Glaucoma (Proceedings)

Glaucoma is a complicated and often frustrating cause of vision loss in small animals.  The pathogenesis of glaucoma is only partially understood, however the end result is loss of retinal ganglion cell function, axonal destruction in the optic nerve, and vision loss.  Because clinical signs of glaucoma have been described in humans without overt increases in intraocular pressure (IOP), and because optic nerve microcirculation and retinal ganglion cell function impairment have been observed before elevations in IOP in Beagle dogs with hereditary glaucoma, elevated IOP is now considered a ‘risk factor' for glaucoma, not the primary cause.  Moreover, glaucoma is considered to be a group of many diseases (rather than one single disease) with a common outcome.

Normal aqueous humor dynamics involves the production of aqueous humor by the nonpigmented epithelial cells of the ciliary body (via active transport, passive diffusion and ultrafiltration), with concurrent drainage from the globe via multiple mechanisms.  In the dog and cat, most aqueous humor exits the eye through the iridocorneal angle and trabecular meshwork (‘conventional outflow'), with a smaller volume exiting the globe through uveoscleral vasculature (‘unconventional outflow').  To maintain a stable intraocular pressure, the rate of drainage must match the rate of aqueous humor formation.  Diurnal variations in intraocular pressure have been observed in most species studied, and in the dog, intraocular pressure tends to decrease mildly with age.  A ‘normal' intraocular pressure in any given patient depends on multiple variables but intraocular pressures in excess of 25-30mmHg in the dog and cat are generally concerning.

Accurate evaluation of intraocular pressure can be difficult due to patient noncompliance or a multitude of other factors.  Patient positioning, increased jugular pressure, tonometer used, excessive eyelid manipulation during measurements, corneal thickness and cleanliness of the tonometer have all been identified as factors contributing to erroneous IOP estimation.

 In the dog, glaucoma is most commonly diagnosed as a primary disease.  Abnormalities in iridocorneal anatomy can be observed on biomicroscopic evaluation (gonioscopy).  These visible abnormalities are considered to be linked to microscopic abnormalities in the conventional drainage system as a whole.  Dogs with abnormally appearing iridocorneal angles (excessively narrow or closed) are considered ‘goniodysgenic', and are at risk of bilateral glaucoma in their lifetimes.  Primary glaucomas have been classified as either ‘open angle' or ‘closed angle' in both human and veterinary medicine.  Open angle glaucoma is most common in humans while in the dog the lion's share of cases are closed angle.  The difference is clinically significant, as open angle glaucomas are generally chronic, milder (increases in IOP of a few points are considered significant), and more responsive to medical therapy, while closed angle glaucoma as observed in the dog is generally associated with an acute, marked increase in IOP that is accompanied by pain and acute vision loss.  It is also significant in that due to availability of funding, the majority of pharmacologic studies evaluating anti-glaucoma drugs are based on treatment of open angle glaucomas (including veterinary studies, in which a rare colony of Beagles with open angle glaucoma is the target of most pharmacologic medical research).  In the cat, a rare form of glaucoma known as Feline Aqueous Humor Misdirection Syndrome (FAHMS) has been described in which changes in the anterior vitreous face result in aqueous humor accumulation in the vitreal chamber (rather than the anterior chamber), resulting in progressive anterior chamber shallowing and elevations in intraocular pressure.  Most feline glaucomas, however, are secondary to chronic intraocular inflammation and can be especially difficult to treat given the dearth of effective anti-glaucoma medications in this species. 

Common causes of secondary glaucoma include uveitis, intraocular hemorrhage, intraocular surgery, lens instability, retinal detachment, and intraocular neoplasia. The pathogenesis of the secondary glaucomas usually involves either pre-iridal fibrovascular membrane (PIFVM) development (in the cases of uveitis, intraocular hemorrhage, intraocular surgery, lens instability, retinal detachment and occasionally neoplasia), direct obstruction of the conventional outflow system (also in the case of lens instability and neoplasia), or both.  PIFVMs develop over the anterior or posterior surface of the iris and grow anteriorly to occlude the iridocorneal angle.  There is to date no known treatment available to prevent the development of these membranes in eyes at risk.

Commonly applied medical therapies for glaucoma are outlined below. 

