Verteporfin Therapy Combined with Intravitreal Triamcinolone in All Types of Choroidal Neovascularization due to Age-Related Macular Degeneration

 
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Verteporfin Therapy Combined with
Intravitreal Triamcinolone in All Types
of Choroidal Neovascularization due to
Age-Related Macular Degeneration
Albert J. Augustin, MD,1 Ursula Schmidt-Erfurth, MD2

   Objective: To evaluate the efficacy and safety of photodynamic therapy with verteporfin combined with
intravitreal triamcinolone in choroidal neovascularization secondary to age-related macular degeneration (AMD).
   Design: Prospective, noncomparative, interventional case series.
   Participants: One hundred eighty-four patients undergoing treatment for neovascular AMD at one retinal referral
center.
   Methods: One hundred eighty-four eyes of 184 consecutive patients (63.6% female, 36.4% male) with a
mean age of 76.5 years and a follow-up of a median of 38.8 weeks (range, 12–103) were included in a case series.
One hundred forty-eight (80.4%) patients had subfoveal choroidal neovascularization, 19 patients (10.3%) had
juxtafoveal choroidal neovascularization, and 17 patients (9.2%) had extrafoveal choroidal neovascularization.
Verteporfin photodynamic therapy was performed using the recommended standard procedure. A solution
containing 25 mg of triamcinolone was injected intravitreally 16 hours after photodynamic therapy in 184 patients.
The combined therapy procedure was repeated at the 3-month follow-up visits whenever persistent choroidal
neovascularization leakage was documented angiographically.
   Main Outcome Measures: Mean change in best-refracted visual acuity (VA) between baseline and the last
visit, and number of treatments necessary to achieve absence of leakage.
   Results: Visual acuity improved in the majority of patients (baseline VA, mean 20/125) by a mean increase
of 1.22 Snellen lines and 1.43 lines using laser interferometry (P⬍0.01). The mean number of required treatments
was 1.21. Twenty-three eyes (12.5%) required 2 treatments, 6 eyes (3.26%) required 3 treatments, and 1 eye
(0.5%) required 4 treatments. The combination treatment including laser and intravitreal steroid administration
was well tolerated. Forty-six patients (25%) required glaucoma therapy due to a transient steroid-induced
intraocular pressure (IOP) increase. Twelve patients (6.5%) were on topical medication for preexisting glaucoma.
Two patients (1%) whose IOP increase could not be controlled with topical therapy required surgery.
   Conclusions: Verteporfin photodynamic therapy combined with intravitreal triamcinolone may improve the
outcome of standard verteporfin photodynamic therapy in the treatment of choroidal neovascularization sec-
ondary to AMD. A significant improvement in VA was observed in a majority of treated patients and was
maintained during the maximum follow-up. In addition, retreatment rates were lower than anticipated.
Ophthalmology 2006;113:14 –22 © 2006 by the American Academy of Ophthalmology.

Photodynamic therapy with verteporfin was shown to be                       photodynamic therapy with verteporfin significantly re-
effective in 2 clinical trials in patients with classic subfoveal           duced the risk of moderate-to-severe vision loss in patients
choroidal neovascularization secondary to age-related mac-                  with occult and no classic choroidal neovascularization after
ular degeneration (AMD).1–3 In addition, the Verteporfin in                 AMD.4 The treatment is generally safe and well tolerated,
Photodynamic Therapy Study showed that, after 2 years,                      and substantial vision loss can often be prevented.
                                                                                The pathogenesis of choroidal neovascularization is mul-
Originally received: March 22, 2005.                                        tifactorial, involving oxidative and inflammatory events as
Accepted: September 1, 2005.                    Manuscript no. 2005-256.    well as photodynamic processes.5,6 The mechanisms in-
1
  Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany.      clude cell-mediated inflammation, leukocyte adhesion and
2
  Department of Ophthalmology, Medical University of Vienna, Vienna,        extravasation, angiogenesis, and matrix deposition and re-
Austria.                                                                    modeling. These features resemble those of wound healing,
Dr Schmidt-Erfurth is an inventor on the patent on the use of verteporfin   although they differ somewhat from the normal tissue repair
therapy in ocular neovascular disease under the guidelines of the Wellman   response.6 There is also increasing evidence that enhanced
Laboratories of Photomedicine, Harvard Medical School, Boston, Massa-
chusetts (institutional Patent Policy and Procedures).
                                                                            expression of vascular endothelial growth factor (VEGF)
*Correspondence and reprint requests to Albert J. Augustin, MD, Depart-
                                                                            may be responsible for vascular exudation and neovascu-
ment of Ophthalmology, Klinikum Karlsruhe, Moltkestrasse 90, 76133          larization in AMD.5 Photodynamic therapy itself, by trig-
Karlsruhe, Germany. E-mail: 106020.560@compuserve.com.                      gering the generation of free radicals and lipid peroxides,

