Pharmaceutical, Laser, and Surgical Treatments for Glaucoma: An Update

Lorne B. Yudcovitch, O.D, M.S., F.A.A.O.

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Clinical trials

Treatment algorithm

Physiology of aqueous production and outflow

Damage produced by glaucoma

Pharmaceutical treatment of glaucoma

Neuroprotection

Gene therapy/neuroregeneration

Laser treatment

Surgical treatment

Summary

INTRODUCTION

Glaucoma is one of the leading causes of blindness in the developed world. Recent advances in examination techniques and instrumentation, e.g., pachymetry, selective automated perimetry and scanning laser ophthalmoscopy, have resulted in earlier diagnoses and more effective monitoring of progression for this group of diseases.

Current research and clinical findings obtained over the last decade have also greatly expanded the therapeutic armamentarium that care providers can use for the management of glaucoma. Never before has there been such a wide range of treatments for this disease.

This course is designed to provide the reader with a summary of landmark studies, clinical management flowcharts, and a review of glaucoma treatment modalities.

CLINICAL TRIALS

Many large-scale prospective, randomized clinical trials designed to assess the efficacy of glaucoma treatment have been conducted over the last several years. These studies have focused on the role of lowering intraocular pressure (IOP) in the prevention of glaucomatous field loss and optic nerve damage. A summary of these studies is presented in Table 1.

Table 1. Summary of Clinical Trials

Study
Description
Summary
Collaborative Normal Tension Glaucoma Study (NTGS) Compared topical drug and/or surgical treatment to no treatment for normal-tension glaucoma patients Over 10 years, it was found that a 30% IOP reduction cut glaucoma progression by 50%
Advanced Glaucoma Intervention Study (AGIS) Compared effect of trabecular surgery type on black and white glaucoma patients After 10 years, IOP was lower for both racial groups (but the best surgery type was race-specific)
Collaborative Initial Glaucoma Treatment Study (CIGTS) Compared trabecular surgery first versus topical drug treatment first for glaucoma patients Both groups had equal IOP reductions after 5 years
Ocular Hypertensive Treatment Study (OHTS) Compared topical drug treatment versus no treatment for ocular hypertensives Treatment reduced progression to glaucoma by over 50%
Early Manifest Glaucoma Trial (EMGT) Compared effects of Argon Laser Trabeculoplasty (ALT) plus betaxolol treatment versus no treatment over an average period of 6 years Argon Laser Trabeculoplasty plus betaxolol reduced progression of glaucoma by 50% more than progression without treatment

The studies cited in Table 1 demonstrate that lowering IOP can reduce the rate of glaucomatous field and optic nerve change. The studies also suggest that to reduce the damage caused by open angle glaucoma, clinicians should strive to lower IOP by the following percentages for patients with the diagnoses specified. (Table 2.)

Table 2. Target IOP Reductions Required to Reduce the Rate of Open Angle Glaucoma-Related Damage

Diagnosis
Target IOP Reduction
Ocular hypertensive patients who have risk factors such as ethnicity, vascular compromise, etc.
20%
Early glaucoma patients who have been identified by field loss
30%
Patients with moderate to severe glaucoma as identified by field loss and optic nerve head appearance
40 to 50%

However, the reduction percentages in Table 2 do not take into account individual variability in optic nerve structural damage and functional loss from glaucoma. As such, target pressures or target pressure reductions for individual patients may deviate from these general IOP reduction percentages. Doctors must take into account all risk factors and examination information before determining the amount of IOP reduction desired.

TREATMENT ALGORITHM

Current treatments for glaucoma can be divided into three main modalities:

Based on these three treatment modalities, Figure 1 shows a basic flow chart for glaucoma patient treatment decision-making. It should be noted that this decision-making flow chart is based on a North American treatment perspective with pharmaceutical treatment provided first and surgical treatment provided only when pharmaceutical treatment is no longer effective. The European treatment perspective typically involves providing surgical and/or laser treatment first and then adding pharmaceutical treatment later if warranted.

IOP = Intra-Ocular Pressure, VF = Visual Field, ONH = Optic Nerve Head, ALT = Argon Laser Trabeculoplasty, SLT = Selective Laser Trabeculoplasty. Modified from American Optometric Association (AOA)/American Academy of Ophthalmology (AAO) Practice Guidelines (1996)/Preferred Practice Patterns (2002).

*AOA and AAO recommend more frequent visits (e.g., 2 days, 1 week, 1 month, 2 months) if inadequate IOP control, treatment side-effects, or rapid progression is noted. Initiating treatment would also require more frequent visits to assess efficacy.

Figure 1. Basic decision-making algorithm for glaucoma management.

It goes without saying that definitively diagnosed glaucoma should be treated. However, increasing evidence shows that ocular hypertension in one or both eyes should also be considered as an indication for treatment. Risk factors, such as age, family history of glaucoma, ethnicity, and vascular disease should be included in the treatment decision-making process. The care provider must weigh the benefits of treatment against short and long-term safety, efficacy, expense, and lifestyle change issues that can directly or indirectly affect the patient.

PHYSIOLOGY OF AQUEOUS PRODUCTION AND OUTFLOW

To understand the mechanisms by which pharmaceutical, laser, and surgical treatments reduce glaucoma progression, it is necessary to review the structural and functional elements of the eye that are associated with glaucomatous damage.

Intraocular pressure is maintained by three main elements:

Figure 2 shows the basic structures involved in aqueous production and outflow.

Figure 2. Basic anterior chamber structures involved in aqueous production, movement, and outflow. Top: normal aqueous flow from the ciliary body to the trabecular meshwork and Schlemm’s canal. Bottom: normal aqueous uveoscleral outflow from the ciliary body to other ocular tissues. (Figure from http://www.xalatan.com/hcp/image_library/anatomy_and_physiology/G_013_28_glaucoma_conventional_aqueous_outflow.asp)

The ciliary body secretes aqueous fluid primarily from the non-pigmented ciliary epithelium. This active secretion utilizes the enzyme carbonic anhydrase and provides about 80% of the aqueous production. The other 20% occurs by passive secretion via ultra-filtration and diffusion from the ciliary body. Figure 3 presents a schematic diagram of the tissues in this region.

Figure 3. Non-pigmented ciliary body histological section showing the ciliary processes and ciliary muscle. The darkly-stained layer of cells along the edge of the ciliary processes is the non-pigmented ciliary epithelium where the action of enzyme carbonic anhydrase produces aqueous. (Figure from http://www.xalatan.com/hcp/image_library/glaucoma/G_068_49_glaucoma_carbonic_anhydrase_inhibitors_cais_.asp)

Eighty to 90% of aqueous outflow occurs primarily through the trabecular meshwork in the anterior chamber of the eye. Aqueous enters the trabecular meshwork after flowing through the pupil from the posterior chamber. The cellular matrix of the trabecular meshwork facilitates aqueous outflow via metabolic phagocytosis.

