Corneal edema refers to the accumulation of excess fluid in the corneal layers, with a loss of corneal clarity, resulting in vision loss. The normal cornea maintains a state of 78% hydration due to a complex interplay between stromal swelling pressure, the barrier function of the epithelium and endothelium, endothelial pump, tear evaporation and intraocular pressure . Any condition that interferes with this balance causes a loss of homeostasis and accumulation of fluid.
1. The Natural History of Corneal Edema
In the early stages of corneal edema, reduced vision is often related to an irregular corneal surface and can interfere significantly with daily activities. This impact on vision is often underestimated by quantitative visual acuity measurements in standard lighting conditions using high contrast charts, as in a refracting lane.
Initially, these patients often experience blurred vision on awakening, owing to the accumulation of fluid in the closed eye state during sleep. As the day progresses, clarity may improve due to the increase in surface evaporation and the massaging action of blinking. This unique history is, therefore, used as an early indicator of failing endothelial function.
As the condition worsens, epithelial edema results in the formation of blebs and bullae, which can rupture during blinks, exposing corneal nerves, resulting in episodes of distressing pain, tearing, blurred vision and redness.
Repeated episodes of epithelial loss can cause constant stimulation of the limbal stem cells and gradual loss of function leading to superficial corneal vascularization. Loss of stromal compactness from the edema and the recurrent inflammation can induce stromal vascularization, as well. Over time, pannus formation and subepithelial fibrosis result in a quiet corneal surface, with loss of vision.
While there are many causes for corneal edema, the occurrence after cataract surgery is particularly distressing to the patient and the surgeon, since good outcomes after the procedure are now the norm. With the improvement in techniques and instrumentation, the incidence of pseudophakic corneal edema has been steadily decreasing, and its current incidence is estimated to be about 0.1 – 0.3% .
2. Causes of Pseudophakic Corneal Edema
Although transient corneal edema after cataract surgery is not uncommon, irreversible loss of corneal function necessitating further management is not often seen.
When it does occur, there can be multiple factors including a pre-existing condition like Fuchs’ endothelial dystrophy or Posterior polymorphous endothelial dystrophy with a compromised endothelial state which was not detected during the preoperative evaluation. Other conditions like pseudoexfoliation, chronic uveitis, chronic angle-closure glaucoma, past trauma and increasing age can also result in poor endothelial function, which may not be able to withstand the rigors of routine cataract surgery.
Studies have shown that the mean endothelial cell loss after cataract surgery can be up to 15%  and, is not different comparing phacoemulsification with manual small incision surgery. While a healthy cornea with a normal endothelial count can withstand this endothelial loss without compromise in function, a cornea with a pre-existing low endothelial cell count may decompensate, even after uncomplicated cataract surgery.
Trauma to the endothelium can also occur during surgery, from the instruments used, the ultrasound energy delivered into the anterior chamber, contact with the cataract - either due to chatter during phacoemulsification or contact during nucleus extraction in manual small incision surgery. While some of these difficulties may be due to ocular characteristics like poor corneal visibility during surgery, shallow anterior chamber, non-dilating pupil, or a dense cataract, it can also be due to machine failure, surgeon inexperience or an inappropriate choice of surgical technique.
Intra-operative complications such as posterior capsule rent and vitreous disturbance can result in extensive maneuvers to prevent nucleus drop and increased surgical time which can affect endothelial health. The use of various intracameral fluids during surgery may result in toxicity and loss of endothelial function. The detachment of the Descemet’s membrane (DM) can also result in a similar outcome.
Postoperatively, the toxic anterior segment syndrome (TASS) is implicated in early-onset extensive corneal edema. Extensive vitreous, iris or IOL endothelial contact can also result in corneal edema over time. An increase in intraocular pressure (IOP) in the post-operative period or gross hypotony can also result in corneal edema.
