摘要
目的
以渗出型年龄相关性黄斑变性(AMD)为重点，从分析脉络膜新生血管(CNV)在光学相干断层成像(OCT)、眼底荧光造影(FA)和吲哚菁绿脉络膜造影上的特征入手，探讨与之相关的色素上皮(RPE)形态改变对疾病临床转归的影响。
资料和方法
1．描述2000年10月～2003年12月就诊于解放军总医院眼科的233例黄斑区CNV患者的概况：分析OCT在揭示与CNV相关的RPE形态学改变方面的优势。
2．选取做过OCT检查的渗出型AMD140人171只眼，应用Osiris医学图像分析软件测量其中存在色素上皮脱离(PED)的113只患眼的PED的角度、高度和基底直径，分析PED形态与RPE裂孔发生的关系。
3．选取所有做过OCT的黄斑区CNV患者，包括渗出型AMD 140人171只眼和非AMD62人74只眼，对比分析CNV类型及其相应的RPE形态学改变与黄斑囊样水肿(CME)的关系。
4．选取同期做过OCT和眼底造影检查的黄斑区CNV患者，包括渗出型AMD73人83只眼，非AMD37人40只眼，分析视网膜-脉络膜血管吻合(RCA)形成与PED的关系；再选取同期做过OCT和同步FA／ICGA检查的、处于病变活动期的渗出型AMD患者40人43只眼，分析其视网膜下新牛血管(SRN)的起源。
结果
1．黄斑区CNV患者中渗出型AMD占绝大多数(69.10％)，其余依次足中渗(17.60％)、病理性近视(8.15％)、脉络膜炎(3.86％)、脉络膜
军医进修学院临床医学博士学位论文
中文摘要
裂伤(0.86%)和血管样纹(0.43%)。渗出型AMD患者以男性明显
居多(>2:1)，男性患者的平均年龄显著高女性(尸二0.0013);渗出型
AMD患眼PED的发生率(77.93%)显著高于非AMD的CNV患眼
(39.62%)，而且，其PED的高度和基底直径(0 .30士o.20mm和2.02
士l.23mm)也显著高于非AMD的CNV患眼(0.21士0.lmm和0.99
士0.34mm)。
渗出型AMD患眼的PED裂孔最多见于PED的边缘(69.12%)，有裂
孔发生的PED的角度和高度显著大于无裂孔者，而且以裂孔发生在
边缘的PED的角度和高度更大。
渗出型AMD患眼黄斑囊样水肿(CME)的发生率(52.05%)显著高
于非AMD的CNV患眼(24.32%);处于AMD病变活动期的CME
患眼多为结合型CNV(76.32%)和GassZ型CNV(18.42%)，而无
CME的AMD患眼多为Gassl型CNV(82.61%)，统计学上差异显著
(P=0 .0000)。
渗出型AMD患眼中45.33%有RCA形成，其中参与RCA形成的视
网膜血管以小静脉居多;与无RCA患眼相比，PED裂孔明显多见于
RCA患眼(分别为51 .52%和88.67%，尸二0.0030):AMD患眼的RCA
发生率显著高于非AMD的CNV患眼(15%，尸荀.0010);RCA患眼
新生血管复合体的主体起源于脉络膜。
结论
1.渗出型AMD患者男性居多与就诊人群中军人比例高相关，多数女性
患病较早可能与更年期后体内性激素水平失衡相关:OCT在早期发现
与CNV相关的RPE断面结构改变上具有优势。
2.渗出型AMD患眼PED边缘裂孔的发生与PED的角度和高度呈正相
关，其中与角度的关系更为密切;OCT在早期发现和随访PED微裂
军医进修学院临床医学博士学位论文
中文摘要
孔方面具有优势。
3侵入视网膜感觉层下生长的CNV不断渗出、出血是导致黄斑囊样水
肿形成的直接原因。但是，与RPE断裂相关的外血一视网膜屏障破坏，
尤其是RPE细胞本身的功能减退可能是CNV最终能导致黄斑囊样水
肿形成且持续时间较长的根源。
4 RCA形成在临床上并不少见，尤其多见于渗出型AMD，虽然多与PED
并存，但是，两者之间无直接的因果关系;PED裂孔发生与RCA形
成密切相关，RPE细胞功能减退以及即E裂孔形成引起的视网膜感
觉层下色素上皮衍生因子(PEDF)与血管内皮生长因子(VEGF)比
例失衡很可能是RCA更多见于渗出型AMD的根本原因;视网膜血
管参与RCA形成可能只是一个继发的过程。
Objectives
To analyze the effects of the morphological changes of retinal pigment epithelium (RPE) on the outcome of choroidal neovascularization (CNV), with highlight on exudative age-related macular degeneration (AMD), by means of evaluating the characteristics of CNV on optical coherence tomography (OCX), fluorecein angiography and indocyanine green angiography. Material and methods
1. The general profile of 233 consecutive patients with CNV examined at the Ophthalmic Department of the PLA General Hospital between October 2000 and December 2003 was described. The advantages of OCT in disclosing the morphological changes of RPE associated with CNV were evaluated.
