13 Bullous Keratopathy and Endothelial Keratoplasty Abstract Persistent corneal stromal edema with associated epithelial bullae following intraocular surgery is termed corneal decompensation or bullous keratopathy. This may account for a suboptimal outcome following cataract surgery. Identifying a patient at risk of corneal decompensation allows for appropriate counseling in relation to the increased risk of an adverse outcome, and management options should that adverse outcome occur. This chapter describes the clinical features of bullous keratopathy and how to identify a patient at risk of developing bullous keratopathy. Surgical considerations such as preoperative workup, intraocular lens selection, and appropriate modifications to cataract surgery for these patients will be discussed. The chapter will also address the diagnosis and management of bullous keratopathy. Keywords: bullous keratopathy, corneal edema, endothelial cell loss, endothelial dystrophy, endothelial keratoplasty, Descemet’s stripping automated endothelial keratoplasty, Descemet’s membrane endothelial keratoplasty Persistent corneal stromal edema following intraocular surgery with associated epithelial bullae is termed bullous keratopathy. The term aphakic or pseudophakic is added, depending on the lens status of the eye (ABK/PBK). These conditions are characterized by endothelial cell compromise causing pain and loss of vision. ABK and PBK are important causes of poor visual outcomes following cataract surgery, and are a leading indication for keratoplasty.1 Frequent causes of corneal endothelial failure include prior intraocular surgery, corneal endothelial dystrophy, or failure of an existing corneal transplant. Other less common causes include trauma, acute-angle closure glaucoma, and iridocorneal endothelial syndrome. Certain conditions, such as prior ocular trauma, prolonged or complicated cataract surgery, retained crystalline lens fragments, toxic anterior segment syndrome (TASS), unstable intraocular lenses (IOLs), or glaucoma drainage devices, may increase the risk of significant endothelial cell loss, although all intraocular surgery would be expected to cause some cell loss. Bullous keratopathy may account for a suboptimal outcome following cataract surgery in patients with or without risk factors. If a patient does have risk factors, preoperative counseling and surgical planning are essential in achieving the best possible outcome for the patient. If bullous keratopathy does occur, a good outcome with a satisfied patient will depend on good communication and appropriate management. Patients with preexisting corneal endothelial cell failure might benefit from a combined procedure, most commonly cataract surgery combined with endothelial keratoplasty (EK). If cataract surgery is planned alone, intraocular surgery may be modified to reduce the chance of further endothelial cell loss. If endothelial cell failure does occur and persist, then EK might be considered as a secondary procedure. Identifying risk factors, performing preoperative workup, modifying cataract surgery, selecting an appropriate IOL, and diagnosing and managing postcataract surgery bullous keratopathy will be the focus of this chapter. Careful examination of the cornea is an important part of the preoperative workup for cataract surgery. Identifying a patient at risk allows for appropriate counseling in relation to the increased risk of the procedure, potential for adverse outcome, and management options should that adverse outcome occur. Preoperative Considerations • Corneal guttata. • Pseudoexfoliation (PXF). • Angle-closure glaucoma. • Density of cataract. • Corneal endothelial dystrophy: • Postinfectious: • Postintraocular surgery: • Past ocular trauma. • Iridocorneal endothelial syndrome. The most important factors to identify preoperatively are the presence of corneal guttata and/or abnormalities in endothelial cell count or morphology. A history of prior intraocular surgery, acute-angle closure glaucoma, ocular trauma, or previous significant corneal infections might suggest increased risk, prompting further investigation. Preoperative slit-lamp examination would routinely be used to assess type and density of cataract, and any specific challenging features. Risk factors for corneal edema should be considered at the same time. Corneal guttae are small excrescences on Descemet’s membrane (DM) that occur due to overproduction of basement membrane ( Corneal guttae are best identified at the slit lamp on retroillumination with a dilated pupil ( Pseudoexfoliation (PXF) syndrome is an important risk factor to identify due to the increased risk of surgical complication, as well as an association with abnormal DM and increased rate of endothelial cell loss.3 Early identification of these risk factors allows for counseling of the patient prior to cataract surgery, consideration of appropriate surgical modifications, selection of an appropriate IOL, and/or consideration of cataract surgery combined with corneal transplant procedure. The surgeon and patient should discuss the severity and impact of both the cataract and the corneal endothelial disease. Symptoms such as early morning blur that clears throughout the day and difficulty driving at night may indicate symptomatic endothelial cell disease. The visual requirements of the patient