Canine Keratoconjunctivitis Sicca—What Do I Do When Cyclosporine Does Not Work?
Prior to and especially since the introduction of cyclosporine as a treatment for canine dry eye, I think we have had a strong tendency to consider keratoconjunctivitis sicca (KCS) as a simple deficiency of aqueous tear production. To be sure, this is justified (and reinforced on a daily basis in our clinics) because the vast majority of our canine patients respond so remarkably to topical administration of cyclosporine. Therefore, we sometimes need to remind ourselves that the nasolacrimal system consists of complex secretory, distributional, and drainage components all of which must act in superb harmony to effectively protect the corneal and conjunctival surfaces. In some ways, the fact that 0.2% cyclosporine ointment (Optimmune®) is so effective in the majority of KCS patients has made treating tear film disease truly fascinating. I enjoy the challenge of thinking about and better managing those less common cases that are unresponsive or only partially responsive to immunomodulatory stimulation of aqueous tear production. A complete but brief review of nasolacrimal anatomy and physiology is a necessary first step.
A Clinician’s Approach to the Lacrimal Unit
- Orbital and third eyelid lacrimal glands that produce the aqueous component of tears.
- Tarsal (or meibomian) glands, which are modified sebaceous glands that secrete an oily fluid similar to sebum and responsible for reducing evaporation of the aqueous component of the tears.
- Conjunctival goblet cells, especially those in the ventral fornix, that produce mucin, which improves retention of the aqueous tears by the hydrophobic corneal epithelium.
Distribution and Loss
The composite pre-ocular tear film produced by lacrimal, tarsal and conjunctival glands is critical for corneal, conjunctival, and general ocular health. It is distributed by normal blinking and movements of the third eyelid and globe before pooling in a space referred to as the “lacrimal lake” between the anterior faces of the cornea and third eyelid and the posterior margin of the lower eyelid. A percentage of tears determined in large part by tearfilm stability (and therefore composition), ocular surface topography, and blink rate (determined in part by skull shape, corneal sensitivity, emotional state) then evaporates or is lost over the eyelid margins. Excess tears drain via upper or lower nasolacrimal puncta into the nasolacrimal system.
Qualitative vs. Quantitative Tear Film Deficiencies
Classically, qualitative deficiencies describe biochemical alteration of a component of the tear film, while quantitative deficiencies describe decreased volume of a tear component. Because the aqueous component of tears comprises the major volume of the tear film, qualitative tear film disturbance and KCS are sometimes considered synonymous. The majority of canine KCS is believed to be due to an idiopathic, but immune mediated dacryoadenitis involving the lacrimal glands. These cases are most likely to respond to therapy with topical cyclosporine A (CsA). This treatment is so reliably successful in immune-mediated dacryoadenitis, that I wonder if failure to consider other causes of KCS is possibly the most common cause of poor response to this standard therapy.
Using the “DAMNIT” List to Direct Examination and Testing
As the internists have taught us, a logical approach to apparently idiopathic or disease or cases unresponsive to “best guess” therapy is very wise. I think this is particularly true for canine dry eye patients unresponsive to topical administration of CsA. Here’s a few causes I consider (for completeness, I have included feline as well as canine causes):
Developmental KCS (acinar hypoplasia) is reasonably common in Yorkshire terriers and other toy breeds and is often associated with absolute sicca (STT = 0). Curiously, this can be unilateral. As might be expected, this form of KCS is unlikely to respond to topical CsA and is one of the more challenging forms to treat, usually requiring parotid duct transposition.
Autoimmune disease with mononuclear cell infiltration and fibrosis of the lacrimal gland is the most common etiology for KCS in dogs. The stimulus for this disease is unknown, however, the observation that it occurs more commonly in some breeds suggests that a familial predisposition may exist. Commonly-affected breeds are West Highland White Terriers, Bulldogs, and Cocker Spaniels. These patients seem the most likely to respond to CsA.
Metabolic causes of KCS are limited. Although some studies suggest an association between KCS and certain endocrine diseases such as diabetes and hypothyroidism, this is not universally proven. Regardless, concurrent treatment of any endocrinopathy and topical application of CsA would appear wise and may improve prognosis.