As a side-note, it is thought that steroids (topical or oral) can interfere with metabolic function of the trabecular meshwork cells thus producing decreased aqueous outflow and subsequent elevation of IOP. Patients who demonstrate this side-effect are termed steroid responders and may be at higher risk for developing glaucoma than are non-responders. Approximately 15% of the population can potentially develop elevated IOP from steroid use.

From the trabecular meshwork, aqueous flows from Schlemm’s canal to collector channels and venous plexi. It then exits from the eye through the episcleral veins. Episcleral venous pressure level can affect the outflow with higher venous pressure reducing the outflow. Figure 4 shows a schematic of the trabecular meshwork and venous collector channels.

Figure 4. Schematic anatomical cross-section of the trabecular meshwork (pink cross-bridges) and venous collector channels (blue) involved in aqueous outflow. (Image from http://www.xalatan.com/hcp/image_library/anatomy_and_physiology/G_013_26_glaucoma_trabecular_meshwork.asp)

An additional 10 to 20% of the eye's aqueous exits via the through uveoscleral pathway. Following this pathway, aqueous enters tissues in the anterior chamber angle and passes through the ciliary muscle into the supraciliary and suprachoroidal spaces. It then exits the eye via the sclera.

DAMAGE PRODUCED BY GLAUCOMA

In the literature, there are several theories that explain the relationship between elevated IOP and glaucoma damage. Three of the most widely accepted are referred to as the direct mechanical damage, ischemia, and apoptosis theories.

Direct Mechanical Damage

In this theory, IOP directly damages nerve fibers by compression, which interferes with axoplasmic flow and cellular function. This leads to death of optic nerve fibers. Figure 5 illustrates this theory.

Figure 5. Direct mechanical theory of glaucomatous damage. (Image from http://whyfiles.org/225drug_receptors/index.php?g=3.txt)

Ischemic Theory

In this theory, increased IOP causes optic nerve fiber death by interfering with circulation of blood to and from the optic nerve head. Lack of proper circulation can occur via compromise of retinal and/or choroidal vasculature around the optic nerve. Figure 6 shows a simplified schematic diagram of the vasculature associated with the optic nerve.

Figure 6. Simplified schematic cross-section of choroidal and retinal vasculature perfusion of the optic nerve. (Image from http://www.xalatan.com/hcp/image_library/anatomy_and_physiology/G_012_21_glaucoma_optic_nerve_blood_supply.asp)

Apoptosis (Programmed Cell Death) Theory

This theory holds that cells die without causing inflammation when their lifespan has been reached or when they have become damage beyond repair. Mediators such as glutamate on N-Methyl-D-Aspartate (NMDA) receptors, free radicals, lack of Brain-Derived Neurotrophic Factor (BDNF), and genetics (e.g. the TIGR/MYOC gene) may be involved in this programmed death. Figure 7 illustrates the theory.

Figure 7. Apoptosis theory. (Image from http://ghr.nlm.nih.gov/ghr/picture/apoptosis_process)

Other Theories and Considerations

It is possible that glaucomatous damage may result from a combination of these theoretical mechanisms or by another mechanism entirely. In addition, different mechanisms may be involved in different types of glaucoma. For instance, acute angle closure glaucoma and the very high IOPs it can produce might cause primarily direct mechanical damage to the optic nerve. (Figure 8.)

Figure 8. Acute angle closure glaucoma versus open angle glaucoma. Top: open angle glaucoma. Note the open trabecular meshwork. Bottom: closed angle glaucoma. Note the obstruction of the trabecular meshwork by the peripheral iris. (Images from http://www.davidsoneye.com/glaucoma.htm)

On the other side of the glaucoma spectrum, normal tension glaucoma, in which the patient's IOP is in the normal range, might involve ischemic-based damage as indicated by the greater frequency of Drance/splinter hemorrhages associated with this type of glaucoma. (Figure 9.)

However, there is controversy amongst some clinicians and researchers as to whether normotensive glaucoma even exists. Some have suggested that masquerading conditions such as ischemic optic neuropathy and reduced carotid vascular perfusion might mimic the appearance of normotensive glaucoma.

Figure 9. Drance (splinter) hemorrhage associated with normotensive glaucoma. These hemorrhages typically appear on the inferior-temporal optic disc margin.

Regardless of the damage mechanism, current clinical treatments still involve one primary goal: IOP reduction. Although researchers are exploring other ways to slow or halt glaucomatous damage (e.g., neuroprotection and increasing papillary vascular perfusion), the main treatment goal is still, as it has been for decades, reducing IOP. IOP reduction can be achieved by reducing aqueous production and/or by increasing aqueous outflow.

PHARMACEUTICAL TREATMENT OF GLAUCOMA

Beta-Blockers

Beta-receptors are localized on many body surfaces including vascular and respiratory tissues. These receptors are divided into two main types: beta 1 and beta 2.

Beta 1 receptors are present in blood vessel walls and heart muscle. When beta 1 receptors are stimulated, tachycardia (i.e., increased heart rate) and increased cardiac output results. When these receptors are blocked, bradycardia (i.e., slowed heart rate) and decreased cardiac output results.

Beta 2 receptors are present in bronchial musculature. When these receptors are stimulated, bronchial dilation results, and, when beta 2 receptors are blocked, bronchospasm/constriction results. There is some mild cross sensitivity of these receptor functions in each tissue, but the basic division holds.

The post-synaptic tissue and the concentration of associated beta receptors vary depending on body tissue type. More beta 1 receptors are located on the heart to stimulate an increased heart rate, whereas more beta 2 receptors are located in the bronchial tubules of the lungs to stimulate bronchial dilation. Beta receptors also serve to dilate peripheral vasculature.

A second set of receptors, termed alpha receptors, also exist in body tissues. Alpha 1 receptors tend to constrict peripheral vasculature, and alpha 2 receptors tend to have a negative feedback effect on vascular constriction by inhibiting it.

Figure 10. Alpha 1, alpha 2, beta 1, and beta 2 receptor types. (Image from http://cmbi.bjmu.edu.cn/hyper-book/ch02/ch02-11.htm)

Beta-receptor blocking drugs, also called beta-blockers, have been utilized for decades to reduce systemic blood pressure. It was later discovered that the non-pigmented ciliary epithelium was laden with beta-receptors which, when stimulated, facilitated aqueous production in the eye. Beta-blocking drugs were thus able to reduce aqueous production in the eye by blocking beta-receptors. A typical IOP decrease with once or twice daily topical beta-blocker administration ranges between 10 to 25%, depending on the type of beta-blocker used and dosage schedule.

