Clinicopathological correlation in exudative age-related macular degeneration: recurrent choroidal neovascularization

Purpose: To report the pathology of surgically removed submacular tissue in recurrent choroidal neovascularization after laser photocoagulation of classic choroidal neovascularization in age-related macular degeneration. Methods: A recurrent subfoveal choroidal neovascular membrane was surgically removed in two patients. The recurrence was identified as a classic membrane on fluorescein angiography at the foveal border of the laser scar. A net was visualized in the early venous phase of the indocyanine green angiogram, with associated late hyperfluorescence. Both patients had undergone laser photocoagulation for a classic interpapillomacular choroidal neovascular membrane about 1 1/2 years earlier. The specimens were serially sectioned and stained with hematoxylin–eosin, periodic acid–Schiff, Masson trichrome and phosphotungstic acid–hematoxylin. Results: The two specimens consisted of subretinal fibrovascular tissue with fibrin exudation. Fibrovascular tissue bordered subretinal fibrous tissue adherent to Bruch’s membrane and remnants of the choroid in one patient. The fibrovascular portion most likely corresponded to the recurrence, whereas the fibrous portion represented the original membrane, being obliterated after photocoagulation. Some peripapillary tissue was additionally removed in the other patient. The latter lesion was invisible on fluorescein angiography but stained in the late phase of indocyanine green angiography and corresponded histopathologically to poorly vascularized intra-Bruch’s fibrovascular tissue. Granular deposits, periodic acid–Schiff positive and metachromatically purple on Masson trichrome stain, representing diffuse drusen (basal laminar/linear deposits), were identified in the three specimens. Conclusion: A subretinal fibrovascular membrane corresponded with the classic recurrent choroidal neovascularization. Received: 14 June 2000 Revised: 4 September 2000 Accepted: 13 September 2000     

Angiographic and flow patterns of retinal choroidal anastomoses in age-related macular degeneration with occult choroidal neovascularization

OBJECTIVE: To identify the angiographic features of retinal choroidal anastomoses (RCAs) in patients with newly diagnosed occult choroidal neovascularization (CNV) in the setting of age-related macular degeneration (AMD) and to determine the sequence of flow between the RCA and the CNV. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: The angiograms of 205 eyes of 153 consecutive patients with occult CNV on fluorescein angiography (FA) and focal hot spots on indocyanine green angiography (ICGA) were evaluated retrospectively. METHODS OF TESTING: Red-free photographs and sequential digital fluorescein and indocyanine green angiograms obtained by confocal scanning laser ophthalmoscope (the Heidelberg Retina Angiograph; Heidelberg Engineering GmbH, Dossenheim, Germany). MAIN OUTCOME MEASURES: The angiograms were evaluated for the presence of RCA. The following angiographic characteristics were recorded: number and type of anastomoses, location, distance from fovea, area of CNV, presence of pigment epithelium detachment (PED), cystoid macular edema on FA, and intraretinal leakage on ICGA. The direction of flow between the RCA and the CNV was identified by analyzing high-speed angiograms. RESULTS: Retinal choroidal anastomoses were identified in 57 eyes (28%), in 49 of 154 eyes with PED (32%), and in 8 of 51 eyes without PED (16%). Of 109 anastomoses, 70% were venous and 30% were arterial. Ninety-six percent of the eyes had at least one venous anastomosis, 49% of the eyes had an arterial anastomosis, and 46% of the eyes had both. Cystoid macular edema was seen on FA in 37 eyes (65%), and intraretinal indocyanine green leakage was noted in 52 eyes (91%). Twenty-two eyes that underwent high-speed ICGA were analyzed for the direction of flow. All 15 eyes having arterial and venous anastomoses demonstrated a filling pattern from the retinal arteriole to the CNV, followed by the retinal venule. Seven eyes with venous RCA showed flow sequence from the CNV to the collecting retinal venule. CONCLUSIONS: Our study supports the presence of RCA in the early stages of acute exudative AMD with occult CNV, mainly with serous PED. High-speed angiography helps to identify the filling sequence of the RCA and the CNV, and therefore may guide the clinician in planning treatment strategies.     

