GLAUCOMA ROUNDS, Dr. Munger Pictures for Rounds  Glaucoma Handout

HANDOUT

Getting the Drop on Glaucoma: The Medical and Surgical Management of Glaucoma

Robert J. Munger, D.V.M., D.A.C.V.O.
Animal Ophthalmology Clinic
Dallas, Texas


TABLE OF CONTENTS

INTRODUCTION

GETTING THE DROP ON GLAUCOMA

CLINICAL SIGNS

TYPES OF GLAUCOMA AND BREED PREDISPOSITION

STAGES OF GLAUCOMA

DIAGNOSTIC PROCEDURES

GLAUCOMA THERAPY

MEDICAL THERAPY

  • Parasympathomimetic agents
  • Sympathomimetic agents
  • Beta-adrenergic blocking agents
  • Hyperosmotic agents
  • Carbonic anhydrase inhibitors
  • Alpha2-adrenoreceptor agonists

SURGICAL THERAPY FOR VISUAL EYES

  • Placement of a glaucoma shunt or gonioimplant
  • Laser cyclophotocoagulation

SURGICAL THERAPY FOR BLIND EYES

  • Enucleation
  • Evisceration and intraocular prosthesis
  • Intravitreal injection of gentamicin

BOTTOM LINE


INTRODUCTION                                          [Back to the TOP]

By far the most difficult management problem we encounter in a referral ophthalmology practice is restoring a client’s confidence in a veterinarian when they feel (rightly or wrongly) that their pet’s eye problem has been mismanaged prior to referral. This is especially true if a second veterinarian refers them. The comments and questions often go something like, "How come my veterinarian didn’t see this?" or "Why didn’t my veterinarian recognize my dog had glaucoma?" or "Why didn’t they refer me earlier?" This latter question is particularly difficult if the client had asked about referral. And, as always, the kicker is, "I’ve already spent hundreds of dollars!" (We feel lucky if they don’t say "thousands"!) Today, in the short time we have I want to prepare you to recognize the early warning signs of a serious eye problem and give you the tools to manage it in the early stages and guide your clients to the best possible resolution of the problem.

 

GETTING THE DROP ON GLAUCOMA                         [Back to the TOP]

Clinically, glaucoma is generally defined as the rise in intraocular pressure (IOP) beyond that compatible with vision. Some recent research has documented that processes detrimental to retinal function may be active well in advance of the pressure rise in primary glaucoma, but detection of such processes is extremely difficult and does not lend itself well to clinical practice. One thing is certain. By the time the cornea is edematous, the episcleral vessels are injected, the lens is subluxated and the eye is buphthalmic, vision is irreversibly lost. Indeed, vision may be lost long before these signs are evident with irreversible retinal and optic nerve damage occurring within hours. The "30-30" rule states that "pressures higher than 30 mmHg for 30 hours results in loss of vision", but when pressures are very high, vision may be lost in as little as 4 hours.


CLINICAL SIGNS
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While there are admittedly many causes for loss of the normal pupillary reflex the presence of a dilated and poorly responsive pupil should immediately raise your suspicion for glaucoma until it can be ruled out by further diagnostic test. Rule outs include mydriatics, iris atrophy, retinopathy, optic neuropathy, and oculomotor neuropathy. Conjunctival congestion is common and is too often misdiagnosed as simple conjunctivitis (especially in breeds predisposed to allergic conjunctivitis such as cocker spaniels, basset hounds, etc.). Congestion of episcleral vessels and corneal edema occur next, and may be mistaken for uveitis, which may or may not be concurrently present. If the glaucoma is secondary to uveitis, the pupil may be miotic, and, in severe cases, posterior synechiae and iris bombe may already be present. The only definitive diagnostic tool (unless the eye is rock hard) is tonometry, and, if this is not available, the clinician should advise the owner of the possibility of glaucoma and begin glaucoma treatment pending accurate determination of the pressure. When uveitis is present, intraocular pressure should normally be low, and the presence of a normal intraocular pressure in such cases is indicative of secondary glaucoma. Therapy for both glaucoma and uveitis should be instituted immediately.