2. One hundred and seventy-one eyes of 140 exudative AMD patients underwent OCT examination were selected, with 113 eyes presented with pigment epithelium detachment (PED). Osiris medical imaging software (version 4.18) was used to measure the angle, height and base diameter of PED. The relationship between the morphology of PED and the evolution of RPE tear was evaluated.
3. Patients underwent OCT examination were all selected, including 171 eyes of 140 patients with exudative AMD and 74 eyes of 62 patients with CNV secondary to non-AMD. The correlation between the types of CNV, the morphological changes of RPE and the development of cystoid macular edema (CME) was analyzed.
4. Patients underwent both OCT and fluorecein angiography (FA) examinations were selected, including 83 eyes of 73 patients with exudative AMD and 47 eyes of 40 patients with CNV secondary to non-AMD. The correlation between Retinal-Choroidal Anastomosis (RCA) and FED was evaluated. Forty-three eyes of 40 patients with active AMD lesions underwent OCT and simultaneous fluorescein and indocyanine green angiography (FA/ICGA) examinations were further investigated for the sources of subretinal neovascularization. Results
1. The majority of patients with CNV were secondary to exudative AMD (69.10%); the minority was associated with CEC (17.60%), pathologic myopia (8.15%), choroiditis (3.86%), choroidal rupture (0.86%) and angiod streaks (0.43%) in descending order. Men with exudative AMD were more than two times as much as women, and the mean age of men was significantly older than women (P=0.0013). FED was much more common in exudative AMD than in non-AMD (77.93% versus 39.62%). The height and base diameter of FED associated with AMD (0.30 ± 0.20mm and 2.02±1.23mm) were significantly greater than that of non-AMD(0.21 ± 0.1 mm and 0.99 ± 0.34mm).
2. FED tear associated with exudative AMD occurred more often at the edge (69.12%). Compared with FED without tear, FED with tear had significantly larger angle and higher height. FED with marginal tear showed even larger angle and higher height as compared with FED with non-marginal tear.
3. The incidence of CME was significantly higher in exudative AMD than in
non-AMD (52.05% versus 24.32%). In the active phase of exudative AMD, most of eyes with CME had either a combined CNV complex (76.32%) or a Gass 2 type CNV (18.42%), whereas, most of eyes without CME had Gass 1 type CNV (82.61%). The difference was statistically significant CP=0.0000).
4. Forty-five point thirty-three percent of eyes with exudative AMD were found to have RCA; most of the anastomotic connection involved the retinal vein. Compared with eyes without RCA, FED tear was a more common sign in eyes with RCA (88.67% versus 51.52%, P=0.0030). The incidence of RCA formation was significantly higher in AMD than in non-AMD (45.33% versus 15%, P=0.0010). Eyes with RCA had their main portion of neovascular complex originated from choroid. Conclusions
1. The higher proportion of old army men in this series was the reason for men with exudative AMD outnumbered women. It might be associated with imbalance of sex hormone after menopause for most women suffered from exudative AMD earlier than men. OCT is superior in visualizing the early structural changes of RPE associated with CNV.
2. The occurrence of marginal FED tear associate
引文
1. Ergun E, Maar N, Radner W, et al. Scotoma size and reading speed in patients with subfoveal occult choroidal neovascularization in age-related macular degeneration. Ophthalmology 2003; 110: 65-69.
2. Borger PH, yon Leeuwen R, Hulsman CAA, et al. Is there a direct association between age-related eye diseases and mortality? Ophthalmology 2003; 110: 1292-1296.
