Partial Stenosis and Complete Punctal Closure Following Topical Netarsudil Use for Glaucoma : Journal of Glaucoma

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New Understandings of Glaucoma: Brief Report

Partial Stenosis and Complete Punctal Closure Following Topical Netarsudil Use for Glaucoma

Rashad, Ramy MD, MBA; Zhu, Catherine MD; Kupcha, Anna C. MD; Distefano, Alberto G. MD; Kefella, Haben MD; Desai, Manishi A. MD

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doi: 10.1097/IJG.0000000000002124
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Abstract

Netarsudil (Rhopressa, Aerie Pharmaceuticals, Irvine, CA) is a Rho-kinase inhibitor, which was FDA approved for the treatment of ocular hypertension and open angle glaucoma in 2017. It primarily works by inhibiting a Rho-associated protein kinase, which increases aqueous outflow through the conventional outflow pathway by the expansion of the juxtacanalicular trabecular meshwork and dilation of the episcleral veins.1,2

Because of its advent into the market, several large clinical trials have demonstrated its safety profile and efficacy in intraocular pressure lowering for ocular hypertension and open angle glaucoma.3–5 In addition, various other studies have demonstrated its benefit as an off-label adjunct pressure-lowering therapy in patients already on maximum medical therapy in other forms of glaucoma.6–8

Documented adverse effects of this novel topical glaucoma medication as observed in clinical studies and reports include conjunctival hyperemia, corneal verticillata, corneal edema, conjunctival hemorrhage, instillation site pain and erythema, corneal staining, blurred vision, increased lacrimation, eyelid erythema, and reduced visual acuity.3,5,6,9 However, punctal stenosis is not a well-documented potential adverse effect, with a single case series published to date.10 We described a series of patients who developed partial or complete punctal stenosis after the use of topical netarsudil, as well as the reversal of punctal disease after drug cessation.

PATIENTS AND METHODS

This retrospective noncomparative study was approved by our Institutional Review Board and adhered to the provisions of the Declaration of Helsinki for research. We identified all patients seen within our outpatient glaucoma clinics at a tertiary care centre between 2018 and 2022 who developed punctal stenosis in the ipsilateral eye(s) to the side topical netarsudil was used. Clinical data were collected, which included patient age, sex, glaucoma type, topical glaucoma therapy and start date, date of eye surgeries, systemic illnesses, systemic medications, date of initiation of topical netarsudil, date of reported symptoms or documentation of punctal stenosis, types of symptoms, and date of discontinuing therapy (if stopped). Clinical slit-lamp photographs were obtained before and after discontinuation of netarsudil therapy when available to document punctal changes.

A careful chart review was undertaken for thorough consideration of alternative causes of acquired punctal stenosis, including initiation of other topical glaucoma medications, recent intraocular or eyelid surgeries, recent illnesses, and systemic and topical medications.

Pubmed and Google Scholar database search was conducted for all articles published between 1988 and 2022 using a combination of the following terms: “netarsudil and punctal stenosis” and “rho-kinase inhibitor and punctal stenosis.” Additional articles found by reference searching were also reviewed.

RESULTS

Sixteen eyes of 10 patients (4 male, 6 female) treated with topical netarsudil that subsequently developed punctal stenosis were included in the study. The patient demographics, clinical diagnosis, intraocular pressure-lowering therapy, and punctal stenosis details are provided in Table 1. The mean age of included patients was 70.7±11.37 (range, 51–89) years. Five patients were diagnosed with open angle glaucoma, 3 with mixed mechanism glaucoma, 1 with normal tension glaucoma, and 1 with chronic angle closure glaucoma. The mean number of antiglaucoma medications (topical and oral) was 4.0±0.77. All patients were seen for multiple interval visits between initiation of topical netarusdil and the development of punctal changes. None of the patients had been initiated on any other topical glaucoma drops within 6 months of starting topical netarsudil. One patient had a bilateral upper blepharoplasty 4 months after starting netarsudil, but none of the other patients had undergone any type of periocular or intraocular surgery within 1 year of initiating topical netarsudil. Four patients had a documented diagnosis of dry eye syndrome at least 6 months before starting topical netarsudil, none of whom had other documented eyelid findings. No other potential alternative etiologies of acquired punctal stenosis were found in any of the patients.

