Background

Corneal edema occurs for many reasons, but it is often a sequela of intraocular surgery. Corneal edema resulting from cataract extraction is called either pseudophakic bullous keratopathy (PBK) or aphakic bullous keratopathy (ABK). Knowledge of the structure of the cornea and the proper functioning of its layers is fundamental to understanding corneal edema.

Pathophysiology
Bullous keratopathy occurs when the corneal endothelium becomes damaged and, as a result, the cornea swells. The inner cell layer of the cornea, the endothelium, is responsible for maintaining the cornea in a relatively dehydrated state. As endothelial cells are damaged, the remaining cells rearrange themselves to cover the posterior corneal surface. The remaining endothelial cells become irregularly shaped and enlarged, and their pump functions begin to fail. As the endothelium becomes increasingly unable to act as a pump to deturgesce the cornea, the stroma begins to swell, especially in the central cornea. As the stroma swells, the cornea thickens and folds are seen in the Descemet membrane. The edema may fluctuate in response to changing intraocular pressure with higher pressures leading to more edema. At this point, maintenance of intraocular pressure at a low level is important. The combination of variable endothelial function and variable intraocular pressure determines the extent of corneal edema. Epithelial edema manifests as fluid accumulation between the basal epithelial cells. With increased fluid accumulation, blisters and then bullae develop. Epithelial edema may result from anterior movement of aqueous and fluid in the stroma driven by intraocular pressure. With a small amount of epithelial edema, environmental factors (eg, temperature, humidity) may affect evaporation of tears with blinking. At night with the eye closed, epithelial edema typically worsens due to a lack of tear evaporation. This results in symptoms that are generally worse in the morning hours. Patients with bullous keratopathy demonstrate decreased visual acuity and can have symptoms of pain or discomfort. Decreased visual acuity is related to the inability of the stroma to maintain its deturgescence, which often is followed by epithelial edema. Epithelial edema can be responsible for great changes in visual acuity due to irregularity in the corneal refractive surface. Examination with contact lens over refraction may be the best way to confirm the status of the posterior segment. Pain associated with bullous keratopathy can be due to swelling of the epithelium with resultant stretching of corneal nerves or rupture of bullae with exposure of corneal nerve endings to an often noxious environment. Bullae rupture results in pain, photophobia, and epiphora. Subsequent epithelial defects predispose the cornea to infection and can contribute to the development of anterior uveitis.

Epidemiology
Frequency
United States Prior to implantation of intraocular lenses, in the era of intracapsular cataract extraction and postoperative aphakia, the rate of ABK was reported to be less than 1% in uncomplicated cases without vitreous loss. Early results with implantation of anterior chamber intraocular lenses by Barraquer in the 1950s, while initially promising, ultimately resulted in corneal decompensation in half of the postoperative eyes. As intraocular lenses have evolved, these rates have steadily dropped. In the modern era, numerous closed loop anterior chamber intraocular lenses have consistently resulted in an elevated risk of PBK relative to flexible open loop anterior chamber and posterior chamber intraocular lenses. Despite improved surgical techniques, PBK remains a leading indication for penetrating keratoplasty because of the high volume of cataract surgery performed. Several studies in the 1980s demonstrated rates of corneal decompensation after uncomplicated extracapsular cataract extraction with posterior chamber intraocular lens placement to be 0.1-0.5%. In the setting of vitreous loss, the rate of corneal edema 4 years postoperatively has been reported to increase to 2.4%.

Mortality/Morbidity
Corneal bullae may cause pain.

Age
Most cataract surgery is performed after age 65 years; thus, this condition is more frequent in elderly persons.

History
By definition, bullous keratopathy occurs after cataract extraction. The edema may be present immediately after cataract surgery, or it may occur years later. Typical symptoms include poor vision and discomfort or pain. Mild stromal edema alone does not cause severe visual loss. However, mild epithelial edema can cause a significant drop in vision. Stromal edema alone does not cause much, if any, discomfort. Mild epithelial edema causes some discomfort, while epithelial bullae and especially ruptured bullae can cause moderate to severe pain.

