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In recent years, photodynamic therapy (PDT) using verteporfin has emerged as an important method for treating certain subtypes of choroidal neovascularization (CNV) in age-related macular degeneration.1 Despite the significant beneficial effects, a 4% risk of acute severe vision decrease has been reported for patients undergoing PDT with verteporfin.2 An initial thermally enhanced photochemical impact on the macula appears to induce changes in the choriocapillaris to arrest the progression of the neovascularized complex without significant permanent damage to the choriocapillaris, retinal pigment epithelium, and photoreceptors.3 There have been a few cases, however, of transient choroidal ischemia, where normal choroidal vessels have shown evidence of transient delay. The ischemic change in these eyes evolves without clinical evidence of permanent damage. This is a report of a choroidal infarction observed in the treatment of CNV in age-related macular degeneration using standard methods of PDT with verteporfin.
Case 1. In an otherwise healthy 81-year-old woman diagnosed with age-related macular degeneration associated with subfoveal occult CNV in the right eye (Figure 1), PDT was performed according to a standard protocol using 6 mg of verteporfin per square meter of body surface area over 10 minutes (Visudyne; CIBA Vision Corp, Duluth, Ga). Five minutes after completion of the infusion, photoactivation was started using light at a wavelength of 689 nm (Coherent Opal Photoactivator; Coherent Inc, Palo Alto, Calif). The visual acuity was 20/80 OD and 10/400 OS. In the past, the left eye underwent laser photocoagulation and PDT without any adverse effects. Approximately 60 seconds into the laser treatment, the patient began complaining of pain in the right eye. The pain escalated through the remainder of the treatment and persisted for hours. Immediately following completion of the treatment, visual acuity decreased to 10/400 OD; intraocular pressure measurement and anterior segment examination results remained normal. The first angiography was repeated after 3 weeks at which time the visual acuity was 10/400. Funduscopy showed an oak-leaf pattern of pigmentation in the macula. Fluorescein angiography (FA) revealed an area of choroidal nonperfusion within the macula that persisted on late frames (Figure 2A). Indocyanine green angiogram confirmed a choroidal occlusion, and early- and late-phase angiograms showed continuous hypofluorescence in the macula (Figure 2B and C). After 3 months, macular pigmentation developed in the oak-leaf pattern previously seen on angiography (Figure 3A) and evidence of choroidal nonperfusion remained (Figure 3B). Visual acuity did not change from 10/400 OD at the latest follow-up. Furthermore, a new area of classic CNV developed at the edge of the choroidal insult.
Pretreatment late-phase fluorescein angiogram of the right eye from case 1 demonstrating choroidal neovascularization in the macula of the right eye.
Series of angiograms from case 1 taken 3 weeks following photodynamic therapy with verteporfin. A, Late-phase fluorescein angiogram showing stippled fluorescence in an oak-leaf pattern with staining around the edges corresponding to the area of choroidal infarction. B, Early-phase indocyanine green angiogram of the right eye showing paucity of both capillaries and larger choroidal vessels within the central macula. C, Late-phase indocyanine green angiogram demonstrating continued hypofluorescence of the choroidal circulation within the macula.
Photographs of the right eye from case 1 taken 3 months after photodynamic therapy with verteporfin. A, Color fundus photograph demonstrating macular pigmentation in the identical pattern seen previously with angiography to correspond with choroidal infarction. In addition, hemorrhage is seen nasal to the pigmentation, signifying recurrence of neovascularization. B, Midphase indocyanine green angiogram demonstrating continued hypofluorescence consistent with nonperfusion of choroidal capillaries as well as larger vessels.
Case 2. A 90-year-old woman diagnosed with age-related macular degeneration in the right eye was experiencing worsening metamorphopsia. Visual acuity was 20/100, and FA revealed occult CNV associated with confluent soft drusen (Figure 4). The patient underwent PDT with verteporfin followed immediately by an intravitreal injection of triamcinolone acetonide according to a previously described protocol.4 She complained of severe visual deterioration 1 day following treatment. Fluorescein angiogram 3 weeks following treatment revealed an area of hypofluorescence at the macula that persisted through late phases of the study (Figure 5). The vision did not improve during the 3-month follow-up, although a new classic CNV developed at the border of the previous treatment area.
Pretreatment late-phase fluorescein angiogram from case 2 demonstrating occult choroidal neovascularization associated with confluent drusen and atrophy in the right eye.
