Current glaucoma therapy (Proceedings)

During this talk, we will be discussing currently available medical and surgical therapies for glaucoma in veterinary medicine, with emphasis on what is new and updated, as well as when their use is appropriate. Treatment of canine glaucoma is highlighted, although species variations will be touched upon where appropriate. We are fortunate in some ways that glaucoma is a prevalent human condition and so the many research dollars have been spent, and are being spent, on the study of its treatment. Although the precise differences between the primary glaucomas of humans and dogs are beyond the scope of this lecture, it is important to realize that there are some key differences between the two conditions, as well as between the ocular anatomies of the species, and so the efficacies of different therapies may vary. Common denominators of most glaucomas include elevated intraocular pressure, retinal ganglion cell death, and subsequent vision loss, and so surgical and medical therapies are aimed at one or more of these areas. Some surgical procedures, like cyclophotocoagulation and goniovalve implantation, can be translated across species, while others like trabeculoplasty are less useful. The pharmaceutical industry has provided a number of heavily researched anti-glaucoma drugs. Most are effective in domestic animal species. Some of these drugs act to lower aqueous humor production, some act to improve aqueous humor outflow, some have a combined intraocular pressure (IOP)-lowering effect, and more recently some are being used to provide a neuroprotective effect.

Anti-glaucoma drugs which act to decrease aqueous production include beta-blockers (timolol, betaxolol) and carbonic anhydrase inhibitors (methazolamide, dorzolamide). Although some systemic beta-blockers have an IOP-lowering effect, only topical agents are used for this purpose. Even these may have side effects. Timolol is a non-specific beta-blocker, and so could precipitate a feline asthma attack or aggravate heart disease in predisposed patients. Although this risk appears to be low, the risk could be obviated by the use of a beta-1-selective agent like betaxolol. Timolol appears more effective in the cat than dog. Carbonic anhydrase inhibitors effectively lower IOP in the dog and cat by competitive inhibition of the carbonic anhydrase II within the ciliary body epithelium which is critical for aqueous prodction. The advent of effective topical versions has been advantageous. The topical CAIs act only on ciliary body CA-II, whereas oral versions like methazolamide act on this ubiquitous enzyme within other body tissues. Oral CAIs can result in noticeable side effects including hypokalemia, acidemia, and hyperpnea. The side effect profile and advent of effective alternatives explain the decreased availability of systemic formulations. Although there may be some benefit in rapidity of onset, at least beyond the first several days there should not be a significant benefit to co-administration of systemic and topical CAIs. A combination drug of topical 2% dorzolamide and 0.5% timolol exists and its twice daily use is particularly useful for cats, which are resistant to frequent drop administration.

Glaucoma drugs which lower intraocular pressure by improving aqueous outflow include prostaglandin analogs like latanoprost, direct-acting parasympathomimetics like pilocarpine, and indirect-acting parasympathomimetics like demecarium bromide. All may cause some degree of blood aqueous barrier (BAB) breakdown and have a miotic effect which may limit their usefulness in glaucomas with an inflammatory component and with anterior lens luxation, respectively. Prostaglandin analogs are a newer class of drugs which are potent topically active ocular hypotensive agents with a prolonged duration of action. They are modifications of prostaglandin F2-alpha, which act through FP receptors to lower aqueous production when administered at low concentrations. They act by promoting an increase in the alternative or uveosleral aqueous outflow pathway. This is mediated through matrix metalloproteinases which are believed to remodel the extracellular matrix (ECM) within the uveosceral outflow pathway. Latanaprost is typically prescribed for once-daily administration initially, although it can be administered twice daily once its efficacy wanes. Since their action is local, there are no known systemic side effects. Local side effects include direct ocular irritation and blood aqueous barrier breakdown, so they may not be the best first choice for secondary glaucoma. The irritative effect is so severe in the horse as to make their use contraindicated. Apparently because the IOP-lowering effect of prostaglandins is mediated through different (EP not FP) receptors, prostaglandin analogs are ineffective in cats. Not only are they well-tolerated and effective for maintenance therapy in the dog, but may have a place in emergency glaucoma therapy in this species as well. This seems counterintuitive since enzyme-mediated changes in the ECM take several days. It has been suggested by Miller et al. that the often rapid IOP-lowering effect (within 10-20minutes) seen with latanoprost in the acute glaucoma patients is due to its profound miotic effect. The rapid change in pupil size is suspected to break a functional "reverse pupillary block" present in some acute glaucoma patients and exacerbating their condition. Releasing this blockage of aqueous outflow due to a temporary connection between the iris and the lens restores normal flow. Parasympathomimetics are thought to act through cholinergic receptors to contract the ciliary muscles, thus widening the iridocorneal angle and promoting conventional aqueous outflow. This effect is less pronounced in nonprimates. Pilocarpine's benefit in IOP-lowering effect may be outweighed by its sometimes profound local irritative and intraocular inflammatory effects and need for frequent administration. Demecarium bromide is equally effective and, although it can have comparable local effects, has a prolonged duration of action. It is typically administered one to two times daily, although its hypotensive effect actually lasts even longer. It is no longer available commercially, but is readily available through veterinary compounding pharmacists. In contrast to pilocarpine, a direct acting parasympathomimetic drug, however, demecarium bromide does provide a small risk of systemic toxicity. This occurs because demecarium acts by indirectly by reversibly binding acetylcholinesterase. By inhibiting acetylcholinesterase in this manner, acetylcholine activity is potentiated, and SLUD signs occur. Such reactions are uncommon, most likely to occur in cats and very small dogs, and are reversible with discontinuation of the drug.