Osmotic agents

Osmotic agents are commonly used in emergency management of glaucoma due to rapid efficacy.  They are administered systemically and distributed to extracellular fluids (ie plasma), increasing plasma osmolality.  When plasma osmolality exceeds that of the intraocular fluid, water diffuses from the aqueous and vitreous humor down-gradient to plasma, essentially dehydrating the vitreal and aqueous chambers.  Mannitol is administered IV at dosages ranging from 1-2 g/kg over 30 minutes.  The reduction in IOP generally begins within 30 minutes-1 hour with effects lasting from 6-10 hours.  Mannitol is not metabolized and therefore can be administered to diabetic patients.  It should be administered through a filter given its propensity to form crystals.  Glycerin is easy to administer, inexpensive and does not require intravenous access or special storage.  It is administered orally at a dosage of 1-2 g/kg.  A reduction in IOP should be observed within an hour of administration and can last as long as 10 hours.  Administration may result in vomiting.  Glycerin should NOT be administered to diabetics, as it is metabolized to glucose and will result in hyperglycemia.  Isosorbide can be administered orally like glycerin but unlike glycerin, will not result in hyperglycemia.  The recommended dosage in dogs is 1-1.5 g/kg; efficacy in one report was similar to that of glycerin.  Use of hyperosmotic agents is contraindicated in uveitic eyes due to the increased permeability of inflamed eyes.  They should not be administered with fluids (and water should be withheld for ~2 hours post-administration).  Due to the expected increase in intravascular volume associated with these agents, hyperosmotics should not be administered in patients with significant cardiovascular disease.

Carbonic anhydrase inhibitors (CAIs)

Carbonic anhydrase inhibitors inhibit formation of bicarbonate in the ciliary body that is necessary for production of aqueous humor.  Commonly used topical agents include dorzolamide (Trusopt®) and brinzolamide (Azopt®).  Oral CAIs include methazolamide and acetazolamide. Dorzolamide is available as a generic and is fairly cost effective.  Topical CAIs can be administered 2-3 times daily.  Maximum efficacy may take 4-5 days to achieve but decreased aqueous humor production occurs within 30 minutes – a few hours of dosing.  The topical CAIs can be used in dogs and cats and are effective in both species. They can be used in all types of glaucoma, have no effect on pupil size, and do not contribute to intraocular inflammation.  Dorzolamide is available as a combination drug with timolol (Cosopt®), which is now available as a generic.  The efficacy of topical CAIs has been shown to be of equal efficacy to that of systemic CAIs.  Methazolamide is dosed at 2-5mg/kg PO q12h and is available as a 50mg tablet.  Acetazolamide is available as 125mg and 500mg tablets.  The recommended dosage is 4-8mg/kg PO q8-12 hours.  Commonly reported side effects of systemic CAIs include PU/PD, GI upset and panting (to compensate for metabolic acidosis).  Systemic CAIs should not be used in patients with respiratory compromise.  Cats appear to be more susceptible to metabolic acidosis and therefore systemic CAIs should be used with extreme caution in this species.

Beta-blockers

Beta blockers are very effective for reduction of IOP in humans and are the most commonly prescribed class of drugs for the treatment of glaucoma in people.  Timolol is the most widely used of these medications in both human and veterinary medicine, but other topical beta blockers are available, including levobunolol, betaxolol, metipranolol and carteolol.  Beta blockers reduce IOP by decreasing aqueous humor production but the exact mechanism of this effect is not completely understood.  In the dog and cat their efficacy is considered relatively poor and bradycardia and mild (bilateral) miosis associated with their use has been documented.  Their use in equine glaucoma appears more promising.  In veterinary medicine, timolol 0.5% is administered twice daily.  Use with caution in patients with cardiovascular disease.

Prostaglandin analogs

The prostaglandin analogs appear to be the most effective drugs in the treatment of canine glaucoma.  These drugs increase aqueous ouflow (with no effect on aqueous production).  The mechanism of action is mediated through binding to prostanoid FP receptors.  In the dog and human, activation of the prostanoid FP receptor results in increased uveoscleral outflow (ie unconventional outflow) through remodeling of the ciliary body musculature.  Increased conventional outflow also occurs through morphological changes in the trabecular meshwork.  The most commonly prescribed prostaglandin analog in veterinary medicine is latanoprost (Xalatan®), which is now available as a generic.  Other available PG analogs include bimatoprost and travaprost.  In the cat, latanoprost and other PG analogs are ineffective because activation of prostanoid EP receptors is required for similar effects in this species.  The prostaglandin analogs are generally administered q12h in dogs (once daily in humans).  In the dog, PG analogs result in maked miosis and because they work through activation of inflammatory mediators, should not be used in cases of secondary glaucoma caused by anterior lens luxation or chronic uveitis.

Other classes

Other, less commonly utilized anti-glaucoma drug classes include the cholinergic agonists (pilocarpine, carbachol, demecarium bromide, echothiophate iodide), adrenergic agonists (dipivefrin), and alpha2-adrenergic agonists (apraclonidine, brimonidine).  Due to associated local side effects, lack of availability and/or systemic side effects, they are seldom used.

Surgical therapy

The recommended surgical options often depend on whether vision is considered salvageable.  Surgical options for the visual eye consist of laser ciliary body destruction and gonioimplants.

Endolaser cyclophotocoagulation (ECP)

ECP is a relatively new surgical option.  A diode laser is used to target the pigmented tissue of the ciliary body, thereby destroying the adjacent nonpigmented epithelium.  The advantage of this procedure is that the laser is built into an endoscopic probe, allowing for localization and direct treatment of the ciliary processes with little bystander damage. Because the laser energy is likely to induce cataract development the process is often combined with phacoemulsification.  No studies evaluating the long term efficacy of this surgery have been published, however preliminary results are promising.