Neoplasia of the lacrimal glands is rare; however, glandular dysfunction can be seen in association with any form of orbital disease, particularly cellulitis or space-occupying masses. Exophthalmos or strabismus with reduced globe retropulsion should arouse suspicion of such a cause and prompt orbital imaging. Hypovitaminosis A has been associated with nutritional KCS; however, this is most common in food animals.
Infectious etiologies of reduced aqueous production include distemper virus in dogs and feline herpesvirus (FHV-1) in cats. In these diseases, signs of KCS are usually overshadowed by more overt ocular or systemic lesions. However, assessment of tear production and supplementation of the tear film when necessary should be a routine part of management of these diseases. Unlike other causes of KCS, tear production usually resumes if the primary infectious etiology is resolved. Perhaps of more relevance is the way in which infectious diseases may 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 fibers 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; however, etodolac (EtoGesic®) appears to be associated with a rapid onset of usually absolute sicca poorly responsive to cessation of the drug and/or administration of cyclosporine. General anesthesia and sedation can also cause a temporary depression of STT values.
Regardless of cause, the pathogenesis and end result of deficient aqueous production is multifactorial. Surface dehydration, hypoxia and necrosis of surface tissues, accumulation of exudates, and secondary infections are important mechanisms.
Clinical signs will always be the initial alert that tear film dysfunction should be considered. The classic signs of aqueous tear film deficiency are familiar, with the hallmark clinical sign being accumulation of tenacious, adherent mucopurulent discharge over the corneal surface, conjunctiva, and eyelids. The mechanisms underlying this are likely over-production of mucins to compensate for aqueous deficiency as well as reduced hydration and flushing of those mucins secreted. It should come as no surprise to us, therefore, that analogous mechanisms are at play in mucin or lipid deficiency. For example, reductions in the quantity or quality of ocular surface mucins should be expected to cause a compensatory increase in aqueous production (and likely a less visible increase in lipid production) as well as a tear film that is less well “anchored” to the ocular surface. In other words, one of the signs of qualitative tear film deficiency may well be… epiphora!!
Somewhat irrespective of which tear component is deficient, the secondary corneal changes are relatively non-specific and reflect the chronic, irritating nature of the disease. These include a lackluster corneal surface (especially with aqueous deficiency), superficial corneal vascularization and pigmentation, and sometimes (if the onset of dry eye is acute) corneal ulceration. Ocular discomfort and conjunctival thickening due to squamous metaplasia are also common.
I am always careful to thoroughly assess all visible conjunctival regions (especially the deep fornicial regions) using both diffuse and a slit beam. In particular, I look for evidence of thickening/cellular infiltrate, chemosis, hyperemia, follicles, papillary conjunctivitis, or excessive folding. I also pay particular attention to the meibomian gland profiles visible through the palpebral conjunctiva and any glandular secretions naturally occurring or forcibly expressed from the gland orifices. Look particularly for secretions that are more difficult to express, more opaque than translucent, thicker or “waxier” than normal, or those that form a small inspissated “bubble” from the orifice (so-called “choked” meibomian glands).
The “workhorse” of dry eye testing in veterinary medicine is of course is Schirmer’s tear test type 1 (STT-1). In dogs, I consider STT values less than 15 mm/minute in conjunction with consistent clinical signs diagnostic. However, it is important to recall that the STT-1 result merely reflects the volume of tear film in the lacrimal lake plus the volume of reflex tears stimulated to be produced and released by the STT strip gently abrading the cornea. It is interesting to ponder, therefore, the effects of lid conformation, emotional state, corneal sensitivity, placement of the STT strip (medially, centrally or laterally in the ventral conjunctival fornix), lacrimal gland function, and patency of the lacrimal gland ductules. I am confident that a patient could have normal tear production but a sufficiently dysfunctional tear delivery system (due to conjunctivitis-induced compression of the lacrimal gland ductules) to (likely reversibly) reduce his STT-1 result. I do not routinely use STT-2 (STT following topical anesthesia) or STT-3 (STT following or during a noxious stimuli) in canine patients but am beginning to appreciate their value in cats.