The first use of a beta-blocker for glaucoma treatment occurred in 1978 and involved topical timolol ophthalmic drops. This drug was considered the gold standard of treatment for several years until other treatments became available. Table 3 lists several common topical beta-blockers now used for glaucoma treatment and their unique characteristics.

Table 3. Topical Beta-blockers Commonly Used for Glaucoma Treatment

Generic Name
Trade Name
Receptors
Concentration
Dose
Clinical Pearl
Timolol Timoptic® Beta 1 and 2 0.25%, 0.50% BID Former gold standard
Timolol Timpotic XE® Beta 1 and 2 0.25%, 0.50% QD XE is gel form
Timolol Betimol® Beta 1 and 2 0.25%, 0.50% BID Hemihydrate
Betaxolol Betoptic® Beta 1 0.50% BID Betaxon (newer)
Betaxolol Betoptic S® Beta 1 0.25% (susp) BID More selective
Levobunolol Betagan® Beta 1 and 2 0.25%, 0.50% BID or QD Longest half-life
Meti-pranolol Optipranolol® Beta 1 and 2 0.30% BID Rare uveitis risk
Carteolol Ocupress® Beta 1 and 2 1.0% BID Intrinsic sympathomimetic activity

A gel form of timolol (XE gel®) is currently very popular as a once per day treatment because the gel formulation is well-retained on the ocular surface.

Levobunolol, although not utilized as frequently as other beta-blockers, has the longest half-life of the topical beta-blockers.

Also of note is the beta-blocker betaxolol (Betoptic®, Betoptic S®, Betaxon®), which is the only listed beta-blocker selectively affecting beta 1 receptors. It is available in both solution and suspension forms. Although there is some crossover of receptor stimulation, the beta 1 selectivity of this drug may help to reduce potential side-effects.

Carteolol (Ocupress®) is thought to have some minimal intrinsic sympathomimetic activity due to the reduced crossing of this medication through the blood-brain barrier.

Figure 11. Several topical beta-blockers used in glaucoma treatment. Shown from left to right are: timolol (generic), metipranolol (Optipranolol®), levobunolol (generic), betaxolol (Betoptic S®), and carteolol (Ocupress®). (Images from http://www.falconpharma.com/Pages/TimololGFS.html, http://www.walgreens.com/library/finddrug/druginfo1.jsp?id=8900, http://www.falconpharma.com/Pages/Levobunolol.html, http://www.canadadrugsonline.com/DrugMoreInfo167.aspx, and http://www.revoptom.com/drugguide.asp?show=view&articleid=3)

Beta-blockers are additive in effect with almost every other type of glaucoma medication. Oral beta-blockers (e.g. atenolol, metoprolol, nadolol, etc.), which are used for treating systemic hypertension can also reduce IOP as a beneficial side-effect. An approximately 30% reduction in IOP has been noted with certain systemic beta-blockers.

Because of potentially serious systemic side-effects, contraindications to the use of beta-blockers include bronchial constriction/asthma, chronic obstructive pulmonary disease (COPD), bradycardia and/or congestive heart failure, and uncontrolled diabetes or hyperlipidemia. Blood pressure, pulse, and neurological/respiratory/ blood status should all be evaluated before and during treatment with a beta-blocker, and the beta-blockers should be discontinued if any adverse symptoms arise. Some of the more common side-effects of topical and systemic beta-blockers are listed in Table 4.

Table 4. Potential Side-effects of Beta-blockers

Ocular Sting/burn, blur, punctate keratitis
Central Nervous System Depression, fatigue, decreased libido, headaches, dizziness, hallucinations
Heart Bradycardia, arrhythmia, palpitation, congestive heart failure
Lungs Bronchospasm, restricted breathing, respiratory failure
Hematological Aggravate lipid levels, masking of hypoglycemia

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CAIs), as the name implies, inhibit the enzyme carbonic anhydrase on the non-pigmented ciliary epithelium and thus reduce aqueous production. A list of some currently available carbonic anhydrase inhibitors is presented in Table 5.

Table 5. Carbonic Anhydrase Inhibitors Currently Used for Treatment of Glaucoma

Generic Name
Trade Name
Concentration
Dose
Clinical Pearl
Dorzolamide Trusopt® 2% solution TID First topical CAI commonly used
Brinzolamide Azopt® 1% suspension TID Less sting/burn
Dorzolamide combined with timolol Cosopt® 2% dorzolamide plus 1% timolol solution BID or QD Synergistic IOP reduction
Acetazolamide Diamox®/ Diamox Sequels® 250 mg and 500 mg enteric-coated 500 mg by mouth in single dose Emergency use for reduction of very high IOP
Methazolamide Neptazane® 25 mg and 50 mg tablets 50 mg by mouth in single dose Less side-effects than Diamox®

Figure 12. Topical and oral carbonic anhydrase inhibitors used in glaucoma treatment. From left to right: drozolamide (Trusopt®), brinzolamide (Azopt®), dorzolamide plus timolol (Cosopt®), acetazolamide (Diamox®, Diamox Sequel®), and methazolamide (Neptazane®). Images from http://www.avclinic.com/Trusopt.htm, http://vocuspr.vocus.com/vocuspr30/xsl/alcon/Query.asp?Entity=PRAsset&PublishType=Photo+Library&XSL=PRResources, http://www.msdi.cz/content/hcp/products/cosopt.html, and Physician’s Desk Reference 2001.)

Topical CAI treatment typically results in a 15 to 20% decrease in IOP with a one-drop three-times-a-day regimen. The combination CAI-beta-blocker Cosopt® can achieve a potential 30% decrease in IOP due to the synergistic effect of its two drugs.

Orally administered CAIs (acetazolamide, methazolamide, and the less commonly used daranide) are known for their use in treating and preventing cerebral edema (e.g., mountain sickness) by reducing swelling of neural tissues.

CAIs can achieve over a 30% reduction in IOP, but their many potential side-effects (Table 6) preclude their use for treating glaucoma over long periods of time. Typically oral CAIs are used only for a short period of time to treat acute angle closure glaucoma or other causes of extremely elevated IOP.

Table 6. Potential Side-effects of CAIs

Ocular Punctate keratitis, ocular allergy, sting/burn/discomfort, decreased endothelial cell function
Central Nervous System Headaches, nausea, fatigue, tinnitus, parasthesias in the extremities
Hematological Blood dyscrasias, anemia, electrolyte imbalances
Immune Sulfa allergy
Digestive Bitter taste, loss of appetite

Because of potentially serious side-effects, CAIs are contraindicated for patients who have sulfa allergies, blood dyscrasias (e.g., sickle-cell anemia), kidney dysfunction, and corneal epithelial or endothelial compromise resulting from trauma or corneal surgery.