Physical
The cornea consists of 5 layers, as follows: The first or outermost layer is a multilayered epithelial sheet of superficial nonkeratinized stratified squamous epithelium, covering 2-3 layers of closely packed transitional cells, and a basal layer of columnar cells anchored to the underlying basement membrane. The second layer, called the Bowman layer, is made of collagen fibrils. The third layer is the stroma, which is made of collagen producing fibroblasts, ground substance, and collagen lamellae. This layer accounts for 90% of the corneal thickness. The fourth layer is the Descemet membrane, which is the basement layer of the corneal endothelium. Part of it is formed in utero, while part is laid down by the corneal endothelium throughout life. The fifth or innermost layer is the endothelium, which is a single layer of hexagonal cells that face the anterior chamber with their basal surfaces against the Descemet membrane.

Physiology
The endothelium is responsible for maintaining the deturgescence of the corneal stroma. Endothelial cells do not divide well. Thus, the number of endothelial cells is maximal at birth and decreases naturally as the body ages. As the number of endothelial cells decreases, the degree of pleomorphism (cells of different shapes) and polymegathism (cells of different sizes) increases. The remaining endothelial cells spread and thin out over the inner corneal surface. Although cell density decreases due to cataract extraction, intraocular lens implantation, clear corneal transplants, increased intraocular pressure, and ocular inflammation, it is not solely the decrease in endothelial cells that determines corneal swelling. Hydration of the cornea is kept in balance by multiple opposing forces. The epithelium and the endothelium restrict rapid fluid movements. Both the corneal epithelium and endothelium are now known to be permeable to solutes and act as imperfect semipermeable barriers. The resistance to electrolytes in the epithelium is about 100 times higher than in the endothelium. The tendency of the stroma to swell is termed the swelling pressure, which tends to pull fluid into the cornea. The swelling pressure is counteracted by the intraocular pressure, which tends to flatten the cornea and thus decreases the imbibition of fluid into the cornea. The endothelial pump secretes sodium and bicarbonate into the aqueous humor, providing the osmotic pressure to pull water out of the corneal stroma. This is counterbalanced by the swelling pressure, which tends to pull water into the cornea. When the endothelium is compromised, as in the case of pseudophakic bullous keratopathy, the ability of the endothelium to maintain osmotic pressure begins to fail. As the corneal stroma imbibes fluid, it begins to thicken, causing folds to develop in the Descemet membrane. The corneal epithelium can also become edematous. Corneal epithelial edema appears to be a function of intraocular pressure. In cases of high intraocular pressure, epithelial edema can develop with little or no stromal edema, as in the case of angle-closure glaucoma. Alternatively, in an eye with hypotony and advanced pseudophakic bullous keratopathy, there can be no epithelial edema even though there is extensive stromal edema. It appears that intraocular pressure causes the edema to advance to more superficial layers. Clinically, epithelial edema is characterized by fluid-filled cysts or bullae between epithelial cells. Epithelial edema is typically seen

in more advanced cases of pseudophakic bullous keratopathy, and these bullae frequently cause pain.