3. Brown MM, Brown GC, Sharma S, et al. Quality of life associated with visual loss. Ophthalmology 2003; 110: 1076-1081.
4. Gass JDM. Update Clinicopathological Classification of Subretinal Neovascularization. American Society of Retina Specialists Online Journal [serial online] Jan 2003-[cited 2003 May 26; 3(1)[98 screens].
5. Thylefors B. A global initiative for the elimination of avoidable blindness. Am J Ophthalmol. 1998; 125: 90-93.
6. Evans JR. Risk factors for age-related macular degeneration. Prog Retinal Eye Res. 2001; 20: 227-253.
7. Treatment of age-related macular degeneration with photodynamic therapy and verteporfin in photodynamic therapy study groups. Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report No. 1. Am J Ophthalmol 2003; 136: 407-418.
8. Bressler NM, Bressler SB, Gragoudas ES. Clinical characteristics of choroidal neovascular membranes. Arch Ophthalmol 1987; 105: 209-213.
9. Fine SL. Early detection of extrafoveal neovascular membranes by daily
central field evaluation. Ophthalmology 1985; 92: 603-609.
10. Holz FG, Jorzik J, Schutt F, et al. Agreement among ophthalmologists in evaluation fluorescein angiograms in patients with neovascular age-related macular degeneration for photodynamic therapy eligibility (FLAP-Study). Ophthalmology 2003; 110: 400-405.
11. Gass JD. Biomicroscopic and histologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. Am J Ophthalmol 1994; 118: 285-298.
12. Age-Related Eye Disease Study Group. Age-Related Eye Disease Study (AREDS) phase Ⅱ manual of operations. Potomac, MD; EMMES Corp, 1992.
13. Haffner SM, Newcomb PA, Marcus PM, et al. Relation of sex hormones and dehydroepiandrosterone sulfate(DHEA-SO4) to cardiovascular risk factors in postmenopausal women. Am J Epidemiol 1995; 142: 925-934.
14. Gordon T, Karmel WB, Hjortland MC, et al. Menopause and coronary heart disease: the Framingham Study. Ann Int Med 1978; 89: 157-161.
15. Stampfer MJ, Colditz GA, Willett WC, et al. Postmenopausal oestrogen therapy and cardiovascular disease: 10-year follow-up from the nurses' health study. N Engl J Med 1991; 325: 756-762.
16. Centofanti M, Zarfati D, Manni GL, et al. The influence of oestrogen on the pulsatile ocular blood flow. Acta Ophthalmol Scand 2000; 232: 38-39.
17. Toker E, Yenice O, Akpinar I, et al. The influence of sex hormones on ocular blood flow in women. Acta Ophthalmol Scand 2003; 81: 617-624.
18. Friedman E. A hemodynamic model of the pathogenesis of age-related macular degeneration. Am J Ophthalmol 1997 124: 677-682.
19. Friedman E, Krupsky S, Lane A, et al. Ocular blood flow velocity in
age-related macular degeneration. Ophthalmology 1995 102: 640-646.
20. Piguet B, Palmvang IB, Chisholm IH, et al. Evolution of age-related macular degeneration with choroidal perfusion abnormality. Am J Ophthalmol 1992; 113: 657-663.
21. Green GL, Gilna P, Waterfield M, et al. Sequence and expression of human estrogen receptor complementary DNA. Science. 1986; 231: 1150-1154.
22. White R, Less JA, Needham M, et al. Structural organization and expression of the mouse estrogen receptor. Mol Endocrinol. 1987; 1: 744-745.
23. Enmark E, Pelto-Huikko M, Gustafsson JA. Human estrogen receptor β-gene structure, chromosomal localization, and expression pattern. J Clin Endocrinol Metab. 1997; 82: 4258-4265.
24. Tremblay GB, Tremblay A, Copeland NG, et al. Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor β. Mol Endocrinol. 1997; 11: 353-365.
25. Munaut C, Lambert V, Noel A, et al. Presence of estrogen receptor type β in human retina. Br J Ophthalmol. 2001; 85: 877-882.
26. Marin-Castao ME, Elliot SJ, Potier M, et al. Regulation of estrogen receptors and MMP-2 expression by estrogens in human retinal pigment epithelium. Invest Ophthalmol Vis Sci. 2003; 44: 50-59.
