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

A corneal ulcer is defined as a lesion that involves degradation of the corneal stroma. This condition is associated with inflammation, either sterile or infectious. The primary purpose of this article is to highlight the pathogenesis of noninfectious stromal ulceration. The immune mechanisms of autoimmune ulcerative keratitis, particularly peripheral, are not included within this article.

Pathophysiology

An understanding of the pathophysiology of sterile corneal ulceration requires a review of the processes involved in epithelial and stromal wound healing, as well as an examination of the role of precorneal tear film, corneal nerves, proteolytic enzymes, and cytokines.

Epithelial wound healing

Corneal ulceration always begins with an epithelial defect. A persistent epithelial defect allows the corneal stroma to be exposed to the external environment and permits the process of stromal degradation.

Epithelial cell migration occurs centripetally until a defect is covered completely. Epithelial cells adjacent to the area of the defect flatten, lose their hemidesmosome attachments, and migrate on transient focal contact zones that are formed between cytoplasmic actin filaments and extracellular matrix proteins. Vinculin, integrin, fibronectin, fibrinogen, and fibrin are found in the region of these contact zones, which are formed continuously and cleaved to allow for cell migration. Plasmin is the protease responsible for cleaving fibrinogen and fibrin at these focal contact zones. The basement membrane is also important for epithelial migration, and abnormalities in basement membrane structure, whether due to trauma (eg, recurrent erosion syndrome) or dystrophy (eg, basement membrane dystrophy), can lead to persistence of corneal epithelial defects and stromal ulceration.

A sufficient supply of progenitor stem cells to facilitate epithelial cell proliferation is important for the cornea. A deficiency of limbal stem cells, either from disease (eg, aniridia) or trauma (eg, chemical burn), can preclude adequate epithelial wound healing, resulting in a persistent epithelial defect and allowing for stromal ulceration. Limbal stem cell transplantation (autograft, allograft, or ex vivo expansion) may be necessary in these cases.

Stromal wound healing

Stromal wound healing occurs via stromal keratocyte migration, proliferation, and deposition of extracellular matrix molecules, including collagen (specifically type III), adhesion proteins (eg, fibronectin, laminin), and glycosaminoglycans. These processes are facilitated by a phenotypic change among quiescent keratocytes to become active myofibroblasts, a task mediated by transforming growth factor beta (of presumptive epithelial origin).

Stromal necrosis and degradation

Matrix metalloproteinases (MMPs) are a group of structurally related endopeptidases that require a metal cofactor. To date, more than 25 have been identified and are categorized into 6 groups according to their substrate specificity. The main function of metalloproteinases is to degrade extracellular matrix and basement membrane components. With respect to corneal wound healing and ulceration, MMP-1, MMP-2, MMP-8, and MMP-9 appear to be the most important. MMP-2 and MMP-9 are known as gelatinases and are involved in cleaving collagen types IV, V, VII, and X, as well as fibronectin, laminin, elastin, and gelatins. MMP-1 (neutrophil collagenase) and MMP-8 (fibroblast or keratocyte collagenase) are involved in cleaving collagen types I, II, and III.

Barely detected in unwounded cornea, MMPs are strongly induced during wound healing. Metalloproteinases are secreted as proenzymes by neutrophils, injured epithelial cells, and keratocytes. They are activated by proteolytic cleavage of the N-terminal region in the extracellular compartment. In vivo, tissue inhibitors of metalloproteinases (TIMPs) inhibit collagenase activity. TIMPs represent a multigene family that includes at least 4 members. They exert their action by blocking the activation of MMPs and inhibiting proteinase activity.

MMP-9 is expressed by basal (replicating) epithelium and is thought to be important in the degradation of the basement lamina. In chemical injuries, this step always precedes the degradation of stromal extracellular matrix by MMP-1 and MMP-8. The collagenolytic activity of these latter enzymes reach a nadir of activity at approximately 3 weeks following injury, a time frame that parallels the peak of collagen synthesis activity in an alkali burn animal model. A relatively higher degree of collagenolysis relative to synthesis is thought to result in degradation, progressive corneal thinning, and, hence, ulceration of the corneal stroma. In vivo, this balance is moderated by cytokines secreted by the epithelium, stromal keratocytes, and inflammatory cells.

MMPs are induced at the transcriptional level by a variety of cytokines and growth factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), epidermal growth factor (EGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), and transforming growth factor-beta (TGF-beta).

