Postoperative Corneal Melt 

Updated: Aug 29, 2019
Author: Arun Verma, MD; Chief Editor: Hampton Roy, Sr, MD 

Overview

Background

Postoperative corneal melts may be associated with infectious, inflammatory, or trophic causes. Dellen effects associated with structural or mechanical eyelid problems also may contribute to corneal melts. Nutritional causes are less common in developed countries. Proper management is directed at identifying and correcting associated conditions while supporting the corneal tissue at risk to minimize scarring and to prevent perforation.

The two most common causes of corneal melt are herpes simplex virus (HSV) keratitis and retained lenticular material. Although medroxyprogesterone may not influence the underlying incidence of melt-related complications, which are likely to be associated with other risk factors, especially HSV, it may have a protective effect with regard to melt onset and severity (Hicks, 2003; Eguchi, 2004). Although a history of HSV keratitis was a contraindication to AlphaCor in the past (Hicks, 2002), a history of HSV alone is no longer considered a contraindication. In cases of corneal melt, however, HSV should be ruled out. Progressive melts are treated with lamellar grafts or are “reversed” for repeated attempts at penetrating keratoplasty (PKP).

Pathophysiology

Corneal epithelial defects begin the melting process. Failure to reepithelialize leads either to infection or to a trophic process. Immune mediators and collagenase enzymes attack the exposed stroma, and inflammatory cells further compound progression of ulcerative melting. The corneal epithelium plays a very important role in maintaining the health of the corneal surface. This is because of its rapid self-growing capacity. Important progenitor cells are located at the limbus, which multiply and migrate to the area of disease. These cells are known as limbal stem cells, and their deficiency plays a very important role in postoperative corneal problems.

Among all corneal insults, chronic inflammation at the limbus appears to be a common denominator for postoperative corneal melting. The limbal stem cells serve as a proliferative barrier between corneal and conjunctival epithelia. Conditions that severely damage the limbal stem cells can result in an invasion of conjunctival epithelium onto the corneal surface. This process of conjunctivalization results in thickened, irregular, unstable epithelium often with secondary neovascularization and inflammatory cell infiltration. Epithelial defects are common in a conjunctivalized corneal surface and may lead to corneal ulceration, melting, and loss of vision.

A cornea denuded of epithelium resists collagenolysis poorly. Any delay in reepithelialization can favor corneal melting. For example, damage to the deep limbal crypts and their normal reserves of basal epithelial cells may destroy important sources for reepithelialization of the cornea. It also is possible that the chemically burned eye, metabolically deprived from changes in pH and glucose levels of the anterior chamber, may need the normally insignificant limbal vascular routes of nutrition to survive. If these routes are no longer functional because of massive thrombosis, then the integrity of the cornea is threatened, and sterile necrosis leading to melting syndrome may be inevitable.

Gottsch and Liu propose that a natural protein triggers an immune assault on the eye that can lead to corneal melt. They discovered that Mooren ulcer, the painful ulceration of the cornea, is an autoimmune disorder. The body launches an attack on CO-ag (cornea-associated antigen), located only in the cornea.

Epidemiology

Frequency

United States

Postoperative corneal melts do not occur frequently. However, they tend to occur more in patients with the predisposing factors listed in Causes.

Mortality/Morbidity

Depending on the severity and location of the melt, the vision may be minimally or severely affected.

Race

Postoperative corneal melts are more common in less advanced counties, where nutritional deficiencies play a major part in the health of the cornea.

Sex

Because corneal melts are common in people with collagen disorders and in those with rheumatoid arthritis, they tend to occur more often in females than in males.

Age

Postoperative corneal melts commonly occur in patients with compromised corneas who are in their fourth or fifth decades or even in those who are elderly.

Prognosis

Prognosis depends on the reason for and the extent of the melting. Conditions that are reversible or easily controlled have a better prognosis. Nonperforated melts have better prognosis than perforations.

Corneal melting (including post-operative corneal melting), a condition that may lead to corneal perforation (open injury), is often an indication of a systemic disease, such as rheumatoid arthritis or lupus, therefore requiring systemic treatment rather than just topical eye drop application.

It is extremely important that patients be treated by an expert physician who specializes and understands the process of eye melt, which can be a presenting sign of a serious systemic disorder that can benefit dramatically with systemic treatment. The team of physicians and ophthalmologists should be experts at providing ocular and systemic care to patients with such disorders. Drugs used in the treatment of these eye diseases can have significant adverse effects, including bone marrow suppression, and improper use or dosages can be devastating. However, the corneal melt itself can be equally devastating to one’s vision, potentially leading to perforation of the cornea and/or loss of vision. Therefore, the risks and benefits are heavily weighed, and an informed decision is made as to the best course of treatment.

 

Presentation

History

Postoperative corneal melt can occur with almost all the intraocular operations. The major operations are listed below.

Pterygium excision

Corneal melts can infrequently follow a routine surgical removal of pterygium. Postoperative corneal melts have been seen in 2 apparently healthy young patients within 2 weeks of routine excision of the pterygia. No evident predisposing factors were present in one patient (a male aged 28 y), whereas the other patient (a female aged 38 y) had rheumatoid disease.

A 59-year-old man underwent pterygium excision with intraoperative application of 0.2 mg/mL (0.02%) mitomycin-C placed on the scleral bed for 3 minutes. A sliding conjunctival flap was used to cover the exposed limbus and sclera. Five weeks after the original surgery, the patient had mild trauma and noted decreased vision. At that time, it was noted that he had a corneoscleral melt with perforation. The patient was treated with a lamellar transplant in this area.

Intraoperative single-dose application of topical mitomycin-C can be associated with serious complications. A detailed report with serious, vision-threatening complications associated with mitomycin-C use after pterygium surgery has been published. The complications included iritis, severe secondary glaucoma, corneal edema, corectopia, sudden-onset mature cataracts, scleral calcification, and corneal melt leading to perforation.

A separate case report describes a 36-year-old woman who had a corneal infiltrate, corneoscleral ulceration, a pupil peaked toward the ulceration (globe perforation not mentioned), hypotony, vitreous exudates, optic disc hyperemia, and macular edema after using 0.2 mg/mL of mitomycin-C 3 times daily for 3 weeks after pterygium surgery. Although topical mitomycin-C is effective as an adjunct to pterygium surgery and may reduce recurrence, the safety and efficacy of various concentrations and dosing schedules need further definition.

