To evaluate the morphologic retinal and choroidal changes after verteporfin photodynamic therapy (PDT) with and without ranibizumab for polypoidal choroidal vasculopathy using spectral-domain optical coherence tomography.
Retrospective, comparative series.
The enhanced depth imaging optical coherence tomography technique was used in this retrospective, comparative series to measure the subfoveal retinal and choroidal thicknesses before and after treatment.
Twenty-seven eyes with polypoidal choroidal vasculopathy were examined retrospectively. Sixteen eyes were treated with PDT monotherapy (PDT group). Eleven eyes were treated with PDT after intravitreal ranibizumab injection (ranibizumab plus PDT group). The polypoidal lesions regressed in all cases at 3 months. The mean retinal thickness, including the retinal detachment, increased from 401 ± 157 μm before treatment to 506 ± 182 μm 2 days after PDT ( P < .001) and decreased to 365 ± 116 μm by 1 week after treatment ( P = .03) and 265 ± 127 μm by 6 months after treatment ( P < .001). The mean choroidal thickness increased from 269 ± 107 μm before treatment to 336 ± 96 μm 2 days after PDT treatment ( P < .001 compared with baseline) and decreased to 262 ± 96 μm by 1 week after treatment ( P = .24) and 229 ± 104 μm by 6 months ( P < .001). Although the choroidal thickness showed a similar trend with both therapies, the retinal thickness in the ranibizumab plus PDT group remained thinner than that in the PDT group until 6 months after treatment.
PDT was associated with decreased retinal and choroidal thicknesses. Combination therapy reduced the transient exudation after PDT in some cases, and monthly intravitreal ranibizumab injections maintained retinal thinning and seemed to improve vision better than PDT monotherapy.
Verteporfin photodynamic therapy ([PDT], Visudine; Novartis, Basel, Switzerland) is an established treatment for age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). However, complications after PDT have been reported, such as transient subretinal or intraretinal fluid accumulation within 1 week after PDT and more severe and potential permanent vision loss secondary to subretinal bleeding. PDT using verteporfin for AMD also can cause choriocapillaris damage and vascular remodeling in the underlying choroid.
Intravitreal ranibizumab (Lucentis; Genentech, South San Francisco, California, USA), an anti–vascular endothelial growth factor (VEGF) therapy, is the most commonly used therapy for AMD, although the efficacy of anti-VEGF therapy for PCV may be less than that for typical choroidal neovascularization associated with AMD. Since PDT is thought to induce VEGF expression, combination therapy comprising PDT and pharmacologic agents to inhibit VEGF expression also has been reported to increase the efficacy of both PDT and pharmacologic agents.
Spectral-domain optical coherence tomography (OCT) detects morphologic changes in the neurosensory retina in a variety of retinal and choroidal diseases. Recently, Spaide and associates reported a new method, enhanced depth imaging (EDI) OCT, to evaluate the choroidal status.
In the current study, we retrospectively evaluated visual acuity (VA) changes and retinal and choroidal alterations after PDT for PCV using this noninvasive OCT technique. We also compared these changes after PDT with and without intravitreal injection of ranibizumab.
The clinical examinations for diagnosis of PCV included indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens or noncontact lens, digital fluorescein angiography, and indocyanine green angiography (ICGA). We used a digital imaging system with an infrared camera and standard fundus camera (TRC-50 IX/IMAGEnet H1024 system; Topcon, Tokyo, Japan) and a confocal laser scanning system (HRA-2; Heidelberg Engineering, Dossenheim, Germany). The best-corrected visual acuity (BCVA) was measured with a Japanese standard decimal visual chart and converted to the logarithm of the minimal angle of resolution (logMAR) scale for analysis. All eyes were examined with the Heidelberg Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany).
In the current study, diagnostic criteria for PCV were proposed based on ICGA findings, which imaged the characteristic aneurysmal lesions. All patients with PCV had choroidal neovascularization on fluorescein angiography, which was identified as PCV on ICGA. Choroidal vascular hyperpermeability, seen as hyperfluorescence in middle-phase ICGA images, also was evaluated.
Consecutive patients with PCV were treated with PDT monotherapy (PDT group) between January 2009 and May 2009 and were treated with the combination therapy of intravitreal ranibizumab and PDT (ranibizumab plus PDT group) between June 2009 and October 2009. Ranibizumab became available for medical use in Japan in March 2009.
The patients in the ranibizumab plus PDT group were treated 1 or 2 days before PDT with intravitreal ranibizumab (0.5 mg/0.05 mL) injected 3.5 to 4.0 mm posterior to the corneal limbus into the vitreous cavity using a 30-gauge needle after topical anesthesia was applied. Consecutive monthly intravitreal ranibizumab injections were administered for 3 months.
