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Combined Photodynamic Therapy and Intravitreal Triamcinolone Acetonide Injection for Neovascular Age-Related Macular Degeneration With Pigment Epithelium Detachment
Abstract
To report the outcome of combined verteporfin photodynamic therapy (PDT) and intravitreal triamcinolone acetonide (IVTA) for the treatment of choroidal neovascularization (CNV) with serous pigment epithelium detachment (PED) due to age-related macular degeneration (AMD).
The files of all consecutive patients with CNV and serous PED who received PDT and IVTA either primarily (primary treatment group) or following previous unsuccessful PDT (secondary treatment group) were reviewed for visual and angiographic results.
Ten patients (11 eyes) were included. Mean number of PDT sessions was 3.18; 8 eyes received one IVTA injection and 3 eyes received two IVTA injections. Thirty-six percent of patients retained their initial visual acuity after a mean follow-up of 15.3 months. Loss of 3 or more Snellen lines was noted in 2 of 3 eyes in the primary treatment group and 5 of 8 eyes in the secondary treatment group. Increased intraocular pressure developed in 3 patients and was controlled by topical medications.
Although combined PDT and IVTA may be considered for CNV with serous PED in patients with poor prognosis with PDT alone, the regimen as administered in this small series was not beneficial. Further studies are required to determine whether alternate sequences, timing, or doses would yield a better outcome.
... American Journal of Ophthalmology Case Reports 9 (2018) [18][19][20][21][22] Heidelburg Spectralis OCT in-built software. CMT was obtained by measuring the distance between the foveal depression (if significant IRF, the expected area of depression) and Bruch's membrane. ...
... [13][14][15][16][17] Results with photodynamic therapy have been unsatisfactory, 6-8 even when combined with triamcinolone acetonide. 18 With the era of anti-VEGF treatments, attempts have been made to treat with intravitreal bevacizumab, ranibizumab, and aflibercept. Studies evaluating intravitreal bevacizumab have shown minimal effect on PED size. ...
Purpose
This pilot study evaluated the combination of photodynamic therapy (PDT) and anti-vascular endothelial growth factor (anti-VEGF) as a treatment in patients with a pigment epithelial detachment (PED) due to exudative age-related degeneration (AMD).
Methods
We analyzed seven consecutive patients between September 1, 2015 and September 1, 2017 with a PED secondary to exudative AMD who were treated with full fluence standard PDT and a series of monthly intravitreal anti-VEGF injections. Follow-up ranged between 3 and 24 months. Variables collected for the purpose of this study included baseline best-corrected visual acuity converted to logMAR (logarithm of minimum angle of resolution), central macular thickness, and maximum PED height. This information was then reviewed at subsequent follow-ups.
Results
The PED completely resolved in 4/7 eyes while three patients had a significant improvement in PED size with a corresponding improvement in visual acuity. Initial PED heights ranged from 147 to 423 μm and was reduced by an average of 255.7 μm (83.2% average reduction, range −143 to - 405 μm). Initial CMT ranged from 223 to 719 μm and was reduced by an average of 225.7 μm (54.4% average reduction, range −88 to - 529 μm). Mean logMAR VA improved from 0.669 (Snellen equivalent 20/93, [20/40 to 20/200]) to 0.269 (Snellen equivalent 20/37, [20/25 to 20/80]) at last follow-up. No complications were observed in our patients.
Conclusions and Importance
PED in the setting of exudative AMD showed an excellent response to a combined multimodal approach that includes PDT with intravitreal anti-VEGF injection followed by a monthly anti-VEGF schedule. Most importantly, visual acuity showed a significant improvement from baseline. If confirmed by future studies, this would offer another treatment avenue for this difficult-to-treat consequence of exudative AMD.
... Even if the course of the disease in terms of vision could not be changed significantly, the number of required PDT treatments could be reduced. 18,19 In addition, the effectiveness of intravitreously injected VEGF inhibitors has been analysed in clinical studies. [20][21][22][23] However, the results of all the different therapeutic procedures have not been compared up to now. ...
