The U.S. Food and Drug Administration (FDA) approved PDT in the year 2000 for treatment of subfoveal choroidal neovascularization (CNV) with specific features in age-related macular degeneration (AMD), and it was subsequently approved for myopia and ocular histoplasmosis syndrome. Its efficacy to treat other vascular disorders and tumors of the eye is currently being investigated.

The mechanism of PDT action resides in the photosensitized oxidation of biological matter. When the photosensitizing agent is activated by the delivered light energy, the agent is transformed from its ground state to a higher energy singlet activated molecule. For the more efficient photosensitizers, the higher energy state decays into a lower energy, more stable molecule referred to as a triplet sensitizer. This triplet sensitizer can undergo either a Type I or Type II reaction. The Type I reaction generates superoxide anions, whereas Type II reactions result in production of singlet oxygen.⁹ These by-products are believed to be responsible for the localized tissue damage produced by PDT. In vivo studies after PDT show the immediate onset of vascular stasis and hemorrhage.² These observations, along with work done on PDT for systemic tumors, provided a framework for initial studies of PDT for ocular tumors and neovascularization.^8,10–14

The ideal light energy dose, or fluence, to safely treat CNV was modeled on primate and early-phase studies that varied the parameters of laser irradiance, fluence, and treatment duration.⁸ Preliminary clinical studies demonstrated untoward effects of retinal vascular closure when a light energy dose of 150 J/cm² was administered.²⁰ This led to the recommendation in the phase III prospective clinical trials for PDT treatment at 50 J/cm². Repetition of PDT treatment every 12 weeks was allowed if recurrent CNV leakage was present on fluorescein angiography and examination.^21–23 The irradiance of 600 mW/cm² used for PDT is markedly less than that used for thermal laser photocoagulation (which is typically in the range of 100 to 1000 W/cm²).⁸ Figures 1D and E demonstrate the typical CNV hypoperfusion on fluorescein angiogram noted at 4 weeks status-post PDT with verteporfin for predominantly classic CNV in AMD (Fig. 1A to C).

Fig. 1. A. Color fundus photograph of subfoveal CNV in a patient with AMD as well as myopia. B. Early-phase FA (35 seconds) demonstrates predominantly classic subfoveal CNV (as defined by the TAP study).23 C. Late-phase FA (3:20) demonstrates hyperfluorescent leakage from subfoveal CNV. D. Early-phase FA (42 seconds) at day 7 status post verteporfin-PDT demonstrates the typical ring of hypofluorescence corresponding to the treated area. E. Late phase FA (3:01) at day 7 status post verteporfin-PDT demonstrates a small, central area of fluorescein staining.

Table 1. Photosensitizing Agents Used for Photodynamic Therapy

Newer second-generation photosensitizing agents have been developed due to the side effect of prolonged cutaneous sun sensitivity with first-generation agents that required avoidance of sunlight for 4 to 6 weeks after PDT. These agents have been investigated in recent human studies for ophthalmic disease. The second-generation photosensitizers have a longer wavelength of absorption, which permits for deeper tissue penetration of the treatment effect. Additional advantages of the second-generation agents include more rapid clearance from the body, shorter duration of cutaneous light sensitivity, and greater affinity of these agents to concentrate in the proliferating cells of neovascular tissue.^26,27

The agent benzoporphyrin derivative monoacid (BPD-MA or verteporfin) was approved by the FDA in April 2000 for the treatment of specific types of subfoveal CNV. This photosensitizing agent is commercially available under the trade name Visudyne (Novartis Ophthalmics, Duluth, GA). Verteporfin is administered intravenously and has a peak absorption of 692 nm.²⁸ This agent appears to have preferential uptake in low-density lipoproteins (LDL) in human plasma. The photosensitizer-LDL complex is then delivered to neovascular tissue, which has an increased proportion of LDL-receptors compared with normal vascular endothelium. This effect may localize verteporfin in proliferating endothelial cells of ocular neovascular tissue. Experimental studies using fluorescein and ICG angiography have shown verteporfin reaches the choroidal and then retinal vasculature within 5 and 15 seconds, respectively. Clearance from the retina is completed by 30 minutes following injection of verteporfin. Experimental CNV collects verteporfin approximately 10 seconds after injection and the photosensitizer may remain in the complex for up to 1 hour.²

