Ocular manifestations of systemic disease--when the eye is not the primary disease (Proceedings)

Often the eyes are not the cause of the primary ocular signs, they are simply the easiest place to visibly see the effects.  Instead of the window to the soul, they can be the window to early diagnosis for your patient if you just know to look for it. 

The best place to begin for an eye exam is the same as with any another complaint, a complete history and physical examination.  Tunnel vision on the ocular disease can lead to missing important abnormalities elsewhere.  Systemic disease can affect the eyes bilaterally or unilaterally (or has maybe just shown up in one eye first), and therefore should be ruled out even when just one eye has the obvious problem.  When suspected, you can go through the general DAMNIT-V scheme to work through differential diagnoses.  There is an extensive list of possibilities of which we will only be able to briefly touch on a few today in this hour.  First, identify which parts of the eye are involved to help generate your list of differentials.  Often it is unclear at first whether or not systemic disease is involved, and the safest course is to initially assume that there may be a risk to the general health of the animal.

A minimum data base including a chemistry profile, complete blood count, and urinalysis are always a good start.  Then, based on your exam findings, you might want to also go ahead and check blood pressure, clotting times, or serology for infectious diseases you may be worried about based on your region or the pet's travel history.  Advanced imaging such as thoracic radiographs, abdominal ultrasound and MRI, CT, or ultrasound of the globe/orbit/skull may also be indicated. 

Now that you have determined, at least partially, what part of the eye is affected and started going through your differentials, remember there are many conditions that can affect the eyes (or are at least suspected of affecting the eyes) and we can't test for all of them from the start.  I warn owners that I recommend starting with tests for some of the more common infectious diseases, but the tests are not perfect and we often do not get an answer from them; however, I will feel more comfortable continuing to adjust a treatment plan if we have done them and they come back normal.

Let's start with a frequent emergency call we receive that strikes fear into the owner and the family  veterinarian – you have a patient with hyphema.  This certainly can occur with trauma or other primary ocular disease (retinal detachment, intraocular neoplasia), but with no history of injury or previous eye problems, you should first investigate systemic causes.  Usually the owner will bring the pet in reasonably quickly when an eye fills with blood, so hopefully there is a second one for you to examine looking for signs of disease not obscured by the hyphema.  If the intraocular pressure is low in this eye, it does not need to come over on an emergency referral unless you or the owners are more comfortable with that. 

If a pet has a known predisposing health condition to have high blood pressure (renal or thyroid disease, hyperadrenocorticism, diabetes mellitus), hypertension should be at the top of your list.  Even without other systemic disease, we do find a number of patients where no other primary cause is identified.  Coagulopathies and infectious diseases, while less common, can lead to intraocular bleeding.  I always recommend taking a radiograph of the skull having had numerous owners who swear there is no way “Princess” could possibly have been shot to, low and behold, find a radio-opaque foreign body rattling around the orbit (or neck).  Though unusual, some of the same causes of hyphema may similarly result in cerebrovascular accidents manifesting as visual or behavior changes attributed to acute visual loss. 

Diabetes mellitus is well known to cause cataracts in dogs (approximately 80% of diabetic dogs within the first year or so of diagnosis), but it can have other affects on the eyes including a decrease in corneal sensitivity and dry eye, corneal endothelial cell changes (leading to edema), and retinal changes.  Diabetic cataracts can form rapidly and are not related to the degree of diabetic control.  Whether or not the owners are interested in cataract surgery, these dogs should be closely followed as the cataracts cause severe lens-induced uveitis in many patients that requires treatment with anti-inflammatory drops. 

Untreated this leads to scarring and secondary glaucoma.  If caught early, many can be controlled simply with topical non-steroidal drops, but severe swelling of the lens may occur, because of the osmotic nature of the cataract formation, causing the lens capsule to tear with a large amount of lens material suddenly entering the eye.  When this happens, it leads to severe phacoclastic uveitis that does not respond well to medical therapy and cataract surgery must be performed as soon as possible to salvage the eye. 

