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Objective: To evaluate the effect of photo-dynamic therapy in the destruction of experimental pigmented choroidal melanoma using a liposomal preparation of benzoporphyrin derivative (BPD), verteporfin., Methods: Pigmented choroidal tumors were established in 44 New Zealand albino rabbit eyes. Animals were treated with daily injections of cyclosporine. Funduscopic examinations and ultrasonography were used to follow the tumor growth. When the tumor exceeded 2 mm in thickness (tumor height ranged from 2.0 - 4.6 mm), the rabbits were divided into three groups. In the 10 rabbits in the control group, 6 were treated with laser 120 - 150 J/cm(2) for tumors with the height range of 2.1 - 3.0 mm without photo-dynamic therapy, and 4 were not treated at all. The benzoporphyrin derivative was injected intravenously (1 mg/kg) for the rabbits in treatment group I (14 rabbits) and II (20 rabbits), and 692 nm argon-pumped dye laser at different light doses 60 - 150 J/cm(2) was used to irradiate the tumors. After the treatment for 4 - 6 weeks, the rabbits were sacrificed and the therapeutic results were observed., Results: In treatment group I, the irradiation dose was 60 - 80 J/cm(2) and the tumor height was < 3 mm, in comparison with that of the control group the difference being very significant (P < 0.001). In the treatment group II, the thickness of the tumor was 3.0 - 4.6 mm and the irradiation dose was > 80 J/cm(2) (P < 0.001, companed with the control group). In contrast, the tumor grew continuously in all the animals in the control group and filled most of the vitreous cavity by 2 - 3 weeks., Conclusion: These data suggest that photodynamic therapy have a role in the management of pigmented choroidal melanomas.

Purpose: To develop a model of verteporfin photodynamic therapy (PDT) for experimental choroidal neovascularization CNV in the rat., Methods: A laser injury model was used to induce experimental CNV in rats. The transit and accumulation of the photosensitizer verteporfin was assessed angiographically in CNV lesions, to determine the optimal time for delivery of light energy. The CNV lesions were then treated with verteporfin PDT, with two doses of verteporfin (3.0 and 6.0 mg/m(2)) and four activating doses of light energy (10, 25, 50, and 100 J/cm(2)). Closure of the CNV was assessed both angiographically and histologically. Verteporfin PDT was also performed on areas of normal choroid and retina at the two verteporfin doses and four light energy doses. The effect of these treatments on these structures was also assessed angiographically and histologically., Results: Peak verteporfin intensities in the CNV were detected at 15 to 20 minutes after intravenous injection. Rates of closure of the CNV varied as a function of the dose of verteporfin and of the activating light energy. Angiographic closure of the CNV correlated with damage to the neovascular complex, as seen with light and electron microscopy. Damage to areas of normal choroid and retina treated with verteporfin PDT also varied as a function of the verteporfin and light energy doses., Conclusions: Verteporfin PDT for experimental CNV in the rat is a feasible, effective, and reproducible model that can be used for testing the efficacy of adjunctive therapy to verteporfin PDT.

Functional magnetic resonance imaging (MRI), using monocrystalline iron oxide nanoparticles (MION) as a new intravascular contrast agent, was adapted for a rabbit model of pigmented choroidal melanoma. Three-dimensionally spoiled gradient recalled sequences were used for the quantitative assessment of blood volume and cellular uptake. In all ocular tissues studied, MION reduced the T(2)-weighted signal intensity within 0.5 h and at 24 h (both p < 0.05) after the injection. In individual tumors, MION reduced the T(2)-weighted signal intensity by 46-78% within 0.5 h and by 24-48% at 24 h. In addition, MION increased the T(1)-weighted signal intensity in all tissues. T(2) yielded a higher sensitivity than T(1)-weighted images. Functional MRI with MION is a noninvasive technique with regard to the eye, permitting measurement of blood volume and cellular uptake of the contrast agent. Further study is necessary to determine the feasibility of this technique for the tumor diagnosis and evaluation of tumor viability following treatments., (Copyright 2002 S. Karger AG, Basel)

Purpose: To investigate the expression of pigment epithelium-derived factor (PEDF) in the rat laser-injury model of choroidal neovascularization (CNV)., Methods: Retinas were immunostained for PEDF at different times (1, 2, and 3 weeks) after laser injury. Levels of PEDF protein in the vitreous at 1, 3, 7, 14, and 28 days after laser injury were also assayed by Western blot., Results: Protein levels of PEDF in the vitreous were increased during the first 7 days after CNV induction. Immunostaining for PEDF was observed throughout normal nonlasered control retinas, sham-lasered retinas, and areas remote to laser lesions, which were generally more intense in the outer nuclear layer (ONL) and less intense in the internal nuclear layer (INL). Decreased expression of PEDF was observed in flanking areas adjacent to the injury site and was confined mainly to the ONL. In the injury sites, immunostaining within the ONL was either absent or decreased for up to 3 weeks after laser injury (the duration of the study). Preadsorption of the anti-PEDF antibody with the immunizing peptide blocked specific labeling in the retina., Conclusions: These results demonstrate an inverse correlation of expression of PEDF and formation of CNV in the experimental model and suggest that decreased expression of PEDF plays a permissive role in the formation of CNV. PEDF analogues may be a reasonable treatment strategy for CNV.

Objective: To evaluate the safety and efficacy of intravitreal injections of an antigen-binding fragment of a recombinant humanized monoclonal antibody directed toward vascular endothelial growth factor (rhuFab VEGF) in a monkey model of choroidal neovascularization (CNV)., Methods: In phase 1 of the study, each animal received intravitreal injections, 500 microg per eye, of rhuFab VEGF in one eye (prevention eye), while the contralateral eye received rhuFab VEGF vehicle (control eye) at 2-week intervals. On day 21, laser photocoagulation was performed to induce CNV. In phase 2, the vehicle-treated eye was crossed over and both eyes received 500 microg of rhuFab VEGF beginning 21 days following laser-induced injury at days 42 and 56. The eyes were monitored by ophthalmic examinations, color photographs, and fluorescein angiography., Results: rhuFab VEGF did not cause any ocular hemorrhages. All eyes treated with rhuFab VEGF developed acute anterior chamber inflammation within 24 hours of the first injection that resolved within 1 week, and this inflammation was less severe with subsequent injections. The incidence of CNV, defined angiographically, was significantly lower in the prevention eyes than the control eyes (P<.001). Subsequent treatments were associated with less leakage in eyes with established CNV that were crossed over from the control eyes to the treatment eyes (P =.001)., Conclusions: Intravitreal rhuFab VEGF injections prevented formation of clinically significant CNV in cynomolgus monkeys and decreased leakage of already formed CNV with no significant toxic effects., Clinical Relevance: This study provides the nonclinical proof of principle for ongoing clinical studies of intravitreally injected rhuFab VEGF in patients with neovascular age-related macular degeneration.

