Long-term Results of Photodynamic Therapy for Choroidal Neovascularization in Japanese Patients With Pathologic Myopia




Objective


To determine the results of photodynamic therapy (PDT) in highly myopic eyes with choroidal neovascularization (CNV).


Design


Open-label, consecutive, interventional case series.


Methods


Forty-eight eyes of 46 consecutive Japanese patients with a myopic CNV were studied. The eyes were treated with PDT and were followed up from 1 to 4 years. The best-corrected visual acuities (BCVAs) at the baseline and after the PDT were compared. Multivariate regression analyses were used to determine the factors that were significantly associated with the BCVA at 3 or 4 years.


Results


The mean follow-up period was 3.2 years. Sixty-nine percent of the patients obtained angiographic closure by a single PDT treatment, and the average number of PDT treatments was 1.4. Chorioretinal atrophy developed in 61% of the eyes at 3 years and in 70% of the eyes at 4 years. The BCVA did not change significantly after the PDT. Multivariate regression analyses showed that the BCVA at 3 years was significantly correlated with the baseline BCVA and area of chorioretinal atrophy. Analyses of the 20 patients at 4 years or more showed that in 5 of 7 (71.4%) patients with juxtafoveal CNV, chorioretinal atrophy did not develop and that all had BCVA of 0.5 or better. However, in 12 of the 13 patients with a subfoveal CNV, chorioretinal atrophy developed at 4 years, and 10 of these patients had BCVA of 0.1 or worse.


Conclusions


In highly myopic patients, 69% obtained angiographic closure by a single PDT treatment, and recurrence was rare. These findings indicate that PDT is still a good option for treating CNVs in highly myopic patients.


Pathologic myopia is a major cause of irreversible vision decrease. In some Asian countries, pathologic myopia is the most frequent cause of visual impairment; the Tajimi Study reported that myopic macular degeneration was the leading cause of unilateral or bilateral blindness in Japan. Pathologic myopia is the second most frequent cause of low vision or blindness in Chinese persons who are older than 40 years.


Pathologic myopia is the primary cause of choroidal neovascularization (CNV) in individuals younger than 50 years. We reported that CNV developed in 10.2% of highly myopic patients during a follow-up of at least 3 years. We determined the natural history of myopic CNV, and we showed that the visual acuity of patients with myopic CNV decreases to less than 0.1 by 5 to 10 years after the development of CNV.


Photodynamic therapy (PDT) with verteporfin (Visudyne; QLT Inc, Vancouver, Canada) is a well-established treatment for CNVs associated with various diseases, including age-related macular degeneration. The Verteporfin in Photodynamic Therapy (VIP) study of patients with subfoveal CNV secondary to pathologic myopia reported that PDT with verteporfin stabilized the visual acuity in 72% of the patients for 1 year. Other studies also have reported favorable outcomes for PDT treatment for myopic CNV. Although there have been many reports on the effect of PDT against myopic CNV, the follow-up periods of these studies were relatively short. A PubMed search identified only 2 reports with a follow-up period of 3 years or more after PDT.


In our natural history study of myopic CNV, we showed that chorioretinal atrophy can develop long after CNV has regressed, which then leads to a decrease in the visual acuity. Thus, without long-term follow-up, it is difficult to determine the effectiveness of any treatment for myopic CNV.


Recently, Ruiz-Moreno and associates reported the 4-year outcome of 36 patients who received PDT for myopic CNV. Unfortunately, they only studied eyes with subfoveal CNV, and nonsubfoveal CNVs, which make up approximately 20% of cases of myopic CNV, were not studied. In addition, they did not report the incidence of chorioretinal atrophy around the regressed CNV. The visual outcome was analyzed as a whole, and no detailed analysis was made of each patient.


Thus, the purpose of this study was to determine the long-term visual and anatomic outcomes of PDT in highly myopic patients with a subfoveal or juxtafoveal CNV. Because a chorioretinal atrophy can develop around a regressed myopic CNV and can lead to a decrease in vision, it was important to determine whether the PDT influenced the development of a chorioretinal atrophy. We found that 69% of the patients obtained angiographic closure of the CNV in the first year after a single PDT treatment and that a recurrence of CNV thereafter was not common. In patients who were followed up for 4 years or more after PDT, 71.4% of the patients with juxtafoveal CNV retained good vision without chorioretinal atrophy developing.