Despite the utility of the STT, there are many other potentially underused tests that are of value—particularly in those patients who are unresponsive to topically applied CsA. I like to use an assessment of blink rate and effectiveness. It amazes me—especially in many brachycephalic breeds how poorly and infrequently they blink. Unless they have a remarkably increased tearfilm stability to compensate for this, one must assume that they have greater evaporative losses than dolichocephalic dogs. Perhaps these are patients who would benefit from a medial canthoplasty. Our best clinical test of tear film stability in vivo appears to be the tear film breakup time (TFBUT). Although patient compliance sometimes makes this test difficult, I believe that it provides highly valuable information in select patients. As we learn more about this test, we would do well to pay attention to what the physicians have known for some time about performing this test very consistently especially with regards timing relative to the rest of the exam, amount of fluorescein applied. I think that the specially prepared Dry Eye Test (DET) strips by Amcon Labs (www.dryeyetest.com/) are worth considering. The normal range has not been established using sufficiently large population of normal dogs of various skull shapes, but most manuscripts to date report mean ± SD values of around 20 ± 5 seconds.
In patients where the clinical exam suggests it may be informative, I consider culture and sensitivity and cytology of expressed mebum and/or an eyelid (meibomian gland) and/or conjunctival biopsy. If I am interested primarily in the conjunctiva (and especially the goblet cells) I simply do a snip biopsy of the fornicial conjunctiva under topical anesthesia. In patients where I am more interested in the entire qualitative tear film unit I do a full-thickness punch biopsy from dermis to conjunctiva through an affected area of the eyelid. If there is marginal disease, I consider a wedge biopsy. In all cases, I work with our in-house ocular pathologist to ensure goblet cell density (GCD) is reported. These are typically calculated (and reported) as a percentage of the non-goblet conjunctival epithelial cells. Like TFBUT, the number of normal dogs which have been sampled and assessed in a uniform manner is insufficient to permit the statement yet of a true reference range, and there is much variation in GCD according to site sampled; however the GCD of the palpebral/fornicial sites (which are the most readily sampled) are typically reported to be around 20–30%. The periodic acid Schiff (PAS) staining technique can greatly facilitate counts.
An often overlooked but critical component of the exam of some dry-eye patients is assessment of corneal sensitivity (or corneal touch threshold—CTT) using the Cochet-Bonnet aesthesiometer. If we recall the critical role of the trigeminal nerve in sensing ocular surface dryness, reflex and basal tearing, reflex and basal blinking, and carriage of the parasympathetic fibers of lacrimation as well as trophic factors for the ocular surface, it is difficult to underrate the importance of normal function of this nerve to the lacrimal unit. It is involved in the afferent and efferent arm of tear production and delivery, and in tear distribution and retention via normal lid position and blinking.
In all cases, the ocular surface should be stained with vital dyes. It is critical to recall that these stain the corneal epithelium (rose bengal or lissamine green) or subepithelial collagen (fluorescein) of both conjunctiva and cornea and the entire visible ocular surface should be examined following stain application.
Recalling the DAMNIT list facilitates an efficient but directed examination of the body systems and signs sometimes associated with those less common causes of KCS are essential. I include a thorough history directed at the known causes, followed by examination for associated systemic diseases, a thorough assessment of cranial nerve function, especially palpebral and corneal reflexes, and careful evaluation of upper, lower, and third eyelids. This must include assessment of their position in relationship to the cornea, and appearance of eyelid margins, cilia, and the meibomian glands and orifices. Globe retropulsion and jaw opening, “slipping” the oral mucous membranes, and assessment of the nares for dryness is also essential—sometimes in association with an otic exam. Culture and sensitivity, along with cytology is unnecessary as microbial overgrowth is secondary and typically responds as soon as tear production is improved.
My five main treatment goals:
- Always diagnose and treat the underlying cause if possible. (This is especially important in patients unresponsive to CsA)
- Minimize further tear loss and maximize tear distribution
- Stimulate of tear production (CsA irrespective of cause)
- Supplement the tear film in a manner that considers which of the components is inadequate
- Treat or prevent secondary infection
Thorough attention to the “DAMNIT” list, a careful assessment of history and clinical signs, and appropriate diagnostic testing will facilitate recognition of any underlying cause, expedite appropriate treatment, and improve prognosis for full return of secretory function.