Purpose: The localization and site of action of photosensitizers in the eye may be important for photodynamic therapy for fundus disorders but remain poorly understood for most agents. We investigated the intraocular localization of xanthene, phthalocyanine, and chlorin photosensitizers by using fluorescence microscopy and digital fundus fluorescence angiography., Methods: Rose bengal (40 mg/kg), aluminum phthalocyanine tetrasulfonate (CASPc) (5 mg/kg), or chlorin e6 (2 mg/kg) was intravenously administered to albino rabbits. The eyes were enucleated and examined by means of fluorescence microscopy 5, 20, 60, and 120 minutes and 24 hours after dye injection. In vivo digital fundus fluorescence angiography with use of rose bengal (2-4 mg/kg), CASPc (2 mg/kg), and chlorin e6 (2 mg/kg) was performed., Results: For all agents studied pathologically, there was moderate fluorescence from the choroid and retinal pigment epithelium 5 minutes after dye injection. Mild fluorescence detected from the photoreceptor outer segments at 5 minutes was increased at 20 minutes. Angiographic studies with use of rose bengal, CASPc, and chlorin e6 revealed differences in the pattern and rate of photosensitizer accumulation., Conclusions: Rose bengal, CASPc, and chlorin e6 accumulate rapidly in the choroid and retinal pigment epithelium and less rapidly in the outer retina. Differences in ocular localization of these photosensitizers were demonstrated. The significance of these findings for potential photodynamic therapy with these agents requires further investigation.

Purpose: To quantitate long-term risk of local treatment failure after proton irradiation of choroidal/ciliary body melanomas and to evaluate risk of metastasis-related deaths after local failure., Methods: We followed prospectively 1,922 patients treated at the Harvard Cyclotron between January 1975 and December 1996 for local recurrences of their tumors. Mortality surveillance was completed through June 1999. For analysis, patient follow-up continued until tumor regrowth was detected or, in patients without recurrence, until the date of the last dilated examination prior to April 1998. Actuarial methods were used to calculate rates of recurrence and metastatic deaths. Cox regression models were constructed to evaluate risk factors for these outcomes., Results: Median ocular follow-up after irradiation was 5.2 years. Local recurrence was documented in 45 patients by ultrasound and/or sequential fundus photographs; in 17 more patients, the eye was enucleated due to suspected but unconfirmed tumor growth. Recurrences were documented between 2 months and 11.3 years after irradiation. The 5- and 10-year rates of regrowth, including suspected cases, were 3.2% (95% confidence interval [CI], 2.5%-4.2%), and 4.3% (95% CI, 3.3%-5.6%). Among the 45 documented recurrences, about one half (21) occurred at the margin, presumably due to treatment planning errors. The remaining cases represented extrascleral extensions (nine cases), ring melanomas (six cases), or uncontrolled tumor (nine cases). Recurrence of the tumor was independently related to risk of tumor-related death., Conclusion: These data, based on relatively long-term follow-up, demonstrate that excellent local control is maintained after proton therapy and that patients with recurrences experience poorer survival.

Objective: To describe early and unusual features in 16 patients with deferoxamine-induced retinal toxicity and to assess the role of diagnostic tests in the diagnosis and management of patients with the disorder., Design: Retrospective, observational case series., Participants: Sixteen patients with deferoxamine retinopathy identified from members of the Vitreous, Retina, and Macula societies of the United States. INTERVENTION/TESTING: The patients underwent complete ophthalmologic examination. Most patients were also evaluated by fluorescein angiography and electrophysiologic testing. The diagnosis was based on the medical history, systemic and ocular findings, and the results of electrophysiologic tests., Main Outcome Measures: Ocular symptoms, ophthalmoscopic, fluoroangiographic, and electrophysiologic findings., Results: We confirmed previously reported findings in patients with established disease, including macular and/or peripheral pigmentary changes, reduced electroretinographic (ERG) amplitudes, and reduced electrooculographic (EOG) light-peak to dark-trough ratios. Peripapillary, papillomacular, and paramacular patterns of retinal pigment epithelial (RPE) degeneration were each observed in one patient. Diffuse RPE or outer retinal fluorescence by fluorescein angiography was a marker for active retinopathy both at the onset of disease and during recurrence and preceded the development of RPE pigment mottling., Conclusions: Unusual patterns of deferoxamine retinopathy may occur in addition to the foveomacular and/or peripheral patterns previously described. Fluorescein angiography is particularly useful for determining whether there is ongoing retinal/RPE injury. ERG and EOG testing may indicate earlier or more widespread injury than is suggested by fundus examination alone. Patients who do not discontinue deferoxamine after the development of retinopathy risk further retinal/RPE injury and visual deterioration.

Purpose: To report a patient who presented with photopsias, night blindness, exudative retinal detachments, and melanoma-associated retinopathy in her right eye 23 years after the left eye was enucleated for a choroidal melanoma., Methods: Assessment of fundus findings, fluorescein angiograms, and electroretinograms., Results: The patient had recurrent exudative detachments of the macula in her right eye and electroretinogram responses consistent with the diagnosis of melanoma-associated retinopathy. The abdominal computed tomography (CT) scan was negative, but 13 months later, CT scanning revealed many masses in her liver. Fine-needle biopsy confirmed the diagnosis of metastatic melanoma., Conclusion: To our knowledge, this is the first report of melanoma-associated retinopathy in a patient with a previous choroidal melanoma.

Purpose: We examined untreated and irradiated choroidal melanomas with color Doppler imaging (CDI), a noninvasive method providing quantitative measures of blood flow, to determine if the tumor vessel damage associated with irradiation can be detected using this technology., Methods: CDI was performed on 122 untreated and 76 previously irradiated tumors using a Q2000 color Doppler ultrasound unit. Spectral analysis was performed on all detectable vascular regions within the tumor to obtain estimates of the peak systolic and end diastolic flow velocities and resistive index ((syst-diast)/syst)., Results: Vessels were detected in 93% of the untreated tumors and in 63% of the treated tumors (p<0.001, X2), and the median number of vascular regions found was higher among untreated tumors (3 vs 1, p=0.001, Wilcoxon Rank Sum). The effect of treatment status on the detection of tumor vessels was significant (p=0.039), controlling for age, sex, largest tumor pretreatment diameter, and tumor height at CDI in a logistic regression model. Mean resistive index was lower in the untreated tumors (0.53 vs 0.58, p=0.0050), controlling for tumor height and other covariates in an analysis of variance., Conclusions: On examination with CDI, irradiated tumors had fewer detectable vascular regions and greater resistance to flow than untreated tumors, a pattern consistent with known radiation effects.

