The posterior segment--the hidden world of the eye (Proceedings)

Disorders of the vasculature

Hypertension

Systemic hypertension is a relatively common disease in older cats and is often related to hyperthyroidism or renal failure. The most common reason for presentation to an ophthalmologist is blindness. Retinal detachment is thought to be associated primarily from plasma effusion from diseased choroidal vessels.

Pathogenesis is similar to that in other species.  The blood-retinal barrier has tight cell junctions between the endothelial cells of the retinal vessels and tight cell junctions between the retinal pigmented epithelial cells.  Initially, there is an alteration in retinal blood flow and autoregulation.  This is followed by constriction of arterioles to regulate blood flow, then generalized dilation of arterioles, discontinuity of endothelial cells and finally a breakdown of the blood-retinal-barrier.  Damage occurs to the tight junctions and endothelial cells.  In the retinal pigmented epithelium the damage is due to choroidal ischemia.  Leakage of fluid occurs subretinally and intraretinally.

Ocular manifestations of systemic hypertension are typically bilateral. Cats can appear to present with concurrent neurologic signs. Often cats present with absent PLR's, partial or complete blindness.  Retinal arterial tortuosity, localized or generalized narrowing, or dilation of vessels can be observed on funduscopic evaluation.  Retinal hemorrhage (preretinal, intraretinal, subretinal, iris, ciliary body, choroid) can also be observed.  Hyphema and bleeding in the vitreous cavity is not uncommon. 

Hyphema most commonly associated with retinal and/or choroidal bleeding, which migrates to the anterior chamber.  Retinal edema and focal bullae are more obvious early in the course of the disease process.  Later, retinal detachment with or without tears are noted followed by retinal degeneration.  Some patients may develop secondary glaucoma.  Histopathologically, enlarged retinal arterioles are observed with fibrinoid necrosis.

Treatment involves control the underlying disease, such as renal, thyroid, or cardiac disease.  Amlodipine 0.625mg PO q24h is a good starting place but many cats are controlled with BID dosing.  Benazepril may be considered and has been show to have some blood pressure lowering effect.  Enalapril and propranolol tend to be ineffective and sodium-restricted diets are not recommended.  A cardiac consult should be considered.  Reevaluations of blood pressure should occur within 7-10 days of starting medication.  Some cats may become too hypotensive!  Blood pressure should be monitored every 4 months once normotensive and the underlying disease controlled.  Once the primary disease is controlled many cats will need less amlodipine, so monitor carefully.

The prognosis for vision varies between patients.   Morphologic retinal recovery is optimal if reattached within 7 days.  Visual recovery is poor if detachment lasts longer than a few weeks since photoreceptors degenerate rapidly.  Those cats that have retinal tears carry a poor prognosis for visual recovery.

Hyperlipidemia

Hyperlipidemia in characterized by an increase in serum triglycerides and/or cholesterol.  It can occur from accelerated production or delayed degradation of lipoproteins.  Four classes of transport systems are known: chylomicrons, VLDL, LDL, and HDL.  Hypertriglyceridemia is the abnormal function of chylomicron/VLDL.  Hypercholesterolemia is the abnormal function of HDL/LDL.

Hyperlipidemia is defined as an increased concentration of triglycerides, cholesterol, or both, in the blood. In the fasted state, hyperlipidemia is an abnormal finding that represents either accelerated production or delayed degradation of lipoproteins. The lipoproteins function as a carrier system to transport insoluble triglycerides and cholesterol through the blood. These lipoproteins consists of a triglyceride and cholesterol ester core surrounded by a surface layer of cholesterol, phospholipid, and apolipoproteins. There are four major classes of lipoproteins which differ in the lipid and apoprotein content and physicochemical characteristics, including size, density, and electrophoretic mobility.

Chylomicrons and VLDL's are primarily involved in triglyceride metabolism, whereas HDL's and LDL's are involved in cholesterol metabolism. Hypertriglyceridemia can develop secondary to increased chylomicron production (excessive dietary intake of lipid), ineffective clearance of the chylomicron particle, increased VLDL production, and ineffective clearance of the VLDL particle.  Hypercholesterolemia can arise from increased production of the LDL precursor particle (VLDL) or as a result of reduced clearance of the LDL or HDL particle.

Cases of hyperlipidemia are classified based on etiology.  Postprandial is the most common cause of hyperlipidemia in the dog and cat. This is a normal physiologic manifestation that will resolve within 2-10 hours.  Primary hypertriglyceridemias include the idiopathic hyperlipidemia of Miniature Schnauzers and hyperchylomicronemia of cats. Idiopathic condition in Schnauzers is characterized by severe hypertriglyceridemia due to excessive VLDL particles with or without concurrent hyperchylomicronemia, and by mild hypercholesterolemia.

