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D. R. Markle, R. Zuckerman; Non-Invasive Fluorescence Anisotropy Imaging: A Rationale Means of Directing Panretinal Photocoagulation and Early Detection of Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2256.
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Tissue hypoxia has long been proposed to be the first stage stimulus for neovascularization through the VEGF pathway. And the beneficial effects of panretinal photocoagulation (PRP) are thought to be derived from relieving the hypoxic stimulus1,2. However, PRP involves surgical ablation of photoreceptors that cause loss of peripheral vision. A non-invasive method that could detect hypoxic regions would not only lead to early detection but could be used to direct laser burns to hypoxic regions while avoiding areas that are metabolically normal, thereby reducing peripheral vision loss. The Biometric Imaging Metabolic Mapper (Zuckerman et al., IOVS, 46: 4759, 2005; Zuckerman, IOVS, 47: 3344, 2006) is the first noninvasive technology capable of probing tissue hypoxia in space, time and depth in the living human eye. We therefore searched for the metabolic consequences of diabetes in select patients and normal control subjects before conducting formal clinical trials.
Mitochondrial flavoprotein fluorescence anisotropy was mapped in the temporal retinas of patients with NPDR, mild PDR and age-and gender-matched controls as well in a few diabetic patients without frank retinopathy. Patients were staged by color fundus photography and fluorescein angiography following accepted norms.
In patients with PDR in whom PRP was performed we measured the level of tissue oxygenation over laser burns and found tissue oxygenation to be significantly elevated (P< 0.001). Metabolism prior to neovascularization in NPDR was depressed by 7.5 +/- 1.1% in room air and by 11.1 +/- 2.5% during 100% O2 inspiration, P<0.0001. Mild PDR revealed massive depression of metabolism (64 +/- 7.5%, P=0.0007). Moreover, capillary dropout was revealed as a widening of frequency histograms of NPDR and PDR patients. One of five diabetic patients (duration of diabetes ≈ 10 yrs) without frank retinopathy showed depression of metabolism in the absence of any visual sign of disease.
Metabolic mapping provided the first evidence that hypoxia precedes neovascularization in diabetic retinopathy thereby fulfilling one necessary condition to accept the hypothesis that tissue hypoxia upregulates genes that express VEGF in DR. Metabolic mapping proved to be a highly sensitive, spatially discriminative technique that may be used for early detection and guiding laser treatment in real time in patients with diabetic retinopathy.1. Zuckerman R, Weiter J., Exp Eye Res 1980;30:117-27.2. Weiter J, Zuckerman R., Ophthalmology 1980;87:1133-39.
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