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Original article

Small laser spot versus standard laser spot photodynamic therapy for idiopathic choroidal neovascularization: a randomized controlled study

Xiao-xin, LI; Yong, TAO

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doi: 10.3760/cma.j.issn.0366-6999.2012.24.018
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Abstract

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.

METHODS

Study design

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).

Verteporfin PDT

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).

Figure 1.
Figure 1.:
Schematic photo of PDT with small spot size and standard spot size. GLD: greatest linear diameter of choroidal neovascularization.

Follow-up

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.

Secondary treatment

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

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.

RESULTS

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).

Table 1
Table 1:
Comparison of patient information at baseline between the study group (small laser spot size) and the control group (standard laser spot size)

Visual outcome

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.

Figure 2.
Figure 2.:
Best corrected visual acuity (BCVA, ETDRS letters) of the study group (small laser spot size) and the control group (standard laser spot size) at baseline and follow-ups. *P <0.05.

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).

Figure 3.
Figure 3.:
Change of best corrected visual acuity (BCVA, ETDRS letters) of the study group (small spot size) and the control group (standard spot size) at follow-ups. *P <0.05.

RPE damage

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.

Table 2
Table 2:
Quadrants of alteration of RPE of the study group (small spot size) and the control group (standard spot size) at follow-ups
Figure 4.
Figure 4.:
Fundus fluorescein angiography of one case with idiopathic choroidal neovascularization (ICNV) before (A) and at 12 months after (B) standard spot size PDT and another case with ICNV before (C) and at 12 months after (D) small spot size PDT. The alteration of RPE after treatment which was shown as hyperfluorescence around choroidal neovascularization between the two cases differed remarkably (B, D).

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.

Table 3
Table 3:
Number of cases with decreased or unchanged leakage size of choroidal neovascularization in the study group (small laser spot size) and the control group (standard laser spot size) at follow-ups

OCT results

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).

Table 4
Table 4:
Number of cases with reduced subretinal fluid height measured by optic coherence tomography in the study group (small laser spot size) and the control group (standard laser spot size) at follow-ups
Figure 5.
Figure 5.:
Optical coherence tomography showed the complete absorption of subretinal fluid of one case with ICNV before (A) and at 12 months after (B) standard spot size PDT.

Recurrent rate

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).

DISCUSSION

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.

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Keywords:

idiopathic choroidal neovascularization; subfoveal; photodynamic therapy; small laser spot

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