Methods


This was a prospective, interventional case series of 60 eyes of 57 consecutive patients with myopic CNV who were treated with PDT between October 2004 and November 2006. Before the approval of the use of an intravitreous injection of bevacizumab (IVB) was obtained from the Ethics Committee of the Tokyo Medical and Dental University, we treated all of the eligible patients with myopic CNV with PDT alone. After December 2006, we switched the treatment for myopic CNV to IVB in all of the eligible eyes. Thus, we present the findings obtained from patients who received PDT alone, and the findings in some of the patients were published earlier.


The inclusion criteria were: (1) myopic refractive error (spherical equivalent) of more than −6 diopters (D) or axial length of more than 26.5 mm; (2) greatest linear dimension (GLD) of the lesion of 5400 μm or less; and (3) active CNV determined by clinical observations and fluorescein angiography (FA). The exclusion criteria were: (1) any ocular diseases other than pathologic myopia, for example, large drusen, multifocal choroiditis, or punctuate inner choroidopathy associated with CNV or any other significant ocular diseases that would compromise vision in the study eye; (2) active hepatitis or clinically significant liver disease; (3) earlier treatment of the CNV in the study eye such as macular laser photocoagulation, surgical extraction of CNV, or macular translocation; (4) porphyria or other porphyrin sensitivity; (5) history of intraocular surgery within 6 months on the study eye; and (6) less than 1 year of follow-up after PDT. The location of CNV was classified as subfoveal if the CNV included the central fovea and was classified as juxtafoveal if the CNV did not include the central fovea but the margin of CNV was within 200 μm from the foveal center.


The best-corrected visual acuity (BCVA) was determined with a Landolt C chart, and the decimal BCVAs were converted to the logarithm of minimal angle of resolution (logMAR) units for statistical analyses. A comprehensive ocular examination, including dilated funduscopy and macular examinations with a contact lens or a +78-D lens, color fundus photography, and FA, was performed.


PDT was performed after the procedures described in the VIP study and TAP study protocols. In short, the spot size was determined by the GLD of the CNV lesion measured on a fluorescein angiogram using the software of the imaging system (PDT/MPS software; Topcon, Tokyo, Japan). The PDT/MPS software measures the GLD based on the axial length of the eye, and the area of the CNV also was calculated using the same software. An additional 1000 μm was added to the GLD to provide a 500-μm rim of treatment around the lesion. The standard dose and timing were used for the verteporfin infusion (6 mg/m 2 of body surface area over a 10-minute period), and the laser light (690 nm; 50 J/cm 2 for 83 seconds) was delivered 15 minutes after the start of the infusion. The follow-up examinations were scheduled at 3-month intervals. Retreatment was performed if CNV leakage was observed in the FAs at the 3-month examinations.


The area of a chorioretinal atrophy was determined by the hypofluorescent area in the fundus autofluorescence images as well as by choriocapillaris filling defects in the FA. The size of the chorioretinal atrophy was measured with the software of the imaging system (PDT/MPS software). We examined the chorioretinal atrophy that developed around the myopic CNV alone, and the pre-existing patchy areas of chorioretinal atrophy were not analyzed.


Statistical Analyses


The significance of the changes in the BCVA and the size of CNV or chorioretinal atrophy after PDT were determined by paired t tests. The differences in the CNV area, area of chorioretinal atrophy, and BCVA between groups were analyzed using the Mann–Whitney U test. A P value of .05 was accepted as being statistically significant.


Univariate and multivariate regression analyses were used to determine whether significant associations existed between the BCVA at 3 years or 4 years and the patient age, BCVA at the baseline, area of the CNV at the baseline, area of lesion, area of the CNV at 3 years or at 4 years, and the area of chorioretinal atrophy at 3 years or 4 years. The lesion was defined according to the criteria of the VIP study. Thus, the lesion included the CNV, blood, hypofluorescence not from visible blood, or a serous detachment of the retinal pigmented epithelium. The statistical analyses were performed with SAS software version 8.02 (SAS Institute, Inc, Cary, North Carolina, USA).