Of the secondary causes of hyperlipidemia, hypothyroidism is the most common cause in the dog. This can be attributed to both a decrease in lipid synthesis and degradation (lipid degradation more severely affected). Other secondary causes include diabetes mellitus, Cushing's syndrome, pancreatitis, cholestasis, and drug induced (glucocorticoids, megesterol acetate in cats).

The presence of lipemic serum suggests that the animal is hypertriglyceridemic. Lactescence refers to the opaque and milk-like appearance of plasma sample that occurs when the elevation of the triglyceride level is sufficiently high. Conversely, animals that are purely hypercholesterolemic do not exhibit lipemic or lactescent serum, as cholesterol particles are to small to refract light. Levels are considered elevated if triglyceride exceeds 150mg/ml (dog) and cholesterol exceeds 300mg/ml (dog) on a fasted (12-16hrs) sample.

Systemic clinical signs that can be seen in this condition include seizures, behavioral changes, abdominal pain, anorexia, vomiting, diarrhea, and peripheral neuropathy (tibial and/or radial nerve paralysis).

Treatment for this condition is multifactorial: identify and correct/treat underlying causes (endocrine disorders), dietary modifications (low fat, high fiber), omega 3 FA's (10-30 mg/kg PO Q 24hrs) which reduce serum cholesterol/triglyceride by decreasing synthesis of VLDL and LDL.  Gemfibrozil (7.5-10 mg/kg PO BID) is a fibric acid derivative that reduces triglyceride and VLDL production, may increase HDL's.  Chitosan (150-300 mg PO 30 minutes before meal) binds lipids in GI tract decreasing absorption.  Niacin (50-300 mg/day/dog divided into two doses daily) reduces hepatic triglyceride synthesis but can have some side effects (pruritis of face).  Heparin (10 IU/kg subcutaneous injection) leads to increased release of lipoprotein lipase, there by increasing the clearance of circulating lipids and increasing plasma levels of free fA's.

Depending on the quantity and class of elevated lipoprotein, hyperlipidemia may produce ocular lesions.  Visible lipemia in the dog is produced by elevations of triglyceride levels, and can be detected in the ocular vessels of the conjunctiva and retina (lipemia retinalis) as pink, engorged vessels. It is most easily observed in the retinal vessels over the non-tapetal region. Hyperlipidemia may also manifest with lipids in the anterior chamber.

A prerequisite for gaining access into the anterior chamber by the large, lipid-laden molecules is alteration of the blood-aqueous barrier, presumably resulting from preexisting uveitis. It is unclear whether the lipids incite or are the result of uveitis. This syndrome is usually unilateral, which would argue against hyperlipidemia inciting uveitis. Hyperlipidemia characterized by elevated cholesterol levels may result in corneal lipidosis with varying patterns. A rapid, diffuse, irritating, bilateral corneal stromal syndrome has been observed in hypothyroid dogs with elevated cholesterol. Certain breeds, such as the Shetland Sheepdog and Collie, may be predisposed.

Toxic-enrofloxacin

In 1997, enrofloxacin labelling changed from a dose of 2.5 mg/kg BID to 5-20 mg/kg/d. Soon after, cases of acute and severe retinal degeneration and blindness were presenting in cats receiving enrofloxacin. Fluoroquinolone metabolism in cats is not clear, but in dogs, it is 40% is metabolized to ciprofloxaxin.  Ciprofloxacin is further transformed to metabolites that are excreted in the urine. Decreased GFR has been shown to increase plasma levels of the primary metabolite of marbofloxacin in the dog.  Enrofloxacin is the drug most identified with retinal degeneration in the cat, all fluoroquinolones should be considered potentially toxic

The retina can degenerate rapidly. Tapetal hyperreflectivity and retinal vessel attenuation can be seen even in cats given a single dose of enrofloxacin.  Granular appearance followed by a diffuse grey color to the visual streak within 3 days has been observed. Mild vascular attenuation can be present within 4 days and severe within 7 days.  Blindness is usually permanent.  ERG amplitudes are extinguished due to the outer retinal degeneration.  Histopathology has shown diffuse retinal degeneration, especially in outer layers and hypertrophy and swelling of RPE cells

Risk factors include: increased age, renal or hepatic impairment, increased dose and duration of administration, and intravenous administration.  Impaired renal or hepatic function results in increased plasma levels and decreased drug clearance.  When used, dose should be kept as low as possible, and should be administered for a minimum amount of time, and should never exceed 5 mg/kg/d.

Toxic-ivermectin

Most all dogs that I have examined for Ivermectin toxicity have a similar history.  Dogs tend to be in the vicinity of where a horse was dewormed within the past 24-72 hours.

We remember that GABA is the primary inhibitory neurotransmitter in mammals. 

