Evaluating and treating retinal disease (Proceedings)

A thorough fundic evaluation is important in diagnosing retinal disease. At the beginning of the exam the menace response, dazzle reflex and the pupillary light reflexes should be assessed. Abnormalities on the neuro-ophthalmic portion of the exam may augment interpretation of fundic findings. Additionally, behavioral testing such as ability to navigate a maze, to follow a dropped cotton ball, etc should be performed. Maze testing should be performed under both photopic and scotopic conditions. Dilation of the pupil, after initial examination and checking intraocular pressures to confirm that glaucoma is not present, should be performed. This allows visualization of the optic nerve as well as the peripheral retina. Visualization of the retina may be performed using an indirect lens and a transilluminator, otoscope, or penlight as a light source. A good quality 20D lens is a basic lens to start an evaluation. Most ophthalmologists use an indirect ophthalmoscope that is binocular and adds 0.5 D of magnification. Additionally, just as a refresher the use of an indirect lens makes the image upside down and backwards – important in localizing the lesion!

If the retina is not visible due to cataract formation or interference by opaque ocular media then other diagnostics need to be utilized. Ocular ultrasound and the electroretinogram (ERG) may be utilized to assess the retina if it cannot be directly visualized. Ocular ultrasound involves the use of a 12mHz probe (most commonly used) for assessing the optic nerve and retrobulbar area. Other available probes range from 20 to 50 mHz and are mostly used for diagnostics of the anterior segment. B mode ultrasound is generally utilized for evaluation of the globe. Very sensitive and lightweight ERG equipment is now available to facilitate retinal evaluation. The ERG may yield valuable information even when the retina is visible. The ERG machine may also be used to perform other electrodiagnostics such as visually evoked potentials, pattern ERG's, and multifocal ERG's. Gross intraocular details may also be noted on MRI and CT, however these are not optimum modalities for diagnosis. Other testing includes angiography, scanning laser ophthalmoscopy, and optical coherence tomography.

DNA testing is becoming more widely available for early diagnosis of many inherited retinal diseases. Mutation detection tests are specific to the actual genetic defect and are thus the most accurate and sensitive. Linkage tests use a DNA marker close to the actual genetic defect and although very informative, they are not as specific and sensitive as testing for the actual mutation. These tests are easily performed on blood or often a cheek swab of oral mucosa. Optigen is one of the many companies that perform these tests. CERF clinics offer basic screening for retinal disease using ophthalmoscopy and are important in detecting new abnormalities and mutations.

Inherited and developmental retinal abnormalities are a significant cause of visual disturbance. Collie Eye Anomaly (CEA) may range in severity; choroidal hypoplasia is the least severe manifestation and is often termed grade 1 CEA, optic nerve colobomas, retinal detachment, and hemorrhage are more severe manifestations which may lead to blindness as well as other complications like glaucoma. Merle Ocular Dysgenesis is another inherited and developmental abnormality that may be vision threatening. Choroidal hypoplasia and posterior staphylomas are associated with vision disturbance; microphthalmia and iris/anterior segment abnormalities may also be involved. Iris sphincter dysplasia in Dalmations has been added to the CERF list of inherited abnormalities recently.

Retinal dysplasias may be non-vision compromising or lead to blindness depending on the severity. Retinal folds result from incongruity in the growth of different layers of the retina creating a rosette formation when examining histopathologically. These folds may resolve as the animal grows; this may lead to confusion in the CERF exam with a normal or abnormal exam depending on the age at exam. When this occurs the term "go normal" is often used to describe the situation; breeds that are predisposed to this progression should be examined at 6-8 weeks to try to catch the folds before they resolve. Even if the folds "go normal", the genetic defect is still present and may result in a more serious manifestation in offspring. Often these animals pass their CERF but have a note on their certificate. Folds that do not resolve are considered multifocal retinal dysplasia, but do not usually affect visual acuity. Geographic retinal dysplasia may lead to visual abnormalities and complete dysplasia with retinal detachment is blinding.

Labrador retrievers and Samoyeds have a syndrome of dwarfism with retinal dysplasia. The skeletal manifestations are recessive and the ocular involvement is incomplete dominant. The complete name is dwarfism with retinal dysplasia (drd)1 in Labradors and drd2 in Samoyeds. Serous retinopathy and retinal pigment epithelium dysplasia is present in Great Pyrenees. Multifocal serous retinal detachments begin to develop at the age of 11 weeks. Central lesions develop first and then progressively peripheral lesions occur until the age of about 20 weeks. Abnormalities are present on angiography with blockage in flow of fluorescein dye. The lesions are stable and more do not develop after the age of 20 weeks. The ERG is positive and stable. Recent research is suggestive that the same gene that causes vitelliform macular dystrophy2 in people causes this abnormality in the Great Pyrenees.