and clinical features of both their cataract and corneal disease will help determine the most appropriate procedure, whether that be cataract surgery alone or cataract surgery combined with EK. Fig. 13.1 Slit-lamp photo demonstrating corneal guttata. Once a patient has been identified as at increased risk for corneal endothelial cell failure, further preoperative investigation is warranted. Central corneal thickness should be measured and documented. Specular microscopy may be beneficial, not only to quantify risk, but also to aid in patient counseling. Endothelial cell density and morphology can be considered ( Accuracy of biometry is often reduced in the setting of endothelial disease. This may lead to difficulty in IOL selection. Biometry should be performed as early as possible on patients with potential for corneal decompensation, ideally prior to progression of their corneal disease. It may also be useful to compare the biometry to the other eye, which may have a more normal endothelial appearance. Keratometry values are difficult to quantify, and particularly axis of astigmatism can be difficult in the presence of endothelial disease. Measuring keratometry values by multiple methods is recommended. The various factors that influence the decision to perform a cataract surgery alone versus the combined procedure are highlighted. Fig. 13.3 Specular microscopy in a patient with a low endothelial cell count and a high degree of polymegathism and pleomorphism. Fig. 13.4 Specular microscopy showing midperipheral corneal guttata with healthy intervening corneal endothelial cells. Fig. 13.5 Specular microscopy showing more advanced central corneal guttata with minimal intervening endothelial cells. Preoperative Investigations • Central corneal thickness. • Specular microscopy. • Biometry. • Corneal tomography/topography. • Manual keratometry. Factors Influencing Decision to do Cataract Surgery Alone versus Combined Procedure • Severity and impact of each feature. • Symptoms (early morning blur). • Visual requirements of patient. • Degree/confluence of guttata. • Increasing/asymmetric corneal thickness. • Epithelial or stromal edema. IOL selection is complex in the presence of corneal endothelial disease, due to a difficulty in gaining accurate preoperative measurements, as well as the uncertain effect on corneal function and therefore power postoperatively. In addition, if the patient goes on to require EK, the corneal power will further change, and that change will be unpredictable. General considerations include the type of IOL, the material of the IOL, and the power. Monofocal IOLs are usually appropriate. Multifocal IOLs and extended depth of focus IOLs are generally not recommended for patients with endothelial cell compromise. Toric IOLs may have a place, and should be considered on a case-by-case basis depending on accuracy and reproducibility of measurements. Hydrophilic material is known to have the potential to opacify when it comes into contact with air or gas. There have been several cases reported of IOL opacity post-EK in patients with hydrophilic IOLs.4 It is therefore recommended to avoid hydrophilic IOLs in patients who may go on to require EK in the future. EK is associated with a hyperopic shift, of varying magnitude. The reason for this is multifactorial, and includes the addition of a concave lenticule (in the case of DSAEK), and an unpredictable amount of corneal deturgescence with Descemet’s stripping automated endothelial keratoplasty (DSAEK) and DM endothelial keratoplasty (DMEK). Up to 1.5-diopter hyperopic shift in spherical equivalent has been reported after DSAEK,5 and a lesser shift after ultrathin (UT) DSAEK6 and DMEK.7 The range is great, and predictability is difficult. Common targets for patients undergoing combined cataract surgery and EK would be −0.5 – −0.75 for DMEK and −0.75 – −1.5D for DSAEK or UT DSAEK. If the patient is undergoing cataract surgery alone, this hyperopic shift should still be taken into account, in case EK is required in the future. Surgeons should then aim to reduce the chance of postoperative hypermetropia where possible, by selecting a myopic target. Surgery can be adapted to minimize the endothelial cell loss during cataract surgery in patients who are at increased risk. Endothelial cell loss can be minimized by performing phacoemulsification away from the cornea in the iris plane and minimizing the phacoemulsification energy emitted. For dense cataracts, using a dispersive and cohesive ophthalmic viscoelastic device (OVD) with a soft-shell technique has been shown to lower endothelial cell loss at 3 months, when compared to a cohesive OVD alone.8,9 Advanced phacoemulsification technologies such as torsional ultrasound likely reduce the energy.10,11 Nuclear disassembly by phaco-chop as opposed to divide and conquer has been shown to be beneficial in the moderately dense cases.12 A number of different phacoemulsification hand-piece tips have been reported recently, but have not been shown to greatly alter endothelial cell loss.13 For very dense cataracts, manual small-incision cataract surgery (MSICS) might provide some advantage. However, a meta-analysis of randomized controlled trials found that there were no significant differences in endothelial cell loss between the two techniques. Phacoemulsification was superior to