Diabetic retinopathy takes several years to develop, so it is not as well recognized in our veterinary patients, but there has been a higher incidence of retinal hemorrhages/microaneurysms in diabetics after cataract surgery suggesting this is a potentially relevant process occurring in the retinas as well. 

In addition to diabetes mellitus, Cushing's disease and hypothyroidism, have been associated with keratoconjunctivitis sicca, non-healing ulcers, corneal changes, hyperlipidemia, and, as previously discussed, systemic hypertension.  Dry eye treatment should include treatment for any potential metabolic disease if present, and these pets may need additional supplementation when you are anesthetizing them for procedures even when not clinical for ocular disease. 

Elevated lipid levels may be apparent as corneal deposits (corneal lipidosis), as a milky white haze in the anterior chamber (aqueous lipidosis), or even visible within the retinal vessels (lipemia retinalis).  This should be assessed and potentially treated prior to performing cataract surgery.  Other metabolic disease such as lysosomal storage diseases, polycythemia, hypocalcemia, or vitamin and zinc deficiencies may cause ocular signs, but are rare.

Immune-mediated disease can affect almost anywhere in and around the eye.  Severe inflammation of the eyelids can be due to an immune mediated blepharitis and biopsy is recommended for diagnosis.  Keratoconjunctivitis sicca and chronic superficial keratitis are also associated with immune-mediated inflammatory disease.  Less well documented are cases of uveitis or optic neuritis where no other diagnosis is found and they are found to be “steroid responsive”. 

We do have evidence that uveodermatologic syndrome (or Vogt-Koyanagi-Harada-like syndrome, aka VKH) is immune-mediated and can be diagnosed on histopathology of the dermal lesions (or ocular tissue as many of these dogs eventually lose the eyes to the severe panuveitis or glaucoma).  The classic breed is the Akita, but many other breeds have been described with this process believed to be an immune-mediated destruction of melanocytes.  Ocular inflammation generally precedes the vitiligo and poliosis and is difficult to control, generally requiring combination immune suppressive therapy for life. 

There is currently debate regarding the cause and potential treatment of what may be several conditions previously all called Sudden Acquired Retinal Degeneration Syndrome (SARDS).  In the past, multiple theories regarding the cause of the sudden vision loss have included immune-mediated disease, toxic damage, and the influence of adrenal hormones due to a significant number of affected patients exhibiting “Cushing's like” signs around the time of diagnosis.  Dogs will acutely go blind over days to weeks with relatively normal looking retinas and no other signs of ocular disease.  The diagnosis is made by performing an electroretinogram (ERG) which shows absent waveforms indicative of sudden death of the photoreceptors. 

Over the next several months, the retinas become atrophied on exam as the damage becomes more apparent.  Historically, owners have been told that the acute blindness is untreatable and permanent, but they do not need to worry about complications other than the blindness.  More recently, research at Iowa State University is suggesting there is a group of these that are truly an Immune Mediated Retinopathy (IMR) that may be, to some extent, treated with combinations of corticosteroids, doxycycline, and intravenous (or Intravitreal) human immunoglobulins (IVIg) and that it may in some cases represent a paraneoplastic process.  This is still considered experimental and not widely accepted at this time, but can be discussed with your clients if they are willing to pursue any available treatment options.

Primary intraocular tumors do not tend to cause considerable inflammation, but can lead to blindness, pupil changes, bleeding and/or secondary glaucoma as they progress.  Secondary tumors are more likely to be associated with significant uveitis.  The most common metastatic neoplasia visible in the eyes is lymphosarcoma which usually results in bilateral uveitis, but also can manifest as retinal hemorrhages or infrequently eyelid/orbital masses.

There are also a large number of infectious agents that can cause ocular disease and your differential list will vary based on which of these are endemic in your region (or where the pet has been).  Fungal disease tends to cause granulomatous chorioretinitis (via hematogenous spread), which may not be visible with certain organisms due to anterior segment inflammation, and may present unilaterally or bilaterally.  Aspergillus spp., Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus gattii or neoformans, Candida albicans, and Histoplasma capsulatum are the most often diagnosed organisms.