Beta radiation after surgical removal of pterygia: Among the less commonly reported complications of beta radiation treatment after pterygium removal are ptosis, iris atrophy, corneal ulceration, bacterial corneoscleritis, and fungal panophthalmitis. Mitomycin-C and beta radiation must be used with caution, knowing that complications may occur months to years later. Future studies may elucidate the cause of these delayed complications and allow better selection of adjunctive therapy after pterygium surgery.

Corneal refractive surgery including radial keratotomy

Serious complications can occur following radial keratotomy procedure. Bacterial keratitis with corneal melting has been reported in the early postoperative periods. Most of the infections are located in the inferior portions of the cornea within the incision sites. Cottinger et al believe that the delayed infections were secondary to epithelial erosions and dry eye tendencies.[1]

In cases where rheumatoid arthritis only manifests in the joints, patients usually do very well with LASIK. According to Maloney, corneal melting is very unusual in a patient without extra-articular disease, though such cases may occur; he cites a study published by Foster and colleagues that showed that corneal melting following cataract surgery could be the first manifestation of extra-articular disease.

These rare cases tend to happen in much older patients. Also, they almost always occur in patients where the disease is active and not well controlled. In general, the patients undertaken for LASIK should be relatively young, with well-controlled disease and good tear function. Consultation with the patient’s rheumatologist is recommended to ensure the disease is well controlled. Patients themselves can also be helpful in this regard.

Enbrel (etanercept) and other immune response modulators are also making LASIK more viable in these patients. This new class of drug has revolutionized the treatment of rheumatoid arthritis. As a result of these new medications, the disease is less damaging and far better controlled than it was a decade or two ago.

Proper informed consent is also crucial before allowing any patient with an autoimmune disorder to undergo LASIK. Many surgeons consider the disease to be a contraindication for LASIK due to the potential for corneal melting.

While LASIK can be a good bet for many of these patients, the study results should by no means be extrapolated to photorefractive keratectomy (PRK). According to Maloney, PRK may be less safe than LASIK in these cases. PRK creates a large epithelial defect. Because nonhealing epithelial defects cause ulceration, there is the concern that such epithelial defects may predispose these patients to ulceration.[2]

The study results also have no bearing on whether or not such patients are at increased risk of dry eye. A prospective study would be needed.

Patients can present with symptoms of recurrent erosions. Most likely, an epithelial plug surfaces from the radial incision, is traumatically ruptured, and becomes secondarily infected. Similarly, epithelial cysts rupture spontaneously in the postoperative period leading to stromal inflammation and this may be the pathogenesis of corneal ulcers and melts. Wounds tend to heal slower and gape more when a radial incision bisects a transverse or circumferential incision, which also can contribute to postoperative corneal melting syndrome.

Anterior corneal epithelial basement membrane changes, similar to those seen in epithelial basement membrane dystrophy, often are observed after radial keratotomy (RK). These changes tend to be transient, lasting less than 3 months in most eyes. They infrequently are associated with clinical symptoms or recurrent epithelial erosion.

A most unusual complication of refractive keratotomy is the late development of bacterial and fungal ulcerative keratitis. All infiltrates are noted to be contiguous with the keratotomy scars. The persistent epithelial plug in the keratotomy wound is implicated in delayed bacterial and fungal keratitis, leading to postoperative corneal melting.

Epikeratophakia

Failure of epikeratoplasty procedures because of postoperative corneal melts and perforation has been reported. The common suggestion is that the presently used process of tissue preparation may be deleterious to the structure of the donor lenticule and may adversely affect surface reepithelialization. The placement of the lenticule above the recipient's Bowman layer may be an additional retardant to postoperative reepithelialization.

Keratomileusis

A few resurfacing problems have been reported after keratomileusis procedure for myopia. Patients can develop nonhealing epithelial defect leading to corneal ulceration and corneal melt.

Excimer laser PRK and LASIK surgery

Absolute contraindication for photorefractive excimer and LASIK lasers would be rheumatoid diseases because of potential corneal melting ulcers. Patients can develop extensive epithelial ingrowth and keratolysis along with stromal melts. This complication can be treated by lifting the flap and removing the epithelium from the interface.

LASIK: Corneal melting ulceration and fine striaelike infiltrates were noticed 1 day postoperatively. No response occurred to intensive topical antibiotic in the form of hourly ofloxacin 3%, and satellite lesions developed on day 4. No bacterial or fungal organisms were identified. Intensive fortified vancomycin (50 mg/mL) was added. Complications at 6 months included epithelial ingrowth, corneal flap melting, and decentered ablation.

Progressive keratolysis (stromal melt) can result in irregular astigmatism, photophobia, ciliary injection, and loss of vision. The pathogenesis is not completely understood, although the epithelial ingrowth in the interface is always present and epithelial stromal interaction with production of proteases may be involved. Epithelial ingrowth may develop in the lamellar interface after LASIK and may be associated with melting of the edge of the flap.

Keratoplasty

Epithelial problems after penetrating keratoplasty include defects secondary to cell loss during or after surgery, epithelial irregularity and superficial punctate keratopathy secondary to an inadequate tear film, localized trauma from aberrant eyelashes or eyelid scarring, and delayed or poor healing secondary to toxic keratitis medicamentosa from topical drops. Persistent epithelial defects increase the chances of graft infection, corneal melting, and failure.

Infectious crystalline keratopathy is a serious, nonsuppurative, bacterial infection of the graft that may occur in patients maintained on chronic topical corticosteroids. Several different organisms, with Streptococcus viridans and anaerobic bacteria being the most frequent isolates, cause this infection. Culture results often are negative; therefore, corneal biopsy for histologic examination and microbiologic evaluation is recommended for accurate diagnosis.

Epithelial irregularity or haziness secondary to chronic ocular surface disease, such as keratoconjunctivitis sicca or blepharitis, can cause decreased vision and may put the eye at risk of other problems such as infectious keratitis, corneal melting, or stromal scarring.

