Responses to Photodynamic Therapy in Patients With Polypoidal Choroidal Vasculopathy Consisting of Polyps Resembling Grape Clusters




Purpose


To investigate the responses to photodynamic therapy (PDT) in patients with polypoidal choroidal vasculopathy (PCV) that show large aneurysmal dilation with internal angio-architecture consisting of diverse patterns of curvilinear vessels and polyps resembling grape clusters.


Design


Retrospective, interventional case series.


Methods


Twenty-two eyes of 22 patients were included. All patients initially received PDT monotreatment. The main outcome measures were the rates of complete polyp regression on indocyanine green angiography and initial favorable responses observed clinically. Also, the rates of recurrent exudative changes were evaluated at the 2-year follow-up. We focused on changes in the vascular features and their clinical association.


Results


Complete regression of polypoidal lesions was observed in 21 eyes (95%) after a mean of 1.7 PDTs. However, favorable clinical responses were achieved in only 9 eyes (41%), and 6 of them had recurrent exudation. Main vessels, previously consisting of the polypoidal lesion frame, persisted. Additionally, aberrant vessels with a thin radiating or tortuous configuration were observed in the area where large aneurysmal dilation was present. Leakage from this vascular complex or an expanded vascular complex was observed in a total of 14 eyes (64%) during the 2-year follow-up, contributing to persistent (8 eyes) or recurrent (6 eyes) exudation. This seemed to represent secondary choroidal neovascularization (CNV). In another 4 eyes (18%), fibrous changes developed immediately after PDT. Polyps recurred in 8 eyes (38%).


Conclusions


This PCV pattern frequently evolved into typical CNV after PDT, resulting in persistent or recurrent exudation despite the disappearance of polypoidal structures.


It is generally accepted that polypoidal choroidal vasculopathy (PCV) has a better visual prognosis than does typical neovascular age-related macular degeneration (AMD), as progression is slow and subretinal fibrous proliferation is unusual. Abnormal vasculature in patients with PCV consists of a branching vascular network with polypoidal lesions at the lesion borders. However, marked variability is observed in the size, morphology, and pattern of the abnormal vasculature. Uyama and associates noted that a cluster of grape-like polypoidal lesions was active and tended to bleed or leak. They concluded that development of such lesions indicates a high risk for severe visual loss. Sho and associates reported that this pattern of polypoidal lesions was observed in 10 of 110 eyes with PCV (9%) and was closely associated with development of typical choroidal neovascularization (CNV) and fibrous proliferation. Additionally, in a series of 12 eyes, Tateiwa and associates reported that clustered polypoidal dilations formed at the end of large vascular networks expanding across the retinal vascular arcade and caused large serous and/or hemorrhagic pigment epithelial detachments (PEDs). They suggested that this type of PCV lesion had the characteristics of CNV observed in exudative AMD.


Many reports have demonstrated excellent short-term efficacy of photodynamic therapy (PDT) for treating PCV. Complete polyp regression was achieved in 80% to 95% of cases, which was well translated into resolution of the exudative changes and stabilization or improvement of the vision at the 1-year follow-up. Persistence of the branching vascular network and polyp recurrence remain key limitations of PDT, and the visual outcomes at 3 or even 2 years are not as good as those at 1 year. Small vascular lesions, better initial vision, less hemorrhage, and the absence of subfoveal polyps have been suggested as pretreatment factors favoring better visual outcomes.


However, no study has investigated the treatment response to PDT in patients with clustered polyps. Furthermore, no widely recognized criteria have been reported for clustered polyps. We investigated the responses to PDT in a subset group of patients with PCV showing characteristic features on indocyanine green angiography (ICGA): large aneurysmal dilation in the late phase of ICGA, with internal angio-architecture consisting of diverse patterns of curvilinear vessels and polyps resembling grape clusters in the earlier phase.


Methods


A total of 180 patients (205 eyes) newly diagnosed with PCV underwent PDT with verteporfin (Visudyne, Novartis Pharma AG, Basel, Switzerland) monotherapy as an initial treatment between December 2003 and March 2008 at Seoul St. Mary’s Hospital (known as Kangnam St. Mary’s Hospital before May 2009), The Catholic University of Korea. The diagnosis of PCV was based on ICGA findings of polypoidal dilations with or without branching vascular network. According to the observation by Yuzawa and associates, a cluster of grape-like polypoidal lesions in this study was defined as follows: 1) large reddish-orange aneurysmal dilation with the longest axis of 1500 μm or longer on a fundus photograph; 2) a hyperfluorescence corresponding to the aneurysmal dilation on late-phase ICGA; 3) appearance of curvilinear, tortuous, or looped vessels branching into smaller vessels first, followed by sprouting of numerous polyps of diverse size from these vessels showing an appearance similar to grapes in the earlier phase of ICGA ( Figure 1 ) . Patients with symptomatic lesions involving the macula and recent-onset (within the last 6 months) visual symptoms were selected for study, to include 22 patients (22 eyes) with at least 24 months of follow-up. Although 26 consecutive patients (27 eyes) were eligible, 4 patients (5 eyes) were excluded for lack of follow-up. Patients with progressed PCV, showing a cluster of polypoidal dilations at the margin of widespread retinal pigment epithelial (RPE) atrophy in the posterior pole, were excluded, as were patients with previous treatment for PCV. Lesions with coexisting typical CNV were also excluded.




