Ординатура / Офтальмология / Английские материалы / Small Animal Ophthalmology Secrets_Riis_2002

190 Uveitis: Ocular Manifestations of Systemic Disease in Dogs

In those noninfectious immune-mediated systemic diseases that are characterized by their prolonged nature, such as uveodermatologic syndrome (similar to Vogt-Koyanagi-Harada disease in humans), anti-inflammatory or immunosuppressive drugs such as azathioprine are often used. The usual dosage is 2 mg/kg/day for 5 days, then I mglkg/day for 10 days, then 0.5 mg/kg/day thereafter for maintenance. Oral cyclosporine (5 mglkg/day) is beginning to be used more frequently as well. For whatever reason, if systemic corticosteroids cannot be used to control uveitis, oral nonsteroidal anti-inflammatory drugs (NSAlDs) such as aspirin may be used at an anti-in- flammatory dosage rate of 15 mg/kg three times daily.

Most cases of uveitis associated with systemic diseases include the iris and ciliary body (anterior uveitis). Topical ophthalmic medications are formulated in such a way that they enter, to some extent, the anterior and posterior chamber structures. Therefore, topical anti-inflammato- ries, particularly dexamethasone 0.1 % and prednisolone acetate I %, are usually used. Depending on the intensity of the anterior uveitis they may be used as frequently as 4 times daily. In the case of preexisting corneal ulceration, direct intraocular invasion by systemic mycotic agents, or other situation where topical corticosteroids are contraindicated, topical NSAIDs may be used. Available topical NSAIDs include diclofenac 0.1 %, f1urbiprofen 0.03%, ketorolac 0.5%, indomethacin I%, and suprofen I%. In addition, in cases of marked anterior uveitis, a combination of both topical corticosteroids and topical NSAIDs may be used.

Mydriatics, such as atropine sulfate I %, have often been advocated to treat anterior uveitis to prevent posterior synechiae formation and to inhibit eye pain. The use of mydriatics, however, must be weighed against the possibility of iridocorneal angle compromise including obstruction because mydriatics may actually promote increases in intraocular pressure (glaucoma). Glaucoma secondary to anterior uveitis is particularly common in certain breeds that have an inherited predisposition for glaucoma such as the American cocker spaniel. In cases where glaucoma is present or presumed to be likely, topical antiglaucoma therapy such as carbonic anhydrase inhibitor drugs (dorzolamide 2%, brinzolamide 1%) may be used to suppress aqueous humor production at a dosage of I drop three times daily.

Topical antimicrobials notoriously have poor anterior chamber penetration capabilities. Usually systemic antimicrobials have a greater ability to enter the intraocular structures through a compromised blood-ocular barrier that occurs with uveitis. Subconjunctival administration of certain antimicrobials such as gentamicin (10-20 mg) and cefazolin sodium (100 mg) may be given. Also, intracameral (into the anterior chamber) delivery of certain antimicrobial drugs, such as fluconazole in the case of systemic mycotic infections, have also been used.

BIBLIOGRAPHY

I. Aquirre GL, Gross SL: Ocular manifestations of selected systemic diseases. In Compendium Collection: Ophthalmology in Small Animal Practice. Trenton, NJ, Veterinary Learning Systems, 1996, pp 89-98.

2.Bistner S, Shaw D, Riis RC: Diseases of the uveal tract (Parts I-III). In Compendium Collection: Ophthalmology in Small Animal Practice. Trenton, NJ, Veterinary Learning Systems, 1996, pp 161-185.

3.Collins BK, Moore CPo Diseases and surgery of the canine anterior uvea. In Gelatt KN (ed): Veterinary Ophthalmology, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 1999, pp 755-795.

4.Gilger BC: Ocular manifestations of systemic infectious diseases. In Bonagura JD (ed): Kirk's Current Veterinary Therapy: Small Animal Practice, 13th ed. Philadelphia, W.B. Saunders, 2000, pp 276---279.

5.Hakanson N, Forrester SO: Uveitis in the dog and cat. Vet CIin North Am Small Anim Pract 20:715-735, 1990.

6.Johnson BC, Miller WW: Recognizing ocular signs of systemic diseases in dogs. Vet Med 85: 1076-1090, 1990.

7.Kern TJ: Canine uveitis. In Bonagura JO (ed): Kirk's Current Veterinary Therapy: Small Animal Practice, 12th ed. Philadelphia, W.B. Saunders, 1995, pp 1248-1253.

8.Komaromy AM, Brooks DE, Kallberg ME, et al: Hyphema. Part I. Pathophysiological considerations. Comp Cont Educ 21:1064-1069,1999.

9.Khrone SO, Vestre W A: Ocular use of anti-inflammatory drugs in companion animals. In Compendium Collection: Ophthalmology in Small Animal Practice. Trenton, NJ, Veterinary Learning Systems, 1996, pp 252-278.

10. Martin CL: Ocular manifestations of systemic disease. Part I. The dog. In Gelatt KN (ed): Veterinary Ophthalmology, 3rd ed. Baltimore, Lippincott Williams & Wilkins, 1999, pp 1401-1448.

