 |
|
Histopathological Changes Following Photodynamic Therapy in Human Eyes
Arch Ophthalmol. 2002;120:835-844.
To identify histopathological changes induced by photodynamic therapy
(PDT), 2 human eyes received PDT using verteporfin 1 week before enucleation
for large malignant melanoma. Two light doses, 50 and 100 J/cm2,
were applied to unaffected chorioretinal areas and the optic disc using the
standard procedure recommended for patients with age-related macular degeneration
(ARMD).
Characteristic hypofluorescence following PDT was documented angiographically
1 week later. The enucleated globes were processed for standard light and
electron microscopy.
The PDT-treated areas revealed uniform occlusion of the choriocapillary
layer. Vascular endothelial cells were swollen, detached from the basement
membrane, and showed rupture and fragmentation to complete degeneration. Capillary
lumina were filled with cell debris, fibrin, and thrombocytes. Remaining intact
endothelial cells seemed to generate novel vascular channels by recanalization
of the obliterated lumen. The overlying retinal pigment epithelium (RPE) showed
no significant alteration. Photoreceptors and optic nerve exposed to verteporfin
and 100 J/cm2 of light were structurally unremarkable.
Photodynamic therapy induces at a dosage used clinically in the treatment
of ARMD a selective destruction of vascular endothelial cells within the choriocapillary
layer. Recanalization of the physiological choroid is observed as early as
1 week following PDT. Neural structures, photoreceptors, and RPE remained
intact.
The therapeutic benefit of PDT using verteporfin in the treatment of
predominantly classic choroidal neovascularization (CNV) has introduced a
novel strategy into the management of exudative ARMD. A prospective, randomized,
double-masked clinical trial1 demonstrated
that verteporfin PDT reduces the risk of severe visual loss, preserves contrast
sensitivity, and may even improve visual acuity in a subgroup of patients.
The results of the Treatment of Age-Related Macular Degeneration With Photodynamic
Therapy Study Group provided the rationale for the recent approval of the
method by the health authorities. Meanwhile, thousands of patients with neovascular
ARMD received PDT following the guidelines of the Treatment of Age-Related
Macular Degeneration With Photodynamic Therapy trial.
The characteristic features observed in patients undergoing PDT seem
to be well characterized: clinical exudation of serous fluid, blood, and lipids
is halted; and retinal edema resolves.2
By angiography, cessation of leakage from classic CNV is documented,3 which usually recurs and requires repeated treatment
applications to achieve long-term absence of exudative activity.4
However, despite thorough clinical and angiographic evaluation, the knowledge
of the photodynamic effects on human ocular structures is limited and mostly
based on observation of the secondary phenomena induced by PDT than a revelation
of primary mechanisms.
A histopathological evaluation from animal studies has detected changes
within the physiological choroid and the RPE and laser-induced CNV.5-6 In patients, PDT-associated findings
seem to be contradictory: retinal function is maintained or improved, while
homogeneous choroidal hypofluorescence seen angiographically may be consistent
with choroidal nonperfusion.7
To identify the structural effects induced by PDT, intact retinal, RPE,
and choroidal layers of human eyes that were scheduled for enucleation were
exposed to verteporfin therapy. Light and electron microscopic evaluation
was performed, with particular emphasis on photoreceptor, RPE, and choriocapillary
alterations.
Patients and Methods
The study protocol was compiled using the Declaration of Helsinki, and
approved by the institutional ethics committee. Informed consent was obtained
from each patient, specifically indicating the scientific nature of the photodynamic
procedure with no therapeutic relevance in respect to the underlying malignancy.
Patients
Two eyes of 2 patients received PDT. Both organs were scheduled for
enucleation because of malignant melanoma of the uvea too large for conservative
management. Tumors were located anteriorly so that the posterior pole was
accessible ophthalmoscopically and for photosensibilization. Patient 1 was
a 72-year-old man who had a large tumor reaching the ciliary body in the supranasal
quadrant, with a tumor base of 35 mm radially and 36 mm at the equator and
a height of 12 mm. Patient 2, an 85-year-old woman, was seen with a prominent
tumor mass located superiorly at the 12-o'clock position. The tumor size was
24 mm vertically and 23 mm horizontally, and it reached 12 mm in height. Localized
exudative retinal detachments were associated with the malignancies. Both
eyes showed mild age-related degenerative changes of the macular area with
some scattered drusen.