FIGURE 1


Images of polypoidal choroidal vasculopathy with polyps resembling grape clusters as defined in this study. (Top left) Fundus photograph shows a large reddish-orange aneurysmal dilation. (Top right) Indocyanine green angiography (ICGA) at 20 seconds shows curvilinear and looped vessels branching into smaller vessels within the aneurysmal dilation. (Bottom left) Numerous polyps of diverse size sprouting from these vessels, giving the appearance of grapes, are observed on ICGA at 43 seconds. (Bottom right) Late-phase ICGA shows a relatively homogenous hyperfluorescence at the area corresponding to the large aneurysmal dilation.


PDT was administered in a full-fluence dose according to the standard protocols of the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy Study after obtaining informed consent. However, the laser-spot size was chosen according to ICGA findings to cover all polyps and the branching vascular network plus an extra margin of 1 mm. Retreatment was applied at 3- to 4-month intervals, and the endpoint of the treatment was complete regression of the polypoidal lesions on ICGA. However, additional PDT was not performed consecutively if complete polyp regression was not achieved after 3 consecutive PDTs, or if there were persistent exudative changes despite polyp regression. Additional PDT was not performed when fibrous scarring developed. We defined initial favorable responses to PDT as complete regression of polyps on ICGA, a decrease or flattening of PED, resolution of macular exudative changes confirmed by optical coherence tomography (OCT) and/or cessation of leakage on fluorescein angiography (FA), maintenance or improvement of visual acuity, and a quiescent period of at least 6 months with no treatment. For the eyes not showing initial favorable responses and eyes showing recurrent serous changes after initial favorable responses, further treatments were performed using PDT, laser, intravitreal injection of 4 mg triamcinolone acetonide (Dongkwang Pharmaceutical, Seoul, South Korea), or an intravitreal injection of 1.25 mg of bevacizumab (Avastin, Genentech, Inc, San Francisco, California, USA). However, these treatments were not performed according to a uniformly designed protocol.


All patients received a comprehensive ocular examination including measurement of best-corrected Snellen visual acuity (BCVA) and dilated fundus examination with slit-lamp biomicroscopy at baseline and at each follow-up visit. During the period in which PDT monotreatments were used, all patients were regularly followed up at 3- to 4-month intervals, and FA, ICGA, and OCT were performed at each visit as well as at baseline. After this period, follow-up intervals were 1 to 4 months depending on lesion activity and/or switched treatment modality, and FA, ICGA, and OCT were performed at times determined on a patient-by-patient basis. ICGA was performed with a confocal scanning laser ophthalmoscope (SLO) (Heidelberg Retina Angiograph, Heidelberg Engineering, Heidelberg, Germany). For the OCT examination, Stratus OCT (Carl Zeiss Meditec, Dublin, California, USA) was used primarily, and spectral-domain OCT (Cirrus OCT, Carl Zeiss Meditec) was also used once it became available.


The main outcome measures were the rates of complete polyp regression on ICGA after PDT and the initial favorable responses observed clinically. The rates of recurrent exudative changes were evaluated in eyes with initial favorable responses at 2 years. Additionally, the changes in vascular features on ICGA and their association with clinical features were evaluated.




Results


Baseline Characteristics


The Table summarizes patient characteristics and their treatment results. We studied 22 eyes in 22 patients, 9 of whom were women. The mean age of the patients was 66 years (range, 55–83 years). The mean follow-up period was 43.8 months (range, 24–94 months). Location of the polypoidal lesions was subfoveal or juxtafoveal in 19 eyes and extrafoveal in 3 eyes. The mean length of the longest axis of aneurysmal dilation was 1678 μm (range, 1500–2230 μm), and the mean greatest linear dimension of the entire PCV lesion was 3040 μm (range, 1810–4560 μm). Twenty-one eyes (95%) presented with PED larger than 1 disc diameter in size (range, 1–4 disc diameters): serous PED in 12 eyes and hemorrhagic PED in 9 eyes. Fellow eye findings were a disciform scar in 4 eyes and PCV in 2 eyes. No abnormalities were observed in 16 fellow eyes. The median baseline BCVA was 20/63 (range, 20/200–20/32).



