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From the University of Lübeck, Lübeck, Germany.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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METHODS. In a prospective clinical trial, patients with subfoveal CNV were treated with PDT and verteporfin. Indocyanine green angiography (ICG-A), using a confocal laser scanning system with tomographic sections, was performed continuously 1 week before and 1, 4, and 12 weeks after and a mean long-term follow-up of 16.5 months after the final PDT. Vascular changes were localized tomographically and quantified on the level of the CNV and collateral choroid according to early lesion size, late hyperfluorescence, and persistence or recurrence. Data were analyzed separately from 38 eyes in a single- and 12 eyes in a multiple-treatment regimen.
RESULTS. CNV lesions were significantly reduced in size and late hyperfluorescence. However, 54% of lesions primarily demonstrated persistence, typically of the choroidal feeding complex, which was only detectable by ICG-A. Regrowth from the feeding vessel occurred regularly, but did not reach baseline dimensions. Collateral choroid exposed to photoactivation exhibited choriocapillary occlusion. Progressive recanalization was documented within 4 to 12 weeks after both single and multiple PDT. Residual changes in the choroidal filling pattern often persisted during long-term follow-up.
CONCLUSIONS. Tomographic ICG-A after PDT reveals persistence of CNV and/or the feeder vessel and a reduction in perfusion within the entire photosensitized area, including the surrounding choroid. Repair mechanisms occur slowly in neovascular and normal choroidal structures.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Although the clinical outcomes of verteporfin therapy have been established, the knowledge of how PDT acts at the target vascular site—including the choroidal neovascular complex and the surrounding choroid—is less clear. Conventional fluorescein angiography (FA) initially shows homogenous choroidal hypofluorescence, suggesting the complete disappearance of the CNV. Subsequently, there appears to be a high rate of de novo lesion recurrence. Although these findings may be pathognomonic, they cannot be explained by visual acuity tests or by the means of ophthalmoscopy and FA alone.7 However, indocyanine green angiography (ICG-A) has been shown to offer an alternative to FA to elucidate vaso-occlusive effects, changes in perfusion, and vascular repair mechanisms.8
This study reports an ICG-A pilot trial in patients with subfoveal CNV, using high-resolution confocal laser scanning to take tomographic section images during a single- and a multiple-treatment regimen of PDT. Characteristic ICG-A patterns after PDT were defined qualitatively and quantitatively in 38 eyes that received a single PDT course and a separate group of 12 eyes that were treated repeatedly within a short interval. The size of the early-phase vascular net and late-phase hyperfluorescence, presumably consistent with leakage activity of CNV, were monitored. Collateral choroidal changes were analyzed based on the presence or recovery of posttreatment hypofluorescence. The crucial problem of recurrence was investigated by tomographic evaluation of primary CNV occlusion and the origin of recurrence and or persistence.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Inclusion Criteria
Patients with clinical signs of CNV, regardless of cause, were
eligible. The CNV had to involve the geometric center of the foveal
avascular zone and demonstrate evidence of a classic component by
conventional FA. The greatest linear dimension (GLD) of the entire
lesion could not exceed 5400 µm. Best corrected visual acuity was
measured on Early-Treatment Diabetic Retinopathy Study (ETDRS) charts
and had to be 20/40 or worse.
Photodynamic Therapy
All treatment regimens involved intravenous infusion of
verteporfin (Novartis Ophthalmics, Duluth, GA), followed by irradiation
15 to 20 minutes after the start of sensitizer administration with
light at 689 nm delivered by an ocular photoactivation diode and
laser-linked slit lamp (Coherent Inc., Palo Alto, CA). The drug dose
was either 6 or 12 mg/m2 body surface area in the
single-treatment regimen and 6 mg/m2 in
the retreatment group (Table 1)
. The irradiance delivered was constant at 600
mW/cm2. Light doses according to protocol were
50, 75, or 100 J/cm2 in the single-treatment
group and 100 J/cm2 for all participants who were
retreated (Table 1) . The size of the treatment beam on the retina was
based on the GLD of the entire lesion as measured on FA, including a
safety margin of 300 µm. Fluorescein angiograms at 3 weeks after PDT
were used to determine the need for retreatment in the
repeated-treatment group. If leakage persisted or reappeared, two
additional courses of PDT were applied at 4-week intervals. The size of
the treatment beam included the area of leakage plus the 300-µm
safety margin.
