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Photodynamic Therapy to Control Fibrosis in Human Glaucomatous Eyes After Trabeculectomy
A Clinical Pilot Study
Michael Diestelhorst, MD;
Salvatore Grisanti, MD
Arch Ophthalmol. 2002;120:130-134.
ABSTRACT
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Objective To evaluate the safety, tolerability, and clinical effect on intraocular
pressure (IOP) of a carboxyfluorescein ester as an adjunctive antifibrotic
therapy in human glaucomatous eyes to control postoperative wound healing
after trabeculectomy.
Methods In 10 human glaucomatous eyes with high IOPs that underwent 1 to 3 previous
surgical procedures for glaucoma, 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester was applied 15 minutes prior to trabeculectomy via a subconjunctival
injection followed by intraoperative illumination with diffuse blue light
(450-490 nm; approximately 51.9 x 103 candelas/m2)
for 8 minutes. Antifibrotic efficacy was established by clinical response,
postoperative IOP reduction, slitlamp examination, and filtering bleb site
photographs. Success was defined as an IOP less than 21 mm Hg from baseline
without the eye receiving any antiglaucomatous medication or an application
of antimetabolites.
Results The mean (SD) IOP on the day before surgery was 37.2 (11.2) mm Hg. The
IOP was 16.6 (3.8) mm Hg in 8 successful eyes after a mean (SD) follow-up
of 400.1 (38.1) days (P<.001). Two eyes showed
scarring at the site of the filtering bleb within 1 month. In 1 eye with pseudoexfoliation
glaucoma IOP decreased to 17 mm Hg but needed topical antiglaucomatous medication.
Clinical examination revealed none of the following: blebitis, uveitis, endophthalmitis,
or toxic damage of the adjacent tissues.
Conclusions We report our findings about the first 10 consecutive human glaucomatous
eyes treated with a single dose of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester
during trabeculectomy. In contrast to chemotherapeutic agents, cellular photoablation
acts only on cells having incorporated 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester
and having been exposed to light of an appropriate wavelength. Though safety
and efficacy demand a controlled randomized study, our method seems to be
an effective therapeutic approach to control postoperative fibrosis in human
glaucomatous eyes with a poor surgical prognosis. Multiple factors such as
dose of light, means of application, wavelength, irradiation area, total dose
of the dye, and multiple dosing may be altered in the future to improve the
antifibrotic effect of photodynamic therapy during surgery for glaucoma.
INTRODUCTION
TRABECULECTOMY is the most frequently applied surgical method to reduce
intraocular pressure (IOP) in patients with glaucoma. The wound healing process
at the site of the filtration area, however, causes failure in about 30% of
these cases within 6 to 8 weeks after surgery.1
Characteristically fibroblasts from Tenon capsule and episclera lead to a
fibroproliferative response that involves and closes the created
fistula.2-15
To increase the success rates of filtering surgery, agents such as mitomycin
C and fluorouracil4, 16-34
have been used perioperatively as an antifibrotic therapy. Despite their positive
effect on the success rates of filtering surgery in patients with a poor surgical
prognosis, diffusion into adjacent ocular tissues causes toxic effects.35-36 New surgical complications, such
as blebitis, endophthalmitis, and hypotonic maculopathy, and an increased
incidence of already known postoperative complications have limited its clinical
use and stimulated the search for clinically less harmful alternatives.37-38
Photodynamic therapy (PDT) is a selective and localized treatment based
on the photosensitized oxidation of biological matter.39-42
A photosensitizer can be used as a mediator of controlled light-induced cell
toxicity. The mechanism of action is reported to be due to type I and II photooxidative
reactions. Oxygen is transformed into singlet oxygen that oxidizes amino acids,
nucleic acids, and unsaturated fatty acids. Within hours, the cytotoxic effect
is seen at cell membranes (blebs), plasma membranes, mitochondria, lysosomes,
and nuclei. Selective activation of the photosensitizer by the application
of light at an appropriate wavelength limits the drug effect to a selected
area.40-41
This carboxyfluorescein ester has been shown to inhibit the proliferation
of human Tenon fibroblasts in vitro after using the combined treatment of
10 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxy
fluorescein, acetoxymethyl ester and irradiation for 10 minutes.39
In living eyes of pigmented rabbits 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxy fluorescein, acetoxymethyl ester
was shown to effectively inhibit scarring after filtration surgery and demonstrated
a dose-response curve from 40 µg to 100 µg after irradiation for
10 minutes.40 The objective of this open-label
phase 2 study was to investigate the effect of cellular photoablation mediated
by 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxy
fluorescein, acetoxymethyl ester therapy on the postoperative fibrosis after
filtration surgery in human glaucomatous eyes with a poor prognosis.