Verteporfin is primarily eliminated from the blood through hepatic metabolism within the first 24 hours.¹⁴ This rapid clearance of more than 50% of the injected photosensitizing agent significantly decreases the amount of time that patients are at risk of cutaneous light toxicity. This has been confirmed with favorable systemic side effect profiles using verteporfin in the following prospective studies: The Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study and The Verteporfin in Photodynamic Therapy (VIP) Study.^23,30–32

Other second-generation photosensitizing agents have been investigated for treatment of exudative AMD. Tin ethyl etiopurpurin (SnET2) has been studied in animal models and human CNV as well as for ciliary body ablation.^33,34 Lutetium texaphyrin (Lu-Tex) is activated by 732 nm wavelength of light. This agent has a unique property of having an emission band at 750 nm, which permits it to secondarily function as an angiographic agent to image the posterior segment circulation.³⁵

Before the approval of PDT for subfoveal CNV in AMD, thermal laser photocoagulation was the only treatment with efficacy demonstrated by the multicenter Macular Photocoagulation Studies (MPS). However, laser treatment of subfoveal CNV produces immediate and permanent central visual loss due to full-thickness retinal destruction induced by thermal photocoagulation. The MPS subfoveal studies demonstrated that at 2 years after randomization, the mean vision was 20/320 in subfoveal laser treated eyes compared with 20/500 in observed cases.³⁶ Owing to the minimal potential for visual improvement for tasks involving discriminative acuity, thermal laser was recommended primarily for patients who were agreeable to the immediate visual decline demonstrated in the MPS trial, and had a purely classic subfoveal lesion no greater than 3.5 MPS disc areas.^36–39 Only a limited number of eyes with subfoveal CNV lesions fulfilled these criteria. Thermal laser photocoagulation is also unsatisfactory as long-term therapy for CNV in any location owing to the high recurrence rate of CNV leakage and the full-thickness neurosensory retinal destruction that it produces. Moreover, it has only been recommended to treat classic CNV. The approval of PDT in the year 2000 offers a new therapy of CNV that is potentially less destructive. It has increased the proportion of AMD patients who are candidates for a form of treatment for subfoveal CNV, and it does not appear to produce thermal neurosensory retina damage.

Table 2. Characteristics of the TAP and VIP Studies

The 1-year results demonstrated an overall benefit in the primary outcome measure, which was to determine whether verteporfin-PDT could prevent moderate visual loss (defined as loss of at least 15-letters or three lines on the ETDRS chart). Sixty-one percent (61%) of the verteporfin-PDT treated eyes lost less than 15 letters on the ETDRS chart compared with 46% in the placebo group (p < 0.001). Subgroup analysis revealed the greatest benefit in eyes that had “predominantly classic” CNV at baseline, which was defined as CNV composed of equal to or greater than 50% classic component. More than two thirds of patients (67%) treated with verteporfin-PDT with “predominantly classic” CNV had less than 15-letter loss after 1 year compared with 39% in the placebo group (p < 0.001).²³

The PDT treatment benefit for “predominantly classic” CNV remained at the 2-year evaluation (59% versus 31% for verteporfin-PDT vs. placebo respectively, p < 0.001).⁴⁰ Severe visual loss, defined as 30 letters or six lines of visual loss, was significantly lower in the verteporfin-PDT group over the 2-year period (15% versus 36% for verteporfin PDT versus placebo respectively, p < 0.001). The findings of improved visual outcome after verteporfin-PDT were found to be independent of prior thermal laser photocoagulation, phakic status, and prior use of micronutrients.⁴¹ From these findings, PDT with verteporfin for “predominantly classic” CNV in the setting of AMD was recommended to prevent visual loss when compared with observation.

For the subgroups of eyes with “minimally classic” CNV (defined as having less than 50% classic CNV) in the TAP trial, verteporfin-PDT did not appear to protect patients from losing 15 letters from baseline at both the 1 and 2-year mark. Although contrast sensitivity and fluorescein angiographic outcomes were significantly better at 1 and 2 years in the verteporfin-PDT group compared with placebo for “minimally classic” and “purely occult” CNV, over half of the patients experienced moderate visual loss (15-letter loss) in both the first and second year following treatment in both groups. Thus, the initial TAP report did not show visual acuity efficacy for verteporfin-PDT of “minimally classic” CNV in AMD.^23,40

