Effect of Netarsudil 0.02% on a Patient with Fuchs Corneal Dystrophy and Radial Keratotomy

Abstract

This study reports an unusual case of dramatic change in visual acuity, pachymetry, and corneal topography in a patient with a history of Fuchs dystrophy and radial keratotomy following the use of Rho-kinase (ROCK) inhibitor. A patient with a history of 8-cut radial keratotomy (RK), astigmatic keratotomy (AK), and Fuchs dystrophy showed dramatic changes in visual acuity, pachymetry, and corneal topography after using one drop of netarsudil 0.02%. The dramatic effect of netarsudil in our patient may be due to increased penetration of a rho-kinase inhibitor from the corneal incisions, facilitating the effect on corneal endothelium, resulting in a dramatic improvement in corneal pachymetry. This suggests a potential role for corneal incisions to improve the effectiveness of rho-kinase inhibitors in patients with Fuchs dystrophy.

1. Introduction

Fuchs corneal dystrophy is a corneal endothelial dystrophy that usually presents with guttae on the endothelium. Over time, as the guttae progress, patients have endothelial dysfunction and resultant corneal edema. Treatment of Fuchs dystrophy has evolved. Early-stage disease is managed with hypertonic saline, but as the disease progresses, patients often require cornea transplantation to improve their vision. The current standard of care is Descemet’s membrane endothelial keratoplasty (DMEK). While DMEK surgery is well-tolerated and has a good safety and efficacy profile, it can be cumbersome for patients and has a small but significant risk of complications, including pupillary block, glaucoma, and infections [1]. Recently, options such as Descemet’s stripping only (DSO) or injectable endothelial cells with or without adjuvant ROCK inhibitors have gained much interest [2].

Rho-kinase (ROCK) inhibitors are a new class of medications approved in the United States in 2017 for the treatment of glaucoma. Decreased intraocular pressure was felt to be due to its inhibition of trabecular meshwork contraction and enhancement of the aqueous humor drainage [3,4]. But an interesting side effect of ROCK inhibitors is their effect on corneal endothelial cells. They seem to promote corneal endothelial cell migration, survival, and contraction [5,6,7,8,9]. Due to this effect, ROCK inhibitors have been used in patients with endothelial pathology, specifically Fuchs’ corneal dystrophy [2]. However, there are no case reports of large refractive shifts after ROCK inhibitor use, especially in radial keratotomy.

Radial keratotomy, a refractive surgical procedure involving radial incisions, was used to treat myopia. It was often coupled with arcuate keratotomy incisions to treat astigmatism. Radial keratotomy was effective at treating myopia, but a large drawback of the procedure was its progressive hyperopic shift and diurnal variations even years after radial keratotomy [10,11,12].

This study reports an unusual case of acute change in visual acuity, manifest refraction, pachymetry, and corneal topography in a patient with a history of 8× cut radial keratotomy (RK) and Fuchs corneal dystrophy (FCD) after using netarsudil 0.02%. This effect of netarsudil, a rho-kinase (ROCK) inhibitor, in our patient may be due to the increased penetration of the ROCK inhibitor from corneal incisions, amplifying its effect on the endothelium. This suggests a potential role for corneal incisions to improve the effectiveness of ROCK inhibitors in patients with Fuchs dystrophy, although any utility of corneal incisions in this setting needs to be balanced against their potential for refractive instability.

2. Case Presentation

A female in her 60s with a history of radial keratotomy (RK) and astigmatic keratotomy (AK), ocular hypertension, pseudophakia, and symptomatic FCD in both eyes presented for a second opinion. She had longstanding suboptimal vision due to irregular astigmatism from her RK incisions. However, she had noticed further deterioration in the vision from her right eye and was noted to have visually significant guttae. She was recommended Descemet’s membrane endothelial keratoplasty (DMEK) in her right eye. The patient wished for a nonsurgical option and presented for further evaluation. She was aware of studies showing improved corneal edema in FCD patients with netarsudil 0.02%. Given her history of ocular hypertension, she requested a trial of netarsudil 0.02%.

The patient’s baseline best-corrected visual acuity (BVCA) was 20/30 in both eyes, with a flat and steep keratometry of 37.6D/40.0D in the right eye and 38.4D/42.0D in the left eye, and a central corneal thickness (CCT) of 540 µm in the right and 512 µm in the left eye. These values are displayed in

Table 1. Chronological timeline of the patient’s best corrected visual acuity (BCVA) and central corneal thickness (CCT) at baseline, two days post netarsudil 0.02% use, ten days post netarsudil 0.02% use, 19 days post netarsudil 0.02% use, and eight months post netarsudil 0.02% use. At eight months, she had undergone Descemet’s membrane endothelial keratoplasty (DMEK). Pachymetry was measured in µm (micrometers). Blank cells represent data that was not obtained at the time of her visit. OD = oculus dexter (right eye), OS = oculus sinister (left eye), BCVA = best corrected visual acuity, DMEK = Descement membrane endothelial keratoplasty.