In general, any bacterial infection that causes bacteremia or septicemia can lead to inflammation in the eyes, but this is rare without pre-existing ocular disease to disrupt the blood-aqueous barrier.  There are certain agents more closely associated with being a causative agent in the development of uveitis, hyphema, and chorioretinitis or retinal detachment and these include Bartonella spp., Borrelia burgdorferi, Brucella canis, and Leptospira spp as well as rickettsial disease (Ehrlichia and Rickettsia rickettsii).

Viral disease comes to mind more for feline ocular disease, but can be implicated in canine patients in some instances. 

·         Canine distemper virus can present acutely in dogs and ferrets as serous to mucopurulent ocular discharge, chemosis, KCS, and severe ulcerative corneal disease.  There also may be chorioretinitis and acute blindness from optic neuritis. 

·         Papillomaviruses are seen in several species and may cause lesions on the eyelids, conjunctiva or cornea of dogs.  These typically manifest 4-8 weeks after infection and regress after another 4-8 weeks.  Ocular forms do not always regress or may need to be addressed if they are causing irritation. 

·         Herpesvirus has been reported to cause corneal disease rarely in adult dogs, but is a major source of ophthalmic disease in cats.  Over 90% of cats are seropositive to feline herpesvirus type 1 (FHV-1) and about half of the latently infected cats are suspected to intermittently shed the virus throughout their lives.  Cats can have disease either due to direct active viral infection and replication, or also during recrudescence via an immune-mediated response.  It often occurs unilaterally (even repeatedly in the same eye) and has been associated with discharge, squinting, conjunctivitis, neonatal ophthalmia, symblepharon, corneal ulcers (dendritic, geographic, indolent, deep stromal), stromal keratitis, eosinophilic keratitis, sequestrum formation, perforation, and uveitis. 

·         Feline Immunodeficiency Virus is similar to FHV-1 in that it is suspected to cause disease via direct infection or by inciting inappropriate immune response, but it also may allow ocular disease by increasing the susceptibility to opportunistic secondary infections (such as toxoplasmosis).  Some consider the finding of “snow banking” or pars planitis, where white cellular deposits are present throughout the anterior vitreous, indicative of intermediate uveitis caused by FIV.

·         Feline Infectious Peritonitis (in the dry form) may result in bilateral granulomatous uveitis with hypopyon, “mutton fat” keratic precipitates, hyphema, and pyogranulomatous chorioretinitis with possible retinal hemorrhage/hyphema, retinal detachment, and optic neuritis. 

·         Feline Leukemia Virus is also associated with uveitis, but is better known for the propensity of spread of malignant cells to the uveal tract resulting in thickening or nodules on the iris.   As the inflammation and infiltration progress, secondary glaucoma occurs and abnormal cells can be obtained via aqueocentesis.  Pupil abnormalities are sometimes noted by the owner either from infiltrative cells affecting mobility of the pupil or due to neurologic effects on the ciliary ganglia.

Parasites including Dirofilaria immitis, Oncocerca, Ancyclostoma, and Toxocara can invade ocular tissue and parasitic protozoal disease such as Leishmania, Neospora, and Toxoplasma have been reported as well.

Protothecosis is a rare disease caused by an algae with a wide environmental distribution.  Any dog with uveitis and hemorrhagic diarrhea should have this as a consideration and a urinalysis may contain the organism leading to detection. 

References

Beam S, Correa MT, Davidson MG.  A retrospective cohort study on the development of cataracts in dogs with diabetes mellitus: 200 cases. Vet Ophthalmol 1999; 2:169-172.

Landry MP, Herring IP, Panciera DL.  Fundoscopic findings following cataract extraction by means of phacoemulsification in diabetic dogs:  52 cases (1993-2003).  JAVMA. 2004 Sep 1;225(5):709-16.

Gelatt KN.  Veterinary Ophthalmology, 4th ed.  Lippincott Williams and Wilkins.  2007

http://vetmed.iastate.edu/vmc/small-animal/medical-services/ophthalmology-service/sards/treatment