Degenerative retinal disease may progress quickly in the first year of life to blindness or more slowly with some vision remaining until death. Rod/cone, rod, and photoreceptor dysplasias generally progress within the first year of life. Irish setters have been identified with rcd1 (rod cone dysplasia type 1) associated with a biochemical defect in the subunit of cyclic guanosine-monophosphate metabolism. Onset occurs at 3-4 months of age and blindness by 1 year. ERG is the best way to diagnose this and is abnormal by the age of 2 months. Night vision abnormalities and then blindness develop. The Collie has been described with rcd2; similar progression occurs however the causative gene is different. The Welsh Cardigan Corgi also has a retinal dysplasia resulting from yet a different mutation; rcd3 was identified in the 70's and affected dogs never develop normal cone function and rod function quickly degenerates leading to blindness. Lastly, Norwegian Elkhounds have a dysplasia of the rod cells resulting in blindness that develops by 3-5 years. The ERG is abnormal at 6 weeks of age and is the easiest way to diagnose the disorder. The genetic mutation appears to have disappeared from the breed as there is not any recently described affected dogs. The Schnauzer also has a photoreceptor dysplasia, however it is very slow in progression, but may be diagnosed early by ERG. The dark adapted b-wave response and the flicker response are abnormal by 2 months of age. Classic fundoscopic changes are not evident until 2-5 years. Cone-rod dystrophy affects a few breeds including the Pit Bull terrier, the Short-haired Dachshund and the Long-haired Dachshund. These three breeds have very early abnormal ERG findings and vision decreases in the first few years of life with night vision affected first. Inheritance appears to autosomal recessive for all the breeds.

Inherited rod-cone dysplasias and degeneration occur in the cat but are not nearly as prevalent as in dogs. The Abyssinian has an autosomal dominant dysplasia that affects kittens by 4 weeks and progresses quickly to complete degeneration at a year. An autosomal recessive rod-cone degeneration is also described in the Abyssinian. This is more typical of PRA in the dog; the disease affects young adults at approximately 2 years and progresses over another 2-4 years to complete degeneration. Photoreceptors are affected initially; outer segments first then inner segments. ERG results demonstrate decreased amplitudes and increased implicit times; angiography findings show vascular constriction.

Classic progressive retinal atrophy is usually a late onset disease. Affected dogs have normal vision in the early years of life. Over time subtle changes may develop in low light conditions; these are not always noted by the owner. Many patients present in end-stage disease because they have adapted to their environment as vision has deteriorated; they present only when they are taken out of the normal setting or some obvious sign of blindness occurs, such as refusal to go down stairs. Ophthalmoscopic examination is usually sufficient at this time to diagnose the disease. Indirect ophthalmoscopy reveals retinal vascular attenuation and thinning of the retina leading to hyperreflectivity. Associated abnormalities are the development of cataracts from the toxicity caused by the retinal degenerative by-products, lens–induced uveitis, glaucoma, and lens luxations. The disease is inherited in an autosomal recessive pattern in most breeds and a genetic test has been developed for many breeds. Confirmation of the disease by genetic test or ERG is always an option for the owner. ERG results generally manifest as a decrease in the amplitude of the scotopic b-wave in the early stage. Later, implicit time is prolonged and then the photopic recording is affected with decreased amplitude and increased implicit time. In addition to ERG abnormalities, histopathology findings are confirmatory; rod and cone outer segments are affected with degeneration and vacuolation. The Siberian Husky has a retinal degeneration that is x-linked and Mastiffs have a dominant PRA. Fundic evaluation of affected Mastiffs reveals multifocal areas of retinal thinning in the central fundus. The peripheral retina appears normal, although over time retinal degeneration progresses with advanced degeneration noted between 5-11 years. The disease is different from classic PRA and similar in dark adaptation findings and photoreceptor degeneration to human patients with retinitis pigmentosa (RP). Cats also have an autosomal recessive inherited retinal degeneration syndrome with similarities to RP.

Retinal pigment epithelial dystrophy or central PRA, as it was previously named, is a retinal degenerative disease that is characterized by the accumulation of tan pigment foci in the central retina. Over time the area affected increases and zones of hyperreflectivity develop around the spots in both the tapetum and nontapetum. As the disease progresses the areas coalesce and end-stage disease appears very similar to classic PRA due to the generalized retinal atrophy. Behavioral signs of disease do not occur until late in progression similar to PRA. Since the peripheral retina is initially spared vision may actually improve under low lighting when the pupil is dilated and the peripheral retina may absorb more light. Some affected dogs do not progress to blindness. As with classic PRA, cataracts may develop associated with retinal degenerative by-products. Briards have a high incidence of the disease in the UK; affected dogs have a primary abnormality in cholesterol metabolism. Histopathology studies show that the initial lesion is in the RPE; the RPE cell hypertrophies, accumulates lipopigment, and the overlying photoreceptors degenerate. The lipopigment results from peroxidation of the rod outer segment lipids.