Keratoprosthesis

In any design in which the keratoprosthesis is anchored exclusively to the cornea, conjunctiva often grows across the keratoprosthesis or retracts, causing corneal melting. A high rate of spontaneous extrusion occurs. Keratoprosthesis may be associated with early or delayed corneal melting.[3, 4]

Glaucoma surgeries

Routine filtration operation and filtration operation performed in conjunction with subconjunctival injection of 5-FU

Corneal and conjunctival epithelial toxicity, manifested as punctate epithelial erosions, corneal epithelial defects, and primary conjunctival wound leaks, is the most common complication of postoperative subconjunctival 5-FU injection. Epithelial defects, leading to corneal thinning and ultimately late corneal melts also can occur.

Eyes with limited limbal stem cells populations, such as those with Stevens-Johnson syndrome, pseudopemphigoid, and alkali injury should not receive 5-FU for fear of permanently reducing the limbal stem cell pool. Presence of preexisting corneal epithelial edema, a risk factor for the development of corneal epithelial defects, also has been associated with serious bacterial corneal infections, thinning, and corneal melting in eyes that received 5-FU after filtration surgery.

Routine filtration operation performed in conjunction with topical mitomycin

Routine filtration surgery along with the use of topical mitomycin-C also can cause postoperative corneal melts, although the incidence reported is not very high.

Trabeculectomy and trabeculectomy using local mitomycin drops

Corneal melt has been reported with Molteno shunt valve operation. After blunt trauma, the secondary plate of a double-plated Molteno implant became completely dislodged anteriorly onto the patient's cornea. The corneal tissue entrapped beneath the avulsed plate was found to have extensive melting requiring emergency explantation of the Molteno implant and corneal grafting.

Progressive postoperative corneal melt has been reported after Nd:YAG or argon therapy. Postoperative corneal ulcers have been reported with argon laser trabeculoplasty.

Transscleral cyclophotocoagulation (TSCPC): TSCPC infrequently can cause corneal epithelial defects leading to postoperative corneal melts. This can be prevented by use of contact lens during noncontact Nd:YAG cyclophotocoagulation.

Pulsed dye sclerostomy: The most common complication of this procedure includes localized corneal edema with peripheral melts adjacent to the sclerostomy site. The debate continues over whether the thermal effects are beneficial or detrimental to the scleral collagen and the corneal collagen. This controversy will be resolved once appropriate laser systems are available. The most common complication of Nd:YAG ab interno laser sclerostomy includes ruptured blebs and corneal stromal and epithelial melts. Nd:YAG cyclophotocoagulation reduces this complication.

Vitrectomy (intraoperative corneal complication)

The corneas of diabetic patients are vulnerable to recurrent erosion. Therefore, prior to and during surgery, every effort should be made to avoid corneal trauma. In the immediate preoperative period, corneal contact such as tonometry, contact lens examinations, and electroretinography, should be minimized. The cornea must not be touched by solutions used for sterile preparation of the operative field. During the vitrectomy, the cornea must be moistened frequently. Despite these measures, the epithelium of diabetic patients is much more likely to become opaque during vitrectomy than is that of nondiabetic patients.

Diabetes mellitus predisposes to these complications for 2 reasons. First, diabetic corneas have slightly decreased sensation; therefore, a neurotrophic component may contribute to their intraoperative and postoperative complications. Second, the adhesion between the epithelium and the stroma is abnormally weak in diabetic patients. Indeed, the epithelium in diabetic patients can be brushed off easily with a cotton-tipped applicator, whereas that of nondiabetic patients must be removed with a scalpel. Intraocular irrigating solutions are toxic to the corneal endothelium.

Formerly, as many as 15% of diabetic patients had significant postoperative corneal decompensation, infections, and melts. As many as 3% required a corneal transplant. More recent studies show a marked decrease in corneal complications.

Vitreous surgery

Keratopathy (eg, epithelial or stromal edema, band or bullous keratopathy) is another frequent problem after vitreous surgery for severe proliferative vitreoretinopathy (PVR). In phase 2 of the Silicone Study, in group 1, 33% of eyes that received C3 F8 and 30% of those that received silicone oil developed keratopathy by the last follow-up examination. In group 2, an even higher prevalence of keratopathy was noted with 45% of eyes receiving C3 F8 eyes and 43% of eyes receiving silicone oil noted to have developed keratopathy by the last follow-up visit. As expected, keratopathy was much more frequent in eyes in which anatomic reattachment failed.

Scleral buckling

Scleral buckling operation for detached retina can cause postoperative corneal or scleral melt from an encircling band or a circumscribed buckle.

Corneal clouding

During scleral buckling procedures, adequate visualization throughout the case is critical to the success of the operation. Corneal clouding is a common intraoperative problem. This usually is caused by epithelial edema from increased intraocular pressure, which occurs during scleral depression. The epithelium also may become damaged by desiccation or mechanical trauma during the procedure. Mild amounts of epithelial edema may be resolved with topical glycerine or by rolling the epithelium with a dry cotton-tipped applicator. Extensive epithelial edema usually requires debridement with a rounded blade. The debrided epithelial cells are removed with a cellulose sponge to prevent dispersion, which may result in epithelial inclusion cysts. These in turn may cause postoperative corneal melts.

Pars plana vitrectomy

Rubeosis and endophthalmitis have occurred in less than 0.5% of cases. Rarely, late corneal complications in the form of peripheral melts have been reported. Peripheral melts also can occur after penetrating keratoplasty operation, especially in those patients receiving antiglaucoma drugs, most of which are toxic to the cornea and promote an inflammatory response postkeratoplasty. The surgeon should control intraocular pressure before keratoplasty, with a filtration operation, if necessary.

Cataract

Central sterile corneal ulceration and melting has been reported days to weeks after otherwise unremarkable cataract surgery in patients who have rheumatoid arthritis with keratoconjunctivitis sicca.[5]

Phaco surgery (retained lens material causing corneal problems): One third to one half of eyes with sufficient retained lens fragments considered for vitrectomy present with some degree of corneal decompensation. In most cases, this is transient keratopathy and probably reflects the trauma of the cataract surgery and an increase in intraocular pressure. In approximately 10% of patients (20-30% of those eyes presenting with keratopathy), corneal edema will persist, resulting in bullous keratopathy and often requiring keratoplasty. Postoperative corneal ulcers and melts also have been reported. Postoperative use of nonsteroidal anti-inflammatory drops also has been implicated in sterile corneal melts after cataract surgery.