... Only some authors have described post-therapeutic visual loss associated with this treatment modality, whereas most authors report a higher rate of stabilization of both BCVA and morphological changes. 18,19,33 We can confirm these results of significant stabilization of vision during a follow-up period of 24 weeks. Nevertheless, the rate of RPE ruptures still remained high. ...
To investigate the therapeutic effects of different treatments on serous pigment epithelium detachment (PED) in age-related macular degeneration (AMD).
A total of 328 patients suffering from serous PED in AMD were retrospectively analysed. We treated only patients with documented visual deterioration: 86 patients with bevacizumab, 128 with ranibizumab, 60 with pegaptanib, and 54 with photodynamic therapy (PDT) combined with intravitreal triamcinolone acetonide (IVTA). Best-corrected vision was determined in the logarithm of the minimal angle of resolution (logMAR). We also analysed morphological findings such as full foveal thickness by optical coherence tomography (OCT), manually calculated height of PED as measured by OCT, and fluorescence angiography.
The mean follow-up was 42.4 weeks. The best-corrected visual acuity of 0.78 logMAR before treatment could be improved by about 0.066 logMAR after treatment. Retinal thickness decreased in all patients with PED, in the mean by about 64.06 microm, and the mean value of the manually calculated height decreased by about 0.98 units. All functional and morphological results proved to be significantly better after injection of ranibizumab and bevacizumab than after pegaptanib and the combined treatment with PDT and IVTA. In all, 41 (12.5%) of our patients developed a tear of the retinal pigment epithelium (RPE).
The therapeutic results were significantly better in patients treated with bevacizumab and ranibizumab than in those treated with pegaptanib or with a combination of PDT and IVTA. Even with treatment, tears of the RPE or only a partial flattening of the PED always indicated a worse prognosis in eyes with exudative AMD than in eyes with classic choroidal neovascularization.
... More recently, publications have appeared on the use of combination therapy in exudative AMD. A number of studies have demonstrated improved outcomes for patients with this disorder treated with combination of laser therapy, anti-VEGF agents and triamcinolone acetonide (TA) [8][9][10]. ...
Background: Although a variety of approaches are available for treating retinal pigment epithelial detachment (PED) associated with age-related macular degeneration (AMD), no unified methodology has yet been approved and/or overwhelmingly favored. Purpose: To investigate the effect of a long-acting steroid on the structural and functional RPE features in serous PED associated with AMD in long-term follow-up study, and to improve the efficacy of treatment of this disorder through the use of steroid therapy based on the findings of this investigation. Materials and Methods: Fifty-two patients (54 eyes) with serous PED associated with AMD were followed up for 36 months. They were divided into subtenon and intravitreal groups comprising 30 patients (32 eyes) and 22 patients (22 eyes), respectively, and treated with 0.5 ml (40 mg) subtenon triamcinolone acetonide (TA) suspension and 0.1 ml (4 mg) intravitreal TA crystals, respectively, as needed. Results: We found significant reductions in the height and length of PED in the intravitreal group (from 486 (SD 187) μm to 256 (SD 139) μm, P = 0.005; and from 1859 (SD 911) μm to 1112 (SD 451) μm, P = 0.04, respectively) and in the subtenon group (from 446 (SD 199) μm to 231 (SD 107) μm, P = 0.0001; and from 2055 (SD 587) μm to 1423 (SD 465) μm, P = 0.02, respectively). In study eyes, the visual acuity remained stable throughout the 36-month follow-up period, irrespective of the route of administration of TA. Conclusion: The use of subtenon and intravitreal TA in serous PED associated with AMD is efficacious for maintaining the anatomical structure of the retina.
... Many treatments, such as laser photocoagulation and PDT have been used to treat PED that is associated with ARMD. In PDT studies, it has been reported that the VA of patients did not increase and that, in some cases, the patient's VA decreased due to the development of RPE tears, depending on the treatment or the natural course of the disease (14,15) . Consequently, on the basis of the association between PED and inflammation, IVTA treatment was added to the PDT. ...