Studies have shown a role for the extracellular matrix metalloproteinase inducer (EMMPRIN), a cell membrane glycoprotein enriched on epithelial cells in MMP induction during corneal wound healing. EMMPRIN was markedly induced in the anterior stroma of ulcerated corneas. It has been shown that it is up-regulated on epithelial cells by EGF and TGF-beta. This, in turn, induces fibroblasts, by direct interaction, to increase their own level of EMMPRIN, leading to induction of MMP. Inhibition of EMMPRIN may represent a promising future therapeutic strategy in situations of excess extracellular matrix degradation associated with chronic wound healing.

Since all metalloproteinase enzymes require metal cofactors Ca2+ and Zn2+, such chelating agents as ethylenediaminetetraacetic acid (EDTA), acetylcysteine, and penicillamine inhibit collagenase activity. Tetracyclines also possess anticollagenolytic activity. Endogenous TIMPs and alpha2-macroglobulin have metalloproteinase inhibitory activity and are probably the main inhibitors of MMPs in vivo.

As a result of collagen breakdown, tripeptide products of collagen are released. These are chemotactic for neutrophils, which migrate into the injured tissue where they release additional MMPs as well as superoxide radicals. These agents potentiate further collagenolytic action and corneal degradation. Superoxide dismutase (SOD) enzymatically reduces the superoxide radical to hydrogen peroxide, thus effectively eliminating highly reactive oxygen metabolites before any further damage. Isozymes of SOD are widely found in the corneas of mammals. Therefore, the use of topical SOD is helpful in preventing corneal damage. Studies have shown a beneficial effect of lecithinated SOD, which is retained on the ocular surface longer than native SOD when applied as an eye drop solution.

The role of corneal nerves

The cornea is densely innervated by fibers of the ophthalmic division of the trigeminal nerve and sympathetic nerve fibers from the superior cervical ganglion. The corneal epithelium is supplied by approximately 1000 small axons. Decreased corneal sensation from denervation can result in stromal ulceration and perforation. These ulcers result from decreased metabolic and mitotic rates in the corneal epithelium and reduced acetylcholine and choline acetyltransferase concentrations. A decrease in tearing, protective reflexes, and blink rate are associated with decreased corneal sensation.

In 1954, the classic experiment by Sigelman et al demonstrated that ocular surface changes associated with neurotropic keratitis in denervated animals persist despite tarsorrhaphy, suggesting a trophic effect of corneal nerves. The exact mechanism of this trophic effect is not definitively known. Evidence suggests that sensory neuron loss leads to a severe depletion of acetylcholine in an otherwise acetylcholine rich tissue, resulting in a relative decrease in epithelial cell growth.

Other studies attributed the depletion of substance P associated with sensory denervation as the cause of the changes associated with neurotrophic keratitis. It has been reported that substance P administered with insulinlike growth factor 1 (IGF-1) or EGF synergistically facilitate corneal epithelial migration and adhesion. Nakamura and coworkers determined that only the four-amino-acid sequence (FGLM) from the C terminal of substance P is necessary. This finding has implications for the clinical use of topically applied neuropeptides, since full-length peptides are more readily degraded and inactivated by peptidases in the tear film and corneal epithelium.

Recent clinical trials of nerve growth factor (NGF) by Bonini et al demonstrated a beneficial effect in promoting corneal epithelial wound healing and, possibly, in improving sensitivity in patients with neurotrophic keratitis. The mechanism of action of NGF on the ocular surface is not well defined. It may involve a direct mechanism of sensory innervation and the proliferation and differentiation of epithelial cells. An indirect mechanism, such as increasing the neuropeptides that promote epithelial healing or invoking immune cells through the release of cytokines, could also be involved.

The role of the precorneal tear film in ulceration

The exposure of the bare corneal stroma to its environment secondary to deficient or impaired epithelial wound healing is thought to contribute to stromal degradation through environmental factors, cytokines, lytic enzymes, and neutrophils in the tear film. Direct neutrophil adhesion to the corneal stroma theoretically allows hydrolytic and collagenolytic enzymes, including MMP-8 (neutrophil collagenase), to contribute to the degradation of the corneal stromal extracellular matrix. Dohlman et al and subsequently Kenyon et al demonstrated that a glued on methylacrylate lens applied to a rabbit alkali burn model of corneal ulceration protected the stroma from collagenolysis by neutrophils and injured epithelial cells. Keratocyte fibroblasts also may contribute to this milieu. The prevention of neutrophil infiltration and promotion of epithelialization is thought to be at least one of the mechanisms responsible for the beneficial effect of amniotic membrane graft use in preventing stromal ulceration.