14        © 2006 by the American Academy of Ophthalmology                                                   ISSN 0161-6420/06/$–see front matter
          Published by Elsevier Inc.                                                                            doi:10.1016/j.ophtha.2005.09.002
Augustin and Schmidt-Erfurth 䡠 Verteporfin PDT and Triamcinolone in CNV Secondary to AMD

may also contribute to the phototoxicity-induced VEGF                       ments in patients with choroidal neovascularization second-
expression that has been observed in collateral choroids                    ary to AMD.
after each photodynamic therapy application.7
    Steroids have a number of anti-angiogenic, antifibrotic,
and antipermeability properties that can contribute to the                  Materials and Methods
stabilization of the blood–retina barrier, resorption of exu-
dation, and downregulation of inflammatory stimuli (Kaiser                  Patients with all types of choroidal neovascularization secondary
PK, unpublished data). Intravitreal administration of corti-                to AMD were included in this prospective interventional case
costeroidlike triamcinolone acetonide (TA) has been used in                 series. Recruitment was drawn from patients who presented at a
a host of eye diseases, including AMD, diabetic macular                     tertiary referral center. At baseline, all patients underwent a stan-
edema, retinal vein occlusion, and uveitis, for its anti-                   dardized ophthalmological examination, including VA measure-
                                                                            ment using Snellen charts, slit-lamp and fundus examination, and
edematous and anti-angiogenic effects.8 Intravitreal TA                     assessment of IOP. Intraocular pressure was determined weekly
monotherapy has been found to increase visual acuity (VA)                   until 4 weeks, then in 6-week intervals. Fluorescein angiography
in patients with exudative AMD,8,9 although these benefi-                   (FA) was performed to identify lesion type and location and to
cial effects were transient. In addition, intravitreal TA and               determine whether active choroidal neovascularization leakage
photocoagulation were used successfully in the treatment of                 was present. Laser interferometry was used successfully to deter-
subfoveal recurrence of choroidal neovascularization.10                     mine retinal function before cataract surgery due to the ability to
Other studies using intravitreal TA monotherapy did not                     circumvent lens opacities.15 All patients were reevaluated every
show a similar effect.11,12                                                 12 weeks.
    A number of pilot studies have investigated the use of                      After oral informed consent was given, each participant signed
verteporfin photodynamic therapy in combination with in-                    a written consent form, which described the experimental nature of
                                                                            the triamcinolone procedure and potential risks. The study protocol
travitreal TA (Table 1).13,14 These studies have evaluated                  adhered to the European Good Clinical Practice Guidelines and the
the effects of 4 mg of intravitreal TA after verteporfin                    Declaration of Helsinki.
photodynamic therapy in patients with subfoveal or juxtafo-                     Photodynamic therapy with verteporfin (Visudyne, Novartis
veal choroidal neovascularization. All of these studies re-                 Ophthalmics, Basel, Switzerland) was performed according to the
ported positive VA outcomes and were associated with a                      recommended standard procedure.1,2 Within a mean of 16 hours
cessation of fluorescein leakage on angiography. The com-                   after photodynamic therapy (⫾1.5 hours), patients received retro-
bination was well tolerated, with treatable adverse effects                 bulbar anesthesia, and the ocular surface was disinfected using
such as cataract progression and a transient increase in                    polyvidone iodine solution. Retrobulbar anesthesia was used
intraocular pressure (IOP). However, there were few pa-                     to exclude eye movements and to avoid lens or retinal damage
tients in these studies, follow-up was limited, and lesion                  due to fixation problems of the eye. Twenty-five milligrams
                                                                            of preservative-free crystalline TA (prepared from Volon A,
types were not well defined. Thus, this therapeutic ap-                     Triamcinolon-Acetonide, Dermapharm AG, Grunwald, Ger-
proach, though promising, warrants further investigation.                   many) in a volume of 0.2-ml solution, was administered intra-
The aim of the present study is to provide preliminary                      vitreally through pars plana injection using a 27-gauge needle.
efficacy and safety data to help determine whether verte-                   Preservative-free TA was prepared by the institutional pharmacy
porfin photodynamic therapy combined with intravitreal TA                   using the method previously described by Jonas et al.8 The actual
can improve VA and reduce the overall number of treat-                      dose of administered TA was determined by high-performance