II. Martin CL, Stiles J: Ocular infections. In Greene CE (ed): Infectious Diseases of the Dog and Cat, 2nd ed. Philadelphia, W.B. Saunders, 1998, pp 658-672.

12.Rathbone-Gionfriddo J: The causes, diagnosis and treatment of uveitis. Vet Med 90:278-284,1995.

13.Stiles J: Canine rickettsial infections: Infectious diseases of the eye. Vet Clin North Am Small Anim Pract

30:1135-1149.2000.

14.Ward DA: Oculomycosis. In Bonagura JD (ed): Kirk's Current Veterinary Therapy: Small Animal Prac-

tice, 12th ed. Philadelphia, W.B. Saunders, 1995, pp 1257-1261.

15. Willis AM: Canine viral infections: Infectious diseases of the eye. Vet Clin North Am Small Anim Pract 30:1119-1133,2000.

Figure 6. Same Shetland sheepdog as Figure 2 showing lip depigmentation

Figure 7. Same Shetland sheepdog as Figure 2 showing early nasal planum depigmentation.

6.Is there a known etiology for the syndrome?

No, but melanin is highly suspected as being a part of this syndrome, both in humans and

dogs. Antimelanin antibodies have been demonstrated, and the syndrome is responsive to immune suppression therapy.

7. What is the treatment for this syndrome?

Both topical and systemic corticosteroids are recommended, but long-term use has typical undesirable side effects. Initially, use prednisolone (1 mg/kg twice a day), but taper the dose systemically while adding azathioprine (2 mg/kg/day) for 1 week and reduce the daily frequency to every other day; over the course of weeks reduce even further to every third day. Every 2 weeks, monitor

Figure 8. Shetland sheepdog as a puppy (A), as a 2-year-old (B), as a 3-year-old (C), and at 3 years showing complete loss of nasal. iris, and nontapetal pigment but still visual (D). (Courtesy of Dr. D. Walton.)

the white blood cell count while on azathioprine (Imuran). If the count falls to :5 2000, discontinue until it regains normal levels, then return to an every other or every third day administration. The owners will monitor lid or lip pigmentation and eye comfort signs. If the uveitis is severe, give 0.1 ml of 40 mg/ml methylprednisolone (Depo-Medrol) subconjunctivally. After topical anesthesia, the injection is given into the dorsolateral fornix. The subconjunctival injection may be repeated in 2-3 weeks, if necessary. Topical antibiotic-corticosteroids are also used as is cyclosporine.

8. How successful is treatment?

Resolution of most signs are possible, but just when things look good a recurrence may happen. The prognosis for long-term control is poor. Many patients can be maintained on Imuran every third day for years. Aggressive treatment is vital initially for saving the vision; once that has been achieved, the long-term control depends on owner compliance and observational skills.

9.What are the histopathologic findings in eyes lost to this syndrome?

These eyes show severe granulomatous panuveitis. Within the iris and choroid are infiltrates of

chronic inflammatory cells, histiocytes, and macrophages containing melanin granules consistent with antimelanocytic autoimmunity. Destruction of the vascular choroid by these infiltrates leads to retinal detachment as well as retinal infiltrates. A breakdown in the blood-retinal barrier and exposure to retinal-specific antigens leading to antiretinal antibodies compounds the uveitis complex.

10.Does the skin histopathology aid the diagnosis?

Yes, biopsies of the lips at the mucocutaneous junctions show lichenoid pathology with his-

tiocytic cells, plasma cells, and chronic inflammatory cells.

11. Are other species known to develop this syndrome?

Yes, including Arabian, Camergue, Lippezan, and Percheron horses, Sinclair minipigs, and Dam chickens.

12.What are the current etiology hypotheses?

Autocytotoxic

Immune or autoimmune Neurochemical

13.Have any other therapies been tried besides immunosuppression?

Yes. Immunomodulators have been tried when the patient has become intolerant to conven-

tional therapy. The most success has been with tetracycline and niacinamide given orally three times a day over extended time periods (6-9 months). The dosing is rather broad for dogs: (dogs :5 50 pounds, 250 mg of tetracycline and niacinamide three times per day; dogs> 50 pounds, 500 mg of both three times per day).

BIBLIOGRAPHY

I. Asakukra I: Vogt-Koyanagi-Harada syndrome (uveitis diffusa acuta) in the dog. Jpn J Vet Med 673:445-455,1977.

2.Gwin RW, Wyman M, Ketring K, et al: Idiopathic uveitis and exudative retinal detachment in the dog. J Am Anim Hasp Assoc 16:153-170, 1980.

3.Inomata H, Rao NA: Depigmented atrophic lesions in sunset glow fundi of Vogt-Koyanagi-Harada disease. Am J Ophthalmol 131:607--{j14, 2001.

4.Kern TJ. Walton D, Riis RC, et al: Uveitis associated with poliosis and vitiligo in 6 dogs. JAm Anim Hosp Assoc 187:408-414,1985.

