May 2012
Volume 53, Issue 5
Articles  |   May 2012
Framing Glaucoma Questions: What are the Opportunities for Glaucoma Treatment? A Personal Perspective
Author Affiliations & Notes
  • David L. Epstein
    From the Duke Eye Center, Durham, North Carolina.
  • Corresponding author: David Epstein, Duke Eye Center, 2351 Erwin Road, DUMC 3802, Durham, NC 27710;
Investigative Ophthalmology & Visual Science May 2012, Vol.53, 2462-2463. doi:
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      David L. Epstein; Framing Glaucoma Questions: What are the Opportunities for Glaucoma Treatment? A Personal Perspective. Invest. Ophthalmol. Vis. Sci. 2012;53(5):2462-2463. doi:

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      © ARVO (1962-2015); The Authors (2016-present)

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More than 100 years ago, the treatment of glaucoma was among the most advanced of ophthalmology disciplines, encompassing both specific medical therapy (pilocarpine) and surgical therapy (filtration). 1 At that time, there were no specific treatments for retinal or corneal disease, and primitive techniques, such as couching, were being used for cataract surgery. A century later, however, the understanding of glaucoma and therapy for the disease seem to lag behind those in almost all other ophthalmology disciplines. 
Open-angle glaucoma is, in general, a disease of two tissues: the trabecular meshwork/Schlemm's canal conventional outflow system, which is responsible for intraocular pressure elevation, and the ganglion cells/axons/optic nerve complex, which is responsible for the visual loss in glaucoma. 2 Yet, there are no truly effective therapies for either of these two diseased tissues. 2 4 For example, prostaglandins target primarily the uveoscleral outflow pathway, 5,6 and β-blockers decrease inflow, acting at the ciliary body. 7,8 Although pilocarpine and similar “miotic” drugs can increase outflow, their effects are primarily on the ciliary muscle, increasing tension in the trabecular meshwork. 9 That is, there is no direct intrinsic effect on the conventional outflow pathway tissue. Although epinephrine-like compounds can increase conventional outflow facility, 10 its multiple effects on intraocular pressure are complex, 11,12 and there are many nonresponder patients. 13 Such compounds are no longer used to treat glaucoma. Rho kinase inhibitors are under study as novel drugs that target the conventional outflow pathway. 14  
A fundamental tenet of medicine is to identify diseased tissues and target them for specific therapy. 3 Unfortunately, in almost all forms of open-angle glaucoma, the true pathogenic mechanism in either tissue is not understood, and therefore no true disease targets for drugs have been identified. 2  
To make matters worse, early glaucoma is not detectable. 15,16 Further, although intraocular pressure is a very accurate measurement at one time point, a patient's integrated mean intraocular pressure (the equivalent of glycosylated hemoglobin in diabetes) between patient visits is unknown. 2 Finally, despite multiple methods and new technologies, progression of early glaucoma is not detectable with certainty. 17  
Primary open-angle glaucoma (POAG) is a diagnosis of exclusion, 2 rendered when a physician looks into the eyes of a patient with typically somewhat symmetrical bilateral disease and observes no specific abnormalities (e.g., no pigment accumulation or exfoliation). Most likely, there are also multiple subtypes of POAG, each with its own genetic and environmental components. After all, it usually takes decades to develop POAG, yet no subcategories have been established for what are likely multiple subtypes. 
Taking all these factors into account, a new paradigm shift is needed in therapy for glaucoma, from one of palliation to one of prevention and restoration. New advances in detection and treatment as outlined in the subsequent sections have the potential to bring about this shift. 
 Disclosure: D.L. Epstein, None
Duke-Elder WS . Textbook of Ophthalmology. St. Louis: C. V. Mosby Co; 1941:3280–3429.
Epstein DL Allingham RR Schuman JS , eds. Chandler and Grant's Glaucoma. 4th ed. Media, PA: Williams & Wilkins; 1997:3–6,120–129,137–182,183–234.
Epstein DL . Open angle glaucoma: why not a cure? (editorial). Arch Ophthalmol 1987;105(9):1187–1188. [CrossRef] [PubMed]
Epstein DL . Will there be a remedy to reverse the changes in the trabecular meshwork and the optic nerve?—a personal point-of-view on glaucoma therapy. J Glaucoma. 1993;2:138–140. [PubMed]
Gabelt BT Kaufman PL . The effect of prostaglandin F2 alpha on trabecular outflow facility in cynomolgus monkeys. Exp Eye Res. 1990;51(1):87–91. [CrossRef] [PubMed]
Toris CB Gabelt BT Kaufman PL . Update on the mechanism of action of topical prostaglandins for intraocular pressure reduction. Surv Ophthalmol. 2008;53(suppl 1):S107–S120. [CrossRef] [PubMed]
Coakes RL Brubaker RF . The mechanism of timolol in lowering intraocular pressure in the normal eye. Arch Ophthalmol. 1978;96:2045–2048. [CrossRef] [PubMed]
Yablonski ME Zimmerman TJ Waltman SR Becker B . A fluorophotometric study of the effect of topical timolol on aqueous humor dynamics. Exp Eye Res. 1978;27:135–142. [CrossRef] [PubMed]
Kaufman PL Barany EH . Loss of acute pilocarpine effect on outflow facility following surgical disinsertion and retrodisplacement of the ciliary muscle from the sclera spur in the cynomolgus monkey. Invest Ophthalmol Vis Sci. 1976;15:793.
Allen RC Epstein DL . Additive effect of betaxolol and epinephrine in primary open angle glaucoma. Arch Ophthalmol. 1986;104(8):1178–1184. [CrossRef] [PubMed]
Cyrlin MN Thomas JV Epstein DL . Additive effect of epinephrine to timolol therapy in primary open angle glaucoma. Arch Ophthalmol. 1982;100(3):414–418. [CrossRef] [PubMed]
Townsend DJ Brubaker RF . Immediate effect of epinephrine on aqueous formation in the normal human eye as measured by fluorophotometry. Invest Ophthalmol Vis Sci. 1980;19:259–269.
Alexander DW Berson FG Epstein DL . A clinical trial of timolol and epinephrine in the treatment of open angle glaucoma. Ophthalmology. 1988;95(2):247–251. [CrossRef] [PubMed]
Williams RD Novack GD van Haarlem T Kopczynski C . AR-12286 Phase 2A Study Group. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am J Ophthalmol. 2011;152(5):834–841. [CrossRef] [PubMed]
Quigley HA Green WR . The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology. 1979;86:1803–1827. [CrossRef] [PubMed]
Quigley HA Addicks EM Green WR Maumenee AE . Optic nerve damage in human glaucoma II: the site of injury and susceptibility to damage. Arch Ophthalmol. 1981;99:635–649. [CrossRef] [PubMed]
Leung CK Cheung CY Weinreb RN . Evaluation of retinal nerve fiber layer progression in glaucoma: a study on optical coherence tomography guided progression analysis. Invest Ophthalmol Vis Sci. 2010;51(1):217–222. [CrossRef] [PubMed]

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