Transscleral cyclophotocoagulation (TSCPC)

TSCPC involves laser ablation of the ciliary body, similarly to ECP.  Both Nd:YAG and diode lasers have been utilized. The main difference between TSCPC and ECP is that TSCPC does not involve direct visualization of the ciliary body.  Rather, external landmarks are used to position the laser probe over the external surface of the eye and the laser energy is directed through the sclera.  Possible post-operative complications include excessive intraocular inflammation (with the potential to induce retinal detachment), cataract development, hyphema, and, as with any glaucoma surgery short of enucleation or evisceration, uncontrolled intraocular pressure.  One retrospective study quoted a ~50% success rate in terms of IOP control with a ~20% success rate in terms of vision 1 year post-treatment.  Immediate post-operative spikes in IOP are common and can result in post-operative vision loss.

Gonioimplants/valves

Gonioimplants facilitate drainage of aqueous humor through a tubing system implanted directly into the anterior chamber.  Both valved and nonvalved implants exist.  Valved systems allow for egress of aqueous humor at intraocular pressures >12mmHg, while nonvalved systems are limited only by resistance of the tubing itself.  Although these shunt systems are generally efficacious in the short term, post-operative uveitis with fibrin development and valve occlusion, requiring intracameral tissue plasminogen activator administration, is relatively common.  The long term efficacy of shunts is limited by avascular bleb development, in which an avascular fibrotic capsule develops around the base of the device.  This fibrosis is observed so commonly that gonioimplant failure is generally considered inevitable, and implant placement is often combined with a cyclodestructive procedure to provide more long term control of IOP.

Eyes that have lost vision are most commonly treated with one of the following surgeries to improve quality of life by controlling pain related to elevated IOP. 

Enucleation

Enucleation is probably the most commonly performed ‘surgery of comfort' for glaucoma.  Possible post-operative complications include hemorrhage, post-operative fistulas or mucocele development caused by incomplete removal of conjunctival, caruncular or third eyelid glandular tissue, and, rarely, orbital emphysema.  In the cat, the optic nerve is relatively short and excessive traction on the enucleated globe must be avoided during surgery to prevent damage to the optic chiasm and contralateral blindness.

Cyclocryothermy

Cyclocryothermy allows for reduction in IOP without loss of the globe.  This procedure is generally reserved for the canine and has a reported ~80% success rate.  Either nitrous gas or liquid nitrogen can be used.  Using external landmarks to estimate the site of probe placement, the cryotherapy is applied externally. The ‘cryodose' applied depends on the pre-operative intraocular pressure.  The biggest advantage is that the surgery is noninvasive; post-operative therapy generally involves anti-inflammatories (often continued for life).  Disadvantages include the potential for persistently elevated IOP, cataract development, hyphema, retinal detachment and globe phthisis.

Chemical ciliary body ablation

Pharmacologic ablation of the ciliary body can be performed with gentamicin, or, as more recently described, cidofovir.  Gentamicin is cytotoxic to both the ciliary body and retina and therefore should never be used in a visual eye.  Even in blind eyes, however, this procedure should be used with caution as retrospective pathologic studies have reported an increased incidence of intraocular tumor development post-operatively.  The outcome of this procedure is also the least predictable of the cyclodestructive procedures, with published reports citing a ~65% success rate.  Other possible post-operative complications include cataract development, retinal detachment, hyphema, chronic uveitis and phthisis.  Intravitreal gentamicin should NOT be administered to patients with renal compromise, as the drug is detectable in plasma post-operatively. 

Evisceration and Intrascleral prosthesis (ISP)

ISP surgery involves creating a 180 degree limbal incision at the corneoscleral junction, removal of all intraocular contents, and replacement of these contents with an silicone intraocular prosthetic.  The advantages of ISP include complete resolution of glaucoma and maintenance of a ‘cosmetic' globe.  Disadvantages include the potential for recurrent corneal ulcerations due to decreased corneal sensitivity (caused both by historical glaucoma and transection of corneal nerves intraoperatively) and the potential for KCS.  ISPs should generally be avoided in eyes with underlying intraocular neoplasia, pre-operative keratitis or KCS.

Unfortunately, glaucoma remains a disease with no effective ‘cure', and although primary glaucoma often presents initially as a unilateral process, most ‘at-risk' dogs will develop glaucoma in the contralateral eye within 1 year of diagnosis.  Initiating prophylactic anti-glaucoma treatment in the normotensive eye has been shown to delay the onset of glaucoma in a dog at risk by as much as 18 months.  Client education and early intervention can delay vision loss and improve quality of life for your patients.

References

Plummer, C.E., Regnier, A. & Gelatt, K.N. (2013) The Canine Glaucomas.  In: Veterinary Ophthalmology (ed. Gelatt, K.N.), 5th ed., Vol.2, pp.1050-1145.  Ames: Wiley-Blackwell.