Age-related macular degeneration (AMD) is the leading cause of severe visual loss in people over 50 years of age. In the Beaver dam eye study,1 Blue mountains eye study2 and the Rotterdam study report3 the prevalence rates are 1.7% in the US, 1.4% in Australia and 1.2% in Netherlands respectively. The Arvind comprehensive eye study found out an age-adjusted prevalence of 3.1% which rapidly increased with age.4
Approximately 50-60% of patients with advanced AMD develop severe visual acuity (VA) loss within five years. The loss of central vision caused by choroidal neovascularization (CNV) due to AMD has a profound impact on the quality of life of affected patients.
Photodynamic therapy (PDT) using verteporfin is the standard therapy in patients with subfoveal CNV due to neovascular AMD.567 But, visual outcomes, as described by the treatment of AMD with PDT (TAP), are not very satisfactory.6 Reactivation and persistence of CNV is not uncommon and frequent retreatments may be required which often compromises the success of therapy.
Intravitreal triamcinolone acetonide (IVTA) by virtue of its antiangiogenic and anti-inflammatory property has been shown to be efficacious for the treatment of exudative AMD both in animal models and human trials.89101112 A number of pilot studies have investigated the use of combined PDT with verteporfin and IVTA.111213141516171819 The majority of these studies reported positive VA outcomes. Spaide et al.13 Augustin et al.16 reported that combined PDT and IVTA therapy achieves better results in AMD-associated CNVs by reducing the frequency of PDT treatments needed to stop CNV growth and by improving visual outcome. Thus this therapeutic approach appears to be a promising one for subfoveal CNVs due to AMD.
The aim of this study was to analyze the results of VA and contrast sensitivity in Indian eyes having subfoveal CNV due to wet AMD one year after treatment with PDT along with IVTA.
Materials and Methods
Twenty-three eyes of 23 consecutive patients were enrolled in the study. All were diagnosed as CNV with subfoveal involvement due to wet AMD. All the participating patients signed an informed consent. To be eligible for the study, patients had to have CNV under the geometric center of the fovea with the lesion less than 5000 mm in the greatest linear dimension (GLD). No restriction as to the type of CNV (predominantly classic, minimally classic or occult) was made. Those patients who were treated earlier with laser or PDT and who had other macular pathologies were excluded from this study. Each patient underwent distance VA measurement using an early treatment diabetic retinopathy study chart (ETDRS), Snellen's chart and contrast sensitivity measurement by Pelli Robson's chart, an ophthalmic examination including slit-lamp biomicroscopy using +90D lens.
The diagnosis of CNV was based on clinical evaluation, fundus fluorescein angiography (FFA), indocyanine green angiography in some cases and optical coherence tomography (OCT) (Zeiss Stratus OCT Model 3000).
Patients were treated with standard PDT using verteporfin (visudyne) comprising a 10-min intravenous infusion of verteporfin 6 mg/m2 body surface area followed by activation 10 min later by a 689 nm diode laser delivering energy of 50J/cm2 at an intensity of 600 mw/ cm2 for 83 seconds using a spot size with a diameter 1000 micron larger than GLD of the lesion. Any area of hypofluorescense due to overlying blood or a serous detachment of the retinal pigment epithelium (RPE) contiguous with CNV was considered to be part of GLD of the lesion. Each patient was instructed to wear protective sunglasses and not to expose their eyes and exposed body surfaces to sunlight for the next 48h. They were then given an intravitreal injection of 4 mg of triamcinolone acetonide one week later (Kenacort 40 mg/ml) at the superotemporal quadrant 3.5 to 4.0 mm posterior to the limbus maintaining a strict asepsis protocol. Patients were observed closely for any adverse effects. If the intraocular pressure (IOP) exceeded 24 mmHg at any time period, the patients were given topical medication to reduce the IOP.
All the patients were examined at one-month, three-month, six-month and one-year intervals for distance VA measurement using both ETDRS and Snellen's chart and contrast sensitivity measurement by Pelli Robson's chart. FFA was done at baseline and at three months only to determine the effect of PDT along with IVTA. The OCT was repeated at three months, six months and one year. The decision to retreat with PDT along with IVTA was based on the appearance of leakage on angiography and OCT. Visual improvement or deterioration was defined as ³ 2 lines change and stabilization as < 2 lines change. Improvement in contrast sensitivity was defined as increase in contrast sensitivity score by 0.15 or more on Pelli Robson charts.