Further subgroup analysis of the “predominantly classic” CNV group demonstrated better visual outcomes in “predominantly classic” lesions without an occult component that were treated with verteporfin-PDT. It was also noted that these same lesions (classic CNV without an occult component) were smaller in size and had a lower baseline visual acuity compared with predominantly classic lesions with an occult component.⁴¹ These potential confounders, smaller lesion size and worse presenting visual acuity, were then applied to the “minimally classic” lesions that initially did not appear to benefit from verteporfin therapy compared to the “predominantly classic” CNV lesions.^23,40,41 It was found in the TAP study that “minimally classic” lesions, in fact, did have larger lesions and better presenting visual acuity than the “predominantly classic' lesions. From this finding, it has been theorized that certain “minimally classic” CNV lesions with smaller size and worse presenting visual acuity may benefit from PDT. A prospective, randomized trial named Verteporfin in Minimally Classic CNV Trial (VIM) is currently in progress to evaluate verteporfin in eyes with “minimally classic” CNV with smaller size and worse presenting visual acuity.

The most recent reports from the TAP trial have reported on the continued follow-up and use of verteporfin-PDT beyond 24 months of the original TAP-study design. The results of visual acuity and contrast sensitivity, along with any additional side effects with additional verteporfin-PDT administration, have been documented. The use of verteporfin-PDT appears to have minimal safety issues when used repeatedly for recurrent CNV in AMD. The patients from the original study with predominantly classic CNV received an additional 1.3 treatments between 24 and 36 months. Visual acuity appeared to stabilize with only a few patients experiencing moderate visual loss in this time period.⁴²

Contrast sensitivity using Pelli-Robson charts was also analyzed for the subgroups within the first 24 months of the TAP study. In addition to favorable contrast sensitivity scores paralleling visual outcomes for “predominantly classic” CNV, patients with “minimally classic” CNV also lost fewer letters on the Pelli-Robson chart compared to placebo over the 24 months. The potential correlation between improved contrast sensitivity and reduced visual disability suggest that verteporfin-PDT may have a positive impact on patient's daily visual function.⁴³

The 12-month data after randomization did not demonstrate a treatment effect for verteporfin-PDT compared with placebo for the primary outcome measure, which was moderate visual loss (defined as loss of at least 15 letters or three ETDRS lines). Approximately one half of both verteporfin-PDT and placebo groups had moderate visual loss at the 12 month examination (p=0.52). Similar rates of visual loss at the 12-month examination were noted with subgroup analysis of the eyes classified as “purely occult” CNV (with no classic CNV), which comprised over 70% of the entire cohort of patients.

The visual outcomes between the verteporfin-PDT and the placebo groups did diverge, however, by the 2-year mark. Twenty-four–month results demonstrated visual benefit from verteporfin-PDT for both the entire group and the subgroup of “purely occult” CNV. Thus, a smaller proportion of the verteporfin-PDT eyes experienced moderate visual loss compared with the placebo eyes when the results were analyzed for the entire group (54% versus 67%, p = 0.023). The subgroup of “purely occult” eyes with no classic CNV show similar treatment benefit with 55% of verteporfin-PDT eyes compared with 68% of placebo patients experiencing loss of at least 15 letters (p = 0.032). In both of these groups, however, the greatest decline in visual acuity was observed in the first 12 months following the initial verteporfin-PDT treatment. This was the same time frame (12-month results) in which no difference between verteporfin-PDT and placebo groups experiencing moderate visual loss was demonstrated. One hypothesis to account for the visual benefit of verteporfin-PDT demonstrated by 24 months, but not in the initial 12-month data, is that the PDT treatment parameters used in the VIP trial may not be optimal for occult CNV. Ongoing studies address these findings and are re-evaluating the parameters used for PDT.

Secondary measures of visual loss in the VIP study also demonstrated a treatment benefit. Severe vision loss of at least 30 letters or six lines was noted in 30% of the verteporfin-PDT group and 47% of the placebo group at 24 months (p = 0.001). The “purely occult” with no classic CNV also demonstrated a decreased risk of severe vision loss at 2 years with only 29% of the verteporfin group versus 47% of the placebo group (p = 0.004). Other secondary outcomes such as angiographic appearance and mean change in visual acuity appeared to favor the verteporfin-PDT treatment at both 12- and 24-month examinations.

Although the VIP Study demonstrated a visual benefit for “purely occult” with no classic CNV that demonstrated signs of progression in the setting of AMD, the outcomes were not as compelling as the results of “predominantly classic” CNV in the TAP trial. However, further analysis of the lesion composition in this group did highlight a subgroup that appeared to benefit substantially from verteporfin-PDT. Patients who either had smaller initial lesions (no greater than 4 MPS disc areas³⁶) or a presenting visual acuity of worse than 20/50^-1 at baseline demonstrated a greater visual benefit from verteporfin-PDT. If the lesion was less than four disc diameters, 49% verteporfin group versus 75% of the placebo group experienced moderate visual loss (p < 0.001). If the initial visual acuity was worse than 20/50^-1, only 29% of the verteporfin group versus 48% of the placebo group experienced moderate visual loss (p < 0.001). Lesions that were found to be larger than four disc diameters with visual acuity better than 20/50 did not appear to benefit from verteporfin-PDT.

