Complications in Retinal Surgery: A review of Corneal Changes following Vitreoretinal Procedures

Abstract

Purpose:

The purpose of this article is to discuss the early- and late-onset corneal complications that can occur following vitreoretinal surgery.

Methods:

A systematic review of the literature was conducted using PubMed and Google Scholar databases. Articles detailing the clinical findings and the associations between surgical techniques, irrigating solutions, and microsurgical instruments used for vitreoretinal surgery and postoperative corneal complications were included in this review.

Results:

Vitreoretinal surgery can be associated with corneal complications such as persistent corneal epithelial defects, neurotrophic keratopathy, band keratopathy, ocular surface disruption, and endothelial cell damage. Risk factors for the development of cornea complications after posterior segment surgery include history of uncontrolled diabetes mellitus, aphakia or pseudophakia, disrupted anterior lens capsule integrity, use of irrigating solutions without appropriate buffers, use of contact viewing lenses intraoperatively, intraocular gases or silicone oil after vitrectomy, and prolonged duration of surgery.

Conclusions:

Corneal complications secondary to vitreoretinal surgery are multifactorial, but more commonly arise in diabetic patients, those with preexisting ocular comorbidities, and under certain surgical-related conditions. Special pre-, peri-, and postoperative considerations, with a focus on early identification and management of risk factors, are required to help decrease the incidence of corneal complications.

INTRODUCTION

Vitreoretinal procedures such as pars plana vitrectomy (PPV) and scleral buckling are among the most commonly performed ophthalmological interventions.¹ Vitreoretinal surgery has been associated with considerable anterior segment morbidities including epithelial cell damage (persistent corneal epithelial defects, neurotrophic keratopathy, ocular surface disease, band keratopathy, transient refractive errors, etc.) and endothelial cell damage, which can result in discomfort and compromised visual outcomes.^2–5 Despite improvements in surgical techniques, implementation of smaller-gauge surgical instrumentations, and improved ocular irrigation solutions, the incidence of postoperative corneal complications after vitreoretinal surgery is estimated to be between 6–50.5%.^2–5 Risk factors include a history of previous vitrectomy, preoperative aphakia and pseudophakia, prolonged duration of surgery, use of contact viewing lens for vitrectomy, intraoperative epithelial debridement, loss of anterior capsule integrity, intraoperative lensectomy, and the use of adjunctive intraocular long-acting expansile gases or silicone oil (SO) in aphakic and pseudophakic eyes.^6,7

The purpose of this article is to provide ophthalmologists with an overview of potential corneal complications associated with vitreoretinal surgery. A systematic review of the literature was conducted using English-language PubMed and Google Scholar databases. We identified 2867 articles, from which 77 articles were included in this review. Articles were included if they described the characterization and clinical findings of postoperative corneal complications associated with different surgical techniques, tamponade agents, irrigating solutions, buffers, and microsurgical instruments utilized for vitreoretinal surgery.

Persistent corneal epithelial defects

The development of persistent corneal epithelial defects (PCED) is relatively common and represents a challenge in the postoperative period of patients after PPV, with a reported incidence that ranges between 11.9–22.4% (Figure 1).^2,8 The pathogenesis of PCED is unclear, but it is thought to involve a mechanical trauma to the cornea that triggers the unregulated activity of the urokinase-like plasminogen activator. This, in turn, weakens the attachments between the epithelial cells and the basement membrane molecules and upregulates the generation of plasmin, resulting in the degradation of the basement membrane components and the synthesis of type I collagenase in the stroma.^9,10

Figure 1. Individual with persistent corneal epithelial defect secondary to complex retinal detachment repair, silicone oil placement, and removal.

Slit lamp examination showing a central epithelial defect.

