Photodynamic therapy with verteporfin for choroidal neovascularization in patients with angioid streaks1

Photodynamic Therapy With Verteporfin for Choroidal Neovascularization in Patients With Angioid Streaks MURAT KARACORLU, MD, MSC, SERRA KARACORLU, MD, HAKAN OZDEMIR, MD, AND CEM MAT, MD

● PURPOSE:

To evaluate safety and efficacy of photodynamic therapy with verteporfin for subfoveal choroidal neovascularization associated with angioid streaks. ● DESIGN: Prospective interventional case series. ● METHODS: Eight patients (eight eyes) with subfoveal choroidal neovascularization secondary to angioid streaks were reviewed. Standardized protocol refraction, visual acuity testing, ophthalmologic examinations, color photographs, fluorescein angiograms and indocyanine angiograms were used to evaluate the results of photodynamic therapy with verteporfin. Follow up ranged from 6 to 12 months with a mean (ⴞ SD) of 8.75 (ⴞ 2.37) months. ● RESULTS: Photodynamic therapy with verteporfin was well tolerated in patients with choroidal neovascularization related to angioid streaks. No deterioration in visual acuity was observed. Increase in median best-corrected visual acuity was 1.37 lines (SD ⴞ 1.59 lines, range 1–5 lines) at the last follow up. Two (25%) patients had no improvement of visual acuity. At the last follow up three (37.5%) patients showed no leakage and three (37.5%) patients had minimal leakage from choroidal neovascularization. Photodynamic therapy related ocular complications were not reported in any case. ● CONCLUSIONS: Photodynamic therapy with verteporfin generally achieved short-term cessation of or decrease of fluorescein leakage from subfoveal choroidal neovascularization without loss of vision in patients with angioid streaks. Further studies with longer follow up are necessary to confirm whether verteporfin therapy is beneficial for subfoveal choroidal neovascularization related to angioid streaks. (Am J Ophthalmol 2002;134: 360 –366. © 2002 by Elsevier Science Inc. All rights reserved.) Accepted for publication May 1, 2002. InternetAdvance publication at ajo.com May 22, 2002. From the The Istanbul Retina Institute, Istanbul, Turkey (M.K., S.K., H.O.), and the Department of Dermatology, Cerrahpasa School of Medicine, University of Istanbul, Istanbul, Turkey (C.M.). Reprint requests to Murat Karacorlu, MD, MSc, The Istanbul Retina Institute, Valikonagi, Sinoplu Cemal S., No:1/6, 80200 Nisantasi, Istanbul, Turkey; fax: (⫹90) 212 233-2425; e-mail: [email protected]

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NGIOID STREAKS ARE IRREGULAR TAPERING LIN-

ear breaks in the Bruch membrane that typically emanate from the optic disk. Choroidal neovascularization (CNV) is the major cause of vision loss associated with angioid streaks.1 The pathogenesis of CNV associated with angioid streaks is believed to be related to cracks in the Bruch membrane.2 This complication has been reported in clinical series to occur in 70% to 86% of patients with angioid streaks.3,4 The poor natural history of many subfoveal CNV lesions and the limitations of conventional laser photocoagulation for these lesions have prompted the search for alternative treatment modalities including photodynamic therapy (PDT).5 PDT is a relatively selective form of treatment for subfoveal CNV. Unlike conventional laser photocoagulation, PDT can close CNV with minimal or no detectable damage to the surrounding tissues. Therefore, it allows the clinician to treat subfoveal CNV without immediately adversely affecting central visual function.6 The aim of this study is to describe the results of PDT with verteporfin on the CNV, visual acuity, and safety in patients with subfoveal CNV caused by angioid streaks.

DESIGN THIS STUDY WAS DONE AS A PROSPECTIVE INTERVEN-

tional case series.

METHODS WE REVIEWED EIGHT PATIENTS (EIGHT EYES) WITH SUBFO-

veal CNV secondary to angioid streaks who were treated with PDT. All of the patients had positive skin biopsy for pseudoxanthoma elasticum. Best-corrected visual acuity (BCVA) was determined using standard Snellen charts. A complete ocular examination was performed including slit-lamp examination, noncontact lens biomicroscopy of the fundus, and color and monochromatic fundus photography using a standard fundus camera (Topcon TRC 50IA,

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TABLE 1. Demographics and Outcome of Study Patients Patient no

Age

Sex

Eye

PE

Refraction (dioptri)

No of PDT

Follow up (month)

