Lori J. Best, DVM; Diane V.H. Hendrix, DVM, Diplomate ACVO; and Daniel A. Ward, DVM, PhD, Diplomate ACVO
Keratoconjunctivitis sicca (KCS), is a relatively common condition in dogs, although the diagnosis is often overlooked. This article provides guidance on the pathophysiology, causes, diagnosis, and medical and surgical treatment for this condition.
Keratoconjunctivitis sicca (KCS) is a relatively common condition in dogs. Although KCS can be diagnosed readily with a thorough ophthalmic examination, the diagnosis is often overlooked.
KCS is an inflammatory condition of the cornea and conjunctiva, secondary to a deficiency of the precorneal tear film (PTF). KCS is categorized by tear film deficiency:
• Quantitative KCS is a decrease in the aqueous component of the tear film as measured with the Schirmer tear test (STT); it is recognized more commonly in veterinary medicine.
• Qualitative KCS is a decrease in the lipid or mucin components of the tear film and diagnosed by documenting decreased tear film breakup time (TBUT).
The Lacrimal System & Tear Film
Normal PTF is estimated to be anywhere from 3 to 45 microns thick in humans and, in most species, is composed of aqueous, lipid, and mucin layers, which were once thought to be present in a laminar arrangement (Table 1).1,2 More recent evidence suggests that PTF may resemble a muco-aqueous pool covered in a very thin lipid layer rather than a trilaminar structure.3
Lacrimal secretion is stimulated via sensory input from the cornea, periocular structures, and globe. The ophthalmic and maxillary divisions of the trigeminal nerve serve as the afferent part of the reflex arc; then motor input travels to the lacrimal glands via the parasympathetic division of the facial nerve as the efferent arc. Tears are then secreted following contraction of lacrimal acinar myoepithelium.
Tear film deficiencies lead to:
• Chronic inflammation of the ocular surface secondary to increased surface friction
• Secondary infection
• Dehydration and malnutrition of the corneal and conjunctival epithelium.
This latter combination makes ulcerations more prone to infection, possibly resulting in keratomalacia and perforation.
Chronic surface irritation results in:
• Conjunctival hyperemia
• Squamous metaplasia of the surface epithelium
• Hyperkeratinization of the surface epithelium
• Thickening of the corneal epithelium.
Inflammatory cells and blood vessels enter the anterior corneal stroma, depositing pigment, lipids, and calcium. The vascularization and deposits stabilize the cornea and make it less susceptible to ulceration; however, their presence can result in vision loss.
Causes of quantitative KCS—organized by type of cause—are listed in Table 2. The most common cause is immune-mediated lacrimal adenitis. Transient decreases in tear production can be iatrogenically caused by:
• General anesthesia: Significantly decreases tear production for up to 24 H4
• Xylazine, medetomidine, and butorphanol: Significantly decrease tear production temporarily5,6
• Topical or systemic atropine: Causes secondary decrease in tear production that is not clinically significant in most dogs.
Therefore, artificial tear ointments are important adjuncts to sedation and anesthesia regimens, and should be continued until dogs are fully responsive and consistently blinking appropriately.
