Diagnosis and treatment of dry eye in dogs

March 17, 2021
Ron Ofri, DVM, PhD, DECVO

Dr. Ofri is a professor of comparative ophthalmology at the Koret School of Veterinary Medicine at Hebrew University of Jerusalem in Rehovot, Israel.

dvm360, dvm360 April 2021, Volume 54,

Keratoconjunctivitis sicca is among the more common ocular conditions seen in dogs. Here is a look at what causes dry eye and how to manage it.

Tears play an important role in maintaining the health of the ocular surfaces because they supply the metabolic requirements of the avascular cornea. Tears also contribute to ocular defenses, as they contain globulins and other antimicrobial factors, and wash away foreign bodies and dirt. Finally, tears contribute to lubrication of the ocular surfaces, and to the optical refraction of the eye. Although the tear film is rich in (outer) lipid and (inner) mucin, most of these physiologic functions are conducted through the aqueous layer.

In dogs, about two-thirds of the aqueous layer is produced in the main lacrimal gland, with the balance produced primarily by the lacrimal gland of the third eyelid. After washing over the ocular surfaces, tears flow through the puncta into the nasolacrimal system, draining into the nasal or oral cavity. Diseases of the lacrimal system may be roughly divided into problems of production (which may be insufficient or excessive) and problems of reduced drainage.

Etiology of keratoconjunctivitis sicca

The most common tear deficiency is caused by reduced production of the aqueous layer of the tear film, which causes quantitative tear deficiency and leads to inflammation of the conjunctiva and cornea known as keratoconjunctivitis sicca (KCS), or dry eye. KCS is a very common canine eye disease with a reported incidence of up to 1.5% in North America.1 By contrast, the incidence of dry eye in cats is very low.

Autoimmune KCS

Local immune-mediated disease is widely accepted as the most common cause of KCS on the basis of histopathology of the lacrimal glands and the clinical response to immunomodulating therapy. The disorder is characterized by a lymphocytic–plasmacytic infiltrate of the acinar epithelial cells of the lacrimal gland.

Autoimmmune KCS is generally thought to be caused by a disruption of the blood–tear barrier protecting the immune-privileged lacrimal glands, allowing the immune-mediated destruction of these tissues. Indeed, some dogs with KCS have circulating autoantibodies against the orbital and nictitans lacrimal glands. This form of the disease most likely has a genetic component, as it is more prevalent in some breeds (ie, spaniels, bulldogs, and brachycephalic breeds).

Endocrinologic diseases

Lacrimal gland secretions are reduced in endocrinologic disorders, including diabetes, hyperadrenocorticism, and hypothyroidism. The clinical presentation is usually bilateral and there is no breed predisposition. Although KCS may be the only clinical sign observed by the owner, it usually appears concomitantly with other systemic signs of the endocrinologic disease. Dogs with diabetes have been shown to have alterations in the mucin component of tears and lower corneal sensitivity in addition to reduced Schirmer tear test 1 (STT-1) values.

Systemic infectious diseases

Some infectious diseases may induce KCS in the dog and cat, as the infectious agent causes lacrimal gland adenitis. Distemper2 and leishmaniasis3 are the 2 most common infectious causes in dogs, and feline herpesvirus-14 is the most common infectious cause in cats.

Neurogenic KCS

A primary loss of parasympathetic innervation to the lacrimal gland (cranial nerve [CN] VII) can lead to quantitative KCS. Some affected animals may have a history of unilateral orbital traumatic or inflammatory disease, whereas otitis media/interna may be the primary cause in others. Because the parasympathetic branch of CN VII innervates the lateral nasal glands, dogs with neurogenic KCS may also present with dryness and crusting of the ipsilateral nostril (xeromycteria) if the lesion is proximal to the pterygopalatine ganglion.

Diagnosing dry eye

Clinical signs

Quantitative KCS is typically manifested by several clinical signs: mucoid or mucopurulent ocular discharge, blepharospasm, conjunctival hyperemia, corneal vascularization and pigmentation, a dry and lusterless cornea, and corneal ulceration.

Mucoid or mucopurulent ocular discharge is the most consistent clinical sign in canine KCS. In quantitative KCS, the reduction in the aqueous component of the tear film may result in compensatory conjunctival cell hyperplasia and increased mucin production, thus inducing a thick serous or seromucoid discharge that often sticks to the cornea and conjunctiva as ropy strands. With time, this discharge will become mucopurulent due to inflammatory cell infiltration of the ocular surface, or it may become septic if secondary infection has occurred (Figures 1-3).