In addition, cytokines, such as hepatocyte growth factor (HGF), keratocyte growth factor (KGF), and EGF, are produced by the lacrimal gland and, thus, are present in tears. HGF is upregulated in response to corneal injury in parallel with increased aqueous tear production. In the wounded cornea, these cytokines may play an important role in regulating epithelial healing. Inflammatory cytokines, including IL-1alpha, are detectable in normal human tears and may be important in causing further degradation of the corneal stroma either directly by inducing keratocyte apoptosis or by recruiting inflammatory cells via their chemotactic properties. In addition, an irregular tear film and a decreased tear film breakup time over the area of the bare stroma can cause a delle effect that may contribute to an unfavorable cellular environment for the viability and proliferation of stromal keratocytes.

The role of cytokines

The complex autocrine and paracrine functions of the cytokines involved in the interactions between the corneal epithelium and stromal keratocytes are important in achieving the appropriate responses to corneal wound healing. These responses are orchestrated by complex interactions between the cytokines secreted by each of these cell types. While their precise triggers and interactions are still being elucidated, cytokines can induce and mediate many of the fundamental steps involved in wound healing.

When the epithelium is injured, the cornea responds by synthesizing several growth factors and cytokines that regulate the repair of the tissue.

Epithelial cell migration, proliferation, and differentiation are influenced by the stromal keratocyte cytokines, KGF and HGF. The cornea is not unique with respect to the stromal-epithelial interactions of these 2 cytokines, which are mediators of similar interactions in the breast, skin, and lung. Although the expression profiles of these cytokines lend themselves toward a linear interpretation of their stromal-epithelial interactions, these cytokines clearly are modulated further in vivo by the effects of other cytokines and truncated receptors of these molecules.

In what is likely to be merely the tip of the iceberg with respect to the understanding of cytokine-cytokine interactions, both KGF and HGF mRNA production are altered by the fibroblast cytokines, EGF, TGF-alpha, PDGF, and IL-1. In addition, EGF, PDGF, IL-1alpha, IL-6, and TNF at low concentrations appear to enhance fibronectin (FN)-induced epithelial cell migration.

Not to be eclipsed by stromal influences, epithelial cells modulate important keratocyte responses to epithelial cell injury. Keratocyte wound healing processes, including MMP production and regulation, HGF and KGF production, and keratocyte apoptosis, are mediated via various cytokines, including stimulators like IL-1 and soluble Fas ligand and major inhibitor TGF-beta2. Anterior stromal keratocyte cell death is an important feature of corneal wounding and stromal degradation.

Beyond keratocyte cell death caused by mechanical injury or necrosis associated with neutrophil infiltration, IL-1– and Fas ligand–mediated apoptosis is an important stromal response to epithelial injury. Since both of these cytokines can be produced by keratocytes, autocrine modulation of these responses may occur. IL-1 and PDGF also regulate MMP expression in stromal keratocytes. The exact keratocyte response to IL-1 is likely to be determined by the cytokine milieu in which the targeted keratocyte resides. Other cytokine systems that have demonstrated fibroblast apoptosis include TNF and bone morphogenic protein (BMP).

Meticulous control of these cytokines conceivably allows for more predictable corneal wound healing. Topical KGF has been shown to accelerate epithelial wound healing in a rabbit model of corneal ulceration. Since its effects are mediated through a paracrine pathway, topical use of cytokines (eg, KGF) may prove to be especially effective in ocular disorders accompanied by loss of epithelium that require corneal limbal stem cell proliferation.

Platelet-activating factor (PAF) is a potent bioactive lipid that is generated in the cornea after injury. Studies have shown that corneal cells synthesize PAF as early as 30 minutes after injury and increased accumulation is observed at later times, which is, in part, due to the presence of inflammatory cells that arrive at the cornea and actively produce PAF. PAF is a strong inflammatory mediator and inducer of the expression of specific genes, such as some metalloproteinases, urokinase plasminogen activators, and TIMPs. It delays corneal epithelial wound healing by inhibiting adhesion of epithelial cells to the basement membrane and by increasing apoptosis of stromal cells. All these activities exerted by PAF are receptor mediated. Corneal epithelial cells, keratocytes, and endothelial cells express the PAF receptor, and, in corneal epithelial cells, injury up-regulates PAF receptor gene expression. The role of PAF receptor antagonists in preventing corneal injury is under investigation.