Results


The clinical characteristics of the patients at the initial examination (baseline) are shown in Table 1 . Their average age was 53.1 ± 15.9 years, with a range of 19 to 81 years, and the average refractive error (spherical equivalent) of the eyes that were not pseudophakic was −11.6 ± 3.5 D, with a range of −6.5 to −21.0 D. The average axial length was 28.5 ± 1.5 mm, with a range of 26.1 to 32.4 mm. The baseline BCVA was 0.63 ± 0.44 logMAR units, with a range of 0 to 2.0 logMAR units. Thirty-two eyes had a subfoveal CNV, 14 eyes had a juxtafoveal CNV, and 2 eyes had an extrafoveal CNV. The baseline BCVA in the 22 eyes with a subfoveal CNV was 0.77 ± 0.44 logMAR units, which was significantly poorer than the baseline BCVA in the 14 eyes with a juxtafoveal CNV (0.39 ± 0.27; P = .004).



TABLE 1

Clinical Characteristics of Patients Treated with Photodynamic Therapy against Myopic Choroidal Neovascularization








































Gender, no. Patients (eyes)
Male 12 (12)
Female 34 (36)
Mean age ± SD (yrs) 53.1 ± 15.9
Mean refractive error ± SD (D) –11.6 ± 3.5
Mean axial length ± SD (mm) 28.5 ± 1.5
Mean baseline VA ± SD (logMAR) 0.63 ± 0.44
Mean size of CNV ± SD (mm 2 ) 1.95 ± 1.53
Location of CNV, no. of eyes (%)
Subfoveal 32 (66.7)
Juxtafoveal 14 (29.2)
Extrafoveal 2 (4.1)

CNV = choroidal neovascularization; D = diopters; logMAR = logarithm of minimal angle of resolution; SD = standard deviation; VA = visual acuity; yrs = years.


The mean follow-up period after PDT was 3.2 ± 1.1 years, with a range of 1.0 to 5.0 years. Thirty-three eyes of 31 patients completed the 3-year follow-up after the PDT, and 20 eyes of 18 patients completed the 4-year follow-up after the PDT. Fifteen patients (15 eyes) dropped out during the follow-up period. The reasons for dropping out included: patient selected to switch to IVB and patients not returning to the hospital for personal reasons. More precisely, 8 patients selected to change their treatment to IVB, with 4 patients changing in the second year and 4 patients changing in the third year. Seven patients declined to visit the hospital, 1 patient in the second year and 6 patients in the third year.


Anatomic Outcomes of All Patients


The patients received an average of 1.4 ± 0.8 treatments during the follow-up period: 33 eyes (68.8%) required only 1 PDT treatment, 11 eyes (22.9%) required 2 PDT sessions, 2 eyes (4.2%) required 3 PDT sessions, and 2 eyes (4.2%) required 4 PDT sessions. The average area of the CNV at baseline was 1.95 ± 1.53 mm 2 ( Table 1 ), and it was not significantly changed at 1.97 ± 1.67 mm 2 at the final examination ( P > .05, paired t test). FA showed dye leakage in 4 eyes (8.3%) at 1 year after PDT, in 3 eyes (7.0%) at 2 years after PDR, and in 0 eyes at 3 years and thereafter after PDT.


Chorioretinal atrophy was present in 24 (50.0%) of 48 eyes at 1 year, in 25 (58.1%) of 43 eyes at 2 years, in 20 (60.6%) of 33 eyes at 3 years, and in 14 (70.0%) of 20 eyes at 4 years after PDT. The mean area of the chorioretinal atrophy was 1.09 ± 1.80 mm 2 , 1.56 ± 2.05 mm 2 , 1.97 ± 2.13 mm 2 , and 2.80 ± 2.42 mm 2 at 1, 2, 3, and 4 years after PDT, respectively.


