Diagnostic Ophthalmology

History and clinical signs

A 9-month-old, 1.7 kg, spayed female Ragdoll cat was referred to the ophthalmology service at the Western College of Veterinary Medicine (WCVM) for evaluation of chronic bilateral conjunctivitis. Previous treatment with 0.3% ofloxacin (Ocuflox; Allergan, Markham, Ontario), q6h, bilaterally for 14 d resulted in moderate improvement; however, the condition had not resolved. The most recent therapy was topical 0.1% idoxuridine ophthalmic solution, q6h, bilaterally for 21 d, which resulted in no improvement.

Neuro-ophthalmic examination revealed normal menace responses and normal palpebral, oculocephalic, and direct and consensual pupillary light reflexes bilaterally. Schirmer tear test 1 (Schirmer Tear Test Strips; Alcon Canada, Mississauga, Ontario) values were 11 mm/min in both eyes. Intraocular pressures estimated by rebound tonometry (Tonvet; Tiolat, Helsinki, Finland) were 26 and 27 mmHg in the right and left eyes, respectively. Direct examination revealed serous-mucoid ocular discharge with brown crusts around the eyelids bilaterally. Biomicroscopic (Kowa SL-17 Portable Slit Lamp; Kowa Co, Tokyo, Japan) examination of both eyes was similar, and revealed moderate conjunctival hyperemia and chemosis. Indirect ophthalmoscopic (Heine Omega 200; Heine Instruments Canada, Kitchener, Ontario) examinations were completed bilaterally and were unremarkable. Fluorescein stain (Fluorets; Bausch & Lomb Canada, Markham, Ontario) was negative bilaterally. Photographs of the left and right eyes are provided for your assessment (Figure 1).

Figure 1.

Photograph of the right (a) and left (b) eyes of a 9-month-old spayed female Ragdoll cat, pre- (b) and post- (a) pharmacological mydriasis.

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

The clinical diagnosis was bilateral conjunctivitis. The most common differentials for feline conjunctivitis are the infectious agents feline herpesvirus type 1 (FHV-1), Chlamydia felis (C. felis), feline calicivirus (FCV), and Mycoplasma spp. (1–4). Non-infectious causes for feline conjunctivitis include feline eosinophilic conjunctivitis, lipogranulomatous conjunctivitis, tearfilm or eyelid abnormalities, and neoplasia (5,6).

Prioritizing the differential diagnoses for feline conjunctivitis requires careful assessment of the history, signalment, and clinical manifestations. Infectious agents are the most frequent cause of feline conjunctivitis and should be the first consideration in the absence of obvious non-infectious causes. Clinical findings that can help differentiate infectious causes of conjunctivitis include whether clinical signs are unilateral or bilateral, and the presence or absence of corneal disease and upper respiratory tract disease (URD).

FHV-1 is extremely prevalent in the feline population and a frequent cause of ocular disease (4,7). Primary infection typically occurs in kittens and clinical manifestations during this time commonly include URD, in addition to bilateral conjunctivitis. Following primary infection, the virus establishes latency within neurons of the trigeminal ganglia (7). Latent virus can subsequently become reactivated and travel peripherally along sensory axons into epithelial tissues, producing unilateral keratoconjunctivitis without signs of URD or with milder signs of URD than in primary disease (8). The virus is epitheliotropic and commonly causes superficial corneal ulceration. Dendritic (superficial, branching) ulcers are considered pathognomonic (2,3), and unilateral keratoconjunctivitis in an adult cat with a history of URD is highly suspicious for FHV-1. It is the only infectious cause of conjunctivitis that incites primary corneal pathology.

Chlamydia felis (C. felis, formerly known as Chlamydophila felis and Chlamydia psittaci var. felis) is another common cause of feline conjunctivitis (2–4), often affecting cats < 1 y of age (9) and rarely affecting those over 5 y (3). Acute infection typically manifests with unilateral conjunctivitis; however, this becomes bilateral within 1 to 3 wk (10). Conjunctival hyperemia, chemosis, serous to mucopurulent ocular discharge, and blepharospasm are commonly described (10). Mild fever, nasal discharge, and sneezing may occur in the acute phase in kittens but are not prevalent or consistent (11–13). Mild bilateral conjunctivitis may persist for months, and chronicity often leads to conjunctival lymphoid follicular hyperplasia, although this is not pathognomonic (11–13). In contrast to FHV-1, C. felis does not affect the cornea and, therefore, corneal ulceration does not typically occur unless co-infection with FHV-1 is present (13).

Feline calicivirus is a cause of URD and oral mucosal ulcerations in kittens (3). Although the role of this virus in causing conjunctivitis in cats has been questioned in the past, a recent study of cats with URD as well as ocular surface disease reported ocular samples analyzed by polymerase chain reaction (PCR) were positive for FCV alone in 17% of cats (14). Conjunctivitis is bilateral, and may be mild to severe, depending on the virus strain. Infection with FCV is most common in kittens housed in shelters (15).