PDT was performed in both groups using the standard dose (6 mg/m 2 ) of verteporfin according to the protocol of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy studies, except for the greatest linear dimension (GLD). The GLD and treatment spot size were measured on ICGA (ICG-guided PDT) to reduce the exposed area. The diameter of the PDT treatment spot size was the GLD plus 1 mm. A 689-nm laser system (Carl Zeiss, Dublin, California, USA) was used, and 50 J/cm 2 of energy was delivered with an 83-second exposure time. Angiographic evaluation in all cases was examined at 3 months after PDT, and additional treatment was performed if needed.
The retinal thickness, defined as the distance between the inner surface of the neurosensory retina and the inner surface of the retinal pigment epithelium, including retinal detachments at the fovea, also was measured at the same time. Spaide and associates reported observing the morphologic choroidal changes using the EDI OCT technique, which obtained inverted and highlighted choroidal images by moving the OCT device close to the eye. All images were obtained using an eye-tracking system, and 100 scans were averaged automatically to improve the signal-to-noise ratio. We measured the choroidal thickness, defined as the zonal area between the outer surface of the retinal pigment epithelium and the inner scleral surface, from vertical and horizontal sections under the center of the fovea from OCT data, and these were averaged.
In the PDT group, the retinal and choroidal thicknesses at the center of the fovea were measured using the EDI OCT before PDT (baseline) and after PDT at 2 days, 1 week, and 1, 3, and 6 months. In the ranibizumab plus PDT group, the retinal and choroidal thicknesses at the center of the fovea also were measured by EDI OCT before intravitreal injection of ranibizumab (baseline), before PDT on day 1 or 2 after the intravitreal ranibizumab injection (day 0), and after PDT at 2 days, 1 week, and 1, 3, and 6 months. OCT was performed at all visits. The patients who received their first PDT treatments remained in the hospital for 2 days to avoid sun exposure.
The reported measurements obtained from the OCT images represented the average of all the measurements. The coauthors (I.M., Y.S., M.S.) were masked to the treatment status. The VAs are expressed as decimal equivalents and logMAR equivalents. The BCVA and the measurement of the choroidal and retinal thickness were analyzed using the Wilcoxon signed-rank test (SPSS software version 17.0; SPSS, Inc, Chicago, Illinois, USA), and P = .05 or less was considered significant.
Twenty-seven eyes of 27 consecutive patients with newly diagnosed PCV were included. Sixteen eyes of 16 patients (12 men, 4 women; mean age, 71.8 years) comprised the PDT group. Eleven eyes of 11 patients (6 men, 5 women; mean age, 71.0 years) comprised the ranibizumab plus PDT group. The lesion area included the fovea in all cases. The mean GLD for PDT was 3013 ± 1059 μm in the PDT group and 2905 ± 1122 μm in the ranibizumab plus PDT group. ICGA showed that the polypoidal lesions in all cases in both groups regressed at 3 months. One eye in the ranibizumab plus PDT group needed retreatment; 3 eyes in the PDT group needed retreatment for the exudative findings during the follow-up period. One patient in each group did not return for the 6-month visit.
The mean retinal thickness increased significantly ( P < .001) from 401 ± 157 μm at baseline to 506 ± 182 μm on day 2 after PDT and decreased to 365 ± 116 μm by 1 week ( P = .03), 274 ± 102 μm by 1 month ( P < .001), 271 ± 174 μm by 3 months ( P < .001), and 265 ± 127 μm by 6 months ( P < .001). The mean choroidal thickness increased from 269 ± 107 μm at baseline to 336 ± 96 μm on day 2 after PDT ( P < .001) and decreased to 262 ± 96 μm by 1 week ( P = .24), 232 ± 96 μm by 1 month ( P < .001), 225 ± 95 μm by 3 months ( P < .001), and 229 ± 104 μm by 6 months ( P < .001). The mean choroidal thickness of 16 eyes with choroidal vascular hyperpermeability in middle-phase baseline ICGA images was thicker than in 11 eyes without hyperpermeability (323 ± 99 μm vs 191 ± 60 μm; P < .001, Mann–Whitney U test).
The mean subfoveal retinal and choroidal thicknesses at baseline and the changes during follow-up in both groups are summarized in the Table . Figures 1 and 2 show representative cases in the PDT group. Figures 3 and 4 show representative cases in the ranibizumab plus PDT group.