5.Murphy CJ, Bellhom RW, Thirkill C: Antiretinal antibodies associated with Vogt-Koyanagi-Harada-like syndrome in a dog. J Am Anim Hosp Assoc 27:399-402,1991.

6.Read RW, Rechodouni A, Butani N, et al: Complications and prognostic factors in Vogt- Koyanagi-Harada disease. Am J Ophthalmol 131:599--606,200 I.

7.Read RW, Holland GN, Rao NA, et al: Revised diagnostic criteria for Vogt-Koyanagi- Harada disease: Report of an international committee on nomenclature. Am J Ophthalmol 131:647-652. 200 I.

much money has been spent trying to find an etiology to no avail, this disease has become recognized as a possible immune-mediated uveitis unique to the breed.

6, So the disease can self-destruct the eyes?

Yes. The uveitis may be unilateral at first, but usually becomes bilateral. The chronic uveitis creates posterior synechiae, postinflammatory cataracts, and ultimately glaucoma. The glaucomatous globes usually end up enucleated or eviscerated.

7.What would the outcome be if the eyes were prophylactively treated for glaucoma in the initial uveitis stages?

Adding an intraocular pressure-reducing medication to an eye that is hypotonic does not help prevent the occlusion of the drainage angles. If the medication is directed at the aqueous production, a balance of outflow versus production may be maintained for a while. Unfortunately, the outcome is always the same in the long run despite anti-inflammatory and antiglaucoma medication.

8.To what extent has the treatment of the uveitis been explored?

The use of topical medication has been extended to parental immunosuppressive doses of prednisolone, azathioprine, and cyclosporine. These medications each have positive effects but also their own adverse effects. Usually because of the latter, the dose frequency is tapered off, and that is when a recurrence of the uveitis causes more damage. To avoid this, start with prednisolone orally and subconjunctivally, and later add azathioprine for long-term maintenance while decreasing the prednisolone. Topically, the frequency of dexamethasone and cyclosporine administration should depend on the need and comfort.

9. Iris cysts are commonly seen in golden retrievers; are they related to this disease?

Iridociliary cysts are often seen along with pigmentary uveitis. They are also seen frequently in golden retriever glaucoma (13 out of 18 cases in one study), leading to the conclusion that they may be important in the pathogenesis of glaucoma. Although glaucoma and pigmentary uveitis have cysts in common and most pigmentary uveitis cases end up with glaucoma, a direct relationship between cysts and uveitis in unproven (Fig. 2).

10. Has histopathology given any clues to this syndrome?

No. The role of histopathology should be to permit a diagnosis that clinical examinations were unable to make. However, most eyes sectioned are those that have end-stage glaucoma. These eyes have usually been treated with antiglaucoma and immunosuppressive medications both topically and systemically. Recently, this author evaluated the uveal tract from a golden retriever with this history. The uveal tract showed few cellular infiltrates (lymphocytes and plasma cells), indicating that the medications were doing their job. Special stains of IgA, IgG, IgM, CD79a , BLA36. and CD) were essentially unhelpful. A review of other patient files for cases of pigmentary uveitis and glaucoma untreated with immunosuppressive medication revealed similar cellular responses.

11. Explain the theory behind use of these special stains.

Immunophenotypic analysis uses antibodies that specifically bind to marker molecules on the cell surface membrane, cytoplasm, or nucleus. The major application of this type of analysis has been to classify lymphomas based on the cell origin (i.e., B-cells or T-cells). Veterinary researchers attempt to use the markers to diagnose and stage tumors and monitor the response. CD79 stains membrane markers of B-cell differentiation. CD) and CD4 stain membrane markers of T- cell differentiation.

An immune theory is presumed for the etiology of pigmentary uveitis in golden retrievers mainly because some relief is obtained by the symptomatic treatment results. Because lymphocytes and plasma cells are involved with immunoregulation, cell-mediated immunity, antibody production, suppression of other T-cells, tolerance, cytotoxicity, and probably many unknown immune activities, their presence is expected in pigmentary uveitis.

Figure 2. A typical finding in a golden retriever: a free-floating iris cyst in the anterior chamber as well as several attached cysts in the posterior chamber.

12. What is the best way to classify this uveitis?

The etiology of pigmentary uveitis in golden retrievers is unknown. Histopathology does not bring us more precision on the etiology, at least not yet. Therefore, the preferred classification based on the clinical signs rather than the pathologic signs prevails.

BIBLIOGRAPHY

I. Deehr AJ, Dubielzig RR: Glaucoma in golden retrievers. Trans Am Coll Vet OphthalmoI28:105, 1997.

2.Ocular Disorders Presumed to be Inherited in Purebred Dogs, 2nd ed. West Lafayette, IN, Genetics Committee of the American College of Veterinary Ophthalmology, 1996.

3.Sapienza JS, Sirno-Domenech FJ, Prades-Sapienza A: Golden retriever uveitis: 75 cases (1994-1999). Vet Ophthalmol 3:241-246, 2000.