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The present and future of glaucoma treatment

ByDale K. Heuer, MD

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Glaucoma therapy has made considerable progress in recent years, and indications are that various treatments may soon improve ophthalmologists¡¯ abilities to manage this disease. The three main treatment categories remain medical therapy, laser surgery and incisional surgery. This article discusses aspects of these methods and examines the future of glaucoma therapeutics.

Balancing risks and benefits

Dale K. Heuer

Before considering the various treatments for glaucoma, ophthalmologists must remember the main therapeutic goal: to prevent functionally significant visual impairment in a patient¡¯s lifetime. Given that goal, treatments must balance the benefits and risks of treatment along with the quality of life impact.

This leads to the conclusion that treatments should be used for patients at greatest risk for developing such functional impairment from glaucoma. The enhanced ocular hypertension to primary open-angle glaucoma conversion risk calculator can be used to assess ocular hypertensives¡¯ risk.¹ Among patients who already have glaucoma, ophthalmologists need to be able to better predict and quantify glaucoma progression to determine whether an individual patient¡¯s current therapy is adequate, or if he or she warrants intensification of therapy.

Aside from those at highest risk, it would also be best to target patients who are most likely to benefit from the treatments. Little in the literature addresses this topic, although some studies have been conducted. The Normal-Tension Glaucoma Study found that patients with a family history of glaucoma are more likely to benefit from treatment, whereas patients with a personal history of cardiovascular disease were not likely to benefit.² Also in that study, patients without baseline disc hemorrhage and patients with mild disc excavation benefited more from treatment.

Regarding the main therapeutic goal of preventing functionally significant visual impairment in a patient¡¯s lifetime, it is crucial that ophthalmologists obtain a better understanding of IOP targets. From what level should ophthalmologists aim to lower a patient¡¯s IOP? Some possibilities include the maximum pressure a patient presents with or the average IOP over time. Minimizing long-term IOP fluctuation may also be an important consideration. Continuous IOP monitoring in an animal model has also shown that substantial variation in IOP also occurs even over very short periods of time; hopefully within the next five years continuous IOP monitoring in patients will be available, enabling ophthalmologists to gain a better understanding of IOP and its relationship to glaucoma progression.

Medical therapy

The first treatment category for glaucoma is ocular hypotensive medical treatment. A variety of medications are currently under investigation, some of which will hopefully become available for use within 5 years. These drugs include anecortave acetate, angiotensin II antagonists, apraclonidine/brimonidine analogues (with nitric oxide-donating properties), calcium channel blockers, calcium-activated potassium (maxi-K) channel blockers, mifepristones (RU486; corticosteroid receptor antagonists), prostaglandin analogues with nitric oxide donating properties, rho-kinase inhibitors, selective ¡Ø_1A adrenergic agonists, selective ¦Â₁ adrenergic agonists, selective muscarinic compounds, serotonin 5-HT2A receptor antagonists, sphingosine-1-phosphate (S1P) agonists, synthetic peptide molecules that bind cell receptors for fibronectin and trabecular meshwork cytoskeleton disrupters.³

Additional fixed-combination products (such as a prostaglandin analog and beta blockers, or a prostaglandin and a topical carbonic anhydrase inhibitor or a ¡Ø₁-adrenergic agonist) would be welcome additions to our therapeutic arsenal. Fixed combination prostaglandin analog and beta-blocker are available in other countries, but the U. S. Food and Drug Administration has not approved these products, so it remains unlikely that they will become available in the near future.

Patient adherence to medications is critically important, but reliably accurate methods of monitoring adherence are not available. Thus, it would be advantageous to have drug delivery options in addition to eye drops, possibly including punctal plugs, subconjunctival injections, peribulbar injections, intracameral injections and intravitreal injections.

Laser surgery

Trabeculoplasty is another useful glaucoma treatment. The Glaucoma Laser Trial, the initial results of which were published in 1990, illustrated the benefit associated with trabeculoplasty among patients with glaucoma.⁴ After 2 years, IOP was lower in the laser-first eyes (Figure 1). Furthermore, IOP control was achieved without additional medications in 44% of the eyes that had undergone initial laser surgery vs. only 30% of the eyes in which the initial treatment was timolol. However, this trial randomized eyes rather than patients, such that all of the laser-first eyes received the potentially substantial crossover effect of beta-blockers.

