Posterior Segment Complications of Endothelial Keratoplasty

Abstract

Endothelial keratoplasty is the most commonly performed type of corneal transplant in the United States, currently accounting for 60% of total grafts. The anterior segment complications are well documented; however, the posterior segment complications may not be as familiar to the anterior segment surgeon. These include endophthalmitis, cystoid macular edema (CME), choroidal detachment, graft dislocation to the posterior segment, and retinal detachment. CME is the most common postoperative retinal complication with a reported incidence of up to 12.5%, which usually responds well to topical therapy. This article will review the incidence, prevention and management of posterior segment complications after endothelial keratoplasty.

Introduction

Endothelial keratoplasty (EK) is the most commonly performed corneal transplant in the United States (U.S.) according to the Eye Bank Association of America (EBAA). ¹ In 2018, about 60% (30,336) of 50,878 corneal tissues in the U.S. were used for EK. ¹ Approximately 64% (19,526) of the EKs were used for Descemet Stripping Endothelial Keratoplasties (DSEK) and 36% (10,773) were for Descemet Membrane Endothelial Keratoplasties (DMEK) procedures, with less than 0.12% used for Pre-Descemet Endothelial Keratoplasty (PDEK) or other types of EK. ^2,3 For the purposes of this review, the acronym DSEK will be used to cover all forms of posterior lamellar techniques that include stromal tissue (whether preparation was automated or performed manually). ⁴

The anterior segment complications of EKs, such as graft detachments, reverse pupillary block, rejection episodes, and graft failures are well documented, and corneal surgeons are familiar with their relative risks and management. ^4–8 However, posterior segment complications are often overlooked and may also limit visual acuity. ⁹ Corneal and vitreoretinal surgeons must therefore be aware of the signs and symptoms of these potential complications and their management.

Currently, the most common diagnoses requiring EK are posterior corneal dystrophies (53%), mainly Fuchs Endothelial Dystrophy (FED). ¹ Other indications, such as bullous keratopathy or repeat keratoplasty, might be expected to have a higher overall complication rate due to other ocular comorbidities or multiple previous surgeries. ^9,10 The purpose of this review article is to establish the incidence, treatment, and prevention of posterior segment complications including endophthalmitis, cystoid macular edema, vitreous in the anterior chamber, cystoid macular edema, posteriorly dislocated corneal graft, choroidal detachment, and retinal detachment (Table 1).

Table 1.

Summary of incidence of posterior segment complications after endothelial keratoplasty based on the literature search.

Clinical Scenario	Incidence	Reference
Endophthalmitis	0.041-0.2%	8,9,13,15,22
Cystoid Macular Edema	0-13.3%	7,9,50–64
Retinal Detachment	0-1.6%	7,9
Suprachoroidal hemorrhage	0-0.05%	9

Endophthalmitis

Incidence and causes

While the overall incidence of post-keratoplasty endophthalmitis is relatively low, the incidence of reported postoperative fungal infections has been rising after the introduction of endothelial grafts. ^11–14 The increased risk has been partly attributed to the increased processing time required for endothelial graft preparation, resulting in longer and larger fluctuations in tissue temperature. ^12,15,16 Up to 2.1% of corneal tissues have positive fungal rim cultures, with Candida species being the most commonly identified organism; unfortunately, 5.6-13.5% of these patients will subsequently develop clinical infections. ^14,17–19 These infections usually start as a limited keratitis but can quickly progress to endophthalmitis (Figure 1). ^{12,13,15,16,20}

Figure 1. Fungal Endophthalmitis Following DSAEK.

External slit lamp photograph of a 66-year-old man who developed pain in the left eye two months following DSAEK. The eye was painful, vision was markedly decreased, and a B-scan ultrasonography revealed vitreous membranes. The patient underwent removal of the graft, temporary keratoprosthesis, removal of his intraocular lens, pars plana vitrectomy, injection of anti-fungal agents and penetrating keratoplasty. While cultures were negative, pathological examination of the infected graft disclosed fungal elements, believed to have originated from the initial graft. Figure courtesy of Harry Flynn, Jr. MD.