Purpose: To examine the effect of combining angiostatin with photodynamic therapy (PDT) using Lutetium Texaphyrin (Lu-Tex; Alcon, Fort Worth, TX) as a photosensitizer in bovine retinal capillary endothelial (BRCE) and retinal pigment epithelial (RPE) cells and to determine the mode of PDT-induced cell death in these cell lines., Methods: Cultured BRCE and RPE cells were incubated with angiostatin (500 ng/ml) for 18 hours and subjected to Lu-Tex/PDT, using treatment parameters previously optimized (3 microgram/ml Lu-Tex for 30 minutes followed by timed irradiation at 732 nm). Cellular survival was assessed after a 1-week cellular proliferation. Data were analyzed using Student's t-test. Caspase 3 activity was monitored in cells after PDT using a fluorogenic substrate, (Asp-Glu-Val-Asp)-AFC (7-amino-4-trifluoromethyl coumarin) [DEVD-AFC], of caspase 3. After PDT, expression of Bcl-2, Bcl-x(L), Bax, and Bak was also examined in cell lysates by Western blot analysis., Results: A synergistic cytotoxic effect of angiostatin and Lu-Tex/PDT was observed in BRCE cells at all fluences used (5, 10, and 20 J/cm(2); P

Background: Ciliary body location is an established prognostic factor for metastasis-related death from uveal melanoma. We evaluated alternative approaches for classifying this covariate when constructing predictive models of patient survival., Methods and Design: The analyses were based on a consecutive series of 1848 primary choroidal and/or ciliary body melanoma patients treated with proton beam irradiation (70 cobalt gray equivalent in 5 fractions) at the Harvard Cyclotron Laboratory, Boston, Mass, between July 1975 and December 1995. For each patient, the anatomic site of the tumor was classified according to an estimate of the proportion of the tumor base lying anterior to the ora serrata. Using proportional hazards regression, we estimated relative risk ratios and death rates from melanoma metastasis according to the extent of ciliary body involvement. All estimates were adjusted for other established prognostic factors., Results: Patients were followed up through April 30, 1998; none were lost to follow-up. Of 1848 patients analyzed, 378 died of melanoma metastasis. The median follow-up period among survivors was 9.5 years. Ciliary body origin (>50% of tumor base anterior to the ora serrata) was positively associated with tumor pigmentation (P<.001), tumor height (P<.001), and extrascleral extension of the tumor (P<.001). Compared with tumors involving only the choroid, melanoma-associated death rates increased with the proportion of the tumor base lying within the ciliary body (P =. 006); the multivariate-adjusted relative risk ratio for greater than 75% involvement was 2.30 (95% confidence interval [CI], 1.26-4.23). The covariate-adjusted 5-year death rates for ciliary body origin and choroidal origin were 15.9% (95% CI, 11.3%-21.2%) and 9.8% (95% CI, 8.3%-11.7%), respectively., Conclusion: Patients with melanomas of presumed ciliary body origin seem to be subject to a higher risk of death resulting from melanoma metastasis. Arch Ophthalmol. 2000;118:1066-1070

This study attempts to document the occurrence of tumors with respect to clock hour location and distance from the macula and to evaluate tumor location in relation to retinal topography and light dose distribution on the retinal sphere. Analysis of patterns of tumor initiation may provide new evidence to clarify the controversy regarding the possible light-related etiology of choroidal melanoma. Incident cases of choroidal and ciliary body melanoma in Massachusetts residents diagnosed between 1984 and 1993 were the basis for analysis. Conventional fundus drawings and photos were used to assess the initiation site of each tumor. The initiation site was defined as the intersect between the largest tumor diameter and the largest perpendicular diameter of the tumor. Initiation sites were recorded using spherical coordinates. The retinal sphere was divided into 61 mutually exclusive sectors defined according to clock hour and anteroposterior distance from the macula. Rates of initiation were computed for each sector, overall, and according to gender and other clinical factors. Results were similar in left and right eyes; therefore, these were combined in analysis. Tumor initiation had a predilection for the macula (P < 0.0001). Overall, no significant clock hour preference was observed (P = 0.63). However, the parafoveal zone showed a strong circular trend (P < 0.01), with highest rates occurring in the temporal region, and the lowest rates occurring in the nasal region. Rates of occurrence in six progressively more anterior concentric zones (designated as the foveal, parafoveal, posterior, peripheral, anterior, and ciliary body zones) were 21.4, 14.2, 12.1, 8.9, 4.5, and 4.3 counts per spherical unit per 1000 eyes, respectively. Concentric zone location did not vary by gender (P = 0.93) or laterality (P = 0.78). However, posterior location was associated with light iris color (P = 0.01). Tumor diameters were largest in the peripheral region of the fundus and smallest in the macular and ciliary body zone (P < 0.001). Clock hour location was not influenced by gender (P = 0.74), laterality (P = 0.53), iris color (P = 0.84), or tumor diameter (P = 0.73). Results suggest that tumor initiation is not uniformly distributed, with rates of occurrence concentrated in the macular area and decreasing monotonically with distance from the macula to the ciliary body. This pattern is consistent with the retinal topography and correlates positively with the dose distribution of solar light on the retinal sphere.

Objective: To determine if a reduction in proton radiation dose from the standard dose of 70 cobalt gray equivalents (CGE) to 50 CGE would decrease radiation-induced complications, thereby improving visual prognosis, without compromising local tumor control for patients with uveal melanoma at high risk of these complications., Design: Randomized, double-masked clinical trial., Participants: A total of 188 patients with small or medium-sized choroidal melanomas (<15 mm in diameter and <5 mm in height) near the optic disc or macula (within 4 disc diameters of either structure)., Methods: Patients were treated with proton beam therapy at doses of either 50 CGE or 70 CGE between October 1989 and July 1994, and followed up biannually through April 1998. Outcomes included visual acuity, radiation complications, melanoma recurrence, and metastasis., Results: Proportions of patients retaining visual acuity of at least 20/200 were similar in the 2 dose groups at 5 years after radiation (approximately 55%). Similar numbers of patients in each group experienced tumor regrowth (2 patients at 50 CGE vs 3 patients at 70 CGE; P>.99) and metastasis (7 patients at 50 CGE vs 8 patients at 70 CGE;P=.79). Five-year rates of radiation maculopathy also were similar (for both groups, approximately 75% for tumors within 1 disc diameter and 40% for tumors >1 disc diameter from the macula). Rates of radiation papillopathy were nonsignificantly decreased in the 50-CGE treatment group when tumors were located 1 disc diameter or less from the optic disc (P=.20). Patients treated with the lower dose also experienced significantly less visual field loss., Conclusions: This level of dose reduction did not result in a lesser degree of visual acuity loss. The lower-dose group did experience significantly less visual field loss. Local tumor recurrence and metastatic death rates were similar in both dose groups. Arch Ophthalmol. 2000;118:773-778

Purpose: To investigate the feasibility of transscleral drug delivery to the choroid and retina., Methods: An osmotic pump was used to deliver IgG across the sclera of pigmented rabbits, and levels were measured in the choroid, retina, vitreous humor, aqueous humor, orbit, and plasma over 28 days. This method was then used to deliver an anti-intercellular adhesion molecule-1 (ICAM-1) monoclonal antibody (mAb), and its effect on inhibiting vascular endothelial growth factor (VEGF)-induced leukostasis in the choroid and retina was determined by measuring tissue myeloperoxidase (MPO) activity., Results: Levels of retinal and choroidal IgG were significantly higher than baseline at all points up to 28 days (P < or = 0.01). IgG levels in the orbit, vitreous humor, aqueous humor, and plasma were negligible (P > 0.05). MPO activity in the choroid of eyes treated with anti-ICAM-1 mAb was 80% less (P = 0.01) than in eyes receiving an equal rate of delivery of an isotype control antibody. Inhibition of MPO activity in the retina was 70% (P = 0.01). The plasma concentration of anti-ICAM-1 mAb was 31,000-fold less than the concentration in the osmotic pump., Conclusions: Minimally invasive transscleral delivery can be used to deliver therapeutic levels of bioactive drugs to the choroid and retina with negligible systemic absorption. This method of ocular drug delivery may be used in the treatment of a variety of chorioretinal disorders.

