The usual topics were covered at Subspecialty Day this year. Below are highlighted some of the discussions that provided new conclusions and thoughts.
Highlights on the intraocular pressure (IOP) discussion:
A complex relationship exists between IOP, central corneal thickness (CCT), and corneal material properties. All forms of IOP measurement involve some degree of corneal deformation. A stiffer, thicker, steeper cornea is more difficult to deform which will lead to greater error in the IOP measurement. Corneal stiffness is described using the material property terms, modulus of elasticity (Young’s modulus) and viscoelasticity. It turns out that the cornea’s modulus of elasticity and viscoelasticity may dwarf the effects of central corneal thickness when it comes to estimating actual IOP. Unfortunately, we do not know the values for these measures in the human cornea, although we do know that the values are not static, creating an even more complex situation. For example, the cornea’s stiffness can change with increasing degrees of deformation, increasing IOP, and with age. Given all these unknown variables, it is nearly impossible to measure the true intraocular pressure and to devise a conversion factor. Non-contact tonometry is most affected by biomechanical resistance, followed by Goldmann applanation tonometry, and then Dynamic Contour Tonometry. A side note is that people are looking into associations between corneal biomechanical properties and glaucoma risk, because perhaps a flimsy cornea reflects a flimsy lamina cribrosa and susceptibility to nerve damage.
Jamie Brandt, M.D. nicely summarized our current state of interpreting IOP levels. He noted that it is not worth adjusting IOP for central corneal thickness (CCT). Doing so would be correcting a measurement that is inherently imprecise—a correction factor won’t get you a more accurate number—and the impact of CCT is probably less than we think as we now better understand the effect of the cornea’s material properties. Also, a single IOP measurement is a random single sample in a chronic and dynamic disease. His advice is to recognize the cornea as being thin or thick and not to over interpret or overly depend on single IOP measurements because being more precise is not supported by data.
IOP fluctuation as an independent risk factor for glaucoma was also heavily debated. Dr. Joe Caprioli, MD offered one interpretation of the existing literature. He pointed out that whether or not IOP fluctuation is an independent risk factor depends on the population being studied. Fluctuation did not appear to be significant in the Ocular Hypertension Treatment Study (OHTS), European Glaucoma Prevention Study (EGPS), or Early Manifest Glaucoma Trial (EMGT), studies in which glaucoma was in an early stage of development and IOPs were high; here the data suggest that mean IOP is the predominant risk factor. Data do suggest that IOP fluctuation is damaging in patients with low IOP, such as in the Advanced Glaucoma Intervention Study (AGIS), Collaborative Initial Glaucoma Treatment Study (CIGTS), and in a study by Hong et al. (in press, Archives Ophthalmology 2007). In these studies patients have moderate to advanced glaucoma and low, treated IOPs. Therefore, there may be different risk at different points along the glaucoma continuum.
Highlights on new pharmaceutical products discussed:
A summary of pharmaceutical products in development/trials for possible future use was given. Unfortunately, the information was limited. Many compounds with various mechanisms of action are being studied but the information is not public knowledge at this time.
A new class of agents being investigated for use by a number of companies is the Rho-kinase (ROCK) inhibitors. Rho-kinase has been identified as an important therapeutic target in cardiovascular medicine and appears to have applications in glaucoma, as well. Rho-kinase (ROCK) is one of the downstream effectors of a small G-protein Rho. The Rho–ROCK pathway has an important role in mediating various cellular functions, including contraction, actin cytoskeleton organization, cell adhesion and motility, proliferation, cytokinesis and gene expression. In preliminary animal ocular studies it appears to increase outflow by widening extracellular spaces.
There are also new developments in the steroid arena. Anecortave acetate is a cortisene, and lacks the usual anti-inflammatory and immunosuppressive properties of glucocorticoids. In a case series the drug was shown to have a sustained IOP-lowering effect when given via a subtenon/anterior juxtascleral injection; further study is needed. Mifepristone (RU486) is also being studied to treat corticosteroid-induced glaucoma.