Several risk factors predispose patients to developing PCED. These include a prior history of diabetes mellitus and preexisting anterior segment abnormalities such as dry eye, limbal stem cell deficiency, neurotrophic keratitis, etc. Among surgical-related risk factors are protracted duration of surgery, ocular lubrication with 2.5% hydroxypropyl methylcellulose, mechanical intraoperative debridement, intravitreal tamponade with perfluoropropane (C₃F₈) gas tamponade, and assistance by a surgeon-in-training.^2,8

The consequences of an untreated PCED include increased risk of infection, anterior stromal scarring, corneal melt, corneal neovascularization, ulceration, perforation, and significant vision loss. Thus, PCEDs should be treated within 7–10 days to avoid secondary complications.¹¹ The current standard therapy includes aggressive lubrication with preservative-free artificial tears, ocular ointments, broad-spectrum antibiotic drops, bandage soft contact lenses, and punctal plugs. Interventions such as corneal epithelial debridement and tarsorrhaphy are considered if the initial medical management proves ineffective.¹¹ In cases refractory to standard management, additional treatment strategies include amniotic membrane grafting, autologous serum eye drops, cenegermin eye drops (Oxervate, Dompé U.S. Inc, Boston, MA), scleral contact lenses, and transplantation of corneal epithelial stem cells.^11–13

Neurotrophic Keratopathy

Corneal sensation is provided by the ophthalmic branch of the trigeminal nerve, predominantly via the long ciliary nerves.¹⁴ The long ciliary nerves are crucial in maintaining the integrity of the corneal epithelium through the expression of neurotrophic factors such as substance P, calcitonin gene-related peptide, norepinephrine, acetylcholine, neurotensin, and vasoactive intestinal polypeptide. These factors, which modulate corneal homeostasis, wound healing, and the corneal reflex arc, stimulate the proliferation and reformation of the epithelial surface.^15,16 Corneal denervation results in the loss of the trophic influences supplied by corneal nerve fibers and impairs corneal sensation, which is necessary for the activation of the corneal reflex arc. Thus, a neurotrophic cornea imposes an increased risk of corneal ulcers and vision loss.^14,16

The development of neurotrophic keratopathy following vitreoretinal surgery is thought to occur secondary to thermal or freezing injuries of the long and short ciliary nerves in the suprachoroidal space. This has been observed with confluent retinopexy for retinal detachments¹⁷ and transscleral cyclodiode laser for glaucoma surgery.¹⁶ Studies by Patel et al. reported ciliary nerve damage in diabetic patients following diode panretinal photocoagulation,¹⁸ and Menchini et al. noted ciliary nerve damage and reduced corneal sensitivity after argon and krypton retinal lasers.¹⁹ In Banerjee et al., neurotrophic keratopathy was observed secondary to long ciliary nerve damage in patients that underwent vitrectomy surgery with endolaser and SO tamponade for retinal detachment.¹⁴ In that case, the temporal relationship between the surgery and the onset of the keratopathy (5–10 weeks postoperative) favored the endolaser over the SO as the potential cause.

Diabetic Keratopathy

The corneas of diabetic patients are known to be particularly susceptible to surgical stress compared to their healthy counterparts. Therefore, diabetic keratopathy is the most common factor that affects corneal epithelial healing (47–64%).²⁰ It is an underdiagnosed subtype of diabetic neuropathy that delays corneal epithelial regeneration and causes endothelial cell dysfunction and loss of pump function following vitreoretinal surgery.^8,21 The mechanism of damage is thought to occur due to the accumulation of advanced glycation end products in the corneal epithelial basement membrane from long-term hyperglycemia. This accumulation induces inflammation and increases oxidative stress, thus hindering the production of Nerve Growth Factor (NGF) and sphingolipid, which are both important for neuronal health and myeling creation.^4,20 Hyperglycemia also induces Insulin Growth Factor Binding Protein 3 (IGFBP3) release, which competitively inhibits Insulin Growth Factor-1 (IGF-1), halting epithelial cell proliferation and amplifying apoptosis during the process of healing of epithelial defects.²⁰ Thus, diabetic patients are more prone to developing neurotrophic ulcers compared to nondiabetic individuals, with a reported incidence of 18%.²²

Ocular Surface Disease

Limited studies have been conducted regarding the effects of vitreoretinal surgery on the ocular surface, but the changes seen are likely multifactorial in origin. Larger peritomy sites, longer procedures, use of extended scleral depression, and suture placement may disrupt the conjunctival epithelium and temporarily alter the tear film stability, resulting in transient worsening of dry eyes. These factors also increase postoperative discomfort and inflammation, negatively impacting the ocular surface.^23–26 It is possible that ocular surface disease arising after vitreoretinal surgery may be in part due to the underlying presence of neurotrophic keratopathy, as discussed above.¹⁶ Similar to other ocular surgeries such as phacoemulsification²⁷ and keratorefractive procedures,²⁸ dry eye symptoms can occur following vitreoretinal surgery during the immediate postoperative period.^23–25