Descriptive statistics to determine mean, standard deviation and frequency distribution was performed using SPSS. The ETDRS VA was converted into corresponding log mar values. To see significant trend within the variable ET (log mar value of ETDRS VA) two ways ANOVA with post hoc analysis and pairedttest for contrast sensitivity were used. P value < 0.05 was considered to be statistically significant.
Twenty-three eyes of 23 patients were enrolled in the study (12 male, 11 female, mean age 65 ± 4.7 years). Of these 23 eyes 14 (61%) were of classic type, seven (30%) were of occult type and the remaining two (10%) were of the minimally classic type. Table 1 shows the baseline demographics, baseline, six months and 12 months VA and contrast sensitivity values.
Initial VA ranged from 20/32 to 20/800 (mean 20/170) and final VA ranged from 20/40 to 20/500 (mean 20/130) at the end of one year of follow-up. The mean baseline VA in ETDRS log mar value was 0.765 (SD=0.3511), the mean baseline contrast sensitivity value was 0.633 (SD=0.467). All the patients underwent one-year follow-up. Repeat PDT along with IVTA was done in three eyes (13%).
The mean VA changed to 0.691(SD=0.277) at the end of six months and to 0.700 (SD=0.28) at the end of one year of follow-up (P = 0.097 relative to baseline, repeated measures two-way analysis of variance test) [Fig. 1]. The VA stabilized in 19 (82%) eyes and two eyes (9%) had a loss of two lines or more at 12 months' follow-up. Two patients (9%) had an improvement of two lines or more.
The mean contrast sensitivity value improved to 0.743 (SD=0.469) at the end of six months follow-up and to 0.757 (SD=0.43) at the end of one year follow-up. (P < 0.001, relative to baseline). Contrast sensitivity also improved in 16/23 eyes (70%) while it remained the same in five eyes (21%) and deteriorated in the remaining two (10%) eyes [Fig. 2]. There were no significant changes in either VA or contrast sensitivity between six months and one year as is evident from Figs. 1 and 2.
Fig. 3a and b show the baseline FFA and OCT of an eye with subfoveal CNV. Fig. 4a and b show one year post PDT+IVTA of the same eye.
Lesion type, patient age had no influence on the outcome; however, on multiregression analysis baseline VA had a borderline statistically significant correlation with final VA (P=0.059) - that is eye with better baseline VA was more likely to have better final VA outcomes. The median number of PDT+ IVTA was one (mean 1.26, range 1 to 3).
In six eyes (27%), an increase in IOP was observed which required medication. There were no cases of endophthalmitis. Four eyes (18%) developed visually significant cataract which required surgery at six to nine months following combination therapy possibly as a complication of IVTA. Postsurgery VA improved to precataract level of vision.
With longer follow-ups cataract occurrence in a few treated eyes remains a possibility.
Although the advent of PDT with verteporfin has dramatically modified our management of CNV, the mechanism of preferential endothelial injury, angio-occlusion and obliteration of the neovascular network does not address the underlying pathogenetic drive of angiogenic stimulation. Thus, reperfusion of obliterated vessels and up-regulation of vascular endothelial growth factor (VEGF) occurs, with consequent loss of vision.21 Reducing vascular reperfusion and in combination use of an anti-VEGF and anti-inflammatory agent should significantly alter the vision loss as well as decrease the number of PDT retreatments. In the TAP and verteporfin in PDT (VIP) studies, which examined the effect of PDT with verteporfin, patients experienced mean changes in VA of -2.2 lines in the TAP study and -3.1 lines in the VIP trial for patients with occult and no classic CNV at one year.67
Our understanding of choroidal neovascularization continues to evolve. Formerly, it was assumed that a defect/break in the Bruch's membrane was necessary for new vessels to gain access to the sub-pigment epithelial space, but we now understand that choriocapillary budding can penetrate the Bruch's membrane. The angiogenic drive is VEGF-derived from RPE cells and recruited macrophages and possibly photoreceptor fragments.2223 Arresting the initiation or reactivation of choriocapillary neovascularization by modifying the angiogenic cascade either via VEGF (blocking VEGF receptors or inactivating the VEGF molecule by ranibizumab/bevacizumab) or further down the intracellular sequence (anecortave acetate) is the rationale behind the use of VEGF inhibitors.24
Triamcinolone acetonide has been used to modify the process of choroidal neovascularization.1112 Corticosteroids have a multitude of anti-inflammatory effects and also seem to have direct anti-angiogenic properties. Steroids have an inhibitory effect on angiogenesis, fibrotic activity and inflammatory reaction by reducing the migration and activation of inflammatory cells. Up-regulation of extracellular matrix protein plasminogen activator inhibitor by steroids results in a direct angiostatic effect. Besides steroids down-regulate intercellular adhesion molecule (ICAM) expression, an important stimulus in the development of CNV and an inflammatory mediator released by PDT. Corticosteroids also stabilize endothelial and basement membranes and reduce vascular permeability with beneficial effects.