Blepharospasm is a sign of marked discomfort induced by frictional irritation as the eyelids move over a dryer ocular surface. Severe signs of discomfort more often accompany acute and severe cases of KCS, whereas blepharospasm and pain are very subtle in chronic cases.

Eyes with reduced tear production often appear red and irritated. Conjunctival hyperemia usually involves both the palpebral and bulbar conjunctiva, although the former is commonly affected first. Varying degrees of conjunctival thickening and chemosis may also be seen.

Because the superficial cornea receives most of its metabolic support from the tear film, reduced tear production leads to superficial corneal vascularization aimed at replacing the lost metabolic support. Along with vascularization, inflammatory cells, edema, pigment (melanin), lipids, and calcium may be secondarily deposited in the cornea, inducing, in very chronic cases, severe corneal opacity leading to reduced vision. Over time, the corneal epithelium thickens due to squamous metaplasia and hyperkeratinization. Nonetheless, at this stage the cornea is typically less susceptible to ulceration, and if an ulcer develops it may be less painful because of loss of corneal sensation.

When the tear film is deficient, the cornea loses its clear, moist, and bright appearance, appearing dull and lusterless.

Dry eyes are prone to corneal ulceration because corneal epithelial cells are more readily exfoliated by the greater friction associated with blinking over the roughened, keratinized epithelium of the palpebral conjunctiva. Additionally, in the acute phase of the disease, the tear film becomes hypertonic, leading to dehydration of the ocular surface epithelium, and resulting in generalized thinning of the corneal epithelium (Figure 4).

These ulcers can become complicated (melting ulcers or perforations) because the ocular surface immunity and antiprotease levels are severely reduced. Central corneal ulceration or perforation is more often seen in acute and severe cases of KCS. Conversely, eyes suffering from more chronic KCS show an insidious onset of disease and present with an accumulation of thick mucoid to mucopurulent discharge, pigmentary keratitis, corneal vascularization, and, less frequently, corneal ulceration.

Schirmer tear test 1

The diagnosis of canine quantitative KCS is relatively straightforward. Although there are a number of ways to diagnose the disorder, the most common is the STT-1 (Figure 5). Readings of less than 15 mm/minute in dogs presenting with characteristic clinical signs are pathognomonic of the disease.

Medical treatment dry eye

Principles of treatment

KCS treatment has 3 main objectives: restoring natural tear production, maintaining hydration and lubrication of the ocular surface while lacrimostimulants achieve their effect, and restoring or maintaining corneal transparency. These aims should be achieved using medical therapy; surgery should be recommended only if medical treatment fails. Owners should be aware that in most cases treatment must be lifelong.

Although the response to medical treatment is often positive, in some patients (usually those with very low pretreatment STT-1 values) treatment may not be entirely successful. However, even if treatment does not restore normal tear production, patient comfort and vision can often be maintained using topical treatment.

Grossly, medical management of KCS consists of nonspecific drugs (eg, artificial tears, or lacrimomimetics) and specific medications aimed at treating the underlying primary cause (eg, lacrimostimulants). Supporting treatments include eyewash and removal of excess mucus, as well as artificial tears. The latter play an important role in improving ocular health while waiting for lacrimostimulating treatment to achieve its effect, or when such treatment fails to raise tear production to adequate levels. In general, artificial tears need to be viscous to reduce friction and secondary ocular surface inflammation.

Topical anti-inflammatories and antibiotics may be prescribed, if needed. In most cases multiple topical medications are needed initially, and these must be administered 5 minutes apart, in order of density. Ointments must be given last, because they are oily and can inhibit penetration of other topical drugs.

Lacrimostimulating therapy

Lacrimostimulants are divided into immunomodulating and cholinergic agents. Immunomodulating agents are commonly used and can be extremely effective in treating and controlling immune-mediated KCS by stimulating natural production of the tear film’s aqueous component.

Topical cyclosporine and tacrolimus are the cornerstone of KCS immunomodulating therapy. Their exact mechanism of action is not fully understood, but both are calcineurin inhibitors that reversibly inhibit proliferation of T-helper cells and prevent the release of proinflammatory cytokines. These cells and their associated mediators appear to play a role in the immune-mediated suppression of lacrimal gland function. Topical cyclosporine is commercially available as a 0.2% ointment and in concentrations of 0.5% to 2% in compounded solutions in an olive or corn oil base. However, the compounded formulations may be more irritating, and 2% cyclosporine may suppress systemic lymphocytes in small dogs, especially following long-term use.