Adrenergic Agonists That Increase Aqueous Outflow

Dipivefrin (Propine®)

Dipivefrin (Propine®), also known as Dipivalyl epinephrine (DPE), was one of the first drugs discovered to lower IOP (Figure 13). Propine® is not itself an active drug, but it is converted in the body to epinephrine, which can reduce aqueous production. Propine® is used instead of simply administering epinephrine because Propine’s® lipid solubility allows it to be absorbed 17 times better than epinephrine.

Once converted to epinephrine by enzymes in the cornea and other tissues, the epinephrine stimulates both alpha and beta receptors of the intraocular tissues. This initially causes an increase in IOP for between 2 and 5 hours, but later there is a prolonged decrease in IOP. The primary mechanism of epinephrine action involves facilitating the uveoscleral outflow of aqueous, and usually results in a 15 to 20% decrease in IOP.

Propine® is available in 0.1% solution, but is no longer a commonly used glaucoma treatment because newer, more effective, and safer drug alternatives are available. The drug is mentioned here to provide historical perspective regarding glaucoma treatment.

Figure 13. Propine 0.1% ophthalmic solution. (Image from http://www.kodc.or.kr/cmed/cmed111.asp?code=000033)

Propine® is contraindicated for patients with hypertension, heart or vascular disease, and those who have had cataract surgery. (Table 7.)

Table 7. Potential Side-effects of Propine®/Epinephrine

Ocular Pupil dilation, adenochrome deposits, irritation/lacrimation, initial IOP elevation, cystoid macular edema in pseudophakes
Cardiovascular Tachycardia, arrhythmias, hypertension
Central Nervous System Headaches, anxiety

Alpha-2 Agonists – Apraclonidine and Brimonidine

Both apraclonidine and brimonidine are topical derivatives of clonidine, a drug that can be used for treating systemic hypertension. They stimulate alpha 2 receptors located in the non-pigmented ciliary epithelium and cause both a decrease in aqueous production and an increase in uveoscleral outflow.

Apraclonidine (0.5% apraclonidine ophthalmic solution, trade name lopidine®) was the first clinically used alpha agonist glaucoma medication. Initially used for short-term therapy of patients with angle closure or who had been on maximally tolerated pharmacotherapy therapy and who required further IOP reduction, it is administered one drop two-to-three times daily (Figure 14). Reports of up to 40% reduction in IOP with 1% apraclonidine have been noted after anterior segment laser treatment (e.g., iridotomy, trabeculoplasty, posterior capsulotomy), but this degree of reduction is typically not seen in patients who have not had surgery.

Figure 14. Apraclonidine (lopidine®). (Image from http://vocuspr.vocus.com/vocuspr30/xsl/alcon/Query.asp?Entity=PRAsset&PublishType=Photo+Library&XSL=PRResources)

Potential side-effects of apraclonidine include eyelid retraction, mydriasis, conjunctival blanching, and/or ocular allergy (20 to 30% of individuals who take apraclonidine develop an ocular allergy). Dry mouth, headache, fatigue, and/or lethargy may also accompany use of apraclonidine.

Patients who take monoamine oxidase (MAO) inhibitors, and those who have severe cardiovascular disease, low blood pressure, or bradycardia should not take apraclonidine.

Patients taking apraclonidine may exhibit tachyphylaxis (reduced medication effect) over time, so short-term use is recommended.

Like apraclonidine, the newer drug brimonidine stimulates alpha 2 receptors causing a decrease in aqueous production and an increase in uveoscleral outflow. Brimonidine reduces IOP approximately 25 to 30% when used three times daily (although twice daily may be just as effective). Because of allergic responses found when the initial commercial formulation of brimonidine 0.2% (Alphagan®) was introduced, a newer 0.15% solution with Purite preservative was developed (Alphagan P®). The original 0.2% solution is now available generically. The Food and Drug Administration in the United States jas recently approved a 0.1% formulation of Alphagan that purports to have greater bioavailability and thus comparative efficacy to the original 0.2% formulation.

Figure 15. Brimonidine formulations. From left to right: brimonidine 0.2% (Alphagan®, brimonidine 0.15% with Purite preservative (Alphagan P®), and brimonidine 0.2% (generic). (Images from http://www.allergan.com/site/products/consumers/home.asp?id=alphagan&largeText=, http://www.allergan.com/site/products/consumers/home.asp?id=alphagan_p, and http://www.falconpharma.com/Pages/Brimonidine.html)

Tachyphylaxis can develop with brimonidine use, but the frequency of development is less than with apraclonidine, which makes brimonidine potentially more useful for long-term treatment. Brimonidine also tends to produce fewer ocular allergic responses than apraclonidine. It is additive with beta-blockers and carbonic anhydrase inhibitors in lowering IOP, and has a relatively safe systemic profile making it drug of choice when others are contraindicated.

Possible side-effects include ocular hyperemia, burning/stinging, blur, foreign body sensation, and allergic reactions. Systemically, dry mouth, headache, fatigue or lethargy can occur. Like apraclonidine, concomitant use with MAO inhibitors is contraindicated, as is use with severe cardiovascular disease, depression, and cerebral or coronary insufficiency. Brimonidine may cause respiratory and cardiac depression in infants; it is contraindicated in patients under 2 years of age, and should only be used with caution for older pediatric patients and nursing mothers.

Cholinergic Agonists

Parasympathomimetic drugs including carbachol and pilocarpine work by directly stimulating autonomic nervous system acetylcholine (ACh) receptors. The pupillary sphincter muscle is rich in ACh receptors, which, when stimulated, lead to sphincter muscle contraction and pupil constriction. The long ciliary muscles of the ciliary body also have ACh receptors, which result in muscle constriction. This constriction opens the trabecular meshwork spaces, thus facilitating aqueous outflow.

Carbachol is an older cholinergic agonist that is no longer used for glaucoma treatment. Pilocarpine is still utilized in cases of acute angle closure glaucoma because the iris sphincter contraction (miosis) produced the drug helps to pull the iris root away from trabecular meshwork. It is also used rarely in cases of pigmentary glaucoma when aqueous outflow is impeded by pigment in the trabecular meshwork, and in open angle glaucomas when other maximal medicinal therapy has not been effective.

Figure 16. Pilocarpine gel and drop formulations. Images from http://www.falconpharma.com/Pages/Pilocarpine.html, and http://www.wallsrx.com//services/cpident.cfm?photo=&cpnum=488&gname=)

Pilocarpine is available in several forms and concentrations. The most common is 0.25% to 10% ophthalmic solution (trade names: Pilocar®, Pilostat®, Pilagan®, Akarpine®, Ocu-Carpine®, and Isoptocarpine®).

A typical dosage regimen for pilocarpine solution is QID. Concentrations above 4% are typically no more effective in lowering IOP than are lesser concentrations, and rare pupillary blockage due to sphincter constriction may occur with concentrations exceeding 2%.