Baseline VA

Last VA

Last FFA

1 2 3 4 5 6 7 8

33 56 47 35 44 42 50 45

Male Female Male Male Female Female Male Female

Right Left Right Left Right Right Right Left

⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹

⫺2.00 ⫹0.50 ⫺0.50 ⫺1.50 ⫺1.00 ⫺2.00 ⫺0.50 ⫺0.50

1 2 1 1 1 1 1 2

12 12 12 8 8 8 6 6

1/10 1/10 3/10 1/10 3/10 7/10 1/10 2/10

2/10 3/10 4/10 1/10 8/10 8/10 1/10 3/10

Min* Min No leakage† Mod‡ No leakage No leakage Progression§ Min

FFA ⫽ fundus fluorescein angiography; PE ⫽ pseudoxanthoma elasticum; PDT ⫽ photodynamic therapy; VA ⫽ best-corrected visual acuity. *Area of choroidal neovascularization occupying ⬍50% of the area of CNV noted at baseline. † No choroidal neovascularization within the area of the lesion at baseline. ‡ Area of choroidal neovascularization occupying ⬎50% of the area of CNV noted at baseline. § Leakage from the choroidal neovascularization beyond the area of the lesion noted at baseline.

Topcon Corporation, Paramus, New Jersey, USA). Fundus fluorescein and indocyanine angiograms were performed simultaneously on a Heidelberg Scanning Laser Ophthalmoscope (Heidelberg Engineering, Heidelberg, Germany). Choroidal neovascularization was considered to be secondary to angioid streaks when features such as dark bands of irregular contour that radiate from the optic nerve head, atropic retinal pigment epithelium, and classical “peau d’orange” appearance were present. Fluorescein and indocyanine green angiographic criteria included evidence of leakage from CNV caused by angioid streaks in which CNV extended under the center of the foveal avascular zone. The greatest linear dimension of the entire lesion had to be 5400 ␮m or less on the retina. Follow-up examinations were scheduled at 1 and 3 months after PDT. At the follow up the CNV evaluation was done according to a grading system developed to assess both the size of the CNV lesion and the presence or absence of leakage from the CNV components. The extent of fluorescein leakage was graded as follows: (1) progression (leakage from the CNV beyond the area of the lesion noted at baseline); (2) moderate leakage (area of CNV occupying ⬎ 50% of the area of CNV noted at baseline and no progression); (3) minimal leakage (area of CNV occupying ⬍ 50% of the area of CNV noted at baseline); and (4) absence of leakage (no CNV within the area of the lesion noted at baseline). Retreatments were considered when minimal leakage was observed at 3-month intervals. Verteporfin (Visudyne; Novartis Ophthalmic AG, Hettlinger Switzerland) is reconstituted with sterile water and diluted with 5% dextrose to achieve a drug dose of 6 mg/m2 body surface area (BSA) and a total infusion volume of 30 VOL. 134, NO. 3

ml. The solution is infused intravenously at a rate of 3 ml/min over 10 minutes. Laser (Coherent, Palo Alto, California, USA) application is carried out at 15 minutes after the start of the infusion. The spot size is determined by measuring the greatest linear dimension (GLD) of the entire lesion and an additional 1000 ␮m is added to this value. The time to deliver 50 J/cm2 laser dose is 83 seconds.

RESULTS EIGHT PATIENTS (EIGHT EYES) WITH SUBFOVEAL CNV FROM

angioid streaks were enrolled. Four (50%) of these patients

FIGURE 1. Best-corrected visual acuity at baseline compared with last follow up (n ⴝ 8).

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FIGURE 2. Fluorescein angiogram of left eye before photodynamic therapy (top left) shows well-defined hyperfluorescence due to choroidal neovascularization. Fluorescein angiogram 4 months after photodynamic therapy (top right) and at the last follow up (bottom left) shows decrease of hyperfluorescence within the area of the lesion at baseline.

lines, range 1–5 lines) at the last follow up. Greatest visual acuity improvement was noted in patient 5 with an initial visual acuity of 0.3. Her final visual acuity was five lines better than baseline at the last follow-up examination. Two (25%) patients had no improvement of their vision at the last follow-up examination. No patients had deterioration in visual acuity (Figure 1). At the last follow-up examination, three (37.5%) patients had minimal leakage within the area of the CNV lesions (Figure 2). Three (37.5%) patients showed no CNV leakage at the last follow-up examination (Figures 3

were women. Patients had a mean (⫾ SD) age distribution of 44 (⫾ 7.52) years. Follow-up time ranged from 6 to 12 months with a mean of 8.75 (⫾ 2.37) months. Bestcorrected visual acuity at screening ranged from 0.1 to 0.7. Six (75%) patients were treated once and two (25%) patients were treated twice (Table 1). Retreatments were applied 12 weeks after previous PDT treatment, with the final follow up at 12 weeks after the last treatment. There was no loss to follow up of any of these patients during the trial. Increase in median BCVA was 1.37 lines (SD ⫾ 1.59 362