The VIP study also observed an adverse event after verteporfin-PDT that was not prevalent in the TAP trials. Ten patients (4%) in the verteporfin-PDT group experienced loss of at least 20 letters of vision within seven days of verteporfin-PDT. This contrasted to less than 1% of the patients losing vision in this manner after verteporfin-PDT in the TAP study.⁴⁰ In the VIP study, eight of these 10 patients had pretreatment “purely occult” with no classic CNV. Nine of 10 patients experienced this visual loss after their initial treatment with verteporfin. Subretinal pigment epithelium hemorrhage or choroidal hypoperfusion were noted only in a minority of these patients, and an identifiable cause for the vision loss could not be found in more than half of these patients. Although vision marginally improved over time in half of these patients, most patients did not recover a substantial amount of their pretreatment visual acuity. The VIP Study recommended including this risk of visual loss when requesting consent from patients for verteporfin-PDT, especially if the lesion is composed of occult CNV with no classic component.³⁰

The Verteporfin Early Retreatment (VER) trial will evaluate whether earlier retreatment at 6 weeks, compared to 3 months after verteporfin-PDT for “predominantly classic” CNV, will be more effective to reduce the risk of moderate visual loss. This study is a product of analysis of the predominantly classic CNV group in the TAP study. In this group, 75% of the visual loss, or approximately 2 lines of acuity, occurred within the first 6 months of treatment before stabilizing.^23,40 A hypothetical disadvantage of early retreatment may be potential damage to the retinal or choroidal vasculature, or to neurosensory retina cells. The effect of early retreatment on the retinal structure and visual acuity will be evaluated in this study.

The Verteporfin with Altered (Delayed) Light in Occult (VALIO) CNV trial is a phase II trial to evaluate light application 30 minutes after verteporfin infusion instead of the standard 15-minute interval used in the TAP and VIP studies. The unimpressive 12-month VIP treatment results for “purely occult CNV” spurred interest to evaluate whether there were more effective treatment parameters for occult CNV. It is hypothesized that prolonging the time for light application after verteporfin infusion may be more efficacious way to treat occult CNV. The delayed application may result in less verteporfin in the choroidal circulation and more pooled verteporfin in the CNV, which could possibly produce a more selective treatment effect for occult CNV.

PDT has also been suggested as an adjuvant therapy in AMD, and it has been evaluated in small studies as a combination treatment with intravitreal corticosteroid, ICG feeder vessel laser therapy, and laser photocoagulation. A recent report noted an increase of identifiable feeder vessels to neovascular complexes associated with AMD from 22% pre-PDT to 84% of persistent neovascular lesions post-PDT.⁵⁰ This retrospective study of 156 eyes may lead to evaluation of PDT combined with the experimental therapy of directed laser photocoagulation of feeder vessels identified with high-speed ICG angiography. Future prospective studies may identify combination therapies with PDT that ultimately permanently close CNV complexes or prolong the time interval between PDT retreatments.

The classic and occult components of CNV are outlined in Figure 2. The percent of the CNV that is classic can then be determined as a proportion of the total CNV. In Figure 2A and B, the area of classic CNV measures 978 square microns and the total lesion measures 11,180 square microns. The classic component is thus 9% of the entire CNV and this lesion is classified as “minimally classic” CNV (defined as less than 50% classic CNV).^23,40 The fluorescein angiogram demonstrates another mixed classic and occult CNV lesion in Figure 3. Using digital area measurements, the lesion in Figures 3A and B is composed of 79% classic CNV and fulfils the criteria for predominantly classic, subfoveal CNV that may benefit from verteporfin-PDT based on TAP findings.^23,40 The TAP studies also demonstrated a visual benefit in eyes that had prior nonfoveal, thermal laser photocoagulation and subsequent recurrence of CNV below the fovea.^23,40 In Figure 4A, subfoveal CNV recurrence in an eye with prior thermal photocoagulation is demonstrated. One month following verteporfin-PDT treatment, Figures 4B (early phase) and 4C (late phase) demonstrate characteristic hypofluorescence of the treated subfoveal CNV on fluorescein angiography.