27. Atkinson SJ, Patterson MI, Butler MJ, et al. Membrane type 1 matrix metalloproteinase and gelatinase A synergistically degrade type 1 collagen in a cell model. FEBS Lett. 2001; 491: 222-226.
28. Deryugina EI, Bourdon MA, Reisfeld RA, et al. Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix melalloproteinase-2. Cancer Res. 1998; 58: 3743-3750.
29. Zhuge Y, Xu J. Racl mediates type Ⅰ collagen-dependent MMP-2 activation: role in cell invasion across collagen barrier. J Biol Chem. 2001; 276: 16248-16256.
30. Cousins SW, Marin-Castafio ME, Espinosa-Heidmann DG, et al. Female gender, estrogen loss, and sub-RPE deposit formation in aged mice. Invest Ophthalmol Vis Sci. 2003; 44: 1221-1229.
31. VanNewkirk MR, Nanjan MB, Wang JJ, et al. The prevalence of age-related maculopathy: the visual impairment project. Ophthalmology. 2000; 107(8): 1593-600.
32. Vingerling JR, Dielemans I, Witteman JCM, et al. Macular degeneration and menopause: a case-control study. BMJ, 1995; 310: 1570-1571.
33. Eye Disease Case-Control Study Group. Risks factors for age-related macular degeneration. Arch Opthalmol, 1992; 110: 1701-1708.
34. Huang D, Swasson EA, Lin CP, et al. Optical coherence tomography. Science 1991; 254: 1178-1181.
35. Hee MR, Puliafito GA, Wong C, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995; 113: 1019-1029.
36. Hee MR, Iaztt JA, Swanson EA, et al. Optical coherence tomography of the human retina. Arch Ophthalmol 1995; 113: 325-332.
37. Iida T, Hagimura N, Sato T, et al. Optical coherence tomographic features of idiopathic submacular choroidai neovascularization. Am J Ophthalmol,2000,130: 763-768,
38. Brancato R, Introini U, Pierro L, et al. Optical coherence tomography (OCT)angiomatous prolifieration(RAP) in retinal. Eur J Ophthalmol.
2002; 12(6): 467-72.
39. Green WR, McDonnel PJ, Yeo JH. Pathological features of senile macular degeneration. Ophthalmology. 1985: 92: 615-627.
40. Gass JDM. Stereoscopic Atlas of Macular diseases: Diagnosis and Treatment. 3rd ed. St. Louis: CV Mosby, 1987.
41. Holz FG, Sheraidah G, Pauleikhoff D, et al. Analysis of lipid deposits extracted from human macular and peripheral Bruch's membrane. Arch Ophthalmol. 1994; 112: 402-406.
42. Hoskin A, Bird AC, Sehmi K. Tears of detached retinal pigment epithelium. Br J Ophthalmol 1981; 65: 417-422.
43. Schoeppner G, Chuang EL, Bird AC. The risk of fellow eye visual loss with unilateral retinal pigment epithelial tears. Am J Ophthalmol 1989;108: 683-685.
44. Scott IU, Schein OD, West S, et al. Functional status and quality of life measurement among ophthalmic patients. Arch Ophthalmol 1994; 112: 329-335.
45. Guyer DR, Yannuzzi LA, Slakter JS, et al. Digital indocyanine-gren of occult choroidal neovascularization. Ophthalmology 1994; 101: 1727-1737.
46. Chang B, Yannuzzi LA, Ladas I, et al. Choroidal neovascularization in second eyes of patients with unilateral exudative age-related macular degeneration.Ophthalmology 1995; 102: 1380-1386.
47. Gass JDM. Pathogenesis of tears of the retinal pigment epithelium. Br J Ophthalmol 1984; 68: 513-519.
48. Gass JDM. Retinal pigment epithelial rip during krypton red laser photocoagulation. Am J Ophthalmol 1984; 98: 700-706.
49. Krishan NR, Chandra SR, Stevens TS. Diagnosis and pathogenesis of retinal pigment epithelial tears. 1985; 100: 698-707.
50. Green SN, Yarian D. Acute tears of the retinal pigment epithelium. Retina 1983; 3: 16-20.
51. Giovannini A, Amato G, Mariotti C, et al. Opthical coherence tomography in the assessment of retinal pigment epithelial tear. Retina 2000; 20: 37-40.
