Refractory Corneal Ulcers
Refractory corneal ulcers are superficial ulcerations that are not progressive yet also fail to heal within 5-7 days. The most common type of refractory corneal ulcers in dogs is a chronic corneal epithelial defect (CCED), otherwise known as an indolent ulcer. CCEDs are due to a failure of the epithelial cells to develop normal attachments to the underlying basement membrane. Any condition that interferes with normal epithelialization or epithelial cell adhesion can result in a CCED.
Causes of Refractory Corneal Ulcers
The first step in the management of a refractory corneal ulcer is to determine the underlying etiology. A thorough physical and ophthalmic examination is essential to identify factors that could be contributing to the refractive healing state. Refractory corneal ulcers can be caused by primary corneal disease or secondary to other processes. Eyelid abnormalities are quite common and may lead to a non-healing corneal ulcer. Specifically, persistent corneal trauma from distichia, ectopic cilia, entropion, or eyelid masses will interfere with normal cellular healing. Abnormalities that preclude normal blinking can predispose to refractory ulceration; lagophthalmos (incomplete blinking) may be associated with poor eyelid conformation, buphthalmos, exophthalmos, or cranial nerve deficits. Keratoconjunctivitis sicca (KCS, dry eye) is exceedingly common in dogs, and both quantitative and qualitative tear film abnormalities will interfere with normal corneal healing and result in a refractory corneal ulcer. A variety of primary corneal diseases will prevent or delay normal cell healing. Lipid, cholesterol, or calcium deposition in the cornea will inhibit the formation of strong cellular attachments. Corneal edema can lead to the formation of bullae, or fluid pockets, in the anterior corneal stroma. These areas are predisposed to ulceration that is often refractory in nature. The excessive stromal fluid inhibits normal epithelial cell attachment to the underlying stroma. Finally, superficial refractory ulceration that has no discernable underlying cause is known as spontaneous chronic corneal epithelial defects, or SCCEDs (“Boxer ulcers”, indolent ulcers).
Superficial Chronic Corneal Epithelial Defects
The boxer is the most common breed to develop SCCEDs, comprising approximately 25% of cases. Other breeds that have been reported to have an increased incidence of SCCEDs include poodle and poodle crosses, Welsh Corgis, Labrador retrievers, and German Shepherds and their crosses. The average age of dogs affected with SCCEDs is 7-9 years with no dramatic sex predilection. SCCEDs are often easily diagnosed by recognizing the typical clinical appearance of a superficial ulcer with a non-adherent epithelial border. Fluorescein stain can be classically seen diffusing under this loose lip of epithelial cells and appears as a less intense ring of stain uptake. SCCEDs are most often located in the axial or paraxial cornea and are vascularized approximately 60% of the time. Without proper treatment, SCCEDs may persistent for months to even years with an average time to referral of 7.5 weeks.
Normal corneal wound healing is accomplished via epithelial cell migration to cover the exposed stroma, followed by epithelial cell proliferation to restore the normal thickness of the epithelial layer. The epithelial cells develop firm attachments to the anterior corneal stroma via adhesion complexes. SCCEDs develop when the formation of these epithelial-stromal adhesions is inhibited. Thus, SCCEDs ulcers are often noted to epithelialize normally, however this newly formed epithelium is easily denuded contributing to the refractory nature of healing. SCCEDs have been studied histologically and multiple hallmark alterations in the normal healing process have been described. In almost all SCCEDs samples, the epithelial cells adjacent to the ulcer are poorly attached to the underlying stroma. Finally, there is formation of an acellular, hyalinized zone, which covers the exposed corneal stroma. This abnormal zone is now considered to contribute significantly to the pathophysiology of SCCEDs, as it interferes with the formation of strong epithelial-stromal adhesion complexes.
Treatment of Refractory Corneal Ulcers
Superficial corneal ulcerations are quite painful, as the corneal nerve density is greatest in this region. Despite the underlying cause, refractory corneal ulcers should be treated with topical prophylactic antibiotic therapy (every 8-12 hours), and a topical cycloplegic (e.g. atropine). Oral non-steroidal anti-inflammatories or additional pain medications are beneficial in controlling the discomfort, and a hard, plastic E-collar is necessary to prevent self-trauma. As previously discussed, refractory corneal ulcers have a variety of causes, and all efforts should be made to identify and treat any predisposing conditions.
Treatment of Superficial Chronic Corneal Epithelial Defects
Both medical and surgical methods for the treatment SCCEDs have been described. The foundation and crucial first step in all successful SCCEDs treatment modalities is epithelial debridement. Using a sterile cotton-tipped applicator to remove the loose epithelium can be safely performed after application of topical anesthetic. Normal epithelium is quite firmly adhered, and thus will not be removed with gentle debridement. Epithelial debridement on its own has a reported success rate of about 50%. Techniques that aim to remove or disrupt the acellular, hyalinized superficial stromal zone have improved published success rates over epithelial debridement alone.
The most recently reported therapy for SCCEDs is diamond burr debridement (DBD). DBD is performed using a handheld, battery powered polishing burr and has been described in human ophthalmology for the treatment of superficial, refractory ulcerations. The DBD technique was investigated histologically in dogs and shown to safely remove the epithelial basement membrane (and presumably the stromal hyalinized zone) without penetrating deeper into the corneal stroma. Recently, the DBD technique in conjunction with bandage contact lens (BCL) placement was evaluated in a clinical setting in dogs with a success rate of 92.5% after a single treatement. Minimal complications were noted, and 95% of dogs retained the contact lens during the study. The BCL is thought to improve healing by protecting the migrating epithelial cells, as well as improve patient comfort by covering the exposed corneal nerves. Overall, DBD is considered advantageous due to the minimal cost, lack of specialized equipment needed, ease of the procedure, and little adverse effects.
In clinical practice, the author treats SCCEDs in dogs with epithelial debridement, DBD, BCL placement, and oral doxycycline in addition to the standard topical antibiotic, and often oral NSAIDs therapy as for any corneal ulcer. Tetracyclines are known to modulate the expression of certain growth factors involved in corneal wound healing, and dogs that were treated with either topical oxytetracycline ophthalmic ointment or oral doxycycline healed faster than the control group. Anecdotally, a success rate of 90-95% is seen in the author’s practice, with an approximate 30% BCL retention rate.