Idiopathic choroidal neovascularization (ICNV) is a disorder due to choroidal neovascularization (CNV) affecting individuals who do not have evidence of intraocular pathological myopia (PM), inflammation, ocular trauma, chorioretinal scars or dystrophy.1 Although ICNV is relatively uncommon, it affects young patients (aged <50 years) and thus may have a significant impact on vision and life quality over a patient's lifespan.2
Subfoveal CNV destroys central vision and it has been repeatedly shown by several different centers that photodynamic therapy (PDT) can prevent severe deterioration of visual damage or improve visual outcome of subfoveal CNV due to exudative age-related macular degeneration,3,4 central serous chorioretinopathy,5 and others including ICNV.6,7 Currently, PDT is usually applied according to the recommendations of the treatment of age-related macular degenceration with photodynamic therapy (TAP)8,9 and verteporfin in PDT (VIP)10,11 studies. However, these studies focused only on CNV due to exudative age-related macular degeneration and pathologic myopia. The standard method of PDT was to use a laser spot to cover CNV with 1000 μm more than the maximum diameter of the lesion. In Postelmans et al's12 reports, severe RPE alterations were observed in the treatment area following standard PDT for classic CNV.
Therefore, since in most of the subjects with ICNV, the CNV observed by fundus fluorescein angiography was usually small and with clear boundary, we performed PDT with small laser spot for this kind of lesion to maximally protect the normal surrounding tissue (mainly the retinal pigment epithelium (RPE) of the subject, expecting to reduce vision damage after treatment.
The present clinical research was a randomized, open and controlled study. Patients were followed up in intervals over a span of 12 months. ICNV patients were enrolled and randomly divided into two groups for PDT treatment, i.e., a study group with small laser spot and a control group with standard laser spot. A series of randomized numbers was provided by a statistical center and each number was enclosed in an envelope. Each patient chose an envelope; if the number in it was odd, then PDT with small laser spot would be performed, and if the number was even, PDT with standard laser spot would be performed. Before the envelope being opened, the name, age, gender and enrolment number of the patient were recorded on the envelope. The envelopes were sent to a data review center in a fixed interval.
Patients diagnosed with ICNV were aged less than 45 years, developing loss of central vision secondary to serous and hemorrhagic detachment of the macula caused by CNV arising in the macular or peripheral fundus without any other evidence of intraocular diseases. None of the patients underwent any previous therapy that would interfere with this study including intravitreal anti-VEGF drugs or triamcinolone.
Inclusion criteria were age <45 years, acute vision decreasing due to a single CNV in the foveal avascular zone without other fundus abnormalities, clear media for fundus examination and fundus fluorescein angiography (FFA), a single lesion in an eye, greatest linear dimension (GLD) of CNV ≤1200 μm, leakage of CNV in FFA, over 50% boundary of CNV being classic type, subretinal fluid shown by OCT, adaptation to the requirements of this study and sufficient physical ability for attending follow-ups spread over a duration of 12 months. Signed informed consent was obtained from all patients according to the requirements of the Institutional Review Board (IRB) before treatment.
Exclusion criteria included signs of age-related macular degeneration, GLD >1200 μm, refraction error >-6.00 diopter, CNV due to other diseases such as tuberculosis and histotoxoplasmosis, exact clinical drusen, previous PDT, transpupillary thermotherapy and other types of laser treatments, porphyria, allergy to fluorescein, porphyrin and verteporfin, allergy to sunshine or strong man-made light, pregnancy or breast-feeding, medium or severe liver damage and active or out-of-control systemic diseases.
Subjects enrolled in this study were outpatients. Complete information including the benefits and possible after-effects of the study was provided to the subjects. The study complied with the Declaration of Helsinki and was approved by the local ethics committee (People's Hospital, Peking University).
Treatment was provided according to the recommendations of the TAP8,9 and VIP10,11 studies. Verteporfin (6 mg/m2 of body surface area) was administered by intravenous infusion in a volume of 30 ml over 10 minutes. At 15 minutes after the start of the infusion, a 689 nm laser source was used to deliver 50 J/cm2 over 83 seconds. The spot diameter sizes were GLD+500 μm in the study group (small spot size) and GLD+1000 μm in the control group (standard spot size, Figure 1).
In addition to the baseline examination, all patients were scheduled for follow-up visits at 1 week, 1 month, 3 months (±2 weeks), 6 months (±2 weeks), 9 months (±2 weeks) and 12 months (±2 weeks) after initial PDT treatment. At each scheduled follow-up, VA measurements, ophthalmoscopic examination, FFA and optic coherence tomography (OCT) were performed. Change of subretinal fluid was measured by OCT, and the lesion area of CNV (mm2) and alterations of the RPE with window defects in fluorescein angiography (quadrants, plotted by the center point of CNV) were evaluated by reading of FFA photos. OCT and FFA readings were noted by a team with three specialists.
