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[Study on the experimental model of krypton laser-induced choroidal neovascularization in the rats].

OBJECTIVE: To evaluate the feasibility of krypton laser-induced choroidal neovascularization (CNV) model in the Brown Norway rats in order to establish the foundation for studying the mechanism of CNV and for the development of treatment for CNV. METHODS: Experimental eyes in 33 rats were received a series of 10 krypton red laser (647 nm) lesions per eye (360 mW, 50 micro m, 0.05 s). Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed, then the rats were sacrificed immediately, the eyes were enucleated and processed for histopathologic examination and transmission electron microscopy on days 3, 7, 14, 21, 28 and 56. RESULTS: CNV was firstly appeared on day 7 after photocoagulation, reaching the peak on day 21. The incidence of CNV was 76.0%. Disciform leakage staining appeared in the FFA. ICGA showed that the disciform area was filled with CNV. CNV was ascertained by light microscopy and electron microscopy. The thickness of laser-induced CNV was increased from day 7 to day 21 (P < 0.01) and no significant progress occurred after day 21 (P > 0.05). CONCLUSIONS: The present studies demonstrated that krypton laser photocoagulation could be used to produce choroidal neovascularization experimental model in the Brown Norway rat. CNV can be induced rapidly by the method, persists for a long period and at a high successful rate.

Animals↗

Management of eyes with both idiopathic macular hole and choroidal neovascularization.

PURPOSE: To describe the characteristics, treatment, and outcome of five eyes with both choroidal neovascularization (CNV) and macular hole. METHODS: Medical records of five patients with both macular hole and CNV were reviewed. RESULTS: All eyes had full-thickness macular holes. Most eyes had atypical-appearing macular holes (subretinal hemorrhage, prominent subretinal fluid, or discoloration at the hole margin) at presentation or subsequently when CNV developed. Fluorescein angiography (FA) confirmed the presence of CNV in each eye. Three eyes underwent combined macular hole repair and CNV removal, and sustained closure of these macular holes was achieved. A fourth eye underwent successful argon laser photocoagulation of extrafoveal CNV, and macular hole surgery was declined. The final eye underwent two macular hole repairs before sustained closure was achieved. Final visual acuity, ranging from 20/100 to hand motions, was limited by macular pathology and/or cataract. CONCLUSIONS: Choroidal neovascularization can occur in association with a macular hole. In eyes with an atypical-appearing macular hole, FA should be obtained to detect CNV. Excision of the CNV can be done safely in conjunction with macular hole surgery. Final visual acuity may be limited by cumulative retinal and retinal pigment epithelium damage, especially in eyes with underlying macular disease.

Adult↗

Reticular dystrophy of the retinal pigment epithelium and choroidal neovascularization. A fluorescein and ICGV study.

We report the clinical history of 2 patients affected with reticular dystrophy of the retinal pigment epithelium and central choroidal neovascularization. With time, spontaneous reduction of the subretinal fluid associated with consequent improvement of the visual acuity has been noted in our first case. The second patient showed a stable fibrotic subfoveal choroidal neovascularization. Conventional fluorescein angiography and indocyanine green videoangiography findings are illustrated. The differential diagnosis between other reticular pigmented lesions often associated with choroidal neovascularization is discussed.

Adult↗

Clinicopathologic features of surgically excised choroidal neovascular membranes.