Notably, no cases of post-EK fungal infection had been published at the time of the American Academy of Ophthalmology (AAO) sponsored Ophthalmic Technology Assessment of DSEK in 2009.⁴ It was later that year that Shih et al. published a series describing one case of fungal endophthalmitis in 126 corneal transplants. ⁸ Though smaller case series have estimated the incidence of fungal infections to range between 0.5-0.7%, ^8,21 more recently, a large retrospective study reported a 90-day cumulative incidence of 0.03% for postoperative endophthalmitis. ⁹ Large clinical series and reports by the Eye Bank Association of America (EBAA) suggest that the incidence may vary between 0-0.2%. ^13,15,22

Treatment

Post- keratoplasty fungal infections may be challenging to treat.^23–25 Most reports describe poor visual and anatomical outcomes. ^16,26–33 Aggressive treatment may be necessary, and the corneal graft may need to be replaced, often with a penetrating keratoplasty (PKP). ³⁴

Early and aggressive surgical intervention for interface fungal keratitis can result in good visual results. ³⁴ So in the presence of any signs of posterior segment infection or membranes, a vitrectomy should be performed. ^27–29,31 Silicone oil can be used as a tamponade in eyes with concomitant retinal detachment, in eyes with poor visual prognosis, or in the presence of particularly virulent organisms. In select situations, removal of the graft and the intraocular lens should also be considered. Anterior chamber and vitreous cultures should be obtained, and the original graft should also be sent for culture and pathological examination. In cases in which yeast is suspected due to delayed clinical presentation, growth on the corneal mate, or a positive rim culture, then both topical and intravitreal steroids should be initially avoided, and treatment should include the injection of the appropriate intravitreal antifungal, usually amphotericin B. Other types of fungi might require different antifungals, such as Voriconazole.

Prevention

In Europe where corneas are preserved in organ culture media, antifungal supplementation effectively reduces the rates of positive rim cultures. ^35–37 In the United States, corneal tissue is traditionally stored in cold storage media (CSM) without antifungal coverage. With the rising incidence of fungal infections and associated high morbidity and costs of fungal complications, some U.S. eye banks have started supplementing CSM with antifungals. Several studies have demonstrated the effectiveness of antifungal supplementation, and of all the different types of antifungal therapies studied, amphotericin B is the least expensive and can reduce in vitro fungal cultures by 86-100%.^38–41 Gibbons et al. and Chiang et al. evaluated the cost-effectiveness of antifungal supplementation and found that amphotericin B supplementation could be cost-effective in reducing the risk of fungal infections with endothelial grafts.^42,43

However, the hypothermic conditions may affect the pharmacokinetics of amphotericin. ¹⁶ A recent publication evaluated the effects of adding 0.255 ug/ml amphotericin to Optisol solution (Bausch & Lomb Inc, Bridgewater, NJ).⁴⁴ The antifungal supplementation failed to inhibit growth of Candida albicans, C. parapsilosis, and C. glabrata, which may be related to the study’s methodology. ⁴⁴ Unlike other studies that placed the yeast in the conservation media, so as to mimic real-world scenarios, Tran et al. placed the fungus directly onto the corneoscleral rims, which could potentially result in formation of a resistant biofilm, explaining the decreased effectivity of antifungal prophylaxis.

Another approach to decrease bacterial and fungal colonization of tissue is to improve tissue preparation conditions, such as using lamellar hoods, ensuring sterile environments, minimizing tissue temperature fluctuation, and optimizing the use of antiseptics. By doubling the exposure time of povidone iodine 5% during the corneal donor preparation, from 5 minutes to 10 minutes, Salisbury et al. were able to decrease the prevalence of positive bacterial rim cultures from 6.5% to 4.0% and decrease positive fungal rim cultures 2.9% to 0.6%. ⁴⁵

Corneal rim culture is not routinely performed at all centers, but it may provide invaluable data. Early fungal rim cultures may help warn surgeons of a possible infection, sometimes even before any clinical signs or symptoms are detected in the recipient. ^18,19 Palioura et al. reported on a pair of corneas from the same donor causing fungal endophthalmitis in two different DSEK recipients. ³¹ Currently, there is no consensus as to how to manage a positive rim culture when the recipient has no signs of infection. However, most physicians make a distinction on whether a bacterial or fungal pathogen is identified in the culture, and most agree on the importance of informing the patient and making them a part of the decision-making process. ¹⁸ The different management strategies include removing the graft, which may be considered when there are fungal elements isolated, especially if the donor mate has already developed a clinical infection. ³¹ More conservative approaches include prophylactic treatment with either oral, intracameral, or topical agents, or simply close follow-up in the postoperative period. ^14,46–49