Causes
Preoperative risk factors Preoperative clinical specular microscopy is used to examine the quality and quantity of endothelial cells. In using this tool, no correlation has been found between the preoperative endothelial cell density or degree of postoperative cell loss and the subsequent development of corneal edema. Significant correlation has been found between variation in cell shape and size and the development of postoperative corneal edema. Endothelium with a greater degree of pleomorphism reacts more adversely to intraocular surgery and requires a longer time for corneal deturgescence. As corneal deturgescence is maintained by the metabolic pump of endothelial cells and by tight cellular junctions, cells with greater variation in size may not fit together as well, leaving gaps and compromising the endothelial structural barrier. Patients with Fuchs' endothelial corneal dystrophy which characterized by corneal guttata on histopathologic examination have a higher incidence of PBK. Pseudoexfoliation syndrome has been associated with an increased incidence of PBK. Intraoperative risk factors Surgical trauma, most commonly during cataract extraction, can damage the endothelium, causing a period of postoperative edema that resolves in most cases. Knowledge of the preoperative status of corneal endothelium may prompt the surgeon to take additional measure to reduce this complication. The type of cataract surgery also has an impact on how much trauma occurs to the endothelium and the resultant pseudophakic or aphakic corneal edema (see Frequency). Lenses made of polymethylmethacrylate adhere instantaneously to the endothelial surface when contact upon lens insertion occurs. With subsequent separation of the 2 surfaces, the anterior membranes of the endothelial cells are torn off. Viscoelastics can be used to reduce touch between the cornea and the intraocular lens during lens insertion. By initially deepening the anterior chamber, the risk of endothelial damage in the event of chamber shallowing is minimized. Reusable cannulas with viscoelastic can result in toxic residues being introduced into the eye; therefore, disposable cannulas should be used whenever possible. A comparison of viscoelastic substances showed that no difference occurred in endothelial cell count, iritis, or corneal edema after cataract surgery with polymethylmethacrylate intraocular lens placement using either polyacrylamide or sodium hyaluronate. It has also been found that methylcellulose does not protect the corneal endothelium as effectively as sodium hyaluronate during phacoemulsification. The protective benefit of sodium hyaluronate is improved further when used in combination with chondroitin sulfate (making Viscoat). While mechanical trauma to the endothelium during surgery is considered to be the most significant factor influencing postoperative corneal edema, other factors can adversely affect the endothelium. Toxic substances used to disinfect instruments may inadvertently be introduced into the eye if inadequate rinsing of instruments allows some of the substances to remain in the small lumens of the instruments. Water, not saline, should be used to rinse the instruments. Intraocular irrigation solutions must be appropriate; otherwise, endothelial injury and corneal edema will occur. Increasingly, topical and intracameral anesthesia have gained popularity and must be used appropriately. Up to 0.5 mL of 1% preservative-free lidocaine has been shown to result in no change of endothelial cell count at 3 months postoperatively, while numerous other preparations of lidocaine and other anesthetics have resulted in significant endothelial cell loss and corneal toxicity. Intraocular medications that have resulted in corneal toxicity include epinephrine (now available preservative free), benzalkonium chloride-preserved viscoelastic, vancomycin at doses greater than 1 mg/mL, and inadvertent exposure of the endothelium to 5% povidone-iodine. Detachment of the Descemet membrane, possibly more common with clear corneal incisions, will result in postoperative corneal edema. Postoperative causes Routine uncomplicated phacoemulsification surgery has been reported to result in 9% endothelial cell loss at 1 year postoperatively. Regardless of what surgery type was used and whether an intraocular lens is implanted, continuing endothelial loss of greater than the usual 1% per year occurs in patients who have undergone cataract extraction. Corneal edema usually develops within 1 year after the endothelial cell density

falls below 500 cells/mm, but no absolute lower limit to the number of cells has been found to be associated with stromal edema. The type of lens implanted is also significant in determining the amount of endothelial cell loss over time. Persistent low-grade inflammation and intermittent contact of the implant with the corneal endothelium may be causes of PBK. Iris supported lenses may cause greater endothelial loss as high-speed photographic evaluation of them indicates that they can contact the endothelium during ocular saccades. Anterior chamber lenses of the closed loop design have been responsible for a large amount of corneal pathology, while open loop design lenses have been shown to have a significantly lower rate of complications and subsequent explantation.

