Light at the End of the Tunnel? What's New (and Old) in the Management of Glaucoma
Gillian J. McLellan, BVMS, PhD, DVOphthal, DECVO, DACVO, MRCVS
School of Medicine & Public Health and School of Veterinary Medicine, University of Wisconsin - Madison, Madison, WI, USA
Treatment Goals & Philosophies
The major goal in glaucoma management remains the lowering of IOP, to a point that prevents or slows loss of vision and eliminates pain. Currently available therapies generally either reduce aqueous production or increase aqueous outflow. Particularly in the management of acute congestive glaucoma in dogs, more than one component of aqueous humor dynamics should be targeted in order to maximize IOP reduction. Combining treatments that reduce aqueous production, with treatments that increase outflow generally have a greater impact on IOP than targeting either alone.
Glaucoma Treatment Should be Tailored for the Individual
When selecting a treatment strategy, the following are important considerations:
Is the glaucoma primary or secondary?
What are the specific mechanisms for IOP elevation?
Are these mechanisms reversible or irreversible?
What is the potential for vision in the affected eye?
Is the contralateral eye at risk?
What is the likelihood of owner and patient compliance?
Is the cost of therapy acceptable to the owner?
Does the drug actually work in this individual?
Medical Therapy to Reduce Aqueous Production
Carbonic Anhydrase Inhibitors (CAIs): These drugs reduce aqueous humor formation and IOP by reducing the secretion of bicarbonate ions (with sodium ions and water) into the posterior chamber. Oral CAIs (acetazolamide, methazolamide and dichlorphenamide) historically played a key role in the medical management of canine glaucoma but significant systemic side-effects were common, in part related to hypokalemia and metabolic acidosis. These drugs have now been superseded by topical CAIs, dorzolamide 2% and brinzolamide 1% that effectively lower IOP in normal and glaucomatous dogs and cats (both applied TID). Local side effects, including conjunctivitis and blepharitis, have been reported following application of CAIs. Cats may show signs of inappetence and hyper-salivation, perhaps related to an unpleasant taste.
Beta-blockers: These reduce IOP by inhibiting aqueous secretion and, to a lesser extent, enhance aqueous production. Timolol maleate BID leads to a modest IOP reduction at available concentrations (0.25 and 0.5%). Although more effective, higher concentrations may lower heart rate. In dogs, timolol applied in combination with dorzolamide 2% has a greater IOP-lowering effect than either drug alone. Cats are more sensitive to systemic effects and timolol should be used with caution in cats with cardiovascular or respiratory disease.
Medical Therapy to Increase Aqueous Outflow
Prostaglandin (PG) Analogs: The FP receptor agonists, including latanoprost 0.005% (Xalatan, Pharmacia) and travoprost 0.004% (Travatan, Alcon), and the prostamide bimatoprost (Lumigan, Allergan) have a potent IOP-lowering effect in dogs (around 65–75% reduction) in glaucomatous dogs. However, they do not lower IOP in about 20% of normal dogs, or in normal cats and do not have a sustained effect in cats with glaucoma. There are distinct species, and individual differences in ocular PG receptor distribution and consequently in the effects and efficacy of topical PG analogs for glaucoma. Intense pupil constriction is seen in dogs and cats but not in humans, and in some animals compromises vision. Use of PG analogs is contraindicated in patients at risk for pupil block by a luxated lens or prolapsed vitreous, and increase the risk of anterior synechiae in uveitis.
The mechanisms by which topical PGs reduce IOP remain unclear. In humans and primates, their effect involves alteration of the ciliary body tissue, enhancing uveoscleral outflow, and maximal reduction in IOP is at 8–12h post-treatment. In glaucomatous dogs, in contrast, dramatic and rapid reduction in IOP may be observed within 30–60 min of treatment. The speed of this response may reflect the reversal of relative pupil block by the intense miosis, or a rapid and dramatic reduction in aqueous formation. Although labeled for human use once daily, BID application of PG analogs, or evening application if only applied once daily, is recommended in dogs, to minimize fluctuations in IOP.
Miotics: This class includes direct acting cholinergic drugs such as pilocarpine, and longer acting acetylcholinesterase inhibitors, such as demecarium bromide and echothiophate iodide. The indirect acting drugs have the advantage of both potency and prolonged duration of action (up to 55h) but are no longer widely, commercially available. Cholinergics result in increased aqueous outflow by contraction of the iris sphincter and ciliary muscles. Pilocarpine drops have a low pH and can cause ocular irritation. These drugs can also lead to a transient breakdown in the blood-ocular barrier, which may intensify concurrent or underlying uveitis. Systemic absorption may occur in cats.