Minimization of Tear Loss and Maximization of Tear Distribution
Minimization of tear loss and maximization of tear distribution relies on a thorough assessment of lid anatomy and function. Many dogs with only marginal tear production can be made more comfortable with correction of mild ectropion or entropion, removal of distichia, and/or reduction of palpebral fissure size.
Stimulation of Normal Tear Production Remains the Main Goal of Medical Therapy
Tear replacement products are no substitute for improved production of endogenous tears with their multitude of immunologic and nutritive factors, and appropriate pH and osmolarity. Cyclosporine remains the most effective drug for this purpose in my opinion. In addition to its ability to reduce immune-mediated infiltration of the lacrimal gland, this compound 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 remodeling 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 weeks. It is important that the client be instructed to apply CsA 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 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% CsA 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.
Information regarding tacrolimus is encouraging. This drug acts by a similar mechanism to CsA but is more potent and operates via a different cellular receptor. Reports confirm that it is effective in some cases that are unresponsive to CsA. It is compounded in various ways by many pharmacies. To date I am aware of data for a 0.02% aqueous and a 0.03% suspension in olive oil only. Although its safety and efficacy as an ophthalmic drug in dogs have been preliminarily tested, 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 and squamous cell carcinoma. The FDA currently 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 too. Consider recommending that clients wear gloves when handling this product and that children do not administer the drug to their pets.
Some advocate use of topical corticosteroids to further reduce dacryoadenitis. This has some rationale but requires caution in an eye that is already more prone to ulceration. Addition of a topical, penetrating steroid such as dexamethasone or prednisolone after initial treatment with CsA has successfully promoted some tear production and improved corneal health may be justified.
Cholinergic agents such as pilocarpine may be used to provide parasympathetic stimulation of the lacrimal gland. This alternative mechanism might be expected to be more physiologic and, therefore, likely to succeed in cases of neurogenic KCS than more common cases of immune-mediated dacryoadenitis. Topical use of this drug is very irritating, produces a noticeable uveitis, and may not provide adequate drug concentrations at neurologic synapses. 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 systemic toxicity in each animal. Signs of toxicity include vomiting, diarrhea, and bradycardia. Ophthalmic pilocarpine is used orally usually 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 diarrhea) are observed. The drug is discontinued for 24 hours or until GI signs abate and then re-instituted at the highest dose which did not produce signs of toxicity. Because of the different mechanism by which CsA 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, and my personal experience supports this. I use 2.5% phenylephrine. While this seems counter-intuitive at first, it appears that there are smooth muscle fibers associated with the lacrimal glands that act via contraction to express tears over the eyes. Thus the initial use of pilocarpine to stimulate tear production followed by the addition of phenylephrine to stimulate tear secretion has been advocated by some. We have tried this with remarkable results in a small number of dogs.
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. As such, application of tear supplements can have a dilutional effect on those tears being naturally produced. In addition, any product (and especially the preservatives most contain) can cause surface irritation. Finally, tear supplement solutions may require extremely frequent application to be effective. These factors have made this a problematic area in veterinary medicine. Commercial introduction of hyaluronan tear replacement products has provided an important adjunctive therapy for most dogs with KCS. These products have mucinomimetic properties and some are available in a preservative-free formulation. They are extremely well tolerated in dogs and cats. I typically use hyaluronans early in the treatment schedule while CsA is being introduced but often continue them even if adequate tear production returns.
Secondary infection is common when tear quality or quantity declines. This is best treated with a well-tolerated, reasonably broad-spectrum antibiotic with the major goal being control of normal gram-positive flora overgrowth. Triple antibiotic (neomycin-polymyxin-bacitracin) ophthalmic ointment is an excellent choice. This 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
It is my opinion that parotid duct transposition (PDT) is associated with significant complications in some patients and does not obviate the need for ongoing medical management. Therefore, medical management is the preferred method of treatment and should always be attempted first. I reserve PDT for those cases in which a thorough clinical examination has failed to reveal a cause and which have not responded to protracted and multiple medical therapies—typically patients with congenital glandular aplasia/hypoplasia.