Time After Netarsudil 0.02% Use	Eye	BCVA	Refraction	Pachymetry (µm)	Keratometry (Flat/Steep) (Diopters)
Baseline	OD	20/30	+1.25 + 2.00 × 80	540	37.6/40.0
	OS	20/30	+1.25 + 0.75 × 95	512	38.4/42.0
2 days	OD	20/50	−1.00 + 1.75 × 80	508	41.2/42.0
	OS	20/50	−4.50 + 0.75 × 165	480	41.2/42.0
10 days	OD	20/40	+0.25 + 1.75 × 70	528	--
	OS	20/40 +1	−2.5 + 0.75 × 135	514	--
19 days	OD	20/40 −2	−0.25 + 1.75 × 70	532	--
	OS	20/40 +1	−2.50 + 0.75 × 135	514	--
8 months *	OD	20/20	+1.50 + 2.00 × 85	--	--
	OS	20/25	−2.50 + 0.75 × 140	--	--

* At this point, she had undergone DMEK in her right eye.

. The patient’s baseline axial curvature and corneal thickness maps are displayed in Figure 1. Slit lamp exam revealed dense 3+ guttae in the central cornea along with 8 × RK and 2 × AKs in both eyes. Her peripheral corneas were clear without guttae. After a discussion of risks and benefits, the patient was prescribed netarsudil 0.02% nightly in both eyes.

She returned two days later after she woke up with bilateral blurred vision out of proportion to her usual inter-day fluctuations after using netarsudil 0.02% at night for the past two days. Her exam with her current correction showed 20/150 OD (right eye) and 20/400 OS (left eye), which improved with a new refraction to 20/50 OD (−1.00 + 1.75 × 80) and 20/50 OS (−4.50 + 0.75 × 165). She was noted to have a significant decrease in corneal thickness (508/480 µm) and keratometry (41.2/42.0D OD, 41.2/42.0D OS) (Table 1) (Figure 1). Her exam was otherwise normal, with normal intraocular lens position and a normal dilated fundus exam. Optical coherence tomography (OCT) of her macula was similarly normal bilaterally. This change was thought to be due to netarsudil 0.02%, and she was asked to stop the medication. She returned eight days later, and at that time, her BCVA was 20/40 OD (+0.25 + 1.75 × 70) and 20/40 + 1 OS (−2.5 + 0.75 × 135). Her exam nine days later was essentially unchanged. Of note, all the patient’s visits and measurements were performed at approximately the same time, during mid-morning clinic. The patient’s intraocular pressure (IOP) during all these visits remained normal.

When she returned eight months later, she had undergone DMEK surgery in her right eye with another provider, while her left eye remained stable. Her BVCA was 20/20 OD (+1.50 + 2.00 × 85) and 20/25 OS (−2.50 + 0.75 × 140). The cornea had a clear transplant in her right eye, while her left eye continued to have 3+ guttae.

3. Discussion

We present a case of a patient with FCD and a history of RK and AK who experienced a pronounced change in visual acuity, pachymetry, and corneal topography after using netarsudil 0.02%. Although improvement in corneal edema with a ROCK inhibitor is consistent with published experience in FCD, the dramatic effect observed in this case after just a few days was surprising and suggests that corneal incisions, while not without inherent risks, may facilitate the delivery of netarsudil 0.02% to the endothelial cells.

A confounding variable in this case is that RK and FCD themselves can cause fluctuations in refraction, topography, and corneal thickness. This is especially true in the case of radial keratotomy, where diurnal fluctuations cause myopic shift and steeper keratometry [10]. All the patient’s visits were in the morning, theoretically minimizing diurnal variations. While we acknowledge that some of the fluctuations could be due to RK and FCD, and the patient had experienced some subjective fluctuations before using netarsudil 0.02%, she reported a very significant change in vision immediately after using the medication, which was unlike her previous baseline fluctuations, suggesting that netarsudil 0.02% caused her new symptoms. The degree of myopic shift was also substantially more than the previously published amount (0.36D) [12].