Lee et al. reported a decrease in tear film stability and worsening of dry eye symptoms as determined by the Ocular Surface Disease Index questionnaire (OSDI; Allergan Inc., Irvine, CA) in individuals receiving sutures after 23-gauge vitrectomy, compared with individuals that did not require sutures.²⁵ Suturing of the conjunctiva and the Tenon’s capsule can elicit a transient inflammatory response, which can subsequently impair surface goblet cells.^25,29 Additionally, these symptoms seem to improve over time, as reported by Fujita et al., who documented a recovery of inflammatory cytokines within a week post-PPV with treatment with bethamethasone.³⁰

Notably, corneal clarity during vitrectomy is of paramount importance to maintain visibility during critical intraoperative maneuvers, and it is often decreased because of corneal epithelial edema.³¹ The use of 2.5% hydroxypropyl methylcellulose, an intraoperative ocular lubricant used to aid visualization of vitreoretinal surgery, has been shown to reduce corneal clarity as it contains the preservative benzalkonium chloride, which has the potential for deep corneal penetration that can induce prolonged corneal inflammation, neurotoxicity, and decreased aqueous tear production.^32–34 In contrast, 0.3% hydroxypropyl methylcellulose has been found to be less damaging to the corneal epithelium as it contains sodium perborate as a preservative, which produces hydrogen peroxide and its inert salt, sodium borate. Hydrogen peroxide is less toxic than benzalkonium chloride at the concentrations used, and ultimately releases additional oxygen to what may be a hypoxic epithelium.³⁴ Similarly, sodium chondroitin sulfate 3%-sodium hyalunorate 4% may improve corneal clarity during vitreoretinal procedures as it does not contain preservatives, reduces fluid accumulation as it is hyperosmolar relative to the cornea, and has dispersive properties which may confer protection to the epithelium.³³

In the event of inadvertent corneal edema, intentional epithelial debridement may be performed to improve intraoperative visualization.⁶ Likewise, in the case of severe anterior segment opacities impeding a clear view to perform a PPV, an endoscopic vitrectomy can be used to circumvent the poor view, allowing for a corneal transplant as a staged procedure instead of a combined one.³⁵ This technique allows for visualization of anterior structures such as the ciliary bodies and the sub-iris space.³⁵

Effect of long-acting expansile gases

Studies have shown that the use of long-acting expansile gases for intraocular tamponade, such as C₃F_8, may have a compressive effect on the endothelium of aphakic eyes or those with disruptions to the lens-iris diaphragm, increasing the intraocular pressure (IOP).³⁶ This induces corneal damage by affecting the endothelial pump and causing morphologic cellular damage, which reduces the barrier function of the endothelium.^2,36 Thus, it is imperative to closely monitor these patients during the postoperative period and manage increased IOP as appropriate.

Band Keratopathy

Band Keratopathy (BK) is a corneal degenerative disease characterized by calcium deposition in the superficial layers of the cornea, including the basal epithelium, epithelial basement membrane, and Bowman’s membrane (Figures 2A and 2B). The pathophysiology of BK can be multifactorial, oftentimes resulting from chronic inflammation, corneal ulcers, chemical burns and multiple surgeries.³⁷ However, it has been reported that SO can contribute to the development of BK,³⁸ which usually occurs following prolonged SO contact with the corneal endothelium,^38–40 with an incidence of 6–28%.^38,39,41,42 SO blocks the transport of nutrients from the aqueous humor, leading to a lower endothelial metabolic rate.⁴³ This results in a reduction of lactic acid production, with no change in the rate of carbon dioxide loss due to constant evaporation.⁴³ Thus, there is an net pH increase in the superficial corneal layers, which facilitates precipitation of calcium salts.⁴³ Eyes with aphakia and/or partial or complete iris defects are particularly susceptible to the development of BK after SO tamponade given the increased possibility of SO entry into the anterior chamber. Techniques to try to prevent the anterior migration of SO include the placement of barrier sutures across the anterior chamber to simulate an iris diaphragm, reducing SO-corneal contact.⁴⁴ However, these interventions have had variable results, particularly in cases of hypotonic eyes.^44,45

Figure 2. Individual with development of band keratopathy three months after undergoing PPV with placement of silicone oil and lensectomy with endolaser.