Photodynamic Therapy
Photodynamic therapy using verteporfin was applied 7 days before the
scheduled enucleation. Retinochoroidal areas without involvement by the tumor
or the accompanying serous detachment were selected by ophthalmoscopy and
angiography. The procedure was performed according to the approved treatment
recommendations for patients with ARMD. Verteporfin was administered intravenously
by infusion of 6 mg of drug per square meter of body surface area over 10
minutes. Photoactivation was started 5 minutes after the completion of the
administration, with light at a wavelength of 689 nm delivered by a diode
laser and a laser-link slitlamp (Coherent Inc, Palo Alto, Calif). Two areas
per eye were treated subsequently, a first one with a total light dose of
50 J/cm2 followed by a second one with application of a light dose
of 100 J/cm2, both at an irradiance constant of 600 mW/cm2. Exposures are shown schematically in Figure 1A and B. In eye 1, the 100-J/cm2 spot had a diameter
of 5000 µm and was positioned superiorly to the optic nerve, including
the disc (Figure 1A). The 50-J/cm2 spot with a diameter of 3000 µm was directed onto the retina
below the optic nerve head. In eye 2, the area receiving 50 J/cm2
was located central to the temporal inferior vascular arcade, while the 100-J/cm2 spot was placed below the vascular arcade (Figure 1B).
|
|
|
|
Figure 1. Eye 1 (A) and eye 2 (B) showing
the location of the tumor (A), the associated retinal detachment (B), and
the laser spots exposed to 50 J/cm2 (C) and 100 J/cm2
(D) of light. Treatment spots were placed on areas without involvement of
the tumor or detachment. Globe 1 was bisected vertically through the laser
spots. Globe 2 was first bisected horizontally, followed by a vertical section
adjacent to laser spot D.
|
|
|
Clinical Documentation
Visual acuity was examined before, 1 day after, and 1 week after PDT,
and was unchanged, with 20/400 in patient 1 and 20/100 in patient 2. No additional
field defects were described by the patients. Ophthalmoscopically, no change
in the clinical appearance of the retina, the RPE, or the choroid was noted;
treated areas were indistinguishable from the surrounding retina. Fluorescein
angiography (FA) and indocyanine green angiography (ICGA) were performed to
localize and quantify the vascular effects before and 1 week after PDT.
Histopathological Evaluation
Immediately after surgical removal, the globes were fixed in a combination
of 4% paraformaldehyde and 1% glutaraldehyde in a 0.1M phosphate buffer for
5 days and processed for routine paraffin embedding. A macroscopic examination
and transillumination were performed, and the tumor dimensions were measured.
Angiographic images were used to locate PDT-treated areas before dissection
of the posterior pole. Globe 1 was bisected along the laser spots and processed
for light and transmission electron microscopy. Globe 2 was reembedded from
paraffin into epoxy resin for electron microscopy.
For light microscopy, 8-µm-thick paraffin sections were stained
with hematoxylin-eosin and periodic acid–Schiff. For electron microscopy,
tissue specimens containing the choroid and retina of the PDT-treated areas
and untreated control areas were postfixed in 2% buffered osmium tetroxide
and embedded in epoxy resin (Epon) according to the standard method. Semithin
sections (1 µm) were stained with toluidine blue O; ultrathin sections
(0.2 µm) were stained with uranyl acetate–lead citrate and examined
with an electron microscope (LEO 906E; Zeiss, Oberkochen, Germany).
Results
Angiography
By FA, light-exposed areas revealed homogeneous hypofluorescence characteristic
for PDT, with no difference in fluorescence intensity between the 2 different
light doses. Indocyanine green angiography provided a more detailed image
of the choroidal vasculature and the extent of vaso-occlusion. In patient
1, the image taken 1 week after PDT was partially obscured by the bullous
serous detachment associated with the tumor located in the nasal periphery.
However, a round hypofluorescent area with a sharp demarcation during early
ICGA was documented in the 50- and the 100-J/cm2 spot (Figure 2A). Retinal perfusion was not compromised
with the higher-dose treatment, including the optic nerve. In late ICGA, hypofluorescence
was still present, with scattered areas of leakage from larger choroidal vessels
(Figure 2B). No pathologic exudation
was seen from the vasculature of the optic nerve.
|
|
|
|
Figure 2. Eye 1. Early (A) and late (B)
phases of indocyanine green angiography (ICGA), with demarcation of the 2
spots exposed to 100 J/cm2 superiorly, including the optic nerve,
and 50 J/cm2 inferiorly. The increasing serous detachment originating
from the tumor partially covers the nasal aspect of the image. The arrows
indicate the borders of choroidal hypofluorescence. Eye 2. Early (C) and late
(D) phases of ICGA, with hypofluorescent areas treated with 50 J/cm2 of light central and 100 J/cm2 of light peripheral to the
vascular arcade.
|
|
|
In patient 2, the central spot that illuminated with 50 J/cm2
of light showed absence of the choriocapillary background fluorescence but
maintenance of the vascular pattern of medium- and larger-caliber vessels
without any reduction in fluorescent demarcation of these vessels during early
ICGA (Figure 2C). The area that
had received 100 J/cm2 of light demonstrated choriocapillary loss
combined with a marked decrease in the overall density of choroidal vessels.
Late-phase ICGA showed the persistence of hypofluorescence in both areas,
with exudation from the margins and the remaining patent vessels within the
lesions (Figure 2D).