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Analysis of Tomographic Sections
ICG-A analysis was performed separately by two independent
investigators. Because a phase I/II trial is not randomized, patients’
names were replaced by numbers, and images were evaluated in random
order to avoid any bias. Lesion size was measured in square millimeters
by manual planimetry (software version 1.10, package IR1, ver.
1.08; Heidelberg Engineering, Heidelberg, Germany). All ICG-A images of
the tomographic sections were screened for distinct delineation of CNV
and choroidal effects. The appropriate section demonstrating the focal
plane of the lesion was selected from tomographic series, contrast
enhanced, and corrected for brightness to achieve optimal
high-resolution imaging.
PDT-induced changes were differentiated into effects on the CNV complex and collateral effects within adjacent physiological choroid included in the treated area. The size of the CNV was measured as the area covered by a neovascular net during early-phase ICG-A, and late hyperfluorescence was defined as the area showing increased fluorescence during late-phase ICG-A, consistent with either leakage or staining originating from the underlying choriocapillaris. Hyperfluorescence was measured as hyperfluorescence lesion compared with background, using an identical reference area in each image with a threshold of at least 20% above background fluorescence intensity (identified with the scanning laser ophthalmoscope software fluorescence analysis). Both, CNV size and late hyperfluorescence were determined independently by two masked investigators. Leakage activity appears to be an important factor, because it allows detection of the entire dimension of persistent CNV activity. Changes at the level of the collateral choroid were characterized by the size of the area exhibiting hypofluorescence in early- and late-phase ICG-A. All parameters, including pre-existent hypofluorescence surrounding a lesion, were identically determined before PDT (Table 2) .
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Statistical analysis was performed for all parameters examined. Readings of the two investigators were averaged. Analysis of deviations indicated individual differences without statistical significance among measurements of identical angiograms by different readers (interindividual variability <5%). The SEM was determined for size and fluorescence intensity. Evaluation was performed with the Wilcoxon rank-sum test; statistical significance was accepted at 0.01.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Multiple-Treatment Regimen.
PDT applications were repeated at 4-week intervals in a smaller group
of 12 patients. Phenomena similar to those in the single-treatment
regimen were observed; however, some of the effects appeared to be
additive, whereas others were not. As before, CNV was documented in all
pretreatment angiograms (Fig. 3A
). One week after treatment, the neovascular net became smaller and less
fluorescent (Fig. 3B)
. CNV then continued to decrease with every
additional PDT course (Fig. 3C) and the lesion was smallest 1 week
after the third application (Fig. 3D)
. During the follow-up interval
after the final PDT session, lesions recovered and enlarged again
without reaching their original sizes (Fig. 3E)
. Final lesions were
generally larger in the retreatment group than in the single-treatment
group compared with baseline. The area exhibiting late
hyperfluorescence showed stabilization after the final treatment
session. Because there was no difference in the angiographic pattern in
the single-treatment group in relation to the different light doses
used, the increase in size of the neovascular network was probably not
related to the unique light dose of 100 J/cm2
applied in the retreatment group.
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Choroidal hypofluorescence was evaluated regarding the area of reduced fluorescence over time, which is indicative of choroidal perfusion changes. The size of post-PDT hypofluorescence was largest 1 week after PDT and decreased slowly during follow-up (Fig. 5) . Early-phase hypofluorescence regularly covered a larger area than the hypofluorescence in the late frames. The mean area of hypofluorescence was, on average, 11.95 mm2 during early- and 11.23 mm2 during late-phase ICG-A.
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Multiple-Treatment Regimen.
The area of posttreatment hypofluorescence was always larger than the
irregular zone of reduced fluorescence surrounding the lesion before
PDT (Fig. 3A)
. Hypofluorescence was round and homogenous, with
larger-caliber vessels seen in early-phase ICG-A (Fig. 3B)
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Persistent hypofluorescence was documented in all patients after the
second (Fig. 3C)
and third (Fig. 3D) PDT and subsequently at 3 and 16.5
months. However, the area showing reduced fluorescence became smaller,
and the extent of hypofluorescence became less intense within 3 months
(Fig. 3E) .
