Diagnostic Ophthalmology

History and clinical signs

An 11-year-old, castrated male Quarter horse that had a history of chronic corneal ulceration of the right eye was examined at the ophthalmology service at the Western College of Veterinary Medicine. The ulcer had been evaluated by the referring veterinarian 10 days previously and treatment was initiated with topical ofloxacin 0.3% antibiotic solution (PMS-Ofloxacin; Pharmascience, Montreal, Quebec) and atropine sulphate 1% (Isopto-atropine; Alcon Canada, Mississauga, Ontario), q6h through a subpalpebral lavage system (Mila International, Florence, Kentucky, USA), as well as oral phenylbutazone (Phenylbutazone tablets; Dominion Veterinary Laboratories, Winnipeg, Manitoba), 2 g, q12h. There was initial improvement followed by worsening of clinical signs which prompted a change in medication and referral. At the time of referral the horse was being treated with topical tobramycin 0.3% (Tobrex; Alcon Canada), q2h, Miconazole 1% (NCSU CVM Pharmacy), q6h, diclofenac sodium 0.1% (Voltaren ophtha; Novartis, Mississauga, Ontario), q6h, and atropine sulphate 1%, q6h as well as flunixin meglumine (Flunazin; Vétoquinol Canada, Lavaltrie, Quebec), 1.1 mg/kg body weight (BW), q12h, IV.

The menace responses, and palpebral and occulocephalic reflexes were present bilaterally. The right pupil was dilated and the direct and consensual pupillary light reflexes were absent in this eye due to atropine therapy. The direct and consensual pupillary light reflexes were present in the left eye. Schirmer tear test (Schirmer Tear Test Strips; Alcon Canada) values were 26 and 27 mm/min in the right and left eye, respectively. The intraocular pressures were estimated with a rebound tonometer (Tonvet; Tiolat, Helsinki, Finland) and were 9 and 22 mmHg in the right and left eye, respectively. Fluorescein staining (Fluorets, Bausch & Lomb Canada, Markham, Ontario) was positive over a 20 × 10 mm lesion in the right cornea. On direct examination there was moderate blepharospasm, conjunctival hyperemia, and mucopurulent ocular discharge in the right eye. Biomicroscopic examination (Osram 64222; Carl Zeiss Canada, Don Mills, Ontario) revealed a superficial corneal ulcer with a white/yellow plaque on its surface. Corneal vascularization was present circumferentially, extending 3 mm into the cornea. Diffuse corneal edema surrounded the ulcer and moderate aqueous flare was present in the anterior chamber. Due to the extensive corneal opacities, examination of the fundus was not possible in the right eye. The left eye was pharmacologically dilated (Mydriacyl; Alcon Canada) and indirect ophthalmoscopic (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) examination was normal in this eye. A photograph of the right eye is provided for your assessment (Figure 1).

Figure 1.

Photograph of the right eye of an 11-year-old Quarter horse. (A hair is adhered to the central area of the corneal surface).

What are your clinical diagnosis, differential diagnoses, therapeutic plan, and prognosis?

Discussion

Our clinical diagnosis was a complex corneal ulcer and anterior uveitis in the right eye. Differential diagnoses for a non-healing ulcer include infection with bacteria or fungi; eosinophilic keratoconjunctivitis; indolent corneal ulceration due to a basement membrane defect; ongoing mechanical trauma such as ectopic cilia, eyelid defects, conjunctival and corneal foreign bodies; and corneal dessication due to reduced tear production, exposure keratitis, neurotrophic or neuroparalytic keratitis.

Complex corneal ulceration is a clinical category of corneal ulcers which includes those that are infected, melting, or deep/perforated. We suspected a fungal infection of this ulcer based on the history and clinical appearance. The clinical manifestations of an infected corneal ulcer include photophobia, blepharospasm, corneal edema, lacrimation and often a purulent ocular discharge. The ulcer may have rough edges, and there is frequently a yellow/white infiltrate of inflammatory cells in the ulcer bed. Corneal vascularization will develop with chronicity. Fungal keratitis may occasionally contain a plaque that appears like cake frosting (1). The clinical manifestations are generally similar whether the ulcer is infected by bacteria, fungi, or both. Fungal keratitis, however, will fail to respond to conventional antibiotic therapy. Anterior uveitis tends to be moderate to severe in complex ulcers. Manifestations of anterior uveitis include miosis, ciliary spasm causing pain and photophobia, lacrimation, corneal edema, aqueous flare, and a lowered intraocular pressure.

The diagnosis of a complex corneal ulcer is based on clinical manifestations and positive fluorescein staining. Further diagnostic testing in all cases of complex corneal ulcers, and any ulcer not responding to therapy, should include aerobic and anaerobic bacterial and fungal culture and sensitivity and corneal ulcer cytology. If surgery is part of the therapeutic plan, keratectomy specimens removed at the time of surgery are submitted for histopathology to further examine for potential microbial colonization of these lesions. Bacterial cultures taken from this ulcer prior to referral showed growth of Bacillus sp. and anaerobic cocci on subculture, indicating low numbers were present. This was likely due to previous antibiotic therapy. Cytologic examination of scrapings made at the time of referral showed nests of branching fungal hyphae and degenerative neutrophils. A diagnosis of a mixed bacterial and fungal keratitis (keratomycosis) was confirmed.