Angiographic characteristics in patients undergoing macular translocation for subfoveal choroidal neovascularization secondary to age-related macular degeneration

PURPOSE: To review in a standardized fashion pre- and postoperative fluorescein angiographic characteristics in patients undergoing limited macular translocation (LMT) with scleral imbrication to treat subfoveal choroidal neovascularization (SFCNV) secondary to age-related macular degeneration (AMD). The current study was undertaken to assess any potential effects of the translocation procedure on altering the angiographic characteristics of SFCNV before laser photocoagulation. METHODS: A consecutive series of patients undergoing LMT for AMD was identified retrospectively. The pre- and postoperative fluorescein angiograms were reviewed in a masked fashion. Angiographic characteristics evaluated included pre- and postoperative lesion components, stability of lesion, and the amount of retinal translocation obtained. RESULTS: Eighty-eight patients (90 eyes) had angiograms of adequate quality to permit evaluation. Time between the preoperative and the prelaser angiogram ranged from 2 to 84 days (median 7.5 days). Neovascular complexes remained unchanged or decreased in size in 79% of patients. There was no statistically significant difference in lesion size between the pre- and postoperative periods (P = 0.34). Retinal movement ranged from 160 microm to 3,320 microm (median 960 microm), with 61% of cases undergoing effective translocation (i.e., the fovea was moved away from the neovascular complex). None of the lesion components or demographic factors evaluated affected the amount of translocation obtained. Larger lesions were more likely to remain subfoveal following translocation (P = 0.004). CONCLUSION: The size and lesion characteristics appear relatively stable following translocation. Amount of retinal movement is not associated with angiographic lesion characteristics. Only size was associated with achievement of desired translocation in the final model, with large lesions being less likely to achieve desired translocation. In our study group, the amount of retinal translocation was variable with 61% of cases undergoing effective translocation.     

Foveolar choroidal circulation and choroidal neovascularization in age-related macular degeneration

PURPOSE: To investigate in a longitudinal study whether foveolar choroidal blood flow changes are associated with the development of choroidal neovascularization (CNV) in AMD. METHODS: Relative foveolar choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) were assessed in 135 patients with AMD, at baseline and then annually with laser Doppler flowmetry. All study eyes had visual acuity of 20/40 or better and no CNV at the time of enrollment. Comparison of foveolar choroidal circulatory measurements at baseline and their change before the development of CNV was made between eyes that had CNV and those that did not. RESULTS: CNV developed in 28 eyes during the study. Baseline average foveolar ChBVol and ChBFlow in these eyes were 24% (P < 0.0001) and 20% (P = 0.0007) lower than that observed in the 165 eyes in which CNV did not develop. In the eyes with CNV, foveolar ChBVol and ChBFlow decreased by 9.6% and 11.5% before the formation of CNV, whereas in the eyes that did not, they increased by 6.7% (P = 0.006) and 2.8% (P = 0.004), respectively. Eyes with lower baseline foveolar ChBFlow were more likely (risk ratio = 3.47, 95% CI: 1.24-8.70) to show visual loss of three or more lines than were eyes with a higher baseline ChBFlow (P = 0.005). CONCLUSIONS: The development of CNV and visual loss are associated with lower choroidal circulatory parameters at baseline. In addition, the results suggest that decreases in the foveolar choroidal circulation precede the development of CNV in AMD and may play some role in its development.     

Molecular mechanism of choroidal neovascularization in age-related macular degeneration

The exudative form of age-related macular degeneration (AMD) is characterized by choroidal neovascularization (CNV). Retinal pigment epithelial cells (RPE) secrete various angiogenesis-related factors, especially vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). The imbalance between the VEGF and PEDF secreted by RPE is a key contributor to the development of CNV in AMD. The earliest clinical hallmark of AMD is the presence of drusen. Although drusen are an epidemiological risk factor for the development of CNV, the mechanism of how drusen induce the development of CNV remains unclear. Recent proteome analysis demonstrated that amyloid beta (Abeta) deposition was specific to drusen from eyes with AMD. We focused on Abeta and investigated the effect of Abeta on cultured human RPE cells as well as ocular findings in neprilysin gene-disrupted mice, which leads to an increased deposition of Abeta. Our study demonstrates that Abeta accumulation affects the balance between VEGF and PEDF in the RPE, and reproduces features characteristic of human AMD, such as RPE atrophy and basal deposit formation in neprilysin gene-disrupted mice.     