                Table 1. Pilot Studies of Verteporfin Photodynamic Therapy–Intravitreal Triamcinolone Acetonide

                   Author          No. of Patients         Visual Acuity Change            Follow-up          Retreatment Rate
               Spaide et al*           12                          2.4                     6   mos                   1.08
               Spaide et al*           11                          0.1                     6   mos                   0
               Spaide et al†           13                          2.5                    12   mos                   1.24
               Spaide et al†           13                          0.44                   12   mos                   1.2
               Rechtman et al‡         14             7% gained ⱖ30 letters               18   mos                   2.57
                                                      50% were stable
                                                      14% lost 15–29 letters
                                                      29% lost ⱖ30 letters
               Roth et al§             73 eyes        74–87% stable or improvement        Up to 6 mos     Up to 35% required one
                                                        of VA                                              additional treatment

               VA ⫽ visual acuity.
               *Spaide RF, Sorensen J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcin-
               olone acetonide for choroidal neovascularization. Ophthalmology 2003;110:1517–25.
               †
                 Spaide RF, Sorensen J, Maranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of
               triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2005;112:301– 4.
               ‡
                 Rechtman E, Danis RP, Pratt LM, Harris A. Intravitreal triamcinolone with photodynamic therapy for subfoveal
               choroidal neovascularization in age related macular degeneration. Br J Ophthalmol 2004;88:344 –7.
               §
                 Roth DB, Yarian DL, Green SN, et al. Intravitreal triamcinolone combined with photodynamic therapy for choroid
               neovascularization associated with age-related macular degeneration. Poster presented at: Association for Research in
               Vision and Ophthalmology Annual Meeting, April 27, 2004; Fort Lauderdale, Florida.

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Ophthalmology Volume 113, Number 1, January 2006