3. Assessing Post-Cataract Surgery Corneal Edema
In a well-performed cataract surgery in a healthy eye, a clear cornea on the first post-operative day is the expected outcome. If corneal edema is noted in the post-operative period, a careful evaluation is required to assess the possible causes for the same. A revaluation of the fellow eye endothelium will help determine if pre-existing corneal dystrophy was missed.
In the operated eye, the location, extent, and degree of edema are noted. Edema can be localized or diffuse; localized edema can be peripheral, paracentral, or involving the visual axis. The edema can be mostly epithelial, stromal or can involve both layers. There may be extensive folds in the DM or broad bands of haze - striate keratopathy. The edema can also be associated with the prominent thickening of the corneal stroma.
A careful evaluation of the cornea using a slit beam in a dark room with high illumination and magnification is necessary to detect the presence of a DM detachment. It can be planar (1 to 2 mm separation from the corneal stroma) or non-planar with more extensive separation . The morphology of the DM detachment, if present, must be noted - the location, the area of maximum separation, association with any of the surgical wounds, tears in the DM, loss of DM and the fluid present in the interface (clear as in aqueous, or cloudy as with viscoelastic). It is essential to document these findings carefully in a detailed drawing as worsening of edema in the subsequent days can make such an examination difficult. Dilating the pupil and using retro-illumination can help discern these details better.
The presence of significant anterior chamber (AC) inflammation, especially the presence of fibrin or hypopyon must be noted, as also evidence of AC disorganization - iris damage, vitreous in the AC, IOL malpositioning, deposits on the IOL, wound leaks and burns, and retained lens material. These may provide a clue to the possible etiology of the edema and help plan the surgical management.
The IOP is recorded, an increase in IOP can cause diffuse epithelial edema, and gross hypotony can cause stromal swelling due to an increase in stromal swelling pressure in conjunction with endothelial dysfunction. Assessment of the posterior segment is necessary to rule out endophthalmitis with inflammation and corneal edema. A healthy red glow and indirect ophthalmoscopy can help.
Other investigations that can help include, anterior segment optical coherence tomography (AS-OCT) to study the layers of the cornea and detect subtle DM detachments, specular microscopy to look at the endothelial cell count and morphology, pachymetry to document corneal thickness, and B-scan ultrasonography to assess the posterior segment in case the edema precludes indirect ophthalmoscopy. Ultrasound Biomicroscopy (UBM) can help detect retro-iridial etiology such as IOL malposition and posterior chamber lens remnants.
4. Management - Acute, Intermediate and Long-Term
Early-onset corneal edema after cataract surgery can be due to endothelial trauma, increased IOP, TASS, DM detachment, endophthalmitis or hypotony. Unrelated oral medication like Amantadine can result in corneal edema and if in use, can be stopped.
The assessment of the eye helps determine the cause and accordingly evolve the treatment plan. If surgical trauma has caused endothelial dysfunction, and if edema is not extensive, it could improve over time. In such an instance, waiting with supportive treatment with hyperosmotic agents - hypertonic saline drops and ointment may be all that is required. Corneal edema that persists beyond a month is usually indicative of severe trauma, and it is considered that the endothelium may not recover.
Inflammation, IOP, physical contact of IOL or lens material with the endothelium, resulting in corneal edema, must be managed appropriately, as must endophthalmitis. If the corneal edema is due to a DM detachment, procedures for reattaching the DM must be considered.
Conservative management includes the use of topical steroids, as is the usual post-cataract protocol, cycloplegics if there is significant AC inflammation, and IOP lowering agents as required.
While using topical IOP lowering agents, it may be prudent to avoid topical carbonic anhydrase inhibitors like Dorzolamide as they can interfere with endothelial function. Ripasudil, a Rho-Kinase inhibitor (ROCK), is now available for the lowering of IOP, and since it has been postulated to have some benefits in inducing endothelial mitosis and migration, can be considered .