TABLE 1 - Patient Demographics and Clinical Information
Patient Age Range (y) Sex Glaucoma Subtype No. Antiglaucoma Medications Known Dry Eye Disease Laterality of Netarsudil Use Duration of Netarsudil Use Until Documentation of Punctal Disease (mo) Slit Lamp Findings Netarsudil Discontinued Improvement in Symptoms after Discontinuation Improvement in Stenosis Post Discontinuation
1 80s M Open angle 4 Yes Both eyes 24.7 Slit-like narrowing of all 4 puncta Yes Yes Yes
2 60s M Open angle 5 Yes Right eye only 5.7 Complete closure of right upper and lower puncta, normal left puncta Yes Yes Yes
3 50s F Open angle 5 No Right eye only 26.7 Narrowing of right upper and lower puncta No NA NA
4 70s F Mixed mechanisms 3 No Both eyes 21.3 Narrowing of upper and lower puncta in both eyes Yes Yes Yes
5 60s F Mixed mechanisms 3 No Both eyes 5 Slit-like narrowing of bilateral lower puncta Yes Yes Yes
6 70s M Chronic angle closure 3 No Both eyes 11 Complete closure of upper and lower puncta both eyes Yes Yes Yes
7 70s F Mixed mechanisms 5 Yes Right eye only 25.7 Complete closure of right upper and lower puncta. Normal left punctum Yes Yes Yes
8 50s M Normal tension 4 No Both eyes 26.3 Slit-like narrowing of right upper and lower puncta, absent upper and lower left puncta Yes* Yes Yes
9 60s F Open angle 4 Yes Both eyes 5.4 Narrowing of bilateral upper and lower puncta Yes Yes Yes
10 80s F Open angle 4 No Right eye only 32.2 Narrowing of right upper and lower punctum No NA NA
*Left eye has only given the unilateral report of epiphora.
F indicates female; M, male; NA, not applicable.

Four patients with unilateral use of topical netarsudil developed unilateral stenosis and 6 patients using topical netarsudil bilaterally developed bilateral punctal stenosis. None of the patients with unilateral use of netarsudil developed punctal changes on the non-netarsudil side. The time from initiation of topical netarsudil to the documentation of punctal stenosis or associated symptoms ranged from 5 to 32.2 months (18.41±9.94). The most commonly reported side effects at the visit when punctal disease was diagnosed were epiphora (90%, 9/10 patients), conjunctival hyperemia (80%, 8/10 patients), and pruritus (20%, 2/10 patients).

Six patients developed punctal narrowing in the ipsilateral eye(s) to the use of topical netarsudil; Figure 1 demonstrates representative photos of punctal narrowing in 2 of these patients. Three patients developed complete punctal closure of both the upper and lower eyelids in the eye(s) ipsilateral to the use of the topical medication; representative photos from 1 patient are demonstrated in Figure 2. One patient on bilateral topical netarsudil developed unilateral slit-like narrowing of the upper and lower puncta in 1 eye and complete closure of both puncta in the other eye.

F1
FIGURE 1:
Representative slit-lamp photos from 2 patients documenting slit-type punctal narrowing after the use of topical netarsudil.
F2
FIGURE 2:
Slit-lamp photos from 1 patient showing complete closure of the right upper punctum (A) and left lower punctum (B) 150 days after initiation on topical netarsudil in both eyes.

In the 4 patients with findings of complete punctal closure, discontinuation of netarsudil led to clinical reappearance of the punctal opening, ranging from 31 to 83 days after drug cessation (45.75±21.57 d), as illustrated in Figures 3 and 4. Figure 5 illustrates punctal reappearance and improvement in the degree of stenosis over the course of 2 months after discontinuation of topical netarsudil in 1 of our patients.