Pilocarpine is also available in 4% gel, which is administered as a one half inch (1.0 cm) long strip placed in the lower cul-de-sac at bedtime, and as a membrane-controlled drug delivery vehicle (Ocusert®) in 1% (Pilo-20®) and 2 to 3% (Pilo-40®) concentrations. One Ocusert is placed in the lower cul-de-sac and left in place for 1 week, at which time it is replaced. This delivery vehicle may help patients who have difficulty instilling drops or who have compliance/lifestyle issues that preclude frequent dosing.

As a side note, pilocarpine is also used in 0.125% concentration for the diagnosis of Adie’s pupil.

Although pilocarpine has a unique mechanism for lowering IOP, its effect on open angle glaucoma is typically no greater than a 20% reduction in IOP. Its best use is for cases of acute angle closure glaucoma when immediate treatment is required. Over time, tachyphylaxis can occur and this will require higher concentrations of pilocarpine to maintain IOP reduction. Coupled with this, several ocular and systemic side-effects can occur with pilocarpine (Table 8 ). Together these make pilocarpine a lesser-desired glaucoma medication.

Table 8. Ocular and Systemic Side-Effects of Pilocarpine.

Ocular
Systemic
Miosis causing decreased night vision, reduced visual field, permanent miosis with chronic use (sphincter muscle atrophy), blur vision if the patient has central cataracts.

Ciliary muscle spasm causing fluctuating vision, induced myopia, and brow-ache, which frequently occurs at the start of therapy, but usually regresses after a few weeks. The ache typically begins 15 minutes following treatment and usually lasts 2 to 3 hours. Ocuserts® produce a less intense miosis and visual disturbance sensation.

Retinal detachment, which is especially a concern with pre-existing retinal disease or high myopia.

Pupillary blockage due to sphincter constriction. This is a rare occurrence and is usually experienced only with 2% or higher concentration.

Foreign body sensation with Ocuserts.

Blood-aqueous barrier breakdown.

Induced myopia in younger patients
Abdominal pain, diarrhea, nausea, and vomiting.

Hypotension.

Bradycardia.

Salivation.

Perspiration.

Bronchospasm.

Headache.

Because of varied and potentially serious side-effects, pilocarpine is be contraindicated in patients under 40 years of age, patients with cataracts (especially posterior subcapsular cataracts), patients with inflammatory or vascular glaucoma, and patients with a history or risk of retinal detachments (e.g., high myopia or lattice degeneration). Patients should be educated on the signs and symptoms of retinal detachment (e.g., flashes, floaters), and dilated indirect ophthalmoscopy examinations should be performed to rule-out cataract and retinal problems before beginning treatment.

The IOP-lowering effect of pilocarpine and prostaglandins may be reduced when treating glaucoma with both medications at once, as is discussed in the next section. Therefore, this combination of drugs is contraindicated for use in glaucoma therapy.

Prostaglandins/Prostamide

The cyclo-oxygenase pathway in the body (Figure 17) includes a cascade of mediators that respond to both internal and external tissue insults. Some of the mediators in this pathway are prostaglandins, which contribute to the inflammatory response. Recently, it was discovered that prostaglandin derivatives, even in very small concentrations, could serve as potent drugs for lowering IOP. The mechanism of prostaglandin-mediated IOP reduction presumably involves increasing uveoscleral aqueous outflow by loosening the intercellular spaces on the ciliary body face. IOP reduction produced by using one drop each evening is typically between 30 and 35%.

Figure 17. Cyclo-oxygenase pathway in the inflammatory response. Prostaglandins are a product of this cascade. (Image from http://www.ovc.uoguelph.ca/BioMed/Courses/Public/Pharmacology/pharmsite/98-409/Inflammation/Inflam.html)

The first prostaglandin readily available for ophthalmic use was latanoprost 0.005% solution (Xalatan®). This drug was followed by travoprost 0.004% solution (Travatan®) and bimatoprost 0.03% solution (Lumigan®).

Figure 18. Ophthalmic prostaglandins for glaucoma treatment. From left to right: latanoprost 0.005% (Xalatan®), travoprost 0.004% (Travatan®, and bimatoprost 0.03% (Lumigan®). (Images from http://www.canadadrugsonline.com/DrugMoreInfo2213.aspx, http://www.alconlabs.com/mx/Aj/products/Farma/Travatan.jhtml, and http://www.allergan.com/site/products/consumers/home.asp?id=lumigan)

Bimatoprost is an amide-based prostaglandin rather than an ester-based prostaglandin like latanoprost and travoprost. In the eye, esterases (protein catalysts) convert ester-based drugs into their free-acid (biologically active) forms more efficiently than amidases. As such, the ester-based latanoprost and travoprost may have more effect in the eye than bimatoprost. This can explain why bimatoprost is formulated at a higher concentration than are the other prostaglandins. It also may explain why there might be a slightly higher local effect on the ocular surface tissues produced by bimatoprost as opposed the other prostaglandins.

Several studies have shown that each of the prostaglandin ophthalmic solutions is comparatively effective for lowering IOP. One study has shown that travoprost may be more effective for Blacks than for Caucasians in lowering IOP.

A summary of the prostaglandins is provided in Table 9.

Table 9. Summary of Prostaglandins Used to Treat Glaucoma.

Generic
Trade Name
Concentration
Dose
Clinical Pearl
Latanoprost Xalatan® 0.005% One drop at bedtime Refrigeration required after 1 month
Travoprost Travatan® 0.004% One drop at bedtime Possibly better effect with blacks
Bimatoprost Lumigan® 0.03% One drop at bedtime Potentially more local side-effects

At the time this course was being prepared, combination prostaglandin-timolol drops are in the process of approval by the US Food and Drug Administration, as well as other newer prostaglandin analogues for topical glaucoma treatment use.

Prostaglandins have various side-effects, many of which are unique as compared with other glaucoma medications. These side-effects include hypertrichosis (eyelash lengthening and thickening), growth of inferior periocular hair follicles particularly on the inferior and infero-nasal adnexae, subtle hyperpigmentation of the iris over a period of 6 to 12 months (particularly with mixed-iris color eyes), possible re-activation of herpes simplex virus in previously infected individuals, and possible cystoid macular edema in pseudophakes or aphakes. Conjunctivitis is also not uncommon with this class of medications, and it tends to persist for an average 1 to 4 months after onset of treatment. Patients have complained of ocular irritation either upon instillation or upon awakening after instilling the drug the night before. Iritis is also a rare side-effect. See Table 10 for a list of potential ocular side-effects associated with prostaglandins.