A, Red-free photograph of the right eye in case 2 performed 3 weeks after photodynamic therapy with verteporfin showing drusen, atrophy, and an area hemorrhage located between the fovea and the optic disc. B, Midphase fluorescein angiogram taken immediately following the photograph in A demonstrating a large area of choroidal nonperfusion extending from the macula to the temporal periphery, including multiple triangular infarcts.
Case 3. An 82-year-old woman with a disciform scar in the left eye complained of metamorphopsia in the right eye and a visual acuity of 20/80. Fluorescein angiogram revealed extrafoveal occult CNV in the right eye, and PDT was performed. The visual acuity decreased significantly after treatment to counting fingers. Repeat FA showed a triangular area of hypofluorescence, including the fovea and the temporal retina. At the 3-month follow-up, the triangular hypofluorescence of the macula remained on FA (Figure 6), the involved retina became atrophic, and the visual acuity remained at counting fingers.
A, Fluorescein angiogram of the right eye in case 3 performed 4 weeks after photodynamic therapy revealed a triangular hypofluorescent area, including the fovea and temporal retina. B, Three months after treatment, the hypofluorescence of the macula remained on the fluorescein angiogram.
Case 4. An 83-year-old man had a visual acuity of 20/200 OD. Fluorescein angiography showed juxtafoveal atrophy of the retinal pigment epithelium and an occult subfoveal CNV. Photodynamic therapy was performed using standard settings. The patient noticed deterioration in vision on the first day after treatment. Three months later, a subretinal hemorrhage developed temporal to the right fovea, the atrophic area enlarged to include the fovea, and visual acuity measured 20/320 OD. Fundus photograph revealed a jigsaw pattern of pigmentation that was more prominent on FA (Figure 7).
Fluorescein angiogram of the right eye in case 4 performed 3 months after photodynamic therapy showed an atrophic area at the fovea with adjacent subretinal hemorrhage. Temporal was a jigsaw pattern of pigmentation.
Case 5. A 78-year-old woman with neovascular age-related macular degeneration in the right eye had a visual acuity of 20/200. Fluorescein angiography revealed a large subfoveal minimally classic CNV lesion. Photodynamic therapy was performed immediately followed by an intravitreal injection of 4 mg of triamcinolone acetonide. The visual acuity deteriorated to 20/400 OD 1 day after treatment. Fluorescein angiography repeated after 4 weeks revealed a large area of choroidal nonperfusion in the macula accompanied by pigmentation of the retinal pigment epithelium temporal to the fovea. At the last visit, 6 months after initial treatment, the visual acuity was 10/400 OD and the FA showed persistent choroidal infarction in the macula (Figure 8).
Fluorescein angiogram of the right eye in case 5 performed 3 months after photodynamic therapy followed by triamcinolone acetonide injection revealed a hypofluorescent area of choroidal nonperfusion at the macula.
Case 6. A 93-year-old man diagnosed with age-related macular degeneration associated with subfoveal occult CNV in the right eye was treated with combined PDT and intravitreal triamcinolone injection in the right eye. Visual acuity was initially 20/200 OD and decreased to 20/400 one day after treatment. Intraocular pressure, recorded after intraocular injection and on each follow-up visit, remained between 10 and 17 mm Hg. Fundus examination 4 weeks after treatment revealed a triangular pigmentation in the macula. Fluorescein angiography at this time showed an area of choroidal nonperfusion in the macula. Indocyanine green angiography showed choroidal hypofluorescence in all phases, confirming a choroidal infarction (Figure 9). At the last visit 1 year after treatment, there was no change in FA images: the hypofluorescence remained. The visual acuity was unchanged at 20/400.
Three months after combined therapy, a midphase indocyanine green angiogram of the right eye in case 6 revealed a large area of hypofluorescence consistent with choroidal infarction.
Case 7. Photodynamic therapy with verteporfin was performed in a 75-year-old man with right subfoveal minimally classic CNV. The visual acuity was 20/100 before treatment. A decrease in vision was noted the week following treatment. Early FA images revealed a circular hypofluorescence of the treated area with an adjacent triangular area of choroidal nonperfusion extending into the temporal periphery that persisted into late frames. One month later, the visual acuity improved to 20/60 and the FA showed a triangular infarct of Amalric sparing the fovea.