Keratomycosis occurs more frequently in horses than other domestic species. Fungi are part of the normal flora of the equine conjunctiva and can invade the cornea if the epithelial barrier is compromised. Fungi may also infect the cornea through inoculation by contaminated objects, especially those of plant origin. The progression of keratomycosis is favored by the use of topical corticosteroids and prolonged use of topical antibiotics (2,3). Fungal keratitis is more common in warm, humid environments such as the southern USA; however, a few cases are seen yearly in western North America (3,4). The most frequently reported isolates are Aspergillus sp., Fusarium sp., and Candida sp., although these vary depending on location (5,6). Mixed bacterial and fungal infections occur in about 30% of cases (3–5). Pseudomonas, Staphylococcus, and Streptococcus species are frequently isolated in equine bacterial keratitis and mixed infections (3,5).

Treatment of fungal keratitis is aimed at halting fungal growth, controlling uveitis, and preventing corneal perforation. A combination of medical and surgical therapy is often required. As mixed infections are common, topical antibiotics are indicated in all cases to prevent and treat bacterial infection. The choice of antimicrobial agents is ideally based on results of culture and sensitivity but these results may not be available for several days. The only commercially available ophthalmic antifungal preparation is natamycin (Natacyn; Alcon Laboratories, Fort Worth, Texas, USA) which has a broad spectrum against filamentous fungi and yeast. However, natamycin, is not commercially available in Canada. Miconazole 1% to 2% is commonly used as the initial choice for treating confirmed or suspected fungal keratitis. Although there is no ophthalmic preparation available, the intravenous solution may be formulated for use on the eye. Alternatively, miconazole 2% vaginal preparations are also well-tolerated by the eye. Voriconazole is a newer antifungal with a broad spectrum and excellent corneal penetration in horses following topical administration (7). It has recently been shown to be the most effective antifungal against pathogenic fungi in vitro (8). A 1% solution formulated from the intravenous form is suggested as the most appropriate concentration for topical application. Silver sulfadiazine is a topical antimicrobial agent with both antifungal and antibacterial activity and may also be useful in keratomycosis (9). Frequency and duration of medical therapy are important considerations. Some authors recommend initiating antifungal treatment at 4 to 6 times daily as uveitis is often magnified following treatment at higher frequencies due to fungal death (10). An extended duration of therapy is usually required.

Control of secondary uveitis is essential in all complex corneal ulcers. The mainstay of treatment for secondary uveitis is a combination of anti-inflammatory and anticholinergic therapy. Systemic non-steroidal anti-inflammatory drugs (NSAIDs) should be used to reduce pain and help control secondary uveitis. Topical NSAIDs applied up to 4 times daily are also recommended to reduce anterior uveitis in all cases of complex corneal ulceration. Topically applied anticholinergics (1% to 2% atropine) are essential as well. They reduce protein and cellular leakage from inflamed uveal blood vessels and dilate the pupil which protects the eye from development of posterior synechia. Topical anticholinergics relax ciliary muscle spasm, which is a major factor in discomfort associated with uveitis (10). These may be applied up to 4 times daily in cases of severe uveitis.

Following initiation of appropriate medical treatment, prompt referral to an ophthalmologist for evaluation and possible surgery is recommended in all cases of complex corneal ulceration. Surgery is indicated for corneal ulcers unresponsive to medical therapy, that are very deep, or that progress despite treatment. Keratectomy is useful to remove infectious organisms and necrotic corneal tissue. This is often combined with conjunctival or corneal grafting procedures. A conjunctival pedicle graft is most often used as it improves corneal strength and can prevent perforation, and it is rich in vascular channels providing a direct route for mounting an immune response against the infecting organism (10).

Surgery was completed in this horse due to a lack of response to medical therapy. A lamellar keratectomy was completed to remove infected corneal tissue and this tissue was submitted for histopathology and fungal culture. A vascularized conjunctival pedicle graft was then sutured into the corneal defect. Microscopic examination of the keratectomy specimen confirmed the pre-surgical diagnosis of keratomycosis and Aspergillus sp. was isolated from the corneal tissue. Topical therapy with miconazole 1% q6h, ofloxacin 0.3%, q6h, diclofenac sodium 0.1%, q6h, and atropine sulphate 1%, q12h, was continued through the subpalpebral lavage system for 3 wk following surgery. Re-evaluation 3 wk after surgery revealed a comfortable eye. The conjunctival graft was healing and incorporated into the cornea. The remainder of the ocular examination was normal. The subpalpebral lavage system was removed and all ocular medications were discontinued.

The prognosis for keratomycosis is guarded (1–5). Eyes affected by superficial ulcers tend to have a better prognosis, while those with deep furrows or corneal perforation have a poor prognosis for retaining vision and are more likely to require enucleation (1,3). Keratomycosis is usually slow to respond to medical therapy alone and requires several weeks of therapy. A combination of medical and surgical treatment is associated with faster resolution and more positive outcomes (4,5,11). All cases of complex corneal ulceration benefit from consultation with a veterinary ophthalmologist.