Rectus muscle surgery

Rectus muscle surgery is rare cause of postoperative corneal melt.

Physical

Physical findings can range from very mild, which may mimic keratoconjunctivitis, to severe, with ring infiltration and descemetocele formation and perforation. Postoperative corneal melt can be confused in its early phases with simple keratitis and may even coexist with bacterial or viral keratitis. Ophthalmologists must maintain a high index of suspicion for this condition. Postoperative corneal melt typically follows exposure of an epithelially compromised cornea to a contaminated source. Epithelial compromise includes all the previously described conditions and procedures, epithelial disease such as dry eye, and ocular injuries such as abrasions or foreign bodies.

Corneal refractive surgery radial keratotomy

Serious complications can occur following radial keratotomy procedure. There have been reports of bacterial keratitis with corneal melting in the early postoperative periods. Most of the infections are located in the inferior portions of the cornea, within the incision sites. Cottinger et al believe that the delayed infections were secondary to epithelial erosions and dry eye tendencies.[1]

Patients can present with symptoms of recurrent erosions. Most likely, an epithelial plug surfaces from the radial incision, is traumatically ruptured, and becomes secondarily infected. Similarly epithelial cysts rupture spontaneously in the postoperative period leading to stromal inflammation; this may be the pathogenesis of corneal ulcers and melts. Wounds tend to heal slower and gape more when a radial incision bisects transverse or circumferential incision, which can contribute to postoperative corneal melting syndrome.

Anterior corneal epithelial basement membrane changes, similar to those seen in epithelial basement membrane dystrophy, often are observed after RK. These changes tend to be transient, lasting less than 3 months in most eyes. They infrequently are associated with clinical symptoms or recurrent epithelial erosion.

A most unusual complication of refractive keratotomy is the late development of bacterial and fungal ulcerative keratitis. All infiltrates are noted to be contiguous with the keratotomy scars. The persistent epithelial plug in the keratotomy wound is implicated in delayed bacterial and fungal keratitis, leading to postoperative corneal melting. Corneal melting ulceration and fine striaelike infiltrates were noticed 1 day postoperatively.

Complications at 6 months included epithelial ingrowth, corneal flap melting, and decentered ablation. Progressive keratolysis (stromal melt) can result in irregular astigmatism, photophobia, ciliary injection, and loss of vision. The pathogenesis is not completely understood, although the epithelial ingrowth in the interface is always present and epithelial stromal interaction with production of proteases may be involved. Epithelial ingrowth may develop in the lamellar interface after LASIK and may be associated with melting of the edge of the flap.

Causes

See the list below:

  • Skin conditions

    • Herpes zoster

    • Incontinentia pigmenti (Block-Sulzberger syndrome)

    • Lichen planus

    • Molluscum contagiosum

    • Palmoplantar keratosis

    • Pityriasis rubra pilaris

    • Psoriasis

    • Acne rosacea

    • Benign mucosal pemphigoid

    • Dermatitis herpetiformis

    • Leprosy

    • Lyell disease (toxic epidermal necrolysis or scalded skin syndrome)

    • Lymphopathia venereum

    • Pemphigus foliaceus (Cazenave disease)

    • Ectodermal dysplasia (anhidrotic)

    • Ichthyosis

  • Vitamin deficiency

    • Ariboflavinosis keratopathy

    • Vitamin A deficiency

    • Vitamin B-2 deficiency (Addison pernicious anemia syndrome)

    • Pellagra (avitaminosis B-2)

  • Collagen disorders

    • Polyarteritis nodosa (Kussmaul disease)

    • Rheumatoid arthritis (Sjögren syndrome, secretoinhibitory syndrome)

    • Scleroderma (progressive systemic sclerosis)

    • Systemic lupus erythematosus (Kaposi-Libman Sacks syndrome)

  • Systemic diseases

    • Tuberculosis (scrofulous keratitis)

    • Upper respiratory infection

    • Gout

    • Vaccinia

    • Haemophilus influenzae

    • Hypoparathyroidism

    • Leprosy (Hansen disease)

    • Lymphopathia venereum

    • Deerfly fever (tularemia)

    • Mumps

    • Brucellosis

    • Trypanosomiasis

    • Filariasis

    • Hodgkin disease

    • Sarcoidosis

  • Drugs

    • Steroid therapy

    • Topical anesthesia abuse

    • Stevens-Johnson syndrome (erythema multiforme exudativum)

    • Topical nonsteroidal anti-inflammatory agents

  • Ocular predisposing factors

    • Phlyctenular keratoconjunctivitis

    • Superior limbic keratoconjunctivitis (micropannus)

    • Trachoma

    • Terrien disease (senile marginal atrophy)

    • Vernal conjunctivitis

  • Preexisting corneal dellen plays an important role in postoperative corneal melting. Dellen can develop in the following:

    • Following wearing of contact lenses

    • Limbal vasosclerosis (elderly patients)

    • Lagophthalmos

    • Lengthy administration of cocaine

    • Postcataract section

    • Swelling of perilimbal tissues

    • Allergic conjunctival edema

    • Episcleritis

    • Filtering blebs

    • Limbal tumor

    • Postoperative advancement of rectus muscle

    • Postoperative retinal detachment

    • Pinguecula

    • Subconjunctival effusion or injection with hemeralopia

  • Delayed corneal wound healing followed by corneal melting may occur because of the following drugs:

    • Adenine arabinoside

    • Adrenal cortex injections

    • Aldosterones

    • Alpha-chymotrypsin

    • Azathioprine

    • Betamethasone

    • Butacaine

    • Cocaine

    • Cortisone

    • Dexamethasone

    • Fluorometholone

    • Fluprednisolone

    • Hydrocortisone

    • Prednisolone

    • Sulfacetamide

    • Sulfamethizole

    • Tetracaine

    • Triamcinolone

  • Marginal ring ulcers/melts may occur in the following:

    • Acute leukemia

    • Bacillary dysentery

    • Brucellosis

    • Dengue fever

    • Gonococcal arthritis

    • Hookworm infestation

    • Influenza

    • Possibly porphyria trigger mechanisms

  • Acquired immunodeficiency syndrome (AIDS): Culture-negative peripheral corneal melting has been observed in a patient with AIDS.