Plasminogen is synthesized in the cornea and can be activated to plasmin by plasminogen activator. This synthesis is stimulated by IL-1alpha and IL-1beta. Plasmin is able, in turn, to activate latent collagenase. This system could lead to the collagen degradation of corneal ulceration. Studies have demonstrated that uPA (urokinase plasminogen activator), but not tPA (tissue plasminogen activator), is induced in the migrating epithelial cells during corneal epithelial wound healing. Amiloride, a specific uPA inhibitor, effectively decreases uPA activity in the cornea as well as in the tear fluid and favorably affects corneal healing.

Cytokines and trophic factors from corneal nerves, the tear film, the conjunctiva, conjunctival vessels, the endothelium, and the anterior chamber may have important modulating effects on corneal epithelial and stromal healing responses and, thus, corneal ulceration.

Frequency

United States

The incidence rate depends on the etiology of the corneal ulcer.

Mortality/Morbidity

Corneal scarring, decreased vision, neovascularization, perforation, and blindness are associated with this condition.

Sex

Because of an increased incidence of injuries, this condition may be seen more frequently in males than females.

CLINICAL

Section 3 of 10  

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

History

• In diagnosing this condition, differentiating between infectious and noninfectious etiologies is crucial. Since the clinical management of any corneal ulcer is dependent on its etiology, obtaining all of the salient factors (eg, endogenous, exogenous, local) is important. Therapies for sterile persistent ulcerations should be considered only after adequately addressing infectious and systemic factors.
• Key points to assess in obtaining the history of a patient with a corneal ulcer include the following:
• • Prior ocular history - Prior ocular and adnexal surgery, recurrent episodes or infections (eg, herpes), and corneal dystrophy
  • Past medical history - Immune status, collagen vascular diseases, systemic infections, diabetes, malnutrition, alcoholism, and chronic debilitating diseases
  • History of trauma - Foreign bodies and their origin (eg, soil, vegetation, water), chemical splashes, and lid lacerations
  • Contact lens use - Type, frequency, duration, overnight use, and hygiene
  • Medications - Ocular and otherwise
  • History of present illness - Duration, ocular symptoms (eg, degree of pain vs clinical impression), and chronicity
  • Social history - Patient from an area endemic for certain infectious processes, nutritional status, and any alcohol abuse
• The etiology of a sterile ulcer is often multifactorial; in this setting, identifying the coconspirators in this process is important. A thorough evaluation to identify potential factors, including medications (medicamentosa), impaired corneal sensation (neurotrophic), exposure (eg, lagophthalmos), and reduced tear production (sicca), is necessary in most cases of persistent noninfectious ulceration.

Physical

• The physical examination should begin with a gestalt impression of the entire patient, with attention to the following:
• • General health of the patient - Skin lesions, skeletal abnormalities, mental status, degree of discomfort, hearing aids, scars, and limitations to ambulation that may indicate a systemic illness
  • Local ocular adnexa and related organs - Eyelids, lacrimal system, blink rate, scars, mucous membranes (eg, lips/mouth, conjunctiva), orbit, symmetry, and evidence of inflammation or infection
  • Palpation - If indicated for orbital resiliency (thyroid/exposure), lymphadenopathy, and lacrimal or other adnexal masses
  • Observation - Lagophthalmos and blink rate
  • Assessment of vital signs of the eye - Visual function, corneal sensation, tonometry, pupil function, and motility of the eye (Corneal sensation should be checked prior to tonometry.)
• On slit lamp examination of the cornea, note the appearance of and evaluate the following:
• • Conjunctiva, sclera, and lids - Erythema, pattern of injection (ciliary flush, diffuse or deep), perilimbal nodules, discharge, lid closure, lid margin disease, and flipped upper lid to exclude foreign body and floppy eyelid syndrome
  • Tear film - Degree, symmetry, regularity, and presence of debris
  • Epithelium - Location of epithelial defect (localized or diffuse), regularity, and microcysts
  • Stroma - Thinning and presence/pattern of infiltrates (eg, ring, feathery, radial)
  • Endothelium - Keratic precipitates
  • Anterior chamber - Hypopyon and inflammation
  • Corneal sensation
  • Symmetry between the eyes
  • Fluorescein examination
  • Dilated examination (if necessary)

Causes

A thorough history and physical examination should allow a clinician to narrow down the differential diagnosis.