52. Chuang EL, Bird AC. Repair after tears of the retinal pigment epithelium. Eye 1988; 2: 106-113.
53. Spaide RF, Armstrong D, Browne R. Choroidal neovascularization in age-related macular degeneration. What is the cause? Retina 2003; 23(5): 595-614.
54. Spraul CW, Lang GE, Grossniklaus HE, et al. Histologic and morphometric analysis of the choroids, Bruch's membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Surv Ophthalmol 1999; 44(suppl 1): S10-S32.
55. Meyer CH, Toth CA. Retinal pigment epithelial tear with vitreomacular attachment: a novel pathogenic feature. Graefes Arch Clin Exp Ophthalmol.2001; 239(5): 325-333.
56. Gross-Jendroska M, Flaxel CJ, Schwartz SD, et al. Treatment of pigment epithelial detachments due to age-related macular degeneration with intra-ocular C3F8 injection. Aust N Z J Ophthalmol 1998; 26: 311-317.
57. Alm A. Ocular circulation. In: Hart WM Jr, ed Adler's Physiology of the Eye: Clinical Application, 9th ed. St Louis: C.V. Mosby, 1992: 212-214.
58. Alm A. Physiology of choroidal circulation. In: Yannuzzi LA, Flower RW,Slakter JS, eds. Indocyanine Green Angiography. St Louis: C. V. Mosby,1997; 39-41.
59. Wang YS, Friedrichs U, Eichler W, et al. Inhibitory effects of triamcinolone acetonide on bFGF-induced migration and tube formation in choroidal microvascular endothelial cells. Graefes Arch Clin Exp Ophthalmol 2002; 240: 42-48.
60. Perretti M, Ahluwalia A. The microcirculation and inflammation: site of action for glucocorticoids. Microcirculation 2000; 7: 147-161.
61. Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol 1997; 16: 398-406.
62. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with Verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003; 110: 1517-1525.
63. Rogers AH, Martidis A, Greenberg PB, et al: Optical coherence tomography findings following photodynamic therapy of choroidal neovascularization. Am J Ophthalmol 2002; 134: 566-576.
64. Lanzetta P, Michieletto P, Pirracchio A, et al. Early vascular changes induced by transpupillary thermotherapy of choroidal neovascularization.Ophthalmology 2002; 109; 1098-1104.
65. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS report no 8. Age-related Eye Disease Study Research Group. Arch Opthalmol 2001; 119:1417-1436.
66. Seddon JM. Epidemiology of age-related macular degeneration. In: Ryan SJ,ed Retina. St. Louis: Mosby, 2001: 1039-1050.
67. Axer-Siegel R, Ehrlich R, Yassur Y, et al. Photodynamic therapy for age-related macular degeneration in a clinical setting: visual results and angiographic patterns. Am J Ophthalmol, 2004; 137(2): 258-64.
68. Ting TD, Oh M, Cox TA, et al. Decreased visual acuity associated with cystoid macular edema in neovascular age-related macular degeneration. Arch Ophthalmol 2002; 120: 731-737.
69. Guidelines for using verteporfin(Visudyne) in photodynamic therapy to treat choroidal neovascularization due to age-related macular degeneration and other causes. Retina 22: 6-18,2002.
70. Dick JSB. Macular edema. International Ophthalmology Clinics 1999; 39: 1-18.
71. Soubrane G, Coscas G, Larcheveque F. Macular degeneration related to age and cystoid macular edema: apropos of 95 cases(100 eyes). J Fr Ophthalmol. 1988; 11: 711-720.
72. Freund KB, Yannuzzi LA, Sorenson JA. Age-related macular degeneration and choroidal neovascularization. Am J Ophthalmol 1993; 115: 786-791.
73. Stevens TS, Bressler NM, Maguire MG, et al. Occult choroidal neovascularization in age-related macular degeneration: a natural history study. Arch Ophthalmol. 1997; 115: 345-350.
74. Soubrane G, Coscas G, Francais X, et al. Occult subretinal new vessels in age-related macular degeneration: natural history and early laser treatment.Ophthalmology. 1990; 97: 649-657.