Complications

Complications include infection, bleeding, endophthalmitis, severe visual loss, and blindness.

 

DDx

 

Workup

Laboratory Studies

Investigations

Impression cytology to detect conjunctivalization for diagnosing stem cell deficiency. Identifying the underlying cause is as important as making the diagnosis of the perforation. In trauma, the history often is sufficient to make the diagnosis. In infections, laboratory confirmation is important, and scraping and culture are often essential.

At times, corneal biopsy may be necessary and may be part of the definitive treatment of the perforation, with the excised cornea at keratoplasty being used to make the diagnosis.

External ocular examination including evaluation of lid function and anatomy, testing of corneal sensation, and evaluation of tear function may help to establish the etiologic diagnosis.

In noninfectious inflammatory corneal melting, an evaluation for systemic inflammatory disease may be necessary.

Tests to rule out collagen vascular disease

The erythrocyte sedimentation rate may be elevated in cases of orbital inflammation, but this should bring to mind the possibility of a concurrent systemic disease such as one of the collagen vascular diseases.

Circulating immune complexes may deposit in the limbal vasculature, triggering complement activation, influx of inflammatory cells, and release of enzymes and mediators. The result is a limbal vasculitis; the subsequent loss of vascular integrity facilitates leakage of inflammatory cells and mediators into the peripheral cornea. Immune complexes may leak into the peripheral cornea as well, sparking complement activation, especially with the increased concentration of C1 in the peripheral cornea. Also, it is possible that autoantibodies to corneal epithelial and/or stromal antigen may arrive via the limbal vasculature or via the tear film and play a role. T cells and activated macrophages have been found in active rheumatoid arthritis associated corneal melts, suggesting cell-mediated mechanisms. Collagenase produced by the adjacent conjunctiva and keratocytes and polymorphonuclear leukocytes (PMNs) in the cornea promote stromal dissolution.

In a reported case of postoperative corneal melt, light microscopy revealed a thickened corneal epithelium with an irregular Bowman layer and mild infiltration of the superficial stroma with inflammatory cells, mostly lymphocytes but some PMNs. The adjacent conjunctiva also showed some infiltration by lymphocytes. Immunohistochemistry showed expression of class II antigens on less than 25% of corneal epithelial cells and keratocytes compared with 75-100% of cells in a Mooren ulcer specimen. Less than 5% of lymphocytes were B cells, versus 25-50% in the Mooren specimen. Also, T-cell numbers were much lower in the corneal melt cases; the ratio of helper T cells to suppressor/cytotoxic T cells was 1:1, compared with 2.4:1 for the Mooren sample.

Since all the collagen vascular diseases are basically immune complex diseases, there would be finding of circulating immune complexes. There is great variability from disease to disease in the frequency of positive immune-complex assays. In some diseases, such as systemic lupus erythematosus (SLE), there is a high frequency of positive immune-complex assays. In others, the frequency of positive assays may be much lower.

Examination of tissues using immunofluorescent techniques to detect immune deposits is also important in establishing the diagnosis of immune-complex disease. Immune complexes deposited in tissues may be evanescent. In fact, it has been suggested that the levels of serum C4 and C3 are the most sensitive indexes of disease activity of SLE.

Other tests may suggest indirectly the presence of immune-complex disease. For example, the finding of immunoglobulin M (IgM) cryoprecipitates suggests the presence of immune complexes. The presence of antinuclear antibodies suggests autoimmunity, as does the presence of a number of tissue-component–specific antibodies. Similarly, the presence of specific antigen such as hepatitis-B surface antigen in the circulation together with appropriate clinical symptoms may suggest an immune-complex disease. Many patients with these diseases have an elevated erythrocyte sedimentation rate.

In SLE, the presence of characteristic antibodies such as anti-DNA, anti-Sm, and anti-RNP confirms the diagnosis of SLE. Antinuclear antibodies are the best screening tests. High serum levels of antinuclear antibodies anti-DNA and low levels of complement usually reflect disease activity.

Serum levels of cryoglobulins or other immune complexes occasionally correlate with disease activity. Total functional hemolytic complement (CH50) levels are the most sensitive measure of complement activation. Quantitative levels of C3 and C4 are widely available. Hematologic abnormalities are common and include anemia (usually normochromic, normocytic but occasionally hemolytic), leucopenia, lymphopenia, and thrombocytopenia. In some patients, the Westergren erythrocyte sedimentation rate correlates with disease activity. Urinalysis and serum creatinine should be measured periodically in these patients.

In patients with rheumatoid arthritis, no tests are specific, but, rheumatoid factors, which are autoantibodies reactive with Fc portion of immunoglobulin G (IgG), are found in more than two thirds of the patients. Widely used tests detect IgM rheumatoid factors.

Rheumatoid factor is present in about 75% of patients with Sjögren syndrome even when symptoms of arthritis are absent. Antinuclear antibodies are present in about 70% of patients, and a positive lupus erythematosus (LE) cell test occurs in about 25% of patients. Two antinuclear antibodies, SS-A and SS-B, usually are associated with Sjögren syndrome. SS-B antibodies are found in up to 70% of patients and are fairly specific for the diagnosis of this disease. SS-A antibodies are found in up to 14% of patients. There is a high incidence of antibodies against Epstein-Barr virus nuclear antigen and human leukocyte antigen Dw3 (HLA-Dw3).

Collagen vascular diseases such as rheumatoid arthritis, polyarteritis nodosa, and Wegener granulomatosis can be associated with sterile peripheral corneal melting ulceration, either with or without adjacent scleritis. The pathophysiology of such ulceration undoubtedly is linked to the underlying autoimmune mechanisms of each of these diseases and is probably similar for all. This is supported clinically by the fact that those patients with rheumatoid arthritis who develop necrotizing scleritis or peripheral ulcerative keratitis have an increased mortality rate because of systemic vasculitis.

Histologic Findings

Histologic findings include loss of limbal stem cells and stromal cells.