• Infectious causes (which need to be ruled out first) include the following:
• • Bacterial (focal infiltrate)
  • Fungal (vegetable matter, eg, branch; appearance of satellite lesions; feathery borders to infiltrate; chronic)
  • Acanthamoeba (contact lens wear, tap water, soil, severe pain out of proportion to the appearance, radial keratitis, ring ulcer)
  • Herpes simplex virus (history, dendrites, decreased sensation, disciform keratitis, increased intraocular pressure)
  • Herpes zoster virus (vesicles over dermatome; pseudodendrites, no true terminal bulbs; decreased sensation; increased intraocular pressure)
  • Contact lens related (infectious or noninfectious)
• Noninfectious causes include the following:
• • Chemical burns, including alkali/acid burn (check pH)
  • Thermal/radiation burns (history)
  • Sicca (filaments, Sjögren syndrome)
  • Neurotrophic (decreased sensation, may have minimal pain, rolled edges, oval, lower one half of cornea, may be quite thin, herpes zoster virus/herpes simplex virus, postsurgery, fifth-nerve palsy, chemical burns, abuse of topical anesthetics, neurotrophic keratitis, diabetes mellitus, multiple sclerosis)
  • Exposure (lagophthalmos, lid abnormalities, inadequate blink, facial palsy, proptosis, thyroid disease)
  • Medicamentosa (drops)
  • Atopic (history, follicles/papillae)
  • Vitamin A deficiency (primary deficiency due to prolonged dietary deprivation; secondary deficiency due to diseases that interfere with fat absorption and storage, eg, celiac disease, cystic fibrosis, cholestasis)
  • Basement membrane abnormalities (microcysts, evidence of map-dot-fingerprint or anterior stromal dystrophies, history of trauma, other dystrophy)
  • Factitious
• Immune-related causes (usually peripheral) include the following:
• • Wegener granulomatosis
  • Rheumatoid arthritis
  • Other collagen vascular diseases (indicated from history and associated systemic findings)

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

Lab Studies

• Given the morbidity of missing an infectious ulcer, the importance of performing corneal smears and cultures cannot be overemphasized. Infectious etiologies should be ruled out initially by performing smears and cultures.
• Corneal scraping also is indicated to evaluate for infectious etiologies.
• Perform a workup to rule out infectious or systemic inflammatory diseases (eg, collagen vascular, autoimmune) as clinically indicated. Systemic testing (eg, blood work) may be necessary in certain patients.
• The precise stains and cultures depend on clinical suspicion.
• • Stains - Gram stain, Giemsa, Calcofluor white, acid-fast bacillus (AFB), and Gomori
  • Cultures - Sabouraud agar, blood/chocolate agar, thioglycolate solution, and Page solution (then Escherichia coli overlay)

Procedures

• If clinically indicated, performing a biopsy of the presumed infectious ulcer is recommended to identify the causative organism.

TREATMENT

Section 6 of 10  

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

Medical Care

Individual treatment should be tailored toward the coconspirators that are identified by the history and physical examination. Again, the importance of first excluding infectious etiologies is paramount. Once identified, each contributing factor needs to be treated appropriately. All toxic drops should be eliminated if medicamentosa is suspected. Lagophthalmos should be treated with copious lubrication, with taping for variable amounts of time, beginning with sleeping hours. Tarsorrhaphy is indicated if previous method fails. Patients with sicca need copious lubrication and punctal plugs. Evaluate these patients for systemic rheumatologic disease if suspected by clinical history or examination. If immune disease is suspected, systemic immunomodulatory therapy may be necessary. Treatment modalities are outlined below.