Ceroid lipofuscinosis affects the nervous system including the retina. Pigment accumulates in cells leading to degeneration. Many species are affected by this disease, including man. Often cortical blindness develops before retinal degeneration is severe enough to cause blindness. Typical changes are noted on ERG and histopathology. Tibetan terriers have been extensively studied in relation to this disease.

Acquired disease may also cause retinal degeneration and lead to blindness. In many cases the disease may be treated and degeneration halted. So far little therapy exists for inherited forms of retinal degeneration, however in acquired disease the prognosis is often better. Broad classification of acquired disease includes infectious, immune-mediated, toxic, nutritional, metabolic, radiation, neoplastic, and secondary to other ocular disease. Infection may be sub-divided into: viral, bacterial, fungal, algal, protozoal, and parasitic. Viral diseases include distemper, canine herpesvirus, mokola virus; tickborne diseases are ehrlichiosis, rocky mountain spotted fever, and bartonellosis; bacterial chorioretinitis may be caused by leptospirosis and brucellosis; mycotic disease include apergillosis, blastomycosis, histoplasmosis, cryptococcosis, coccidioidomycosis, and candidiasis; protothecosis is the main algal agent leading to chorioretinitis; protozoal disease is caused by toxoplasmosis, neosporosis, and leishmaniasis; lastly, parasitic disease includes toxocariasis, ophthalmyiasis, and angiostrongylosis. Most of these infectious agents cause systemic signs and ophthalmic findings may be interpreted as an ocular manifestation of systemic disease. Treatment of the chorioretinitis and associated uveitis usually involves topical and oral anti-inflammatories, with steroids the preferred drug. Subconjunctival or intravitreal injections of steroids may be administered as well. Associated ocular surface involvement and glaucoma may require additional medication. Specific drug therapies are outlined for each disease and the reader is referred to internal medicine or specific publications on infectious disease for more detailed treatment and specific drugs for systemic therapy.

Sudden acquired retinal degeneration syndrome (SARDS) results in an acute onset of blindness with a normal fundoscopic exam. A negative ERG is needed to confirm the diagnosis. The history often includes changes in appetite and water intake. Evaluation of bloodwork, urinalysis, and testing for Cushing's disease is often warranted. Over time the retina will atrophy as the disease occurs from sudden apoptosis of photoreceptor cells. Recent research indicates that this may be an immune-mediated disease. IVIG therapy is in the experimental stages and has shown some improvement; in many cases the improvement does not result in functional vision or the improvement deteriorates to blindness over time. There is some indication for treating the disease with high dose oral steroids and subconjunctival steroid injections. Many ophthalmologists recommend Ocuvite, a neutraceutical with anti-oxidants and lutein.

Metabolic causes of retinal disease and usually chorioretinitis are hypertension, diabetes mellitus, hyperlipidemia, and immune-mediated thrombocytopenia. Treatment for each disease as dictated by internal medicine texts should accompany medication for the ocular manifestations. Uveitis develops with each of these disease so topical steroids or for diabetics topical nonsteroidal anti-inflammatories should be instituted. Oral anti-inflammatories also need to be administered and diet changes for hyperlipidemia are necessary. A low fat, high fiber diet is recommended for hyperlipidemia.

Nutritional causes of retinopathy in dogs are vitamins A and E deficiency. Retinal changes similar to those of RPED are noted with multifocal accumulations of tan pigment in the central retina. Over time the whole retina is affected and inclusions of lipid were noted in the RPE cells on histopathology; adjacent photoreceptor degeneration was noted. Supplementation with the appropriate vitamin increased vision and halted the disease. Taurine deficiency has been documented in cats. Although taurine is stored in the liver, the retina and the heart have the highest concentrations of taurine. General dietary requirements are 500-750 ppm; if deficient hyperreflective lesions develop first in the central retina and then spread peripherally, leading to visual deficits and blindness. The appearance of the retinal lesions is considered pathognomonic with 5 progressive stages. Most commercial diets available have adequate amounts of this amino acid to prevent retinal degeneration.

Radiation is also toxic to the retina and results in degeneration and blindness. The severity depends on the total dose of radiation and how close the radiation field is to the retina. The outer retinal layers are affected first. Ganglion cell and optic nerve axons may be affected over the long term. Other changes from radiation such as cataract formation will also have an effect on vision.

Other causes of retinal inflammation and degeneration include drug toxicity. The most recently described toxicity involves Baytril in cats. Current label recommendations are safe for the retina, but overdosage may lead to acute retinal toxicity with vascular attenuation, thinning and hyperreflectivity, and blindness. Mildly affected cases may recover vision if the drug is stopped immediately. Other cases are permanently blind.

Other causes of retinal degeneration include ocular disease such as glaucoma, cataract formation, trauma and neoplasia. Intraocular tumors may lead to blindness in the affected eye. Other systemic tumors may metastasize to the eye or lead to ocular manifestations such as uveitis and retinal detachment. Lymphoma may manifest as panuveitis including retinal detachment.

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.