75. Dvorak HF, Brown LF, Detmar M, et al. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.Am J Pathol 1995; 146: 1029-1039.
76. Roberts WG, Palade GE. Increased microvascular permeability and endothelial
fenestration induced by vascular endothelial growth factor. J Cell Sci 1995; 108: 2369-2379.
77. Connolly DT, Heuvelman DM, Nelson R, et al. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 1989; 84: 1470-1478.
78. Gass JDM. Pathophysiologic and histopathologic bases for interpretation of fluorescein angiography. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St Louis, Mo: Mosby-Year Book Inc; 1997: 40-41.
79. Grossniklaus HE, Cingle KA, Yoon YD, et al. Correlation of histologic 2-dimensional reconstruction and confocal scanning laser microscopic imaging of choroidal neovascularization in eyes with age-related maculopathy. Arch Ophthalmol. 2000; 118(5): 625-9.
80. Penfold PL, Killingsworth MC, Sarks SH. Senile macular degeneration: the involvement of immunocompetent cells. Graefes Arch Clin Exp Ophthalmol.1985; 223: 69-76.
81. Kvanta A, Algvere PV, Berglin L, et al. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci 1996; 37: 1929-1934.
82. Berger AS, Conway M, Del Priore LV, et al. Submacular surgery for subfoveal choroidal neovascular membranes in patients with presumed ocular histoplasmosis. Arch Ophthalmol 1997; 115: 991-996.
83. Gass JDM. Stereoscopic Atlas of Macular Diseases. 4th ed. St Louis: Mosby, 1997; 84: 26-32.
84. Wachtlin J, Heimann H, Behme T, et al. Long-term results after photodynamic therapy with vertiporfin for choroidal neovascularizations secondary to
inflammatory chorioretinal diseases. Graefes Arch Clin Exp Ophthalmol. 2003; 241: 899-906.
85. Macular Photocoagulation Study Group. Argon laser photocoagulation for idiopathic neovascularization. Results of a randomized clinical trial. Arch Ophthalmol 1983; 101: 1358-1361.
86. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol 1993; 111: 1200-1209.
87. Secretan M, Kuhn D, Soubrane G, et al. Long-term visual outcome of choroidal neovascularization in pathologic myopia: natural history and laser treatment. Eur J Ophthalmol 1997; 7: 307-316.
88. Sears J, Jr. Capone A, Sr. Aaberg T, et al. Surgical management of subfoveal neovascularization in children. Ophthalmology 1999; 106: 920-924.
89. Lopez PF, Grossniklaus HE, Lambert HM, et al. Pathologic features of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1991; 112: 647-56.
90. Saxe SJ, Grossniklaus HE, Lopez PF, et al. Ultrastructural features of surgically excised subretinal neovasular membranes in the ocular histoplasmosis syndrome. Arch Ophthalmol 1993; 111: 88-95.
91. Grossniklaus HE, Martinez JA, Brown VB, et al. Immunohistochemical and histochemical properties of surgically excised subretinal neovascular membranes in age-related macular degeneration. Am J Ophthalmol 1992;114: 464-72.
92. Grossniklaus HE, Hutchinson AK, Capone Jr A, et al. Clinicopathologic features of surgically excised choroidal neovascular membranes.
Ophthalmology 1994; 101: 1099-111.
93. Grossniklaus HE, Green WR. Histopathologic and ultrastructural findings of surgically excised choroidal neovascularization. Submacular Surgery Trials Research Group. Arch Ophthalmol 1998; 116: 745-9.
94. Curcio CA, Millican CL. Basal linear deposit and large drusen are specific for early age-related maculopathy. Arch Ophthalmol 1999; 117: 329-339.
95. Dorey CK, Wu G, Ebenstein D, et al. Cell loss in the aging retina. Relationship to lipofuscin accumulation and macular degeneration. Invest Ophthalmol Vis Sci 1989; 30: 1691-1699.
96. Li W, Yanoff M, Li Y, et al. Artificial senescence of bovine retinal pigment epithelial cells induced by near-ultraviolet in vitro. Mech Ageing Dev 1999; 110: 137-155.
97. Tombran-Tink J, Shivaram SM, Chader GJ, et al. Expression, secretion, and age-related downregulation of pigment epithelium-derived factor, a serpin with neurotrophic activity. J Neurosci 1995; 15: 4992-5003.
