AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 is caused by changes in the corneal endothelium, which allow the cornea to be in an abnormal state of hydration. 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. Any pathologic process that affects the endothelial cells results in cornea guttata due to overproduction of the Descemet membrane.

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. 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.

Patients with bullous keratopathy demonstrate decreased visual acuity and pain or discomfort. Decreased visual acuity is related to inability of the stroma to maintain 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. As the edema progresses, 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.

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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

By definition, this condition occurs after cataract extraction. The edema may be present immediately after cataract surgery or 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 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 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 deturgescence of the corneal stroma. Endothelial cells do not divide. 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 and polymegathism 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.
  • A damaged endothelial cell responds by producing a new Descemet membrane, which differs qualitatively from the cornea's original Descemet membrane. Irregularities in the density and surface characteristics of this new substance are referred to as cornea guttata. On slit lamp examination, these irregularities give a characteristic beaten silver appearance to the thickened Descemet membrane.
  • The endothelium also acts as a barrier, separating the stroma from the aqueous humor. Its prime function is to transfer, by way of a sodium/bicarbonate pump, water from the stroma into the aqueous humor, an energy dependent process that derives oxygen from the aqueous humor.

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.
  • An increased incidence of cornea guttata or Fuchs endothelial corneal dystrophy is seen on histopathologic examination of host corneal buttons removed during penetrating keratoplasty for 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 help 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% povidine-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 primary causes.
  • 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 need for subsequent explantation.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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, the basic 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 simple fact of corneal decompensation.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Therapy for PBK and ABK is performed to reduce discomfort or to increase 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.  
• • 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 an environment in which surface dehydration to help maintain deturgescence is defective.
  • 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 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. A Gunderson-type flap 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 
• 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 penetrating keratoplasty. Penetrating 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 penetrating keratoplasty must be made after weighing the risks of infection, secondary glaucoma, and graft rejection; however, penetrating keratoplasty remains the treatment most likely to markedly improve visual acuity.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Drug Category: Hypertonic agents

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

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Patients should receive follow-up care 24-48 hours until the epithelial defect heals; otherwise, follow-up care should be scheduled every 1-6 months, depending on symptoms.

In/Out Patient Meds

• Sodium chloride 5%
• Antibiotics to prevent infections for epithelial defect
• Intraocular pressure lowering agents to reduce corneal edema when bandage contact lenses are used

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Early detection and treatment may prevent worsening of the condition. Patients may perceive the development of corneal decompensation to be a result of malpractice that occurred during the cataract surgery.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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2. Gicquel JJ, Guigou S, Bejjani RA, Briat B, Ellies P, Dighiero P. Ultrasound biomicroscopy study of the Verisyse aphakic intraocular lens combined with penetrating keratoplasty in pseudophakic bullous keratopathy. J Cataract Refract Surg. Mar 2007;33(3):455-64. [Medline].
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18. Kozarsky AM, Stopak S, Waring GO 3rd, Stulting RD, Wilson LA, Cavanagh HD, et al. Results of penetrating keratoplasty for pseudophakic corneal edema with retention of intraocular lens. Ophthalmology. Oct 1984;91(10):1141-6. [Medline].
19. Leibowitz HM, Rosenthal P. Hydrophilic contact lenses in corneal disease. II. Bullous keratopathy. Arch Ophthalmol. Mar 1971;85(3):283-5. [Medline].
20. Marisi A, Aquavella JV. Hypertonic saline solution in corneal edema. Ann Ophthalmol. Feb 1975;7(2):229-33. [Medline].
21. Mortimer C, Sutton H, Henderson C. Efficacy of polyacrylamide vs. sodium hyaluronate in cataract surgery. Can J Ophthalmol. Apr 1991;26(3):144-7. [Medline].
22. Pedersen OO. Comparison of the protective effects of methylcellulose and sodium hyaluronate on corneal swelling following phacoemulsification of senile cataracts. J Cataract Refract Surg. Sep 1990;16(5):594-6. [Medline].
23. Rao GN, Aquavella JV, Goldberg SH, Berk SL. Pseudophakic bullous keratopathy. Relationship to preoperative corneal endothelial status. Ophthalmology. Oct 1984;91(10):1135-40. [Medline].
24. Rao GN, John T, Ishida N, Aquavella JV. Recovery of corneal sensitivity in grafts following penetrating keratoplasty. Ophthalmology. Oct 1985;92(10):1408-11. [Medline].
25. Schraepen P, Koppen C, Tassignon MJ. Visual acuity after penetrating keratoplasty for pseudophakic and aphakic bullous keratopathy. J Cataract Refract Surg. Mar 2003;29(3):482-6. [Medline].
26. Smith RE, McDonald HR, Nesburn AB, Minckler DS. Penetrating keratoplasty: changing indications, 1947 to 1978. Arch Ophthalmol. Jul 1980;98(7):1226-9. [Medline].
27. Sugar A. An analysis of corneal endothelial and graft survival in pseudophakic bullous keratopathy. Trans Am Ophthalmol Soc. 1989;87:762-801. [Medline].
28. Takahashi GH, Leibowitz HM. Hydrophilic contact lenses in corneal disease. 3. Topical hypertonic saline therapy in bullous keratopathy. Arch Ophthalmol. Aug 1971;86(2):133-7. [Medline].
29. Vajpayee RB, Sharma N, Jhanji V, Titiyal JS, Tandon R. One donor cornea for 3 recipients: a new concept for corneal transplantation surgery. Arch Ophthalmol. Apr 2007;125(4):552-4. [Medline].
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Article Last Updated: Feb 19, 2008