After qualifying for verteporfin-PDT based on clinical and fluorescein angiographic findings, informed consent is carefully obtained. Contraindications to PDT include porphyria, severe liver disease, pregnancy, or a known hypersensitivity to a photosensitizing agent. The greatest linear dimension (GLD) is determined with caliper measurement across the longest digital fluorescein angiographic diameter of leakage. The size of the area to be treated using the nonthermal 689 nm light should have a 500 μm border around the CNV, so a total of 1,000 μm should be added to the greatest diameter (or GLD) of CNV. The treatment area should extend no closer than 200 μm to the optic nerve, as recommended by the TAP studies.^23,40 In Figure 3C, the area of CNV to be treated would be 4,184 plus 1,000 μm, or 5,184 microns.

Verteporfin, which is stored as a dry powder, is reconstituted with sterile water and diluted with 5% dextrose solution immediately before use. This solution is infused intravenously over 10 minutes, preferably through a large cubital or cephalic vein. Constant monitoring during the entire infusion is imperative to avoid photosensitizer extravasation, which can have serious dermatological consequences. The calculated dose of verteporfin is 6.0 mg/m² body surface area; thus, the accurate weight of the patient should be obtained before treatment. The 689-nm diode laser light treatment begins 15 minutes after commencing the verteporfin infusion. The laser treatment is delivered at the slit lamp through a diode-coated contact lens. Laser treatment is applied for 83 seconds, which produces a total energy dose of 50 J/cm².

In the scenario of a patient presenting with subfoveal CNV lesions in both eyes qualifying for verteporfin-PDT, guidelines have been outlined for concurrent bilateral treatment (see package insert provided by Visudyne, Novartis Ophthalmics). This technique consists of injecting an identical dose of verteporfin (6.0 mg/m²) as when treating only one eye. The CNV that appears more aggressive should be treated first at the standard 15-minute post-injection time. Immediately following the conclusion of light application in the first eye, laser settings should be adjusted to introduce the correct treatment-size parameter for the CNV in the fellow eye. Treatment for the fellow eye should commence no later than 20 minutes after commencement of verteporfin infusion. This technique is not recommended for the initial PDT treatment in patients with bilateral, eligible CNV lesions. In this case, unilateral verteporfin-PDT should be administered with follow-up in one week for treatment of the fellow eye. This can identify any safety issues that may arise from PDT. Once the fellow eye is treated, following treatments at the three-month interval can be administered concurrently if evidence of leakage is present in both eyes.

Post-treatment precautions include avoidance of direct sunlight or bright indoor lights. A wide-brimmed hat, gloves, long pants, long sleeves, and protection of the eyes and face from direct sunlight are required for travel immediately after PDT. Complete avoidance of direct sunlight is strictly prescribed for 5 days following verteporfin-PDT. This is to prevent potentially serious skin burns and photosensitivity that may occur from residual, circulating photosensitizer after PDT.

Infusion-related back pain has been reported to occur on successive infusions of verteporfin. A recent, nonrandomized study has estimated an incidence of back pain in up to 10% of infusions.⁵¹ There was no difference between patients who received oral hydration 30 minutes before injection compared with patients who did not receive this before injection. The only significant risk factor for infusion-related pain was a prior episode of pain with verteporfin injection. Also, infusion-related pain is not limited to back pain, and the episode subsides with cessation of infusion. Other sites of infusion-related pain have included leg, groin, chest, buttock, arm, and shoulder.⁵¹ It has been theorized that the mechanism of pain is related to neutrophil margination from vascular walls during the infusion.⁵² One small series recommended that intravenous diphenhydramine hydrochloride given before injection may alleviate this adverse event.⁵³

Subfoveal CNV due to ocular histoplasmosis syndrome was evaluated in an uncontrolled, prospective case series.⁵⁴ The 1-year data on 26 patients treated with verteporfin-PDT demonstrated an overall visual acuity improvement, and more than one half of the patients treated experienced some visual improvement. A few patients had significant visual decrease with visual acuity less than 20/200 in one patient at the 12-month examination. Similar to the high myopia study, there were no cases of severe vision loss attributed to PDT as had been described in both the TAP and VIP studies.

