Department of Surgical & Radiological Sciences, University of California, Davis, CA, USA
Keratoconjunctivitis sicca (KCS), or “dry eye,” is a common disease of dogs that, since the introduction of cyclosporine, is usually relatively easily managed. Here, we briefly discuss routine management of KCS but then emphasize those patients where cyclosporine (alone) seems relatively ineffective. How are they best diagnosed? What are the potential causes of such cases? Are all cases of dry eye due to aqueous deficiency only? And what is the latest in therapy?
My five main treatment goals:
1. Diagnose and treat the underlying cause if possible. (Especially in patients unresponsive to cyclosporine.)
2. Minimize further tear loss and maximize tear distribution.
3. Stimulate endogenous tear production.
4. Supplement the tear film in a manner that considers which of the components is deficient.
5. +/- Treat or prevent secondary infection.
Cyclosporine remains the mainstay of therapy in my practice. In addition to its ability to reduce immune-mediated infiltration of the lacrimal gland (the most common cause of KCS in dogs), it has a direct lacrimogenic function, and it promotes mucin production from conjunctival goblet cells. Its direct lacrimogenic function appears to rely on frequent application, while immunosuppression and remodelling of glandular tissue presumably require more chronic use. Therefore, in most cases this drug should be instituted twice daily and the patient rechecked in approximately 2 weeks. It is important that the client be instructed to apply cyclosporine as scheduled right up until the time of recheck examination. Omitting the morning treatment because the dog was going to be examined later that day may cause an artificial depression in Schirmer tear test (STT) values. Clients should also be advised that initial response to therapy is best judged by change in STT values, mucoid discharge, and ocular comfort, rather than decrease in pigmentation or corneal vascularization. Improvement in these corneal changes occurs at a similar rate to that which they occurred—slowly.
Tapering of dose frequency or product concentration is typically not possible and should be based on clinical and measured (STT) responses. Failure to respond to 0.2% cyclosporine BID is a reason to trial a higher concentration such as 1% or 2%. In my experience, increased frequency beyond BID does not have a satisfactory effect.
Tacrolimus acts by a similar mechanism to cyclosporine but is more potent and operates via a different cellular receptor. It is effective in some dogs that are unresponsive to cyclosporine. I typically have it compounded as a 0.03% suspension in oil. An FDA alert in the USA suggests that topical application of this drug as a dermatologic preparation in humans, especially children, may be associated with development of lymphoma or squamous cell carcinoma. The FDA recommends that tacrolimus be used only when other drugs have failed or not been tolerated, and then with caution. I follow this guideline for our veterinary patients. Consider recommending that clients wear gloves when handling this product and that children do not administer the drug to their pets.
Ocular surface inflammation is a central component of dry-eye pathophysiology. Therefore, potent penetrating, topical steroids such as dexamethasone or prednisolone may help but caution is required since dry eyes are more prone to ulceration.
Pilocarpine & Phenylephrine for Neurogenic KCS
Pilocarpine may be used to provide parasympathetic stimulation of the lacrimal gland in neurogenic KCS. Topical use of this drug is very irritating, produces a noticeable uveitis, and may not provide adequate drug concentrations at the orbital lacrimal gland. This has led to the suggestion that oral dosing on an empirical but individualized basis is necessary. This requires that the dose be titrated to just below the level at which systemic signs such as vomiting, diarrhoea, or salivation are seen. Ophthalmic pilocarpine is used orally via a doctored food bolus. One dosage recommendation (credit Dr. Randy Scagliotti) is that 1% pilocarpine is used for dogs <4 kg, 2% for dogs weighing 4–20 kg, and 4% pilocarpine for dogs >20 kg. The initial dose is one drop PO twice daily for three days. This dose is increased by one drop every three days until the earliest signs of toxicity (usually vomiting or anorexia without diarrhoea) are observed. The drug is discontinued for 24 hours or until GI signs abate and then reinstituted at the highest dose which did not produce signs of toxicity.
Because of the different mechanism by which cyclosporine acts and because of its additional desirable effects, the two drugs are expected to be synergistic. There is a case report supporting the addition of a topical sympathomimetic eye drop to this regimen. I use 2.5% phenylephrine topically. There are allegedly smooth muscle fibres in the lacrimal glands that aid tear expression. Thus oral pilocarpine must be used initially to stimulate tear production followed by the addition of topical phenylephrine to stimulate tear secretion.
Supplementation of tears has traditionally been provided in one of three forms: aqueous (“artificial tear”) solutions, more viscous polymers or methylcellulose solutions, and ointments in a petrolatum base. However, no product currently available adequately replaces all of the functions served by tears, and so can have a dilutional effect on those tears being naturally produced. In addition, these products and their preservatives can cause surface irritation. Finally, tear supplement solutions may require extremely frequent application to be effective. I prefer hyaluronan-containing products as they are mucinomimetic, available in preservative-free formulations, and extremely well tolerated.
Secondary infection is common when tear quality or quantity declines. This is best treated with a well-tolerated, reasonably broad-spectrum topical antibiotic but can be discontinued as soon as STT values improve and mucopurulent discharge declines since chronic topical antibiotic therapy is contraindicated for maximal ocular surface health.
Parotid Duct Transposition
Parotid duct transposition (PDT) is associated with significant complications in some patients and does not obviate the need for ongoing medical management. Therefore, I prefer medical management and reserve PDT for those cases in which protracted and multiple medical therapies have not worked—typically patients with congenital glandular aplasia/hypoplasia.
Using the “DAMNIT” List to Direct Examination and Testing
Finding and treating the cause remains the mainstay of KCS therapy. Here’s a list of causes arranged according to the DAMNIT system:
Developmental KCS (acinar hypoplasia) is reasonably common in Yorkshire Terriers and other toy breeds, can be unilateral, and is often associated with absolute sicca (STT=0). This is unlikely to respond to topical cyclosporine and usually requires PDT.
Infectious diseases such as distemper virus in dogs and feline herpesvirus (FHV-1) in cats may reduce aqueous tear production. However, these diseases may also affect tear quality through destruction or dysfunction of the conjunctival goblet cells and meibomian glands. For example, conjunctivitis of any cause, is often associated with reduction in goblet cell density, an unstable tear film and worsening conjunctival (and sometimes corneal) disease—thus setting up a “vicious cycle.” Likewise, bacterial blepharoconjunctivitis or orbital cellulitis may also extend to the tarsal and orbital lacrimal glands respectively. Surgical removal of the third eyelid gland following third eyelid gland prolapse (or cherry eye) can be an iatrogenic cause of KCS.
Traumatic disruption of the lacrimal gland, its blood supply, or innervation (CN V or VII) is a known cause of KCS. Trauma may be anatomically distant from the gland if the nerve or vascular supply is involved. Possibly one of the most common causes of neurologic KCS is injury to the facial nerve, particularly in association with middle ear disease. Neurogenic reduction or failure of blinking due to facial nerve dysfunction and/or dysfunction of the sensory fibres of the trigeminal nerve can exacerbate KCS in these cases. Concurrent desiccation and crusting of the ipsilateral nostril (xeromycteria) strongly suggests neurogenic dysfunction. The most commonly incriminated toxic causes of KCS are sulphur drugs and atropine. General anaesthesia and sedation can also cause a temporary depression of STT values.