Ocular manifestations of systemic disease (Proceedings)

Many systemic diseases may affect the eye and often the first sign of a systemic disease occurs in the eye. When discussing ocular manifestations of systemic disease (OMSD) with clients broad categories may be used such as metabolic, neoplastic and infectious since the majority of diseases that we see fall into these categories. Most textbooks use more detailed etiologic divisions to include congenital, developmental, acquired, neoplastic, nutritional, toxicity, and miscellaneous.

Congenital anomalies are not that common in the general dog and cat population. The ocular abnormality and deafness associated with white coat color is one form of congenital abnormality. The dwarfism noted in Labrador retrievers and Samoyeds is another; this is also associated with ocular abnormalities. Hydrocephalus in both dogs and cats may result in deviation of the globes in a ventrolateral direction and rarely may elicit papilledema.

Developmental diseases include tyrosinemia which is an inborn error of intermediary metabolism. Lysosomal storage diseases, consisting of ceroid lipofuscinosis, fucosidosis, galactocerebrosidosis, gangliosidosis, and mucopolysaccharidosis, are very uncommon. Ceroid lipofuscinosis is seen in both dogs and cats. Tibetan terriers and English setters tend to be affected as adults, with Tibetan terriers experiencing a late onset. Decreased vision, especially in dim light is one of the presenting signs. Other behavioral abnormalities follow. ERG testing reveals decreased retinal activity although the waveforms are not flat. Histopathology reveals retinal abnormalities and cellular inclusions. At this time there is no treatment.

Acquired diseases are the most common type of OMSD. Hypertension often presents with blindness as the first abnormal sign. The hemorrhage and, with progression, retinal detachment seen with hypertension results from vasoconstriction, followed by vessel occlusion and ischemia. Subretinal fluid may develop leading to retinal detachments. Primary and secondary etiologies may occur; renal disease, hyperadrenocorticism, pheochromocytoma, primary aldosteronism, hypothyroidism, and hyperthyroidism are all possible etiologies. Intraocular hemorrhage or effusive retinal detachments should include a blood pressure as part of the diagnostic plan. Treatment is focused on treating the hypertension as well as the underlying cause. Even when the primary disease is treated anti-hypertensive medications may still be necessary as part of the long term treatment plan.

Thrombocytopenia may lead to ocular changes. Infectious disease, neoplasia, drug-induced reactions, and immune-mediated disease are all common etiologies. Infectious diseases include arthropod-borne organisms: Babesia, Borrelia, Cytauxzoon, Dirofilaria, Ehrlichia spp., Leishmania, Rickettsia, etc.; viruses, including canine distemper virus, herpesvirus, parvovirus, adenovirus; fungal and bacterial organisms, including Candida, Histoplasma, Leptospira spp., etc. Neoplastic etiologies include lymphoma, leukemia, and multiple myeloma. Medications that impair platelet production or lead to platelet destruction include chloramphenicol, azathioprine, cyclophosphamide, doxorubicin, etc. Thrombocytopenia may present as both periocular and intraocular hemorrhage and petechiation. Therapy is directed at the underlying cause.

Other hematologic diseases with possible ocular involvement include anemia, hyperlipidemia, hyperviscosity syndrome, icterus, intravenous fluid overload, and polycytemia. Anemia may be associated with pale retinal vasculature and retinal hemorrhages. The pathogenesis of the hemorrhages may be from vessel wall hypoxia resulting from the anemia. In cats, FeLV infection may be associated with anemia and retinal hemorrhages. Mycoplasma haemofelis infection may also lead to anemia in cats. Hyperlipidemia may be associated with lipid-laden retinal vasculature, lipid-laden aqueous uveitis, lipid keratopathy and corneal arcus lesions. Work-up should include fasting CBC and Chemistry, urinalysis and thyroid panel. A dietary history is also important in diagnosis and treatment. Treatment is planned based on diagnostic testing results. Hyperviscosity syndrome and polycythemia may lead to retinal detachments, hemorrhage and uveitis. Treatment is described in many internal medicine texts. Icterus may lead to changes in iris and tapetal coloration. Lastly, i.v. fluid overload may be associated with bullous retinal detachments which resolve once the fluid overload is addressed.

In this area of the country rickettsial diseases may be commonly associated with ocular signs. Canine cyclic thrombocytopenia is caused by Anaplasma platys, a bacterial organism that replicates in platelets. Ophthalmologically, uveitis that is responsive to topical corticosteroids ± atropine may be noted. Oral treatment consists of doxycycline to eliminate the bacteria. Canine ehrlichiosis is a tick-borne disease produced by multiple species (Ehrlichia canis, E. chaffeensis, E. ewingii, E. equii, Anaplasma platys, A. phagocytophila, and Neorickettsia risticii). Clinically, an acute phase, a subclinical phase, and a chronic phase are noted. Different studies report a range in prevalence of ocular lesions from 10-37%. Ocular discharge, chorioretinitis and anterior uveitis may be present during the acute phase. Optic neuritis may also occur. The ocular lesions are a result of decreased platelet numbers or from vasculitis. Treatment includes doxycycline to address the etiologic agent and oral and topical steroids to address the uveitis. Atropine may also be utilized if anterior uveitis is present. Rocky Mountain Spotted Fever is caused by Rickettsia rickettsia, another tick-borne organism. Ocular signs include conjunctivitis, chemosis, petechiation of the conjunctiva, iris, and retina, hyphema, anterior uveitis, retinal edema and vasculitis. Treatment for the ocular signs consists of topical anti-inflammatories ± atropine.