In the world of neuroprotection, Allergan’s investigation of oral memantine is undergoing analysis. However, the “functional measure chosen as the primary endpoint did not show a benefit of memantine preserving visual function.” A company called Neurotech has a core technology platform called Encapsulated Cell Technology (ECT). The current product is 6 mm in length and consists of genetically modified human cells packaged in a semi-permeable hollow fiber membrane with a suture loop at one end to anchor the implant to the sclera. The intravitreal implant allows for long-term, sustained delivery of therapeutic growth factors.
Other news is the development of new prostaglandin agents that will have greater selectivity and potency. New combination products are being launched. Outside the U.S. each of the prostaglandin analogues are available in combination with a beta-blocker. In the U.S. we now have a new brimonidine/timolol combination, as well as the well-known dorzolamide/timolol combo product. There are substantial regulatory hurdles for getting these combination agents approved (USFDA combination policy, 21 CFR 300.50), and therefore it is not expected that other products will be available in the U.S. any time soon.
Highlights from an update of major clinical trials:
AGIS, Advanced Glaucoma Intervention Study—It was reported that 33% of patients lost an important amount of visual function over 10 years of follow-up. Low IOP helped decrease progression, but not completely. In 10 years, loss of visual field or acuity to a level approximating the definition of legal blindness, occurred in 10-15% of eyes and was not statistically significantly different for either the ATT (argon trabeculoplasty first followed by a trabeculectomy followed by another trabeculectomy) or TAT (trabeculectomy first followed by argon trabeculoplasty followed by trabeculectomy) sequence in either race group (White or Black).
CIGTS, Collaborative Initial Glaucoma Treatment Study—At 5 years, there was no difference between the surgical and medical groups, so it is acceptable to offer trabeculectomy as a first-line treatment option when a patient’s preference is to avoid laser/drops. For patients with advanced visual field loss at baseline, progression was less in the surgical group, so initial surgery is an attractive option in patients with advanced disease. On average, neither surgery nor medical treatment groups progressed substantially during 5 years of f/u, indicating that aggressive IOP lowering (35-50%) is successful in halting or dramatically slowing damage.
OHTS, Ocular Hypertension Treatment Study—Clinicians detected only 16% of the disc hemorrhages detected by the optic disc reading center. Occurrence of disk hemorrhage increased the risk of developing POAG; however, 87% of OHTS participants with hemorrhages did not develop POAG during the study follow-up. Thinner corneas tend to show a greater apparent IOP reduction after initiating drops, and blacks and whites respond similarly to beta-blockers and prostaglandin analogues.
EGPS, European Glaucoma Prevention Study—Investigators found that the use of systemic diuretics for systemic hypertension treatment may be important in the development of POAG. More study is necessary.
EMGT, Early Manifest Glaucoma Treatment—Statistical analyses shows that cardiovascular history and thin CCT are important risk factors in high IOP glaucoma. Low blood pressure may be an important risk factor in normal tension glaucoma.
TVT, Trabeculectomy versus Tube Shunt Trial—Patients treated with trabeculectomy with mitomycin-C used less supplemental medication to achieve IOP control, but those with tube shunts were more likely to maintain IOP control and avoid persistent hypotony. The incidence of serious complications resulting in reoperation or vision loss occurred with similar frequency in both groups, but the incidence of other postoperative complications was higher in the trabeculectomy with MMC group. Clear superiority was not demonstrated for one surgery over another, but the study suggests that tube shunts do not have to be reserved for refractory glaucomas.
Highlights from the multifocal lens debate:
Patients with moderate and advanced glaucomatous visual loss may not be good candidates for such lenses. Multifocal IOLs affect contrast sensitivity. Glaucoma patients already have decreased contrast sensitivity. To date, there really isn’t any literature on the influence of multifocal IOLs on contrast sensitivity in glaucoma. Patients with glaucoma may already feel uncomfortable with their night vision, and multifocal IOLs may further limit this vision. These patients should receive an IOL that maximizes their visual quality. Aspheric IOLs may be more appropriate.
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