Smaller case series have now been reported using PDT for miscellaneous conditions with subfoveal CNV. The results have been variable, and no generalized recommendations have been made at this time. Some of these conditions associated with CNV treated with verteporfin-PDT include idiopathic CNV, angioid streaks, choroidal osteoma, fundus flavimaculatus, multifocal choroiditis, idiopathic polypoidal choroidal vasculopathy, and type 2 parafoveal telangectasias. ^55-61 PDT was typically performed owing to a lack of any other proven treatment option. Short-term visual stabilization with no adverse events directly attributable to verteporfin-PDT was noted in some of these cases. The use of PDT for AMD in eyes with co-existing, severe nonproliferative or proliferative diabetic retinopathy has not been properly assessed, because these patients were excluded from the initial verteporfin-PDT studies. One potential concern is whether PDT could exacerbate diabetic retinovascular abnormalities.⁶² There are currently no long-term safety data for these diabetic eyes.

Small series have also reported use PDT for non-CNV lesions. Posterior pole abnormalities including peripapillary capillary hemangiomas, circumscribed choroidal hemangiomas, and central serous chorioretinopathy have been treated with verteporfin-PDT.^63–65 PDT has been investigated as an alternative to mitomycin-C to control fibrosis in eyes status-post trabeculectomy.⁶⁶ Unresponsive iris melanomas have been treated with PDT using hematoporpyrin derivative as the photosensitizing agent.⁶⁷ Further evaluation of PDT as a potential new treatment for various other vascular and oncologic lesions in the eye may be warranted. Moreover, combination of PDT with other treatment modalities may play a role in future therapies. A major rationale for combining PDT with another modality is to prolong or even make the vaso-occlusive effect of PDT more permanent.

1. Dougherty TJ, Grindey GB, Fiel R et al: Photoradiation therapy. II. Cure of animal tumors with hematoporphyrin and light. J Natl Cancer Inst 55:115, 1975

2. Henderson BW, Dougherty TJ: How does photodynamic therapy work? Photochem Photobiol; 55:145, 1992

3. Gomer CJ, Doiron DR, White L et al: Hematoporphyrin derivative photoradiation induced damage to normal and tumor tissue of the pigmented rabbit eye. Curr Eye Res; 3:229, 1984

4. Nanda SK, Hatchell DL, Tiedeman JS et al: A new method for vascular occlusion. Photochemical initiation of thrombosis. Arch Ophthalmol; 105:1121, 1987

5. Stender IM, Na R, Fogh H, et al: Photodynamic therapy with 5-aminolaevulinic acid or placebo for recalcitrant foot and hand warts: Randomised double-blind trial. Lancet 355:963, 2000

6. Wang I, Bendsoe N, Klinteberg CA et al: Photodynamic therapy vs. cryosurgery of basal cell carcinomas: Results of a phase III clinical trial. Br J Dermatol 144:832, 2001

7. Roberts WG, Hasan T: Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents. Cancer Res 52:924, 1992

8. Miller JW, Walsh AW, Kramer M et al: Photodynamic therapy of experimental choroidal neovascularization using lipoprotein-delivered benzoporphyrin. Arch Ophthalmol 113:810, 1995

9. Buettner GR, Oberley LW: The apparent production of superoxide and hydroxyl radicals by hematoporphyrin and light as seen by spin-trapping. FEBS Lett 121:161, 1980

10. Schmidt-Erfurth U, Hasan T, Gragoudas E, Birngruber R: [Selective occlusion of subretinal neovascularization with photodynamic therapy]. Ophthalmologe 91:789, 1994

11. Schmidt-Erfurth U, Bauman W, Gragoudas E et al: Photodynamic therapy of experimental choroidal melanoma using lipoprotein-delivered benzoporphyrin. Ophthalmology; 101:89, 1994

12. Kim RY, Hu LK, Foster BS et al: Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness. Ophthalmology 103:2029, 1996

13. Young LH, Howard MA, Hu LK et al: Photodynamic therapy of pigmented choroidal melanomas using a liposomal preparation of benzoporphyrin derivative. Arch Ophthalmol 114:186, 1996

14. Husain D, Miller JW, Michaud N et al: Intravenous infusion of liposomal benzoporphyrin derivative for photodynamic therapy of experimental choroidal neovascularization. Arch Ophthalmol 114:978, 1996

15. Hager A, Schmidt-Erfurth U, Barbazetto I et al: [Photodynamic therapy: ICG angiography findings]. Ophthalmologe 96:291, 1999

16. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H: Photodynamic effects on choroidal neovascularization and physiological choroid. Invest Ophthalmol Vis Sci 43:830, 2002

17. Flower RW: Expanded hypothesis on the mechanism of photodynamic therapy action on choroidal neovascularization. Retina 19:365, 1999