PURPOSE: The purpose of this study is a descriptive correlation of the clinical, fluorescein angiographic, and pathologic features in a large series of patients who underwent surgical removal of choroidal neovascular membranes. METHODS: The patients' clinical data were recorded for each surgically removed choroidal neovascular membrane received in the authors' laboratory. Fluorescein angiographic characteristics of the membranes, including well-demarcated versus poorly demarcated preoperative appearance, postoperative choroidal atrophy, and membrane recurrence, were recorded whenever possible. The pathologic features of the membranes, including cellular and extracellular constituents, were determined on light and electron microscopic examination. RESULTS: A total of 123 membranes were studied. Underlying diseases in decreasing order of frequency were age-related macular degeneration, ocular histoplasmosis syndrome, myopia, idiopathic and pattern dystrophy. The cellular and extracellular constituents of the membranes were similar, regardless of underlying disease, with the exception of basal laminar deposit, seen almost exclusively in age-related macular degeneration. Well-demarcated membrane components were localized with a central subretinal pigment epithelium fibrovascular core. Poorly demarcated membranes were represented by a subneurosensory retinal (breakthrough) component, although most of these membranes had associated retinal pigment epithelium. Fragments of Bruch's membrane were common in specimens from patients with postoperative choroidal atrophy, and there was generally a lack of vascular channels in membranes that led to recurrence. CONCLUSIONS: This study suggests that choroidal neovascular membranes represent a stereotypic, nonspecific response, regardless of underlying disease. Most membranes are subretinal pigment epithelium, and what is recognized angiographically as a subneurosensory retinal component contains associated retinal pigment epithelium in most instances. Fragments of Bruch's membrane in the specimen correlate with postoperative choroidal atrophy. Lack of vascular channels in the surgical specimen may correlate with a risk for postoperative membrane recurrence.

Adult↗

Indocyanine green angiography-guided photocoagulation of choroidal neovascularization associated with retinal pigment epithelial detachment.

PURPOSE: To determine visual acuity outcome after indocyanine green angiography-guided laser photocoagulation of choroidal neovascularization associated with pigment epithelial detachment in eyes with age-related macular degeneration. METHODS: We retrospectively reviewed pretreatment and posttreatment visual acuity after laser photocoagulation to well-demarcated hyperfluorescent areas seen with indocyanine green angiography adjacent to or within pigment epithelial detachments in 20 eyes of 20 patients with age-related macular degeneration and suspected choroidal neovascularization. RESULTS: Visual acuity before and after laser photocoagulation was followed up for 3 to 24 months (median, 9 months). At 3 months after laser photocoagulation, visual acuity had improved 2 or more Snellen lines in two eyes (10%), worsened by 2 or more lines in 10 (50%), and remained unchanged in eight of 20 (40%). By 6 months after laser photocoagulation, visual acuity had improved by 2 or more lines in two eyes (12%), worsened by 2 or more lines in nine (53%), and remained unchanged in six of 17 (35%). At 9 months after laser photocoagulation, visual acuity had improved by 2 or more lines in one eye (9%), worsened by 2 or more lines in nine (82%), and remained unchanged in one of 11 (9%). CONCLUSIONS: Indocyanine green angiography-guided laser photocoagulation may temporarily stabilize visual acuity in some eyes with choroidal neovascularization associated with pigment epithelial detachments, but final visual acuity decreases with time.

Aged↗

Photodynamic therapy using verteporfin for choroidal neovascularization in angioid streaks.

PURPOSE: To evaluate the efficacy of photodynamic therapy with verteporfin in the management of choroidal neovascularization (CNV) associated with angioid streaks. DESIGN: Retrospective case series. METHODS: Eleven eyes of nine patients with subfoveal or juxtafoveal CNV due to angioid streaks underwent visual acuity testing, ophthalmic examination, color photography, and fluorescein angiography to evaluate the results of photodynamic therapy with verteporfin. Retreatment of persistent CNV was based on criteria from the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Investigation (TAP) except in one case. Follow-up ranged from 5 to 28 months (mean, 17 months). RESULTS: Nine of 11 eyes had subfoveal lesions while two eyes had juxtafoveal lesions on initial examination. Conversion from a choroidal neovascular membrane (CNVM) to a fibrous disciform lesion following photodynamic therapy was observed in nine eyes. Enlargement of the CNVM was noted in seven of these eyes by fluorescein angiography at final follow-up. Initial best-corrected visual acuity (BCVA) ranged from 20/25 to counting fingers (CF) (mean, 20/400; median, 20/200). Final BCVA ranged from 20/20 to CF (mean, 20/600; median, 20/400). Seven eyes with subfoveal CNVM had an initial BCVA of at least 20/200 while only three eyes maintained this level or better at last follow-up. In one patient with a juxtafoveal CNVM in one eye, vision decreased from 20/25 to 20/400 with enlargement and fibrosis of the CNVM and subfoveal extension. In the fellow eye a juxtafoveal CNVM was initially treated and then retreated earlier than TAP criteria at 6 weeks. Vision improved to 20/20 and has remained stable 5 months after the initial treatment. CONCLUSIONS: Verteporfin for choroidal neovascularization-associated with angioid streaks does not appear to significantly alter the course of this disease with most eyes undergoing enlargement and disciform transformation of the neovascular process. However, aggressive management of these patients with biomicroscopic and fluorescein angiographic examination and timely photodynamic therapy with early retreatment when indicated may be beneficial in certain cases.