Pigment epithelial detachment (PED) may be seen in all stages of age-related macular degeneration (ARMD) and may lead to poor prognosis. In this study, we retrospectively examined the effect of anti-VEGF treatments in ARMD patients with vascularized PED.
Medical records of 15 patients with PED secondary to ARMD were reviewed retrospectively. The diagnosis of PED was made with fundoscopy, fundus fluorescein angiography and optical coherence tomography. Patients were treated with intravitreal ranibizumab or/and bevacizumab and followed up for a minimum of one year. PED height and best corrected visual acuity (BCVA) was obtained before the first intravitreal anti-VEGF injection and again at the 1st, 3rd, 6th and 12th month after the injection.
The mean baseline BCVA was 0.71 ± 0.48 logarithm of the minimal angle of resolution (logMAR) unit and the mean baseline PED height was 361 ± 153 µ. The mean injection count per eye was 3.9 ± 2.9. There was a significant reduce in mean PED height (247 ± 177 µ) also in 2 eyes PED completely resolved at the end of the follow up period. The mean BCVA at 12th month (0,69 ± 0,37) were not different from the baseline record.
This retrospective case series showed that intravitreal anti-VEGF therapy preserved vision and reduced PED height in PED patients in a one-year follow-up period.
... [3][4][5][6] The management of patients with PED secondary to AMD is controversial due to the difficulty in specifying the presence of underlying CNV. 4 In addition, therapeutic options for PED are limited and usually provide poor outcome. [7][8][9][10][11][12] Recently, agents inhibiting the activities of the vascular endothelial growth factor (VEGF), such as ranibizumab, bevacizumab and pegaptanib have been used for the treatment of CNV in patients with AMD. [13][14][15] This prospective study reports the efficacy of intravitreal ranibizumab (Lucentis, Novartis, Basel, Switzerland) monotherapy as a treatment for serous and vascular PEDs associated with exudative AMD (CNV-PED). ...
To report the effect of intravitreal ranibizumab therapy for serous and vascular pigment epithelial detachments (PED) associated with choroidal neovascularisation (CNV) secondary to age-related macular degeneration (AMD).
In a prospective study, best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) data were collected for 62 eyes of 62 patients, with serous or vascular PED associated with CNV secondary to AMD. Intravitreal ranibizumab 0.5 mg was administered with a loading phase of three consecutive monthly injections, followed by monthly review with further treatment, as indicated according to the retreatment criteria of the PrONTO study. The change in visual acuity and PED height from baseline to month 12 after the first injection was determined.
Sixty-one eyes of 61 patients (one of the patients developed retinal pigment epithelial tear and was excluded from the study) were assessed at the 12-month follow-up examination. There were two types of PED, including vascular PED in 32 patients (Group A) and serous PED (Group B) in 29 patients. The mean improvement of mean BCVA from baseline to 12 months was 0.09 logMAR (Logarithm of the Minimum Angle of Resolution) in Group A and 0.13 logMAR in Group B. Both groups showed significant improvement of the mean BCVA 12 months after the first injection compared with the baseline value (P < 0.05). In relation to the PED height, the mean decrease of mean PED height from baseline to 12 months was 135 μm in Group A and 180 μm in Group B. Both groups showed significant reduction of the PED height during the follow-up period (P < 0.01). The PED anatomical response to ranibizumab was not correlated with the BCVA improvement in any of the groups. Apart from one patient who developed pigment epithelial tear no other complications were documented.
Ranibizumab is an effective and safe treatment for improving vision in patients with serous and vascular PED, although the anatomical response of the PED to ranibizumab may not correlate directly with the visual outcome.
... In contrast, other groups 19,20 have reported that PDT with verteporfin conferred little treatment benefit, even when combined with intravitreal triamcinolone acetonide. 21 In these trials, treatment was also complicated by subretinal hemorrhage and RPE tears. ...