Light Microscopy
In globe 1, PDT-treated areas were identified superior and inferior
to the optic nerve. Complete occlusion of the choriocapillary vascular lumina
was noted in these areas. Vascular channels were blocked by swollen endothelial
cells that enclosed red blood cells and fibrin. In some segments, the lumen
was completely obliterated, while others demonstrated a residual small opening.
Occlusion was seen throughout the dimensions of the treatment spot and reached
a depth of approximately 150 µm below the Bruch membrane. Small deeper
vessels were also clogged, while larger choroidal vessels showed open lumina
with intact, not deformed, erythrocytes. Areas adjacent to the photosensitized
spot exhibited a regular choroidal vascular structure with open capillary
channels and larger choroidal vessels.
Intact choroidal sections taken from control areas appeared less condensed
and thicker than PDT-treated sections. Retinal pigment epithelial cells were
attached and showed only minor age-related changes, with vacuolization in
the treatment zone and in control areas. Photoreceptors were artificially
detached in some areas, but did not show any structural changes. Capillaries
of the optic nerve head were open and lined with intact endothelial cells.
Neural structures, such as ganglion cells and axons, showed no evidence of
structural alteration, histologic signs related to ischemia, or infiltration
of the nerve.
Choroidal vascular changes seen in globe 2 were identical to findings
observed in globe 1. An occlusion of capillaries of the choroid was seen only
in PDT-exposed areas (Figure 3A).
Endothelial cells were swollen, detached from the basement membrane, and partially
ruptured. Large-caliber vessels appeared to be regular and perfused. However,
the RPE and the Bruch membrane were unchanged. Untreated areas showed vascular
channels with intact endothelial lining (Figure 3B).
|
|
|
|
Figure 3. Light microscopy of a choroidal
section of eye 2 following photodynamic therapy. A, The superficial portion
of the choroid appears condensed, with obliterated vascular lumina within
the capillary layer (arrow), while large vessels remain patent. B, Choriocapillary
vessels and deeper vessels of an untreated area are open (arrow) and contain
red blood cells (original magnification x450).
|
|
|
Electron Microscopy
Photodynamic therapy–treated areas showed occlusion and degenerative
changes of the choriocapillaris (Figure 4A, B, and D, Figure 5A-F,
and Figure 6B-D) compared with untreated
areas with wide open lumina, several rows of loosely organized erythrocytes,
and intact fenestrated endothelia of the capillaries (Figure 4C and Figure 4E, Figure 5G, and Figure 6A). Vascular alterations in the treated areas comprised
swelling of endothelial cells and a few pericytes leading to narrowed, compressed,
capillary lumina with densely packed deformed erythrocytes immured between
the endothelial lining (Figure 4D
and Figure 6B). Alterations further
comprised endothelial shrinkage, ruptures, fragmentations, and the detachment
of cells from their basement membrane up to complete degeneration of the endothelial
lining, leaving denuded vascular basement membranes (Figure 5A and Figure 1B
and Figure 6C). Finally, complete
occlusion of capillary lumina by fibrin, platelets, and cellular debris derived
from endothelial cells, macrophages, and granulocytes was frequently observed
( Figure 4A and Figure 4B and Figure 5C
and D). Erythrocytes in the affected capillaries were often degenerative,
appearing as ghost cells. Granulocytes accumulated in the lumina of affected
capillaries and macrophages seemed to gather in the periphery of degenerated
vessels. Extravasation of erythrocytes and migration of inflammatory cells
into the extracellular space could often be observed (Figure 5B). In case of advanced endothelial degeneration, the original
vessel outline was occasionally delineated by erythrocyte configurations or
by electron-dense blood-plasma accumulations ( Figure 6C and D). Remaining intact endothelial cells appeared to
reorganize into smaller capillaries within the degenerated original vessel
outline, forming a novel vascular lumen (Figure 6D).
|
|
|
|
Figure 4. Light microscopic appearance (1-µm
semithin sections) of the choroid and the retina of patients 1 (A-C) and 2
(D and E) (toluidine blue O). A, The retina and choroid in the area treated
with 100-J/cm2 spots, showing complete obstruction of the choriocapillaris
(arrows) and a slightly vacuolated retinal pigment epithelium (RPE). The deeper
choroidal vessels and the overlying photoreceptor layer (PR) appear normal
(original magnification x350). B, The choroid in the area treated with
50-J/cm2 spots, showing occlusion of the choriocapillaris (arrows),
open deeper vessels, and a rather normal RPE (original magnification x620).
There are minor changes in the RPE (ie, rounding up of the apices is the result
of retinal detachment). C, The choroid in an untreated area showing choriocapillaries
(arrows) with wide-open lumina and a normal-appearing RPE; retinal detachment
and accumulation of subretinal exudate (EX) occurred secondary to tumor development
(original magnification x670). D, The choroid in the photodynamic therapy–treated
area showing occlusion of the choriocapillaris (arrows) due to swelling of
endothelial cells and open deeper vessels (original magnification x630).