TYPES OF GLAUCOMA AND BREED PREDISPOSITION
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Glaucoma may be classified as either primary or secondary and open or narrow (closed) angle. Basically, anything that interferes with the normal circulation of aqueous humor from the eye can result in glaucoma. Primary conditions include congenital malformation of the angle (commonly seen in basset hounds, samoyeds, Siberian huskies, and Australian shepherds with multiple ocular anomalies) and genetically preprogrammed narrowing of the angle (commonly seen in cocker spaniels, chows, shar peis, poodles and Norwegian elkhounds). Occasionally, open angle glaucoma may occur and is most common in beagles, but the most common type of primary glaucoma in dogs is narrow angle. (The opposite occurs in humans and accounts for the reason many humans are successfully treated medically for years if not for the duration of their lives.) Determination of the type of angle abnormality is thus important and requires examination by gonioscopy. In the absence of gonioscopy, primary glaucoma in the dog should be regarded as angle closure until proven otherwise.

Secondary glaucoma occurs from a variety of mechanisms. Luxations or swelling of the lens may result in pupillary block (impaired flow of aqueous into the anterior chamber) by the increased physical contact of the iris with the lens. It may similarly occur with miosis of any cause and with posterior synechiae in uveitis. When the obstruction at the pupil is severe, aqueous accumulates in the posterior chamber and can push the iris anteriorly resulting in iris bombe. In addition, aqueous outflow may be impeded by cells, fibrin, and/or inflammatory debris accumulating in the iridocorneal angle (the most common cause of secondary glaucoma in cats with chronic immune mediated uveitis), or by the base of the iris becoming adhered to the peripheral cornea (peripheral anterior synechiae). The latter is one of the reasons it is so important to reform the anterior chamber quickly after corneal perforations. In some cases, the obstruction of aqueous flow may result in the diversion of aqueous posteriorly behind the vitreous resulting in anterior displacement of the vitreous. This results in an ever-worsening glaucoma with collapse of the anterior chamber. This condition, known as malignant glaucoma, must be recognized quickly and resolved with immediate surgery.

 

STAGES OF GLAUCOMA                          [Back to the TOP]

As stated above, the early stages of glaucoma may be subtle and in primary angle closure a series of transient mild attacks, often occurring late at night, may precede the sustained elevation of intraocular pressure (IOP). Dilation of the pupil, conjunctival congestion, and transient blindness with papilledema are commonly noted. With secondary glaucoma the prodromal signs vary depending upon the predisposing cause. With a sustained acute attack, the episcleral and conjunctival congestion becomes more severe, the cornea becomes edematous, the optic disc is paler and the retinal vessels are narrowed.

Finally, the optic disc becomes cupped and the enlargement of the globe occurs with eventual subluxation of the lens.

 

DIAGNOSTIC PROCEDURES                                  [Back to the TOP]

The most important diagnostic tools are tonometry and gonioscopy. The most commonly utilized instruments for tonometry in veterinary medicine are the Schiotz tonometer, the Mentor Tonopen XLR, and the Mackay Marg PneumotographR (ranked in ascending order of cost). In general, the normal IOP for most animals ranges from 15-25 mmHg with the preferred pressure being in the range of 15-20 mmHg. Struggling, excitement, blepharospasm or pressure on the lids, corneal scarring, and sedation or anesthesia may all affect IOP so these factors must be considered when assessing the significance of pressure measurements. Familiarity with the instrument and techniques will facilitate the examiner’s interpretation of results.

Gonioscopy is the examination of the iridocorneal angle by means of a specially designed lens placed on the cornea with a high viscosity gel or drop. Both eyes should be examined to assess the status of the angles to achieve a realistic prognosis and plan for treatment, which can be explained to the owner. It is irresponsible to treat one eye if the owner of the pet has no idea that the fellow eye may become affected.

 

GLAUCOMA THERAPY                                                   [Back to the TOP]

Glaucoma management requires intensive therapy in which all efforts are directed to rapidly lower intraocular pressure and maintain it in the normal range. A common misconception is that medical therapy alone is sufficient, but, most often, surgical intervention is required (except in certain cases secondary to uveitis). Perhaps no other disease has required so many different medications, been subjected to so many surgical procedures, and frustrated so many clinicians (not to mention their patients), and despite years of combating this blinding disease, we still don’t have a simple cure. Indeed the number of salvage procedures for irreversibly blind eyes is mute testimony to the severity of this problem.

