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    POAG: Enigmatic group of heterogenous diseases?

    Recognition of differences among subtypes may facilitate diagnosis, management


    Recognizing puzzle pieces

    Paracentral OAG

    Dr. Pasquale reported two patients, a father and daughter, who had advanced high-tension glaucoma with untreated IOP of 24 mm Hg upon referral and normal-tension glaucoma with IOP of 18 mm Hg and a hemorrhage on the left optic nerve, respectively. Dr. Pasquale suggested the situation with these related patients has more to do with the genetics of the underlying disease process than with IOP itself.

    Over a 17-year period, the daughter’s glaucoma progressed. A paracentral scotoma in the left eye had advanced. A disc hemorrhage developed later in the right eye, as did a paracentral scotoma despite maximal medical therapy and laser trabeculoplasties.

    “We have to recognize this scenario as a separate entity that is attacking the central vision,” he said. “This is paracentral OAG (PCOAG) and it should be treated as a separate entity.”

    This disease variation is characterized by an optic nerve biomarker in many patients, i.e., a triangular defect in the prelaminar nerve fiber layer.

    In addition, the maximal IOP values in these patients are lower (21 ± 4.5 mm Hg) than in isolated nasal step patients (Park et al. Ophthalmology. 2011;118:1782-1789), according to Dr. Pasquale. The standard deviation indicates that a substantial number of patients had normal IOP, considered as normal-tension glaucoma, and a subset with higher IOP, i.e., high-tension glaucoma.

    “This demonstrates that the stratification by IOP is not serving us well,” he said.

    A second structural biomarker of PCOAG is frequent disc hemorrhages, as well as more hypotension, Raynaud’s phenomenon, and sleep apnea. Another genetic finding in patients with PCOAG is that the caveolin 1/caveolin 2 region contains genome-wide markers for elevated IOP and POAG.

    “When POAG patients are stratified by paracentral loss versus isolated peripheral loss, a stronger association is seen for the top genetic markers with the paracentral cases than with the peripheral loss cases,” he said.

    The caveolin region is important in PCOAG because it is adjacent to endothelial nitric oxide synthase (eNOS) in the membranes, and both regulate nitric oxide production.

    Interestingly, if eNOS is knocked out in a murine model, elevated IOP and reduced outflow facility ensue, according to Dr. Pasquale.

    “Nitric oxide signaling is important for regulating IOP,” he said.

    Recognition of this mechanism is resulting in development of drugs that are nitric oxide donators and those that are rho-kinase inhibitors. These drugs improve endothelial cell signaling by enhancing smooth muscle cell relaxation and might hold promise for PCOAG, he noted.

    Changes in diet--specifically, the addition of vegetable nitrates, a source of nitric oxide—also might help patients with PCOAG by modifying the disease risk (Kang et al. JAMA Ophthalmol. 2016;134:294-303).

    “We found that compared with people who were consuming the lowest quantities of nitrates from vegetables, those with the highest [vegetable consumption] had about a 44% reduction in the risk of PCOAG,” Dr. Pasquale said.

    Clinically, he advised the target IOP in these patients should be low, perhaps less than 10 mm Hg, but certainly below 16 mm Hg.

    African-derived OAG

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