Adult↗

Laser burn intensity and the risk for choroidal neovascularization in the CNVPT Fellow Eye Study.

OBJECTIVE: To explore the relationship between laser burn intensity and the subsequent risk for development of choroidal neovascularization (CNV) in eyes assigned to the treatment group of the Fellow Eye Study (FES) of the Choroidal Neovascularization Prevention Trial (CNVPT), using computerized methods for laser burn quantitation, and to examine the association between laser burn intensity and (1) drusen reduction and (2) visual acuity. METHODS: Color fundus images before and immediately after laser treatment in the CNVPT FES were available for 53 of 59 eyes. Prelaser and postlaser treatment images were analyzed using custom-developed computer software, allowing for laser burn identification and quantitation. As measures of laser burn intensity, we derived integrated burn rating (IBR) (the integral of the normalized intensity difference divided by the burn pixels), and the maximum burn intensity (MAX). We identified CNV using fluorescein angiography. A Cox proportional hazards model was fit to the time to development of CNV. Baseline and 6-month color photographs were used to determine reduction in drusen. Visual acuity was measured using a standardized protocol. RESULTS: The IBR and MAX spanned 4.5 logarithm units. After adjusting for smoking history and predominant drusen size, the risk ratio for CNV per logarithm unit of increasing laser burn intensity for each measure was 2.0 (P =.05) for MAX and 1.7 (P =.07) for IBR. When patients were divided into high- and low-intensity treatment groups of equal size, the high-intensity group had more drusen reduction (57% vs 32%; P =.14). There was no effect of laser intensity on change in visual acuity at 6 months. CONCLUSION: Higher-intensity prophylactic laser applications appear to be associated with a greater risk for development of CNV and with more extensive drusen reduction.

Choroidal Neovascularization↗

Inhibition of TNF-alpha reduces laser-induced choroidal neovascularization.

To investigate the role of the TNF-alpha in the development of laser-induced choroidal neovascularization (CNV) in a mouse model. Four separate laser burns were applied to induce ruptures of Bruch's membrane and subsequent choroidal neovascularization in C57BL/6J mice. TNF-alpha protein expression was semiquantitatively assessed by Western blot analysis of the choroidal and RPE layer from mice with or without laser treatment. To investigate the effect of TNF-alpha inhibition on CNV formation, animals were treated for 7 days via intraperitonealy implanted osmotic pumps either 3 days before or after laser injury with recombinant TNF receptor P75 (etanercept), a chimeric monoclonal antibody (infliximab), or a purified rat anti-mouse/rat TNF monoclonal antibody (TNF-mAb), respectively. Fluorescein angiography, flat-mount preparations, and histopathology were performed at day 7, 10, or 14 after laser treatment. Western blotting demonstrated that TNF-alpha expression was 4.57-fold higher in the choroid and RPE one week after laser injury compared to control mice without laser. When evaluated one and two weeks after laser injury, etanercept and infliximab given from the 3rd day before laser-damage significantly reduced CNV size and pathological fluorescein leakage compared to the control group after laser treatment only. The inhibitory effect of the monoclonal TNF-alpha antibody on CNV formation was evident two weeks after photocoagulation but not after one week. Only etanercept administered 3 days after laser injury still reduced significantly the development of CNV lesions. Histopathology confirmed that CNV lesions in treated mice were smaller in size compared to the control animals without TNF inhibitor treatment. In conclusion, anti-TNF-alpha treatment with different inhibitors reduces both the size and the leakage of laser-induced CNV. These results suggest the involvement of TNF-alpha in the development of laser-induced CNV and its potential use as a therapeutic agent in the age-related macular degeneration.

