Treatment of Keratoconjunctivitis Sicca

Keratoconjunctivitis sicca (KCS) is a progressive inflammation of the cornea and conjunctiva caused by a deficiency in tears. Even though cyclosporine (CsA) has become the treatment of choice for KCS, it is not 100% effective. Therefore, there is a need to find new drugs, which can be used to treat dogs that do not respond to CsA treatment.

Two related drugs that may be promising alternatives to CsA are pimecrolimus and tacrolimus. Two studies will be presented. The first shows that pimecrolimus is just as effective as cyclosporine in improving tear production, and more effective in reducing clinical signs of KCS. The second study shows that tacrolimus improves tear production in dogs that are resistant to cyclosporine therapy. Therefore, these drugs are a promising alternative to topical CsA for treatment of KCS.

Treatment of Melting Corneal Ulcers

Uncomplicated corneal abrasions will heal uneventfully. However, due to microbial infection or to extensive stromal involvement, some corneal ulcers undergo "melting." This process is characterized by rapid and progressive degradation of the corneal stroma, the result of proteinase activity. These enzymes, also known as matrix metalloproteinases (MMPs), are secreted by the infective microorganisms (e.g., Pseudomonas) but are also found in the tear film, white blood cells and corneal cells. If their activity is not inhibited, an ulcer can rapidly progress from a rather superficial lesion to descemetocele and corneal perforation.

Several drugs and substances have recently been shown to have an inhibitory effect on MMP activity. Therefore, these drugs could become important therapeutic agents in the treatment of ulcerative keratitis as they slow down or inhibit the melting process and stromal degradation. The drugs include N-acetyl cysteine, tetracycline and EDTA, all of which bind cofactors required for proteinase activity. However, many clinicians recommend autologous serum as a potent MMP inhibitor, as it contains alpha-2 macroglobulins that bind to proteinases, causing > 90% inhibition in their activity. Serum also contains platelet-derived growth factors and fibronectin, which promote ulcer healing and patient comfort.

Autologous serum may be extracted (following clotting centrifugation) from the patient's blood and dispenses as eyedrops. However, it is also possible to use allogenic serum (from other animals of the same species). Indeed, it may be easier, as we do not have to struggle to draw blood from a patient with a painful eye, and the owners do not need to wait for the serum extraction. Instead, it is possible to prepare a large number of serum bottles from the blood of a donor, freeze them, and dispense them as needed. Serum drops can be applied at a very high frequency (every hour in cases of deep and melting ulcers). Bottles should be discarded a week after thawing (or preparation) due to possible contamination. Advantages of serum include the fact that it is very efficacious, extremely safe (you can't really overdose the patient with serum), cheap and readily available.

Of course, MMP inhibition is only one component in the treatment of corneal ulcers. The patient should be treated with topical (and possibly systemic) antibiotics. Secondary uveitis may be treated with topical (and possibly systemic) antiinflammatories, as well as with topical atropine. The latter serves as an analgesic and helps prevent adhesions. And an Elizabethan collar should be provided.

Unfortunately, some cases will not respond to medical treatment, and surgery (most commonly conjunctival flap) may be required.

Neuroprotective Treatment in Glaucoma

Glaucoma is a common and painful cause of blindness. For many years the disease was defined as an elevation in intraocular pressure (IOP). However, today there is increasing realization that other factors besides IOP are responsible for the death of retinal ganglion cells (RGCs) that leads to loss of vision in glaucoma patients. It is suggested that RGCs damaged by an initial rise in IOP, or due to local ischemia, release various substances into their immediate surroundings. The localized high concentrations of these substances create a hostile microenvironment. Adjacent RGCs, not damaged during the initial insult, undergo secondary degeneration as a result of exposure to this toxic milieu. While many mediators of secondary degeneration have been identified, the two compounds receiving most attention are glutamate, an excitatory neurotransmitter that is toxic in elevated concentrations, and endothelin-1, which causes vasoconstriction and local ischemia in the retina. Indeed, elevated levels of both substances have been demonstrated in eyes of glaucomatous dogs.

An obvious implication of the process of secondary degeneration is that treatment with compounds which inhibit the toxic factors may slow the cascade of secondary degeneration, and protect the undamaged neighboring RGCs. This therapeutic approach is known as neuroprotection and is showing promising experimental results. For example, memantine, a glutamate antagonist, has been shown to be neuroprotective in animal models of glaucoma. Similarly, unoprostone, a potent vasorelaxant, was shown to antagonize the vasoconstrictive effect of endothelin-1 and to improve retinal blood flow in glaucoma patients.

Obviously, such drugs are not expected to restore vision lost prior to initiation of treatment. However, a combination of traditional (hypotensive) and new (neuroprotective) treatments may help preserve vision in patients that still have some vision at presentation, and revolutionize our treatment of glaucoma.

Science Fiction? Restoring Vision in the Blind Patient

Two therapeutic approaches are being tested, aimed at restoring vision to patients blinded by (hereditary) outer retinal diseases. The first approach is based on restoring function to the photoreceptor by replacing the defective gene. This can be done by inserting the missing gene onto a modified virus and injecting it subretinally. Such studies have been conducted in dogs with various forms of inherited photoreceptor diseases by Dr. G. Aguirre (Cornell/Pennsylvania) and Dr. K. Narfstrom (Missouri). The operations have restored vision in a large number of dogs, with some patients already monitored for 7 or more years post-surgery. Success in such feasibility studies in dogs suffering from mutation in the RPE65 gene have led to approval of gene therapy trials in humans suffering from Leber's congenital amaurosis. In Israel, we have used a similar approach to treat sheep suffering from day blindness due to a mutation in cone sodium channels. Again, gene therapy has restored vision in affected sheep, thus hopefully paving the way to treating human achromatopsia patients.

A different therapeutic approach involves use of retinal prostheses. More specifically, the prostheses are usually implanted epiretinally or subretinally, with the former usually fixed to the scleral wall with tacks. The electrodes on these prostheses emit electrical currents that stimulate functional bipolar or ganglion cells that remain despite the destruction of the photoreceptors. These bipolar and ganglion cells then transmit the signal through the afferent visual pathways, as they would do in a normal eye, and produce a visual sensation. Evidence of prosthesis functionality is the fact that stimulation of the retinal electrodes elicits recordable electrical activity in the visual cortex of implanted patients. Retinal prostheses have been successfully implanted in both cats and dogs.

Obviously, in order for the patient to experience (or visualize) more than just spots of light, the prosthesis should be stimulated by light and images. This stimulation may be achieved in a number of ways. A simple approach, adopted in subretinal prostheses, is to mount photodiodes (that capture incoming light and transduce its energy to currents) on the prosthesis. Epiretinal prostheses are more sophisticated and usually rely on visual input from a small camera that is mounted on the head or on goggles. Real-time images of the world, together with the power required for operation, are transmitted to the prosthesis to elicit vision.

Though retinal prosthesis research made considerable progress during the last decade, numerous problems remain. These include the biocompatibility of the prosthesis material; the effect of long-term electrical stimulation on the stimulated retinal tissue; and possible erosion or breakdown of the implant, which would require repeated surgery for replacement. However, the most complex issues remain the related problems of implant power requirements and the heat it generates. Studies have shown that the implant temperature may rise by as much as 0.8° Celsius, with potentially disastrous effects on the neighboring retina. The potential thermal injury limits the number of electrodes that can be mounted on the retinal prosthesis. This, in turn, limits the visual resolution and acuity of the "image" generated by the prosthesis. The technology is in its preliminary stages, but has already been used on humans (and dogs!). See www.2-sight.com for details.