Quantitative analysis revealed a 25% enlargement of the hypofluorescent area at the 1-week follow-up after the second PDT treatment, compared with the area measured after the first PDT treatment (10.6 and 9.9 mm2 early- versus late-phase ICG-A, respectively) which did not reach statistical significance. The size of choroidal hypofluorescence in ICG-A 1 week after the previous treatment was always identical with the size of the treatment spot selected, suggesting an immediate effect of the light exposure. The decrease of this area at 12 weeks after the third PDT was smaller than the more intense resolution of hypofluorescence after a single exposure at that time interval. The dark area remained unchanged in size for up to 4 weeks after the third treatment. Finally, the area with impaired fluorescence became smaller—a slow process in early-phase ICG-A that became faster by late-phase imaging. An area of persistent hypofluorescence covering 6.8 mm2 in early-phase ICG-A and 4.0 mm2 in late-phase ICG-A was still seen after 16.5 months (Fig. 6) .
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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ICG-A has been recognized as a sensitive method to identify classic and occult components of CNV, due to improved transmission of the dye.8 Intravascular ICG, 98% of which is bound by serum proteins, allows distinct imaging of the vascular compartment.9 Confocal ICG-A further improves the optical and digital resolution to approximately 10 µm in the transverse and 300 µm in the longitudinal direction.8 The tomographic technique used provides a precise focus on the plane of interest, such as the CNV membrane, and represents an excellent tool for analyzing vascular alteration.
An important finding is that ICG-A showed that verteporfin therapy had a vaso-occlusive mechanism that affected both CNV and the normal choroid. However, occlusion was not complete: The CNV complex remained patent, at least at the feeder-vessel level. Persistent feeder vessels were the origin of newly developing neovascular proliferation—a true recurrence that occurred in approximately one half of the treated patients. In the other 50% of treated eyes, ICG-A directly demonstrated a patent portion of CNV, which represents, by definition, persistence rather than a recurrence. Multiple PDT applications within short intervals reduced the rate of persistence, but did not influence the frequency of recurrence. However, recurrence showed only limited progression with ICG-A. Even a single PDT treatment led to an involution of the recurrent membrane at a smaller final size than that at baseline.
Evidence of true choroidal occlusion and detection of CNV persistence are the two major findings of this study.
There is intense controversy in the interpretation of hypofluorescence after PDT. By FA, hypofluorescence 1 week after PDT was intense, homogenous, and unstructured. No insight into the extent of choroidal nonperfusion or persistence of neovascular components was possible. Masking by serous fluid or hemoglobin was suspected.10 ICG-A is less susceptible to transmission deficits by masking fluids. Tomographic analysis of hypofluorescence demonstrates loss of the superficial choriocapillary layer in conjunction with maintenance of perfusion of larger choroidal vessels, which remain clearly visible without masking.
The ability of PDT to occlude physiological choroidal vasculature was shown in several experimental studies in a direct dose–response relationship.2 11 12 By confocal ICG-A a single PDT application produced an area of hypofluorescence which, at 1 week, was identical in size to the area of the treatment spot used, consistent with a direct occlusive effect. The similar size of hypofluorescence in early- and late-phase ICG-A suggests complete absence of ICG, caused by a substantial reduction of the perfusion without inflow of ICG from adjacent patent vessels. Experimentally, angiography using verteporfin as a fluorescent marker demonstrated selective accumulation of sensitizer within the CNV complex.13 In fact, substantial undetected amounts of sensitizer must also be localized within physiological vessels, which are usually less sensitive to photochemical damage than proliferating neovasculature.14 Occlusion of normal choriocapillaries is not restricted to PDT using verteporfin, but has also been described with mono-L-aspartyl chlorin e6, a hydrophilic sensitizer.15 16