Case 8. An 88-year-old woman had age-related macular degeneration associated with subfoveal CNV and a visual acuity of 20/250 OS. Photodynamic therapy and an intravitreal triamcinolone injection were performed on the same day. Visual acuity dropped to 20/400 one day later. Intraocular pressure remained between 12 and 18 mm Hg on all follow-up visits, including 30 minutes after intravitreal injection. Six weeks after treatment, FA revealed a large hypofluorescent area in the macula throughout all phases of the study without evidence of CNV activity. Six months following initial treatment, vision remained unchanged and the choroidal nonperfusion remained during FA.
Photodynamic therapy with verteporfin induces selective destruction of vascular endothelial cells within the choriocapillaris layer when used at standard doses.5 Transient choroidal ischemia after PDT with verteporfin in age-related macular degeneration has been observed previously in human and animal studies.6,7 Angiographic hypofluorescence after treatment was related to occlusion of choriocapillaris as well as swelling of the retinal pigment epithelium. The induced ischemia promotes production of proangiogenic factors such as vascular endothelial growth factor and acts as an incentive for new vessel proliferation. Therefore, recurrent neovascularization occurs not only from primary factors related to the disease and its biological environment but also from treatment-induced ischemia. Recanalization of the physiological choroid was observed as early as 1 week following PDT. In histopathological studies, Schmidt-Erfurth et al8 described complete occlusion of choriocapillaris lumina caused by damage to endothelial cells 1 week after PDT. Larger choroidal vessels remained fully patent with intact, nondeformed endothelial cells.8 Neural structures, photoreceptors, retinal capillaries, and the retinal pigment epithelium also remained intact. Recanalization of occluded choriocapillaris was observed within a short interval. In our case series, PDT caused the closure of a choroidal artery, which perfused a large geographic choroidal area. Therefore, the region of the infarction does not necessarily correspond to the treated area. The configuration of choroidal infarction differs depending on location: central macular involvement manifested as a jigsaw pattern as in cases 1 and 4 while a more peripheral insult resulted in the addition of a triangular infarct of Amalric as in cases 2, 3, and 7.9
Photodynamic therapy has a temporary vaso-occlusive mechanism affecting both CNV and normal choroid10; therefore, substantial undetected amounts of photosensitizer may also be localized within physiologic vessels, which are less sensitive to photochemical damage.11 The photothrombotic efficacy of verteporfin depends on the drug and light dose applied. With increasing dosages, retinal and larger choroidal vessels become occluded, leading to infarction.12 In our cases, there was no explanation in terms of the technique to explain the infarction of the choroid. Standard dosages of drug (6 mg/m2 body surface) and light (689 nm, 83 seconds) were used with spot sizes ranging from 2.5 mm2 to 5.5 mm2. These patients received no surgery or laser treatments prior to the PDT although the patient in case 1 previously underwent uncomplicated PDT in the fellow eye. In addition, angiography failed to demonstrate any abnormalities within the retinal circulation, which leads to the conclusion that there may be an increased sensitivity of the choroid in these patients.
Four of the 8 patients were treated with combination PDT and intravitreal triamcinolone. It is unknown whether therapy combining PDT with intravitreal triamcinolone alters the response of the choroid because, to our knowledge, there have been no pathological studies of such eyes. Also unknown is the effect of the transient increase in intraocular pressure associated with intravitreal injections on the choroidal circulation in the presence of PDT; however, no patients developed evidence of prolonged pressure elevation.
It must be noted that all patients in this series had minimally classic or occult membranes, and this may represent a risk factor in the development of choroidal infarcts following PDT. The importance of this article is that patients should be made aware of this rare complication, which includes the possibility of immediate and permanent loss of vision following PDT with verteporfin, especially in patients with purely occult or minimally classic lesions.
Correspondence: Dr Yannuzzi, Vitreous-Retina-Macula Consultants of New York, 519 E 72nd St, Suite 203, New York, NY 10021 (firstname.lastname@example.org).
Financial Disclosure: None.
Funding/Support: This study was supported by the Macula Foundation Inc, New York, NY, and the LuEsther T. Mertz Retinal Research Center, New York.
Klais CM, Ober MD, Freund KB, et al. Choroidal Infarction Following Photodynamic Therapy With Verteporfin. Arch Ophthalmol. 2005;123(8):1149–1153. doi:10.1001/archopht.123.8.1149
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