Tacrolimus has been reported to have 10- to 100-fold higher potency than cyclosporine.5 It is available as a 0.02% and 0.03% compounded suspension in an aqueous or olive oil base. Compared with cyclosporine, tacrolimus shows a slightly higher efficacy, which is why some authors recommend tacrolimus as the drug of choice in advanced canine KCS cases.5

Pimecrolimus is another immunomodulating lacrimostimulant drug that has recently demonstrated encouraging results in canine KCS with a 1% formulation used 3 times daily.6 However, it should be noted that dermal preparations containing tacrolimus and pimecrolimus and intended for humans come with an FDA warning7 stating that “although a causal relationship has not been established, rare cases of malignancy (eg, skin and lymphoma) have been reported in patients” using these drugs, and the creams are not indicated for use in children younger than 2 years of age.

The most commonly used cholinergic agent is pilocarpine. It is a direct-acting parasympathomimetic drug commonly used in cases of neurogenic KCS. Because topical administration of pilocarpine is irritating due to its acidic pH, oral administration of the ophthalmic formulation is generally preferred. The initial dose applied to food is 1 drop of 2% pilocarpine per 10 kg of body weight twice daily. Because the drug may be unpalatable, and the dose is rather small, owners should be instructed to apply the drops to a spoonful of tasty moist food and feed that to the patient. The dose is increased in 1-drop increments every 2 to 3 days until tear production increases or signs of systemic toxicity (including inappetence, hypersalivation, vomiting, diarrhea, or bradycardia) develop.

If systemic adverse effects are observed, pilocarpine should be discontinued for 2 to 3 days until systemic signs abate, and then renewed at a lower dose. Some patients better tolerate the drug if the total daily dose is divided into 3 treatments rather than 2. In my experience, the drug is effective in about 90% of patients with unilateral neurogenic KCS and ipsilateral xeromycteria. Treatment duration is variable (from 3 to 5 months), but in some cases long-term administration may be needed. Topical immunomodulating agents may be prescribed simultaneously to reduce ocular surface inflammation.

Ron Ofri, DVM, PhD, DECVO, is a professor of comparative ophthalmology at the Koret School of Veterinary Medicine at Hebrew University of Jerusalem in Rehovot, Israel.

References

  1. Dodi PL. Immune-mediated keratoconjunctivitis sicca in dogs: current perspectives on management. Vet Med (Auckl). 2015;6:341-347. doi:10.2147/VMRR.S66705
  2. de Almeida DE, Roveratti C, Brito FL, et al. Conjunctival effects of canine distemper virus-induced keratoconjunctivitis sicca. Vet Ophthalmol. 2009;12(4):211-215. doi:10.1111/j.1463-5224.2009.00699.x
  3. Naranjo C, Fondevila D, Leiva M, Roura X, Peña T. Characterization of lacrimal gland lesions and possible pathogenic mechanisms of keratoconjunctivitis sicca in dogs with leishmaniosis. Vet Parasitol. 2005;133(1):37-47. doi:10.1016/j.vetpar.2005.05.017
  4. Lim CC, Cullen CL. Schirmer tear test values and tear film break-up times in cats with conjunctivitis. Vet Ophthalmol. 2005;8(5):305-10. doi:10.1111/j.1463-5224.2005.00403.x
  5. Hendrix DV, Adkins EA, Ward DA, Stuffle J, Skorobohach B. An investigation comparing the efficacy of topical ocular application of tacrolimus and cyclosporine in dogs. Vet Med Int. 2011;2011:487592. doi:10.4061/2011/487592
  6. Ofri R, Lambrou GN, Allgoewer I, et al. Clinical evaluation of pimecrolimus eye drops for treatment of canine keratoconjunctivitis sicca: a comparison with cyclosporine A. Vet J. 2009;179(1):70-7. doi:10.1016/j.tvjl.2007.08.034
  7. FDA approves updated labeling with boxed warning and medication guide for two eczema drugs, Elidel and Protopic. US Food & Drug Administration. January 19, 2006. Accessed March 17, 2021. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-approves-updated-labeling-boxed-warning-and-medication-guide-two-eczema-drugs-elidel-and
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