E, The choroid in an untreated area with an intact choriocapillaris (arrows)
and a normal-appearing RPE (original magnification x630).
|
|
|
|
|
|
|
Figure 5. Electron microscopic appearance
of the choroid and the retina of patient 1 in areas treated with 50 J/cm2 (A and B) and 100 J/cm2 (C-F) of light and in untreated
areas (G). A, A choriocapillary showing rupture and fragmentation of endothelial
cells (ENs) and detachment from their basement membrane (arrows); deformed
erythrocytes fill the vessel lumen. B, A choriocapillary with advanced degeneration
of ENs, leaving a denuded basement membrane (arrows) and extravasation of
erythrocytes. C, A choriocapillary completely obstructed by cell debris, erythrocytes
(E), and fibrin (FI); the asterisk indicates large vacuoles that are present
in the overlying retinal pigment epithelium (RPE). D, Occlusion of the choriocapillaris
and vacuolar degeneration (asterisks) of the RPE. E, The choroid, showing
degenerative changes of the choriocapillaries (arrows), vacuolar changes of
the RPE (asterisks), and intact deeper vessels. F, Intact photoreceptor cells
overlying an area with occluded choriocapillaries. G, An intact choriocapillary
and RPE in an adjacent untreated area. BM indicates Bruch membrane; bar, 3
µm (A and B) and 5 µm (C-G).
|
|
|
|
|
|
|
Figure 6. Electron microscopic appearance
of the choriocapillaris and retinal pigment epithelium (RPE) of patient 2
in untreated areas (A) and photodynamic therapy–treated areas (B-D).
The ultrastructural preservation is suboptimal due to reembedding from paraffin.
A, A normal-appearing choriocapillary and RPE in an untreated central area.
B, A choriocapillary with a compressed lumen and an immured erythrocyte (E)
due to swelling of endothelial cells (ENs); the overlying RPE shows slight
vacuolar degeneration. C, Extensive degeneration of vascular ENs. The arrows
indicate the original capillary lumen. D, The remaining ENs appear to reorganize
into smaller capillaries within the degenerated original capillary outline
(arrows). BD indicates basal laminar deposits; bar, 5 µm (all parts).
|
|
|
Degenerative changes of deeper (outer) choroidal vessels with extravasation
of red blood cells was observed in the 100-J/cm2, but not in the
50-J/cm2, treated spots, where those vessels appeared essentially
normal with wide open lumina (Figure 4A
and Figure 4B and Figure 5E). Capillaries of the optic nerve head consistently appeared
intact after exposure to 100 J/cm2 of light.
The RPE appeared mostly intact over large areas and showed focal vacuolar
degeneration in the 100-J/cm2 treated areas only; partly, bullous
separation of individual pigment epithelial cells from the Bruch membrane
could be observed. The overlying photoreceptor layer appeared intact in all
PDT-treated areas (Figure 5F). Figure 4A and Figure 4D and Figure 5C, Figure 5D, and Figure 5E show areas treated with 100 J/cm2 and, therefore,
represent rather extensive vacuolization of the RPE cytoplasm and separation
from the Bruch membrane.Figure 6,
depicting patient 2, is not quite representative because of reembedding from
paraffin and a rather poor preservation of the ultrastructure. However, slight
alterations of RPE cells, such as intracellular vacuolization indicative of
intracellular edema, were also evident in the areas treated with 50 J/cm2 (Figure 7). Retinal pigment
epithelial cells appeared otherwise normal with regard to their plasma membrane,
cytoplasmic organelles, nuclei, and melanin granules.
|
|
|
|
Figure 7. Electron microscopic appearance
of the retinal pigment epithelium of patient 1 in the area treated with 50
J/cm2 of light. The cells show slight intracellular vacuolization
(asterisk), but appear rather normal and attached to the Bruch membrane (BM);
the underlying choriocapillary shows rupture and fragmentation of its endothelial
lining (EN). The bar indicates 5 µm.
|
|
|
The retinal capillaries appeared generally normal in areas treated with
either 50 or 100 J/cm2 (Figure
8).
|
|
|
|
Figure 8. Electron microscopic appearance
of a retinal capillary of patient 1 in the area treated with 50 J/cm2 of light. The vascular endothelial cells (ENs) show no obvious alterations.
PE indicates pericyte; bar, 3 µm.
|
|
|
Comment
Photodynamic treatments using verteporfin with the procedure recommended
for patients with neovascular ARMD were performed in human eyes. The treatment
effect was controlled by angiographic imaging, and the areas of interest were
identified and subsequently evaluated by light and electron microscopic histologic
features, with the aim to qualify structural changes induced by PDT.
The primary effect of PDT seems to be damage of the choriocapillary
endothelium, as indicated by swelling, fragmentation, detachment from its
basement membrane, and degeneration; however, recanalization of occluded choriocapillaries
seems to occur within a short interval. Significant alterations of the RPE
and the neural retina do not occur.
