Constantin J. Pournaras

Photodynamic Therapy With Verteporfin for Choroidal Neovascularization Caused by Age-related Macular Degeneration: Results of a Single Treatment in a Phase 1 and 2 Study

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.

Regulation of retinal blood flow in health and disease

Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies.

Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-Year results of a randomized clinical trial - VIP report no. 3

PURPOSE To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin in patients with subfoveal choroidal neovascularization (CNV) caused by pathologic myopia. DESIGN AND SETTING Multicenter, double-masked, placebo-controlled, randomized clinical trial at 28 ophthalmology practices in Europe and North America. PARTICIPANTS Patients with subfoveal choroidal neovascular lesions caused by pathologic myopia measuring no more than 5400 micro m and best-corrected visual acuity (approximate Snellen equivalent) of 20/100 or better. METHODS Similar to methods described for 1-year results with follow-up examinations beyond 1 year, continuing every 3 months (except Photograph Reading Center evaluations only at the month 24 examination). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. MAIN OUTCOME MEASURES The primary outcome was the proportion of eyes with fewer than 8 letters (approximately 1.5 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis and using the last observation carried forward method to impute for any missing data. RESULTS Seventy-seven of 81 patients (95%) in the verteporfin group, compared with 36 of 39 patients (92%) in the placebo group, completed the month 24 examination. At this time point, 29 of 81 verteporfin-treated patients (36%) compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P = 0.11). The distribution of change in visual acuity at the month 24 examination was in favor of a benefit for the cases assigned to verteporfin (P = 0.05). This included improvement by at least 5 letters (equivalent to at least 1 line) in 32 verteporfin-treated cases [40%] vs. five placebo-treated cases (13%) and improvement by at least 15 letters (equivalent to at least 3 lines) in 10 verteporfin-treated cases (12%) vs. zero placebo-treated cases. No additional photosensitivity adverse reactions or injection site adverse events were associated with verteporfin therapy in the second year of follow-up. CONCLUSIONS Verteporfin therapy for subfoveal CNV caused by pathologic myopia safely maintained a visual benefit compared with a placebo therapy through 2 years of follow-up. Although the primary outcome was not statistically significantly in favor of verteporfin therapy at 2 years as it had been at 1 year of follow-up, the distribution of change in visual acuity at the month 24 examination was in favor of the verteporfin-treated group and showed that this group was more likely to have improved visual acuity through the month 24 examination. The VIP Study Group recommends verteporfin therapy for subfoveal CNV resulting from pathologic myopia based on both the 1- and 2-year results of this randomized clinical trial.

Effect of lesion size, visual acuity, and lesion composition on visual acuity change with and without verteporfin therapy for choroidal neovascularization secondary to age-related macular degeneration: TAP and VIP report no. 1.

PURPOSE To determine whether differences in baseline lesion size and visual acuity might explain differing results found in three different lesion compositions (predominantly classic, minimally classic, and occult with no classic) among three placebo-controlled, randomized clinical trials evaluating photodynamic therapy with verteporfin (Visudyne, Novartis AG), also termed verteporfin therapy, in patients with subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). METHODS Exploratory analyses were conducted in patients with predominantly classic or minimally classic lesions at enrollment in the Treatment of AMD with Photodynamic Therapy (TAP) Investigation and in AMD patients with occult with no classic CNV in the Verteporfin In Photodynamic Therapy (VIP) Trial. Baseline characteristics of patients among these three lesion compositions were compared. In addition, multiple linear regression modeling was used to explore the effect of baseline lesion size, visual acuity, and lesion composition on mean change in visual acuity from baseline to 24 months. RESULTS At baseline, the mean size of predominantly classic lesions (3.4 disk areas) was smaller than that of minimally classic (4.7 disk areas) and occult with no classic lesions (4.3 disk areas). In the multiple linear regression model of individual lesion compositions, there was a significant treatment-by-lesion-size interaction for minimally classic and occult with no classic lesions, but not for predominantly classic lesions. Interaction between treatment and baseline visual acuity was not significant for any lesion composition. Small verteporfin-treated lesions lost less vision than large verteporfin-treated lesions in each lesion composition. In the multiple linear regression model that included all lesion compositions, lesion size was a more significant predictive factor for the magnitude of treatment benefit than either lesion composition or visual acuity. Smaller (4.0 disk areas or less) minimally classic and occult with no classic lesions had similar visual acuity outcomes to those observed in predominantly classic lesions. CONCLUSIONS Based on exploratory analyses, lesion size in the TAP Investigation and VIP Trial was an important predictor of the magnitude of treatment benefit with verteporfin therapy in occult with no classic and minimally classic lesion compositions. In patients with AMD, treating smaller rather than larger neovascular lesions, regardless of lesion composition, likely will result in a better level of visual acuity.