Bartonella spp. bacteria may cause ocular signs in cats. Cats may be infected with several different species; B. hensalae, B. clarridgeiae, B. elizabethae, B. koehlerae, and B. weissii have been isolated in cats. Uveitis, blepharitis, conjunctivitis, keratitis, and chorioretinitis may occur. Treatment with doxycycline or azithromycin is effective.

Canine distemper virus may cause conjunctivitis with serous to mucopurulent discharge. The virus may be associated with keratoconjunctivitis sicca via an inflammatory reaction of lacrimal gland tissue. Keratitis and corneal ulceration may be associated with the change in tear production. Chorioretinitis and optic neuritis leading to blindness occurs as well. Treatment is mainly symptomatic and supportive in the form of topical lubricants and antibiotics. Prednisone in anti-inflammatory doses is used to treat the optic neuritis.

Feline herpes virus is the most common virus with ocular signs in the cat. Please refer to the presentation on "Feline Conjunctivitis and Keratitis" for more in depth discussion. The feline corona virus may lead to feline infectious peritonitis (FIP) which has ocular manifestations. The most common sign is bilateral granulomatous anterior uveitis. Fibrin and keratic precipitates may be present in the anterior segment and chorioretinitis and retinal vessel cuffing in the posterior segment. Retinal hemorrhages, detachments and optic neuritis may also occur. Treatment for both the ocular manifestations as well as the primary disease is symptomatic. Ocular treatment consists of topical, subconjunctival, and systemic steroidal and non-steroidal anti-inflammatories. Atropine may also be utilized for the uveitis, as well as glaucoma medications for secondary glaucoma.

Feline immunodeficiency virus (FIV) and the feline leukemia virus (FeLV) may both cause ocular manifestations. Anterior uveitis and conjunctivitis occur most frequently with FIV. Pars planitis may also occur leading to posterior lens capsule white precipitates and anterior vitreal precipitates. Treatment for FIV is symptomatic consisting of topical anti-inflammatories. Oral prednisone and atropine may be also be utilized as needed. The anterior uveitis is easier to control than the pars planitis. FeLV may cause anisocoria and spastic pupil syndrome associated with viral effects on the ciliary ganglion and short ciliary nerves. In utero infection with FeLV may lead to retinal dysplasia and diffuse uveitis. The most dramatic effect of FeLV occurs with its association with lymphosarcoma. The uveal tract is a common site for spread of lymphocytes and this leads uveitis. As the disease progresses sever thickening of the iris occurs from lymphocyte infiltration. This is often associated with secondary glaucoma. Treatment of the primary disease and use of topical anti-inflammatories may help to control the uveitis. As the disease progresses glaucoma medications may need to be instituted. Feline panleukopenia virus may cause retinal dysplasia in kittens infected in utero or in the perinatal period. No treatment for the ocular lesions is available.

Toxoplasma gondii may infect both dogs and cats leading to ocular manifestations. Although cats are the definitive host, dogs and other mammals may act as intermediate hosts. Cats are affected more frequently with ocular manifestations. In dogs ocular signs included mononuclear anterior uveitis, retinitis, choroiditis, extraocular myositis, scleritis, and optic neuritis. In cats chorioretinitis is the most common ocular manifestation. Although T. gondii does not usually cause systemic disease in dogs and cats it is a significant cause of ocular lesions in otherwise healthy dogs and cats. It should be on the differential list for uveitis regardless of systemic signs. Treatment consists of oral anti-inflammatories, ± atropine and oral clindamycin at recommended dosages.