Differential Diagnoses
Corneal Edema, Postoperative Dystrophy, Fuchs Endothelial

Procedures
A number of studies can be helpful in confirming the diagnosis and in offering a reasonable prognosis for the patient. A thorough slit lamp examination, confirming increased corneal stromal edema with the Descemet folds and, perhaps, secondary epithelial edema, is most important. Pachymetry readings obtained either by optical methods or with ultrasound can confirm increases in corneal thickness. Central pachymetry values in excess of 590 microns in a pseudophakic eye may be associated with irreversible corneal edema. Specular microscopic studies can also be used to determine the endothelial cell morphology. In the final analysis, visual acuity and the patient's level of functional capacity determine the prognosis. Quite often, corneal edema, while progressive, can afford reasonable levels of visual acuity for many years. Consequently, surgical intervention should be based more upon the patient's needs than upon the degree of corneal decompensation.

Medical Care
Therapy for pseudophakic bullous keratopathy (PBK) and aphakic bullous keratopathy (ABK) is performed to reduce discomfort and/or to improve visual acuity. The corneal edema associated with bullous keratopathy is chronic and usually noninflammatory. A number of treatment options are available. The reduction of intraocular pressure is an important treatment for corneal edema, because increased intraocular pressure can compromise endothelial function and lead to epithelial edema and further endothelial damage. Topical antiglaucomatous medications can help to reduce pressure and can give the endothelium the best chance to deturgesce the cornea. Epinephrine derivatives should be avoided because of the risk of cystoid macular edema. Epithelial edema often can be managed with topical hypertonic agents such as sodium chloride (5%) ointment or drops. In a study to evaluate efficacy, visual acuity was used as the only parameter to monitor therapeutic efficacy. While 61% of eyes had improved visual acuity on the medication, this group included patients with other causes for corneal edema. One third of patients with bullous keratopathy had improvement in visual acuity. Improvement was demonstrated following use of the medication for 3 months. Hydrophilic contact lenses, on an extended-wear basis, can be used to decrease pain associated with epithelial bullae. While these lenses do not reduce the amount of edema, they can improve visual acuity to the extent that they mask surface irregularity. o Hydrophilic extended-wear contact lenses used in association with 5% hypertonic saline can be used as a hypertonic reservoir to constantly bathe the cornea, and, in some cases, they can improve visual acuity by decreasing epithelial and stromal edema. In this way, a lens plus hypertonic saline can compensate for defective surface dehydration. o Pain associated with bullous keratopathy can be due to rupture of the bullae with exposure of corneal nerve endings or swelling of the epithelium, leading to the stretching of nerve endings.

As mentioned earlier, pain associated with bullous keratopathy can be due to rupture of bullae with exposure of corneal nerve endings. Extended-wear hydrophilic bandage lenses can alleviate pain as long as the lens remains in place. It is thought that the lens acts as an effective precorneal protective layer and shields the abnormal epithelium from the environment, preventing bullae from bursting. The lens does not prevent the formation of bullae, but perhaps when new bullae do occur, the corneal nerve endings are not exposed to drying and other noxious stimuli because the lens covers them. Fitting of the lens is an important consideration. Lenses that have excessive movement can further irritate the epithelium and can be uncomfortable. Lenses that are too tight can act as a suction cup and result in inflammation and even anterior uveitis (tight lens syndrome). Furthermore, a greater risk of corneal infection may exist when a bandage contact lens is used in an eye with corneal edema. In the presence of low-grade inflammation, topical steroids can be useful, since low-grade anterior uveitis, not infrequently, is associated with chronic corneal edema.