FA showed rapid disappearance of hypofluorescence after PDT, which contrasts considerably with ICG-A findings that demonstrated persistence of choroidal hypofluorescence over extended periods and, in one subgroup, even after many months. During early-phase ICG-A the rapid perfusion sequence of patent arterioles, capillary lobules, and venules is captured. Any vascular obstacle (e.g., endothelial swelling) can prevent the filling of the regular vascular pattern. A homogenous loss of early perfusion occurred after PDT, consistent with a complete thrombosis of the capillary layer. Late-phase ICG-A documents the diffuse distribution of dye molecules throughout the fenestrations of the choroidal vascular sponge. Leakage from the intact borders or deep layers now leads to fluorescent filling of large parts, particularly in the periphery of the lesion, so that the area of hypofluorescence is typically smaller in late-phase ICG-A, a sequence taken 15 minutes after injection. Obviously, multiple treatments do not enhance or prolong choroidal thrombosis, most likely because the next PDT application hits an area with persistent vascular occlusion, so that less sensitizer and less oxygen are available, and the PDT effect is less intense. Late-phase leakage and recanalization from the borders of the occluded area finally lead to a decrease in the size of the hypofluorescent area. Regarding the regenerative potential of the choriocapillary in patients with AMD, age- or disease-related primary alteration of choriocapillary density and perfusion must be considered. Filling of the choriocapillaries with ICG was delayed in people more than 50 years of age, and areas of hypofluorescence were observed in the macula of patients with AMD.17 18
Accordingly, irregular hypofluorescence before PDT was substantiated in this study group. Whether choroidal nonperfusion facilitates CNV occlusion is speculative. A decrease in flow within the surrounding choroid would also secondarily reduce perfusion of the CNV, where blood flow is primarily more sluggish.19 It is noteworthy that repeated treatments did not prolong choriocapillary nonperfusion and that recovery occurred within the same time frame.
The issue of persistence and/or recurrence has important implications for the clinical application of PDT. FA failed to detect persistence of the feeder vessel and the CNV, per se. The sensitive tomographic analysis of ICG-A features revealed angiographic persistence, defined as a residual neovascular net seen in early-phase ICG-A as early as during the first examination at 1 week after PDT. In addition to an absence of complete occlusion, persistent CNV activity was documented with the residual membrane leaking actively in late phase ICG-A, with an increase in late hyperfluorescence area over time. In contrast with FA, ICG-A was able to demonstrate persistence in nearly half of the treated neovascular lesions. A patent feeder vessel was identified as a potential source of lesion regrowth. CNV membranes were shown to possess one or several choroidal feeder vessels as they originated from physiological choroidal vasculature. Feeder vessel closure alone, using thermal photocoagulation, has been shown to shut down the perfusion of the entire neovascular complex with subsequent resolution of leakage and regression of CNV.20 Flower and Snyder10 have hypothesized that a reduction of choroidal perfusion in the surrounding choroid in CNV influences the perfusion dynamics with a decrease in the afferent and efferent flow of the feeder vessel. In an experimental model of CNV feeder vessels, ICG-A was used to visualize the feeder vessels originating from medium-diameter choroidal channels and to facilitate a selective dye-enhanced photothrombosis. Feeder vessel occlusion was achieved with minimum concomitant damage to overlying retinal tissue—proof of the principal of a method that has not demonstrated its efficacy.21
The evolution of recurrent CNV lesions seems to require specific interpretation. Although recurrences were noted in 87% and 92% of eyes in the single- and multiple-treatment regimens, respectively, after 4 weeks only 50% and 58% demonstrated recurrent lesions at the final visit. In the TAP experience,6 CNV was re-treated until leakage subsided, and therefore there was no chance to monitor the spontaneous behavior of a lesion in which biological changes were induced by a single or a short-term cascade of treatments with a subsequently undisturbed process of involution. It is well known from the spontaneous course that the neovascular leakage activity subsides with time and that even large lesions become fibrotic, arrested in growth, and dry. Additional treatments with renewed choroidal alteration and angiogenic stimulation may trigger more persistent and accelerated regrowth and activity of these lesions and may interfere with the maturation process of the neovascular complex. The TAP data, furthermore focus, on FA findings with active CNV identified by leakage, whereas leakage was not a prominent feature in ICG-A.