 

Treatment

Medical Care

Corneal melting, a condition that may lead to corneal perforation (open injury), is often an indication of a systemic disease, such as rheumatoid arthritis or lupus, and, therefore, requires systemic treatment rather than just topical eye drop application. It is extremely important that patients be treated by an expert physician who specializes and understands the process of eye melt, which can be a presenting sign of serious systemic disorder that can benefit dramatically with systemic treatment. The team of physicians and ophthalmologists should be experts at providing ocular and systemic care to patients with such disorders. Drugs used in the treatment of these eye diseases can have significant adverse effects, including bone marrow suppression, and improper use or dosages can be devastating. However, the corneal melt itself can be equally devastating to one’s vision, potentially leading to perforation of the cornea and/or loss of vision. Therefore, the risks and benefits are heavily weighed, andaninformed decision is made as to the best course of treatment.

Patients who initially present with punctate corneal staining that becomes an epithelial defect may ultimately develop stromal loss. Most of these patients do not complain of pain.

Yang and Kline reported 5 cases of stromal loss among approximately 600 patients, which is an incidence rate of 0.01%.[6] Gelender reported 5 cases of stromal loss, and Insler and colleagues reported 4 cases.[7, 8] All of the patients described by Yang and Kline as well as by Insler and colleagues had associated collagen vascular disease.[6, 8] All but one of these patients had rheumatoid arthritis; the other patient had scleroderma. In Gelender's initial report, only one patient had Stevens-Johnson disease; the other patients were apparently healthy.[7] The findings from the studies performed to detect collagen vascular diseases after the ulcer was detected were negative. More recently, several cases believed to be secondary to the extended use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported.

Acute bacterial, viral, or fungal ulcers usually produce a prominent inflammatory reaction, often with a hypopyon, while eyes with corneal melting appear quieter. Postoperatively, if a surgeon discovers a corneal ulcer in a patient, the ulcer should be cultured. Eye drops that are toxic to the epithelium (eg, steroids, NSAIDs, antibiotics, beta-blockers, epinephrine) should be discontinued.

If the eye is relatively quiet and the problem appears to be a corneal melt rather than an infectious corneal ulcer, frequent lubrication with a nonpreserved drop or ointment should be instituted, and the patient should be monitored closely, particularly if a descemetocele seems imminent. Hospitalization may be necessary. Bandage contact lenses may also be of value, but the patient should be monitored closely because a secondary bacterial ulcer may develop.

Corneal cyanoacrylate gluing is recommended if the cornea appears to be progressively thinning. Healing results in approximately 60% of cases. Spontaneous perforation should be treated with either a lamellar keratoplasty or a penetrating keratoplasty.[9] Gelender reported that a conjunctival flap helps stabilize the cornea.[7] Tarsorrhaphy and punctal occlusion may also be considered. The proteases produced by PMNs and diseased epithelium may contribute to corneal melting. The eye should be treated with nonpreserved lubricating ointments combined with taping the lid shut or tarsorrhaphy unless the eye is inflamed.

Keratoconjunctivitis sicca always should be ruled out and treated appropriately when corneal disease is associated with rheumatoid arthritis because sterile corneal ulceration and melting may be associated with dry eyes. Corneal involvement in rheumatoid arthritis includes keratitis, sclerosing keratitis, keratolysis, and peripheral corneal melting. The marginal corneal ulceration may involve the entire circumference in the limbal area, or it may be in a localized zone and frequently is accompanied by significant pain. Marginal corneal ulceration may be quiet and asymptomatic in other patients, and it occurs with or without associated scleral or episcleral inflammation.

Adequate lubrication with preservative-free tear and ointment supplements is very important. Acetylcysteine (Mucomyst 10-20%), used 4-6 times daily, is a topical collagenase inhibitor that may be beneficial in some patients. Topical high-dose corticosteroids may relieve associated scleritis and prevent progression of ulcerative keratitis. In certain cases, especially in patients with dry eye, topical corticosteroids can enhance melting. Later in the disease process, medroxyprogesterone acetate 1% may be used as a topical anti-inflammatory agent that does not inhibit collagen synthesis. If melting is progressive, a hydrophilic bandage contact lens may be helpful in promoting epithelial resurfacing; in thin corneas with impending perforation, a tissue adhesive may be applied. If the above treatment is ineffective, a 3-5 mm resection of the conjunctiva adjacent to the furrow itself may be performed. Systemic immunosuppression is the definitive therapy.

The use of collagenase inhibitors as adjunctive therapy in the treatment of progressive corneal melting has been disappointing. Both disodium edetic acid and acetylcysteine have been used to inhibit collagenase activity, particularly in Pseudomonas corneal infections. Additional enzyme inhibitors, such as the metalloproteinases, are under investigation and may be of clinical value in the future. The rationale for their use is to prevent corneal tissue destruction, but there has been no clear evidence that they have been of clinical benefit.

Corticosteroids also can predispose to secondary complications, including microbial superinfection, stromal melting, secondary glaucoma, and cataract formation. Once corticosteroids are begun, it often is difficult to discontinue them, and a marked rebound inflammatory response can ensue with a withdrawal that is too abrupt. Patients should be forewarned of the potential for chronic topical corticosteroid treatment, even at low doses. Steroids should not be used in cases of exposure or neurotrophic keratitis because of the possibility of keratolysis.

People have underscored the prophylactic benefit of early, large tarsorrhaphy to prevent initial epithelial erosion with subsequent corneal melting and perforation. Therapeutic soft contact lenses may be a reasonable short-term strategy.

Impending or actual corneal perforation, if less than 1.5 mm in diameter, can be treated successfully with 2-butyl-cyanoacrylate (Histoacryl) adhesive and a therapeutic soft contact lens (eg, Bausch & Lomb plano T). Larger perforations should be treated immediately with scleral or corneal patch grafting. These grafts may need to be covered with conjunctiva (or amniotic membrane) to prevent the same melting process from destroying the scleral or corneal patch graft. Topical steroid therapy should be tapered, and cycloplegics should be added in concert with corneal gluing.

