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EW GLAUCOMA 40 July 2015 by Tony Realini, MD, MPH, EyeWorld Contributing Writer growth and survival of nerve cells. In one phase 1 trial, 11 patients with bilateral POAG received the implant in one eye and continued their IOP-lowering therapy in both eyes. While both implanted and control eyes maintained comparable IOP control, the implanted eye mani- fested improvements in visual field status, nerve fiber layer thickness on OCT, and contrast sensitivity com- pared to untreated fellow eyes. "Results of these early phase studies are suggestive of biological activity with corresponding chang- es in structure and function," Dr. Goldberg said. Clinical implications In addition to the innovative discoveries described above, there are some current IOP-independent interventions that can be offered for some of our patients with glaucoma. "We know from various studies that obstructive sleep apnea (OSA) is a risk factor for glaucoma," Dr. Wax said. Patients with OSA can greatly benefit from weight loss—either through diet and exercise or bariat- ric surgery—and in some cases from don't know the ideal target IOP for patients. Some get worse despite IOP reduction. Adherence also limits the therapeutic benefits," Dr. Quigley said. Ideally, we could develop a neuroprotective agent that works independently of IOP reduction. Un- fortunately, failure to demonstrate a neuroprotective effect of the oral Alzheimer's drug memantine in a pair of long and expensive glaucoma clinical trials dampened enthusiasm and support for neuroprotection research. Despite this, Dr. Quigley remains optimistic about neuropro- tection. A more realistic shorter-term goal might be neuroenhancement, said Jeffrey Goldberg, MD, PhD, Stanford University, Palo Alto, Calif. "Neuroenhancement is the concept of supporting injured RGCs and en- hancing their function before they die," he explained. Neuroenhancement therapies are currently in early-phase hu- man trials, he said. One promising potential therapy is an implant that provides sustained delivery of ciliary neurotrophic factor (CNTF), a growth factor known to promote the therapies to treat or prevent cardi- ac and/or cerebrovascular events. These systemic therapies—such as lipid-lowering agents and blood pressure medications—may play a role in reducing glaucoma risk, Dr. Wax said. "In addition, we have known for years that our glaucoma patients with peripheral vasospasm can benefit from treatment with oral calcium channel blockers." Inflammatory factors "The exact mechanism of retinal ganglion cell death in glaucoma is unclear," said Stuart McKinnon, MD, Duke University, Durham, N.C. One of the many processes likely to be involved is neuroinflammation. The retina is an immune-privileged site, he explained, and inflammation should not occur in the retina or elsewhere in the CNS. However, in animal models and in human glau- coma, evidence is mounting that neuroinflammation may play a role in the process. Key mediators of inflamma- tion—including complement, heat shock protein, and tumor necrosis factor, among others—are activated or upregulated in human eyes with glaucoma. "The potential triggers for these responses may be age-related or attributable to disease-related stress or injury," he said. When better understood, these process may represent novel thera- peutic targets for glaucoma therapy, he added. Fortifying the optic nerve "Glaucoma is a frustrating disease from the standpoint of designing interventional clinical trials," said Harry Quigley, MD, Johns Hopkins University, Baltimore. "The slow rate of glaucoma progression necessi- tates long, expensive trials when the endpoint is a reduction in the rate of disease progression." Considered a holy grail of glau- coma therapy, neuroprotection— treatment given prophylactically to render the optic nerve impervious to damage from a variety of insults— has remained elusive in clinical research. IOP reduction can be considered a form of neuroprotection, but its protective effects are limited. "We Will IOP reduction remain our primary approach? P rimary open-angle glau- coma is considered to be a primary optic neuropa- thy with a multifactorial pathogenesis. Of the many factors associated with the glaucoma disease process, IOP gets most of the attention. IOP is the only modifi- able risk factor for glaucoma, and IOP reduction is the only therapy proven to reduce the risk of both the development and progression of glaucoma at all levels of IOP. Even in normal tension glauco- ma, where elevated IOP is absent, evidence still supports the role of IOP in the disease process. "Elevated IOP is a known risk factor for diagnosis and progression of optic nerve damage and visual field loss even in the normal range of IOP," said Martin Wax, MD, Far Hills, N.J. "But glaucoma is mul- tifactorial and IOP is only one of the factors. Some patients have an IOP-independent component." "In eyes with low IOP," said Robert N. Weinreb, MD, Univer- sity of California, San Diego, "the IOP-independent factors may play a relatively larger role." What are some of these non- IOP factors, and how close are we to developing new strategies for glaucoma therapy? Vascular factors The relative roles of mechanical and ischemic damage to the optic nerve have been discussed by proponents on both sides for decades. Does cupping arise from the mechanical forces attributable to elevated IOP or to ischemia related to impairment of the relevant ocular vascular beds? Both are likely to contribute to the glaucomatous process. "There are many aspects of endothelial cell function that are ab- normal in both normal tension and high tension glaucoma," said Louis Pasquale, MD, Harvard University, Boston. "Vascular and autoregu- latory dysfunction are common both inside and outside the eye in glaucoma." Many patients with vascular risk factors are already receiving systemic How will glaucoma treatment change into the future? continued on page 42 One hypothesis is that POAG is categorized by impaired signaling between: a) the inner wall of Schlemm's canal endothelial cells as well as endothelial cells located in the ciliary body and the posterior longitudinal muscle that helps to set outflow resistance, and b) the ocular vascular endothelial cell and underlying luminal smooth muscle for vessels that supply the retinal ganglion cells. This hypothesis could explain why POAG can occur across the spectrum of IOP. Source: Louis Pasquale, MD The ocular endothelial cell dysfunction hypothesis in primary open-angle glaucoma Normal endothelial cell relaxation: Abnormal endothelial cell relaxation: Relaxed posterior longitudinal muscle Constricted posterior longitudinal muscle

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