Oral steroids are not necessary for the management of post-operative corneal edema unless significant inflammation is present, like in TASS. In such a situation, oral steroids, hourly topical steroids, cycloplegics and if required IOP management can be considered. It has been suggested that if TASS is recognized early, an AC wash may help reduce the load of toxic and help in a better outcome, although this is not a validated approach.
5. Surgical Decision Making – Timing and Approach
With amelioration of aggravating factors and adequate conservative therapy, if endothelial recovery is not noted after three months, surgical options may be considered. Once the decision to proceed with surgery has been made, in persistent loss of endothelial function after cataract surgery, it is better to operate sooner than later. Persistent corneal edema can result in limbal stem cell dysfunction, AC inflammation, further stress on the surviving endothelial cells, vascularization of the cornea, surface irregularity, scarring and fibrosis, and posterior segment changes including cystoid macular edema owing to the changes in the anterior segment.
The choice of surgery depends on the findings in the eye and the experience of the surgeon. In general, there has been a shift in approach to selective lamellar corneal replacement over penetrating keratoplasty (PK) for pseudophakic corneal edema. This shift is due to better intra- and post-operative safety and earlier visual rehabilitation from retention of the corneal surface contour, lack of suture related complications, and a lower rejection rate.
The lamellar approaches started with Deep Lamellar Endothelial Keratoplasty (DLEK), progressed to Descemet’s Stripping Endothelial Keratoplasty (DSEK), Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK), and Descemet’s Membrane Endothelial Keratoplasty (DMEK). Although these procedures offer significant advantages, they have a steep learning curve and do not address corneal stromal scarring and changes in the anterior cornea. The surgeon must thus perform a careful assessment of the cornea and also take into account additional risk factors like size of the cornea and AC, the presence of iris adhesions and loss of iris tissue, glaucoma tubes and blebs, aphakia, dislocated IOL, prior vitrectomy, and vitreous in the AC. All of these can interfere with graft placement, manipulation and adherence in lamellar corneal surgery. However, with increasing experience, surgeons can perform lamellar corneal transplants in these conditions.
6. Penetrating Keratoplasty
In eyes with significant corneal changes in addition to the edema, like vascularization and anterior scarring, a penetrating keratoplasty may be the preferred approach. Penetrating corneal transplants have stood the test of time but can have problems during surgery due to the open sky approach that is used. After surgery, the graft host junction can remain a weak area, and injuries can result in a disruption of the wound with significant morbidity. Suture loosening can result in vascularization, infection and rejection. Even in a well-performed graft with adequate wound healing, contour changes are inevitable, and the resultant irregularity and astigmatism can result in delayed visual recovery and or poor quality of vision. Especially in eyes with significant corneal vascularization, graft rejections can result in poor long-term outcomes. However, in long-standing pseudophakic corneal edema with significant anterior corneal changes, PK remains the treatment of choice .
7. Lamellar Stromal Based Keratoplasty
In order to avoid the disadvantages of the penetrating grafts listed previously, Gerrit Melles described his approach of posterior corneal replacement which has evolved into the currently performed techniques of DSEK and DSAEK. The donor cornea is dissected either manually or using an automated microkeratome to obtain a posterior corneal layer which is 100 to 150 microns in thickness. In the donor, the DM and diseased endothelium are stripped in the central 8 to 9 mm, and a similar-sized donor graft is introduced through a small corneal incision of about 4 mm in size . A variety of techniques of graft insertion have been described to minimize trauma to the endothelium. Once in the AC, the graft is unfolded and centered on the posterior host corneal surface, and an air bubble is used to ensure proper adherence of the donor. With experience, this approach can be used in aphakic, vitrectomized, and eyes with glaucoma tubes and blebs. The closed eye approach provides better intra- and post-operative safety. Retaining the anterior corneal contour allows early visual recovery. Since a lesser amount of corneal tissue is transferred, there is also a lesser risk of endothelial rejection. However, the thickness and regularity of the stromal layer in the donor graft can affect outcomes. Thicker grafts tend to take longer to deturgesce, and hence visual recovery can take longer. The presence of an interface can result in a slightly lesser quality of vision than with a PK, and the more posterior location of the new corneal surface can result in a hyperopic shift.