PATIENTS AND METHODS
All patients had uncontrolled glaucoma due to high IOPs despite maximum
tolerable medical therapy. They were referred to the Department of Ophthalmology,
Center of Ophthalmology, University of Cologne, Cologne, Germany, to undergo
glaucoma surgery. We included only eyes with advanced glaucomatous cupping
of the optic nerve head (glaucoma fere absolutum and glaucoma absolutum; cup-disc
ratio, >0.9).
The study was approved by the ethics review board of the University
of Cologne and followed the guidelines of the Declaration of Helsinki as revised
in Tokyo Japan, and Venice, Italy. Each patient gave written informed consent
after receiving a detailed explanation of the purpose of the study and the
method of surgery.
PHOTOSENSITIZER AND PHOTOACTIVATION
The fluorescent probe, 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester, is a cell membrane permeable compound rendered membrane-impermeable
and fluorescent on cleavage by intracellular esterases. The clinical samples
of the photosensitizer were provided in tuberculin syringes by the pharmacy
of the University of Cologne. A dose of 80 µg was diluted in 300 µL
of balanced salt solution and stored at -70°C.
Surgery and clinical examinations were performed in 10 consecutive eyes
of 5 men and 5 women with glaucoma. All patients were hospitalized before
surgery and remained indoors until the fifth postoperative day. Patients were
examined for safety, tolerability, and efficacy of therapy after 14 days,
and after 1, 3, 6, 9, 12, and 14 months.
SURGICAL PROCEDURE
The surgical procedure was performed under topical or general anesthesia
by one surgeon (M.D.). Fifteen minutes prior to surgery the eye received a
single subconjunctival injection of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl
ester solution in one superior quadrant where the trabeculectomy was to be
performed (Figure 1).
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Figure 1. The anterior segment of a human
glaucomatous eye after subconjunctival injection of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl
ester solution displaying a subconjunctival bleb filled with the yellow solution.
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Following a limbus-based conjunctival flap, the episcleral Tenon and
the subconjunctival tissue were irradiated. Illumination with diffuse blue
light (450-490 nm; approximately 51.9 x 103 candelas/m2) was performed for 8 minutes. Photoactivating light was delivered
by a portable lamp (Zeiss GmbH, Oberkochen, Germany) equipped with a blue
filter fixed at a distance of about 2 cm from the episclera. Light was focused
to an area of about 20 mm in diameter, encompassing the subconjunctival and
episcleral tissues and sparing the cornea, which was covered by tape. The
illuminated area produced a 3.5 x 3.5-mm scleral flap. Since the illuminated
area was well focused, no further mask was needed to minimize light absorption
to adjacent tissues.
A standard trabeculectomy and a full-thickness iridectomy followed.
The scleral flap was closed with two 10/0 nylon sutures. The Tenon capsule
and conjunctiva were closed with a single 8/0 polyglactin (Vicryl) running
suture. At the end of surgery all eyes were treated with a subconjunctival
injection of a water solution of betamethasone and gentamicin sulfate.
Postoperatively all eyes received prednisolone acetate and tobramycin
eye drops for 14 consecutive days. No antiglaucomatous medication or antimetabolites
were applied. The postoperative treatment protocol allowed for subconjunctival
injection of the betamethasone water solution and laser suture lysis of the
2 scleral nylon sutures. Postoperative success was defined as an IOP of less
than 21 mm Hg without the eye receiving any antiglaucomatous medication or
an application of antimetabolites.
