Ischemia from Retinal Vascular Hypertension in Normal Tension Glaucoma: Neuroprotective Role of Folate

Abstract

Normal tension glaucoma is the most common form of glaucoma among people of Asian countries. While treatment to lower pressure in normal tension glaucoma is the standard of care, this is universally acknowledged as insufficient to the task. Recent evidence implicates ischemia and oxidative stress as key stressors of the optic nerve in normal tension glaucoma. Addressing ischemia and oxidative stress have been recommended as neuroprotective strategies. Elevated retinal venous pressure is found in normal tension glaucoma, and this venous hypertension is not adequately addressed with current medications. It increases resistance and reduces perfusion resulting in oxidative stress and localized ischemia. Elevated RVP appears to also be a factor in small vessel ischemia in diabetic retinopathy and macular degeneration.The cause of elevated retinal venous pressure is small vessel endotheliopathy. Endotheliopathic damage may be caused by derangement of methylation and B-vitamin metabolism, resulting in altered microcirculation. This metabolic derangement may be due to either dietary inadequacies, malabsorption, or genetic polymorphisms of the methylation pathways. Restoration of folate and B-12 plasma levels may be accomplished with supplementation using natural forms of these vitamins, specifically L-methylfolate and methylcobalamin. Use of oxidized folate (folic acid) penetrates the blood retinal barrier only after enzymatic converstion of the folic acid to methylfolate. Since there is a limited capacity for folic acid conversion, excess folic acid remains unmetabolized and impedes methylfolate absorption into the retina. Thus, successful nutritional supplementation must employ methylfolate and not folic acid. Such nutritional approaches are valuable adjuncts to standard ophthalmologic treatment, lowering retinal venous pressure and improving perfusion. Improved supply of micronutrients has implications for management of ischemic optic neuropathies, including normal tension glaucoma, nonarteritic ischemic optic neuropathy, and diabetic optic neuropathy and retinopathy.