Visual Outcomes after Photodynamic Therapy in All Patients


The baseline BCVA was 0.63 ± 0.44 logMAR units, with a range of 0 to 2.0 logMAR units. The mean BCVA was 0.57 ± 0.41 logMAR units, with a range of −0.08 to 1.52 at 1 year after PDT (48 eyes); 0.59 ± 0.49 logMAR units, with a range of −0.18 to 1.70 at 2 years after PDT (43 eyes); 0.61 ± 0.49 logMAR units, with a range of −0.08 to 1.40 at 3 years after PDT (33 eyes); and 0.74 ± 0.52 logMAR units, with a range of −0.18 to 1.70 at 4 years after PDT (20 eyes). The differences in the follow-up BCVA from the baseline BCVA was not significant at all times.


The percentages of eyes that showed a change of BCVA by more than 0.2 logMAR units at each follow-up after PDT are shown in Figure 1 . The results showed that the percentage of patients who had a significant decrease of BCVA tended to increase as the follow-up period increased. In the 33 eyes that were followed up for 3 years or more, the baseline BCVA in 12 eyes with a juxtafoveal CNV was significantly better than the baseline BCVA in the 21 eyes with a subfoveal CNV (0.36 ± 0.31 vs 0.76 ± 0.39; P = .0082). Also, the BCVA at 3 years after PDT in eyes with a juxtafoveal CNV was significantly better than the BCVA in eyes with a subfoveal CNV (0.25 ± 0.40 vs 0.82 ± 0.40; P < .001).




FIGURE 1


Bar graph showing the distribution of the percentage of eyes that reflects a change in the best-corrected visual acuity (BCVA) of more than 0.2 logarithm of the minimal angle of resolution units at 1 year, 2 years, 3 years, and 4 years after photodynamic therapy. y = years.


Univariate Analyses (Spearman Correlation Analyses)


Univariate and multiple regression analyses were used to identify the factors that were associated significantly with the BCVA at 3 years (33 eyes) and at 4 years (20 eyes). The associations between BCVA at 3 years after PDT and age, baseline BCVA, size of the CNV at onset, lesion size at baseline, size of CNV at 3 years after PDT, and size of chorioretinal atrophy at 3 years after PDT are summarized in Table 2 . The BCVA at 3 years after PDT was positively and significantly correlated with the baseline BCVA, area of the CNV at the baseline, and the area of the chorioretinal atrophy at 3 years. Also, there was a statistically significant correlation between the BCVA at 4 years and the baseline BCVA ( P = .0009, Spearman correlation analysis; not shown in Table 2 ). The size of the lesion and area of the chorioretinal atrophy at 3 years were significantly correlated ( P < .001).



TABLE 2

Correlation between the Best-Corrected Visual Acuity at 3 Years after Photodynamic Therapy against Myopic Choroidal Neovascularization and Explanatory Variables using Spearman Correlation Analysis
































Variable Correlation Coefficient P Value
Age 0.323 .067
VA at onset (logMAR) 0.699 <.0001
CNV area at onset (mm 2 ) 0.384 .027
Lesion size at onset (mm 2 ) 0.550 .0009
CNV area at 3 years (mm 2 ) 0.414 .017
Area of chorioretinal atrophy at 3 years (mm 2 ) 0.596 .0003

CNV = choroidal neovascularization; logMAR = logarithm of minimal angle of resolution; VA = visual acuity.


Multivariate Analyses


Finally, we sought to identify the possible factors that might have influenced the final visual outcome using multivariate regression analyses, and the results are summarized in Table 3 . This model had a coefficient of determination ( R 2 ) of 0.61. The BCVA at 3 years after PDT was positively and significantly correlated with the baseline BCVA ( P < .001) and the area of the chorioretinal atrophy at 3 years ( P = .038). Also, multivariate regression analysis showed that the BCVA at 4 years was positively correlated with the baseline BCVA ( P = .006, not shown in Table 3 ).



TABLE 3

Correlation between Visual Acuity at 3 Years after Photodynamic Therapy and Prognostic Factors by Multiple Regression Analysis



















Variable Regression Coefficient Standard Error P Value
VA at onset (logMAR) 0.747 0.192 <.001
Area of chorioretinal atrophy at 3 years (mm 2 ) 0.097 0.044 .038

logMAR = logarithm of minimal angle of resolution; VA = visual acuity.