|Case No.||Gender||Age (yrs)||Eye||Treatment||BCVA at Baseline (logMAR)||BCVA at 6 Mos (logMAR)||Permeability a||Retinal Thickness (μm) b||Choroidal Thickness (μm) c|
|Baseline||Day 0||Day 2||1 Wk||1 Mo||3 Mos||6 Mos||Baseline||Day 0||Day 2||1 Wk||1 Mos||3 Mos||6 Mos|
|1||M||56||Left||PDT d||0.6 (0.22)||1.0 (0.00)||Yes||253||268||259||222||235||198||373||421||363||323||324||292|
|2||M||77||Left||PDT||0.1 (1.00)||0.3 (0.52)||Yes||345||512||394||293||293||209||337||414||295||215||204||208|
|3||M||58||Left||PDT||0.4 (0.40)||1.0 (0.00)||Yes||670||610||508||421||410||314||327||402||291||290||284||284|
|4||M||62||Left||PDT||0.6 (0.22)||0.8 (0.10)||Yes||374||465||373||211||190||191||191||251||174||134||129||129|
|5||M||86||Right||PDT||0.2 (0.70)||0.3 (0.52)||Yes||218||258||250||189||149||137||322||420||341||258||280||246|
|6||M||76||Left||PDT||0.5 (0.30)||0.5 (0.30)||Yes||230||297||267||230||279||201||307||352||320||306||282||278|
|7||M||69||Left||PDT||0.7 (0.15)||0.8 (0.10)||Yes||295||589||281||195||160||177||458||492||464||444||424||435|
|8||M||70||Left||PDT||0.6 (0.22)||0.9 (0.05)||Yes||281||438||343||227||216||208||348||364||335||312||307||323|
|9||F||76||Right||PDT||0.2 (0.70)||0.2 (0.70)||Yes||364||451||322||275||175||209||261||281||225||196||206||208|
|10||F||70||Left||PDT||0.4 (0.40)||0.7 (0.15)||Yes||385||436||345||328||321||307||290||306||286||264||243||265|
|11||M||82||Right||PDT||0.08 (1.10)||0.1 (1.00)||No||476||731||379||431||1037||681||250||266||228||216||191||146|
|13||M||86||Right||PDT||0.05 (1.30)||0.03 (1.52)||No||466||505||332||216||277||243||120||234||156||112||116||116|
|14||M||53||Left||PDT||0.3 (0.52)||0.4 (0.40)||No||276||345||234||232||270||326||159||268||177||158||168||178|
|15||F||68||Right||PDT||0.4 (0.40)||0.4 (0.40)||No||368||645||407||190||249||388||217||249||197||183||186||208|
|16||F||77||Right||PDT||0.4 (0.40)||1.2 (−0.08)||No||387||405||338||215||161||174||292||328||312||241||215||213|
|Mean ±||71.8||0.29 (0.53)||0.42 (0.37)||364||469||340||253||287||264||273||331||269||235||229||235|
|17||M||55||Left||Ranibizumab + PDT e||0.5 (0.30)||0.8 (0.10)||Yes||348||313||305||257||190||179||276||604||595||645||510||508||505||508|
|18||M||78||Right||Ranibizumab + PDT||0.24 (0.62)||NA||Yes||542||535||951||516||406||330||NA||260||260||301||241||252||226||NA|
|19||F||67||Left||Ranibizumab + PDT||0.5 (0.30)||1.0 (0.00)||Yes||533||516||536||507||471||244||190||292||289||328||281||262||248||272|
|20||F||74||Left||Ranibizumab + PDT||0.5 (0.30)||0.8 (0.10)||Yes||213||207||544||186||128||150||174||344||351||425||371||311||323||383|
|21||F||72||Right||Ranibizumab + PDT||0.3 (0.52)||0.8 (0.10)||Yes||435||429||434||356||274||139||146||208||216||329||193||169||145||114|
|22||F||84||Right||Ranibizumab + PDT||0.01 (2.00)||0.04 (1.40)||Yes||955||853||1020||726||538||418||557||250||238||350||220||205||173||155|
|23||M||56||Right||Ranibizumab + PDT||0.3 (0.52)||0.4 (0.40)||No||324||328||312||246||221||213||228||248||248||273||229||198||224||245|
|24||M||67||Right||Ranibizumab + PDT||0.5 (0.30)||1.0 (0.00)||No||514||506||494||407||271||173||234||185||190||252||174||149||148||146|
|25||M||77||Left||Ranibizumab + PDT||0.3 (0.52)||0.8 (0.10)||No||476||464||506||394||230||181||188||224||229||401||273||205||164||176|
|26||M||67||Left||Ranibizumab + PDT||0.4 (0.40)||0.3 (0.52)||No||400||404||610||520||380||319||320||111||109||212||114||95||98||91|
|27||F||84||Right||Ranibizumab + PDT||0.5 (0.30)||0.6 (0.22)||No||268||284||444||300||246||388||360||175||165||253||169||158||150||117|
|Mean ±||71.0||0.28 (0.55)||0.51 (0.29)||455||440||559||401||305||248||267||264||262||342||252||228||218||220|
a Choroidal vascular hyperpermeability.
b Choroidal thickness measured using the enhanced depth imaging spectral-domain optical coherence tomography technique.
c Retinal thickness including retinal detachment at the fovea.
d Photodynamic therapy with verteporfin. In the PDT alone group, measurement was at the fovea before PDT (baseline), 2 days after PDT (day 2), 1 week after PDT (1W), 1 month after laser PDT (1M), 3 months after PDT (3M), and 6 months after PDT (6M).
e Intravitreal ranibizumab injection plus PDT. In the ranibizumab plus PDT group, measurement was at the fovea before ranibizumab (baseline), before PDT (day 0), 2 days after PDT (day 2), 1 week after PDT (1W), 1 month after PDT (1M), 3 months after PDT (3M), and 6 months after PDT (6M).