Vascular endothelial damage is the major hallmark of photodynamic tissue
effects and results from the direct interaction of a singlet of oxygen with
the lipids of endothelial cytoplasmic membranes.8
Additional intracellular photo-oxidation causes a rearrangement of the cytoskeleton,
with shrinkage of the endothelial cells and exposure of the basement membrane,
an intensive thrombogenic stimulus.9 Activated
platelets release vasoactive mediators (eg, thromboxane, tumor necrosis factor  ,
and histamine).8 Blood flow stasis is the
result of endothelial swelling, erythrocyte sludging, platelet adhesion, vasoconstriction,
and increased vascular permeability. The release of cytokines, such as interleukin
1 , interleukin 2, and tumor necrosis factor , from attracted
macrophages further facilitates vessel closure.10
The mechanistic sequelae of these phototoxic effects were seen histologically
(Figure 5 and Figure 6): vascular endothelial membranes were discontinuous, and
cells were fragmented. Cellular swelling and detachment from the basement
membrane were common features. Clots consisted of densely packed red blood
cells, thrombocytes, and fibrin. Macrophages were found, consistent with an
inflammatory stimulus. None of the described mechanisms is selective for neovascular
endothelial cells. Hence, intensive damage to physiological vascular structures
should be expected.
In animal studies, the only source of histologic features to date, closure
of choriocapillaris following verteporfin therapy, was proved by light and
electron microscopy.5-6
A direct dose-response relationship was found with capillary occlusion at
lower doses, while higher light doses invariably led to alteration of larger
choroidal vessels and RPE.5 The photothrombotic
efficacy of verteporfin clearly depends on the drug and light dose applied,
with larger-caliber vessels occluded at an increasing dosage.11
Accordingly, occlusive effects were also found in deeper layers and in vessels
with larger lumina in areas exposed to 100 J/cm2 of light in human
eyes. Occlusive choroidal effects are not specific for verteporfin or liposomal
preparations, but have also been described with various other compounds with
hydrophilic or amphiphilic character, such as purlytin, lutetium texaphyrin,
ATX-S10 (Na), and mono-L-aspartyl chlorin e6.12-15
Intensive controversy was raised by the characteristic hypofluorescence
seen regularly after PDT. Hypofluorescence is most pronounced in FA performed
1 week after PDT. Based on the homogeneity and the intensity of hypofluorescence
in an angiographic modality using a low wavelength, like FA, masking of the
underlying fluorescence was suspected (eg, by hemoglobin or an altered RPE).16 The fact that hypofluorescence covers precisely
the area of the treatment spot and resolves slowly during the following weeks
suggests transient choroidal nonperfusion rather than masking—which
was substantiated with correlation of angiographic and histopathological features.
The consistency of histologic results and ICGA imaging is striking because
by ICGA, choriocapillary shutdown was seen in the 50-J/cm2 treated
spot (Figure 3A) and disappearance
of larger vessels occurred in the 100-J/cm2 treated spot (which
was supported by the respective extent of vascular obliteration in histopathological
features). Indocyanine green angiography may, therefore, be recommended as
a useful clinical tool for documentation of photodynamic vascular effects.7, 17-18
How is obvious choriocapillary occlusion compatible with maintenance
of visual function? Histologic features reveal structural integrity of overlying
photoreceptors after an interval of hypothetical hypoxia for as long as 1
week. Microperimetry, a sensitive test of photoreceptor function, demonstrates
improvement of retinal sensitivity within the treated CNV area in 80% of eyes
at 4 weeks.18 The oxygen supply provided
by patent large vessels might guarantee photoreceptor survival. A more convincing
argument is the observation that progression of occlusion is extremely slow.