Miotics are commonly used for prophylactic treatment of "at-risk eyes" (see below), and in the prevention of post-operative ocular hypertension following cataract surgery in dogs. Injection of 0.01% carbachol into the anterior chamber at the conclusion of cataract surgery was found to abolish post-operative IOP spikes following phacoemulsification surgery in dogs. Miotic therapy may also delay the onset of lens luxation and secondary glaucoma in dogs with primary zonular instability.
Alpha-2 Adrenergic Agonists: Apraclonidine 0.5% and Brimonidine 0.2% are potent inhibitors of aqueous production in humans. However, when applied topically they are associated with signs of systemic toxicity (reduction in heart rate in dogs and cats, vomiting in cats) which limits their value in the medical management of glaucoma in veterinary patients.
Surgical Therapy to Reduce Aqueous Production
Cyclodestructive procedures ablate the ciliary epithelium and reduce aqueous formation. Cyclocryotherapy, with externally applied, nitrous oxide or liquid nitrogen, can be effective but is associated with significant swelling and post-operative discomfort. Use of Nd:YAG or Diode LASER for trans-scleral cyclophotocoagulation (CPC) has been shown to reduce IOP in normal and glaucomatous dogs and cats. However, post-op IOP spikes, uveitis, hyphema, secondary cataract formation, ocular hypotony or persistent IOP elevation, are relatively common complications. Diode endoscopic CPC has recently been described in dogs and cats. Direct visualization of the ciliary processes during treatment allows more accurate delivery of LASER energy and verification of tissue response that can lead to a more predictable post-operative reduction in IOP. However, this procedure is more invasive due to the insertion of an endoscopic delivery device into the eye, and in dogs is carried out in conjunction with lens removal. Possible complications of this relatively invasive procedure are similar to trans-scleral CPC. The relatively unpredictable response to LASER therapy and post-operative complications currently argue against the use of these procedures for prophylactic treatment in visual, "at risk" eyes with normal IOPs. These procedures are generally reserved for eyes that retain some vision but are poorly responsive to medical treatment. Pharmacologic ablation of the ciliary epithelium by intravitreal injection of gentamicin should only be considered in irreversibly blind, painful eyes. Cyclodestructive procedures are not recommended in cats.
Surgical Therapy to Increase Aqueous Outflow
The surgical implantation of drainage devices into the anterior chamber is accompanied by a relatively high complication rate. Placement of an Ahmed valved gonioimplant, in conjunction with anti-metabolite therapy to reduce scarring of the subconjunctival "bleb" around the implant, most often mitomycin C, may lead to more successful control of IOP and retention of vision when combined with cyclodestructive procedures (see above) than when performed as a sole procedure.
Prophylaxis & Monitoring
About 30% of dogs with previously diagnosed PACG will go on to develop glaucoma in the opposite eye within months to years of diagnosis. There is compelling evidence to support prophylactic treatment in these "at-risk" eyes. Topical therapy with either a combination of miotic and corticosteroid SID (demecarium bromide 0.25%/betamethasone), or with the topical beta-blocker, betaxolol 0.5% BID, can significantly delay the onset of glaucoma in the "second eye" compared to untreated eyes. Unfortunately, IOP monitoring alone generally fails to identify "early" glaucoma in predisposed eyes. The value of either high resolution ultrasound, to monitor for progressive changes in morphology of the aqueous outflow pathways; or retinoscopy, to detect progressive myopia, in predicting onset of PACG in the "at risk" eye, is currently under investigation in dogs.
Traditional emergency therapy with osmotic agents such as IV mannitol (1–2 g/kg given as a 20% solution over 20 min); topical PG analogs, and even anterior chamber paracentesis, will likely remain an important part of our treatment strategy in many cases, but needs to be followed up with longer-term medical or surgical treatment to control IOP. Given the delay between onset and diagnosis of glaucoma in dogs with PACG, the prognosis for vision is usually very poor in the first affected eye. The "window of opportunity" during which we can intervene to promote cell survival and recovery is extremely narrow. This accentuates the importance of client education, and of prophylactic therapy in "at risk" eyes.
Light at the End of the Tunnel? Future Directions
In glaucoma, adequate control of IOP often does not prevent progression of optic nerve and retinal degeneration once a cascade of cell death has been initiated. Proposed neuro-protective treatments include systemic calcium channel blockers; NMDA-receptor antagonists (e.g., memantine) and neurotrophic factors (e.g., BDNF) but their safety and efficacy has not been established in a clinical setting. Novel drug delivery systems (including slow release implants, microbeads and stem cells) are currently being investigated in a research setting.