TABLE

Clinical Characteristics of Patients With Polypoidal Choriodal Vasculopathy Consisting of Polyps Resembling Grape Clusters and Treatment Results





































































































































































































































































































































































































































Case Sex/Age Location of Polypoidal Lesion Initial Major Fundus Findings Polyp Regression/Required No. of PDT Post-PDT Hm Initial Clinical Response to PDT Recurrence/Time of Recurrence (mo) Origin of Recurrent or Persistent Fluid No. of Additional Tx During 2 Years of FU Final Major Fundus Findings BCVA
PDT IVTA IVB Laser Initial At Time of Stopping PDT 24 Months
1 F/74 Subfoveal Hemorrhagic PED Yes/3 Early disciform scarring Disciform scar 20/100 20/200 20/334
2 F/70 Subfoveal Hemorrhagic PED Yes/1 Yes Early disciform scarring Disciform scar 20/100 20/200 CF
3 F/66 Subfoveal Serous PED Yes/2 Favorable Yes/6 AVC, a later recurrent extrafoveal polyp 2 1 3 1 Mild fibrous change No macular fluid 20/50 20/50 20/63
4 F/71 Subfoveal Hemorrhagic PED Yes/1 Early disciform scarring Disciform scar 20/200 20/500 20/1000
5 M/67 Subfoveal Serous PED Yes/2 Yes Persistent SSRD AVC, a later recurrent juxtafoveal polyp 1 2 Disciform scar 20/63 20/200 20/500
6 M/63 Subfoveal Serous PED Yes/2 Yes Favorable Yes/9 AVC, a later recurrent subfoveal polyp 2 1 5 Mild fibrous change Macular fluid 20/32 20/40 20/200
7 M/61 Subfoveal Serous PED Yes/2 Favorable Yes/9 Recurrent subfoveal polyp, later AVC a 1 6 Disciform scar 20/100 20/32 20/1000
8 F/57 Subfoveal Serous PED Yes/3 Yes Persistent SSRD AVC a 1 1 9 Disciform scar 20/125 20/50 20/500
9 M/64 Extrafoveal Serous PED Yes/1 Favorable Yes/9 AVC a of mesh-like aberrant vessels 1 1 8 Large PED 20/63 20/25 20/63
10 M/66 Subfoveal Hemorrhagic PED Yes/3 Early disciform scarring Disciform scar 20/50 20/125 20/500
11 F/70 Subfoveal Hemorrhagic PED Yes/1 Persistent SSRD AVC a 4 Disciform scar 20/32 20/32 20/500
12 F/65 Subfoveal Serous PED Yes/2 Favorable No No macular fluid RPE atrophy 20/100 20/50 20/40
13 F/75 Subfoveal Serous PED Yes/2 Persistent SSRD AVC a 9 Macular fluid 20/200 20/125 20/160
14 M/60 Subfoveal Hemorrhagic PED Yes/1 Favorable Yes/11 AVC a 5 Mild fibrous change Macular fluid 20/40 20/25 20/500
15 F/57 Juxtafoveal SSRD Yes/3 Persistent SSRD AVC a 6 Macular fluid 20/25 20/25 20/40
16 M/66 Extrafoveal Hemorrhagic PED Yes/1 Yes Persistent PED AVC a of mesh-like aberrant vessels, later recurrent juxtafoveal polyp 2 13 Large PED 20/32 20/40 20/100
17 M/71 Subfoveal Serous PED Yes/1 Favorable No No macular fluid RPE atrophy 20/200 20/125 20/160
18 M/64 Subfoveal Hemorrhagic PED Yes/1 Favorable Yes/9 AVC, a later recurrent extrafoveal polyp 4 1 No macular fluid RPE atrophy 20/160 20/63 20/63
19 M/62 Subfoveal Serous PED Yes/1 Persistent SSRD AVC, a later recurrent subfoveal polyp 2 14 Macular fluid 20/80 20/40 20/40
20 M/55 Subfoveal Serous PED Yes/2 Yes Persistent SSRD AVC, a later recurrent subfoveal polyp 1 12 Large PED 20/40 20/50 20/125
21 M/69 Subfoveal Serous PED No/3 Persistent SSRD Remaining polyps and AVC a 10 Large PED 20/50 20/50 20/100
22 M/83 Extrafoveal Hemorrhagic PED Yes/1 Favorable No No macular fluid 20/50 20/32 20/32

AVC = abnormal vascular complex; BCVA = best-corrected visual acuity; CF = counting fingers; F = female; FU = follow-up; Hm = hemorrhage; IVB = intravitreal bevacizumab; IVTA = intravitreal triamcinolone; M = male; PDT = photodynamic therapy; PED = retinal pigment epithelial detachment; RPE = retinal pigment epithelium; SSRD = serous sensory retinal detachment; Tx = treatment.

a Abnormal vascular complex: a complex of aberrant vessels of diverse configuration, such as linear, tortuous, looping, or branching pattern, observed at the area where large polypoidal lesion was previously located with or without the persistent vessels of branching vascular network, or expansion of this vascular complex.