18. Schmidt-Erfurth U: Indocyanine green angiography and retinal sensitivity after photodynamic therapy of subfoveal choroidal neovascularization. Semin Ophthalmol 14:35, 1999

19. Michels S, Barbazetto I, Schmidt-Erfurth U: [Choroidal changes after photodynamic therapy (PDT). A two-year follow-up study of 38 patients]. Klin Monatsbl Augenheilkd; 217:94, 2000

20. Sickenberg M, Schmidt-Erfurth U, Miller JW et al: A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Arch Ophthalmol 118:327, 2000

21. Miller JW, Schmidt-Erfurth U, Sickenberg M et al: 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. Arch Ophthalmol 117:1161,1999

22. Schmidt-Erfurth U, Miller JW, Sickenberg M et al: Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: Results of retreatments in a phase 1 and 2 study. Arch Ophthalmol; 117:1177, 1999

23. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol 117:1329, 1999

24. Lam S, Kostashuk EC, Coy EP et al: A randomized comparative study of the safety and efficacy of photodynamic therapy using Photofrin II combined with palliative radiotherapy versus palliative radiotherapy alone in patients with inoperable obstructive non-small cell bronchogenic carcinoma. Photochem Photobiol 46:893, 1987

25. Keefe KA, Chahine EB, DiSaia PJ et al: Fluorescence detection of cervical intraepithelial neoplasia for photodynamic therapy with the topical agents 5-aminolevulinic acid and benzoporphyrin-derivative monoacid ring. Am J Obstet Gynecol 184:1164, 2001

26. Kreimer-Birnbaum M: Modified porphyrins, chlorins, phthalocyanines, and purpurins: second-generation photosensitizers for photodynamic therapy. Semin Hematol 26:157, 1989

27. Richter AM, Kelly B, Chow J et al: Preliminary studies on a more effective phototoxic agent than hematoporphyrin. J Natl Cancer Inst 79:1327, 1987

28. Rivellese MJ, Baumal CR: Photodynamic therapy of eye diseases. Ophthalmic Surg Lasers 30:653, 1999

29. Husain D, Kramer M, Kenny AG et al: Effects of photodynamic therapy using verteporfin on experimental choroidal neovascularization and normal retina and choroid up to 7 weeks after treatment. Invest Ophthalmol Vis Sci 40:2322, 1999

30. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2. Am J Ophthalmol 131:541, 2001

31. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial—VIP report no. 1. Ophthalmology 108:841, 2001.

32. Verteporfin in Photodynamic Therapy (VIP) Study Group: Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia. Two-year results of a randomized clinical trial—VIP report no. 3. Ophthalmology 110:667, 2003

33. Baumal C, Puliafito CA, Pieroth L et al: Photodynamic therapy (PDT) of experimental choroidal neovascularization with tin ethyl etiopurpurin, The Association of Research in Vision and Ophthalmology, Fort Lauderdale, FL, April 1996.

34. Renno RZ, Miller JW: Photosensitizer delivery for photodynamic therapy of choroidal neovascularization. Adv Drug Deliv Rev 52:63, 2001

35. Blumenkranz MS WK, Verdooner S: Lutetium texaphyrin angiography: A new method for the evaluation and treatment of retinal and choroidal vascular disorders [abstract]. Invest Ophthalmol Vis Sci 39:S486, 1998

36. Macular Photocoagulation Study Group: Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 109:1220, 1991

37. Macular Photocoagulation Study Group: Laser photocoagulation of subfoveal recurrent neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 109:1232, 1991

38. Macular Photocoagulation Study Group: Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Arch Ophthalmol; 109:1242, 1991

39. Macular Photocoagulation Study Group: Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol 111:1200, 1993

40. Bressler NM: Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: Two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol 119:198, 2001

41. Bressler NM, Arnold J, Benchaboune M et al: Verteporfin therapy of subfoveal choroidal neovascularization in patients with age-related macular degeneration: Additional information regarding baseline lesion composition's impact on vision outcomes—TAP report No. 3. Arch Ophthalmol 120:1443,2002

42. Blumenkranz MS, Bressler NM, Bressler SB et al: 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. Arch Ophthalmol; 120:1307, 2002

43. Rubin GS, Bressler NM: Effects of verteporfin therapy on contrast on sensitivity: Results from the treatment of age-related macular degeneration with photodynamic therapy (TAP) investigation—TAP report No 4. Retina; 22:536, 2002