Purpose: To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size., Methods: Fresh rabbit sclera was mounted in a two-chamber diffusion apparatus, and its permeability to sodium fluorescein, fluorescein isothiocyanate (FITC)-conjugated bovine serum albumin, FITC-IgG, and FITC dextrans ranging in molecular weight from 4 to 150 kDa was determined by fluorescence spectrophotometry. Electron microscopy was used to assess the impact of the experimental design on scleral ultrastructural integrity. The effect of the diffusion apparatus on scleral hydration was examined. Rabbit scleral permeability was compared with previously reported data for human and bovine sclera., Results: Scleral permeability decreased with increasing molecular weight and molecular radius, consistent with previous human and bovine data. Molecular radius was a better predictor of scleral permeability than molecular weight. The sclera was more permeable to globular proteins than to linear dextrans of similar molecular weight. The experimental apparatus did not alter scleral ultrastructure. Permeability of rabbit sclera was similar to human sclera but greater than bovine sclera., Conclusions: Large molecules, such as IgG, diffuse across sclera in a manner consistent with porous diffusion through a fiber matrix. Transscleral delivery of immunoglobulins and other large compounds to the choroid and retina may be feasible.

Objective: To evaluate short-term safety and the effects on visual acuity and fluorescein angiography of single or multiple sessions of photodynamic therapy with verteporfin for choroidal neovascularization (CNV) not related to age-related macular degeneration (AMD), including pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes., Design: A nonrandomized, multicenter, open-label, dose-escalation phase 1 and 2 clinical trial., Setting: Four ophthalmic centers in Europe and North America providing retinal care., Participants: Thirteen patients with subfoveal CNV due to pathologic myopia, the ocular histoplasmosis syndrome, angioid streaks, or idiopathic causes., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of photodynamic therapy treatments with verteporfin. Follow-up ranged from 12 weeks for patients who were treated once to 43 weeks for patients who were treated up to 4 times., Results: Verteporfin therapy was well tolerated in patients with CNV not related to AMD. No deterioration in visual acuity was observed; most patients gained at least 1 line of vision. Reduction in the size of leakage area from classic CNV was noted in all patients as early as 1 week after verteporfin therapy, with complete absence of leakage from classic CNV in almost half of the patients. Improvement in visual acuity after verteporfin therapy was greatest (+6, +8, and +9 lines) in 3 patients with relatively poor initial visual acuity (between 20/200 and 20/800). Up to 4 treatments were found to have short-term safety even with retreatment intervals as short as 4 weeks., Conclusions: Treatment of CNV not related to AMD with verteporfin therapy achieves short-term cessation of fluorescein leakage from CNV in a small number of patients without loss of vision. Further randomized clinical trials including a larger number of patients are under way to confirm whether verteporfin therapy is beneficial for subfoveal CNV not related to AMD.

Objective: Radiation optic neuropathy usually occurs months to years after exposure of the anterior visual pathways to ionizing radiation. It is characterized by high signal on gadolinium-enhanced T1-weighted magnetic resonance imaging. Radiation-induced endothelial cell damage resulting in blood-nerve barrier breakdown is hypothesized to produce this pattern, but histologic evidence of this in the optic nerve is lacking. We attempted to evaluate the effect of radiation on endothelial cells in the optic nerve., Design: Case-controlled histologic study., Methods: We studied the optic nerves of 16 enucleated eyes from patients with uveal melanoma treated with proton beam irradiation, 6 from normal eyes and 5 from eyes with unirradiated uveal melanomas. Binding of Ulex europaeus agglutinin I (UEA-I) lectin was used to identify endothelial cells in single paraffin sections. Transverse and longitudinal sections of vessels were counted in masked fashion., Results: There were 49.4+/-6.9 transversely sectioned endothelial cells per millimeter of nerve in 6 optic nerves exposed to 0 to 1000 cGyE ("low-dose") compared with 17.3+/-5.3 in 10 nerves exposed to 5500 to 7000 cGyE ("high-dose") (P = 0.002). Longitudinally sectioned vessels stained with UEA-I were separately identified, with 11.5+/-2.1 in the low-dose group and 5.6+/-1.6 in the high-dose group (P = 0.044). The thickness and staining of the endothelial cell layer appeared greater in the high-dose group. Endothelial cell counts did not correlate with age, gender, acuity, or interval after irradiation., Conclusions: Increased radiation dosage to the optic nerve correlates with smaller numbers of endothelial cells.

Objective: To determine if anti-vascular endothelial growth factor antibody and a range of dextrans with varying diffusion radii and molecular weights are permeable through experimental choroidal neovascularization (CNV)., Methods: Choroidal neovascularization was induced in 10 cynomolgus monkey retinas by means of argon laser injury. Digital fundus fluorescein angiograms were performed with fluorescein sodium, fluoresceinated IgG antibodies (anti-vascular endothelial growth factor and a control antibody), and fluoresceinated dextrans with molecular weights of 4, 20, 40, 70 and 150 kd. The 40- and 70-kd dextrans straddle the effective diffusion radius of IgG. For each reagent, early and late angiograms were performed in a standardized fashion, with follow-up images obtained to monitor residual fluorescence., Results: Perfusion of retinal vessels and choroidal vasculature was seen with all reagents. Fluorescein and 4- and 20-kd dextran leaked rapidly from the CNV within the first minute. Angiography with the use of 40-kd dextran and fluoresceinated antibody, either anti-vascular endothelial growth factor or control IgG, showed fluorescence within the CNV that increased during the first 1 to 5 hours, with mild leakage from the CNV. By 24 hours, fluorescence in the CNV was minimal, although in some cases persistent fluorescence in the surrounding tissue was evident up to 2 weeks. The 70-kd dextran showed fluorescence within the CNV and leakage in 1 of 3 eyes. The 150-kd dextran showed fluorescence within the CNV but did not demonstrate leakage., Conclusions: Fluoresceinated antibodies and dextran with smaller effective diffusion radii showed CNV perfusion and leakage. Dextrans with larger effective diffusion radii (70 kd and 150 kd) perfused into CNV but did not show leakage consistently., Clinical Relevance: Determining the permeablity of antibodies and molecules of similar size through CNV can help ascertain the feasibility of using intravenously administered antibodies against angiogenic growth factors as a future treatment for choroidal neovascularization.

Age-related macular degeneration is the leading cause of blindness in developing countries. Irradiating the exudative form, in which a choroidal neovascular membrane develops in the subfoveal area, is presently a treatment under investigation. In 1995, Massachusetts General Hospital, collaborating with Massachusetts Eye and Ear Infirmary, initiated a protocol to treat SCNV membranes using the proton beam at the Harvard Cyclotron Laboratory and the EYEPLAN program with a light-field setup. EYEPLAN requires the axial eye length, membrane dimensions, and manipulation of the eye to include a 4.0-mm radial margin around the membrane so that the aperture margin (50% isodose line on the posterior retina) abuts the inferior aspect of the limbus. Review of 100 individually prepared plans showed that 95% of the fabricated apertures were circular (aspect ratio < 1.095) with diameters 9.5 to 15.0 mm. This information was used to develop an automated standard plan. Thirty-nine plans were developed for axial lengths ranging from 21.0 to 25.0 mm and membrane sizes from 1.5 to 6.75 mm in the usual way as the reviewed ones. Circular targets were outlined centered on the fovea. Distal and proximal 90% ranges (modulation) to the target, and doses to macula, optic disc, lens, ciliary body, retina, and globe were calculated. An automated standard plan requiring the same input data, but avoiding the need for individual plans, was developed. The program outputs the aperture diameter, fixation angle for the light-field setup, range and modulation, and calculates dose to the macula and optic nerve and percentage of retina receiving > or = 50% and > or = 90% of the prescribed dose. Individual plans require approximately 1.5 hours; the standard plan, 5 minutes. The standard plan could have treated 86% of the reviewed plans. The automated plan provides accurate and efficient treatment parameters for the majority of patients.