Polyp Regression, Favorable Clinical Responses, and Changes in Vascular Features After Photodynamic Therapy


Polypoidal lesions resembling grape clusters regressed completely on ICGA in 21 of 22 eyes (95%) after a mean of 1.7 PDT (range, 1–3): 10 eyes after a single PDT, 7 eyes after 2 PDTs, and 4 after 3 PDTs. However, favorable clinical responses as defined in our study were achieved in 9 eyes (41%).


All eyes with discernible branching vascular network on pre-PDT ICGA showed persistence of the branching vascular network after PDT. Besides a persistent branching vascular network, aberrant vessels of diverse configuration, such as linear, tortuous, radiating, or a branching pattern, were observed where large polypoidal lesions had been located in all 21 eyes achieving complete regression of polyps. Dot-like hyperfluorescences accompanied some cases. Irregular elevation of the RPE layer was observed on OCT at the corresponding area. Spectral-domain OCT in selected cases showed an irregularly elevated RPE line and a thin, straight, highly reflective line representing the Bruch membrane beneath the RPE line. Between these 2 lines, aberrant vessels were observed as materials of moderate reflectivity. We compared the running course and branching pattern of these aberrant vessels on post-PDT ICGA with those of the main vessels consisting of the frame of polypoidal dilation on pre-PDT ICGA in 10 selected eyes showing clearly definable vasculature. In all eyes, similar configurations were detected between them, at least in part ( Figure 2 ) . The vessels were connected and intermingled with the persistent branching vascular network, when present, and formed an abnormal vascular complex. The abnormal vascular complex had extended beyond the boundary of the pretreatment PCV lesion in 15 eyes. Leakage from this vascular complex was observed on FA, resulting in persistent exudation despite polyp regression in 8 of 22 eyes (36%): persistent PED in 2 eyes and persistent serous sensory retinal detachment in 6 eyes despite a decrease or flattening of PED. Fibrous changes developed in 4 of 22 eyes (18%) ( Figure 3 ) . Post-PDT hemorrhage (hemorrhage within 1 month after PDT) developed in 6 of 22 eyes (27%). In 1 eye, the hemorrhage extended to the temporal vascular arcade, so tissue plasminogen activator and gas were injected to disperse the blood from the fovea.




FIGURE 2


Changes in the vascular features in a polypoidal lesion with grape clusters after photodynamic therapy (PDT). An 83-year-old man presented with serous pigment epithelial detachment (PED) associated with an extrafoveal polypoidal lesion (Case 22). Sensory retinal detachment involved the fovea, and visual acuity was 20/50. (Top left and middle) Images of early-phase indocyanine green angiography (ICGA) reveal internal angio-architecture of the polypoidal lesion, consisting of looped and tortuous vessels and grape-cluster polyps. The proximal part of the main stalk vessel is indicated by arrows. (Top right) Exudative changes involve the fovea on optical coherence tomography (OCT). (Bottom left) Three months after PDT, the polypoidal lesion had regressed, with resolution of macular exudation. Visual acuity improved to 20/32. On ICGA, thin aberrant vessels with a radiating configuration were noted at the area corresponding to where the polypoidal lesion used to be, expanding beyond the margin (arrowheads). The main stalk vessel consisting of the polypoidal lesion frame is persistent (arrows). (Bottom middle) No active leakage was observed on fluorescein angiography in this case. The line corresponds to the section examined with spectral-domain OCT. (Bottom right) Materials of moderate refractivity, representing the aberrant vessels of radiating configuration on ICGA, are observed between elevated retinal pigment epithelium (RPE) and the Bruch membrane (arrowheads). The RPE line is irregularly elevated at the corresponding area of the branching vascular network (arrows). The shadowing is caused by the pigmented scar on the surface of the PED.

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Jan 12, 2017 | Posted by in OPHTHALMOLOGY | Comments Off on Responses to Photodynamic Therapy in Patients With Polypoidal Choroidal Vasculopathy Consisting of Polyps Resembling Grape Clusters

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