For visual eyes we favor medical control followed by surgical intervention with placement of a shunt in the iridocorneal angle (usually an Ahmed valve or similar device) and/or transcleral laser cyclophotocoagulation. Enucleation, evisceration with intraocular prosthesis, and intravitreal injection of gentamicin are our procedures of choice for eyes, which are irreversibly blind.

 

MEDICAL THERAPY                            [Back to the TOP]

Medical regimens include carbonic anhydrase inhibitors (topical and systemic), osmotic agents (oral glycerin and IV mannitol), beta-blockers, adrenergics (sympathomimetics), parasympathomimetics, alpha2-adrenoreceptor agonists (apraclonidine and brimonidine) and latanoprost 0.005% (XalatanR, the new F2 alpha prostaglandin). Not all agents useful in humans have as great an efficacy in small animals, many are relatively expensive, and some may have very undesirable side effects.

Parasympathomimetic agents are used topically for their effects on the parasympathetic receptors in the eye. Two classes exist, the direct acting (cholinergic) agents and the indirect acting cholinesterase inhibitors, which allow acetylcholine to accumulate at the receptors. These agent cause miosis and, while their action in small animals is subject to some debate, evidence suggests they lower IOP by increasing the facility of outflow of aqueous. The most common side effects are they sting on application and can cause brow aches and blurred vision in humans. Table 1 lists the agents commonly available in the U.S.

 

Table 1 - Miotics (Parasympathomimetic Agents)

Generic Name

Trade Name

Concentration

Cholinergic Agents

   

Carbachol

Isopto Carbachol

0.75%-3%

Pilocarpine

Ocusert-Pilo

20, 40 inserts

Pilocarpine HCl Gel

Pilogel-HS gel

4%

Pilocarpine HCl

Akarpine , IsoptoCarpine , Pilocar , Pilostat , and many others

0.25%-10%

Cholinesterase Inhibitors

   

Physostigmine

Isopto Eserine

generics

Eserine ophth. oint.

0.25 & 0.5%

0.25%

Demarcarium bromide

Humorsol

0.25% & 0.5%

Echothiophate iodide

Phospholine Iodide

0.03%, 0.06%, 0.125%, 0.25%

 

Sympathomimetic agents are listed in Table 2 and act on the sympathetic receptors in the eye to increase facility of outflow and improve uveoscleral flow. Dipivephrine causes fewer systemic side effects and less irritation than epinephrine. These agents commonly cause a reddish discoloration of the tears that may lead owners to believe their pet’s eyes are bleeding.

Table 2 – Sympathomimetic Agents

Generic Name

Trade Name

Concentration

Dipivephrine HCl

Propine & generics

0.1%

Epinephrine borate

Epinal

Eppy/N

0.5%, 1%

1%, 2%

Epinephrine HCl

Epifrin

Glaucon

0.5%, 1%, 2%

1%, 2%

 

Beta-adrenergic blocking agents are listed in Table 3 and reduce IOP by blocking Beta-adrenergic receptors in the eye thus decreasing aqueous production. Since there are numerous Beta-adrenergic receptors throughout many organs of the body, side effects are predominantly related to effects on the cardiovascular system (bradycardia and lower blood pressure) and the lungs (aggravating some respiratory conditions). Betaxolol is cardioselective and has the fewest systemic side effects, but other agents may be slightly more effective at lowering IOP. Merck has produced a beta-blocker (Timoptic ) combined with a topical carbonic anhydrase inhibitor (Trusopt ) called Cosopt .

 

Table 3 - Beta-Adrenergic Blocking Agents

Generic Name

Trade Name

Concentration

Betaxolol HCl

Betoptic-S

Betoptic

0.25%

0.5%

Carteolol HCl

Ocupress

1%

Levobunolol HCl

Betagan & generic

0.25%, 0.5%

Metipranolol

OptiPranolol

0.3%

Timolol hemihydrate

Betimol

0.25%, 0.5%

Timolol maleate

Timoptic

0.25%, 0.5%

Timolol maleate (long-acting)

Timoptic - XE

0.25%, 0.5% (once daily app.)