Central serous chorioretinopathy and glucocorticoids

Central serous chorioretinopathy is a relatively common retinal disease characterized by the accumulation of subretinal fluid at the posterior pole of the fundus, creating a circumscribed area of serous retinal detachment. It typically affects young and middle-aged men with no previous medical and family history, and no systemic symptoms or signs. However, it has been noted that central serous chorioretinopathy is associated with different conditions, characterized by exposure to increased levels of endogenous or exogenous glucocorticoids. In fact, central serous chorioretinopathy has been described in patients with endogenous Cushings syndrome. It is also prevalent in patients with type-A behavior, and following stressful events, and pregnancy probably represents a risk factor for central serous chorioretinopathy; these conditions are characterized by endogenous hypercortisolism. In addition, many cases of central serous chorioretinopathy have been described during or following treatment with glucocorticoids, administrated by any route, for various systemic or ocular conditions. Central serous chorioretinopathy, when related to the exposure to exogenous glucocorticoids, has a less prominent male predilection, presents more often with a chronic or atypical form, and is frequently bilateral. Furthermore, treatment of central serous chorioretinopathy with glucocorticoids was found to exacerbate the clinical picture. Based on these observations it could be suggested that glucocorticoids may be involved in the development of central serous chorioretinopathy, even though the exact pathogenic mechanism remains unclear. Glucocorticoids should not be used in the treatment of central serous chorioretinopathy and central serous chorioretinopathy should be added to the list of ocular complications of glucocorticoids.

Verteporfin therapy for subfoveal choroidal neovascularization in age-related macular degeneration: three-year results of an open-label extension of 2 randomized clinical trials--TAP Report no. 5

OBJECTIVE To report vision and safety outcomes from an extension of a 2-year investigation evaluating verteporfin photodynamic therapy in patients with age-related macular degeneration with subfoveal choroidal neovascularization (CNV). DESIGN AND SETTING Open-label extension of selected patients from 2 multicenter, double-masked, placebo-controlled, randomized clinical trials, the Treatment of Age-Related Macular Degeneration With Photodynamic Therapy (TAP) Investigation, at 22 ophthalmology practices in Europe and North America. PARTICIPANTS Patients enrolled in the TAP Investigation and followed up for at least 24 months in whom verteporfin therapy to CNV might reduce the risk of further vision loss. METHODS Before receiving verteporfin therapy in the extension, eligible patients signed a written informed consent form accompanied by an oral consent process approved by local institutional review boards. Methods were similar to those described for 1- and 2-year results, with follow-up examinations beyond 2 years continuing at 3-month intervals with a few exceptions, including that extension patients with fluorescein leakage from CNV were to receive open-label verteporfin therapy irrespective of their original treatment assignment. RESULTS Of 402 patients in the verteporfin group, 351 (87.3%) completed the month 24 examination; 320 (91.2%) of these enrolled in the extension study. The enrolled participants included 124 (78.0%) of the 159 verteporfin-treated patients with lesions composed of predominantly classic CNV at baseline, of whom 105 (84.7%) completed the month 36 examination. Verteporfin-treated patients with this lesion composition at baseline who participated in the extension study, with or without a month 36 examination, appeared more likely to have a younger age, better level of visual acuity, absence of fluorescein leakage from classic CNV, or no progression of classic CNV beyond the baseline boundaries of the lesion at the month 24 examination compared with those who did not enroll in the extension. For the 105 patients with a predominantly classic baseline lesion composition who completed the month 36 examination, an average of 1.3 treatments were given from the month 24 examination up to, but not including, the month 36 examination. A letter score loss in the study eye of at least 15 from baseline for these patients occurred in 39 (37.5%) at the month 24 examination compared with 44 (41.9%) of these patients at the month 36 examination. Visual acuity changed little from the month 24 examination (mean, -1.9 lines) to the month 36 examination (mean, -2.0 lines) for these eyes. Verteporfin-treated patients had little change in the mean visual acuity lost and few or no additional instances of infusion-related back pain or photosensitivity reactions from month 24 to month 36. Two patients originally assigned to placebo had acute severe vision decrease within 7 days after verteporfin treatment during the extension. One patient originally assigned to verteporfin had acute severe vision decrease after verteporfin treatment of the fellow eye during the extension. CONCLUSIONS Vision outcomes for verteporfin-treated patients with predominantly classic lesions at baseline remained relatively stable from month 24 to month 36, although only approximately one third of the verteporfin-treated patients originally enrolled with this lesion composition had a month 36 examination. From these results, the TAP Study Group identified no safety concerns to preclude repeating photodynamic therapy with verteporfin. Additional treatment was judged likely to reduce the risk of further vision loss. Caution appears warranted in the absence of comparison with an untreated group during the extension and since not all patients in the TAP Investigation participated in the TAP Extension.