Detachment of subfoveal choroidal neovascularization in age-related macular degeneration

PURPOSE: To report the entity of partial detachment and folding of subfoveal choroidal neovascularization (CNV) in age-related macular degeneration (ARMD). DESIGN: Interventional case reports. METHODS: Review of the features of CNV detachment in two patients with CNV due to ARMD by contact lens slit-lamp biomicroscopy, fluorescein angiography, optical coherence tomography, and three-dimensional confocal scanning laser indocyanine green (ICG) angiography. RESULTS: One patient out of approximately 300 (0.5%) ARMD patients treated by photodynamic therapy (PDT) developed partial CNV detachment and folding 6 weeks after the second PDT treatment. Another patient out of approximately 100 (1.0%) ARMD patients treated by transpupillary thermotherapy (TTT) developed partial CNV detachment and folding 6 weeks after the second TTT treatment. The CNVs were large (2,500 microm to 4,500 microm) and located between the retina and the retinal pigment epithelium. In each, these findings were clearly visualized by slit-lamp biomicroscopy. Fluorescein angiography demonstrated an associated retinal pigment epithelium tear in one patient. Optical coherence tomography showed distinctive features and confocal scanning laser ICG further delineated the detached folded CNV. The best-corrected visual acuity improved in one patient from 20/80 to 20/40 and in the other from counting fingers at 6 feet to 20/200 after the CNV detachment. CONCLUSIONS: Partial CNV detachment and folding represent a unique, not previously reported, and possibly favorable outcome of PDT and TTT. The low energy and selectivity of these treatments may explain this phenomenon.     

Current treatment of choroidal neovascularization in age-related macular degeneration

Age-related macular degeneration (AMD) is currently the leading cause of severe visual acuity loss in people over the age of 50 in the Western world. Most of the visual loss is due to choroidal neovascularization (CNV). Laser photocoagulation is the only proven treatment for selected cases of AMD; however, it can only be used with less than 20% of patients at the time of diagnosis. Among experimental therapies currently being tested, photodynamic therapy has recently proven its efficacy in randomized multicenter studies for predominantly classic subfoveal pure occult type CNVs.     

Molecular mechanism for choroidal neovascularization in age-related macular degeneration

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is the most common cause of severe visual loss in patients over age 60 years in developed countries. While much is unknown about the underlying pathogenesis of CNV, the increased production of vascular endothelial growth factor(VEGF) by retinal pigment epithelium (RPE) is thought to play a central role in the development of this condition. However, recent studies using gene-manipulated mice question the importance of VEGF alone in promoting CNV. Angiogenesis is thought to result from the balance between angiogenesis stimulation and inhibition. A potent antiangiogenic factor recently has been identified in the retina and shown to be secreted by RPE cells. The inhibitor, pigment epithelium-derived factor(PEDF) is considered the key factor associated with avascularity of the cornea, vitreous, and outer retinal layer of the eye. We recently demonstrated that an imbalance between PEDF and VEGF in RPE cells caused by aging and oxidative stress may contribute to the disregulation of endothelial cell proliferation in CNV. In this review, we also discuss the angiogenic role of inflammatory cells in CNV, age-related changes in Bruch's membrane, and the possibility of the development of animal models reflecting CNV in AMD.     