liquid chromatography measurement. The injection was performed                the 184 patients was treated and documented as the study eye.
using magnifying glasses and with dimmed room light; any direct               There were 67 males and 117 females, with a mean age of 76.5
light exposure of the treated eye was avoided. All injections were            years. The mean lesion size was 3553 ␮m (range, 500 –7700); in
administered in the operating room. A paracentesis was not re-                21 patients, the lesion size was ⱖ5400 ␮m (range, 5500 –7700).
quired for any of the procedures.                                                 The locations of the lesion as determined by FA were subfoveal
    Patients were scheduled for follow-up visits in 3-month inter-            in 148 eyes (80.4%), juxtafoveal in 19 eyes (10.3%), and extrafo-
vals and underwent identical examination procedures, including                veal in 17 eyes (9.2%). The mean VA at baseline was 20/125
best-refracted VA measurement, IOP documentation, slit-lamp and               (range, counting fingers–20/32).
ophthalmoscopic examination, and angiography. If patients                         Figure 1 presents data on the change in VA measured on
showed active choroidal neovascularization leakage at the time of             Snellen charts from baseline to the time of the last follow-up
the regularly scheduled 3-month follow-up visits, they were treated           visit and the change in VA as measured with laser interferom-
using verteporfin and TA as described above.                                  etry. There were significant mean increases in VA at both
    The primary efficacy variable was defined as change in VA                 temporal end points of 1.22 lines (P⬍0.01) and 1.43 lines using
from baseline to the last visit (median follow-up, 38.8 weeks                 the Snellen chart and laser interferometry (P⬍0.01), respec-
[range, 12–103]) as measured using Snellen VA charts. The mean                tively. The 148 patients with subfoveal choroidal neovascular-
VA at the final follow-up visit was compared with baseline mea-               ization experienced a significant mean increase of 1.14 lines
sures using the paired t test to test for statistical significance.           (P⬍0.01), and the 36 eyes with either juxtafoveal or extrafoveal
                                                                              choroidal neovascularization reported an even greater signifi-
                                                                              cant mean gain of 1.53 lines (P⬍0.05).
                                                                                  The majority of patients (n ⫽ 154 [83.69%]) required only 1
Results                                                                       combination treatment. Twenty-three patients (12.5%) received 2
                                                                              combination treatments, 6 (3.26%) received 3 treatments, and 1
A reduction in leakage was documented angiographically for clas-              patient (0.5%) received 4 treatments, due to persistent leakage
sic and occult components using Macular Photocoagulation Study                from the choroidal neovascularization lesion. The mean number of
and Treatment of Age-Related Macular Degeneration with Photo-                 combination treatments was 1.21 for the study eye.
dynamic Therapy criteria. Evaluation was done by an experienced                   One hundred twenty-seven eyes met the eligibility criteria for the
retinologist. The greatest linear diameter was measured if the                Treatment of Age-Related Macular Degeneration with Photodynamic
lesion was judged to be active. Optical coherence tomography                  Therapy study. The mean baseline VA of this specific group was
measurements were not a requirement in any of the verteporfin                 20/160. The mean increase in VA was 1.16 lines (P⬍0.01), and the
studies and were not added to the standard of photodynamic                    mean increase in VA using laser interferometry was 1.35 lines
therapy care in this trial. The response to treatment was indepen-            (P⬍0.01). A mean number of treatments of 1.26 was necessary.
dent of the location; subfoveal choroidal neovascularization (n ⫽             For lesions larger than 5400 ␮m, the entire lesion plus a safety
148) increased in VA by 1.14 lines, and juxtafoveal and subfoveal             margin of 1000 ␮m was covered by the treatment spot.
lesions increased by 1.53 lines. There was no difference in the
response regarding predominantly classic, minimally classic, or
occult lesions.                                                               Response in Different Lesion Types
    One patient (0.5%) had a follow-up of 12 weeks, 3 patients                Lesions responded in a uniform pattern to the combination treatment.
(1.6%) had a follow-up of 16 weeks, and 9 patients (4.9%) were                Independent of lesion composition and lesion size, leakage resolved
observed for a minimum of 3 months. All other patients were                   most intensively after the first administration; residual exudation
observed for 6 months and longer. The average change in vision in             disappeared with additional treatments. In predominantly classic le-
this group with extended follow-up was an increase of 1.2 Snellen             sions, leakage subsided after a single treatment (Fig 2). In minimally
lines.                                                                        classic lesion types, both the classic and the occult component re-
                                                                              sponded (Fig 3). In lesions with retinal angiomatous proliferation, the
Visual Outcome and Treatment Rate                                             retinal angiomatous proliferation complex became dry, and exudation
                                                                              into the surrounding tissue resolved completely (Fig 4).
A total of 184 patients with choroidal neovascularization second-                 Serous detachments of the retinal pigment epithelium (RPE)
ary to AMD were included in the study. The study eye of each of               disappeared over the course of several weeks (Fig 5). In combined

Figure 1. Change in visual acuity (VA) from baseline to the time of the last follow-up, documented by Snellen charts, and the last follow-up result,
documented with laser interferometry. There were significant mean increases in VA with both modalities: end points of 1.18 lines (P⬍0.01) and 1.38 lines
(P⬍0.01) using the Snellen chart and laser interferometry, respectively. logMAR ⫽ logarithm of the minimum angle of resolution.

16
Augustin and Schmidt-Erfurth 䡠 Verteporfin PDT and Triamcinolone in CNV Secondary to AMD

Figure 2. At baseline, a small subfoveal lesion with predominantly classic composition is delineated in early fluorescein angiography (FA) (A) and
demonstrates intensive exudation in late FA (B). After one combination treatment, the lesion is inactive, without neovascular features, in early (C) and
late (D) FA. Visual acuity increased from 20/40 to 20/25 over 12 months.