• Antibiotics are used to treat the ulcer or as a prophylactic but do encourage resistant microbial strains. Long-term use with certain antibiotics may cause medicamentosa, epitheliopathy, and crystal deposits.
• Immunomodulatory medications (eg, cyclophosphamide, cyclosporine, methotrexate, azathioprine) are indicated if necessary. Topical cyclosporin A drops currently are being evaluated in clinical trials.
• Lubrication (eg, artificial tears) is recommended, but preservatives should be avoided.
• For chemical burns, corticosteroids (ie, prednisone) are useful for reducing surface inflammation; however, after 10-14 days, collagen synthesis becomes important in the repair process. Prednisone may alter the balance of collagen synthesis versus degradation. Although they have weaker anti-inflammatory properties, progestational steroids (eg, medroxyprogesterone) demonstrate less suppression of collagen synthesis (wound repair).
• Medroxyprogesterone (eg, Provera)
• Oral tetracycline or minocycline can be combined with topical tetracycline preparations or with other therapeutic modalities, such as topical antibiotics, cycloplegics, ocular hypotensives, sodium citrate, ascorbic acid, and acetylcysteine.
• Use of vitamin A is investigational. Initial trials demonstrated clinical efficacy that was not replicated subsequently.
• Although investigational, fibronectin has been shown to improve epithelialization in vitro; however, clinical trials did not demonstrate efficacy.
• Use of ascorbic acid/citrate for burns only is investigational.
• Serum derived tears are under investigation.
• Cell proliferation and trophic factors (eg, KGF, EGF, NGF) are investigational.
• Recombinant human tumor necrosis factor receptor Fc fusion protein (etanercept) can be used in progressive disease or in cases that are unresponsive to traditional therapies.
• PAF receptor antagonists are under investigation.
• Topical administration of NGF is under investigation.
• Topical application of lecithinated SOD analog (PC-SOD) has proven to be beneficial.
• Metalloproteinase inhibitors
• • Synthetic thiols
  • N-acetylcysteine
  • Cysteine
  • Sodium and calcium EDTA
  • Penicillamine
  • Tetracyclines
  • TIMPs
• Punctal occlusion includes plugs/cautery.
• A primary barrier method (eg, therapeutic soft contact lenses, scleral lenses, glued on contact lens) should be created and used.
• Tissue adhesives are best for impending or actual perforations that are 1 mm or smaller in size. They may be removed or allowed to extrude spontaneously after 6-8 weeks when a fibrovascular scar has formed and eliminated the risk of stromal ulceration.
• Amniotic membrane transplantation (alone or with ex vivo expansion or limbal stem cell transplantation)
• Conjunctival flap/graft or Tenon-plasty (for reestablishment of limbal vascularization in alkali burns)
• Tarsorrhaphy (temporary vs permanent lateral)
• Corneal transplant (lamellar or penetrating) or tectonic graft (temporizing measure until graft bed is vascularized and arrests further ulceration)
• Mucous membrane grafting
• Keratoprosthesis

Surgical Care

See Medical Care for possible surgical treatments.

Consultations

• Corneal specialists
• Neurologist or neuro-ophthalmologist for probable CNS neurotrophic etiology

MEDICATION

Section 7 of 10  

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

As discussed in Medical Care, a number of medications for sterile corneal ulcers refractory to conventional treatment are currently being investigated with respect to their clinical efficacy (eg, fibronectin, vitamin A, ascorbic acid, serum-derived tears, metalloproteinase inhibitors, neurotrophic growth factor). Therefore, standard dosing, indications, treatment regimens, and contraindications with respect to these medications are not available. The authors recommend that interested physicians directly contact clinical investigators for specific treatment regimens currently employed in treatment trials.

Antibiotics often are used prophylactically in treating patients with sterile corneal ulcerations. Specific dosing and medication information on topical antibiotics are not included in this article.

Immunomodulatory treatment regimens are complex, and elaborating on medication dosing and treatment regimens for specific rheumatologic diseases is beyond the scope of this article.

Drug Category: Ophthalmic corticosteroids

Minimize the activity of inflammatory cells and formation of granulomas. Used in symptomatic patients and commonly provides symptomatic improvement.

FOLLOW-UP

Section 8 of 10  

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

Further Outpatient Care

• Patients must receive close follow-up care until resolution of the corneal ulcer.

Deterrence/Prevention

• Patients should wear eye protection to prevent injury to the cornea, especially if the cornea is thin.

Complications

• Complications include corneal scarring, neovascularization, decreased vision, central corneal perforation, and endophthalmitis. Other possible complications include cataract, glaucoma, and blindness.

Prognosis

• Prognosis depends on the severity of the condition and patient response to therapy in addition to associated local and systemic factors.

Patient Education

• For excellent patient education resources, visit eMedicine's Eye and Vision Center. Also, see eMedicine's patient education article Corneal Ulcer.