Adrenergic agonists (epinephrine, dipivefrin, aproclonidine) appear to lower IOP through an unclear combination of improved outflow and decreased production, and are used infrequently in veterinary medicine at this time. Osmotic agents (mannitol, glycerine) used in the emergency treatment of acute glaucoma act to rapidly dehydrate the vitreous humor. They are effective short-acting agents used with the goal of restoring lost vision and buying time while maintenance drugs are beginning to take effect. Memantine is an interesting drug undergoing advanced human clinical trials for use in glaucoma therapy. It has no ocular hypotensive effects, but rather it is purported to have neuroprotective effects on the optic nerve. Retinal ganglion cell (RGC) and optic nerve axon loss are key components of the vision loss seen in glaucoma and the reason for the increasing use of the term glaucomatous optic neuropathy. One factor believed to contribute to RGC death in glaucoma is excitotoxicity mediated by glutamate. NMDA receptors on glaucomatous RGCs are thought to be overactivated by increased concentrations of intraocular glutamate. Memantine is an NMDA receptor antagonist which holds promise for use in a number of medical arenas including glaucoma therapy. To be effective, it must be on board prior to the insult. Although research is still in progress, a sensible use may be to protect the second eye of dogs with primary glaucoma.

Medical therapy is probably the most sensible initial approach to most cases of glaucoma and falls well within the capabilities of a general practitioner. An aggressive medical protocol applied as promptly as possible is most appropriate for acute glaucoma. Sometimes it can be difficult to know for certain whether glaucoma is truly acute in the dog, so it is best to err on the side of caution and treat if there is any suggestion that there was vision in the eye prior to the current episode. Cats rarely exhibit true acute glaucoma. Latanoprost alone, or in combination with other topical glaucoma medications and an oral CAI, may be attempted initially for dogs, followed shortly by IV mannitol if ineffective. Once the IOP is lowered (preferably into the teens), medications must be prescribed to keep the pressure down and the patient should be referred to an ophthalmologist well within 24 hours when at all possible. It is important to realize and emphasize with the client the time-sensitive nature of glaucoma with respect to maintaining vision. An ophthalmologist will be able to differentiate primary and secondary glaucoma, give them a better feel for prognosis, and offer more advanced medical and surgical alternatives.

Unfortunately, glaucoma is by its very nature a chronic, progressive disease, which almost inevitably leads to blindness. Perhaps not surprisingly when we consider how well one-eyed dogs navigate, the majority of clients (and many veterinarians) do not recognize unilateral vision loss. It is unfortunately not uncommon for a client to present their pet only when the eye becomes grossly buphthalmic due to chronicity. Medications can be used for permanently blind eyes as well, but aggressive in-hospital therapy is not indicated. Salvage surgical procedures are appropriate to provide comfort for permanently blind eyes, and are necessary for blind eyes that are no longer medication-responsive. The available surgical procedures for blind eyes will be touched on only briefly in the scope of this talk, but it is important to know that, while enucleation is highly effective, there are also other options available (evisceration with intrascleral prosthesis, cyclocryoablation, pharmacologic ciliary body ablation). Although the advantages of these procedures over enucleation are primarily cosmetic in nature, many is the client that will let their beloved pet suffer rather than lose an eye, and these options offer genuine compromises beneficial to both client and pet.

If you remember nothing else from this lecture, please remember to consider your glaucoma patient's other eye. When an apparently healthy middle aged dog presents to you with an obviously buphthalmic globe, you may be tempted to offer immediate enucleation and send the dog on his way. At this point, prognosis for vision is grave, the animal is in pain, and IOP control is likely to be difficult to achieve, short-term in efficacy, and costly. Therefore, enucleation is a perfectly appropriate option. However, you are doing the client and patient a distinct disservice if you do not recommend referral or at least discuss the possibility of primary glaucoma. For one thing, if the glaucoma is secondary to uveitis without a contributing ocular cause, this could be a sign of systemic illness. For another, it is now standard of care to promote treatment of the "normal" contralateral eye of dogs with a diagnosis of primary glaucoma. Gonioscopic examination is necessary for a diagnosis of the predisposition to this condition, although signalment can be a significant clue. Prophylactic antiglaucoma therapy has been shown to extend the average interval between development of glaucoma in the first eye and the second of dogs with primary glaucoma from 8 to 31 months. Said in another way, failing to institute prophylactic antiglaucoma therapy robs an average primary glaucoma dog of about two years of good vision. Good options for prophylactic therapy include twice daily timolol or once daily demecarium bromide (perhaps combined with a topical steroid to mitigate its inflammatory effect).