Objective: This study evaluated the effect of repeated photodynamic therapy (PDT) applications on normal primate retina and choroid using an intravenous infusion of liposomal benzoporphyrin derivative (verteporfin)., Design: This was an experimental study in a primate model. ANIMALS/CONTROLS: Six cynomolgus monkeys were used as experimental subjects and one monkey was used as a control subject., Intervention: Three consecutive PDT treatments at 2-week intervals were applied over the center of the fovea or the optic nerve of each eye. Verteporfin was delivered by intravenous infusion at a dose of 6 mg/m2, 12 mg/m2, or 18 mg/m2. Laser irradiation was then applied using a diode laser (689 nm) with light doses and spot sizes kept constant., Main Outcome Measures: Findings were documented by fundus photography, fluorescein angiography, and light and electron microscopy., Results: A cumulative dose response was seen angiographically and histologically with more severe damage to the retina and choroid noted at higher dye doses. Photodynamic therapy applied to the macula using the 6-mg/m2 verteporfin dose showed recovery of choriocapillaris, with mild retinal pigment epithelium and outer photoreceptor damage at 6 weeks. At this dose, the optic nerve showed few focal sites of axon atrophy and capillary loss. Treatments over the macula using the 12-mg/m2 and 18-mg/m2 doses led to chronic absence of choriocapillaris and photoreceptors at 6 weeks. One of two optic nerves became atrophic after PDT applications using dye doses of 12 mg/m2, and both optic nerves became atrophic in the 18-mg/m2 dye dose group., Conclusion: Limited damage to the retina, choroid, and optic nerve was present in primates treated with multiple PDT sessions using 6 mg/m2 verteporfin with light doses and the timing of irradiation kept constant. However, PDT using higher dye doses of 12 mg/m2 and 18 mg/m2 led to significant chronic damage to the normal retina, choroid, and optic nerve.

Objectives: To evaluate safety and short-term visual acuity and fluorescein angiographic effects of photodynamic therapy (PDT) after retreatments with verteporfin for choroidal neovascularization (CNV) in age-related macular degeneration (AMD) that demonstrated fluorescein leakage after at least 1 course of PDT., Design: Nonrandomized, multicenter, open-label phase 1 and 2 clinical trial using 2 different retreatment dosage regimens., Setting: Four ophthalmic centers in Europe and North America providing retinal care., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examinations, color photographs, and fluorescein angiograms were used to evaluate the results of multiple PDT treatments. Two regimens (regimens 2 and 4) for treatment and retreatment were chosen from 5 used in a single-treatment study. Both regimens used a verteporfin dose of 6 mg/m2 infused for 10 minutes. However, regimen 2 used a light dose of 100 J/cm2 applied 20 minutes after the start of the verteporfin infusion, whereas regimen 4 used a light dose of 50, 75, or 100 J/cm2 applied 15 minutes after infusion commenced. Posttreatment evaluations were planned in 31 participants up to 3 months after up to 2 retreatments given at 2- or 4-week intervals after initial PDT treatment. Similar posttreatment evaluations were planned after retreatments in 5 additional participants who were reenrolled some time more than 12 weeks after an initial PDT treatment., Results: The average visual acuity change for the 31 participants who had retreatment within 2 to 4 weeks after the initial treatment and a follow-up examination 16 to 20 weeks after the initial treatment was 0.2 lines (range, -4 to 4 lines) in regimen 2 and -1.0 line (range, -5 to 3 lines) in regimen 4. Similar outcomes were noted in the 5 reenrolled participants. Cessation of fluorescein leakage from classic CNV for at least 1 to 4 weeks could be achieved without loss of visual acuity after at least 2 treatments in 2 (6.5%) of 31 patients. Similar to single-treatment effects, the disappearance of leakage was documented regularly at 1 week after each retreatment. Fluorescein leakage reappeared by 4 to 12 weeks after a retreatment in almost all cases. However, compared with baseline, leakage activity appeared to be reduced after multiple PDT courses. For the 31 patients who had follow-up for 3 months after the last retreatment and had received retreatment 2 to 4 weeks after the initial treatment, progression of CNV beyond the area identified before the retreatment was noted in 10 (48%) of the 21 eyes with classic CNV in regimen 2 and 9 (90%) of 10 eyes in regimen 4. The rate and severity of ocular or systemic adverse events were not increased by multiple applications., Conclusions: Multiple applications of PDT with verteporfin achieve repetitive, short-term cessation of fluorescein leakage from CNV secondary to AMD, without loss of visual acuity. This strategy can be used in randomized clinical trials investigating the efficacy of verteporfin in PDT for recurrent fluorescein dye leakage from persistent or recurrent CNV, following an initial or subsequent PDT treatment, with maintenance of visual acuity. Retreatments may achieve progressive cessation of leakage and prevent further growth of CNV and subsequent visual loss.

Objective: To evaluate the safety and short-term visual and fluorescein angiographic effects of a single photodynamic therapy treatment with verteporfin with the use of different dosage regimens in patients with choroidal neovascularization (CNV) from age-related macular degeneration., Design: Nonrandomized, multicenter, open-label, clinical trial using 5 dosage regimens., Setting: Four ophthalmic centers in North America and Europe providing retinal care., Participants: Patients with subfoveal CNV caused by age-related macular degeneration., Methods: Standardized protocol refraction, visual acuity testing, ophthalmic examination, color photographs, and fluorescein angiograms were used to evaluate the effects of a single treatment of photodynamic therapy with verteporfin. Follow-up was planned through 3 months in 97 patients and for less than 3 months in 31 other patients., Results: The mean visual acuity change (and range of change) from baseline at the follow-up examination at week 12 after a single treatment with regimens 1 through 5 was -0.2 (-3 to +2), -0.9 (-9 to +5), -1.6 (-9 to +2), +0.4 (-8 to +7), and +0.1 (-8 to +9) lines, respectively. Only the highest light dose (150 J/cm2) in regimens 2 and 3, which produced angiographic nonperfusion of neurosensory retinal vessels, caused marked vision loss. Some cessation of fluorescein leakage from CNV was achieved without loss of vision when the light dose used was less than 150 J/cm2. Systemic adverse events were rare. Cessation of fluorescein leakage from CNV was noted in all regimens by 1 week after photodynamic therapy. Fluorescein leakage from at least a portion of the CNV reappeared by 4 to 12 weeks after treatment in almost all cases. Progression of classic CNV beyond the area of CNV identified before treatment was noted in 42 (51%) of the 83 eyes with classic CNV followed up for 3 months after a single treatment. Eyes in which the area of any CNV leakage at 12 weeks was less than at baseline had a significantly better visual acuity outcome (+0.8 line) than eyes in which CNV leakage progressed (-0.8 line)., Conclusions: Photodynamic therapy with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of classic CNV in some patients with age-related macular degeneration. Except for nonperfusion of neurosensory retinal vessels at a light dose of 150 J/cm2, no other adverse events were of concern. Randomized clinical trials to investigate whether this new modality can preserve vision in patients with CNV secondary to age-related macular degeneration are justified.

