| Summary: | 博士 === 國立臺灣大學 === 病理學研究所 === 106 === Pars plana vitrectomy (PPV) has been one of the major treatments for various complications of proliferative diabetic retinopathy (PDR). With modern instruments and techniques, the anatomical success rate has been quite high, ranging from 70% to 90%, depending upon the severity of the disease process. Post-operatively, about one third of successfully treated patients develop recurrent vitreous hemorrhage (VH). The bleeding may come from residual fibrovascular tissues or may be related to peripherally located postoperative neovascularization. Recurrent VH not only slows visual recovery but also jeopardizes an otherwise successful operation. Therefore, it is crucial to execution of proper preventive managements for reducing intra- and postoperative preretinal hemorrhage in complicated diabetic vitrectomy (DV). If recurrent vitreous hemorrhage occurs postoperatively, appropriate managements might induce regression of neovasculariation and reduce the possibility of repeated bleeding, thus shortening the reabsorption time and reducing the need for surgery. In our serial studies, we designed several clinical studies and developed some effective surgical methods including (1)intravitreal bevacizumab (1.25 mg) injection 1 week before surgery combined primary silicone oil infusion; (2) combination treatment of anterior retinal cryotherapy (ARC) & intravitreal bevacizumab injection (1.25 mg) and (3) repeated intravitreal bevacizumab injection for post-diabetic vitrectomy VH patients to prevent post-diabetic vitrectomy hemorrhage and to treat post-vitrectomy diabetic vitreous hemorrhage. Our results revealed that these methods were effective and safe for treating recurrent diabetic VH.
In PDR, diabetic fibrovascular proliferation (FVP) is unique for its complex vitreoretinal relationship, the frequent presence of epiretinal membrane (ERM) and the strong proinflammatory and pro-angiogenic environment might resulted in PDR.
ERM formation may occur in various clinical settings. It results from cellular proliferation along the surface of the retina, but the origin of these proliferating cells has been debated. Intraretinal glial cells, other retinal connective tissue cells, and even retinal pigment epithelial cells have been found in surgical specimens of ERM. The pathophysiology of ERM formation may vary widely in different disease conditions. In diabetic retinopathy, ERM may occur before surgery, or develop after successful vitrectomy. Specific features in the post-vitrectomized eye, such as ischemia, inflammation, hemorrhage, and residual fibrovascular membrane, may predispose the eye to ERM formation. To better understand the effect of the ERM on the macular structure and prognosis after its removal in eyes that have undergone DV, a retrospective study was conducted to evaluate the possible risk factors, morphological changes, visual function changes, and the surgical results of ERM after DV. In addition, immunohistochemical studies were performed in preretinal tissues to elucidate the nature of ERM formation after DV. Our results showed the post-DV ERM is a complex tissue with variable vascularity that often presents with widespread distribution, rapid progression, and causes macular distortion. Associated risk factors include active PDR, high FVP grade, post-DV hemorrhage, and residual fibrovascular stumps. Membrane removal surgery may be beneficial in selected cases, but recurrence is not uncommon.
The hyperglycemia that occurs in diabetes increases the production of reactive oxygen species (ROS) and depletes cellular antioxidant defense capacities, resulting in enhanced oxidative stress. Chronic oxidative stress is considered one of the primary causes of diabetic retinopathy. The retina has a high content of unsaturated fatty acids and high oxygen uptake, which increases lipid oxidation and ROS production. This is commonly thought to make the retina more vulnerable than any other tissue to oxidative stress damage.
Inflammation may also play a key role in the development and progression of diabetic retinopathy. ROS are strong stimulators of the transcription factor nuclear factor kappa B (NF-κB), which increases the transcription of inflammatory cytokines and chemokines as well as enzymes responsible for nitric oxide and prostaglandin E2 synthesis. All of these factors are involved in the pathogenesis of diabetic retinopathy. Antioxidants have long been known to inhibit inflammatory responses. In animal models of diabetic retinopathy, antioxidants inhibit NF-κB activity, and reduce leukostasis and leukocyte expression of inducible nitric oxide synthase. Moreover, antioxidants can inhibit the formation of cell-free capillaries and generation of pericyte ghosts in diabetic rats. In addition, antioxidants inhibit the formation of ROS and increase the capabilities of the antioxidant defense enzyme system. Therefore, antioxidants might diminish the biologic damage of oxidative stress in the retina, abate the level of inflammation, and arrest the progression of diabetic retinopathy.
Astaxanthin (AST) and lutein both are from the xanthophyll family of hydroxycarotenoids which contain several double bonds. They could scavenge ROS to be powerful biological antioxidants and anti-inflammatory agents. AST is a more potent antioxidant than other carotenoids, including lutein, β-carotene, canthaxanthin, and zeaxanthin. In our study, we proved the xanthophyll carotenoid AST had neuroprotective effects and would reduce ocular oxidative stress, and inflammation in the STZ diabetic rat model, which might be mediated by downregulation of NF-κB activity.
Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor which has been shown to increase intracellular cyclic adenosine monophosphate levels and then decrease intracellular Ca2+ levels in platelets, resulting in inhibition of platelet aggregation and vasodilation leading to a reduction in arterial pressure. It has been shown to reduce inflammation and improve microcirculation to achieve neuroprotective effects in the retina by inhibiting tumor necrosis factor alpha (TNFα)-induced NF-κB activation and proinflammatory gene expressions.
In our study series, we initially developed new surgical techniques according to the pathogenesis of PDR to treat diabetic vitreous hemorrhage. Subsequently, we studied the unique histopathological features of PDR by histologic sections. In the latest study, we applied AST and cilostazol, both are potent antioxidants, to prevent diabetic retinopathy progressing and to preserve ocular functions.
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