lesions of retinal angiomatous proliferation and a vascularized               vessel diameters and less capillary leakage. The occult component
RPE detachment (Fig 6), a granular pattern of window defects                  stopped leaking, and a slight granular RPE pattern associated
without any leakage was seen after a single photodynamic therapy.             with chronic occult lesions was noted by FA. The fibrotic
Juxtafoveal lesions became inactive, without further growth to-               neovascular branches were well perfused, but did not leak fluid
wards the center of the fovea.                                                during follow-up. Once absence of leakage was achieved, no
    Ophthalmoscopically, there was no difference seen compared                recurrence was noted. The RPE remained unchanged; no signs
with features known from verteporfin monotherapy. The retinal                 of increasing atrophy were seen clinically. Choriocapillary per-
transparency improved with resolving subretinal and intraretinal              fusion was unremarkable by standard FA, and retinal perfusion
fluid; no hemorrhage occurred in any of the treated eyes. Angio-              was not impaired.
graphically, the classic component of the choroidal neovascular-                  When treatment effects were related to lesion size, the mean
ization lesion became more mature in appearance, with larger                  improvement in VA was statistically significant in lesions smaller

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Ophthalmology Volume 113, Number 1, January 2006

Figure 3. In a minimally classic lesion, the area of the classic component identified early during fluorescein angiography (FA) (A) demonstrates more
intensive leakage than the occult portion in late FA (B). At 18 months and after a single treatment, the lesion appears inactive in early FA (C) and with
staining in late FA (D). Vision was 20/100 at baseline and returned to 20/40 during the entire follow-up.

than 4000 ␮m, whereas larger lesions maintained stable vision, but             Two patients whose IOP could not be controlled by topical
the improvement was not statistically significant.                             treatment underwent a successful cyclodestructive procedure
                                                                               and now have their IOP controlled without additional treatment.
                                                                               Cyclodestruction was considered a reliable and riskless proce-
Safety                                                                         dure in the elderly population; a single topical medication was
The treatment was generally well tolerated. Overall, 46 patients               used in all patients. Prostaglandin agents were avoided because
(25%) who did not have an increase in IOP (⬎25 mmHg without                    of the potential proinflammatory activity. All 12 patients (6.5%)
medication) at baseline required the use of topical antiglaucoma-              who had preexisting glaucoma continued their usual medica-
tous therapy due to a transient steroid-induced increase in IOP.               tion. Intraocular pressure was controlled and documented below
Twelve of those 46 patients had received IOP-lowering medication               25 mmHg. No glaucoma patient experienced a decompensation
already before their AMD treatment due to preexisting glaucoma.                of IOP.

18
Augustin and Schmidt-Erfurth 䡠 Verteporfin PDT and Triamcinolone in CNV Secondary to AMD

Figure 4. A retinal angiomatous proliferation (RAP) lesion with feeder vessels was identified in early-phase fluorescein angiography (FA) (A) with
leakage into the surrounding retina (B) leading to a visual acuity of 20/125. C, Three months after combination therapy, the lesion has become atrophic
and demonstrates staining without active leakage. Twelve months after combination therapy, the RAP component is atrophic (D), and leakage has
subsided (E). Vision has improved to 20/50.

    In the present study, 31.5% (48.73% of the phakic eyes) of the            juxtafoveal choroidal neovascularization. Paper presented
treated eyes experienced cataract progression or underwent cata-              at: Association for Research in Vision and Ophthalmology
ract surgery during the mean follow-up period of 43 weeks. No                 Annual Meeting, April 27, 2004; Fort Lauderdale, Florida).
patient experienced inflammation or endophthalmitis.                          Additionally, the mean number of treatments needed during
                                                                              a mean follow-up period of 43 weeks was a low 1.21. This
                                                                              study includes a population of eyes with all types of cho-
Discussion                                                                    roidal neovascularization and clearly demonstrates the im-
                                                                              provement in mean VA through the follow-up period of up
Our results suggest that verteporfin photodynamic therapy                     to 103 weeks. There was no significant change in mean VA
combined with intravitreal TA is beneficial in the treatment                  beyond the 6-month interval, as lesions were generally
of all choroidal neovascularization subtypes secondary to                     inactive after a mean of 1.21 treatments. The VA increase
AMD in our patient population regarding VA outcomes and                       observed was achieved during early follow-up and demon-
the need for retreatment.                                                     strated a plateau during extended follow-up. Therefore, the
    Visual acuity improved in the majority of patients, con-                  length of follow-up is not considered to have an important
sistent with the results of small studies using verteporfin                   influence on outcome. Limitations of this study are clearly
photodynamic therapy combined with intravitreal TA in                         its interventional character, noncomparative nature, and
various choroidal neovascularization subgroups13,14 (Roth                     variability in follow-up. However, because this is the largest
DB, Yarian DL, Green SN et al. Intravitreal triamcinolone                     case series available so far, the information provided may be
combined with photodynamic therapy for choroid neovas-                        used to design subsequent comparative prospective studies.
cularization associated with age-related macular degenera-                        To study the mechanism of combination therapy in more
tion. Paper presented at: Association for Research in Vision                  detail, further studies may address issues such as quantifi-
and Ophthalmology Annual Meeting, April 27, 2004; Fort                        cation of leakage by angiography or optical coherence to-
Lauderdale, Florida) (Spaide RF. Combined photodynamic                        mography measurements of lesion growth and other ana-
therapy with verteporfin and intravitreal triamcinolone for                   tomical features.