Cystoid Macular Edema

Incidence

The reported incidence of cystoid macular edema (CME) after EK varies. ^7,9,50–64 Most case series report an incidence around 6% or less; however, most studies performed ocular coherence tomography (OCT) only if the patients developed clinical signs or symptoms, such as vision loss or less than expected improvement in visual acuity (Figure 2).

Figure 2. Cystoid macular edema following DSEK.

Black and white macular OCT image of a 58-year-old male who had undergone EK in his right eye six weeks prior to this image. He displays classic cystic changes within the retinal layers and vision was about 20/60. After eight weeks of topical therapy with a steroid and NSAID, his best corrected vision had improved to 20/25.

Heinzelmann et al., on the other hand, performed routine OCTs after DMEK combined with cataract surgery and found a higher CME incidence of 13.3% following triple-DMEK, compared to 12% with DMEK alone. ⁵⁶ It has been theorized that the incidence of CME might be higher after DMEK than DSEK due to increased surgical manipulation in the anterior chamber. More inflammatory mediators may be liberated after iris trauma with flatter anterior chambers and fluid wave generation. However, Pedemonte, et al reported an 11% post-DSEK CME rate, similar to the DMEK reported rates. ^56,63

There is some discussion as to whether simultaneous cataract surgery (triple procedure) might increase the incidence of postoperative CME.^51,55 This has not been well-studied yet in a prospective fashion; while Heinzelmann et al. found a small variation in the rate, the study was not sufficiently powered to demonstrate a statistically significant difference. ⁵⁶ Other studies have failed to show a significant difference in CME whether the EK is performed by itself of when coupled with cataract extraction. ^54,56,59 Interestingly, Birbal et al found no difference in the incidence of CME regardless of the lens status at the time of DMEK in a series of 1000 eyes (of which 25.6% were phakic), though no lens surgery was performed concomitantly with DMEK. ⁶⁵

Treatment

Postoperative CME typically resolves and does not have a long-lasting sequela, with most patients attaining good visual outcomes. ⁵⁹ Most studies confirm that a combination of topical steroids and NSAIDs will lead to CME resolution. ⁶⁶ Should the topical therapy fail, sub-Tenon’s or intravitreal injections of short-acting steroids or longer-acting steroid implants may be considered. ⁶⁷ Care should be taken to avoid steroid implants in unicameral eyes or eyes with the absence of the lens capsule or zonular issues as these eyes may experience anterior migration of the implant which could threaten the graft. ⁶⁸ The visual prognosis in patients who develop CME is often excellent, and when appropriately treated, often achieve favorable visual outcomes comparable to patients who did not experience this post-operative complication. ⁶⁶

Prevention

A study performed by Hoerster et al, found that an early, intensified steroid regimen in the postoperative period for DMEKs with simultaneous cataract extraction decreased the incidence of postoperative CME from to 12% to 0%. The authors had previously prescribed topical steroids five times daily but later switched to hourly topical postoperative steroids during the first week.⁵⁷

Given the concern for possible increased postoperative CME, some surgeons will consider sequential rather than combined surgery. Cataract surgery can be performed a few months before the EK or vice versa. Performing an EK first may lead to improved refractive outcomes due to increased accuracy of corneal power estimation after the corneal pathology has been resolved. ⁷

Graft dislocation into the posterior segment

Incidence and causes

Though the frequency of graft detachment, or non-adherence, varies with DSEKs (0-14.5%) and DMEKs (2.4-82%), the exact incidence of posterior dislocation into the vitreous cavity is unknown.^4,5 It is likely rare, but there may be an underreporting bias. ^69–71 For posterior dislocation to occur, a combination of graft non-adherence and a lack of an iris-lens diaphragm is usually necessary. This is most commonly seen in eyes with a marked alteration in the anterior segment anatomy, such as those with a history of trauma, multiple surgeries, or congenital aniridia. ^10,72