Combination therapy of PDT along with IVTA enhances PDT effects, both in terms of visual outcome and in angiographic response. Early decrease in vision during the first three months is usually not observed with combination therapy as compared with monotherapy. Recanalization and recurrence rates are also reduced. Retinal sensitivity recovers quickly with improvement of the central visual field. The PDT provides immediate angio-occlusion of CNV and IVTA prevents inflammation and up-regulation of VEGF, decreases subsequent regrowth of CNV and finally improves VA outcome. This provides reasons for using both verteporfin and triamcinolone together in combination.
Several pilot human trials13141516 have investigated the combination of verteporfin therapy and IVTA in patients with CNV due to AMD. Spaide et al.13 investigated the combination of verteporfin therapy and IVTA in both group of patients who had not previously been treated with PDT and patients who had received previous courses of verteporfin therapy. They found that newly treated patients had a mean improvement of 2.5 lines, 12 months after combination therapy, while patients in the prior PDT group had a mean improvement of 0.44 lines only. The number of retreatments also was lesser in the newly treated group compared to the prior PDT group. Augustin et al.16 reported a mean increase of 1.22 Snellen lines in 184 eyes with CNV secondary to AMD after a median follow-up of 39 weeks with the mean number of treatments of 1.21.
In our present study VA stabilized in 19/23 eyes (82%) while two eyes improved by two or more lines. Only two eyes lost two or more lines of vision. The improvement in contrast sensitivity was also statistically significant. The mean number of treatments in our study was 1.26 during the one-year follow-up period. This is quite low as compared to the treatment numbers reported in VIP study (3.1) and TAP (5.6) studies.
The improvement in VA and contrast sensitivity as shown in our study point to the promising effect of the combination of verteporfin therapy and IVTA. The number of retreatments was also significantly lower than expected in monotherapy trials.
The timing of the injection remains controversial. Various studies have injected triamcinolone at various times in relation to verteporfin therapy. While Spaide et al.13 injected IVTA immediately after verteporfin therapy others have injected triamcinolone either one week after or before verteporfin therapy. Media opacification, either partial or significant, by the crystals or the inflammation from the diluent can make PDT difficult and pretreatment with IVTA one week prior could result in this problem. Treatment on the same day has the advantage of simplicity for the patient, but it is important to ensure that a sterile contact lens gel and lens is used to minimize the risk of endophthalmitis. There is potential problem of modifying the natural vascular repair of "healthy' vessels affected by the PDT. As the goal of the IVTA is to prevent revascularization and subsequent neovascularization, it can be injected one week post PDT. There is no clear trend from the reported cases, nor experimentally, to guide us on timing-prior to, on the day of or a week following PDT. In our study we injected IVTA one week post PDT. In conclusion, the currently available evidence suggests that the risk-benefit ratio favors the combination of PDT with IVTA to reduce the number of retreatments and optimize the final vision. However, no definite conclusions can be made through this interventional case series as it has several limitations including small sample size, lack of randomization and absence of control group.
There is a need for more effective therapeutic options for choroidal neovascularization secondary to AMD. With monotherapy, using either PDT or one of the anti-VEGF drugs, the need for multiple retreatments and the lack of significant improvement in vision are major concerns. Therefore, future treatments are likely to include combinations of verteporfin PDT with corticosteroids, angiostatic steroids or anti-VEGF drugs. Our results, which showed improved VA for the majority of our patients and a reduced need for additional treatments, are consistent with those reported in previous publications. Economic considerations also favor the use of combination therapy in our country.
Source of Support:
Conflict of Interest:
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