Limited macular translocation for subfoveal choroidal neovascularization in age-related macular degeneration

Purpose: To examine the safety and efficacy of limited macular translocation followed by laser photocoagulation in the management of subfoveal choroidal neovascularization (CNV) in age‐related macular degeneration (AMD). Methods: A prospective study was conducted on eight consecutive patients undergoing limited macular translocation followed by laser photocoagulation for the treatment of subfoveal classic CNV form of AMD. Patients were followed up for a minimum of 12 months. The magnitude of foveal translocation, visual outcomes and complications were assessed. Results: In all cases the fovea was successfully translocated inferiorly, with a median displacement of 1.1 mm. Thermal laser photocoagulation was subsequently performed in all cases. Visual acuity improved in five eyes, remained unchanged in two eyes and worsened in one eye. The mean improvement in visual acuity was by 0.19 logMAR. At 12 months, six of the eight patients (75%) achieved Snellen visual acuity of at least 6/15, with four patients (50%) achieving Snellen visual acuity of 6/9. Conclusion: In this small case series, limited macular translocation was found to be an effective and reproducible means of treating small well‐defined subfoveal CNV.     

年龄相关性黄斑变性脉络膜新生血管的治疗策略

年龄相关性黄斑变性(AMD)脉络膜新生血管形成(CNV)的治疗一直是眼科的难题之一。CNV引起黄斑区渗出、出血、纤维瘢痕形成,导致视力丧失。近年来,随着科学技术的发展,出现了一些新的治疗方法及手段。光动力疗法的出现突破了黄斑中心凹治疗的禁区,糖皮质激素、血管内皮生长因子抑制剂治疗和联合治疗给患者视力提高带来了曙光,经瞳孔温热疗法及手术治疗等也在探讨中,并取得了一定的疗效。但新疗法的有效性尚需多中心、大样本的随机临床试验来证实。     

Transpupillary thermotherapy of occult choroidal neovascularization in age-related macular degeneration

PURPOSE: To evaluate the efficacy of transpupillary thermotherapy (TTT) in management of occult subfoveal choroidal neovascularization (CNV) in exudative age-related macular degeneration (AMD). METHODS: Retrospective chart review of eyes that were treated with TTT and had at least 12 weeks of follow-up. Base-line and final ETDRS visual acuity and fluorescein angiography (FA) were compared. RESULTS: For the 48 eyes which met inclusion criteria, mean pre-operative visual acuity was 20/128 (range: 20/50-20/500). Average follow-up was 27 weeks (range: 12 weeks-55 weeks). At 3 months after treatment, 12 eyes (25%) improved 2 lines or more, 18 eyes (37.5%) had no change or 1 line of visual improvement, and 18 eyes (37.5%) worsened 1 or more lines. No significant adverse event was noted during treatment. Three eyes developed large submacular hemorrhage within 2 months of treatment. Based on clinical examination and FA, 61% of the eyes appeared to have reduction of subretinal fluid compared to pre-operative evaluations. CONCLUSION: Visual acuity was stable or improved in 62.5% of eyes in our series and the treatment was well tolerated. Longer follow up and larger number of patients would be required to evaluate the ultimate benefit of TTT in management of occult CNV due to AMD.     

Laser management of subfoveal choroidal neovascularization in age-related macular degeneration

Subfoveal choroidal neovascularization in eyes with age-related macular degeneration is associated with a poor natural prognosis. The Macular Photocoagulation Study Group recently has demonstrated that subfoveal photocoagulation in select cases of subfoveal choroidal neovascularization for patients with age-related macular degeneration effectively prevents severe visual acuity loss and reduces the average loss of contrast sensitivity and reading speed associated with this condition. Eligibility criteria and treatment recommendations from the Macular Photocoagulation Study will be reviewed. Results of alternative strategies for laser photocoagulation of such lesions are also discussed; however, the Macular Photocoagulation Study results stand alone in documenting a long-term treatment benefit of photocoagulation for subfoveal choroidal neovascularization.     