Diffusion of O2 in the retina of anesthetized miniature pigs in normoxia and hyperoxia

Intraretinal oxygen tension (pO2) and local electroretinogram (ERG) were simultaneously measured in miniature pigs using double-barreled recess type microelectrodes. Transretinal pO2 profiles were recorded during normoxia and hyperoxia in areas close to (juxta-arteriolar) or far from (intervascular) retinal arterioles. In normoxia, in both areas, the pO2 decreased from the inner retina and the choroid towards the middle of the retina. In the inner retina the gradient of the juxta-arteriolar pO2 profile was steeper than that of the intervascular profile. This characteristic persisted during the breathing of 100% O2. Analysis of the pO2 profiles shows that, even in hyperoxia, the choroid cannot supply O2 to the whole retina. The results also support the conclusions of previous work (Riva, Pournaras and Tsacopoulos, 1986) indicating that in the normal retina it is not the O2 diffusing from the choroid to the retinal arterioles the induces vasoconstriction of these vessels. In the miniature pig this constriction appears to maintain inner retina tissue pO2 at a constant level during hyperoxia. From the pO2 transretinal profiles and previously published choroidal O2 fluxes and pO2 values near retinal vessels an explanatory working hypothesis is formulated according to which O2 consumption (qO2) of the outer retina increases during hyperoxia in the miniature pig.

Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration.

OBJECTIVE To study the effect of intravitreal (IVT) ranibizumab (Lucentis; Genentech, Inc, San Francisco, CA) on the retinal arteriolar diameter in patients with neovascular age-related macular degeneration (AMD). DESIGN Prospective consecutive interventional case series. PARTICIPANTS Eleven eyes of eleven patients with previously untreated neovascular AMD. METHODS All eyes had 3 monthly IVT injections of ranibizumab. The diameter of the retinal arterioles was measured in vivo with a retinal vessel analyzer (RVA) before the first IVT injection and then 7 and 30 days after the first, second, and third injections. MAIN OUTCOME MEASURES Primary end points were changes in retinal arteriolar diameter and mean arterial pressure (MAP) after IVT ranibizumab. Secondary end points were changes in best-corrected visual acuity (BCVA), central retinal thickness, and intraocular pressure after IVT ranibizumab, and appearance of adverse events during the follow-up period. RESULTS A significant decrease of the retinal arteriolar diameter was observed after each IVT injection of ranibizumab. Thirty days after the first, second, and third injections, there was a mean decrease of 8.1+/-3.2%, 11.5+/-4.4%, and 17.6+/-7.4%, respectively, of the retinal arteriolar diameter compared with baseline values (P<0.01). There was no significant change in MAP during the period of follow-up (P>0.05). Thirty days after the third IVT injection of ranibizumab, mean BCVA improved by 6.5+/-4.9 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central retinal thickness decreased by 91+/-122 microm (P = 0.03). CONCLUSIONS These results suggest that IVT ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular AMD after IVT ranibizumab. Further studies evaluating larger sample sizes are needed to confirm these results and potential adverse effects on the retinal circulation in patients with AMD and retinal vascular diseases. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Experimental Retinal Branch Vein Occlusion in Miniature Pigs Induces Local Tissue Hypoxia and Vasoproliferative Microangiopathy

In miniature pigs, retinal veins were experimentally occluded using argon laser coagulation. Microvascular modifications leading to retinal hemorrhages and retinal edema were observed some hours after the occlusion. These lesions resolved progressively within 3 weeks after the occlusion, but in most cases ischemic retinal territories persisted. Preretinal partial pressure of oxygen (PO2) measurements, using double barrelled O2-sensitive microelectrodes, showed that all the ischemic areas were indeed hypoxic. In half of the experiments, preretinal and intravitreal new vessels grew on the ischemic territories. Tissue hypoxia appears to be a key step in triggering neovascularization. However, the critical level of hypoxia was not determined.

Polypoidal Choroidal Vasculopathy Masquerading as Neovascular Age-Related Macular Degeneration Refractory to Ranibizumab

PURPOSE To report a neovascular age-related macular degeneration pattern refractory to ranibizumab. DESIGN Retrospective, observational case series. METHODS Between March and May 2009, cases with neovascular age-related macular degeneration refractory to ranibizumab were investigated with indocyanine green angiography. We identified 12 eyes of 12 patients with polypoidal choroidal vasculopathy. Refractory to treatment were defined cases with persistent subretinal or intraretinal fluid, or both, after 3 or more consecutive monthly ranibizumab injections regardless of best-corrected visual acuity. RESULTS All patients identified were white, of whom 6 were male. Mean age ± standard deviation at presentation was 75 ± 5.6 years (range, 64 to 81 years); diagnosis, based on fluorescein angiography, comprised occult choroidal neovascularization (CNV) in 8 eyes, and 1 case each of classic-no-occult CNV, minimally classic CNV, predominantly classic CNV, and retinal angiomatous proliferation. Eight cases had switched from courses of other therapy (5 pegaptanib, 1 photodynamic therapy, 1 photodynamic therapy then pegaptanib, 1 bevacizumab). After a mean follow-up of 10.2 ± 4.8 months (range, 3 to 18 months) and 7.6 ± 3.9 ranibizumab injections (range, 3 to 14 injections), indocyanine green angiography revealed polypoidal choroidal vasculopathy lesions in all cases. CONCLUSIONS Neovascular age-related macular degeneration refractory to a course of ranibizumab injections may harbor polypoidal choroidal vasculopathy. In such cases, indocyanine green angiography is a valuable tool for revealing polypoidal lesions.