Short-term follow-up by ICGA demonstrated that choroidal perfusion is not
compromised at all for several hours after PDT. Choroidal darkening only occurs
during the following days and reaches its maximal intensity after 3 days to
1 week.19 Apparently, photoreceptors and
RPE are better capable of tolerating a prolonged reduction in oxygen supply
than an immediate choroidal thrombosis, which is usually associated with significant
visual loss.20-21 A relative
reduction in photoreceptor function, however, defined as a transient visual
disturbance, was reported by 18% of the PDT-treated patients in the Treatment
of Age-Related Macular Degeneration With Photodynamic Therapy trial.1 Although the progression of the disease was halted
successfully, patients lost a mean of 2 lines of visual acuity during follow-up,
which might reflect a residual choriocapillary alteration.1
Recanalization was found in multiple areas of the primarily occluded
choriocapillary. Slow progression of photothrombosis over 1 week in concordance
with increasing recanalization during the same interval might be a competing
mechanism and in summary reduce the extent of ischemia. Recanalization is
illustrated histologically by the formation of novel lumina within previously
occluded channels. Electron microscopy in experimental models showed duplication
of vascular basement membranes indicative of recanalization.22
An intraluminal reorganization would lead to a reduplication of the vascular
wall, potentially with restoration of the vascular barrier. Recanalization
processes might play an important role in the observed change in the biological
features of the CNV complex as well. Cessation of leakage from classic CNV
is the prominent angiographic feature in clinical PDT.1-4
Typically, CNV nets are still delineated in early FA during follow-up, but
become progressively silent with resolution of leakage activity. Histopathological
features reveal a possible mechanism of barrier stabilization in those with
treated CNV with recanalization. Persistent CNV without extravasation would
not further compromise retinal integrity. Such an involutional stabilization
is the therapeutic rationale of various interventions, such as radiotherapy,
antiangiogenesis, and transpupillary thermotherapy, which do not eradicate
CNV but decrease the exudative activity.23-25
Spontaneously regressed CNV histologically exhibits persistent neovascular
channels, however, with lack of exudation due to a restored barrier function
either due to RPE or endothelial reproliferation.26
Recanalization is most likely an important mechanism of CNV recurrence,
particularly because recurrent "growth" and enlargement of CNV occurs at a
faster rate than de novo occurrence of CNV.4
Choroidal ischemia induced by PDT might stimulate growth factor expression
(eg, vascular endothelial growth factor), which is recognized as a major stimulator
of CNV.27-28 Repair of choroidal
damage might be a challenge in elderly eyes because choroidal density and
integrity were compromised with age.29 A
combination therapy of PDT with antiangiogenic agents might, therefore, be
promising in respect to CNV recurrence but problematic in respect to choroidal
regeneration.
Although verteporfin PDT of CNV does not spare the physiological choroidal
capillaries, retinal vessels and neural structures, including photoreceptors
and the optic nerve, remained intact even if exposed to a light dose twice
as high as conventionally used. Moderate RPE changes could be found. Increased
vacuolization was documented, which was partially within normal age-related
limits, at 50 J/cm2 in our patients, who primarily had age-related
macular changes. Whether this damage was a direct consequence of the PDT effect
or developed secondarily due to choriocapillary occlusion for as long as 1
week is difficult to analyze. Determining the histologic features immediately
or shortly after photosensitization is obviously not an option considering
the risk of widespread phototoxic damage during the surgical procedure at
a time of high sensitizer retention. Retinal pigment epithelial cells also
demonstrate a high regenerative potential following structural damage.30-31
The histopathological findings of this study identify important mechanisms
of PDT in human eyes. The extent of vaso-occlusion with concomitant thrombosis
of a normal choriocapillaris is documented, as are active repair mechanisms.
In future clinical applications of PDT, the application of a low light dose
should be considered to allow for appropriate choroidal regeneration in between
treatment intervals and to include choroidal perfusion as a factor for retreatment
indication.
AUTHOR INFORMATION
The Wellman Laboratories of Photomedicine, Massachusetts General Hospital,
Boston, and Dr Schmidt-Erfurth are holders of a patent on the use of verteporfin
and have a proprietary interest under the guidelines of Harvard Medical School,
Boston.
Ursula Schmidt-Erfurth, MD;
Horst Laqua, MD
Luebeck, Germany
Ursula Schlötzer-Schrehard, MD;
Arne Viestenz, MD;
Gottfried O. H. Naumann, MD
Erlangen, Germany
Corresponding author: Ursula Schmidt-Erfurth, MD, Department of Ophthalmology,
University Eye Hospital Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany
(e-mail: uschmidterfurth{at}ophtha.mu-luebeck.de).
REFERENCES
|
1. 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.
FREE FULL TEXT
2. Schmidt-Erfurth U, Miller J, Sickenberg M. Photodynamic therapy of subfoveal choroidal neovascularization: clinical
and angiographic examples. Graefes Arch Clin Exp Ophthalmol. 1998;236:365-374.
FULL TEXT
|
ISI
| PUBMED
3. Miller JW, Schmidt-Erfurth U, Sickenberg M, et al. Photodynamic therapy with verteporfin for choroidal neovascularization
caused by age-related macular degeneration: results of a single treatment
in a phase 1 and 2 study. Arch Ophthalmol. 1999;117:1161-1173.
FREE FULL TEXT
4. Schmidt-Erfurth U, Miller JW, Sickenberg M, et al. Photodynamic therapy with verteporfin for choroidal neovascularization
caused by age-related macular degeneration: results of retreatments in a phase
1 and 2 study. Arch Ophthalmol. 1999;117:1177-1187.
FREE FULL TEXT
5. Schmidt-Erfurth U, Hasan T, Gragoudas E, Michaud N, Flotte TJ, Birngruber R. Vascular targeting in photodynamic occlusion of subretinal vessels. Ophthalmology. 1994;101:1953-1961.
ISI
| PUBMED
6. Kramer M, Miller JW, Michaud N, et al. Lysosomal benzoporphyrin derivative verteporfin in photodynamic therapy:
selective treatment of choroidal neovascularization in monkeys. Ophthalmology. 1996;103:427-438.