Transpupillary thermotherapy of occult choroidal neovascularization in age-related macular degeneration

Purpose. To evaluate the efficacy of transpupillary thermotherapy (TTT) in management of occult subfoveal choroidal neovascularization (CNV) in exudative age-related macular degeneration (AMD). Methods. Retrospective chart review of eyes that were treated with TTT and had at least 12 weeks of follow-up. Base-line and final ETDRS visual acuity and fluorescein angiography (FA) were compared. Results. For the 48 eyes which met inclusion criteria, mean pre-operative visual acuity was 20/128 (range: 20/50–20/500). Average follow-up was 27 weeks (range: 12 weeks–55 weeks). At 3 months after treatment, 12 eyes (25%) improved 2 lines or more, 18 eyes (37.5%) had no change or 1 line of visual improvement, and 18 eyes (37.5%) worsened 1 or more lines. No significant adverse event was noted during treatment. Three eyes developed large submacular hemorrhage within 2 months of treatment. Based on clinical examination and FA, 61% of the eyes appeared to have reduction of subretinal fluid compared to pre-operative evaluations. Conclusion. Visual acuity was stable or improved in 62.5% of eyes in our series and the treatment was well tolerated. Longer follow up and larger number of patients would be required to evaluate the ultimate benefit of TTT in management of occult CNV due to AMD.     

Feeder vessel treatment of choroidal neovascularization in age-related macular degeneration

INTRODUCTION: To report on the results of feeder vessel treatment for choroidal neovascularization in age-related macular degeneration (AMD). MATERIAL AND METHODS: Retrospective study of 40 patients presenting subfoveal classic choroidal neovascularization (CCNV) and/or occult choroidal neovascularization (OCNV) with or without fibrovascular pigment epithelium detachment (PED), based on fluorescein angiography (FA) and indocyanine green angiography (ICG). Visual acuity was measured using Snellen lines and/or ETDRS. The feeder vessels were visualized with high-speed ICG angiography (confocal scanning laser ophthalmoscope, Heidelberg HRA, Heidelberg, Germany). Feeder vessels were identified as very thin vessels with early filling and rapid emptying. Feeder vessel closure was achieved by laser photocoagulation treatment with either minipulse infrared laser therapy (810 nm), microburst, or yellow laser (568 nm). Post-treatment high-speed ICG angiography follow-up was recommended to the patient immediately or the day after the treatment. The number of treatments and location of the feeder vessels in relation to the macula as well as FA, ICG, and visual acuity results were assessed. If necessary, other treatment techniques such as photodynamic therapy (PDT) or transpupillary thermotherapy (TTT) were offered to the patient when leakage was still present. RESULTS: The patients were followed for an average of 6.2 months (2-9 months). Twenty-six women and 14 men (mean age, 72 years; range, 51-95) were included. Eight patients demonstrated classic neovascularization, 32 presented occult neovascularization, including 17 cases of vascularized PED and 15 retrofoveal plaques. The average number of treatments was 1.8 (range, 1-4 treatments). Location of feeder vessels were as follows: nine superior-macular, 18 inferior-macular, six nasal-macular and 11 temporal-macular. Visual acuity improved two lines or more in nine patients (22.5%), decreased 2 lines or less in five patients (12.5%) and was stable in 26 patients (65%). After feeder vessel treatment, seven patients showed improvement of the anatomical aspect of the AMD lesions, with a reduction in leakage. Except for one subretinal hemorrhage, no complications after feeder vessel treatment were observed. CONCLUSION: Feeder vessel treatment is a technique requiring high-speed ICG angiography to detect the feeder vessels located at a distance from the subfoveal OCNV, CCNV, and PED. Although the final visual acuity result was for the most part stabilization, the technique appeared to be safe and reproducible. In patients who were not eligible for other therapies such as PED, feeder vessel treatment seemed to be a reasonable alternative.     

Surgical removal of subfoveal choroidal neovascularization in age-related macular degeneration