Animals↗

Detection of tenascin-C in surgically excised choroidal neovascular membranes.

BACKGROUND: Increase of tenascin-C (TN-C) expression has been found in pathologic tissues in which angiogenesis occurs. The aim of this study was to investigate TN-C expression in human choroidal neovascularization (CNV). METHODS: Ten choroidal neovascular membranes were surgically removed from 10 patients with age-related macular degeneration (n=6) and multifocal choroiditis (n=4). All membranes underwent immunohistochemical evaluation using monoclonal antibodies against TN-C and factor VIII. RESULTS: All membranes were positive for TN-C, which was abundantly and diffusely expressed in the extracellular matrix. CONCLUSIONS: Our results support the concept that TN-C has a role in cell proliferation and neovascularization in humans. TN-C, as a marker of angiogenesis, may provide novel rationales for the development of pharmacologic therapies for neovascular disorders, particularly CNV.

Biomarkers↗

Intravitreal bevacizumab (Avastin) for occult choroidal neovascularization in age-related macular degeneration.

BACKGROUND: The purpose of the study is to report data on short-term safety of intravitreal bevacizumab treatment and its effect on visual function, central retinal thickness, and angiographical changes of occult choroidal neovascularization due to age-related macular degeneration. METHODS: A consecutive interventional case series of 30 patients with active subfoveal occult choroidal neovascularization secondary to age-related macular degeneration was followed after one intravitreal injection of 1.25 mg bevacizumab at baseline and subsequent injections following standardized criteria. At baseline and follow-up visits patients had visual acuity assessment, intraocular pressure measurement, fluorescein angiography, and optical coherence tomography imaging. RESULTS: No serious ocular or systemic adverse events were identified. A significant increase of intraocular pressure or signs of retinal toxicity or endophthalmitis were not detected in any patient. Optical coherence tomography revealed significant decrease (p < 0.001) in central retinal thickness after 1 week, 4 weeks, and 12 weeks, respectively. Fluorescein leakage decreased within 1 week and improvement was maintained at week 12 in the majority of patients. Visual acuity improved or remained stable in 29 of 30 patients; improvement of 3 or more lines was seen in 14 of 30 patients; one patients showed improvement of 6 lines. No patient had severe vision loss of 6 lines or more; moderate vision loss of 3 lines was seen in one patient. Re-injections of bevacizumab according to standard criteria were performed one to two times during the follow-up period of 12 weeks with a re-injection interval of 4 to 18 weeks (median 8 weeks). CONCLUSIONS: Short-term results suggest that intravitreal injection of bevacizumab is well tolerated and for the majority of patients with occult choroidal neovascularization in AMD results in improvement of visual acuity, decrease in central retina thickness, and reduction of angiographic leakage of the lesion. Bevacizumab as intravitreal treatment may provide a novel therapeutic option for selected patients with exudative AMD. Randomized prospective multicenter trials seem justified to further evaluate long term effects and impact of intravitreal bevacizumab on different subtypes of AMD compared to established therapies.

Aged↗

Photodynamic therapy of idiopathic and inflammatory choroidal neovascularization in young adults.

PURPOSE: To evaluate the treatment of subfoveal choroidal neovascularization (CNV) using photodynamic therapy (PDT) with verteporfin (Visudyne; Novartis, Duluth, GA) in young adults. DESIGN: Retrospective noncomparative interventional case series. PARTICIPANTS: Nineteen eyes of 17 patients with classic, subfoveal CNV treated with PDT using verteporfin, excluding eyes with CNV secondary to age-related macular degeneration, angioid streaks, and myopia. MAIN OUTCOME MEASURES: Snellen visual acuity before and after PDT. RESULTS: Nineteen eyes were followed an average of 12.8 months (range, 4-33 months) after PDT. Before treatment, visual acuity measured > or = 20/40 in 0 eyes (0.0%), < 20/40 to > 20/200 in 11 eyes (57.9%), and < or =20/200 in 8 eyes (42.1%). After treatment, visual acuity measured > or =20/40 in four eyes (21.1%), < 20/40 to > 20/200 in eight eyes (42.1%), and < or =20/200 in seven eyes (36.8%). Six eyes (31.6%) underwent retreatment, with only two eyes retreated twice. Four eyes underwent eventual surgical removal of the CNV after PDT. CONCLUSIONS: Photodynamic therapy seems to be useful in stabilizing and improving visual acuity in young adults with subfoveal CNV secondary to idiopathic and inflammatory etiologies.