Clinical and basic research continues to explore how stem cell functions can be modulated by soluble cytokines and how insoluble matrix autologous serum eye drops (frequent preservative-free artificial tears, highly viscous methyl cellulose) probably help promote epithelial healing. A high rate of immune reactions can be expected because of the high immunogenic stimulus of the limbal transplant related to relative abundance of Langerhans cells and human leukocyte antigen DR (HLA-DR) antigens. Effective immunosuppression is considered essential.

Oral cyclosporin A and topical cyclosporin A (0.05%) can be used in melting stromal ulcers. It may be a good alternative mode of achieving ocular immunosuppression.

Tetracyclines encourage epithelialization and arrest stromal melting. They have anticollagenolytic activity and can directly inhibit metalloproteinases. Tetracyclines may also suppress breakdown of connective tissue.[10, 11, 12, 13]

Surgical Care

Single dose application of topical mitomycin can be associated with serious complication (ie, corneal melting leading to perforation). The patient can be treated with lamellar corneal transplant. Epithelial ingrowth may develop in the lamellar interface after LASIK and may be associated with melting of the edge of the flap. This undesirable complication can be treated successfully with early surgical removal of the epithelium and proper reattachment of the flap.

Keratoplasty

Prompt initiation of therapy directed at the specific cause is required to promote epithelial healing. Conjunctival flaps play a less important role in the treatment of perforations than they do in the prevention of progression of corneal melting. Nonetheless, in some leaking descemetoceles and small perforations, conjunctival flaps may serve as a temporizing measure before keratoplasty. However, with the use of tissue adhesives and patch grafting, the use of conjunctival flaps for perforation has become almost obsolete.

Partial-thickness scleral flaps may be dissected with a base at the limbus and then reflected onto the cornea and sutured in place to treat small peripheral corneal perforations. To be most effective, the epithelium and the necrotic material surrounding the leak must be removed, and dissection of a small lamellar bed is helpful in suturing the sclera to the cornea. This technique is cosmetically less acceptable than the use of corneal material but may be of value in emergency situations.

Another technique using autologous cornea has been described in which a small trephine (2 mm) was used to dissect a half-thickness peripheral corneal button, which was sutured in place over a perforation in the cornea of the same eye. The donor site healed without complication, and the perforation was repaired. The most frequently used techniques for definitive repair of perforations involve some form of keratoplasty using donor material. The choice between lamellar and full-thickness penetrating keratoplasty depends on a number of factors, including location and size of the perforation, donor tissue availability, and associated ocular findings. It is better to choose lamellar grafting when the perforation is small and peripheral. Also, when marked anterior segment inflammation and a formed chamber are present, lamellar patch grafting may avoid instrumentation of the anterior chamber and the risk of fibrin outpouring, chamber flattening, and formation of synechiae.

Lamellar keratoplasty depends on the same principles as the use of tissue adhesive, ie, debridement of necrotic material and removal of surrounding epithelium. Additionally, a clean edge for suture placement is necessary and a dry bed is not necessary.

Penetrating keratoplasty for corneal perforation is the most aggressive approach but also may be mandated by the circumstances present. Large perforations, too large to seal with tissue adhesives or lamellar patch grafting, and smaller perforations surrounded by large areas of tissue necrosis may need penetrating grafts. The technique is that of standard penetrating keratoplasty with modifications because of the softness of the eye. With smaller perforations, tissue adhesives may be used to temporarily plug the leak, so that trephination may be performed. Viscoelastics may be used to help form the anterior chamber by injection through the perforation site. Either way, a trephine large enough to surround all the necrotic tissue should be used. A donor cornea that is 0.50 mm larger, then is sutured in place.

Consultations

An internist or rheumatologist may be consulted if a systemic disease is believed to cause the melting.

Prevention

Prevention of epithelial damage at the time of cataract surgery and prompt institution of therapy for dry eyes are important to prevent such a devastating complication.

Restore ocular surface defense by the following:

  • Discontinuing toxic topical medications

  • Punctal occlusion

  • Application of autologous serum

  • Silicone-based scleral contact lens

  • Plastic reconstruction of lash and lid problem

  • Mucous membrane grafting/amniotic membrane transplantation (see below)

    • Facilitates epithelialization

    • Maintains normal epithelial phenotype

    • Reduces stromal inflammation, vascularization, and scarring

    • Allogenic and limbal tissue

  • Avoid epithelial toxic and anesthetic medications.

Further Outpatient Care

Patients with corneal melts and perforations require close follow-up care. Patients with active melts are followed daily until significant improvement is demonstrated. Patients who have had corneal tissue adhesive for a severe melt of perforation are seen the following day and closely thereafter until improvement is seen.

 

Medication

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and to prevent complications. Tissue adhesives can be used with small perforations or descemetoceles with impending perforation.

Tissue adhesives

Class Summary

These agents may be applied under topical anesthesia at the slit lamp. The glue may induce significant inflammation and may be uncomfortable for the patient. They may adhere inadequately, may serve to harbor organisms once polymerized, and often are effective only in small perforations that can be dried readily. These substances polymerize rapidly when in contact with water. The favored adhesive for ocular surgery appears to be isobutyl-2-cyanoacrylate. Patients with progressive corneal melting secondary to ulcerative disease and patients with frank corneal perforations have been successfully treated with these cyanoacrylate adhesives.

The tissue adhesives most commonly used in the United States are cyanoacrylates, usually isobutyl or higher alkyl compounds. None of these are approved for ophthalmic use by the Food and Drug Administration, but N -butyl cyanoacrylate is under evaluation at this time.

N-butyl cyanoacrylate (Nexacryl)

Sterile, nontoxic, biocompatible, hemostatic, and bacteria static. A monomer, but when it comes in contact with moisture it is converted into a polymer. Inert material that solidifies within less than 5-10 seconds. Solidifies rapidly in alkaline media but slowly in acidic media. Does not get absorbed into the blood stream. Bacteria free and unaffected by many other bacteria.

Iso amyl-2 cyanoacrylate is a thickened monomer. Allows rapid wound closure with minimal scarring, reduced risk of subsequent infection, less traumatic, more efficient, precise, and safe.

The cyanoacrylate adhesive may be useful for covering ulcers and sealing perforations, because it can be applied over an ulcer bed and covered with a therapeutic soft contact lens. If glue displaces spontaneously from cornea in a few weeks, it can be reapplied to achieve continued stromal protection.