Table10. Potential Ocular Side-effects Associated with the use of Topical Prostaglandins

Ocular Tissue
Side Effect
Cornea Surface irritation, herpes keratitis
Conjunctiva Conjunctivitis
Iris Pigment darkening, iritis
Lashes/adnexae Eyelash lengthening, follicle growth
Retina Cystoid macular edema in pseudophakes and/or aphakes

Because of the potential side-effects associated with prostaglandins, contraindications for its use include aphakia or pseudophakia, a history of uveitis, YAG posterior capsulotomy, a history of herpes simplex ocular infections, and cosmetic concerns regarding iris color changes.

Also of note, concomitant use of prostaglandins and pilocarpine may also be contraindicated due to the conflicting mechanisms of action for the two medications. It is speculated that prostaglandins serve to loosen the intercellular spaces of the ciliary body to allow aqueous outflow, and pilocarpine indirectly tightens these intercellular spaces due to constriction of ciliary body muscles through direct cholinergic action. Because of these conflicting mechanisms, the ability of one drug to lower IOP may be cancelled by the other drug. As such, use of these medications together on an extended basis is not recommended.

Docosanoids

Uniprostone isopropyl (Rescula®), also known as DHA (docosahexaenoic acid), is a synthetic prostanoid-type drug that can lower IOP by about 15% when applied BID as a 0.15% solution. (Figure 19). Its effect typically begins in about 1 week.

Figure 19. Uniprostone isopropyl ophthalmic solution (Rescula®). (Image from http://www.neogen.com/mannitol.htm)

The mechanism of action for uniprostone is uncertain; possibly activation of trabecular cell potassium channels causes contraction and enhances aqueous outflow through the trabecular meshwork. Uniprostone may also inhibit endothelin, which enhances blood flow and may serve a possible neuroprotective function.

Currently, uniprostone is typically used as an adjunctive treatment along with other glaucoma medications.

Side-effects of uniprostone are similar to the prostaglandins and include superficial punctuate keratitis, possible iris darkening, and possible risk of iritis or ocular herpes simplex infection. No significant systemic side-effects are known for this drug, but, at this time, Rescula® is not available on the US market.

Hyperosmotics

Hyperosmotics are indicated for treatment of acute angle closure glaucoma or other causes of highly elevated IOP (e.g., pressures over 40 mmHg). These medications are for temporary, immediate use only. As the name implies, hyperosmotics cause increased blood serum osmolarity, which pulls water from tissues (including ocular tissues) into the bloodstream. By increasing the osmotic gradient between plasma and the eye, vitreal shrinking occurs, which results in reduced ocular volume and corresponding lowered IOP.

Figure 20. Examples of hyperosmotics used for treatment of glaucoma. Left glycerol 50% (Osmoglyn®) and right mannitol 20% intravenous solution.

A list of hyperosmotics commonly used for IOP reduction is presented in Table 11. Hyperosmotics are either administered orally (drinking liquid medication over cracked ice to prevent nausea and vomiting) or by intra-venous injection (which requires hospitalization). Onset of IOP reduction typically occurs within 15 minutes to 2 hours depending on the medication and route of administration.

Table 11. Hyperosmotics Used in the Acute, Emergency Treatment of Glaucoma

Generic Name
Trade Name
Dose
Route of Administration
Onset
Clinical Pearls
Glycerol 50% Osmoglyn® 1.0 to 1.5g/kg body weight Oral, drink over ice 15 to 30 minutes Avoid with diabetics
Isosorbide 45% Ismotic® 1.5 to 2.0 g/kg body weight Oral, drink over ice 15 to 30 minutes Safe with diabetics
Mannitol 20% - 2.4 to 10g/kg body weight Intravenous 30 to 60 minutes Avoid with renal disease
Urea 30%; 50% - 0.5 to 2.0g/kg body weight 30% intravenous; 50% oral 30 to 60 minutes Many systemic complications

Glycerol can cause hyperglycemia and should be avoided with diabetic patients. Isosorbide is not metabolized into sugar and so is safe to use with diabetics. Currently isosorbide is not available in the US. Mannitol can cause diuresis, headaches, chills, and chest pain. Additionally it should be avoided in patients with kidney disease. Urea has numerous systemic side-effects and is rarely used. All hyperosmotics have nausea and vomiting as a common side-effect.

Alcohol and Marijuana

Occasionally the health care provider may be asked about the benefits of alcohol or marijuana for the treatment of glaucoma. Although both substances can temporarily lower IOP, the effect is minimal and transient compared to more effective prescription medications available. In addition, some care providers regard the numerous side-effects of these substances to preclude their use as viable treatments for glaucoma.

Typical concentrations of ingestible alcohol are 2 to 3ml/kg of body weight of 80 to 100 proof alcohol. The maximum IOP reduction effect occurs in 1 to 2 hours, after which it diminishes. Alcohol inhibits ADH (Anti-Diuretic Hormone), which explains the frequent urination that accompanies alcohol ingestion. Intoxication, central nervous system depression, vomiting, nausea, and addiction are a few of the serious complications of alcohol use.

D-tetrahydrocannabinol is one of the active components in marijuana and is prescribed in some legislated areas for treatment of chronic pain and IOP reduction. Several studies report IOP decreases produced by this substance in animal models.

Inhaled marijuana smoke will lower IOP only slightly and temporarily. The most promising vehicle of administration may involve a topical ocular drop, which is still under development. However, systemic side-effects (and legislation in some areas) currently contraindicate the widespread use of cannabinoids for treatment of glaucoma.

NEUROPROTECTION

Current medicinal therapy for glaucoma focuses on protecting the optic nerve indirectly through lowering of the IOP. The next wave of glaucoma medicinal treatment may involve using a pharmaceutical agent to protect the optic nerve even if the IOP is elevated. Research involving this type of treatment is still in its infancy, but may include use of substances such as those shown in Table 12.

Table 12. Various Potential Neuroprotective Agents.

Mechanism of Protection
Possible Protective Agents
Blood Flow Enhancers Naftidrofuryl, minoxidil, ginko biloba
Sodium Channel Blockers Lamotrigine, topiramate, riluzole
Glutamate Inhibitors Lifarazine, riluzole, felbamate, eliprodil, memantine
Neurotrophins Various neural growth factors that release survival factors
Nitric Oxide Inhibitors Nitroglycerine, possibly ginko biloba
Free Radical Scavengers/Antioxidants Vitamins C and E, catalase, superoxide dismutase
Apoptosis-Related Protease Inhibitors Invirase, Norvir, Crixivan, Viracept, AIDS meds
New Protein Synthesis Inducers MAO-B inhibitor selegine
Genetic Modulators "bax" and "bad" genes stimulate neuron death, "bcl-x" and "bcl-2" suppress it

The potential neuroprotective properties of the beta-1 selective beta-blocker betaxolol, the alpha-2 agonist brimonidine, and the docosanoid uniprostone are also being studied.