44. Bressler NM: Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2. Am J Ophthalmol 133:168, 2002

45. Macular Photocoagulation Study Group: Five-year follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol 111:1189, 1993

46. Macular Photocoagulation Study Group: Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. Arch Ophthalmol 112:500, 1994

47. Jampol LM, Scott L: Treatment of juxtafoveal and extrafoveal choroidal neovascularization in the era of photodynamic therapy with verteporfin. Am J Ophthalmol 134:99, 2002

48. Sharma S, Hollands H, Brown GC et al: Improvement in quality of life from photodynamic therapy: a Canadian perspective. Can J Ophthalmol 36:332, 200

49. Sharma S, Brown GC, Brown MM et al: The cost-effectiveness of photodynamic therapy for fellow eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology 108:2051,2001

50. Piermarocchi S, Lo Giudice G, Sartore M et al: Photodynamic therapy increases the eligibility for feeder vessel treatment of choroidal neovascularization caused by age-related macular degeneration. Am J Ophthalmol 133:572, 2002

51. Borodoker N SR, Maranan L, Murray J et al: Verteporfin infusion-associated pain. Am J Ophthalmol; 133:211,2002

52. Spaide RF, Maranan L: Neutrophil margination as a possible mechanism for verteporfin infusion-associated pain. Am J Ophthalmol 135:549, 2003

53. Tornambe P: Using intravenous diphenhydramine to minimize back pain associated with photodynamic therapy with verteporfin. Arch Ophthalmol 120:872, 2002.

54. Saperstein DA, Rosenfeld PJ, Bressler NM et al: Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome: One-year results of an uncontrolled, prospective case series. Ophthalmology; 109:1499, 2002

55. Spaide RF, Martin ML, Slakter J et al: Treatment of idiopathic subfoveal choroidal neovascular lesions using photodynamic therapy with verteporfin. Am J Ophthalmol; 134:62,2002

56. Karacorlu M, Karacorlu S, Ozdemir H, Mat C: Photodynamic therapy with verteporfin for choroidal neovascularization in patients with angioid streaks. Am J Ophthalmol 134:360, 2002.

57. Battaglia Parodi M, Da Pozzo S, Toto L et al: Photodynamic therapy for choroidal neovascularization associated with choroidal osteoma. Retina 21:660,2001.

58. Valmaggia C, Niederberger H, Helbig H: Photodynamic therapy for choroidal neovascularization in fundus flavimaculatus. Retina 22:111,2002

59. Coquelet P, Postelmans L, Snyers B, Verougstraete C: Successful photodynamic therapy combined with laser photocoagulation in three eyes with classic subfoveal choroidal neovascularisation affecting two patients with multifocal choroiditis: Case reports. Bull Soc Belge Ophtalmol:69, 2002

60. Quaranta M, Mauget-Faysse M, Coscas G: Exudative idiopathic polypoidal choroidal vasculopathy and photodynamic therapy with verteporfin. Am J Ophthalmol; 134:277, 2002

61. Potter MJ, Szabo SM, Chan EY, Morris AH: Photodynamic therapy of a subretinal neovascular membrane in type 2A idiopathic juxtafoveolar retinal telangiectasis. Am J Ophthalmol 133:149,2002

62. Ladd BS, Solomon SD, Bressler NM, Bressler SB: Photodynamic therapy with verteporfin for choroidal neovascularization in patients with diabetic retinopathy. Am J Ophthalmol; 132:659, 2001

63. Schmidt-Erfurth UM, Kusserow C, Barbazetto IA, Laqua H: Benefits and complications of photodynamic therapy of papillary capillary hemangiomas. Ophthalmology 109:1256,2002

64. Madreperla SA: Choroidal hemangioma treated with photodynamic therapy using verteporfin. Arch Ophthalmol 119:1606,2001

65. Barbazetto I, Schmidt-Erfurth U: Photodynamic therapy of choroidal hemangioma: Two case reports. Graefes Arch Clin Exp Ophthalmol 238:214, 2000.

66. Diestelhorst M, Grisanti S: Photodynamic therapy to control fibrosis in human glaucomatous eyes after trabeculectomy: A clinical pilot study. Arch Ophthalmol 120:130, 2002

67. Davidorf J, Davidorf F: Treatment of iris melanoma with photodynamic therapy. Ophthalmic Surg 23:522,1992

68. Stevens TS, Bressler NM, Maguire MG et al: Occult choroidal neovascularization in age-related macular degeneration. A natural history study. Arch Ophthalmol 115:345, 1997