ISI
| PUBMED
7. Schmidt-Erfurth U, Michels S, Hager A, Laqua H. ICG-angiographic analysis of the photodynamic mechanism in the photodynamic
treatment of choroidal neovascularization. Invest Ophthalmol Vis Sci. 1998;39(suppl):S242.
8. Finger VH. Vascular effects of photodynamic therapy. J Clin Laser Med Surg. 1996;14:323-328.
PUBMED
9. Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol. 1992;55:145-157.
ISI
| PUBMED
10. Gollnick SO, Liu X, Owczarczak B, Musser DA, Henderson BW. Altered expression of interleukin 6 and interleukin 10 as a result
of photodynamic therapy in vivo. Cancer Res. 1997;57:3904-3909.
FREE FULL TEXT
11. Lange N, Ballini JP, Waguieres G, van den Bergh H. A new drug-screening procedure for photosensitizing agents used in
photodynamic therapy for CNV. Invest Ophthalmol Vis Sci. 2001;42:38-46.
FREE FULL TEXT
12. Obana A, Gohto Y, Kanas M, Nakajima S, Kaneda K, Miki T. Selective photodynamic effects of the new photosensitizer ATX-S10 (Na)
on choroidal neovascularization in monkeys. Arch Ophthalmol. 2000;118:650-658.
FREE FULL TEXT
13. Blumenkranz MS, Woodburn KW, Qing F, Verdooner S, Kessel D, Miller R. Lutetium texaphyrin (LU-Tex): a potential new agent for ocular fundus
angiography and photodynamic therapy. Am J Ophthalmol. 2000;129:353-362.
FULL TEXT
|
ISI
| PUBMED
14. Mori K, Yoneya S, Ohta M, et al. Angiographic and histologic effects of fundus photodynamic therapy
with a hydrophilic sensitizer (mono-L-aspartyl chlorin e6). Ophthalmology. 1999;106:1384-1391.
FULL TEXT
|
ISI
| PUBMED
15. Thomas EL, Rosen R, Murphy R, et al. Purlytin (SnET2)-photodynamic therapy produces closure of subfoveal
choroidal neovascularization in humans. Invest Ophthalmol Vis Sci. 1998;39(suppl):S242.
16. Flower RW, Snyder WJ. Expanded hypothesis on the mechanism of photodynamic therapy action
on choroidal neovascularization. Retina. 1999;19:365-369.
FULL TEXT
| PUBMED
17. Schmidt-Erfurth U, Michels S, Barbazetto I, Laqua H. Photodynamic effects on choroidal neovascularization and physiological
choroid. Invest Ophthalmol Vis Sci. 2002;43:830-841.
FREE FULL TEXT
18. Schmidt-Erfurth U. Indocyanine green angiography and retinal sensitivity after photodynamic
therapy of subfoveal choroidal neovascularization. Semin Ophthalmol. 1999;14:35-44.
PUBMED
19. Michels S, Schmidt-Erfurth U. Early vascular changes induced by photodynamic therapy using verteporfin. Invest Ophthalmol Vis Sci. 2001;42(suppl):S304.
20. Aug LP, Yap EY, Fam HB. Bilateral choroidal infarction in a patient with antiphospholipid syndrome:
a case report. Clin Exp Ophthalmol. 2000;28:326-328.
FULL TEXT
|
ISI
| PUBMED
21. Hoerauf H, Schmidt-Erfurth U. Combined choroidal and retinal ischemia during interferon therapy:
ICG-angiographic and microperimetric findings. Arch Ophthalmol. 2000;118:580-582.
FREE FULL TEXT
22. Husain D, Kramer M, Kenney AG, et al. Effects of photodynamic therapy using verteporfin on experimental choroidal
neovascularization and normal retina and choroid up to 7 weeks after treatment. Invest Ophthalmol Vis Sci. 1999;40:2322-2331.
FREE FULL TEXT
23. Finger PT, Chakravarthy U, Augsburger JJ. Radiotherapy and the treatment of age-related macular degeneration:
external beam radiation therapy is effective in the treatment of age-related
macular degeneration. Arch Ophthalmol. 1998;116:1507-1511.
FREE FULL TEXT
24. Fung WE. Interferon alpha 2a for treatment of age-related macular degeneration. Am J Ophthalmol. 1991;112:349-350.
ISI
| PUBMED
25. Reichel E, Berrocal A, Ip M, et al. Transpupillary thermotherapy of occult subfoveal choroidal neovascularization
in patients with age-related macular degeneration. Ophthalmology. 1999;106:1908-1914.
FULL TEXT
|
ISI
| PUBMED
26. Miller H, Miller B, Ryan SJ. The role of retinal pigment epithelium in the involution of subretinal
neovascularization. Invest Ophthalmol Vis Sci. 1986;27:1644-1652.
