chlorhexidine eye drops hourly and homatropine three times. At the time of review, cultures grew AK in non-nutrient agar. The ulcer was healing with peripheral scarring; however, the eye remained inflamed. The patient had a headache, eye ache, diffuse corneal edema; secondary glaucoma was suspected as IOP was not measurable and a rise in pressure was noted on digital examination. The patient was admitted and started on intravenous mannitol. Patient was advised oral acetazolamide 250 mg twice daily as well as topical anti-glaucoma medication (AGM). As the IOP remained high on serial follow up, a second AGM was considered along with the combination of brimonidine and timolol (Alfabet PF, His Eyeness Ophthalmics Pvt. Ltd., Bengaluru, India). Prostaglandin analog and topical acetazolamide were not preferred as the eye was inflamed and due to the possibility of endothelial dysfunction, respectively;[1] hence, netarsudil (Netalo 0.02%; Ajanta Pharma, Mumbai, India) was started. On follow-up 2 weeks later, epithelial defect had reduced, infiltrate was healing with a peripheral scar, and keratitis precipitates were noted. The inferior and temporal halves of the corneal ulcer had epithelial bullae [Figure 1]a and [Figure 2]a. The IOP was digitally normal. The patient was advised to continue topical chlorhexidine and AGM. On review a week later though the ulcer was responding to treatment, epithelial bullae were seen in the inferior part of the ulcer, overlying the healing infiltrate [Figure 2]c and [Figure 2]d. the healing infiltration. IOP in RE was 16 mmHg measured using Tono-Pen. The epithelial bullae were debrided as the cornea was scraped to assess the AK cyst load before the initiation of topical steroids for inflammation. The patient was followed up weekly. Even though the keratitis showed signs of healing, the previously scraped inferior half of the ulcer had a recurrence of confluent reticular bullae. The edema was restricted to the epithelium with no stromal edema, suggesting reticular epithelial edema (REE) caused by the Rho-kinase (ROCK) inhibitor. As the IOP had decreased following the initial surge, the patient was taken off netarsudil and advised to continue brimonidine and timolol. On review 3 weeks after stopping netarsudil, keratitis was responding to medication, REE had resolved [Figure 1]c and [Figure 1]d; [Figure 2]b. The patient was advised to continue topical chlorhexidine, homatropine, and AGM. The patient was unable to follow up or obtain medication for the next 3 weeks due to pandemic confinements. The ulcer had worsened despite the REE resolution, necessitating therapeutic keratoplasty later.
Figure 1: Reticular epithelial edema 2 weeks after the initiation of netarsudil (a). Confocal microscopy showing the presence of acanthamoeba cyst in the stroma (b). Resolution of epithelial edema and slow epithelialization in 2nd and 3rd weeks after stopping netasurdil (c and d)

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Figure 2: Slit-lamp image (side profile) slit beam through the reticular bullae (a). Slit view of resolution edema after 3 weeks (b). Magnified image of slit beam through reticular epithelial edema (c and d)

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  Discussion Top

Netarsudil is a ROCK inhibitor and norepinephrine transport inhibitor approved for IOP reduction by the US Food and Drug Administration in December 2017.[2],[3] ROCK and norepinephrine transport inhibitors target the trabecular meshwork, increasing outflow, and decreasing IOP. Conjunctival hyperemia, cornea verticillation, and perilimbal petechial conjunctival hemorrhage are common side effects of topical netarsudil use. REE has been reported in patients on netarsudil since its first report by Fernandez et al.[4] These cases of epithelial edema were mostly seen in diseased corneas with pre-existing stromal edema.[5],[6] As patients patients with corneal edema were excluded from the ROCKET-2 and MERCURY-1 studies, epithelial edema was not reported as a possible side effect.[2],[3] In our case, REE was more prominent in the inferior cornea, as is commonly reported. As in previous reports, epithelial edema resolved within 3 weeks of discontinuing netarsudil. REE recurred even after corneal debridement and resolved only after stopping the drug. ROCK inhibition impairs the cohesive mobility of migrating epithelial sheets, required for wound closure. ROCK inhibitors also regulate and increase the permeability of tight junctions, allowing fluid to move more easily from the stroma into the epithelium. Existing research indicates that the effects of ROCK inhibitors on tight junctions appear to be reversible when the drug is stopped,[7] which could explain the improvement in epithelial edema on discontinuing netarsudil. By inhibiting human tenon fibroblast proliferation, adhesion, and contraction, ROCK inhibitors can improve glaucoma filtering surgery outcomes by reducing scarring and stenosis of the iatrogenic conduit, including subconjunctival scarring. ROCK inhibition, while beneficial in the control and prevention of corneal scarring, may impede wound healing.[8] Rho is recruited to the edge of epithelial wounds and activates ROCK, forming an actin ring around the wound edge, allowing epithelial wounds to heal.[9] ROCK causes myofibroblast contraction in granulation tissue via the same mechanism. ROCK activity was found to be upregulated after alkali trauma in vitro corneal studies, indicating ROCK regulation during wound healing. In corneal scar tissue, collagen III is the most upregulated collagen type. Rock inhibitor inhibited collagen III signaling, indicating more passive tissue regeneration. ROCK inhibition had anti-inflammatory and anti-angiogenic effects comparable to steroids in murine cornea alkali burn models. The ROCK inhibitor outperformed dexamethasone in terms of antifibrotic activity.[10]