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FIGURE 3. Fluorescein angiogram of right eye before photodynamic therapy (top left) shows discrete subfoveal choroidal neovascularization and peripapillary angioid streaks. Fluorescein angiogram 4 weeks after photodynamic therapy (top right) and at the last follow up (bottom left) shows absence of choroidal neovascularization within the area of the lesion at baseline.

and 4). In patient 7, fluorescein and indocyanine green angiography showed leakage from the CNV beyond the area of the lesion noted at baseline at the last visit. In patient 4, even though the angiographic examination showed moderate leakage, visual acuity remained stable. Verteporfin therapy did not cause any systemic complications. No skin photosensitivity reactions were reported after an initial treatment or multiple courses of therapy. No infusion related back pain or photodynamic therapy VOL. 134, NO. 3

related ocular complications were reported. Clinically relevant visual acuity loss of two or more lines was not seen in any of the eight patients during trial.

DISCUSSION CHOROIDAL NEOVASCULARIZATION IS A DEGENERATIVE

condition that, if left unidentified and untreated, can cause

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FIGURE 4. Fluorescein angiogram of right eye before photodynamic therapy (top left) shows subfoveal hyperfluorescence due to choroidal neovascularization. Fluorescein angiogram 4 weeks after photodynamic therapy (top right) and at the last follow up (bottom left) shows no leakage within the area of the lesion at baseline.

severe irreversible central vision loss. It may develop secondary to several disorders of the eye including agerelated macular degeneration (AMD), pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Although the peripheral vision of patients is generally maintained, severe central vision loss as a result of CNV may significantly reduce their ability to undertake basic everyday activities.7 Most patients with macular CNV are not good candidates for conventional laser photocoagulation.8 Investiga364

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tors seek new therapies for CNV that can be used in a larger group of patients than conventional laser therapy. One of these treatments, PDT, involves injection of a photosensitizer followed by irradiation of the photosensitized tissue by nonthermal laser light at the absorption peak of the photosensitizer. The excited photosensitizer generates singlet oxygen or other reactive intermediates which can damage cellular components, including cellular membranes.9 In neovascular tissue, cellular damage to the endothelium can lead to thrombosis of the vessel.10,11 OF

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Verteporfin is a second generation lipophilic photosensitizer with an absorption peak near 690 nm.12 It has been demonstrated to be an effective photosensitizer in vitro and in several in vivo systems.13 PDT with verteporfin is recommended for the treatment of selected patients with AMD and pathologic myopia with subfoveal choroidal neovascularization.14 –16 In phase I/II investigation of verteporfin therapy for the treatment of selected patients with subfoveal CNV secondary to AMD, fluorescein leakage recurred by 12 weeks after the initial treatment, even in patients who had received a maximum tolerated laser dose. The investigators believed that it was highly probable that fluorescein leakage 12 weeks after an initial treatment would result in continued growth of the neovascular lesion, accompanied by progressive vision loss.17,18 According to results of phase III studies of the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) group, the proportion of verteporfin treated patients who required retreatment decreased with each follow-up visit (91% at month 3, 79% at month 6, 70% at month 9, 64% at month 12).19 In phase I/II investigation of verteporfin therapy for the treatment of CNV secondary to pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes, eight patients were treated once, two patients were treated twice, one patient was treated three times and two patients were treated four times in 12 to 43 weeks of follow up.5 In our study, only two (25%) patients out of eight patients were treated twice. Among these two patients, visual acuity of patient 8 improved shortly after an initial PDT treatment and then decreased during the next 3 months when fluorescein leakage from CNV recurred. Visual acuity improved again shortly after subsequent PDT treatment and was one line better than baseline at the last follow-up examination. Visual acuity improved five lines after a single treatment in patient 5. This patient has been followed for 8 months and at the last follow-up examination fluorescein and indocyanine green angiography still showed no leakage from CNV. Only two (25%) patients had no visual improvement at the last follow-up examination. In patient 7, even though fluorescein and indocyanine green angiography showed leakage from the CNV beyond the area of the lesion noted at baseline, his visual acuity remained stable at the last visit. No patients had deterioration in visual acuity. The improvement in visual acuity and the requirement of retreatment seems to be favorable in patients with angioid streaks. In this trial, PDT with verteporfin achieved short-term cessation of fluorescein leakage from CNV without loss of vision or growth of CNV in patients with angioid streaks. Further studies with longer follow up are necessary to confirm whether verteporfin therapy is beneficial for subfoveal choroidal neovascularization related to angioid streaks. VOL. 134, NO. 3

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