Ivermectin is effectively excluded from the CNS by a P-glycoprotein mediated efflux mechanism that is encoded by the multidrug resistance gene MDR1.  Ivermectin stimulates the release of GABA from nerve endings and enhances binding of GABA to its receptor.  Increased GABA mediated activation of chloride channels prevents neuromuscular transmission in arthropods and interneuron-motorneuron transmission in nematodes.  Clinical signs in our patients include mydriasis, blindness, hypersalivation, ataxia, signs of depression, coma, tremors, and death.

Lesions were noted as in the retina, characterized by multifocal retinal edema and folds with low-lying retinal separation.  These findings were- all within a broad horizontal band at the tapetal non-tapetal border, or throughout non-tapetal fundus

ERG's were extinguished or attenuated.  Dissolution of retinal edema coincided with the return of vision and restoration of normal ERG results.  I have found that most all dogs recover from ivermectin-induced blindness with 2 weeks.  Ivermectin levels can also be performed through Antech diagnostics.

Toxic-spinosad/ivermectin

There are some reports of vision loss or blindness associated with Spinosad, Following concomitant extra-label use of ivermectin with spinosad, some dogs have experienced the following clinical signs: trembling/twitching, salivation/drooling, seizures, incoordination, excessive dilation of pupils, blindness and disorientation.

Pulmonary angioinvasive carcinoma

Please consider the following reference:  Cassotis NJ, et al. Angioinvasive pulmonary carcinoma with posterior segment metastasis in four cats. VO 1999; 2: 125-131.  There are many many disease in ophthalmology that can be inferred by funduscopic evaluation: for example differentiating Cryptococcus as opposed to viral retinopathy.  Pulmonary angioinvasive carcinoma in cats has a pathognomoic presentation and you can reach the diagnosis quickly. 

The funduscopic view will reveal large wedge-shaped foci of chorioretinal necrosis (black and tan areas). Peripapillary serous exudate and retinal vascular attenuation are also seen.   Histopathology will reveal columnar-shaped neoplastic cells are seen lining the major choroidal vessel. Panretinal necrosis is also present. A thorough physical exam will often reveal digital swelling or masses. Thoracic radiographs will be supportive of a primary bronchogenic carcinoma.

Sudden acquired retinal degeneration, immune mediated retinopathy (sard/imr)

This is a retinal disorder of an unknown cause but possibly related to an auto-immune, sex-hormone or other endocrine process.  Approximately 4000 cases are seen annually in the United States.  I often see it in purebreds or mixtures of Dachshunds, German Shepherds, and Schnauzers.  Most patients I have examined are female and overweight.  Clinically it resembles how a patient would present with optic neuritis.  SARD should be distinguished from other diseases having no visible pathology on funduscopic evaluation including retrobulbar optic neuritis, tumor at the optic chiasm or other central nervous system disease. 

The history is typically sudden blindness as the name implies but astute guardians will notice a decline over a two-week period.  Patients typically present with pupillary dilation and unresponsive pupils although some may retain a PLR. Patients will have a normal appearing fundus that differentiates it from PRA, but at times on close inspection there may be mild retinal edema and retinal vasculature changes (box-carring).

Dogs generally appear healthy and may have a history of polyuria, polydypsia and weight gain and be suspect Cushingnoid. Changes on labs can include increased serum alkaline phosphatase, serum aminotransferase, cholesterol and possibly bilirubin elevations. Electroretinography will reveal an extinguished (flat) ERG for SARD and possibly some function for IMR.  Red and blue lights are thought to differentiate SARD vs. IMR.  Red light will show an absent PLR and normal PLR with a blue light. IMR cases will have a slow red light response and good blue light response.  Morphologically, abnormalities are diffuse and at the photoreceptor level, targeting both rod and cone outer segments.  Apoptotic cell death occurs that ultimately leads to death of the remaining retinal layers and end stage retinal degeneration.   Ultimately these patients will have the same funduscopic changes as with PRA but in my opinion at a much slower rate. 

Some studies have shown circulating anti-retinal antibodies in dogs, but this has been called in to question. The prognosis is poor for vision and most all patients remain blind. Treatments originating at Iowa State University showed some response in select cases.  SARD patients have been treated with IV or intraocular immunotherapy, like that which is done for human immune-mediated retinopathy. Intravitreal steroid has also been administered to address the suspected inflammatory component. As some patients with SARD/IMR have an underlying systemic disease or neoplasia (paraneoplastic syndrome) they should undergo a thorough work-up including labwork, U/A and abdominal ultrasound to start. Some IMR patients will have some response to combined oral steroids and doxycycline.

Please consider the following reference:

Sansom J, et al. Blood pressure assessment in healthy cats and cats with hypertensive retinopathy. AJVR 2004; 65(2): 245-252.

Maggio F, et al. Ocular lesions associated with with systemic hypertension in cats: 69 cases (1985-1998). JAVMA 2000; 217(5): 695-702.

Retinopathy associated with ivermectin toxicosis in two dogs.  JAVMAv233n2p279-284 '08.