Various techniques have been described for the use of tissue adhesives; all require debridement of necrotic tissue and epithelium surrounding perforation, drying of area to which glue is to be applied, and application of least amount of glue that can cover the defect. Drying of defect can be carried out with cellulose sponges, and air or viscoelastic may be placed behind the perforation to separate tissue and reduce fluid present. The glue itself may be applied to a small plastic disk and then placed over the perforation, applied directly from the tip of a fine needle attached to a tuberculin syringe, or applied with a specially made applicator. The glue may come off and need to be reapplied, at times repeatedly. Usually, because of the rough surface of polymerized glue, a bandage soft contact lens is placed on the eye after the glue has polymerized.

Topical collagenase inhibitors

Class Summary

Mucolytic agent acetylcysteine has been advocated by some authors because they have shown to inhibit the lytic effect of collagenase in presence of, as well as in absence of, corticosteroids. Corneal melting, when it occurs, usually does not occur until after the fifth day following corneal surgery. Thus, it is reasonable to use corticosteroids to suppress the inflammatory response and prevent scarring for at least the first 5-7 days. The exact value of anticollagenase agents such as acetylcysteine has not been proven. Cysteine also inhibits collagenase and is more readily available as acetylcysteine, 10-20% concentration (Mucomyst). Another collagenase inhibitor is penicillamine. The use of collagenase inhibitors as adjunctive therapy in the treatment of progressive corneal melting has been disappointing.

Both disodium edetic acid and acetylcysteine have been used to inhibit collagenase activity, particularly in Pseudomonas corneal infections. These agents should be started if postoperative melting is observed.

Disodium ethylenediaminetetraacetic acid (EDTA) (Endrate) and calcium disodium EDTA (Calcium Disodium Versenate) inhibit collagenase through chelation. Evidence of local effective doses is not available, but 0.2 M irritation has been documented.

Among the many synthetic inhibitors of collagenase is Galardin. This agent appears to prevent the corneal ulceration of alkali injury by diminishing the release from PMNs of matrix metalloproteinases (MMPs) that digest capillary walls to allow extravasation of the PMNs. Any decrease in the number of locally extravasated PMNs decreases the potential pool of MMPs at the site of injury. Galardin further reduces inflammation by preventing release of tumor necrosis factor-a (TNF-a), a cytokine that activates PMNs, from producer cells such as macrophages and activated T cells. Galardin also may block MMPs released from inflammatory cells, corneal fibroblasts, and epithelial cells. It has been tried in cases of postoperative corneal melts.

Other synthetic inhibitors of MMPs include mercaptan (thiol)-containing compounds resembling the drug captopril, which inhibits the metalloproteinase angiotensin-converting enzyme in the treatment of heart failure and hypertension. One of the MMP inhibitors derived in this manner, HSCH2 CH[CH2 CH(CH3)2]CO-Phe-Ala-NH2 (SIMP), is effective in inhibiting corneal ulceration.

The alpha2-macroglobulin of serum is a powerful inhibitor of collagenase and the other MMPs. Alpha1-antitrypsin is considerably less effective against collagenase, but it too has been documented to prevent corneal ulceration after ocular chemical injuries. Blood is drawn into dry, sterile containers containing no anticoagulants clots and yields serum that can be separated and refrigerated until needed. If autologous blood is available, its therapeutic use need not be delayed by testing for human immunodeficiency virus or hepatitis. Gentamicin sulfate sufficient to achieve a concentration of 0.003% can be added to the serum before its administration by drops or by continuous perfusion.

N-acetylcysteine (Mucomyst 10-20%),

Topical collagenase inhibitor that may be beneficial in some patients. Formulated from commercially available Mucomyst, diluted to a 5% or 10% solution with artificial tears, and is applied 4-6 times/d. The 10% acetylcysteine drops can be given several times daily. Mucolytic action of this agent sometimes clears the ulcer. Not harmful to the globe or adnexum and obviously should be tried in pediatric age group before subjecting a child to a general anesthetic.

Ask the pharmacist to supply the acetylcysteine in a dark dropper bottle because of its instability in light.

Adequate lubrication with preservative-free tear and ointment supplements is important. Guidelines for solution have been used safely.

Corticosteroids

Class Summary

Adequate lubrication with preservative-free tear and ointment supplements such as corticosteroids are very important. Corticosteroids modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Immunosuppressive agents

Class Summary

Used for unresponsive severe corneal inflammatory disease or to prevent postoperative corneal melting syndromes in susceptible cases. Immunosuppressive medication may be beneficial. A more direct strategy in immuno intervention involves inhibition of various effector cells. Targeting effector cell products such as cytokines or their receptors has been effective.

Systemic and topical administration has been investigated regarding corneal graft rejection, intermediate and posterior uveitis, and noninfectious, immune-related corneal ulcers and postoperative corneal melts.

Topical CsA is of use in corneal graft rejection and prevention of postoperative corneal melts. A marginal corneal ulceration related to autoimmune disease can be improved through the use of topical and systemic CsA.

Cyclosporine (Sandimmune, Neoral)

Specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Has been used to treat a variety of forms of uveitis, often with good results. Binds to cyclophilin, an intracellular protein, which in turn prevents formation of interleukin 2 and the subsequent recruitment of activated T cells. Oral CsA and topical CsA (0.05%) can be used in melting stromal ulcers. It may be a good alternative mode of achieving ocular immunosuppression. Topical CsA has been shown to prevent postoperative corneal melts and to reduce the incidence of graft rejections in patients at high risk. A marginal corneal ulceration related to autoimmune disease can be improved through the use of topical and systemic CsA.

Cyclosporine has about 30% bioavailability, but there is marked interindividual variability. Cyclosporine specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that the drug be present during the first 24 h of antigenic exposure.

Oral cyclosporine has been used, with apparent efficacy, to treat corneal melting syndromes such as Mooren ulcer and that associated with Wegener granulomatosis.

The use of systemic cyclosporine significantly improves the results of surgery.

Antibiotics

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting.

Doxycycline (Vibramycin, Doryx, Bio-Tab, Vibra-Tabs)

Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.