Fungal diseases may affect both dogs and cats, however are not as common in the midatlantic area as in other parts of the country. Aspergillosis, blastomycosis, histoplasmosis, and cryptococcosis have been diagnosed. Coccidioidomycosis is usually found in the southwest. Aspergillosis results in panuveitis, chorioretinits, exudative retinal detachments and endophthalmitis. Treatment for the uveitis is symptomatic utilizing topical anti-inflammatories. Systemic treatment consists of long term administration of amphotericin B, itraconazole, or fluconazole. Overall prognosis is poor. Blastomycosis results from infection by Blastomyces dermatitidis. Cats are not as commonly affected. Young intact male dogs represent a higher risk group. Ocular involvement in dogs occurs in 48% of cases and 50% of the lesions are bilateral. Ocular signs have been the only lesion present in 3% of cases. The initial lesion is often pyogranulomatous choroiditis resulting anterior uveal inflammation. Retinal and subretinal granulomas develop which progress to exudative retinal detachments. Optic neuritis, retinal and vitreal hemorrhages and orbital cellulitis may also occur. Itraconazole is currently the treatment of choice and prognosis is associated with the degree of pulmonary involvement at the onset of treatment. Topical treatment is as for other uveitides. Up to 80% of dogs may be cured. Histoplasma capsulatum causes ocular signs in 66% of infected dogs. Lesions are observed in the anterior choroid, iris, ciliary body, and sclera. The choroid is the most commonly affected ocular tissue. Posterior segment lesions are similar to other fungal diseases. Treatment is difficult with poor response to antifungal therapy in dogs that have progressed to ocular lesions. Cryptococcosis is less common in dogs than cats. In dogs the most common lesion is granulomatous to pyogranulomatous chorioretinitis. Retinal hemorrhage may be present, as well as mild anterior uveitis. In cats C. neoformans is most commonly reported. Chorioretinitis with granulomatous inflammation and retinal detachments, anterior uveitis, exophthalmos and optic neuritis may occur. Diagnosis may be made based on organisms in vitreal or subretinal fluid aspiration. Fluconazole in combination with amphotericin B is the treatment of choice in dogs. Cats respond better to itraconazole. The prognosis is guarded in dogs due to the frequency of CNS involvement. Cats may be treated successfully but treatment is generally long term.

Metabolic diseases also affect the eye and diabetes mellitus (DM) is the most common disease in dogs and in cats hypertension is the most frequent. 60% of dogs with DM were diagnosed with cataracts at diagnosis of DM; a series of 30 cats with DM had no cataracts. 75% of diabetic dogs develop cataracts in the first year after diagnosis and 80% had cataracts by 16 months after diagnosis. Ocular manifestations of DM include cataract formation with subsequent lens-induced uveitis, corneal endothelial cell loss, corneal endothelial pleomorphism and polymegathism, retinal vascular damage, lower tear production, decreased corneal sensitivity, impaired tear film quality. Cataract surgery is the only modality available at this time to treat diabetic cataracts. Hyperadrenocorticism is another common endocrinopathy in the dog. Ocular signs include progressive or non-healing corneal ulceration, lipid keratopathy and corneal calcification, cataracts, lipemia retinalis and lesions associated with hypertension. Corneal stromal hemorrhage may also occur in the speaker's experience. An association with KCS also is noted. Treatment plans should be based on clinical signs. Lastly, hypothyroidism may cause ocular manifestations in dogs. An association with KCS is noted and corneal lipid deposits and degeneration may occur. The classic form is a peripheral arcus lesion adjacent to the limbus. Lipemia retinalis and lipid-laden aqueous may also occur. Retinal hemorrhages and detachments are less common, but may occur. Treatment for the ocular signs is symptomatic and in addition to primary treatment of the underlying disease.

Toxicities in dogs include sulfa drugs which may cause KCS. The nitrogen-containing pyridine ring in sulfonamides is reported as the lacrimotoxic factor. Many dogs experience a decrease in STT while on sulfonamide therapy but between 4 and 15% experience permanent toxicity. Etodolac, a nonsteroidal anti-inflammatory drugs that inhibits COX-2 has been reported to cause a severe and irreversible KCS in dogs. Ivermectin may cause toxicity in dogs that have a defect in the multiple drug resistance gene (MDR-1). The MDR-1 gene contains the coding for P-glycoprotein which is a key factor in metabolizing and removing ivermectin from the body. Many of the herding breeds are deficient in the MDR-1 gene leading to ivermectin sensitivity. Ocular signs include decreased vision, blindness, optic neuritis, and retinal edema.

Cats may react to fluoroquinolone antibiotics resulting in acute, typically irreversible retinal degeneration. Affected cats develop partial, temporary or total blindness. It is recommended not to exceed more than 5mg/kg PO q 24hr of Baytril. Ivermectin may also cause toxicity in cats leading to blindness and anisocoria.

Neoplasia may have ocular manifestations. The primary neoplasia with ocular manifestations is lymphosarcoma. Ocular manifestations commonly precede systemic manifestations in cats, while in dogs systemic disease is usually present when ocular signs occur. Adenocarcinomas, extraskeletal osteosarcomas, squamous cell carcinoma, plasmacytomas, and multiple myeloma have been reported to metastasize to the eye in cats. In dogs hemangiosarcoma, malignant melanoma, adenocarcinomas, squamous cell carcinoma, transitional carcinoma, mastocytoma, and canine transmissible venereal tumor have been reported to have ocular metastases.

References

1. Veterinary Ophthalmology, 4th ed., Gelatt KN, editor, Blackwell Publishing, Ames IA 2007.

2. Ophthalmic Disease in Veterinary Medicine, Martin CL, Manson Publishing, 2005.