|Table 2. Causes of Quantitative KCS|
|Chronic severe conjunctivitis||Swelling of excretory ductules of lacrimal gland||None||Variable: Permanent if scarring present||Good|
|Immune-mediated lacrimal adenitis (primary KCS)||Immune-mediated destruction of lacrimal tissue with secondary atrophy7||Most common cause of canine KCSb||Lifelong||Good|
|Canine distemper virus8||Lacrimal adenitis||Unvaccinated animals||Variable: Many spontaneously recover||Good to fair: If systemic disease survived, many recover|
|Idiopathic neurogenic9||Idiopathic: Present with ipsilateral dry nose||Middle-aged female dogs||Variable||Good to fair: Some spontaneously resolve|
|Leishmaniasis10||Lacrimal adenitis, especially surrounding lacrimal gland ducts, where amastigotes accumulate||Animals in Mediterranean region or with travel history||Variable||Fair|
|Congenital alacrima||Developmental absence of lacrimal tissue||Yorkshire terrier overrepresented11||Permanent; present at birth||Poor: Often requires surgery|
|Etodolac12||Nitrogen-containing pyrimidine/pyridine rings have direct toxic effect on lacrimal acinar cells||None||Variable||Fair: If etodolac administration < 6 months, more likely to recover|
|Sulfa-derivative medications13 & related compounds14||Nitrogen-containing pyrimidine/pyridine rings have direct toxic effect on lacrimal acinar cells||Typical onset within 30 days of medication initiation5||Variable: May resolve in 45–60 days or sometimes lifelong||Fair: Discontinue medication immediately after decrease in STT|
|Iatrogenic: Removal of third eyelid gland||May decrease tear production and TBUT15||None: History of removal of gland||Variable||Fair|
|Local radiation therapy16||Acute adverse effect of radiation exposure||None||Variable: Dose dependent and patient sensitivity||Fair|
|Trauma to lacrimal gland or nerves9||Decreased production/ distribution of PTF due to decreased blinking and/or increased evaporation secondary to lagophthalmia17||None||Variable||Fair to poor|
|a. Based on initiation of medical management
b. Many breeds are predisposed to primary KCS, including, but not limited to, the American cocker spaniel, cavalier King Charles spaniel, West Highland white terrier, and brachycephalic breeds (eg, English bulldog)18
Clinical signs associated with quantitative KCS are listed in Table 3.
KCS is diagnosed after consideration of:
• History: Ask historical questions that explore previous drug administration, vaccinations, and surgical procedures.
• Ophthalmic Examination: Perform a complete ophthalmic examination in all dogs presenting with new clinical signs (Table 3) or disease progression.
• STT: This test is the cornerstone of quantitative KCS diagnosis; interpret results in light of clinical signs. A Schirmer tear test 1 (STT1)—performed without application of surface anesthetic agents—assesses reflex tear production. Normal production in dogs is > 15 mm/min.
Figure 1. Two-year-old castrated male chihuahua. Note corneal neovascularization and pigmentation, thick and adherent mucopurulent discharge, and keratinization of corneal epithelium; STT was 0 mm/min.
The causes of qualitative tear film deficiency are not completely understood.
• Chronic blepharitis with meibomianitis can lead to decreased production of the lipid layer. Infectious causes of blepharitis include Staphylococcus, Candida, andMalassezia species.19
• Decreased goblet cell density and subsequent mucin layer deficiency are most likely caused by chronic conjunctival inflammation secondary to infectious disease or immune-mediated disease.20
Clinical signs of qualitative tear film deficiency are more subtle than those seen with quantitative disease, and include:
• Mild corneal neovascularization
• Mucus discharge.
If qualitative KCS is suspected based on history and clinical signs:
- STT: Perform a STT to rule out quantitative aqueous deficiency; STT results are normal in patients with qualitative KCS.
- TBUT: Perform a TBUT to assess for deficiency in the PTF’s mucin component.
- Apply 1 drop of fluorescein stain to the eye, holding the eyelids open.
- Under cobalt-blue illumination, examine the cornea. Note how many seconds it takes for dark spots to appear as the PTF “breaks up” the fluorescein layer.
- A normal TBUT is ≥ 20 seconds. Animals with quantitative deficiencies often have a TBUT of < 5 seconds, which indicates an unstable PTF.20
- Conjunctival Biopsy: In cases of suspected mucin deficiency, obtain a conjunctival biopsy specimen to quantitate conjunctival goblet cell density.
- Eyelid Margin Examination: With a focus light and magnifying source, carefully examine the eyelid margin to identify deficiencies of the lipid component, which often occur secondary to blepharitis (Figure 6) or meibomianitis.