98. Cayouette M, Smith SB, Becerra SP, et al. Pigment epithelium-derived factor delays the death of photoreceptors in mouse models of inherited retinal degenerations. Neurobiol Dis 1999; 6: 523-532.
99. Jablonski MM, Tombran-Tink J, Mrazek DA, et al. Pigment epithelium-derived factor supports normal development of photoreceptor neurons and opsin expression after retinal pigment epithelium removal. J Neurosci 2000; 20: 7149-7157.
100. Cao W, Tomran-Tink, Elias R, et al. In vivo protection of photoreceptors from light damage by pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2001; 42: 1646-1652.
101.Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science 1999, 285: 245-248.
102.Mori K, Duh E, Gelhbach P, et al. Pigment epithelium-derived factor inhibits retinal and choroidal neovascularization. J Cell Physiol 2001; 188: 253-263.
103.Holekamp NM, Bouck N, Volpert O. Pigment epithelium-derived factor is deficient in the vitreous of patients with choroidal neovascularization due to age-related macular degeneration. Am J Ophthalmol 2002; 134: 220-227.
104.Becerra SP. Structure-function studies on PEDF a noninhibitory serpin with neurotrophic activity. In: Church FC, editor. Chemistry and biology of serpins. 1997: 224-237.
105.Karakousis PC, John SK, Behling KC, et al. Localization of pigment epithelium derived factor(PEDF) in developing and adult human ocular tissues. Mol Vis 2001; 7: 154-163.
106.Schmidt-Erfurth U, Michels S, Barbazetto I, et al: Photodynamic effects on choroidal neovascularization and physiological choroids. Invest Ophthalmol Vis Sci.2002; 43: 830-841.
107.Campochiaro PA, Morgen KM, Conway BP, et al. Spontaneous involution of subfoveal neovascularization. Am J Ophthalmol 1990; 109: 668-675.
108.Glaser BM, Campochiaro PA, Davis JL Jr, et al. Retinal pigment epithelial cells release inhibitors of neovascularization. Ophthalmology 1987; 94: 780-784.
109.Miller H, Miller B, Ryan SJ. The role of the retinal pigment epithelium in the involution of subretinal neovascularization. Invest Ophthalmol Vis Sci 1986; 27: 1644-1652.
110.Zhu Z, Goodnight R, Sorgente N, et al. Experimental subretinal
neovascularization in the rabbit. Graefes Arch Clin Exp Ophthalmol 1989; 227: 257-262.
111. Miller H, Miller B, Ryan SJ. The role of retinal pigment epithelium in the involution of subretinal neovascularization. Invest Ophthalmol Vis Sci 1986; 27: 1644-1652.
112. Miller H, Miller B, Ishibashi T, et al. Pathogenesis of laser-induced choroidal subretinal neovascularization. Invest Ophthalmol Vis Sci 1990; 31: 899-908.
113. Ferris FL Ⅲ. Senile macular degeneration: Review of epidemiologic features. Am J Epidemiol 1983; 118: 132-151.
114. Pauleikhoff D, Sheraidah G, Marshall J, et al. Biochemical and histochemical analysis of age related lipid deposits in Bruch's membrane. Ophthalmologe 1994; 91: 730-734.
115. Kim SY, Sadda S, Pearlman J, et al. Morphometric analysis of the macula in eyes with disciform age-related macular degeneration. Retina 2002; 22: 471-477.
116. Green WR, Enger C. Age-related macular degeneration histopathologic studies: the 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100: 1519-1535.
117. Gass JDM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment,3rd ed. St Louis: C. V. Mosby, 1987: chap. 6, 392-394.
118. Green WR, Gass JDM. Senile disciform degeneration of the macula. Arch Ophthalmol 1971; 86: 487-494.
119. Bergrnan JF. Oeller's Atlas of Rare Ophthalmoscopic Conditions and Supplementary Plates to the Atlas of Ophthalmoscopy [Snowball T, trans]. Wiesbaden, Germany, 1904, Part C.
120. Hartnett ME, Weiter JJ, Gardts A, et al. Classification of retinal pigment epithelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol, 1992; 230(1): 11-19.
121. Kuhn D, Meunier I, Soubrane G, et al. Imaging of chorioretinal anastomoses in vascularized retinal pigment epithelium detachments. Arch Ophthalmol. 1995; 113(11): 1392-1398.