Treatment

Even though spontaneous reattachment has been reported, early retrieval and reattachment is usually preferred. ⁷³ It is thought that earlier intervention increases the chances of graft survival, ensuring a clearer cornea for surgical visualization, and decreases the risk of complications such as retinal detachment. ^74–76 If the posterior dislocation occurs at the time of initial corneal graft implantation, a vitreoretinal surgeon can immediately retrieve the graft with forceps and allow the cornea surgeon to re-attach the graft. ⁷⁷ If the graft dislocates later, especially if the graft has suffered trauma, a new EK or PKP graft can be considered. ⁷⁶

Prevention

To avoid posterior dislocation, creating a scaffold can help prevent (but not eliminate) the risk of posterior dislocation. Correction of aphakia and/or aniridia before or at the time of EK is something that can be done to improve safety. ^70,78,79 Even a temporary scaffold, such as a hydrophilic methacrylate sheet, can help prevent the graft from migrating to the posterior pole during surgery. ⁸⁰ Other approaches involve placing scaffolding or safety sutures, using a pars plana infusion site, and tamponading with longer-acting gases. A trans-corneal fixation or a temporary “lifeline” safety suture, can be placed in a DSEK graft to anchor it; unfortunately, DMEK grafts are too thin to be sutured. ^81,82 Another technique that can be applied to DMEKs is inserting a pars plana infusion during surgery, which changes the fluid dynamics in the anterior chamber, making it less likely for the graft to migrate posteriorly. ^83,84 Longer-acting gases like sulfa hexafluoride (SF6) can help increase graft adherence and decrease the chance of detachment and subsequent posterior migration. ⁸⁵

Vitreous in the Anterior Chamber

Incidence and causes

Eyes with a history of complex cataract surgery, pseudophakic bullous keratopathy, zonular insufficiency or unstable intraocular lenses may have vitreous prolapse at the time of EK surgery. This can lead to graft non-adherence, graft failure, and possibly retinal detachment in the postoperative period. The exact incidence is unknown.

Treatment

If there is suspicion for vitreous prolapse into the anterior chamber at the time of EK, the corneal surgeon should consider staining with triamcinolone to confirm its presence. Once confirmed, an anterior vitrectomy, done through an anterior or pars plana approach should be performed. Any lens instability should be identified and rectified.

Prevention

Eyes with posterior pressure may be at greater risk of vitreous prolapse during surgery if the anterior chamber is not maintained adequately. A thorough preoperative slit lamp and posterior segment examination should be performed with the potential use of B-scan ultrasonography if the view is inadequate. If vitreous prolapse is identified preoperatively, a concomitant anterior or posterior vitrectomy may be planned prior to surgery. ⁸⁶

Choroidal Detachment

Incidence and causes

Cases of choroidal detachment following EK are seldomly reported in the literature, but the incidence has been estimated to be about 0.05%. ^9,87,88 Most detachments are hemorrhagic, but serous detachments are also possible. Hemorrhagic choroidal detachments, while uncommon, can be potentially devastating if severe. Though there are no studies documenting the comparative risks of choroidal hemorrhage with EK compared to PK, it is felt that the risks are lower as EK is not an open sky procedure. In EK, as in other intraocular surgeries, it is believed that advanced age, systemic hypertension, high myopia, concomitant glaucoma filtering procedures, aphakia, and the use of anti-clotting agents may be risk factors for this condition. ⁸⁹

Treatment

Serous choroidal detachment may be seen in cases with post-operative hypotony and often resolves with conservative management with cycloplegics and topical steroids. Operative wounds should be inspected and treated for persistent leaks. Hemorrhagic choroidal detachments can be managed with observation or with drainage in the operating room. The decision to observe or intervene often depends on the extent on the detachment and the visual potential. When performed in the operating room, drainage may be performed with an anterior chamber infusion though care should be taken not to direct the infusion stream at the graft as it may result in detachment or damage to the endothelial cells. Drainage can be performed between 4 to 8mm posterior to the limbus with a needle, trocar blade, or cut-down approach.