Purpose: To study the long-term effects of photodynamic therapy (PDT), using liposomal benzoporphyrin derivative (BPD) or Verteporfin, on experimental choroidal neovascularization (CNV) and on normal retina and choroid (with no CNV) in the cynomolgus monkey eye., Methods: Photodynamic therapy was performed in 8 cynomolgus monkey eyes with experimental CNV induced by laser injury. The effect of PDT on normal retina and choroid (with no CNV) was studied in 9 monkey eyes. Liposomal BPD was administered intravenously (0.375 mg/kg) either as a bolus, as a slow infusion over 32 minutes, or as a fast infusion over 10 minutes. Photodynamic therapy was performed using light at a wavelength of 689 or 692 nm, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2. Follow-up studies, including fundus photography and FA, were performed at 24 hours after PDT and then weekly. Indocyanine green and BPD angiography were performed in selected cases. Tissues were examined with light and electron microscopy at the end of follow-up., Results: Twenty-three of the 32 areas of CNV treated with PDT showed absence of angiographic leakage at 24 hours. Twenty-eight areas of CNV were followed for 4 weeks; 22 of 28 showed absence of angiographic leakage at 2 weeks; and 20 of 28 at 4 weeks of follow-up. Forty spots on the normal retina and choroid were treated with PDT and were followed for 4 to 7 weeks. These spots showed pigment-laden cells in the outer retina, variably pigmented retinal pigment epithelium (RPE) in the treated area, intact neurosensory retina, and reperfusion of the choriocapillaris., Conclusions: Photodynamic therapy leads to absence of angiographic leakage for at least 4 weeks in experimental CNV in the monkey model. In the normal monkey eye the RPE and choriocapillaris show generalized recovery with preservation of the neurosensory retina 7 weeks after PDT.

Purpose: To evaluate rates of occurrence and risk factors for radiation maculopathy and radiation papillopathy in patients with choroidal melanoma at high risk for these complications., Design: Cohort study., Participants: A total of 558 patients treated with proton irradiation for choroidal melanoma between 1986 and 1996 with small to moderate sized tumors (less than 5 mm in height and 15 mm in diameter) located within 4 disc diameters of the macula or optic nerve and with a median ocular follow-up of 4 years., Methods: Annual and cumulative rates of each endpoint were estimated using life table approaches. Prognostic factors were evaluated using the Cox proportional hazards regression., Main Outcome Measures: Radiation maculopathy, radiation papillopathy, and vision loss to worse than 20/100., Results: Cumulative 5-year rates for radiation maculopathy, radiation papillopathy, and vision loss were 64%, 35%, and 68%, respectively. Complication rates rose as a function of radiation exposure to the macula (P for trend = 0.04) or optic disc (P for trend < 0.001), although dose-response patterns were nonlinear. History of diabetes was a significant risk factor for maculopathy (P < 0.001) and optic neuropathy (P = 0.009)., Conclusions: The onset of radiation vasculopathy is determined primarily by the degree of irradiation exposure to the macula and optic disc. Risk may be enhanced among those with underlying vascular disorders.

On the basis, chiefly, of anecdotal reports of cases of ocular melanoma (OM) occurring in families with inherited susceptibility to breast cancer due to brca2 germline mutations, we examined the frequency of brca2 alterations in a series of 62 ocular melanoma cases. These cases were preferentially selected on the basis of reported family history of breast or ovarian cancer, or OM, although the series also included a randomly selected set of cases without family history of cancer. A total of 7 germline alterations were found, of which 3 were likely to be associated with disease. While all 3 deleterious mutations were found in patients who also had a personal history of breast cancer, only 1 of the 3 families had a family history of breast/ovarian cancer or OM. Although germline brca2 mutations may account for a small proportion of all OM cases, there may be additional loci that contribute to familial aggregation of OM and to the familial association between OM and breast cancer.

Background: Research in cutaneous melanoma suggests that women may experience better tumor-dependent survival than men, and some studies have shown that the advantage is specific to childbearing., Objective: To examine whether childbearing may be a favorable prognostic factor in melanoma of the uveal tract., Design: Prospective follow-up study., Setting: Hospital., Main Outcome Measure: Death from metastatic choroidal melanoma., Methods: We evaluated a consecutive series of 1818 patients with choroidal melanoma, 748 parous and 165 nulliparous women and 905 men, after treatment with proton irradiation. Three hundred fifty-two deaths from metastasis were documented in follow-up., Results: Overall multivariate-adjusted death rates from metastasis were approximately 25% higher in nulliparous women (relative risk [RR], 1.23; 95% confidence interval [CI], 0.83-1.82) and men (RR, 1.25; 95% CI, 1.00-1.56) than in women who had given birth. The protective influence of parity was strongest in the early period following diagnosis and treatment (RR, 1.58; 95% CI, 0.88-2.86, and RR, 1.51; 95% CI, 1.04-2.19, in nulliparous women and men, respectively, during the first 36 months of follow-up). The level of protection increased with the number of live births (P for trend, .04)., Conclusion: These data provide support for the hypothesis that a history of childbearing confers protection from death in choroidal melanoma.

Background: Ocular melanoma may be more prevalent among patients with light irises than those with dark irises., Objective: To examine a large clinical series of patients with intraocular melanoma to determine if light irises are associated with increased risk of death from these tumors., Methods: A total of 1162 patients treated with proton irradiation between 1984 and 1996 were observed through 1997., Results: Iris color in the patients was blue or gray in 48%, green or hazel in 30%, and brown in 23%. Tumors in patients with blue or gray irises were less heavily pigmented (P<.001) and closer to the optic disc and macula (P<.001). Five- and 10-year metastasis-related death rates were 0.14 and 0.21, respectively, for those with blue or gray irises and 0.10 and 0.15, respectively, for those with darker irises (P = .02). In a Cox proportional hazards regression controlling for tumor characteristics, patients with blue or gray irises died of metastatic disease at a rate 1.90 times (95% confidence interval, 1.26-2.85) that of patients with brown irises. The rate of metastatic death was not significantly elevated for those with green or hazel irises (relative risk, 1.43; 95% confidence interval, 0.91-2.23)., Conclusion: Patients with blue or gray irises appear to be at increased risk of metastatic death from choroidal melanoma, independent of other risk factors.