122. Lafaut BA, Aisenbrey S, Broecke CV, et al. Clinicopathological correlation of deep retinal vascular anomalous complex in age-related macular degeneration. Br J Ophthalmol, 2000; 84(11): 1269-1274.
123. Hartnett ME, Weiter JJ, Staurenghi G, et al. Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology, 1996; 103(12): 2042-2053.
124. Slakter JS, Yannuzzi LA, Schneider U, et al. Retinal choroidal anastomoses and occult choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2000; 107(4): 742-753.
125. Yannuzzi LA, Negrao S, Iida T, et al. Retinal angiomatous proliferation in age-related macular degeneration. Retina, 2001; 21 (5): 416-434.
126. Gass JDM, Agarwal A, Lavina AM, Tawansy KA. Focal inner retinal hemorrhages in patients with drusen. An early sign of occult choroidal neovascularization and chorioretinal anastomosis. Retina 2003; 23: 741-751.
127. Gass JDM. Stereoscopic Atlas of Macular diseases: Diagnosis and Treatment. 3rd ed. St. Louis: CV Mosby, 1987: 64-65.
128. Macular Photocoagulation Study Group. Argon laser photocoagulation for histoplasmosis: results of a randomized clinical trial. Arch Ophthalmol 1983; 101: 1347-1357.
129. Axer-Siegel R, Bourla D, et al. Angiographic and flow patterns of retinal choroidal anastomoses in age-related macular degeneration with occult choroidal neovascularization. Ophthalmology 2002; 109: 1726-1736.
130. Kim I, Ryan AM, Rohan R, et al. Constitutive expression of VEGF, VEGFR-1, and VEGFR-2 in normal eyes. Invest Ophthalmol Vis Sci 1999; 40: 2115-2121.
131. Blaauwgeers HG, Holtkamp GM, Rutten H, et al. Polarized vascular endothelial growth factor secretion by human retinal pigment epithelium and localization of vascular endothelial growth factor receptors on the inner choriocapillaris. Evidence for a trophic paracrine relation. Am J Pathol 1999; 155: 421-428.
132. Spilsbury K, Garrett KL, Shen WY, et al. Overexpression of vascular endothelial growth factor (VEGF) in the retinal pigment epithelium leads to the development of choroidal neovascularization. Am J Pathol 2000; 157: 135-144.
133. Baffi J, Byrnes G, chan CC, et al. Choroidal neovascularization in the rat induced by adenovirus mediated expression of vascular endothelial growth factor. Invest Ophthalmol Vis Sci 2000; 41: 3582-3589.
134. Becerra SP, Wu YQ, Montuenga L, et al. Pigment epithelium-derived factor (PEDF) in the monkey eye: apical secretion from the retinal pigment epithelium. Invest Ophthalmol Vis Sci 2001; 42: S772.
135. Mori K, Gehlbach P, Ando A, et al. Regression of ocular neovascularization in response to increased expression of pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2002; 43: 2428-2434.
136. Wu YQ, Notario V, Chader GJ, et al. Identification of pigment epithelium-derived factor in the interphotoreceptor matrix of bovine eyes.
Protein Expr Purif 1995; 6: 447-456.
137. Li W, Yanoff M, Li Y. et al. Artificial senescence of bovine retinal pigment epithelial cells induced by near-ultraviolet in vitro. Mech Ageing Dev 1999; 110: 137-155.
138. Yannuzzi LA, Slakter JS, Sorenson JA, et al. Digital indocyanine green videoangiography and choroidal neovascularization. Retina 1992; 12: 191-223.
139. Iwasaki M, Inomata H. Relation between superficial capillaries and foveal structures in the human retina. Invest Ophthalmol Vis Sci 1986; 27: 1698-1705.
140. Okamoto N, Tobe T, Hackett SF, et al. Transgenic mice with increased expression of vascular endothelial growth factor in the retina: a new model of intraretinal and subretinal neovascularization. Am J Pathol 1997; 151: 281-291.
141. Tobe T, Okamoto N, Vinores MA, et al. Evolution of neovascularization in mice with overexpression of vascular endothelial growth factor in photoreceptors. Invest Ophthalmol Vis Sci 1998; 39: 180-188.