CLINICAL EXAMINATION AND PHOTOGRAPHS
Clinical examination at the slitlamp was performed on designated days
to evaluate both the general appearance, tolerability, and safety of the therapy
in the treated eyes and to measure the IOP and the visual acuity. The IOP
was measured using Goldmann applanation tonometry before and after surgery.
The anterior segment and the site of the filtering bleb was documented by
taking photographs with a 35-mm camera (Nikon Corp, Tokyo, Japan).
STATISTICS
A 2-tailed t test was performed. Statistical
significance was set at P<.05. All values are
given as mean (SD).
RESULTS
We included 5 men and 5 women with a mean age of 63.1 years (age range,
18-85 years); with primary open-angle glaucoma (n = 2), pseudoexfoliation
glaucoma (n = 3), secondary glaucoma (n = 4), or Axenfeld-Rieger syndrome
(n = 1) (Table 1). Most of the
eyes had a history of at least 1 glaucoma surgical intervention that had failed.
The study eyes were evaluated daily within the first 5 postoperative days
and then at designated time points (+14 days, and 1, 3, 6, 9, 12, and 14 months)
thereafter. A mean follow-up was 400.1 (38.1) days. The demographic and clinical
data of the 5 men and 5 women treated with PDT during trabeculectomy are listed
in Table 1.
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Demographic and Clinical Data of 10 Patients Treated With Photodynamic
Therapy During Trabeculectomy*
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The preoperative IOP in 10 eyes ranged from 32 to 60 mm Hg with a mean
of 37.2 (11.2) mm Hg. On the first postoperative day IOP ranged from 2 to
47 mm Hg with a mean of 9 (16) mm Hg. After surgery (duration, 400.1 [38.1]
days), the mean IOP of 8 successful eyes was 16.6 (3.8) mm Hg (P<.001) (Figure 2). One
eye with pseudoexfoliation glaucoma had an IOP of 17 mm Hg at the last examination,
but a topical antiglaucomatous medication (qualified success) was needed.
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Figure 2. Preoperative (n = 10 patients)
and postoperative (n = 8 patients) intraocular pressure (IOP) of study eyes
after trabeculectomy with photodynamic therapy. There was a statistically
significant reduction (P<.001) of mean IOP up
to 400 days. One eye with pseudoexfoliation glaucoma had an IOP of 17 mm Hg
at the last examination, but a topical antiglaucomatous medication (qualified
success) was needed.
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Within the first 5 postoperative days, we saw a shallow anterior chamber,
hypotony, and choroidal detachment due to an IOP of less than 6 mm Hg in 1
eye that resolved without surgical intervention. None of the eyes demonstrated
hypotonic maculopathy. Patients did not report any symptoms of intraocular
pain or other unexpected adverse effects.
In some eyes, the postoperative inflammatory reaction observed at the
slitlamp examination included conjunctival hyperemia and mild anterior chamber
flare (Figure 3). The intraoperative
application of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester did not cause clinically detectable tissue damage at the
cornea or conjunctiva (Figure 4).
No blebitis or endophthalmitis was observed in any eye. The bleb appearance
was variable but within normal ranges. The blebs did not have avascularity
as seen with mitomycin C or fluorouracil therapy.
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Figure 3. The treated eye of patient 5 nineteen
days after surgery. The anterior segment shows no inflammation. There is new
filtration area and basal iridectomy at the 2-o'clock position. A functional
filtration bleb is visible. The intraocular pressure in this eye had decreased
to normal levels.
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Figure 4. The treated eye of patient 5 (see
Figure 3) 4 months after surgery. The anterior segment displays no inflammatory
response. The intraocular pressure in this eye was significantly reduced from
26 to 32 mm Hg to less than 20 mm Hg without the patient receiving any antiglaucomatous
therapy.
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Wound healing was clinically evident as a rise of the IOP and as closure
of the filtration area. This process was prominent in 2 young patients (1
eye with secondary glaucoma due to trauma and 1 eye with Axenfeld-Rieger syndrome).
Both eyes showed scarring within 1 month after surgery despite the application
of PDT.