 

Hyperosmotic agents (Table 4) lower intraocular pressure by dehydrating and shrinking the vitreous. Oral glycerin is easier to administer than IV mannitol and may be used by owners as an emergency first step in medication to control glaucoma.

 

Table 4 - Hyperosmotic Agents

USP or NF Name

Trade Name

Preparation

Dose

Route

Onset &

Duration of Action

Mannitol

Osmitrol

5-20%

0.5-2g/kg

IV

30-60 min/6 h

Glycerin

Glycerol & generics

100%

(USP Pure)

.33 cc/lb.

p.o.*

1-2 h/8 h

* Give with equal volume of water, milk, or melted ice cream. Withhold water for 1.5 h after dose.

 

Carbonic anhydrase inhibitors (CAI’s) are by far the most effective medications for glaucoma in small animals, and are listed in Table 5. They decrease the secretion of aqueous humor, which is catalyzed by the enzyme carbonic anhydrase in the ciliary processes. Carbonic anhydrase is also found in the kidney where it inhibits the loss of bicarbonate into the urine, and CAI’s may thus cause a transient diuresis. (Please note that the pressure lowering effect is not due to diuresis, so use of other classes of diuretics will not lower IOP.) Thus CAI’s can result in the loss of bicarbonate as well as sodium and potassium in the urine. This in turn can result in acidosis, hyperventilation, lethargy and weakness associated with electrolyte imbalance in patients taking the medication. Other side effects include paresthesias, anorexia, gastrointestinal disturbances, altered taste & smell, ureteral colic, a predisposition to form renal calculi, and, rarely, bone marrow suppression. Systemic administration of this class of medications to patients with renal or cardiac disease should be done with caution. However, 2 topical CAI’s (dorzolamide - Trusopt , Merck and brinzolamide - Azopt , Alcon) have been introduced recently which limit systemic effects by virtue of their topical administration and action localized to the eye. Trusopt was the first topical CAI marketed, and we have used it successfully in clinical practice for approximately 2 years. It has been valuable for patients, which experienced severe side effects, or in large dogs in which the cost of systemic CAI’s is high. Some cats exhibit a decrease in appetite that may be related to the metallic taste reported by human patients on the drug. In addition, Trusopt causes a marked stinging sensation after application that is probably due to its acid pH. Azopt is a 1% suspension and should be shaken well before use. It is reported to have efficacy equal to that of Trusopt , and its more neutral pH provides superior comfort. Both topical CAI’s are less effective at lowering intraocular pressure than their systemic counterparts owing at least in part to the decreased aqueous secretion which occurs in an acidotic state.

Table 5 - Carbonic Anhydrase Inhibitors

USP or NF Name

Trade Name

Preparation

Onset/Duration of Action

Acetazolamide

Diamox & generics

125,250 mg tablets

500 mg timed-release capsule

2h/6-8h

Acetazolamide sodium

Diamox Parenteral

500 mg (for IV use)

5-10 min/2 h

Dichlorphenamide

Daranide

50 mg tablets

30 min-1h/8-12 h

Methazolamide

Neptazane and generics

25, 50 mg tablets

2 h/8-12 h

Brinzolamide*

Azopt

1% ophthalmic suspension

2 h/8-12 h

Dorzolamide HCl*

Trusopt , Cosopt

2% ophthalmic solution

(t.i.d. dosing)