Background: Paraneoplastic syndromes are rare conditions associated with cancer that result in serious disease states at unique sites. In 1982, a report of bilateral diffuse uveal melanocytic proliferation associated with nonocular cancers which resulted in blindness was reported. We present a case of a woman with recurrent ovarian cancer who developed this paraneoplastic syndrome., Case: A 55-year-old woman had been diagnosed in 1990 with an ocular melanoma of her right eye and in 1994 with clear cell carcinoma of the ovary. With recurrence of ovarian cancer, new eye lesions were identified in both eyes. After enulcleation of her right eye, an ocular melanoma and diffuse bilateral melanocytic proliferation (BDUMP) were found. The sight in her left eye continued to deteriorate as other signs of BDUMP occurred in the eye. Within 1 month of diagnosis, the patient was blind. She subsequently succumbed to progression of ovarian cancer., Conclusion: Recurrent ovarian cancer is usually an intraabdominal disease that results in gastrointestinal dysfunction. This case illustrates a rare paraneoplastic syndrome associated with ovarian cancer that mimics metastatic disease to the eye, but has a different pathophysiology., (Copyright 1999 Academic Press.)

Objective: To describe the clinical course of affected and unaffected eyes in patients with idiopathic macular holes., Patients: Prospective study of patients with macular holes enrolled in the Eye Disease Case-Control Study., Main Outcome Measures: The best-corrected visual acuity at follow-up was compared with that at baseline. Changes in the macular holes, including increases in size or spontaneous regression, were assessed. The rates of development of new macular holes in fellow unaffected eyes were estimated., Results: Of the 198 patients examined at baseline, 28 (14.1%) died before reevaluation. Of those who survived, 122 (71.8%) had a follow-up examination. Approximately 34% (34.4%) of all eyes with macular holes had an increase in the size of the macular hole. Forty-five percent of eyes had a decrease in visual acuity of 2 or more lines and 27.8%, of 3 or more lines; 40.9% remained stable, with a gain or loss of fewer than 2 lines. The rate of development of a new macular hole during follow-up in fellow eyes that were unaffected at baseline was 4.3% for 3 or fewer years of follow-up, 6.5% for 4 to 5 years of follow-up, and 7.1% for 6 or more years of follow-up. Spontaneous regression of the macular hole occurred in 3 (8.6%) of 35 patients with a follow-up interval of 6 or more years, whereas no regression occurred in patients with a shorter follow-up., Conclusions: The visual acuity of 45.0% of eyes with macular holes deteriorated by 2 or more lines during follow-up. The rate of development of macular holes in unaffected fellow eyes was low.

Objective: Possible risk factors for hemiretinal vein occlusion were identified and compared with risk factor profiles for central and branch retinal vein occlusion., Design: The design was a multicenter case-control study., Methods: The authors identified 79 patients with hemiretinal vein occlusion (HRVO), 258 patients with central retinal vein occlusion (CRVO), 270 patients with branch retinal vein occlusion (BRVO), and 1142 control subjects at 5 clinical centers. Risk factor data were obtained through interviews, clinical examinations, and laboratory analyses of blood specimens., Results: Systemic hypertension and history of diabetes mellitus were associated with increased risk of HRVO. Risk of CRVO increased with history of diabetes, systemic hypertension, and higher erythrocyte sedimentation rate (females only); risk of CRVO decreased with increasing amounts of physical activity and increasing amounts of alcohol consumption. Systemic hypertension, higher body mass index, and higher alpha2-globulin levels were associated with increased risk of BRVO, whereas higher high-density lipoprotein levels and increasing levels of alcohol consumption were associated with decreased risk of BRVO. Glaucoma history was associated with all three types of retinal vein occlusion., Conclusion: Patients presenting with retinal vein occlusion should be evaluated for cardiovascular disease, diabetes, and glaucoma.

Objective: To evaluate whether the removal of the eye after radiotherapy alters the rates of metastatic death in patients with melanoma of the choroid., Patients and Methods: Using an extension of the Cox model, we based our analysis on a cohort of 1541 consecutive patients with unilateral choroidal or ciliary body melanoma treated with protons (70 cobalt-gray equivalent in 5 to 7 fractions) at the Harvard University (Boston, Mass) cyclotron between July 1, 1975, through December 31, 1993, and who were observed prospectively up to September 30, 1995. Patient survival and the status of the treated eye were updated annually., Results: By September 1995 (median follow-up among survivors, 8 years), 137 patients underwent enucleation after radiotherapy for complications (n=103) or tumor regrowth (n=34). The overall 10-year rate of eye retention was 89% (95% confidence interval, 87%-91%). Of the 1541 patients, 300 died of tumor metastasis, 38 following enucleation of the affected eye (mean interval from enucleation to death, 25 months). The multivariate rate ratio for metastatic death associated with enucleation (modeled as a time-dependent covariate) was 0.9 (95% confidence interval, 0.6-1.4) for enucleation due to complications and 3.8 (95% confidence interval, 2.3-6.3) for enucleation associated with tumor regrowth., Conclusions: In the absence of tumor viability, enucleation after primary irradiation for choroidal melanoma has no deleterious effect on patients' survival. Enucleation concurrent with tumor regrowth is associated with high death rates; growth of the tumor in the eye may presage systemic recurrence and death from metastasis.

Purpose: To establish an animal model of extrascleral extension of choroidal melanoma., Methods: Pigmented choroidal tumors were established in nine New Zealand albino rabbit eyes using B16F10 melanoma cell line. The sclerotomy site was not closed in the subgroup of six rabbits where extrascleral extension was desired. For the control group, the sclerotomy site was sutured with 8-0 nylon. Animals were treated with daily injections of cyclosporine and followed by serial fundus examinations, color Doppler imaging, and fundus photography. All tumor-bearing eyes were enucleated at the end of the follow-up period and examined for extrascleral extension., Results: Extrascleral extension of choroidal melanoma occurred in all six animals with open sclerotomy sites. No extrascleral extension was observed in the control group. Color Doppler imaging identified extrascleral extension which was confirmed on gross histology., Conclusions: Our animal model of extrascleral extension of choroidal melanoma requires minimal surgery to establish, and is reproducible and easy to follow with standard diagnostic equipment.

Objectives: To determine whether systemic hyperoxia can reverse retinal hypoxia and decrease vascular endothelial growth factor (VEGF) gene expression in ischemic nonhuman primate retina., Methods: Six eyes of 3 cynomolgus monkeys were studied. Retinal ischemia was induced via laser vein occlusion and confirmed with fluorescein angiography. Animals were randomly assigned to treatment with either 21% or 100% inhaled oxygen. Arterial PO2 was monitored while systemic acid-base status was maintained. An oxygen microelectrode on a micromanipulator was used to measure preretinal oxygen concentrations in ischemic and nonischemic retina in situ. RNA was isolated from fresh whole retinas, and VEGF messenger RNA levels were quantified with Northern blotting., Results: The preretinal PO2 in ischemic retina was less than the PO2 in nonischemic retina in animals breathing 21% oxygen (intervascular zone PO2, 14.3+/-0.53 vs 21.8+/-0.55 mm Hg; P=.002). After 8 hours of systemic hyperoxia (arterial PO2, 512+/-18 mm Hg), the preretinal PO2 in ischemic retina increased to 166.2+/-15.6 mm Hg (21.8% oxygen) and retinal VEGF messenger RNA levels were reduced by an average of 55%., Conclusions: These data demonstrate that systemic hyperoxia can lower retinal VEGF gene expression and reoxygenate ischemic adult primate retina.