MEDICAL MANAGEMENT OF KCS
Primary medical therapy of both quantitative and qualitative KCS consists of tear stimulants and tear replacements. Topical antibiotics and anti-inflammatory drugs are also commonly used.
Dogs with KCS may have increased sensitivity to pain associated with topical medications, because abnormal PTF cannot provide a reflex dilution effect. This may be especially problematic with frequent application of tear replacement medications that contain preservatives; some artificial tear products are available without preservatives, but the lack of preservatives requires single-use ampules, which most owners find inconvenient.
In most patients with KCS, topical therapy is required indefinitely. Clients should be educated about the chronicity of KCS and the necessity of lifelong therapy.
1. Cyclosporine A (CsA)
Mechanism of action.Cyclosporine is an immunomodulator that blocks normal production of interleukin-2, which inhibits proliferation of T-helper and cytotoxic T cells in the lacrimal gland and allows normal lacrimation.21
Cyclosporine also acts as an anti-inflammatory, decreases pigmentation, normalizes goblet cell mucin secretion,22 and directly stimulates lacrimation, but the latter mechanism is still poorly understood.23
Efficacy.Topical preparations are very effective for tear stimulation and reducing inflammation, with 81.8% of dogs showing improvement (Figure 7).24,25 Dogs with a STT < 2 mm/min respond with increased tear secretion in approximately 50% of cases, while dogs with a STT ≥ 2 mm/min have an approximately 80% chance of responding.18
Formulation. CsA is available as Optimmune 0.2% ophthalmic ointment (merck-animal-health-usa.com). Compounded formulations are available in 1% and 2% corn or olive oil solutions; they may be more effective, but may also be more irritating to the eye.
Therapeutic recommendations. Apply ¼-inch strand of topical CsA Q 12 H, with a recheck STT in 1 month. For optimal results, perform the STT approximately 3 to 4 H after application of CsA. Treatment failure can be diagnosed only after 12 weeks of consistent topical application. If treatment fails, attempt treatment Q 8 H or initiate treatment with tacrolimus.
With long-term use, CsA decreases corneal pigmentation and vascularization, even in patients that do not experience increased tear production; therefore, its use is often continued in these patients.18,24
Mechanism of action. Tacrolimus has a similar, but more potent, mechanism of action compared with that of CsA.
Efficacy. Patients that are unresponsive to CsA may respond to tacrolimus.26,27
Formulation. Tacrolimus is generally compounded to a 0.03% ophthalmic aqueous suspension; however, formulations may vary.
Therapeutic recommendations. Apply 1 drop of topical tacrolimus Q 12 H, with a recheck STT in 1 month. Continue treatment for several months before considering treatment failure. In addition to increasing tear production, tacrolimus may decrease clinical signs, such as pigmentation associated with chronic KCS, even if tear production does not increase, but no long-term studies exist.
Tacrolimus use for treating KCS in dogs is off-label; therefore, the U.S. Food and Drug Administration approved therapy—CsA 0.2% ophthalmic ointment (Optimmune)— should be used as first-line treatment, with tacrolimus reserved for cases unresponsive to CsA.
Mechanism of action. Parasympathomimetic drug (stimulates or mimics the parasympathetic nervous sytem). Upregulation of parasympathetic receptors secondary to denervation results in increased sensitivity of the lacrimal system to pilocarpine when compared with the rest of the body.9
Efficacy. May be used to stimulate tear production in cases of neurogenic (quantitative) KCS. These cases are diagnosed when ipsilateral dry nose is present in conjunction with a low result on STT.
Formulation. 1% or 2% solutions
Therapeutic recommendations. Sprinkle 1 to 2 drops of 2% pilocarpine per 10 kg on top of food Q 12 H. Systemic administration of pilocarpine is preferred because it can be irritating when applied topically.28
Note that pilocarpine has a narrow therapeutic window, and while some clinicians advocate increasing the number of drops applied to food by 1 drop each day until systemic adverse effects are observed—such as vomiting, diarrhea, ptyalism, anorexia, and bradycardia—we prefer to avoid these effects by only increasing the total dose by 1 or 2 drops before considering pilocarpine ineffective. Client education about adverse effects is important.