Whether regrowth or recanalization is the reason for subsequent CNV enlargement remains to be determined. The phenomenon of chronically recurrent CNV after PDT may be closely related to choroidal hypofluorescence. Regrowth may be stimulated by relative ischemia of RPE and photoreceptors within the PDT-affected choriocapillary region, with an increase in vascular endothelial growth factor (VEGF) secretion.22 Because choroidal malperfusion may promote recurrence of CNV by reactive angiogenetic stimulation, combination therapy of PDT followed by suppression of angiogenesis appears most promising.
Investigators have learned that, compared with other treatment modalities such as laser photocoagulation, CNV never completely disappears after treatment. With treatment, membranes become smaller and exhibit less leakage than if left to their natural course, but they can still be seen on angiography, even after multiple treatments. Experimentally, an enveloping by proliferating RPE cells promotes the spontaneous involution of persistent CNV.23 In younger patients with idiopathic or myopia-related CNV, neovascular nets remain smaller and regress more often than in AMD, because of the higher regenerative potential of young RPE.24 25 If large parts of a choroidal neovascular lesion remain unperfused for several weeks after PDT, further destructive growth of the membrane can be transiently halted. Adjacent RPE cells may benefit from the interval required for the restoration of the CNV and may migrate and proliferate around the neovascular net. CNV engulfed by RPE is still persistent, but inactive without further growth and late-phase hyperfluorescence as observed with ICG-A. Choroidal vascular nets that are abnormal in their distribution and location may no longer be in an active stage and may be arrested in growth and leakage activity, either by a maturation process alone or by an engulfing RPE barrier.
RPE proliferation was documented in experimental models histologically.2 12 Histology of human eyes exposed to PDT has meanwhile shown that RPE damage is significantly less intense in a human eye than in an animal’s (Schmidt-Erfurth et al., manuscript submitted). The hyperplastic RPE rim seen clinically in treated eyes, with good regression of the membrane, also highlights the regenerative potential of the RPE in a human eye, particularly at younger age. Immunohistology of human specimens has furthermore shown that after PDT, VEGF was produced by choriocapillary endothelial cells and not by RPE cells (Schmidt-Erfurth et al., manuscript submitted).
Clinical investigations should include a search for more selective targeting systems or sensitive angiographic monitoring to select a time interval of optimal sensitizer accumulation to increase the selectivity for CNV. In fact, retreatments reduced the size of the CNV further (Fig. 4) . However, even in the complete absence of the primary lesion, recurrence occurred at the same rate and speed as after a single treatment. At long-term follow-up, the outcome appeared to be even worse in the retreatment group. Therefore, multiple treatments at short intervals did not resolve the problem of chronic progressive disease.
The severity of hypofluorescence intensity was measured separately and was most intense 1 week after PDT, with subsequent recovery to background levels beyond 12 weeks in most cases. There was a high interindividual variability between the absolute levels of hypofluorescence which, in a most interesting finding, was independent of the drug or light dose applied. There was no correlation between the hypofluorescence size or intensity and the degree of CNV persistence or rate of recurrence. There was a tight correlation between persistent and intense hypofluorescence and retinal sensitivity, with a larger scotoma size and increased intensity associated with more intense hypofluorescence.26
Obviously, the occlusive effects on CNV and choroid are independent features. Choroidal nonperfusion within the entire light-exposed area is regularly present after PDT, but the degree of CNV and choroidal occlusive effects varies considerably within the same eye. Subsequent studies have shown that even the time course of thrombosis is different. Whereas the CNV size reaches its minimum as early as 1 day after PDT, intensity and size of choroidal hypofluorescence peak at 1 week.27 Retreatment intervals must be long enough to guarantee complete recovery of choroidal perfusion. Measurements of retinal sensitivity using scanning laser ophthalmoscope microperimetry have revealed that photoreceptor function improves at week 4, when choroidal perfusion seems to recover.26
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Footnotes |
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Submitted for publication February 15, 2001; revised October 8, 2001; accepted November 1, 2001.
Commercial relationships policy: P (US-E); N (all others).
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be marked
"advertisement" in accordance with 18 U.S.C. 
1734
solely to indicate this fact.
Corresponding author: Ursula Schmidt-Erfurth, Professor of Ophthalmology, University Eye Hospital, Medical University Lübeck, Ratzeburger Allee 160, D-23538 Lübeck, Germany; uschmidterfurth{at}ophtha.mu-luebeck.de
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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