8. Descemet’s Membrane Related Procedures
The DMEK approach was described by Melles, to overcome some of the disadvantages of the DSEK surgery described earlier. In this approach, a disc of donor DM and endothelium are carefully stripped - usually 8 to 8.5 mm in diameter. Although this process has a learning curve, various modifications have been described to increase the harvest rate. The original Melles technique  described injecting this scroll of tissue into the AC, using either a glass or plastic injector and once in the eye, small jets of fluid and stroking maneuvers on the corneal surface are used to unfurl the tissue. Air is used judiciously to help in this process, and when the graft is completely unfolded, the AC is filled with air to attach the graft. Although the procedure has a steep learning curve, once mastered, it allows early and excellent visual recovery, as there is no stromal interface and thickness in the graft. Similarly, the lesser transfer of donor tissue results in a lower endothelial rejection rate.
A serendipitous discovery that central DM removal in an eye with early Fuchs’ endothelial dystrophy can result in the clearing of corneal edema resulted in the procedure termed Descemet’s Stripping Only (DSO) or Descemet’s stripping Without Endothelial Keratoplasty (DWEK). In these eyes with a relatively healthy peripheral endothelium when the central diseased endothelium is removed, the peripheral endothelium can migrate centrally, mainly when Rho-kinase inhibitors (ROCK) are also used. These are used as drops, and the commercially available isoforms are Ripasudil and Netarsudil. However, reports of success are variable with some reports of no improvement in the central corneal edema and scarring at the site of DM removal. Hence, this approach still requires validation .
9. Adjunctive Palliative Procedures
Riboflavin and UV-A assisted Corneal Collagen Cross-Linking (CXL), Amniotic membrane transplants (AMT), Conjunctival hooding, Anterior stromal puncture (ASP) and Phototherapeutic Keratectomy (PTK), soft Bandage contact lenses (BCL) can be utilized as therapeutic adjuncts for pain management.
CXL is thought to induce stromal compaction with thinning and less water influx into the cornea and consequently, less fluid in the subepithelial space, thereby reducing bullae formation . It, therefore, helps in managing pain. The mechanism of stromal compaction has also shown to improve visual acuity in some patients transiently.
AMT and conjunctival hooding help in pain control by promoting epithelial cell migration and adhesion to the underlying basement membrane, thereby reducing the formation of epithelial bullae. ASP works by increasing the adhesion of the epithelial cells to the underlying stroma. It induces subepithelial fibrosis which acts as a physical barrier, limiting fluid migration to the subepithelial space. Lastly, PTK helps in decreasing pain perception by ablation of the subepithelial nerve plexus. It also strengthens the adhesions between the epithelial cells and underlying stroma. The role of these adjuncts in the visual rehabilitation of patients with pseudophakic corneal edema remains limited.
10. Experimental and Future Strategies
The most exciting development in this field, however, is the use of cultured corneal endothelial cells, supplemented with a ROCK inhibitor to treat bullous keratopathy - described by Kinoshita et al. . After removing the diseased endothelium in the central 8 mm of the host cornea, cultured cells supplemented with ROCK inhibitor Y-27632 were injected into the eye, and the patients were then placed in a prone position for 3 hours to allow the cells to adhere to the denuded posterior corneal surface. They reported 24-week results in their initial report, with an increase in the central corneal endothelial cell density of more than 500 cells per sq. mm in all 11 eyes, a reduction in corneal thickness to less than 630 microns in 10 of 11 eyes and an improvement in best-corrected visual acuity of 2 or more lines in 9 of the 11 eyes. Further studies in this area could see a gradual shift to a non-surgical approach to the management of corneal edema - the holy grail for corneal surgeons.
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