Tear replacement therapy provides lubrication until tear stimulants are effective. Lifelong tear replacement therapy may be needed in dogs that never respond to CsA or tacrolimus. These medications are available as solutions, gels, and ointments, and have a wide variety of constituents.
- Artificial tear solutions commonly contain 0.1% to 1.4% polyvinyl alcohol. Artificial tear solutions are useful for removing debris and mucus from the ocular surface; however, they are not feasible as monotherapy in most dogs with KCS due to the need for frequent application in order to achieve adequate lubrication.
- Cellulose-based solutions/gels and viscoelastic products are more viscous and have slower evaporation times than artificial tear solutions. They require application Q 4 to 6 H. Examples of cellulose-based solution and viscoelastic products are hydroxypropyl and hyaluronate, respectively.
- Artificial tear formulations containing petrolatum, mineral oil, or lanolin are the most viscous products and provide long-term lubrication, but can result in debris accumulation. They are best suited for patients with:
- Lipid layer deficiencies
- Lagophthalmos (administered prior to sleep)
- Owners who will be absent for long periods.
A severe, mucopurulent discharge suggests a secondary bacterial infection. Generally, use a broad-spectrum ophthalmic antibiotic, such as triple antibiotic ointment (neomycin/bacitracin/polymyxin B) Q 6 to 8 H for approximately 2 weeks. If empirical treatment fails to resolve the discharge, perform culture and sensitivity.
Anti-inflammatory therapy may be useful if conjunctival inflammation is severe, possibly occluding lacrimal excretory ducts. Corticosteroids can be used on a short-term basis (1–4 weeks); discontinue if patient is nonresponsive. Only consider using them, though, in animals with no uptake of fluorescein dye.
Apply topical prednisolone acetate 1% or dexamethasone 0.1% topically Q 6 to 8 H. Use caution when using topical corticosteroids because dogs with KCS can develop ulcerative keratitis, infection, and keratomalacia.
If a patient with KCS has copious mucopurulent discharge, acetylcysteine 5% is often administered; however, its use is not common due to its expense and toxicity to the epithelium. In addition, the mucous layer provides some protection to the cornea. Frequent flushing with sterile eyewash, instead, simply removes mucus without side effects.
SURGICAL MANAGEMENT OF KCS
After 3 to 6 months of medical therapy with no response, surgical treatment for KCS can be considered. Surgery is not always successful and, even when it is, patients often need ongoing topical therapy.29
Treatment of Choice
Parotid duct transposition—in which the parotid duct and papilla are dissected free of the oral mucosa, mobilized, and transposed to the inferior cul-de-sac—is the surgical treatment of choice. Open and closed methods have been described.
This surgery is often performed by a board-certified ophthalmologist due to the difficulty of the procedure in some dogs and often complicated aftercare. Potential complications include severance of the duct, occlusion of the duct secondary to scar formation, development of white mineral crystalline corneal deposits, facial dermatitis, periocular pyoderma, and excessive saliva production.
While superficial, uncomplicated ulcers can be treated with triple antibiotic ointment, CsA, and lubricants, ulcers secondary to KCS are usually complicated and require more intensive therapy.
1. Perform culture and cytologyon stromal ulcers and ulcers with a cellular infiltrate.
2. Apply topical antibiotics Q 2 H to infected ulcers until the cornea stabilizes. Appropriate antibiotics include:
- Ciprofloxacin 0.03% ophthalmic solution, or other ophthalmic fluoroquinolones, used alone or
- Tobramycin 0.03% ophthalmic solution and cefazolin (33 mg/mL in artificial tear solution).