If a leakage of choroidal lesions, which implied active CNV, was observed from FFA at follow-ups, or if the OCT showed presence of subretinal fluid or a larger intra-retinal thickness than the previous follow-up, then a recurrent CNV was considered necessary. Secondary treatment would be provided and the data after secondary treatment were discarded.
Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 16.0, SPSS Inc., USA). Data distributed normally were presented as mean ± standard deviation (SD). Where appropriate, Student's t-test, rank sum test and Chi-square test were used. All P values were two-sided and were considered statistically significant when the values were less than 0.05.
Between September 2007 and September 2008, 52 patients were enrolled in this study (18 male, 34 female; study group: 27 cases, control group: 25 cases). Table 1 shows that age, gender, ETDRS scores, size of CNV membrane and location of CNV between both groups did not vary significantly (P >0.05).
Only at the 1-week follow-up, the BCVA between both groups varied significantly (P=0.033, Figure 2). From the 3-month follow-up till the final follow-up, ETDRS scores were slightly better in the study group than in the control group, while which were not statistically significant.
The improvements of BCVA at follow-ups between both groups are shown in Figure 3. At 6- and 9-month follow-ups, the improvement of BCVA in the study group was nearly two times that in the control group, which was significantly different (6-month follow-up, (25.53±15.01) letters vs. (14.71±11.66) letters, P=0.025; 9-month follow-up, (27.53±17.78) letters vs. (15.59±12.21) letters, P=0.039).
Alterations of the RPE with window defects in FA were noted. In each follow-up, the median of quadrants of RPE lesion in the study group was less or equal to that in the control group (Table 2). At 3- and 6-month follow-ups, the areas of RPE lesion between the two groups varied significantly (Table 2, P <0.001 and P=0.023, respectively). Figure 4 shows the FA of two cases who underwent standard and small size PDT, respectively.
Leakage of CNV
Table 3 shows the number of cases in each group which had decreased or unchanged leakage of CNV in FA after PDT treatment. In each follow-up, the number of cases with decreased or unchanged leakage of CNV did not vary significantly between the two groups.
In both groups, the number of cases that had a reduced height of subretinal fluid in OCT kept increasing with the follow-ups (Table 4, Figure 5). However, between the two groups, the rate did not vary significantly in each follow-up (Table 4).
Ten cases (37.0%) in the study group and eight cases
(32.0%) in the control group suffered from recurrent CNV during the follow-up duration. The rate did not vary significantly (P=0.703).
The present randomized controlled study showed a significantly reduced alteration of RPE (Table 2) and correspondingly higher improvement of visual acuity (6-and 9-month follow-ups, Figure 2) in the small laser spot PDT group than the standard laser spot PDT group at multiple follow-ups. The number of cases that had a reduced subretinal fluid height measured by OCT between the two groups did not vary significantly through all follow-ups.
The features of ICNV varied remarkably from CNV due to exudative age-related macular degeneration and pathologic myopia. ICNV is not accompanied by massive subretinal hemorrhage or exudate, and shows natural degeneration.13–16 The reason why vision loss is not accompanied by atrophic degeneration is due to the recovery mechanism of RPE which suppress neovascularization.17 Therefore, it should be reasonable to consider PDT with less damage size and better protection of RPE for ICNV.
Our previous study found that damage of RPE surrounding the CNV lesion at 1 month after PDT for ICNV occurred at a rate as high as 51.4% in females and 40% in males, if standard PDT was applied.18 Wachtlin et al19 reported the rate as 63.6% (7/11). In this study, the quadrants of alteration of RPE surrounding ICNV observed by FA in the small laser spot PDT group were always less than or equal to those in the control group in each follow-up, and the difference was statistically significant at 3- and 6-month follow-ups (Table 2). Therefore, we may imply that small laser spot PDT provides a real protective effect for RPE. Interestingly, the reduced alteration of RPE did accompany higher improvements of vision (Figure 2), which suggests the value of this kind of treatment for patients.
With smaller laser spot, one should doubt that a potential risk of incomplete destroying of CNV and thereby a higher recurrent rate of CNV may exist. In this study, the recurrent rate (37.0%) in the study group was indeed higher than in the control group (32.0%), while the rate did not vary significantly (P=0.703). Therefore, recurrence of CNV may not be a serious concern of small laser spot PDT for ICNV in reality. In another study with a Chinese population by Su et al,20 standard PDT was performed, and 8.2% (5/61) of the ICNV subjects suffered from recurrent CNV during the 6–36 months follow-up (mean: 19months). Remarkable differences in the recurrent rates between Su et al's study and ours may be due to FA reading variations and inclusion criteria of patients.