FREE FULL TEXT
27. McLeod DS, Lutty GA. High-resolution histologic analysis of the human choroidal vasculature. Invest Ophthalmol Vis Sci. 1994;35:3799-3811.
FREE FULL TEXT
28. Kvanta A, Algvere B, Berghin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration
express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929-1934.
FREE FULL TEXT
29. Kwak N, Okamoto N, Wood J, Campochiaro P. VEGF is major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000;41:3158-3164.
FREE FULL TEXT
30. Heriot WJ, Machemer R. Pigment epithelial repair. Graefes Arch Clin Exp Ophthalmol. 1992;230:91-109.
FULL TEXT
|
ISI
| PUBMED
31. Roider J, Michaud N, Flotte TJ, Birngruber R. Response of the retinal pigment epithelium to selective photocoagulation. Arch Ophthalmol. 1992;110:1786-1792.
FREE FULL TEXT
SECTION EDITOR: W. RICHARD GREEN, MD
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Same-day administration of verteporfin and ranibizumab 0.5 mg in patients with choroidal neovascularisation due to age-related macular degeneration
Schmidt-Erfurth et al.
Br. J. Ophthalmol. 2008;92:1628-1635.
ABSTRACT
| FULL TEXT
A prospective randomised study on low-dose transpupillary thermotherapy versus photodynamic therapy for neovascular age-related macular degeneration
Odergren et al.
Br. J. Ophthalmol. 2008;92:757-761.
ABSTRACT
| FULL TEXT
Treatment of peripapillary choroidal neovascularisation
Postelmans et al.
Br. J. Ophthalmol. 2008;92:721-722.
FULL TEXT
Histopathological findings in postmortem eyes after photodynamic therapy for choroidal neovascularisation in age-related macular degeneration: report of two cases
Kang et al.
Br. J. Ophthalmol. 2007;91:1602-1606.
ABSTRACT
| FULL TEXT
Correlation between Focal Macular Electroretinograms and Angiographic Findings after Photodynamic Therapy
Ishikawa et al.
IOVS 2007;48:2254-2259.
ABSTRACT
| FULL TEXT
Safety enhanced photodynamic therapy with half dose verteporfin for chronic central serous chorioretinopathy: a short term pilot study
Lai et al.
Br. J. Ophthalmol. 2006;90:869-874.
ABSTRACT
| FULL TEXT
Consequences of verteporfin photodynamic therapy on choroidal neovascular membranes.
Tatar et al.
Arch Ophthalmol 2006;124:815-823.
ABSTRACT
| FULL TEXT
Perspectives on verteporfin therapy combined with intravitreal corticosteroids.
Schmidt-Erfurth et al.
Arch Ophthalmol 2006;124:561-563.
FULL TEXT
Effect of Intravitreal Injection of Ranibizumab in Combination with Verteporfin PDT on Normal Primate Retina and Choroid
Kim et al.
IOVS 2006;47:357-363.
ABSTRACT
| FULL TEXT
Influence of Treatment Parameters on Selectivity of Verteporfin Therapy
Michels et al.
IOVS 2006;47:371-376.
ABSTRACT
| FULL TEXT
Ocular Changes after Photodynamic Therapy
Tzekov et al.
IOVS 2006;47:377-385.
ABSTRACT
| FULL TEXT
Choroidal neovascularisation in pathological myopia: an update in management
Chan et al.
Br. J. Ophthalmol. 2005;89:1522-1528.
ABSTRACT
| FULL TEXT
Choroidal Infarction Following Photodynamic Therapy With Verteporfin
Klais et al.
Arch Ophthalmol 2005;123:1149-1153.
FULL TEXT
Macular Function after PDT in Myopic Maculopathy: Psychophysical and Electrophysiological Evaluation
Varano et al.
IOVS 2005;46:1453-1462.
ABSTRACT
| FULL TEXT
Application of femtosecond ultrashort pulse laser to photodynamic therapy mediated by indocyanine green
Sawa et al.
Br. J. Ophthalmol. 2004;88:826-831.
ABSTRACT
| FULL TEXT
Clinicopathological findings of choroidal neovascularisation following verteporfin photodynamic therapy
Gelisken et al.
Br. J. Ophthalmol. 2004;88:207-211.
ABSTRACT
| FULL TEXT
Influence of Photodynamic Therapy on Expression of Vascular Endothelial Growth Factor (VEGF), VEGF Receptor 3, and Pigment Epithelium-Derived Factor
Schmidt-Erfurth et al.
IOVS 2003;44:4473-4480.
ABSTRACT
| FULL TEXT
Macular relocation after photodynamic therapy for recurrent choroidal neovascular membrane: visual results and histopathological findings
Stanga et al.
Br. J. Ophthalmol. 2003;87:975-976.
ABSTRACT
| FULL TEXT
Sequence of Early Vascular Events after Photodynamic Therapy
Michels and Schmidt-Erfurth
IOVS 2003;44:2147-2154.
ABSTRACT
| FULL TEXT
|