MISCELLANEOUS

Section 9 of 10  

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

Medical/Legal Pitfalls

• Failure to promptly diagnose and provide early treatment to prevent visual loss
• Failure to first rule out infectious causes

Special Concerns

• In treating a patient with a corneal ulcer, evaluate for underlying systemic conditions and manage them appropriately.

REFERENCES

Section 10 of 10

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

• Albert DM, Jakobiec FA, eds. In: Principles and Practice of Ophthalmology. 2nd ed. Boston:. WB Saunders Co;2000.
• Barletta JP, Angella G, Balch KC, et al. Inhibition of pseudomonal ulceration in rabbit corneas by a synthetic matrix metalloproteinase inhibitor. Invest Ophthalmol Vis Sci. Jan 1996;37(1):20-8. [Medline].
• Bernauer W, Ficker LA, Watson PG, Dart JK. The management of corneal perforations associated with rheumatoid arthritis. An analysis of 32 eyes. Ophthalmology. Sep 1995;102(9):1325-37. [Medline].
• Bonini S, Lambiase A, Rama P. Topical treatment with nerve growth factor for neurotrophic keratitis. Ophthalmology. Jul 2000;107(7):1347-51; discussion 1351-2. [Medline].
• Dohlman CH, Slansky HH, Laibson PR, et al. Artificial corneal epithelium in acute alkali burns. Ann Ophthalmol. 1969;112.
• Dua HS, Gomes JA, Singh A. Corneal epithelial wound healing. Br J Ophthalmol. May 1994;78(5):401-8. [Medline].
• Gabison EE, Mourah S, Steinfels E. Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction. Am J Pathol. Jan 2005;166(1):209-19. [Medline].
• Geerling G, Joussen AM, Daniels JT, et al. Matrix metalloproteinases in sterile corneal melts. Ann N Y Acad Sci. Jun 30 1999;878:571-4. [Medline].
• Gipson IK, Inatomi T. Extracellular matrix and growth factors in corneal wound healing. Curr Opin Ophthalmol. Aug 1995;6(4):3-10. [Medline].
• He J, Bazan NG, Bazan HE. Alkali-induced corneal stromal melting prevention by a novel platelet-activating factor receptor antagonist. Arch Ophthalmol. Jan 2006;124(1):70-8. [Medline].
• Imanishi J, Kamiyama K, Iguchi I, et al. Growth factors: importance in wound healing and maintenance of transparency of the cornea. Prog Retin Eye Res. Jan 2000;19(1):113-29. [Medline].
• Kaufman HE, et al, eds. The Cornea. 2nd ed. Boston:. Butterworth-Heinemann;1998.
• Kenyon KR, Berman M, Rose J. Prevention of stromal ulceration in the alkali-burned rabbit cornea by glued-on contact lens. Evidence for the role of polymorphonuclear leukocytes in collagen degradation. Invest Ophthalmol Vis Sci. Jun 1979;18(6):570-87. [Medline].
• Nagano T, Nakamura M, Nakata K. Effects of substance P and IGF-1 in corneal epithelial barrier function and wound healing in a rat model of neurotrophic keratopathy. Invest Ophthalmol Vis Sci. Sep 2003;44(9):3810-5. [Medline].
• Nakamura M, Chikama T, Nishida T. Synergistic effect with Phe-Gly-Leu-Met-NH2 of the C-terminal of substance P and insulin-like growth factor-1 on epithelial wound healing of rabbit cornea. Br J Pharmacol. May 1999;127(2):489-97. [Medline].
• Shimmura S, Igarashi R, Yaguchi H. Lecithin-bound superoxide dismutase in the treatment of noninfectious corneal ulcers. Am J Ophthalmol. May 2003;135(5):613-9. [Medline].
• Sigelman S, Friedenwald JS. Mitotic and wound healing activities of the corneal epithelium: effect of sensory denervation. Arch Ophthalmol. 1954;52.
• Watanabe M, Yano W, Kondo S. Up-regulation of urokinase-type plasminogen activator in corneal epithelial cells induced by wounding. Invest Ophthalmol Vis Sci. Aug 2003;44(8):3332-8. [Medline].
• Wilson SE, Liu JJ, Mohan RR. Stromal-epithelial interactions in the cornea. Prog Retin Eye Res. May 1999;18(3):293-309. [Medline].

Article Last Updated: Feb 14, 2007