  Conclusion Top

In conclusion, REE is a commonly encountered but under-reported side effect seen with ROCK inhibitors. To the best of our knowledge, there are no similar case reports of REE in a corneal ulcer. REE resolves once ROCK inhibitors are discontinued. ROCK inhibitors should be used with caution in corneal ulcers as they can delay epithelial healing and may pose a risk of perforation due to delayed scar formation.

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


Conflicts of interest

There are no conflicts of interest.

  References Top

Kelley PS, Dossey AP, Patel D, Whitson JT, Hogan RN, Cavanagh HD. Secondary glaucoma associated with advanced acanthamoeba keratitis. Eye Contact Lens 2006;32:178-82.  Back to cited text no. 1
Kahook MY, Serle JB, Mah FS, Kim T, Raizman MB, Heah T, et al. Long-term safety and ocular hypotensive efficacy evaluation of netarsudil ophthalmic solution: Rho kinase elevated IOP treatment trial (ROCKET-2). Am J Ophthalmol 2019;200:130-7.  Back to cited text no. 2
Brubaker JW, Teymoorian S, Lewis RA, Usner D, McKee HJ, Ramirez N, et al. One year of netarsudil and latanoprost fixed-dose combination for elevated intraocular pressure. Ophthalmol Glaucoma 2020;3:327-38.  Back to cited text no. 3
Fernandez MM. Reticular epithelial edema in edematous corneas treated with netarsudil. Ophthalmology 2018;125:1709.  Back to cited text no. 4
Wisely CE, Liu KC, Gupta D, Carlson AN, Asrani SG, Kim T. Reticular bullous epithelial edema in corneas treated with netarsudil: A case series. Am J Ophthalmol 2020;217:20-6.  Back to cited text no. 5
Moumneh K, Sheybani A, Fellman RL, Godfrey DG, Grover DS. Reticular corneal edema or corneal honeycombing in eyes treated with netarsudil: A case series. J Glaucoma 2020;29:607-10.  Back to cited text no. 6
Yin J, Yu F-SX. Rho kinases regulate corneal epithelial wound healing. Am J Physiol Cell Physiol 2008;295:C378-87.  Back to cited text no. 7
Kim HM, Tran AQ, Yang C, Dagi Glass LR. Netarsudil-related eyelid wound dehiscence. J Glaucoma 2021;30:206-8.  Back to cited text no. 8
Tomasek JJ, Vaughan MB, Kropp BP, Gabbiani G, Martin MD, Haaksma CJ, et al. Contraction of myofibroblasts in granulation tissue is dependent on Rho/Rho kinase/myosin light chain phosphatase activity: Contraction of myofibroblasts is dependent on phosphatase activity. Wound Repair Regen 2006;14:313-20.  Back to cited text no. 9
Sijnave D, Van Bergen T, Castermans K, Kindt N, Vandewalle E, Stassen J-M, et al. Inhibition of Rho-associated kinase prevents pathological wound healing and neovascularization after corneal trauma. Cornea 2015;34:1120-9.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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