F3
FIGURE 3:
Slit-lamp photos of the right eye from 1 patient showing: (A) complete closure of the right lower punctum 171 days after initiation on topical netarsudil, (B) reopening of the right lower punctum 83 days after stopping topical netarsudil, (C) complete closure of the left lower punctum 171 days after initiation of topical netarsudil and (D) reopening of the left lower punctum 83 days after stopping topical netarsudil.
F4
FIGURE 4:
Slit-lamp photos of the right (top row) and left eyes (bottom row) from 1 patient showing: (A) complete closure of the right lower punctum 641 days after initiation on topical netarsudil, (B) reopening of the right lower punctum 36 days after stopping topical netarsudil, (C) absence of the left lower punctum 641 days after initiation on topical netarsudil and (D) reopening of the left lower punctum 36 days after stopping topical netarsudil.
F5
FIGURE 5:
Slit-lamp photos of the right lower punctum showing: (A) complete closure of the right lower punctum 770 days after initiation on topical netarsudil, (B) improvement in stenosis 33 days after stopping topical netarsudil, (C) continued improvement in the degree of stenosis 118 days after stopping topical netarsudil.

Probing and irrigation were performed on only 3 patients, either due to patient time restraints during the visit or because an oculoplastic provider was not present in the clinic at the time of the visit. Probing and irrigation in the 3 patients confirmed some degree of punctal stenosis, but otherwise a patent lacrimal duct system. Topical netarsudil was bilaterally discontinued in 2 patients and unilaterally discontinued in 1 patient given the patient intolerance of epiphora. In patients who discontinued the topical therapy, there was documented improvement in symptoms of tearing and documented improvement in the degree of punctal stenosis on examination.

DISCUSSION

To our knowledge, this is the first study to demonstrate punctal stenosis and complete punctal closure after the use of topical netarsudil, with reversal of these complications upon drug cessation. On literature review, there has only been 1 other report published on punctal stenosis secondary to topical netarsudil, however, the severity of punctal changes that we reported in our patient cohort is novel.10 In 4 of our patients, we described complete punctal closure and loss of landmarks with the reappearance of the punctal opening after cessation of netarsudil. This unique phenomenon is a less frequent side effect of topical antiglaucoma therapies, with an unknown incidence in the current literature.11,12

Though chronic blepharitis is the most common cause of acquired punctal stenosis, several topical antiglaucoma medications, particularly those with preservatives, have been implicated, including timolol, latanoprost, betaxolol, and pilocarpine.13,14 The current proposed mechanism of acquired punctal stenosis is thought to be inflammation leading to eventual fibrotic narrowing and obstruction of the nasolacrimal drainage pathway from the remodeling of connective tissue fibers and chronic inflammation and fibrosis while on topical glaucoma therapy.15,16 No specific data is available on a proposed mechanism for Rho-kinase inhibitor-mediated punctal stenosis, however, these general inflammatory changes are felt to be consistent among all topical drug classes. Furthermore, although these changes can happen anywhere along the nasolacrimal duct system, the puncta and canaliculi seem to be the main anatomic sites of obstruction associated with eye drops.14,17 In our study, nasolacrimal duct probing and irrigation were done in 3 patients, which demonstrated punctal stenosis but an otherwise patent lacrimal duct system.

Both older age and female sex have been recognized as risk factors for punctal stenosis in previous literature.15 It is hypothesized that postmenopausal hormonal changes could explain the sex difference, whereas tissue atrophy and involutional changes occur with aging. Our study similarly demonstrates a slight female predominance (6/10 cases) with a mean age of 70.7 years. Notably, our cohort reflects an older, predominantly female patient population, also likely due to glaucoma being a predominantly age-related condition.

Our study was limited by the retrospective, noncomparative design, and a small number of cases. Although the observational nature of this study cannot prove causality, reversal of symptoms and clinical documentation of reversal of punctal stenosis on the ipsilateral side to topical netarsudil use were highly implicative. In addition, patients with unilateral use of topical netarsudil with documentation of normal puncta in the contralateral eye further corroborate our findings. Interestingly, 1 of our patients on bilateral topical netarsudil developed slit-like narrowing of the puncta in 1 eye and complete closure of both puncta in the other eye.

Further prospective studies are warranted to determine the true frequency and extent of punctal stenosis while on topical netarsudil and to better elucidate the potential cumulative effect of multiple topical therapies on the lacrimal system. From our observational study, topical netarsudil as an adjunct agent may have a higher propensity to cause punctal narrowing or closure. This knowledge is valuable in counseling patients before the use of topical netarsudil and for monitoring adverse effects while on the medication.

REFERENCES

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Keywords:

netarsudil; topical Rho-kinase inhibitor; punctal stenosis; epiphora

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