A. Slit lamp evaluation demonstrating band keratopathy.

B. Anterior segment OCT with presence of thin hyperreflective bands with underlying shadowing around Bowman’s layer (yellow arrows), corresponding to corneal calcium deposits.

Refractive Error

Scleral buckling and PPV are well-known for causing ocular refractive changes and altering the shape of the cornea, inducing astigmatism.^46,47 Scleral buckles increase the anteroposterior axial length of the globe by an average of 0.71–2.02mm, inducing a myopic shift of 1.05–2.75 diopters, particularly with the use of encircling elements.^48,49 With PPV, it is estimated that the mean refraction error may change by −0.15 to −0.85 diopters in pseudophakic individuals.^50–53 The mechanism leading to this myopic shift is uncertain and changes are generally transient. It is believed to be caused by an anterior displacement of the intraocular lens (IOL) with gas tamponade,^52,53 an anterior shift of the lens-iris diaphragm due to the patient’s face-down position, or by a transient increase of central corneal thickness during the immediate postoperative period.⁵⁴ In contrast, SO implantation may lead to a hyperopic shift of 2.02–5.75 diopters.^55–57 However, these changes can be reversed when the oil is removed.^55,57

Postoperative astigmatism following PPV has been largely attributed to the use of scleral cautery and suturing.^58–60 During the immediate postoperative period, vitrectomies can induce corneal astigmatism of 0.3–2.92 diopters^49,61,62 due to an increase in corneal steepening in an asymmetric and irregular configuration.⁶¹ While this can negatively impact the visual outcomes in the immediate postoperative period, they tend to resolve by four months after surgery.^{46,47,58,60,61} These astigmatic changes are more likely to occur with larger gauge surgeries. The use of 20-gauge^60,63 instrumentation has a considerably higher risk of inducing temporary astigmatism postoperatively than the use of 25-gauge^62,63 or 27-gauge devices.⁵⁸ Other techniques like pneumatic retinopexy have been shown to induce a smaller postoperative cylinder.^46,64

Endothelial cell damage

The corneal endothelium has a high metabolic rate but a very limited regenerative capacity, resulting in a progressive reduction in endothelial cell density (ECD) as a result of normal aging.⁶⁵ Ocular surgery can potentially accelerate endothelial cell loss, with intraocular surgery being more detrimental to the corneal endothelium than extraocular surgery. As such, PPV with SO tamponade carries a higher risk of decreasing ECD compared to scleral buckle surgery for rhegmatogenous retinal detachment (RRD). In these cases, a quantitative assessment of the functional reserve of the endothelium through specular microscopy can be particularly useful.⁶⁵ While changes to the corneal endothelium may manifest less acutely and more subtly compared to intraoperative epithelial damage, these changes may lead to significant long-term ocular morbidities, particularly among younger patients and those with prior corneal pathologies.⁶

Effect of silicone oil (SO) use and lens status

SO tamponade is a common endotamponade used for the repair of complex retinal detachments (RDs) with giant retinal tears, proliferative vitreoretinopathy (PVR), viral retinitis, and ocular trauma.⁶⁶ Although it is effective for the management of complex retinal detachments with good anatomical and functional outcomes postoperatively, it can increase the risk of developing long-term corneal complications such as band keratopathy, persistent stromal edema, neovascularization, and endothelial cell damage as discussed earlier.⁶ SO can be categorized based on its molecular weight and viscosity. As such, lighter oils allow for easier injection and faster removal, while heavier oils are less likely to emulsify in the vitreous cavity.⁶⁷ Although there are no reported differences in the rate of corneal complications based on the type of oil, the rate of complications does increase the longer the oil remains inside the vitreous cavity, with a significantly increased risk after 6 months.^38,39,41,42

A considerable risk factor for developing corneal abnormalities with the use of SO is aphakia or pseudophakia given the compromised lens-iris diaphragm, which allows for anterior migration of the SO and subsequent endothelial damage.⁶⁸ Animal studies have shown that exposure to SO increases membrane permeability, disrupting the barrier function of the corneal endothelium.^69,70 Additionally, some components in SO have been shown to induce toxic tissue reactions.⁷¹