3. Use topical atropine to dilate the pupil and decrease ciliary spasm, even though it is associated with decreased tear production. If the patient remains uncomfortable while on atropine therapy, the addition of oral NSAIDs may be considered.
4. Consider conjunctival graft placement in addition to KCS therapy and frequent antibiotic therapy for deep ulcers.
PROGNOSIS & MONITORING
Prognosis depends on the underlying etiology of KCS and the patient’s response to treatment (Table 2). If KCS does not respond to medical therapy, the prognosis is worse for vision retention. In addition, most patients will require lifelong therapy with topical immunosuppressive medications.
Recently, chronic keratitis treated long-term with tacrolimus or CsA has been tenuously associated with increased risk for corneal squamous cell carcinoma.30 However, because the study was retrospective, clinical data are lacking, and KCS alone may have resulted in a predisposition to this condition. While this study is interesting, KCS should be treated as described in this article.
Dogs with a diagnosis of KCS should be evaluated every 6 to 12 months to assess effect of treatment and progression of disease.
CsA = cyclosporine A; KCS = keratoconjunctivitis sicca; PTF = precorneal tear film; STT = Schirmer tear test; STT1 = Schirmer tear test 1; TBUT = tear film breakup time
- King-Smith PE, Fink BA, Fogt N, et al. The thickness of the human precorneal tear film: Evidence from reflection spectra. Invest Ophthalmol Vis Sci 2000; 41(11):3348-3359.
- Prydall JI, Artal P, Wood H, Campbell FW. Study of human precorneal tear film thickness and structure using laser interferometry. Invest Ophthalmol Vis Sci 1992; 33(6):2006-2011.
- Franzco IC. Fluids of the ocular surface: Concepts, functions, and physics. Clin Exp Ophthalmol 2012; 40(6):634-643.
- Herring IP, Pickett JP, Champagne ES, Marini M. Evaluation of aqueous tear production in dogs following general anesthesia. JAAHA 2000; 36(5):427-430.
- Dodam JR, Branson KR, Martin DD. Effects of intramuscular sedative and opioid combinations on tear production in dogs. Vet Ophthalmol 1998; 1(1):57-59.
- Sanchez RF, Mellor D, Mould J. Effects of medetomidine and medetomidine-butorphanol combination on Schirmer tear test 1 readings in dogs. Vet Ophthalmol 2006; 9(1):33-37.
- Kaswan RL, Martin CL, Chapman WL. Keratoconjunctivitis sicca: Histopathologic study of nictitating membrane and lacrimal glands from 28 dogs. Am J Vet Res 1984; 45(1):112-118.
- Martin CL, Kaswan R. Distemper-associated keratoconjunctivitis sicca. JAAHA 1985; 21(3):355-359.
- Matheis FL, Walder-Reinhardt L, Spiess BM. Canine neurogenic keratoconjunctivitis sicca: 11 cases (2006-2010). Vet Ophthalmol 2012; 15(4):288-290.
- Naranjo C, Fondevila D, Leiva M, et al. Characterization of lacrimal gland lesions and possible pathogenic mechanisms of keratoconjunctivitis sicca in dogs with leishmaniosis. Vet Parasit 2005; 133(1):37-47.
- Westermeyer HD, Ward DA, Abrams K. Breed predisposition to congenital alacrima in dogs. Vet Ophthalmol 2009; 12(1):1-5.
- Klauss G, Giuliano EA, Moore CP, et al. Keratoconjunctivitis sicca associated with administration of etodolac in dogs: 211 cases (1992-2002). JAVMA 2007; 230(4):541-547.
- Trepanier LA, Danhoff R, Troll J, Watrous D. Clinical findings in 40 dogs with hypersensitivity associated with administration of potentiated sulfonamides. J Vet Intern Med 2003; 17(5):647-652.
- Bryan GM, Slatter DH. Keratoconjunctivitis sicca induced by phenazopyridine in dogs. Arch Ophthalmol 1973; 90(4):310-311.