Mycoplasma spp. (M. felis and M. gatae) have been isolated from the conjunctiva of clinically normal cats and those with conjunctivitis; however, their role as primary pathogens is ambiguous (1,16,17). The clinical course of conjunctivitis associated with Mycoplasma spp. is comparable to that of C. felis as it is reported to start in 1 eye but become bilateral within a few days (18,19). Clinical manifestations include conjunctival swelling and pallor with serous to mucoid ocular discharge, often with formation of a conjunctival pseudomembrane that may be peeled off (20,21). The role of Mycoplasma spp. as a primary pathogen is unclear as attempts to induce conjunctivitis with Mycoplasma spp. by experimental inoculation have generally been unsuccessful without prior corticosteroid treatment (18–20). Therefore, it is possible that stress or immunosuppression may be required for pathogenicity.

The most common non-infectious cause of feline conjunctivitis is feline eosinophilic conjunctivitis (FEC). This condition may be unilateral or bilateral and may affect conjunctival tissue only or can include corneal involvement (termed feline eosinophilic keratoconjunctivitis). This type of conjunctivitis typically presents with thickened, irregular conjunctiva, with swelling, depigmentation, and erosive changes of the lower eyelid, third eyelid, and medial canthus (6). Corneal involvement, when present, is characterized by vascularization, plaque formation, and white to pink ingrowth of granulation tissue, with or without corneal ulceration (21). Less common non-infectious conditions include lipogranulomatous conjunctivitis, which is associated with nonulcerated, smooth, white conjunctival nodules within the palpebral conjunctiva adjacent to the eyelid margin (5). Nodules often occur in clusters, are usually bilateral, and may involve both upper and lower eyelids (5). Mechanical irritation from the lesions may result in blepharospasm and ocular discharge. Tear-film and eyelid abnormalities such as entropion may also result in conjunctivitis due to mechanical irritation (3).

Regarding the common non-infectious causes of feline conjunctivitis, clinical findings on ocular examination are usually suggestive and can be supported with diagnostic testing. Cytology is most useful in the diagnosis of feline eosinophilic conjunctivitis, as finding 1 eosinophil in a conjunctival or corneal scraping is said to be diagnostic for this condition (4,6). Histopathology from conjunctival biopsy of representative lesions is an excellent means to confirm a diagnosis of feline eosinophilic conjunctivitis or lipogranulomatous conjunctivitis (5,6). Histopathology of FEC lesions typically reveals mixed inflammation with eosinophils, mast cells, lymphocytes, and plasma cells (6). The nodules of lipogranulomatous conjunctivitis consist of lipid droplets and associated granulomatous inflammation surrounding the meibomian glands, reminiscent of canine chalazia (5).

Attempting to differentiate the common infectious causes of feline conjunctivitis using diagnostic testing, however, is often unrewarding and frustrating. Cytology from conjunctival scrapings is often recommended but in practice is limited as a means of differentiating an infectious etiology (4). Intracytoplasmic epithelial cell inclusion bodies are reported with both C. felis and Mycoplasma spp.; however, inclusions are only evident for a short window in the early stage for both, for example, between days 6 and 14 for C. felis (22). When present, C. felis inclusions are more centrally located, whereas those of Mycoplasma spp. tend to cluster near the cell membrane (10,18,19). FHV-1 forms intranuclear epithelial cell inclusion bodies but these are also not commonly detected on conjunctival cytology of infected cats (23). Conjunctival swabs for virus isolation (FHV-1) or culture (C. felis and Mycoplasma spp.) require special transport media and specific laboratory techniques (13). Fluorescent anti-body (FA) testing on conjunctival scrapings may be performed to detect FHV-1 and C. felis but has limited sensitivity (4). Serum antibody titers for C. felis and FHV-1 may be elevated following recent infection; however, these are only useful in unvaccinated cats (13). Polymerase chain reaction testing is available for FHV-1, C. felis, and Mycoplasma spp. and is the most sensitive means of detecting presence of organism DNA in the research setting. However, false positives may occur due to contamination during sampling or testing, and false negatives may occur with inadequate sample collection, storage, and handling (13,24). In addition, PCR testing does not differentiate vaccine from wild-type FHV-1 DNA, which has been detected in 52.5% of clinically normal shelter-housed kittens (25,26). Commercial labs often run PCR for the 3 common conjunctival pathogens concurrently as an ocular panel. When we compared the agreement in PCR test results for these agents from cats with naturally occurring ocular disease in Canada, results were highly inconsistent between labs (24). Thus, the reliability of PCR in confirming a definitive etiology in a clinical setting is questionable.