2 h/8 hr

* Not to be given concurrently with systemic carbonic anhydrase inhibitor

The alpha2-adrenoreceptor agonists are relatively new agents added to the antiglaucoma medical arsenal. Apraclonidine (IopidineR - Alcon Laboratories) reduces aqueous secretion, but only weakly decreases IOP in cats and dogs. Apraclonidine also has a high affinity for the alpha1-adrenoreceptors, which results in ocular side effects such as mydriasis in dogs, miosis in cats, conjunctival blanching, ciliary vasoconstriction, eyelid retraction, and reduction in conjunctival oxygen tension. It is further limited by its side effects in cats (vomiting and irritation) and dogs (irritation), and, in humans, long-term use has been associated with tachyphylaxis and a high incidence of ocular allergies. It is expensive, and we have not used it in our practice. Brimonidine tartrate 0.2% ophthalmic solution (Alphagan Allergan) is a newly introduced alpha2-agonist, which is very selective for alpha2 receptors (30 times more selective than apraclonidine for the alpha2- versus the alpha1-receptors), and is less likely to cause ocular allergy. It lowers intraocular pressure by decreasing aqueous humor production and increasing the uveoscleral outflow. Topical administration produces drug levels in the posterior segment which are adequate to activate alpha 2-adrenoreceptors thus indicating retinal bioavailability. It has been shown to be neuroprotective and may thus be beneficial in limiting damage to the optic nerve and retina associated with glaucoma. In cats and monkeys, brimonidine produced miosis, but it has not been used extensively in cats or dogs so its efficacy in glaucoma in veterinary ophthalmology is unknown. In some cases brimonidine’s effects are mediated by effects on the central nervous system (CNS), so CNS side effects are possible. Since it is newly introduced to the human market for open-angle glaucoma, it may well be expensive and its performance in angle closure glaucoma has yet to be determined.

Latanoprost (XalatanR 0.005%) is a prostaglandin F2-alpha analogue that lowers IOP by increasing the outflow of aqueous humor. It was only recently introduced to the market and has not been used extensively in veterinary medicine. It has shown good results in some patients, and requires only once daily application which somewhat tempers its high cost. However, it can be irritating and chronic use has been reported to increase iridal pigmentation.

Neuroprotective agents have received great interest in the last few years as adjunctive therapy for glaucoma since the identification of elevated levels of excitotoxic amino acids (primarily glutamate) in the vitreous. It is well known that the larger retinal ganglion cells (RGC’s) are more susceptible to damage in glaucoma, and the glutamate has been identified in elevated levels in the vitreous of canine patients with primary glaucoma. It has been hypothesized that damage to the retina may precede the actual pressure rise. Thus medications which could protect the RGC’s from damage would be logical adjuncts for glaucoma therapy in order to protect the neural retina. If dogs and cats could tolerate brimonidine, its neuroprotective properties would thus be beneficial. Research is in progress to discover appropriate neuroprotective agents and to evaluate the role(s) they should play in glaucoma therapy.

SURGICAL THERAPY FOR VISUAL EYES                    [Back to the TOP]

Placement of a glaucoma shunt or gonioimplant is the preferred initial surgical procedure in our practice. The Ahmed valve is the device we have used most in our practice. The device is sutured to the sclera under the conjunctiva and Tenon’s capsule (usually in the superotemporal quadrant) and drains aqueous from the anterior chamber by means of a tube, which is implanted in the anterior chamber via the iridocorneal angle. Intraoperative subconjunctival application of an antifibroproliferative agent (5-flourouracil or mitomycin C) is used to inhibit fibroblastic activity at the site of the implant. When 5-fluorouracil (5-FU) is used it is applied to the exposed sclera via a surgical sponge for 5 minutes prior to the placement of the glaucoma shunt. Subconjunctival injections of 0.05 cc (2.5 mg) are given weekly adjacent to the implant for 8-12 weeks. Corneal and conjunctival irritation are the primary adverse reactions that occur, but the greatest drawback to the use of 5-FU is the requirement for postoperative injections for so long a time. In humans, the application of 0.2-0.4 mg/ml of mitomycin C (MMC) to the sclera for 2-3 minutes via a soaked sponge has been used for its greater effect to eliminate the need for the repeated postoperative injections with 5-FU. In our cases we found that the higher concentration of MMC occasionally resulted in scleral malacia and late postoperative migration of the implants at the surgical site. We have thus decreased the concentration of MMC to 0.1-0.2 mg/ml or use 5-FU in our patients. Ideally the MMC should be prepared fresh, but its cost has led us to prepare aliquots which are frozen and kept in the freezer for future use. This has the disadvantage that the stability of the thawed MMC is unknown.