Adult↗

Socioeconomic status and clinical features of patients undergoing photodynamic therapy or transpupillary thermotherapy for subfoveal choroidal neovascularization due to age-related macular degeneration.

BACKGROUND: The purpose of this study was to compare baseline clinical and socioeconomic features of patients undergoing self-funded photodynamic therapy (PDT) or government-funded subthreshold transpupillary thermotherapy (TTT) with a diode laser for subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). METHODS: Between July 2000 and August 2001, 115 patients with subfoveal choroidal neovascularization secondary to AMD were offered PDT as an initial intervention. If individuals believed that they could not afford or did not want PDT, then TTT was offered. In masked fashion, leakage pattern and lesion size were determined retrospectively from pretreatment angiograms. Baseline visual acuity was determined with autorefraction and subsequent Snellen testing. The mean income of each treatment group was estimated from the average sex-specific income for each subject's postal code, based on the 1996 Canadian census data. The average education level for each subject's postal code was also determined. RESULTS: The patients who were not willing to pay for PDT had significantly worse macular disease before treatment (larger lesions and poorer visual acuity) and a significantly lower mean income than the patients who were willing to pay for PDT. INTERPRETATION: The severity of exudative choroidal neovascularization appears to be associated with lower socioeconomic status.

Aged↗

Surgical removal of subfoveal choroidal neovascularization in presumed ocular histoplasmosis: stability of early visual results.

PURPOSE: The authors assess the stability of visual acuity outcomes after the surgical removal of subfoveal choroidal neovascularization in a large series of patients with presumed ocular histoplasmosis syndrome (POHS). METHODS: A retrospective study of 117 consecutive patients undergoing vitrectomy between February 1990 and December 1994 was performed. All patients underwent the surgical removal of subfoveal choroidal neovascularization due to POHS and had at least 3 months of follow-up. Postoperative Snellen visual acuity was the primary study endpoint. RESULTS: With a median follow-up of 13 months (range, 3-46 months), 35% of patients had postoperative visual acuity of 20/40 or better, and 40% had improvement of three or more Snellen lines after surgery. In a subset of 54 eyes followed for at least 1 year, 91% showed stable or improved vision between the 3- and 12-month time points, and 85% showed stable or improved vision between 3 months and final visit. CONCLUSION: Follow-up of a large number of patients appears to confirm initially encouraging results and to suggest stability of beneficial effect after the surgical removal of subfoveal choroidal neovascularization in POHS.

Adolescent↗

Treatment options In subfoveal choroidal neovascularization secondary to age-related macular degeneration.

Laser photocoagulation of the entire area of the neovascular lesion is the only proven treatment for subfoveal choroidal neovascularization secondary to age-related macular degeneration with a poor natural history. However, there are some limiting factors such as patient eligibility, a significant decline in visual acuity after treatment, and a very low possibility of a final vision of 20/100 or better. Although no large benefit of other treatment modalities, such as indocyanine green videoangiography-guided laser photocoagulation, surgical removal of neovascular membranes, and radiation therapy, has yet been proven, carefully selected patients may be suitable candidates for such treatments. This article reviews the status of treatment modalities for subfoveal choroidal neovascularization secondary to age-related macular degeneration, including laser photocoagulation of the entire area of the neovascular lesion, and discusses factors prognostic of visual outcome in these treatment options.

Choroid↗

Adenoma of the retinal pigment epithelium simulating a juxtapapillary choroidal neovascular membrane.