Prevention

There are no clear methods to ensure prevention of choroidal detachments. Reasonable measures that can be taken, however, are to decrease operative time, inspect all wounds for leaks, and try to avoid prolonged periods of hypotony. ⁹⁰

Retinal detachment

Incidence and causes

The largest retrospective study to report on the incidence of retinal detachment following EK disclosed a rate of between 0.5-1% at one year. ⁹ These rates varied according to EK indication, with 0.5% for Fuchs and up to 1.6% in cases of bullous keratopathy, which probably reflects the more altered anatomy and trauma of eyes with prior intraocular surgeries. This appear consistent with the risk of retinal detachment after other intraocular anterior segment surgeries, such as cataract surgery, and may occur secondary to induction of a posterior vitreous detachment by the initial surgery. Eyes with concomitant complex cataract extraction with vitreous loss may be at greater risk. It has been suggested that posterior migration of an EK graft may be a risk factor for retinal detachment. ⁷⁵

Treatment

As with any retinal detachment surgery, intraoperative visualization is key to achieving anatomic success. In those eyes with a poor view through a hazy cornea, adjunctive measures such as hyperosmotic agents with or without the placement of a bandage contact lens may be attempted to clear the cornea. Temporary placement of viscoelastic in the anterior chamber may also improve the view. As a last resort, the epithelium may be debrided or a full thickness temporary keratoprosthesis can be placed followed by a permanent penetrating keratoplasty if visualization is still limited after more conservative measures. The use of adjunctive periocular, intravitreal or systemic corticosteroids may be considered to decrease post-operative inflammation and potentially lower the likelihood of a subsequent graft rejection.

Prevention

In cases of concomitant complex cataract extraction with vitreous loss, the cornea surgeon may consider a combined approach with a vitreoretinal surgeon to ensure that the periphery is examined for retinal breaks and all vitreous traction have been treated. In cases of posterior dislocation of the EK graft, retrieval should be performed by a vitreoretinal surgeon with either a soft tip cannula or forceps, per surgeon preference. And a complete vitrectomy with a detailed peripheral examination should be performed.

DIFFERENCES BETWEEN KERATOPLASTY TYPES

The types of complications that occur after EK and PKP are similar, but EKs tend to have a lower incidence. Borkar, et al demonstrated that bacterial endophthalmitis is more common with PKPs than EKs, but fungal keratitis/endophthalmitis is more common with EKs. ²² As previously mentioned, CME occurs with all types of grafts. ^55,91 There is insufficient data on PDEK and other emerging EK techniques to make adequate comparisons with them; the EBAA report of 2018 disclosed only 26 tissues used for PDEK. Using the Singapore Corneal transplant registry, Woo et al. reported increased graft survival, less rejections rates, lower incidence of ocular hypertension, and better vision with DMEK compared to DSEK and PKPs; posterior segment complications were not specified.²¹

Future Directions

Descemet’s stripping only (DSO), also referred to as Descemet’s stripping without endothelial keratoplasty (DWEK), is a novel approach to certain endothelial pathologies. It consists of performing a central descetometorhexis and allowing the healthy peripheral endothelium to grow centripetally. ^92,93 DSO is usually aided by the use of topical Rho kinase inhibitors. ⁹⁴ Unfortunately, not everyone is a candidate, and the procedure is presently limited to patients with Fuchs endothelial dystrophy, namely in eyes with healthy peripheral endothelium. DSO is not free of complications, but the lack of an allogeneic graft, minimal intraoperative manipulation, and the shorter surgical times essentially eliminate the risk of dislocation and graft rejection and may decrease the risk of postoperative infections and choroidal detachments. Various types of cell injection therapies are being studied, but large sets of clinical data are not yet available to study the potential adverse effects. ⁹⁵

Conclusions

While posterior segment complications of endothelial keratoplasty are less common than anterior complications such as graft dehiscence or graft failure, early recognition and earlier treatment of these potentially sight-limiting complications may lead to better visual outcomes. A multi-disciplinary approach may be necessary for recalcitrant CME, retinal detachments, posteriorly dislocated grafts, or endophthalmitis. Familiarity with these potential complications may aid in their prevention.