Luis AriasDepartment of Ophthalmology, Bellvitge University Hospital, Barcelona, SpainPurpose: Evaluate the efficacy of pegaptanib, a selective anti-vascular endothelial growth factor (VEGF) agent, and bevacizumab, a nonselective anti-VEGF agent, for retinal pigment epithelial detachment (PED) associated with occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).Methods: Prospective, comparative, nonrandomized pilot study included patients with PED comprising >50% of total lesion in subfoveal location with visual acuity (VA) 20/40–20/400 and lesions either previously untreated or treated only with photodynamic therapy/verteporfin. Seven patients received pegaptanib 0.3 mg intravitreally (IVT); eight received IVT bevacizumab 1.25 mg. Follow-up occurred every 4–6 weeks for 6 months. Reinjection of initial medication occurred if there was intra- or subretinal fluid observed by optical coherence tomography (OCT) or increased PED. Endpoints were mean changes from baseline to month 6 in VA (ETDRS) and foveal thickness.Results: At baseline, mean VA was lower, and mean foveal thickness was greater in pegaptanib versus bevacizumab-treated patients (36.1 vs 49.5 letters; 470.4 vs 321.1 μm). Mean improvements to month 6 in VA and foveal thickness were greater for pegaptanib (VA: +9.1 vs +7.2 letters; foveal thickness: −88.2 vs −52.9 μm). On average, pegaptanib-treated patients had slower but more sustained improvement in VA and foveal thickness; bevacizumab-treated patients showed rapid improvement with a slow return towards baseline. Both agents were well tolerated. Conclusion: Intravitreal injections of pegaptanib or bevacizumab are both efficacious and safe treatments for PED associated with occult CNV secondary to AMD.Keywords: bevacizumab, pegaptanib, retinal pigment epithelial detachment
... In contrast, other groups 19,20 have reported that PDT with verteporfin conferred little treatment benefit, even when combined with intravitreal triamcinolone acetonide. 21 In these trials, treatment was also complicated by subretinal hemorrhage and RPE tears. ...
Evaluate the efficacy of pegaptanib, a selective anti-vascular endothelial growth factor (VEGF) agent, and bevacizumab, a nonselective anti-VEGF agent, for retinal pigment epithelial detachment (PED) associated with occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
Prospective, comparative, nonrandomized pilot study included patients with PED comprising >50% of total lesion in subfoveal location with visual acuity (VA) 20/40-20/400 and lesions either previously untreated or treated only with photodynamic therapy/verteporfin. Seven patients received pegaptanib 0.3 mg intravitreally (IVT); eight received IVT bevacizumab 1.25 mg. Follow-up occurred every 4-6 weeks for 6 months. Reinjection of initial medication occurred if there was intra- or subretinal fluid observed by optical coherence tomography (OCT) or increased PED. Endpoints were mean changes from baseline to month 6 in VA (ETDRS) and foveal thickness.
At baseline, mean VA was lower, and mean foveal thickness was greater in pegaptanib versus bevacizumab-treated patients (36.1 vs 49.5 letters; 470.4 vs 321.1 mum). Mean improvements to month 6 in VA and foveal thickness were greater for pegaptanib (VA: +9.1 vs +7.2 letters; foveal thickness: -88.2 vs -52.9 mum). On average, pegaptanib-treated patients had slower but more sustained improvement in VA and foveal thickness; bevacizumab-treated patients showed rapid improvement with a slow return towards baseline. Both agents were well tolerated.
Intravitreal injections of pegaptanib or bevacizumab are both efficacious and safe treatments for PED associated with occult CNV secondary to AMD.
... There was no considerable difference in the mean gain of VA between eyes with ICS at baseline and eyes with SRF and PED after 3 months. In their small series of 11 eyes, Axer-Siegel et al. (2006) reported a poor outcome after PDT and IVTA combination therapy for eyes diagnosed with CNV and PED. Ting et al. (2002) determined the preva- lence and visual significance of cystoid macular oedema in eyes with neovascular AMD using OCT. ...
To identify characteristic morphological changes of the retina over time and the association with visual function after combined photodynamic therapy (PDT) and intravitreal triamcinolone (IVTA).