Surgical Care
Surgical treatments for bullous keratopathy include enucleation or evisceration, retrobulbar alcohol injection, conjunctival flap, cauterization of the Bowman layer, anterior stromal micropuncture, excimer laser phototherapeutic keratectomy (PTK), annular keratotomy, penetrating keratoplasty, and Descemet stripping automated endothelial keratoplasty (DSAEK). A conjunctival flap is an excellent procedure to decrease pain in eyes with painful bullous keratopathy. With the Gunderson-type flap, the surgeon undermines the superior bulbar conjunctiva and moves in and down to cover the cornea with intact "bridges" nasally and temporally. Amniotic membrane has been used successfully to cover swollen corneas and to decrease pain. Neither of these procedures is designed to improve the vision. Cauterization of the Bowman layer is performed for pain relief. This procedure is thought to produce a dense fibrous barrier between the corneal stroma and the epithelium so that fluid cannot permeate into the epithelial cells and produce bullous changes. Anterior stromal micropuncture and excimer laser PTK also have been used with some success to cause scarring of the superficial cornea and to decrease pain. Annular keratotomy has been used to treat the pain associated with bullous keratopathy in eyes with poor visual potential. A partial-thickness corneal incision is made with a trephine and relieves pain by severing branches of corneal ciliary nerves to decrease corneal sensation. Penetrating keratoplasty and, more recently, DSAEK, in which the diseased corneal endothelium is replaced with healthy donor endothelium, are the only surgical treatments that can relieve pain and restore visual acuity. DSAEK has been shown to have several advantages over traditional penetrating keratoplasty, including faster visual recovery time and more predictable refractive outcome.[1] Importantly, because DSAEK is based on selective component corneal transplantation, it potentially enables a single donor cornea to be used in the treatment of multiple patients whose pathology involves different corneal layers. Visual acuity in an eye with bullous keratopathy also may be affected by cystoid macular edema. In one study, cystoid macular edema was related to poor vision in 62% of those with visual acuity of less than 20/40 and in 36% of all patients treated with penetrating keratoplasty for PBK. Cystoid macular edema is thought to result from excessively traumatic intraocular surgery. In patients with PBK, the intraocular lens may be removed or exchanged at the time of transplant. Displaced lenses causing recurrent uveitis, closed loop, or anterior chamber iris supported lenses generally should be removed. Patients undergoing penetrating keratoplasty with and without intraocular lens removal or exchange fared similarly as far as visual acuity was concerned. Therefore, no adverse effect of retaining a securely fixated intraocular lens was present. Exchange for 1-piece anterior chamber intraocular lenses gives significantly better visual acuity than exchange for sutured posterior chamber intraocular lenses. When the original intraocular lens is retained, graft failure rate for posterior chamber intraocular lenses is less than that for anterior chamber and iris supported lenses. A prospective study of 27 patients with PBK who underwent penetrating keratoplasty, intraocular lens explantation, and secondary Verisyse intraocular lens implantation demonstrated less endothelial cell loss 1 year postoperatively with retropupillary enclavation of the intraocular lens as compared with intraocular lens enclavation in the anterior chamber. [2] The study found that the increased anterior chamber depth enabled by the posterior technique was correlated with greater endothelial cell preservation.[2]

o o

Improved surgical techniques of cataract extraction have resulted in a reduction in the number of bullous keratopathy cases; however, bullous keratopathy still continues to be a major indication for Keratoplasty. Keratoplasty techniques also have improved, but cystoid macular edema associated with previous intraocular surgery may limit improvement in visual acuity. The decision to proceed with keratoplasty or DSAEK must be made after weighing the risks of infection, secondary glaucoma, and graft rejection; however, Keratoplasty remains the treatment most likely to markedly improve visual acuity.

Medication Summary
The goal of medical treatment is to improve visual acuity by deturgescence of the edematous corneal epithelium.

Hypertonic agents
Class Summary
Hypertonic saline solution dehydrates the epithelium and tends to improve acuity.

5% Sodium chloride (Muro 128, Adsorbonac, SalineX, Ak-NaCl)

Dehydrates the cornea.

Inpatient & Outpatient Medications

Sodium chloride 5% Antibiotics to prevent infections for epithelial defects Intraocular pressure lowering agents to reduce corneal edema

Complications
With a deteriorating condition, corneal transplant may be necessary.

Prognosis
Significant corneal edema that persists for 3 months after cataract surgery is unlikely to resolve on its own.

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