GENE THERAPY/NEUROREGENERATION

Genomics is becoming an important component not only of family counseling related to glaucoma, but also of therapeutic care. Isolation of genetic material responsible for morphological changes in the trabecular meshwork matrix has already been achieved. The TIGR/MYOC gene variant mt-1 test for primary open angle glaucoma is now available (InSite Vision, http://www.insitevision.com), and there are other diagnostic kits that can assess the genes associated with other forms of glaucoma.

Figure 21. Insite Vision’s Ocugene genetic glaucoma test. (Image from http://www.insitevision.com/wt/page/ocugene)

Gene therapy works by either turning off ‘bad’ genes or by making genes produce ‘medicine’ to heal or reduce the rate of damage to affected areas. Studies designed to determine whether gene therapy can be applied to glaucomatous damage in the trabecular meshwork and the optic nerve are currently underway. An example is the investigational drug ISV-205, by InSite Vision.

Studies in rehabilitative neurology (e.g., those involving traumatic spinal cord injuries) have involved neural regeneration in animal models. Certain animals (e.g., goldfish) have been found to have a notable ability to regenerate peripheral nerves, including optic nerves. Research into the mechanism(s) by which this occurs is underway and may have future implications for preserving and/or regenerating nerve fibers in eyes with glaucomatous damage.

LASER AND SURGICAL TREATMENTS FOR GLAUCOMA

Non-medicinal therapies for glaucoma include laser and surgical treatments. These are typically indicated for patients whose glaucoma is poorly controlled by medication, for patients who cannot take glaucoma medication because of adverse reactions, or for patients with advanced glaucoma who need additional treatment beyond that which can be provided by medication.

Typically, however, medications are required after surgical treatment to maintain IOP control, but the dosages and types of medications may change from what was taken before surgery.

LASER TREATMENT

Laser treatment designed to reduce IOP has been used for over 20 years. Advantages to laser treatment include the following:

The most commonly used laser treatments for glaucoma include:

Laser Trabeculoplasty (ALT)

Laser trabeculoplasty (also called argon laser trabeculoplasty (ALT), or laser trabeculoplasty or (LTP) is the oldest of the commonly used laser treatments for glaucoma. Originally ALT utilized a short wavelength (blue-green) argon laser, but the procedure now uses a slightly longer wavelength (green) laser.

When used for ALT, the laser is usually applied in evenly spaced spots over 180 degrees or 360 degrees of the trabecular meshwork. The laser burns cause shrinkage and contraction of the trabecular collagen meshwork, which creates openings in the intratrabecular spaces. This increases aqueous outflow (Figure 22). The laser burns also increase metabolic activity in the trabecular meshwork endothelial cells, which causes them to proliferate and facilitate aqueous outflow. The net result is a decrease in IOP, typically between an 8 to 10 mmHg drop.

Figure 22. Schematic diagrams explaining argon laser trabeculoplasty. Top: gonioscopy lens is used to reflect a laser beam onto the trabecular meshwork. Bottom: laser burns are applied in a circumferential pattern along the length of the trabecular meshwork. (Images from http://www.eyemdlink.com/pop/alt.htm and http://eyelearn.med.utoronto.ca/Lectures04-05/Glaucoma/12LaserTherapy.htm)

Usually ALT results in an initial 20 to 30% IOP reduction. However, approximately 50 percent of patients treated with ALT return to pretreatment IOP levels within 5 years and almost 70 percent return to pretreatment levels after 10 years. This reduction in ALT effectiveness over time can occur because of continued glaucomatous progression and/or because of changes in trabecular meshwork structure (e.g., scarring).

The Glaucoma Laser Trial (GLT) demonstrated that 44 percent of glaucomatous eyes had IOP controlled by laser trabeculoplasty versus 30% by topical timolol 0.5% use. Two years following ALT or the beginning of timolol use, the percentage of patients with IOP control was only slightly greater for those who had received ALT.

ALT is not indicated for treatment of angle recession glaucoma, neovascular glaucoma, uveitic glaucoma, or congenital glaucoma.

Selective Laser Trabeculoplasty (SLT)

Selective laser trabeculoplasty (SLT) is a newer form of laser therapy and is performed in a manner similar to ALT. However, SLT uses a frequency-doubled Nd:YAG laser that delivers a low-energy, large-spot, very brief pulses to the trabecular meshwork. This "cooler," "gentler" laser application is thought to stimulate the pigmented trabecular meshwork cells to divide and thus facilitate improved aqueous outflow (Figure 23).

Figure 23. Selective laser trabeculoplasty (SLT). Scanning electron microscopy images of trabecular meshwork with and ALT application (Top) and trabecular meshwork with and SLT application (Bottom). (Images from http://www.revophth.com/index.asp?page=1_361.htm)

The lack of trabecular meshwork scarring produced by SLT may facilitate improved long-term control of IOP as well as allowing the potential for re-treatments. This is unlike ALT, which cannot be repeated on the same trabecular meshwork area.

Initial studies show that both ALT and SLT can initially reduce IOP by about 20%. The energy released into the eye by the laser and the anterior chamber inflammation produced immediately post-SLT are significantly less than for ALT, which results in better tolerance and less patient discomfort. However, many surgeons sill continue to perform ALT as opposed to SLT due to the lower cost of ALT lasers and the greater number of procedures that can be performed with an argon laser.

Although ALT is utilized more as an initial glaucoma treatment in Europe, North American care providers typically resort to laser therapy only after medicinal therapy has become ineffective.

Peripheral Iridotomy (PI)

Peripheral iridotomy (PI) is typically performed to treat narrow angle or angle closure glaucoma. Multiple applications of a YAG laser are focused on the iris root, effectively creating an oval opening in the iris through which aqueous can move from the posterior to the anterior chamber (Figure 24). The hole is typically placed in the superior part of the iris so that it is covered by the patient’s eyelid. This reduces the chance of glare and monocular diplopia that could result from induced polycoria (i.e., light entering the eye through the PI hole.

Figure 24. Peripheral iridotomy. Image from http://www.mrcophth.com/glaucoma/acuteglaucoma.html)

Allowing aqueous flow from the posterior to the anterior chamber through the peripheral iris reduces the chance of angle closure by effectively moving the peripheral iris away from the trabecular meshwork and deepening the anterior chamber. It may also reduce the chance of iris bombe by releasing trapped aqueous and debris behind the iris, but it may paradoxically cause greater risk of irido-lenticular touch and posterior iris-anterior lens adhesions.

Typically both eyes receive PIs at the same time even if only one shows signs of closure. This is because anatomically both eyes usually have narrow angles and thus are both at risk for angle closure glaucoma.

The need for a PI is usually more urgent than for other types of glaucoma procedures because eyes with angle closure typically have the potential for very high IOPs and have a much greater risk of rapid progression to severe field loss.