In this retrospective study, 40 patients (40 eyes) were treated with PDT and same-day IVTA. Optical coherence tomography (OCT), fluorescein angiography (FA) and evaluation of distance visual acuity (VA) were performed. The anatomical changes within intra- and subretinal compartments and their detailed analysis and grading were the main outcome measures.
Intraretinal fluid (IRF) and subretinal fluid (SRF) by OCT decreased until 3 months (p < 0.01). At month 3, intraretinal cystoid spaces (ICS) had resolved or decreased in 84% of eyes, SRF in 58% and pigment epithelial detachment (PED) in 50%. Mean best-corrected VA (BCVA) improved significantly at month 1 (p < 0.01). Mean central retinal thickness (CRT) increased from 334 microm at baseline to 439 microm at day 1 (p = 0.03) before decreasing to 286 microm at day 7 (p = 0.06), 233 microm at month 1 (p = 0.001) and 255 microm at month 3 (p = 0.001).
Combined verteporfin/IVTA therapy induces distinct time-related effects on the retina within the different intra- and subretinal compartments.
... These studies indicate that combined treatment as a first line of management reduces the need for multiple sessions of PDT, avoids further vision loss and improves visual acuity. However, reduction in visual acuity of three or more Snellen lines was noted in two studies.28,31 Except one,30 all of the published studies were nonrandomized. ...
Age-related macular degeneration (AMD) is now considered an important and leading cause of blindness among elderly patients in developed and developing countries. AMD has two forms, dry and wet; both can lead to visual loss. However, occurrence of subfoveal choroidal neovascular (CNV) membrane in the wet form results in severe visual impairment.
Treatment options for choroidal neovascularization are available in order to maintain and in some cases improve vision. Photodynamic therapy (PDT) has been used to treat both classic and occult membranes. It has known to cause choroidal hypoperfusion and production of vascular endothelial growth factor.
Intravitreal steroid can possibly reduce the damage caused due to these undesirable effects. In the recent past, intravitreal injection of triamcinolone acetonide (IVTA) has been used extensively as an adjunct to PDT in AMD in order to reduce the number of PDT sessions and evaluate possible beneficial effects on vision.
This article reviews the pharmacological attributes of triamcinolone, available evidence of its use as monotherapy or combination therapy to treat AMD, ocular side-effects thereof and ongoing clinical trials on IVTA.
The basic conditions in the management of exudative age-related macular degeneration have changed considerably since the last statement of the German professional associations in 2006. While Pegaptanib was approved in Germany already in 2006 Ranibizumab was approved for the treatment of exudative macular degeneration in Germany in February 2007. More over the quality assurance regulations for the photodynamic treatment of choroidal neovascularizations with Verteporfin were modified including the treatment of occult lesions and implementing a simplified classification of extra- and subfoveal lesions. Consequently modification of the recommendations for the non-surgical treatment of exudative age-related macular degeneration appeared inevitable.
Background
To evaluate the efficacy and safety of intravitreal bevacizumab injections in patients with pigment epithelial detachments (PEDs) secondary to age-related macular degeneration (AMD).
Material and methods
In a retrospective interventional case series, 62 eyes of 61 patients were treated with 1.5 mg bevacizumab intravitreally. Baseline and follow-up visits included best-corrected visual acuity and optical coherence tomography (OCT) examinations. Follow-up visits were performed 1, 3, and 6 months after initial treatment. Morphological effects on PED were quantified by repetitively measuring the highest elevation on two perpendicular OCT cross-sections. If height of PED was increased by 50 microns, or intraretinal fluid appeared or increased, or visual acuity decreased more than 5 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, patients were reinjected.
Results
On OCT, PED decreased from 346 ± 148 µm at baseline to 241 ± 159 µm (p < 0.001) at 1 month, 227 ± 193 µm (p < 0.001) at 3 months, and 166 ± 170 µm (p < 0.001) at 6 months. Mean best corrected visual acuity (BCVA) increased from 49 ± 18 letters at baseline to 52 ± 21 letters (p = 0.062) at 1 month. However, 3 and 6 months after initial injection mean BCVA returned to baseline levels (3 months: 49 ± 19 letters, p = 0.518; 6 months: 49 ± 20 letters, p = 0.053). On average, patients received 2.5 injections during the observation period of 6 months. Except for one retinal pigment epithelial (RPE) tear no other ocular or systemic adverse events were noticed. Ocular inflammation was not found in any of the investigated patients.