- Saito A, Izumisawa Y, Yamashita K, Kotani T. The effect of third eyelid gland removal on the ocular surface of dogs. Vet Ophthalmol 2001; 4(1):13-18.
- Spugnini EP, Thrall DE, Price S, et al. Primary irradiation of canine intracranial masses. Vet Radiol Ultrasound 2000; 41(4):377-380.
- Sansom J, Barnett KC. Keratoconjunctivitis sicca in the dog: A review of two hundred cases. J Small Anim Pract 1985; 26(3):121-131.
- Kaswan RL, Salisbury MA. A new perspective on canine keratoconjunctivitis sicca. Treatment with ophthalmic cyclosporine. Vet Clin North Am Small Anim Pract 1990; 20(3):583-613.
- Moore CP. Qualitative tear film disease. Vet Clin North Am Sm Anim Pract 1990; 20(3):565-581.
- Moore CP, Collier LL. Ocular surface disease associated with the loss of conjunctival goblet cells in dogs. JAAHA 1990; 26(5):458-465.
- Hess AD. Mechanisms of action of cyclosporine: Considerations for treatment of autoimmune diseases. Clin Immunol Immunopathol 1993; 68(2):220-228.Moore CP, McHugh JB, Thorne JG, Phillips TE. Effect of cyclosporine on conjunctival mucin in a canine keratoconjunctivitis sicca model. Invest Ophthalmol Vis Sci 2001; 42(3):653-659.
- Palmer SL, Bowen PA, Green K. Tear flow in cyclosporine recipients. Ophthalmol 1995; 102(1):118-121.
- Olivero DK, Davidson MG, English RV, et al. Clinical evaluation of 1% cyclosporine for topical treatment of keratoconjunctivitis sicca in dogs. JAVMA 1991; 199(8):1039-1042.
- Morgan RV, Abrams KL. Topical administration of cyclosporine for treatment of keratoconjunctivitis sicca in dogs. JAVMA 1991; 199(8):1043-1046.
- Berdoulay A, English RV, Nadelstein B. Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca. Vet Ophthalmol 2005; 8(4):225-232.
- Hendrix DVH, Adkins EA, Ward DA, et al. An investigation comparing the efficacy of topical ocular application of tacrolimus and cyclosporine in dogs. Vet Med Inter 2011; 2011:487592.
- Smith EM, Buyukmihci NC, Faryer TB. Effect of topical pilocarpine treatment on tear production in dogs. JAVMA 1994; 205(9):1286-1289.
- Rhodes M, Heinrich C, Featherstone H, et al. Parotid duct transposition in dogs: A retrospective review of 92 eyes from 1999-2009. Vet Ophthalmol 2012; 15(4):213-222.
- Dreyfus J, Schobert CS, Dubielzig RR. Superficial corneal squamous cell carcinoma occurring in dogs with chronic keratitis. Vet Ophthalmol 2011; 14(13):161-168.
Lori J. Best, DVM, is a first-year ophthalmology resident at University of Tennessee College of Veterinary Medicine. She received her DVM from Colorado State University and completed her small animal rotating internship at University of Tennessee.
Diane V.H. Hendrix, DVM, Diplomate ACVO, is a professor of ophthalmology at University of Tennessee College of Veterinary Medicine. She received the Zoetis Distinguished Veterinary Teaching Award in 2013. Dr. Hendrix received her DVM from University of Tennessee and completed her residency in comparative ophthalmology at University of Florida.
Dan A. Ward, DVM, PhD, Diplomate ACVO, is a professor of ophthalmology at University of Tennessee College of Veterinary Medicine. He received the Pfizer Distinguished Professor Award in 2012. Dr. Ward received his DVM from University of Tennessee and completed his ophthalmology residency, PhD in pharmacology, and postdoctoral work in clinical pharmacology at University of Georgia.