OBJECTIVE: To assess the results of surgical excision of subfoveal choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD). DESIGN: Retrospective, interventional, noncomparative case series. PARTICIPANTS AND INTERVENTION: Sixty-four consecutive patients undergoing surgical removal of AMD-related subfoveal CNV were studied. The surgical method included a small retinotomy, subretinal tissue plasminogen activator (t-PA), perfluoro-n-octane, and air-fluid exchange. MAIN OUTCOME MEASURES: Final visual acuity was the main outcome measure; surgical complications and recurrence rates were also assessed. RESULTS: Preoperative visual acuity ranged from 20/100 to 1/200, with a mean of 20/400. Average follow-up was 19 months. The best acuity achieved after surgery ranged from 20/20 to hand motions, with a mean of 20/200. Final visual acuity ranged from 20/50 to light perception, with a mean of 20/400. Final acuity was improved 3 or more lines in 19 eyes (30%) (median, 5 lines), stable in 27 eyes (42%), and 3 or more lines worse in 18 eyes (28%) (median, 4 lines). Factors associated with greater visual improvement included poorer initial acuity, larger CNV size, and smaller subretinal hemorrhage. Analysis of groups similar to Macular Photocoagulation Study subgroups A through D showed an average improvement of 1 line for group C (visual acuity, 20/200 or worse; CNV larger than 2 disc areas). Other preoperative, intraoperative, and postoperative factors, including recurrence and retinal detachment, did not have a significant effect on final visual outcome. CONCLUSIONS: After surgical excision of AMD-related subfoveal CNV, vision improved or stabilized in the majority of patients. Surgery may be of greatest value for patients with poorer vision, larger subfoveal CNV, and minimal hemorrhage. Further evaluation of this technique should be accomplished via completion of a controlled, randomized multicenter study.     

Radiation therapy for small choroidal neovascularization in age-related macular degeneration

PURPOSE: To evaluate the effects of radiation therapy on age-related macular degeneration with subfoveal or juxtafoveal choroidal neovascularization < or =1 disc area. METHODS: Fourteen patients (14 eyes) received a total radiation dose of 10-20 Gy in 5-10 fractions. The mean follow-up time was 22 months. Ten patients (10 eyes) in a control group were followed up for an average of 16 months without treatment. RESULTS: At a 12-month posttreatment examination, funduscopic and angiographic findings showed improvement in 7 eyes (50%), no change in 1 eye (7%), and deterioration in 6 eyes (43%) among the treated patients. The same findings demonstrated improvement in 1 eye (10%), no change in 2 eyes (20%), and deterioration in 7 eyes (70%) among the control patients. This difference was determined to be statistically significant between the two groups by the Mann-Whitney U-test. Visual acuity had improved in 4 eyes (29%), was unchanged in 6 eyes (43%), and had declined in 4 eyes (29%), among the treated patients. Among the control patients, visual acuity had improved in none of the eyes (0%), was unchanged in 6 eyes (60%), and had declined in 4 eyes (40%). The difference in visual acuity between the two groups was not statistically significant. CONCLUSIONS: Radiation therapy inhibited small choroidal neovascularization, as seen by funduscopy and angiography, but its effectiveness in improving visual prognosis was not always evident.     

Angiogenesis in early choroidal neovascularization secondary to age-related macular degeneration

Background: The morphological features of angiogenesis in early choroidal neovascularization secondary to age-related macular degeneration are yet to be fully described. Methods: Six eyes from five patients which on clinical and histological examination showed advanced age-related macular degeneration and early choroidal neovascularization have been studied by transmission electron microscopy. Results: Pre-existing choroidal capillaries and venules showed changes which included endothelial cell budding, pericyte enlargement, endothelial cell sprout formation and the development of intrachoroidal new vessels. In one case, an endothelial cell sprout continuous with an intrachoroidal vessel penetrated Bruch's membrane. Examination of early subretinal pigment epithelial new vessels showed them to spread between the inner layers of Bruch's membrane within the space usually occupied by the basal linear deposit and drusen. New vessel formation took place in blind pouches at the margins of new vessel networks, either in the absence of pericytes or in the presence of mainly myofibroblast-like pericytes. Conclusion: This ultrastructural study describes two phases of new vessel growth associated with the onset of choroidal neovascularization secondary to age-related macular degeneration. The initial intrachoroidal phase appears to be a low-turnover form of neovascularization which may lead to new vessels penetrating Bruch's membrane. Extensive subretinal pigment epithelial neovascularization, on the other hand, results from a high-turnover phase of neovascularization characterized by extensive endothelial cell proliferation and migration. Pericyte phenotypic changes associated with these different phases of neovascularization appear to relate to the dynamics of angiogenesis taking place in each process.