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Ophthalmology Volume 113, Number 1, January 2006

Figure 5. A, Baseline fluorescein angiography images demonstrate a small occult component centrally associated with a large serous pigment epithelial
detachment (PED) in the upper portion of the lesion. B, Exposure of the central component to one standard photodynamic therapy and intravitreal
triamcinolone leads to resolution of leakage and disappearance of the PED within 3 months. C, Resolution of leakage and a stable angiographic appearance
are maintained throughout 18 months’ follow-up. Visual acuity has recovered from 20/125 to 20/50.

   Verteporfin photodynamic therapy alone is effective in                     be as high as 5.6 over 2 years in a recent study of classic
the treatment of choroidal neovascularization secondary to                    subfoveal choroidal neovascularization.4 There are several
AMD. However, the number of retreatments necessary for                        hypotheses for the persistence of choroidal neovasculariza-
persistent choroidal neovascularization closure was found to                  tion and the need for additional treatments after photody-

Figure 6. A deep retinal angiomatous complex (A) is embedded within a fibrovascular pigment epithelial detachment (PED) (B); vision is reduced to
20/100. C, After one treatment, the retinal angiomatous proliferation (RAP) component has disappeared, as seen on the 3-month angiogram. The lesion
remains inactive throughout follow-up, and visual acuity of 20/63 is documented at the 12-month visit. D, The RAP component is absent in early
fluorescein angiography (FA). E, No leakage is seen during late FA.