Cyclophotocoagulation (Cyclophotodestruction)

Cyclophotocoagulation, also known as cyclophotodestruction, involves YAG laser application to destroy the ciliary processes, which results in significantly decreased aqueous production and reduced IOP (Figure 25). It procedure typically involves utilizing an endoscope (microscopic camera) to visualize the ciliary processes prior to photocoagulation (this is called endoscopic cyclophotocoagulation or ECP). However, the procedure can also be performed trans-sclerally at locations near the limbus.

Cyclophotocoagulation entails greater risks than other laser procedures because it is more invasive and causes a larger area of tissue damage. Risks include infection, ischemia, and permanent vision loss. For these reasons, cyclophotocoagulation is usually reserved as a last resort for cases in which other medical or surgical treatments have failed.

Figure 25. Cyclophotocoagulation. (Image from http://www.eyemdlink.com/pop/cyclophotocoagulation.htm)

SURGICAL TREATMENT FOR GLAUCOMA

The aim of most glaucoma surgical treatments is to either mechanically open a new channel for aqueous outflow between the anterior chamber and the subscleral or subconjunctival spaces, or to partially destroy the aqueous producing cells of the eye.

Most of the procedures create a membrane-covered or artificial bleb from which aqueous can be released outside of the eye. However this bleb may become encapsulated or infected causing reduced or no aqueous outflow. The patient usually performs ocular massage on the bleb to maintain the opening and to facilitate outflow into the surrounding periocular tissue. Medications such as 5-fluorouracil (5-FU) or mitomycin C can also be used postoperatively to prevent the fistula from scarring over.

The main types of glaucoma surgeries currently in use include:

Trabeculectomy

Incisional trabeculectomy, like its laser counterpart, has been performed for over 20 years. The procedure involves mechanical formation of an aqueous outflow channel through the sclera and into the subconjunctival space (Figure 26). Aqueous pools in this space forming a fluid sac called a bleb. When performing an incisional iridectomy, a triangular hole is created in the iris periphery, which helps to prevent prolapse of the iris into the newly created channel.

Figure 26. Trabeculectomy. Top: schematic diagram of trabeculectomy. Middle: filtration bleb. These are typically placed superiorly above the limbus, so that the upper eyelid hides the bleb. Bottom: peripheral iridectomy associated with trabeculectomy procedure. (Images from http://www.eyemdlink.com/pop/trabeculectomy.htm, http://www.eyeatlas.com/box/306.htm, and http://www.mrcophth.com/glaucoma/acuteglaucoma.html)

A recent study has also suggested that trabeculectomy improves ocular blood flow to the optic nerve for patients with chronic open angle glaucoma. The mechanism for this increased blood flow is not well understood.

Sclerostomy

Performed less frequently than a trabeculectomy, a sclerostomy involves creation of a channel through the sclera to facilitate aqueous outflow into the scleral tissue and subconjunctival space. Antimetabolites such as 5-FU and mit-C are utilized in a sclerostomy to keep the channel open.

Valve or Tube Implantation

In this procedure, a customized plastic tube or shunt (e.g., Ahmed, Molteno, Baerveldt, ExPRESS, http://www.medcompare.com/spotlight.asp?spotlightid=57) is inserted from the subconjunctival side through a sclerostomy and into the peripheral anterior chamber (Figure 27). An attached receptacle usually serves as a reservoir for aqueous outflow and subsequent absorption by the surrounding tissue. As aqueous is released from the anterior chamber through the tube, IOP is reduced.

Figure 27. Tube implantation. Top: various types of shunts used for glaucoma filtration surgery. Bottom: schematic diagram of tube implantation surgery. (Images from http://www.revoptom.com/special.asp?page=osc/feb02/glaucoma.htm, and http://www.eyemdlink.com/pop/tube_shunt.htm)

Drainage shunts are typically reserved for patients with complicated types of glaucoma (e.g., neovascular or inflammatory) that are unresponsive to medicinal or other surgical treatments, or for patients who have scarring from prior surgery.

The IOP reduction produced by shunt surgery is similar to that produced by incisional trabeculectomy and endoscopic cyclophotocoagulation, but there are serious risks associated with the use of shunts. These include:

Cryocyclodestruction

Like cyclophotocoagulation, the aim of cryocyclodestruction is to destroy the ciliary processes so that aqueous production is reduced and IOP is lowered. Cryocyclodestruction is performed with a cryo (freezing) probe that is applied in an annular pattern just posterior to the limbus. This results in trans-scleral tissue damage.

The goal of cryocyclodestruction is to reduce aqueous production rather than enhance aqueous outflow, so no bleb is created during this procedure. Risks similar to those encountered with cyclophotodestruction are present with cryocyclodestruction.

Combination Surgical Procedures

Occasionally combined cataract-trabecular surgeries are performed when it is felt that the benefits of having both procedures done at once outweigh the risks. Factors in determining to do the procedures together may include:

Candidates must be carefully selected for combination surgery because the surgeries are significantly more invasive for the eye than a single surgery.

Recent literature has shown that combined deep sclerectomy and two-site phacoemulsification with mitomycin-C may give stable, successful outcomes, but combining other techniques may affect complication rates. More information is needed on combined glaucoma-cataract surgical procedures before they can be recommended for a significant number of patients.

SUMMARY

The care provider who manages glaucoma must to stay knowledgeable regarding current research, changing treatment modalities, and standards of clinical care. Each patient will have unique attributes, which may either warrant or preclude the use of certain pharmaceutical, laser, and/or surgical treatments. In addition, the care provider should stay abreast of future neuroprotective and genetic therapies for glaucoma. However, because glaucoma currently still has no cure, today it is necessary to utilize the only available treatments and to maintain IOP at as low a level as practical.

As a wise doctor once said, "Glaucoma therapy involving IOP reduction is at best a race with the patient's life expectancy. Glaucoma cannot be cured so the goal of current therapy is to hold field loss to a minimum until the patient no longer has need of his or her vision." Hopefully, in the not-too-distant future, glaucoma therapy will advance beyond this limited goal and real cures can be discovered.

More Information

Other Pacific University College of Optometry On-Line Continuing Education courses on glaucoma are available from this author. They are: "A Review of Glaucoma Examination Procedures and New Instrumentation” (http://www.opt.pacificu.edu/ce/catalog/12761-GL/GlauYud.html), and “Use of Short Wavelength and Frequency Doubling Perimetry in Glaucoma Diagnosis and Management." (http://www.opt.pacificu.edu/ce/catalog/13902-GL/FieldTest.html)

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Lorne Yudcovitch, O.D., M.S., F.A.A.O.
Pacific University College of Optometry
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yudcovil@pacificu.edu

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