Because of difficulties in establishing a definitive etiological cause for conjunctivitis using diagnostic testing, presumption of cause is often speculated based on a combination of history, clinical course, and clinical signs. A history of previous or coexisting URD is most suggestive of FHV-1. Acute cases that begin bilaterally in young cats are more likely to be FHV-1 or FCV, and presence of oral mucosal ulceration should trigger a higher suspicion of FCV than FHV-1. Cases that begin unilaterally and progress to bilateral involvement are more likely to be related to C. felis or, less likely, Mycoplasma spp. Unilateral conjunctivitis in an adult cat or conjunctivitis associated with corneal ulceration is more suggestive of FHV-1, whereas bilateral conjunctivitis in a young to middle-aged cat without corneal involvement is more likely to be C. felis or, less likely, Mycoplasma spp. Trial therapy for the most likely infectious agent may be pursued to help support a presumptive diagnosis. Successful response to antiviral therapy is supportive of FHV-1, whereas response to specific antimicrobial therapy is supportive of C. felis or Mycoplasma spp.

Chlamydia felis was the most likely cause of conjunctivitis in this young cat. Clinical signs were chronic, bilateral, and limited to the conjunctiva with no history or indication of previous corneal disease or URD, which made FHV-1 less likely. Given that there was no history of previous corticosteroid treatment or indication of systemic immunosuppression, infection with Mycoplasma spp. was also considered less likely.

Chlamydophila spp. are obligate intracellular organisms with cell walls that resemble Gram-negative bacteria (13). Chlamydia felis is primarily a conjunctival pathogen but may also infect the gastrointestinal tract and respiratory system. Clinical signs associated with these systems, however, are usually mild to absent (27). Chlamydia felis has been suspected as a cause of abortion, neonatal mortality, and infertility in catteries but a definitive causative link has not been confirmed (28). Young cats are most likely to be infected with C. felis, as natural immunity develops with age (13,29). Transmission occurs by close contact with infected cats, aerosols, and fomites (13). Asymptomatic carriers exist and may be significant in spreading the organism within the cat population, especially within multi-cat house-holds (30). Persistence of the organism in the genital and gastro-intestinal system is thought to contribute to chronicity of infection, the carrier state, and spread within the cat population (13). Vaccination does not prevent infection, although clinical signs are reduced in severity (12). Co-infection with feline immunodeficiency virus (FIV) can lead to a prolonged duration of clinical signs and development of chronicity (31).

Chlamydia felis is sensitive to tetracyclines, erythromycin, rifampin, fluoroquinolones, and azithromycin (3). Topical therapy with tetracycline, erythromycin, or fluoroquinolones may initially improve conjunctivitis; however, symptoms often return when treatment is withdrawn (32). The systemic nature of C. felis explains why topical therapy alone is insufficient in clearing infection (13). Doxycycline is the treatment of choice for feline chlamydiosis as it is the only antimicrobial that has been shown to successfully clear the infection (11). Various dosing regimens for doxycycline have been investigated. Doxycycline at 25 mg/cat [5 mg/kg body weight (BW)], q12h eliminated clinical and gross pathologic evidence of disease as well as organisms from tissues at necropsy (11). Doxycycline at 10 mg/kg BW, q24h for 7, 14, and 21 d failed to ensure elimination of the organism in 1 study (33). Therefore, at the 10 mg/kg BW dose, at least 28 d is recommended for the best chance of clearance. To minimize the potential for doxycycline-induced esophagitis and stricture, a suspension is recommended. If tablets are used, they should be unbroken, and a water bolus delivered via syringe following their administration (13). Improvement in conjunctivitis may occur within days of initiating systemic therapy; however, owners must be educated to complete the full course of treatment to avoid recurrence. It is recommended that all cats in the household be treated to eliminate asymptomatic carriers as potential sources of re-infection. Chlamydia is considered zoonotic. Transmission of C. felis from cats to humans has been reported (34). In addition, C. pneumoniae, a human pathogen, has recently been detected in a small number of cats with conjunctivitis (35). Although the risk of cat to human transmission appears to be very low (36), it is worth discussing the potential for this with owners and recommending hand washing and proper hygiene when handling affected animals.

For this cat, the lack of response to a recent trial of topical antiviral therapy, combined with a history of an initial improvement, but not resolution, with a topical fluroquinolone was supportive of our presumptive C. felis diagnosis. Further diagnostic testing was not pursued in favor of trial therapy for C. felis. Treatment with systemic doxycycline 10 mg/kg BW, q12h was initiated, and upon re-evaluation 4 wk later, the conjunctivitis had resolved, which further implicated C. felis as the cause of conjunctivitis in this cat.

Conjunctivitis is a very common disorder in cats and can be frustrating as it is frequently chronic or recurrent. Careful examination and evaluation of history, clinical course of disease, and response to previous therapies are often useful in establishing a presumptive diagnosis. Diagnostic testing can be unrewarding and difficult to interpret in a clinical setting. Trial therapies may be required to help validate the presumed diagnosis. Chlamydia felis often responds well to treatment; however, recurrent conjunctivitis may transpire if the organism is not eliminated or if re-infection occurs.