Objective: The purpose of the study is to investigate the relationship between inhaled or intranasal adrenergic agonists and corticosteroids and the development of central serous chorioretinopathy (CSC)., Design: The medical records of three patients with CSC who were found to use inhaled adrenergic agents or corticosteroids or both were identified prospectively. A survey of members of the Retina, Macula, and Vitreous societies and the National Registry of Drug-Induced Ocular Side Effects identified three additional cases., Results: Six patients with CSC were found to be chronic users of corticosteroid (four patients) or both beta adrenergic agonist and corticosteroid (two patients) metered dose inhalers or nasal sprays. In three cases, there was a close temporal correlation between the use of a corticosteroid nasal spray and the development of CSC., Conclusions: These findings suggest that, in patients who are susceptible, the periocular or systemic absorption of inhaled corticosteroids may be sufficient to produce CSC in humans, supporting previous hypotheses regarding the pathogenesis of the disorder. Further studies are needed to confirm this association and to determine whether inhaled adrenergic agents also contribute to the development of this disorder. Patients in whom CSC develops while using corticosteroid inhalers or nasal sprays should be alerted to the possible relationship between CSC and these agents.

Purpose: To evaluate peripheral blood lymphocyte subpopulations in patients with choroidal melanoma., Methods: In this prospective study, peripheral blood lymphocytes of 226 patients afflicted with choroidal melanoma were analyzed by flow cytometry and compared with those of 49 age-matched and gender-matched control subjects. Subpopulations of peripheral blood lymphocytes were further identified by monoclonal antibodies specific to cell-surface markers. Statistical analysis was performed by a Student t test., Results: There was no overall difference between the patients with choroidal melanoma and the control subjects with regard to peripheral blood lymphocyte subpopulations. However, when the patients were divided into subgroups based on their clinical characteristics, differences in natural killer (NK) cell population and activated T cells were noted in two subgroups. Patients with ciliary body involvement showed a statistically significant reduction in NK cells (194 +/- 101 vs 260 +/- 178 per mm3; P = .01). The number of activated T cells in this subgroup of patients was increased but not statistically significantly (7.32 +/- 4.79 vs 6.09 +/- 4.34 per mm3; P = .08). In patients with extrascleral extension, a statistically significant increase in activated T cells was noted (9.84 +/- 7.41 vs 6.25 +/- 4.3 per mm3; P = .02). The NK cells in this subgroup of patients were also reduced, but the reduction did not achieve statistical significance (178 +/- 123 vs 248 +/- 167 per mm3; P = .24)., Conclusions: We noted statistically significant differences in peripheral blood lymphocytes in two subgroups of patients with clinically less favorable choroidal melanoma.

Retinal angiomas are benign vascular hamartomatous lesions with important systemic and visual implications. Early diagnosis and treatment of retinal angiomas with an appropriate systemic workup for associated systemic diseases can prevent visual loss and morbidity and mortality. Tumors less than 3 mm in diameter usually can be ablated with laser photocoagulation. Cryotherapy should be reserved for eyes in which media opacities prohibit use of the laser or the tumor is located in an area of shallow serous detachment or in the extreme peripheral retina. Macular puckers or tractional macular detachments caused by retinal angiomas can be treated effectively by pars plana vitrectomy combined with photocoagulation or cryotherapy to the retinal angioma. Penetrating diathermy is a useful alternative therapy for large tumors but is fraught with risks of hemorrhage and inadvertent retinal breaks with or without vitreous loss or retinal detachment. We have found proton-beam irradiation to be an efficacious and safe treatment for large retinal angiomas (> 3 mm) and for cases complicated by exudative retinal detachments or for tumors involving the optic nerve. We believe this new, noninvasive therapy is a significant advance in the treatment of complicated retinal angiomas or for those tumors that have failed to respond to conventional measures.

Purpose: To study the efficacy of liposomal benzoporphyrin derivative (BPD) (Verteportin) for the angiographic visualization and photodynamic therapy (PDT) of experimental iris neovascularization., Methods: Experimental iris neovascularization was induced in eight cynomolgus monkey eyes by occluding all the branch retinal veins with a dye-yellow (577-nm) laser. Iris angiography was done with sodium fluorescein, indocyanine green (ICG), and liposomal BPD to compare the visualization of normal and neovascular vessels by these three dyes. PDT was performed using an intravenous infusion of liposomal BPD (0.375-0.75 mg/kg), followed by irradiation with 689-nm light from a diode laser/slit-lamp delivery system using 600 mW/cm2 irradiance and 150 J/cm2 fluence. The effect of treatment was followed by iris photography and angiography, and the findings were confirmed by histopathology using light and electron microscopy., Results: Iris fluorescein angiography (FA) showed superficial tortuous and leaky new vessels. Liposomal BPD and ICG angiography of the same eye demonstrated deeper dilated and tortuous iris vessels, with minimal dye leakage. PDT of the iris with irradiation, performed within 20 minutes of the start of dye infusion (0.75 mg/kg), resulted in angiographic and histologic occlusion of iris vessels examined at 24 hours. Three to nine days after PDT, histopathologic examination showed regression of the iris neovascular membrane, with some open vessels., Conclusions: Liposomal BPD and ICG provided angiographic visualization of deeper normal and neovascular iris vessels. PDT using liposomal BPD leads to effective early closure to experimental iris neovascularization.

Background: Choroidal metastases from renal cell carcinoma are uncommon. The authors investigated the clinical characteristics of patients with renal cell carcinoma in whom choroidal metastases developed., Methods: The clinical records of five patients with histopathologically confirmed renal cell carcinoma and choroidal metastases were reviewed retrospectively., Results: In four patients, choroidal metastases were either the sole initial manifestation of disease or were the initial manifestation of metastatic disease. The interval from nephrectomy to the onset of ocular signs ranged from 6 to 18 years. A reddish-orange appearance of the tumor was present in two patients, but no pathognomonic features distinguishing these tumors from other choroidal metastases were identified., Conclusions: Ocular metastases may precede the diagnosis of renal cell carcinoma or may follow it by years or decades. This interval between its ocular and systemic presentation may be so prolonged as to obscure the relation between the choroidal metastases and the primary tumor. In patients with amelanotic or reddish choroidal lesions without known metastatic disease, evaluation of the kidney may be warranted as part of a metastatic workup to exclude metastatic renal cell carcinoma.

Experimental and clinical evidence suggests that tumour angiogenesis plays a role in the tendency for certain neoplasms, including cutaneous melanomas, to metastasize. We evaluated whether tumour vasculature is associated with the rate of metastases in patients with melanoma of the choroid or ciliary body. The study was based on a group of 63 patients enucleated between 1976 and 1984 with paraffin-embedded tissue blocks available for sectioning and with known survival status as of December 1988. Vessel endothelial cells were highlighted with Ulex europaeus agglutinin I (UEA-I) conjugated with peroxidase. UEA-I-stained microvessels were counted at varying levels in the tumour (apex, centre and base) without knowledge of patient outcome. Patients with (n = 30) and without (n = 33) metastases had similar total vessel counts (P = 0.31). There was no evidence of greater vessel density in tumours that had metastasized, by level within the tumour. Similar results were obtained in multivariate analyses. Findings of this study suggest that tumour microvessel density is unrelated to patient survival in uveal melanoma.