20
Augustin and Schmidt-Erfurth 䡠 Verteporfin PDT and Triamcinolone in CNV Secondary to AMD

namic monotherapy. One of the mechanisms of photody-               cularization subtypes and not pretreated with photodynamic
namic action with verteporfin is the production of free            therapy, the mean change in VA was an improvement of 2.4
radicals, which are themselves part of a major pathogenic          lines, with only 1 patient requiring additional treatment.14 In
process of choroidal neovascularization induction. Further,        addition, Rechtman et al showed that, after a median follow-up
after the initial stages of the photodynamic therapy reaction      of 18 months in 14 patients with various choroidal neovas-
and oxidation- or ischemia-induced (and oxidation-induced)         cularization subtypes, combination therapy resulted in vi-
expression of VEGF, VEGF receptor 3 and pigment epithe-            sion gain in 7%, stabilization in 50%, and vision loss in 43%
lium– derived factor can occur in the photodynamic thera-          of all patients, with a treatment rate of 2.6 during the first
py–treated areas.5 This effect may result in another, longer       year.13 Another obvious benefit is the lower number of
lasting stimulus for neovascular growth and leakage. In            retreatments necessary, 1.2, versus 5.6 in the Treatment of
experimental studies, photodynamic therapy was shown to            Age-Related Macular Degeneration with Photodynamic
induce a rapid inflammatory response, including infiltration       Therapy trial. However, these differences should be evalu-
of leukocytes and increased expression of cytokines (e.g.,         ated in a randomized trial.
intracellular adhesion molecule 1, interleukin 6).16 An interval      We observed that verteporfin photodynamic therapy
of 18 hours between verteporfin photodynamic therapy and           combined with intravitreal TA was well tolerated. How-
application of intravitreal TA was selected because a com-         ever, it must be emphasized that the use of intravitreal
plete establishment of the inflammation cascade requires           TA is still experimental and that the experience from its
about 16 hours.16 –18                                              use in various conditions is based on small uncontrolled
    Corticosteroids have antiproliferative, antiinflammatory,      studies.24 Potential complications of intravitreal TA in-
and angiostatic effects and the ability to reduce vascular         clude cataract progression, increased IOP,8,11,13,22,25,26
exudation.19 –21 The rationale for the present study was to        and, rarely, endophthalmitis.25,27
combine verteporfin photodynamic therapy with an appro-               Rechtman et al, using 4-mg intravitreal TA, observed
priate antiinflammatory and anti-angiogenetic drug to an-          that 3 of 6 phakic eyes developed cataract.13 In another
tagonize VEGF expression and inflammatory reactions in             study with 4-mg intravitreal TA and laser treatment, no
the subacute phase after photodynamic therapy. Although            significant effect on cataract progression was observed.10
the mode of action of TA is not known with certainty,              The expected rate of cataract development in this elderly
promising results have been obtained with intravitreal TA
                                                                   patient population should also be kept in mind when eval-
alone in the treatment of various intraocular proliferative,
                                                                   uating the risk of cataract progression with intravitreal TA.
edematous, and neovascular diseases.8 –10,22,23
                                                                      Transient increase in IOP was observed de novo in 34
    The majority of studies have reported beneficial ef-
                                                                   patients (18.4%) in our study, whereas 12 patients (6.5%)
fects on VA from the use of either 4 mg9,10,22,23 or 25
                                                                   were already undergoing treatment for raised IOP. The
mg8,12 of intravitreal TA. However, in the case of AMD
                                                                   transient increase in IOP was controlled by topical anti-
associated with choroidal neovascularization, the effect
was mostly anatomical and did not translate into func-             glaucoma medications, although 2 patients required sur-
tional improvement. Intravitreal TA inhibited neovascu-            gery for persistent increased IOP. Our results are consis-
lar growth in an experimental model of laser-induced               tent with previous studies, which have observed elevated
choroidal neovascularization, a model of limited value             IOP in 25% to 50% of patients treated with intravitreal
for age-related choroidal neovascularization.21 In pa-             TA22,25,26,28 and were usually controlled with topical
tients with subfoveal and juxtafoveal choroidal neovas-            medication alone.22,25,26
cularization, a single administration of intravitreal TA              The rarely reported adverse effect of noninfectious
resulted in 55% stabilization, but 33% of eyes experi-             endophthalmitis has been attributed to the content of benzyl
enced vision loss.23 In predominantly occult lesions, 69%          alcohol in the original formulation of TA.29 We did not
in the intravitreal TA group had stable or improved                observe any form of endophthalmitis or even mild inflam-
lesions on fundus FA, compared with 29% in the control             mation in our study, probably because we removed the
group, with only minor effects on vision outcome.22 A              alcohol before intravitreal TA administration.
single 4-mg intravitreal TA injection in classic choroidal            In conclusion, there is a need for more effective thera-
neovascularization lesions reduced lesion growth at 3              peutic options for choroidal neovascularization secondary to
months but showed no significant difference in lesion              AMD. With monotherapy, using either verteporfin photo-
growth or vision outcome at 12 months.11 After using a             dynamic therapy or one of the anti-VEGF therapies cur-
high dose of 25 mg of intravitreal TA in a single patient          rently approaching regulatory approval, the need for multi-
with occult choroidal neovascularization, VA improved              ple retreatments and the lack of significant improvement in
after each injection but tended to reduce to the base-             vision are major concerns. Therefore, future treatments
line VA with time.12 It thus seems that intravitreal TA            are likely to include combinations of verteporfin photody-
alone is not effective in achieving persistent absence             namic therapy with corticosteroids, angiostatic steroids, or
of choroidal neovascularization leakage or even vision             anti-angiogenic/antipermeability drugs. Our results, which
stabilization.                                                     showed improved VA for the majority of patients and a
    Early results of using a combination of photodynamic           reduced need for additional treatments, are consistent with
therapy and intravitreal TA suggest the potential to improve       those reported in previous publications. We recommend that
visual outcomes while reducing treatment rates. Spaide et al       prospective, randomized, controlled studies be conducted to
reported that, in 13 patients with various choroidal neovas-       confirm our observations.

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Ophthalmology Volume 113, Number 1, January 2006

References                                                                     neovascularisation in age related macular degeneration. Br J
                                                                               Ophthalmol 2004;88:344 –7.
                                                                         14.   Spaide RF, Sorenson J, Maranan L. Combined photodynamic
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