An interesting observation in our patient is the decline in BCVA in the right eye from 20/30 to 20/60 at one week and two weeks after instilling netarsudil 0.02% and the persistent myopic refraction in her left eye eight months after discontinuing netarsudil 0.02%. We suspect that this decline in BCVA in the right eye in the early weeks after instilling netarsudil 0.02% was due to a change in her irregular astigmatism as well as the presence of diffuse guttae on her endothelium. We did not obtain endothelial cell counts or contact lens over-refraction, which is a weakness of our case report.

ROCK inhibitors modulate the RhoA proteins, which control cellular adhesion, membrane permeability, motility, proliferation, differentiation, apoptosis, and extracellular matrix dynamics [13,14]. It does so by increasing trabecular outflow, decreasing episcleral venous pressure, and decreasing aqueous humor production [15]. While the initial use of ROCK inhibitors in ophthalmology was for controlling intraocular pressure, there has been considerable interest in their effect on the cornea. The activation of the ROCK pathway has been shown to cause increased cell contractility and decreased cell proliferation and migration, contributing to corneal endothelial dysfunction [14]. ROCK inhibitors mitigate some of these effects. The effect of ripasudil 0.4% (Glanatec; Koa Co., Ltd., Tokyo, Japan) on corneal endothelial cells is well documented, especially as an adjuvant to descemetorhexis without endothelial keratoplasty (DWEK) surgery in patients with a healthy reserve of peripheral endothelial cells [16]. However, this drug is not available in the United States.

Netarsudil 0.02% [Rhopressa (Aerie Pharmaceuticals, Bedminster, New Jersey, The United States of America)] is a ROCK inhibitor with an added norepinephrine transport inhibitor, used in glaucoma for its decreased production of aqueous humor [17]. It is a water-soluble molecule, absorbed through the cornea, with its highest concentrations in the cornea and conjunctiva [18]. While more unpredictable than ripasudil, it has also shown some effect on the corneal endothelium in FCD. In one study, symptomatic FCD patients treated with netarsudil produced a significant reduction in CCT at one month and three months and an improvement in visual acuity at three months [19]. In another study comparing two dosing regimens of netarsudil, both daily and twice-daily regimens resulted in significantly reduced CCT at week four, with five of the forty patients achieving complete resolution of corneal edema by week four. Corrected distance visual acuity improved by 3.2 letters with daily and 1.5 letters with twice-daily dosing [20]. There are also case reports of netarsudil improving corneal edema in non-FCD patients—iatrogenic Descemet’s detachment after cataract surgery, peripheral corneal edema in iridocorneal endothelial syndrome (ICE syndrome), and penetrating keratoplasty (PK) [8,21].

While there are case reports of post-surgical patients benefiting from netarsudil, we did not find any specific studies that assessed netarsudil’s pharmacokinetics in the presence of deep corneal incisions. We do know from previous studies that epithelial irregularities (via corneal denudement, microneedles, etc.) do allow for increased intraocular penetration of drugs [22,23]. This is an area that needs further study.

In evaluating the benefits of netarsudil use in both FCD and non-FCD patients, it is also important to note medication safety information as well as its recommended treatment schedule. The most common adverse reaction is conjunctival hyperemia (53%), with other common adverse reactions (approximately 20%) including instillation site pain, corneal verticillata, and conjunctival hemorrhage. The conjunctival hyperemia is thought to be due to rho-kinase-mediated inhibition of calcium sensitization, resulting in blood vessel smooth muscle relaxation on the conjunctiva [17]. The corneal verticillata are due to the drug’s ability to accumulate within the corneal epithelial cell lysosomes [24]. The recommended dosage of netarsudil 0.02% is one drop in the affected eye(s) once daily in the evening.

4. Conclusions

Despite successes, factors that predict consistent, reliable efficacy of netarsudil in corneal pathology remain elusive. Drug delivery to the endothelial cells is likely to play a large role. Our case suggests that there may be a role for corneal incisions in facilitating drug availability to endothelial cells. In reports of patients with other similar corneal incisions, the improvement in corneal edema was significant [21]. However, safety concerns of corneal incision must also be considered, as this procedure harbors both intraoperative and postoperative risks. Corneal incisions can lead to irregular astigmatism and, in extreme cases, cause corneal perforations or infections [8]. If corneal arcuate incisions indeed prove to augment the efficacy of ROCK inhibitors, they need to be undertaken with caution after consideration of all potential side effects.

There may also be a role for netarsudil 0.02% in patients with hyperopic shifts after radial keratotomy—our patient’s refraction underwent a large initial myopic shift, and while it partially regressed, it never returned to her hyperopic baseline, suggesting that there may be some long-term efficacy of ROCK inhibitors in preventing refractive fluctuations. This needs to be further studied.