There were limitations in this study. First, although this is a randomized controlled study, the number of patients was medium high. Results from a similar study with more patients would be more convincing. Second, the follow-ups were carried out over one year. For ICNV, which usually occurred in young patients, the follow-ups should be over longer durations than for age-related macular degeneration. However, despite the above limitations, the randomized characteristics of the present study strengthened the results. Further studies on the comparison between small spot laser PDT and other treatments including intravitreal anti-VEGF (vascular endothelia growth factor) drugs or triamcinolone are required.
1. Spaide RF. Choroidal neovascularization in younger patients. Curr Opin Ophthalmol 1999; 10: 177-181.
2. Flaxel CJ. The use of systemic steroids and photodynamic treatment for choroidal neovascularisation in young patients. Br J Ophthalmol 2007; 91: 564-565.
3. Sharma S, Bakal J, Oliver-Fernandez A, Blair J. Photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in age-related macular degeneration: results of an effectiveness study. Arch Ophthalmol 2004; 122: 853-856.
4. Axer-Siegel R, Ehrlich R, Rosenblatt I, Kramer M, Priel E, Yassur Y, et al. Photodynamic therapy for occult choroidal neovascularization with pigment epithelium detachment in age-related macular degeneration. Arch Ophthalmol 2004; 122: 453-459.
5. Ergun E, Tittl M, Stur M. Photodynamic therapy with verteporfin in subfoveal choroidal neovascularization secondary to central serous chorioretinopathy. Arch Ophthalmol 2004; 122: 37-41.
6. Yoo MH, Boo HD, Kim HK. Result of photodynamic therapy for idiopathic subfoveal choroidal neovascularization. Korean J Ophthalmol 2005; 19: 264-268.
7. Ehrlich R, Kramer M, Rosenblatt I, Weinberger D, Mimouni K, Priel E, et al. Photodynamic therapy for choroidal neovascularization in young adult patients. Int Ophthalmol 2010; 30: 345-351.
8. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 1999; 117: 1329-1345.
9. 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 2001; 119: 198-207.
10. Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial—VIP report no. 1. Ophthalmology 2001; 108: 841-852.
11. Verteporfin in Photodynamic Therapy Study Group. 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 2001; 131: 541-560.
12. Postelmans L, Pasteels B, Coquelet P, El Ouardighi H, Verougstraete C, Schmidt-Erfurth U. Severe pigment epithelial alterations in the treatment area following photodynamic therapy for classic choroidal neovascularization in young females. Am J Ophthalmol 2004; 138: 803-808.
13. Campochiaro PA, Morgan KM, Conway BP, Stathos J. Spontaneous involution of subfoveal neovascularization. Am J Ophthalmol 1990; 109: 668-675.
14. Gass JD. Biomicroscopic and histopathologic considerations regarding the feasibility of surgical excision of subfoveal neovascular membranes. Am J Ophthalmol 1994; 118: 285-298.
15. Grossniklaus HE, Gass JD. Clinicopathologic correlations of surgically excised type 1 and type 2 submacular choroidal neovascular membranes. Am J Ophthalmol 1998; 126: 59-69.
16. Grossniklaus HE, Hutchinson AK, Capone AJ, Woolfson J, Lambert HM. Clinicopathologic features of surgically excised choroidal neovascular membranes. Ophthalmology 1994; 101: 1099-1111.
17. Itagaki T, Ohkuma H, Katoh N, Uyama M. Studies on experimental subretinal neovascularization. 2. Regression of the new vessels. Nippon Ganka Gakkai Zasshi 1985; 89: 941-948.
18. Li XX, Zhao MW, Qu JF. Analysis of RPE damage after photodynamic therapy in patients with idiopathic choroidal neovascularization. Chin J Ophthalmol (Chin) 2007; 43: 206-211.
19. Wachtlin J, Wehner A, Heimann H, Foerster MH. Photodynamic treatment with verteporfin for patients with idiopathic choroidal neovascularization. Two-year results. Ophthalmologe 2004; 101: 489-495.
20. Su ZA, Yao K, Shen J, Jiang JK, Fang XY, Lin JJ, et al. Evaluation of photodynamic therapy in idiopathic choroidal neovascularization. Chin J Ophthalmol (Chin) 2007; 43: 509-513.