COMMENT
Photodynamic therapy is an alternative method for the treatment of localized
pathologic conditions, such as skin cancer.42
Specific activation of pertinent drugs at the targeted area should avoid adverse
effects. Photodynamic therapy has also been evaluated for some distinct ophthalmic
diseases, such as ocular tumors, choroidal and corneal neovascularization,
proliferative vitreoretinal disorders, and postoperative fibrosis in glaucoma
surgery.41, 43-47
Hill et al41 investigated the feasibility of
PDT in a rabbit model of filtration surgery. Using ethyl etiopurin, a photosensitizer
traditionally provided by intravenous injection, they showed that subconjunctival
provision could have an effect on filtering bleb survival.41
2'7'-Bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester is a cell membrane–permeable compound rendered membrane
impermeable and fluorescent on cleavage by intracellular esterases.48-50 Exposure of cells
having incorporated 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester to light at an appropriate wavelength leads to cellular
photoablation. The light-induced cytotoxicity of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester
has been demonstrated in in vitro and in vivo studies.39-40
In this study we investigated the antifibrotic effect of a single dose
of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester during glaucoma filtration surgery in human eyes with
a poor surgical prognosis. This treatment model may be an alternative approach
to control the more aggressive wound healing response of human eyes where
filtration surgery had already failed. The use of antimetabolites, such as
fluorouracil and mitomycin C, have prolonged bleb survival. The effect of
the agents depends on drug concentration, total dose, application time, and
method.3, 21 Until now no dose-response
curve of mitomycin C has been demonstrated to be both clinically safe and
effective in human glaucomatous eyes.
Our data reveal that the success of trabeculectomy in human glaucomatous
eyes with a poor surgical prognosis can be prolonged when cellular photoablation
is applied during filtration surgery (Figure
2). Using a single dose of 80 µg of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl
ester, the success of filtration surgery was prolonged for a mean follow-up
of 400 days. This was expressed both in lower IOP levels and prolonged filtration
(Figure 3). The creation of filtration
blebs as evidence of successful surgery was associated with a reduced IOP.
Slitlamp microscopy revealed no detectable damage of the cornea or conjunctiva
(Figure 4).
As 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester is a lipophilic drug, it may diffuse into other tissues
adjacent to the area of subconjunctival injection. However, subconjunctival
injection of 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein,
acetoxymethyl ester followed by illumination and surgery did not cause a conjunctival
defect. Since activation of the dye by illumination is achieved only at the
surface of the tissue, it is inconceivable that the photoablative effect affects
the ciliary body. In preevaluating in vitro studies, cellular photoablation
could only be detected in cells that had incorporated 2'7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl
ester and were exposed to light at an appropriate wavelength.39
In the rabbit model, histologic and morphologic studies did not reveal any
damage to adjacent tissues.40
CONCLUSIONS
Cellular photoablation seems to be an effective therapeutic approach
to control postoperative fibrosis in human glaucomatous eyes with a poor surgical
prognosis. Multiple factors such as light dose, light application, wavelength,
irradiation area, total dose of the dye, or multiple dosing may be altered
in the future to improve the antifibrotic effect of PDT during glaucoma surgery.
The safety and efficacy will be tested in a multicenter, randomized clinical
study in 2002.
AUTHOR INFORMATION
Accepted for publication October 17, 2001.
This study received a research award from the European Glaucoma Society,
London, England, June 8, 2000.
The study was presented in part at the annual meeting of the Association
of Research in Vision and Ophthalmology, Fort Lauderdale, Fla, May 4, 2000.
Corresponding author: Salvatore Grisanti, MD, Center of Ophthalmology,
Eberhard-Karls-University Tübingen, Schleichstrasse 12-15, 72070 Tübingen,
Germany (e-mail: salvatore.grisanti{at}uni-tuebingen.de).
Reprints:
Michael Diestelhorst, MD, Center of Ophthalmology, University of Cologne,
Joseph-Stelzmann-Strasse 9, 50931 Cologne, Germany (e-mail: michael.diestelhorst{at}medizin.uni-koeln.de).
From the Departments of Ophthalmology, Centers of Ophthalmology, University
of Cologne, Cologne, Germany (Drs Diestelhorst and Grisanti), and Eberhard-Karls-University
Tübingen, Tübingen, Germany. Dr Grisanti is now with the Center
of Ophthalmology, Eberhard-Karls-University Tübingen.
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