Surgical options that will be covered in detail are those that have the potential for simultaneously providing long-term IOP control and vision. These procedures are best reserved for ophthalmologists. Like the drugs used to lower IOP, these procedures can be categorized into those aimed at decreasing aqueous production (cyclophotocoagulation) and those aimed at improving aqueous outflow (goniovalves). All are aimed at highly dedicated pet owners, because even initial success is far from a sure thing, follow-up can be intense, the expense is inevitably substantial, and there is never a point at which they become "risk free."

Transcleral cyclophotocoagulation (TSCP) describes a surgical procedure in which laser energy is applied via a contact probe to the sclera 3-4mm behind the limbus, targeting the underlying ciliary body. An 810nm diode laser is used most commonly in veterinary medicine. Transcleral CPC results in coagulative necrosis of ciliary body epithelium. Since the ciliary body epithelium is responsible for aqueous production, partial destruction can be expected to result in decresed IOP and in fact it has been proven effective for IOP control in the dog and horse. Complications are frequent, however, and sometimes result in blindness. Common complications include post-operative ocular hypertension (POH) and uveitis. In spite of its perpetuation of uveitis, TSCP has been used successfully for secondary as well as primary glaucoma. Although POH is by definition a temporary elevation of intraocular pressure induced by a surgical procedure, the devastating effect on vision may be permanent. Therefore, every effort is made to monitor and stabilize these patients' IOPs while hospitalized during their first postoperative 24-48 hours. Often paracentesis is performed immediately postoperatively to this purpose. Less common complications include cataract, retinal detachment, and hemmorhage. A promising variant on this procedure is endocyclophotocoagulation (ECP). Although as yet sparsely available and incompletely studied, ECP has the distinct advantage of providing direct visualization of the ciliary body processes which can be more specifically targeted to receive laser energy. It utilizes the same 810nm diode laser, but as the tissues are targeted directly rather than transclerally, less energy is required to provide the same effect. Whereas in TSCP laser energy is directed blindly according to established average anatomic measurements, ECP has the advantage of greater precision. To its disadvantage, the eye must be entered to allow placement of the endolaser and camera (contained in a single probe) and the limited space within the posterior chamber puts the lens at sufficient risk of direct contact by the probe. It has been suggested that simultaneous lens removal by phacoemulsification may be appropriate since the risk of secondary cataract may be high.

Goniovalves are placed with the goal of providing an artificial egress for aqueous to the outside of the eye. The most common divert aqueous to the subconjunctival space where the fluid is absorbed by the vascular supply of this tissue. Commercial varieties like Ahmed valves are readily available. The most common involve a piece of biocompatible tubing placed into the anterior chamber, which is connected to a larger explant that is sutured into a dorsal subconjunctival pocket. Most, but not all, are valved or unidirectional shunts, which open only when the intraocular pressure exceeds a set number. This helps avoid hypotony. Failure occurs when obstruction occurs at any point in the aqueous outflow pathway. The tubing should be trimmed and placed in such a way as to avoid occlusion by lens, cornea, or iris. Tubing obstruction by fibrin can occur at any time that uveitis is present, but is most common in the early postoperative period. If identified or suspected, intracameral injection of tissue plasminogen activator (TPA) may solve the problem. The most common cause of permanent goniovalve failure is the development of fibrosis at the filtration site. Fibrosis results in diminished permeability of the tissues,sothat aqueous is absorbed progressively less, and the system eventually is stalled. Most if not all traditional valves fail, the only uncertainty is the period of time that may pass before failure. Dogs have a more dramatic inflammatory response than people, so failure may occur sooner. Mitomycin C and 5 florouracil have been investigated for use intraoperatively to treat the implant area in an effort to reduce fibrotic response. A fascinating alternative goniovalve has been developed by Cullen et al. for use in the dog. It was developed to avoid the pitfalls of valve failure from bleb fibrosis. It is based on the theory that depositing aqueous into an epithelium lined cavity would avoid this problem. The valve implant is placed similarly to a traditional goniovalve, but the valved tubing is then extended subconjunctivally and through a preplaced hole into the frontal sinus where it is secured by a proprietary footplate to the periosteum. In spite of a potential for ascending infection, this risk appears low. Once again, the data are somewhat limited, but a combination of gonioimplantation with a cyclodestructive procedure like cyclophotocoagulation may actually be the most promising. At least theoretically, a valve which functions even very short term would provide benefit by eliminating the risk of blindness from early postoperative ocular hypertension and allowing time for the full benefit of the laser to take accumulate. More data is needed, and in progress.