A follow-up analysis of the same study showed that over the 7-year median duration of the study, laser-first eyes had 1.2 mm Hg lower IOP than the timolol-first eyes (P < .001).⁵ Laser-first eyes also had 0.6 dB greater visual field improvement (P < .001) and 0.01 less cup area/disc area increase (P = .005). This evidence should lead to increased early use of trabeculoplasty. The 2005 AAO primary open-angle glaucoma Preferred Practice Pattern survey includes trabeculoplasty as an ¡°appropriate initial therapeutic alternative.¡± Some calculations also suggest that it may be a more cost-effective approach than initial drug therapy.⁶

Endoscopic cyclophotocoagulation (ECP) is another laser surgery option and may be a gentler cyclodestructive method with less damage to the ciliary body than the transscleral approach. Few studies have been conducted on this approach, but two reported that patients who underwent phacoemulsification and an intraocular lens implant with ECP had a slightly greater decrease in IOP and lower dependence on medication compared to those who underwent the same procedure without ECP.^7,8

However, transscleral laser cyclophotocoagulation is still useful in certain settings. Patients with neovascular glaucoma, blind and painful eyes, or those who have had multiple previous procedures could benefit from this method. More studies are needed to clarify the risks in eyes with good central vision. Two studies of transscleral laser cyclophotocoagulation had only 14% and 5% of such patients drop two lines or more, but further work is needed in this area.^9,10

Incisional surgery

Trabeculectomy remains widely performed, but more predictable IOP control and additional improvements to prevent complications are desirable. Ophthalmologists have improved the procedure with regard to smaller inner openings and tighter flap closure, but the biggest advance in this area has been achieved by modulating the wound-healing response with drugs such as corticosteroids, 5-fluorouracil, mitomycin C and tissue plasminogen activator. These advances have led to a higher success rate with trabeculectomy as well as better lowering of IOP, but the success rate of the procedure still does not approach 100%. Furthermore, a host of complications can still occur, including hypotony maculopathy, bleb dysesthesia, bleb leaks, blebitis and bleb-related endophthalmitis.

Progress in glaucoma treatments

Within the next 5 years, the role of aqueous shunts for glaucoma should become clearer as ophthalmologists get longer-term results from multicenter studies, including the Tube vs. Trabeculectomy Study, the 1-year findings of which (including a lower failure rate with aqueous shunts) have been provocative, and the Ahmed vs. Baerveldt Comparison study, recruitment for which has just been completed (Figure 2).^11,12 Progress in glaucoma treatments has no doubt moved more slowly than ophthalmologists had previously hoped, but there is reason for optimism. A blebless procedure that consistently achieves IOPs in the low teens has not yet been developed, but ophthalmologists continue to improve existing procedures and to develop better drugs and surgical methods for glaucoma treatment.

References

1. Ocular Hypertension Treatment Study Group, European Glaucoma Prevention Study Group. Validated prediction model for the development of primary open-angle glaucoma in individuals with ocular hypertension. Ophthalmology. 2007; 114:10-19.
2. Anderson DR, Drance SM, Schulzer M, et al. Factors that predict the benefit of lowering intraocular pressure in normal tension glaucoma. Am J Ophthalmol. 2003;136:820-829.
3. Novack GD. Update on new pharmaceutical products. Paper presented at: the American Academy of Ophthalmology and the American Glaucoma Society Glaucoma 2007 meeting: New Orleans, Louisiana, November 10, 2007.
4. The Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial: Results of argon laser trabeculoplasty versus topical medicine. Ophthalmology. 1990;97:1403-1413.
5. The Glaucoma Laser Trial Research Group. The Glaucoma Laser Trial and glaucoma laser trial follow-up study: Results. Am J Ophthalmol. 1995;120:718-731.
6. Lee R, Hutnik CM. Projected cost comparison of selective laser trabuculoplasty versus glaucoma medication in the Ontario Health Insurance Plan. Can J Ophthalmol. 2006;41:449-456.
7. Mackool RJ. Glaucoma treatment update: endoscopic ciliary body ablation. Ophthalmology Management. May, 2003.
8. Realini T (quoting Burke S). ECP¡¯s role in glaucoma management (in EyeWorld, June 2006; available at http://tinyurl.com/y2qrwc; accessed June 14, 2008).
9. Wilensky JT, Kammer J. Long-term visual outcome of transscleral laser cyclotherapy in eyes with ambulatory vision. Ophthalmology. 2004;111:1389-1392.
10. Egbert PR, Fladoyor S, Budenz DL, et al. Diode laser transscleral cyclophotocoagulation as a primary surgical treatment for primary open-angle glaucoma. Arch Ophthalmol. 2001;119:345-350.
11. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube versus Trabeculectomy Study after 1 year of follow-up. Am J Ophthalmol. 2007;143:9-22.
12. Gedde SJ, Herndon LW, Brandt JD. Surgical complications in the Tube versus Trabeculectomy Study during the first year of follow-up. Am J Ophthalmol. 2007;143:23-31.