Even with the use of antifibroproliferative agents, scarring over the shunt can result in recurrence of the glaucoma due to obstruction of the aqueous flow. When such obstruction due to scarring occurs, surgery to resect the scar tissue capsule and/or medical treatment to further supplement the pressure lowering effect of the valve must be performed. In many cases, we recommend laser cyclophotocoagulation (CPC) be performed just prior to resection the scar tissue around the shunt. The restored function of the shunt often counters the sharp increase in IOP following CPC.

Laser cyclophotocoagulation lowers aqueous production by partial destruction of the ciliary body. Its greatest drawback is the inflammation which occurs postoperatively and which may further severely impair aqueous outflow through the iridocorneal angle. Immediate pressure spikes are extremely common immediately after lasering and must be aggressively controlled. Despite such aggressive therapy, the pressure may remain high and vision may be lost when no alternate route of aqueous drainage (such as a shunt) is present.

 

SURGICAL THERAPY FOR BLIND EYES                    [Back to the TOP]

In view of the potential complications or need for subsequent surgeries with the above procedures, it makes little sense to perform them on eyes which are irreversibly blind. Further, continued medical therapy on such eyes is expensive, may mask the initial stages of angle closure in the fellow eye (provided it has not already been affected), and will eventually fail to control the glaucoma in most cases. Therefore, the owner should be advised regarding alternatives that have a high probability of permanently controlling the glaucoma.

Enucleation is the most obvious and least complicated solution for a blind painful eye. However, it may be difficult for an owner to accept, especially when both eyes are affected. While we all know that animals readily adapt, this situation is extremely distressing to many owner, especially if they are feeling guilty at having neglected early diagnosis and treatment. This situation is further complicated if the owner is angry with their veterinarian for missing the diagnosis or delaying in referral. In most enucleations, permanent tarsorrhaphy is performed to close the orbit, and orbital implants (silicone or PMMA spheres) may be placed in the orbital cones prior to closure to occupy the orbital space and provide more cosmetic facial contours. Such implants are well tolerated and rarely extrude or migrate. Prosthetic eyes can be made for pets, and, when they are desired, the eyelids should be left intact. Artificial eyes must be routinely cleaned and are not always well tolerated, so careful client and patient selection is required.

Evisceration and intraocular prosthesis is a procedure in which a black silicone sphere is placed in the globe after the intraocular contents have been removed. The procedure is performed through a dorsal scleral incision under a conjunctival flap and is designed to allow preservation of the sclera, cornea, and attached adnexae while maintaining the shape of the globe. A black implant is used to provide the best appearance though the cornea, especially when corneal scarring is minimal. Rejection or extrusion of the implant is rare, but postoperative care and treatment are more protracted than for enucleation.

Intravitreal injection of gentamicin is a third procedure that allows preservation of the globe with reasonable prospects for good cosmetic effect. In this procedure, 15 mg of gentamicin mixed with 0.2-0.4 mg of dexamethasone is injected into the vitreous through the superotemporal sclera and pars plana 5 mm posterior to the limbus. A 20-22 gauge needle is used to aspirate 0.5-1.5 cc of vitreous prior to injection of the medication. The needle must be carefully angled to avoid the lens since severe endophthalmitis will result when the lens capsule is perforated. The gentamicin is toxic to the retina and ciliary processes, so chemical ablation of the secretory capacity of the ciliary body is accomplished. Sometimes the procedure is unsuccessful and must either be repeated or a different procedure must be performed. Late severe intraocular hemorrhage may occur in some cases and can scare the owner who is surprised by the occasion. In many cases the globe may become so atrophied that the cosmetic results are unsatisfactory, and the greatest drawback of the procedure is that it is unpredictable. The procedure is inexpensive and requires a very brief anesthesia, so it is ideal in cases where cost is a concern and/or the patient is a poor risk for longer anesthesia. The risks and benefits should be thoroughly discussed with the owner.

 

The Bottom Line

The take home messages for dealing with glaucoma are the following:

Medical therapy is not a permanent solution for most glaucoma cases.

The fellow eye must be examined and the owner taught to recognize early signs.

At best, winning is difficult and therapy must be early and aggressive if vision is to be preserved.

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