Analysis of Patients 4 Years after Photodynamic Therapy


The clinical characteristics of the 20 patients with 4 years of more of follow-up after PDT are shown in Table 4 . Cases 1 through 13 had subfoveal CNV and Cases 14 through 20 had juxtafoveal CNV. Statistical comparisons between the eyes with subfoveal CNV and those with juxtafoveal CNV showed that the eyes with juxtafoveal CNV had significantly smaller CNVs at the baseline ( P = .01), significantly smaller chorioretinal atrophy around the CNV at 4 years after PDT ( P = .007), and significantly better BCVA at 4 years after PDT ( P = .004). In fact, 5 of 7 eyes (71.4%) with juxtafoveal CNV had BCVA of 0.5 or better at 4 years after PDT, whereas only 1 of 13 (7.7%) patients with subfoveal CNV had BCVA of 0.5 or better at 4 years after PDT, and 10 of the 13 (76.9%) patients had BCVA of 0.1 or worse at 4 years after PDT. The BCVA in eyes with subfoveal CNV decreased significantly at 4 years after PDT compared with the BCVA at baseline ( P = .036), whereas there was no significant difference between the BCVA at the baseline and that at 4 years after PDT in the eyes with juxtafoveal CNV.



TABLE 4

Clinical Characteristics and Visual as well as Anatomic Outcomes of the Patients with ≥ 4 Years of Follow-up after PDT































































































































































































































































































































































































































Baseline 1 Year after PDT 4 Years after PDT
Case No. Eye Age (yrs) Gender Refractive Degree (D) Axial Length (mm) BCVA Location of CNV Size of CNV (mm 2 ) Lesion size (mm 2 ) Dye Leakage by FA Development of Chorioretinal Atrophy BCVA Development of Choroidal Atrophy Size of Chorioretinal Atrophy (mm 2 ) Dye Leakage by FA No. of PDT Sessions Total Follow-up (mos)
1 R 20 F –8 27.6 0.1 S 4.3 15.3 + 0.1 + 3.8 1 48
2 R 40 M −17.5 28.9 0.3 S 1.7 13.2 + 0.4 + 3.8 1 48
3 L 41 M −6.5 27.0 0.4 S 2.8 7.3 + 0.6 + 3.8 1 60
4 L 46 F −18.5 32.0 0.1 S 0.9 2.8 + 0.1 + 1.9 1 48
5 L 50 F −16 27.7 0.1 S 0.9 1.3 0.06 0 1 48
6 R 57 F −11.5 28.2 0.3 S 3.4 5.6 + 0.1 + 1.3 1 60
7 L 57 F −13.5 28.2 0.2 S 1.3 3.1 + 0.08 + 2.6 1 60
8 R 59 F −14.5 31.9 0.3 S 1.4 1.8 + 0.05 + 3.8 1 54
9 L 62 F IOL 32.4 0.7 S 1.0 3.1 + + 0.2 + 6.4 2 54
10 R 63 F −13 29.9 0.1 S 2.4 20.4 + 0.1 + 7.6 1 48
11 R 63 F −8 27.3 0.1 S 1.3 2.9 + 0.06 + 5.1 1 48
12 L 65 F −8.5 26.9 0.07 S 4.8 15.3 + 0.08 + 7.0 1 60
13 R 73 M −6 26.9 0.03 S 3.1 12.7 0.02 + 2.5 2 48
14 L 19 F −11 28.9 0.5 J 1.3 2.3 + 0.6 + 1.9 3 48
15 R 38 F −8 26.1 0.8 J 2.8 2.8 1.5 0 2 48
16 R 53 F −13 29.1 0.3 J 0.2 0.2 0.15 0 1 48
17 R 58 F −21 29.6 0.3 J 0.7 1.5 + 0.1 + 4.5 1 48
18 R 62 M −13 28.7 0.5 J 0.3 0.4 1.2 0 1 54
19 R 67 F −8.5 28.2 0.6 J 1.3 1.8 1 0 1 60
20 L 71 F −11 27.9 0.06 J 0.8 0.9 0.5 0 1 48

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Jan 16, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Long-term Results of Photodynamic Therapy for Choroidal Neovascularization in Japanese Patients With Pathologic Myopia
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