MSICS in uncorrected visual acuity and caused less surgically induced astigmatism.14,15,16 For all of these, technique adaptations, surgeon skill, and experience should be considered, as the most important factor is the avoidance of surgical complications. Several features of the irrigating solution may impact the endothelial cell loss. Time, volume, and chemical composition might be considered. No difference in endothelial cell loss at 6 months was found when fortified balanced salt solution (BSS) was compared with Ringer’s lactate irrigating solution.17 Solutions such as BSS Plus (glucose glutathione bicarbonate solution) approximate characteristics of aqueous humor and therefore might provide a theoretical advantage; however, Lucena et al found no significant difference in endothelial cell loss using Ringer’s solution when compared to BSS Plus.18 Intracameral medications such as anesthetic agents, mydriatic agents, and antibiotic agents are frequently used during cataract surgery. One must ensure that the correct concentration of any drug is used to avoid corneal toxicity. Preservative-free lidocaine from 0.1 to 0.5 mL has been found to show no change in endothelial cell count at 3 months, but higher concentrations can cause significant endothelial cell loss.19 Performing femtosecond laser-assisted cataract surgery (FLACS) can reduce the cumulative phacoemulsification energy needed to emulsify and extract a cataract.20 Whether FLACS causes significantly less endothelial cell loss in the long term compared to conventional cataract surgery is unclear.21,22,23 In a prospective comparative cohort study, corneal edema was significantly less with FLACS compared to conventional surgery at 1 day and 3 weeks postoperatively. However, the difference was negligible at 6 months. In the same study, FLACS had significantly less endothelial cell loss at 3 weeks but not at 6 months. Interestingly, eyes that had laser-automated corneal incisions had greater endothelial cell loss at 6 months than eyes with manual corneal incisions.23 A meta-analysis of 9 randomized controlled trials and 15 cohort studies suggested that FLACS is a safer and more effective method for reducing endothelial cell loss than conventional phacoemulsification surgery.24 It is important to note that this conclusion was based mainly on evidence at 3 months postoperatively and that few studies extended follow-up beyond that time. Cataract surgery complicated with vitreous loss is associated with increased endothelial cell loss, and an increased rate of corneal edema.25 Retained nuclear fragments in the anterior chamber can also lead to corneal decompensation.26 When the capsular support is lost, IOL placement must be considered. In a comparative study of IOL placement following complicated cataract surgery, there was no difference in the incidence of corneal decompensation following primary anterior chamber IOL (ACIOL; 12.4%) and secondary scleral-fixated IOL (10.8%) implantation.27 Corneal edema may occur in the early postoperative period after cataract surgery, and in many cases will resolve. Failure to resolve or start improving by 4 weeks postoperatively should start to raise the possibility of persisting bullous keratopathy. A differential diagnosis should be considered, especially if the findings are unexpected and if the patient did not have preexisting risk factors or complicated surgery. DM detachment is important to identify, as this is potentially reversible. DM detachment can be identified at the slit lamp by the presence of a double anterior chamber, particularly with a bright and narrow slit-lamp beam. Anterior segment ocular coherence tomography (ASOCT) may show the detachment. Reattachment may be possible with an injection of air. The surgical procedure and other patients on the same operating list might be considered to help rule out endothelial toxicity or toxic anterior segment syndrome (TASS). Raised intraocular pressure might be associated with microcystic corneal edema that may resolve on normalization of the IOP. Endophthalmitis is associated with pain as well as pan ocular inflammation.
13.1 Introduction
13.2 Risk Factor Identification
Fuchs’ endothelial corneal dystrophy.
Congenital hereditary endothelial dystrophy.
Posterior polymorphous dystrophy.
X-linked corneal endothelial dystrophy.
Herpes simplex virus.
Cytomegalovirus.
Number, type, and complexity of previous intraocular procedures.
Fig. 13.1). They may occur peripherally as part of normal aging, but are considered pathologic and are associated with Fuchs’ endothelial corneal dystrophy (FECD) when they occur centrally. In FECD, corneal guttae are often associated with progressive endothelial cell loss and corneal edema2 and this may be further exacerbated by intraocular surgery.
Fig. 13.2). Appearance is of a dimpled endothelium sometimes described as a beaten metal appearance. Guttata may be sporadic, diffuse, or confluent. Confluent guttae are more likely to be visually symptomatic than sporadic corneal guttata. Corneal edema is visible by either folds in DM, generalized haze, microcystic change, or opacity.
13.3 Preoperative Workup
Fig. 13.3, 
Fig. 13.4, 
Fig. 13.5).
13.4 Intraocular Lens Selection
13.5 Surgical Considerations
13.5.1 Diagnosis of Bullous Keratopathy
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Herpes zoster virus.