We report a case of an adenoma of the retinal pigment epithelium that clinically simulated a juxtapapillary choroidal neovascular membrane in a 60-year-old man. Fluorescein angiography supported the diagnosis of a juxtapapillary choroidal neovascular membrane in his left eye. After 13 years the lesion become slightly pigmented and the optic disc became swollen. The possibility of choroidal melanoma with optic disc invasion was considered, and the eye was enucleated. The lesion proved histopathologically to be an adenoma of the retinal pigment epithelium.

Adenoma↗

Risk factors for choroidal neovascularization and vision loss in the fellow eye study of CNVPT.

PURPOSE: To identify risk factors for the development of choroidal neovascularization (CNV) and vision loss in the Fellow Eye Study of the Choroidal Neovascularization Prevention Trial. METHODS: Retrospective review of 121 patients enrolled in a multicentered, randomized, controlled trial. Patients had neovascular age-related macular degeneration in one eye and more than 10 large drusen in the other eye. Records of patients randomly assigned to laser treatment or observation were reviewed through 4 years of follow-up. Three candidate risk factors for the development of CNV and vision loss were evaluated. RESULTS: Eyes with hyperfluorescent drusen on fluorescein angiography at 3 minutes appeared to have a decreased risk of CNV. Patchy choroidal filling was seen in 14% of patients. Eyes with patchy choroidal perfusion showed a higher risk of developing CNV that was not statistically significant, and the increased risk was present only in treated eyes. Reticular pseudodrusen were present in only three eyes. CONCLUSIONS: Reticular pseudodrusen were rare. Late drusen fluorescence may protect against the development of CNV.

Aged↗

Growth factor localization in choroidal neovascular membranes of age-related macular degeneration.

PURPOSE: Because several polypeptide growth factors are known to influence capillary endothelial cell mitogenesis, the authors investigated the presence of some of these molecules in choroidal neovascular membranes (CNVMs) removed surgically from human subjects with age-related macular degeneration (ARMD). METHODS: The authors performed immunoelectron microscopic studies on surgically removed submacular CNVMs from nine subjects with ARMD and from one subject with ARMD whose eye was studied after death. These were compared with retinal pigment epithelial (RPE) and choroidal tissue from eight normal subjects whose eyes were received after death and one received after massive trauma. RESULTS: RPE cells from the CNVMs were strongly immunoreactive for acidic and basic fibroblast growth factor (aFGF and bFGF) and for transforming growth factor beta (TGF beta). Some of the immunoreactivity was intracytoplasmic, but most was intralysosomal. In addition, some choriocapillary endothelial cells located close to the RPE layer in these CNVMs were immunopositive for bFGF and for FGF receptor. Reaction product for these two substances was located at regular intervals along the endothelial plasma membrane on both the anteluminal and the luminal side of the cells, suggesting a physiological reaction between the growth factor and its receptor. Choriocapillary endothelial cells deeper within the stroma were unreactive to bFGF and FGF receptor antibodies. There was little immunoreactivity for the growth factors in RPE or choriocapillary endothelial cells from normal eyes. The aFGF and bFGF immunoreactivity was highly specific because aFGF positivity was abolished when the antibody was incubated with 10(-6) M aFGF but not a with the same concentration of bFGF, whereas bFGF immunoreactivity was abolished by incubation of the antibody with bFGF but not with aFGF. RPE cells from normal eyes and from eyes affected by ARMD showed strong cytoplasmic immunoreactivity to antibodies for cytoplasmic retinaldehyde-binding protein and superoxide dismutase and weak reactivity to antibodies for vimentin. CONCLUSIONS: These results are consistent with the hypothesis that one or both FGFs are causally related to the development of choroidal neovascularization. The authors have reported similar observations in experimental choroidal neovascularization in pigmented rats after red krypton laser photocoagulation. TGF beta may serve to modulate the effects of these mitogens. The authors suggest that growth factor production is induced in RPE cells after physical or chemical damage. Because of the damage to these cells, FGF molecules can be released from the cells despite the absence of a "signal sequence" in the DNA coding for FGF production.

Aged↗