Friberg et al. examined the effect of vitrectomy on ECD without SO tamponade and found that the lens conferred a protective effect to the corneal endothelium during PPV as it provided a barrier to flow, thereby limiting mechanical endothelial trauma.⁷² Conversely, aphakic eyes that were exposed to a fluid–gas exchange or received simultaneous lensectomy without IOL implantation showed a decrease in ECD. Moreover, Goezinne et al. evaluated the changes in ECD in patients that underwent vitrectomy with SO tamponade, and they found a 19% decrease in ECD at 12 months in phakic eyes that underwent phacoemulsification with IOL implantation.⁷³ They also observed a 39% decrease in ECD at 12 months in aphakic eyes that had started phakic or pseudophakic, but underwent IOL removal or lensectomy to clean the peripheral retina and vitreous base in cases of anterior PVR.⁷³ Similarly, Rosenfeld et al. reported a 13% reduction of ECD at 6 months postoperative in aphakic eyes and a 17% reduction of ECD in eyes undergoing lensectomy combined with PPV, compared with a 0.4% reduction in phakic eyes.⁷⁴

Effect of irrigating solutions

The endothelial Na-K-ATPase pump is responsible for the maintenance of the corneal endothelium and the integrity of its cell-to-cell junctions by regulating the ionic composition of the aqueous humor. Thus, the use of irrigating solutions that resemble the physiological composition of the aqueous humor during surgery is paramount to improving endothelial cell survival.⁷⁵ Edelhauser et al. highlighted the importance of this principle by comparing different irrigating solutions. In animal models, they found minimal degenerative changes in the endothelium with lactated Ringer’s solution containing bicarbonate, reduced glutathione, and adenosine, compared to the irrigating solutions 0.9% Sodium Chloride, Balanced Salt solution (BSS), and lactated Ringer’s solution without added components.⁷⁶ BSS-Plus (Alcon Laboratories, Fort Worth, Texas, USA) contains additional dextrose, glutathione, and bicarbonate, resembling the natural composition of the aqueous humor;⁷⁴ Joussen et al. reported that BSS-Plus induced less short-term corneal swelling compared to Ringer’s solution due to its more physiologic composition.²¹ However, Rosenfeld et al. showed that standard BSS is comparable to BSS-Plus in the incidence of postoperative corneal edema and in preserving the integrity of the corneal endothelium during continuous PPV irrigation.⁷⁴ Similarly, Samuel et al. reported comparable effects of both solutions on the postoperative corneal endothelial cell density and intraoperative corneal epithelial changes.⁷⁷

CONCLUSION

Vitreoretinal surgery can be associated with significant corneal complications, especially with prolonged or complicated surgeries, that ultimately impact the visual outcomes. These complications include epithelial defects, neurotrophic keratitis, ocular surface disease, band keratopathy, refractive errors, and corneal edema due to endothelial cell damage. The presence of preoperative aphakia or pseudophakia, an intraoperative disrupted anterior lens capsule, the use of irrigating solutions without appropriate buffers, adjunctive long-acting intraocular gases in aphakic eyes, and silicone oil during vitreoretinal surgery are all associated with increased incidence of postoperative corneal complications. While these complications tend to be multifactorial, pre-, peri-, and postoperative treatment strategies have been sought to reduce their incidence.

Preoperatively, it is important to assess for prior history of corneal conditions such as neurotrophic ulcers and for systemic diseases such as uncontrolled diabetes mellitus, which should be treated as appropriate. Moreover, several strategies should be taken into consideration when planning vitreoretinal procedures to maximize visual outcomes. For example, minimizing the time SO remains in the eye once the retina has reattached, ensuring IOP optimization after using long-acting expansile gases, minimizing laser contact to the ciliary bodies as much as feasible, using irrigating solutions that resemble the physiological composition of the aqueous humor (such as BSS and BSS plus), applying ocular lubricants that confer protection to the corneal epithelium (such as 0.3% hydroxypropyl methylcellulose and sodium chondroitin sulfate 3%-sodium hyalunorate 4%), and implementing smaller gauge instrumentation (23-, 25- or 27-gauge instrumentations) to minimize traumatic scleral manipulation and intraocular inflammation. A multidisciplinary approach that ensures close follow-up and monitoring of individuals after vitreoretinal surgery is paramount to appropriately manage potential corneal complications when they arise.