Conclusions
The presented data demonstrate a therapeutic effect of intravitreal bevacizumab in patients with specific classes of pigment epithelial detachments secondary to AMD.
Photodynamic therapy with verteporfin was the first approved pharmacological treatment for choroidal neovascularization in patients with age-related macular degeneration, pathologic myopia and ocular histoplasmosis syndrome. With the introduction of anti-VEGF therapy, verteporfin photodynamic therapy is no longer the first line of treatment for neovascular age-related macular degeneration. Ongoing clinical trials will determine the future role of PDT alone or as part of a more individualized combination therapy.
Purpose:
To assess the effects of intravitreal ranibizumab injection in patients affected by pigment epithelial detachment associated with occult subfoveal choroidal neovascularization.
Design:
Prospective, interventional case series.
Methods:
Participants:
Forty eyes of 40 patients were considered for the purpose of the study. Consecutive patients were recruited for a 24-month study. All patients underwent a complete ophthalmic examination, including best-corrected visual acuity on Early Treatment Diabetic Retinopathy Study (ETDRS) charts. After a 3-monthly loading phase, further intravitreal ranibizumab injections were administered on the basis of detection of any type of fluid on optical coherence tomography.
Primary outcome measures:
Changes in mean best-corrected visual acuity at 12 and 24 months and the proportion of eyes losing fewer than 15 letters (corresponding to 3 ETDRS lines) from baseline visual acuity.
Secondary outcome measures:
Changes in central macular thickness on optical coherence tomography and variation in mean area of the entire lesion.
Results:
Forty patients were included. Mean best-corrected visual acuity decreased from 20/66 (58 ETDRS letters) to 20/83 (53 letters) at 12 months and 20/112 (489 ETDRS letters) at 24 months (P = .003). Eighty percent and 67.5% of eyes lost fewer than 3 lines at 12 and 24 months, respectively. Mean central macular thickness passed from 545 μm to 428 μm at 12 months and 426 μm at 24 months. Mean lesion area changed from 6826 μm(2) to 6312 μm(2) at 12 months and 6010 μm(2) at 24 months.
Conclusions:
The treatment of pigment epithelial detachment associated with occult subfoveal choroidal neovascularization with intravitreal ranibizumab injection after a 3-monthly loading phase and pro re nata strategy can lead to partial results over a 24-month follow-up. Further investigations are warranted to establish the best therapeutic approach to this disease.
To review vascularized-pigment epithelial detachment (V-PED) treatment visual outcome, and to assess acute retinal pigment epithelium (RPE) tear incidence.
One hundred and thirty-two eyes of 125 consecutive patients with age-related macular degeneration and V-PED were included. Ninety-four eyes (71.2%) were associated with choroidal new vessels (CNV), 38 (28.8%) with retinal angiomatous proliferation (RAP). Patients, treated over a 10-year period with the time-current therapy, received: verteporfin photodynamic therapy (PDT) (group 1, 38 eyes), combined intravitreal triamcinolone acetonide (IVTA) and PDT (group 2, 44 eyes) or intravitreal anti-VEGF injection (bevacizumab or ranibizumab) (group 3, 50 eyes).
Mean follow-up was 20.5 months. At month 12, all eyes treated with PDT or with IVTA and PDT showed a mean significant severe visual decrease. Eyes with CNV lost -0.67 and -0.37 logMAR (p < 0.01 and p < 0.01 respectively), and eyes with RAP -0.55 and -0.31 logMAR (p < 0.01 and p = 0.01 respectively). RPE tear occurred in 14 eyes (36.8%) and in six eyes (13.6%) in groups 1 and 2 respectively. Eyes treated with anti-VEGF therapy showed slight mean visual acuity decrease at month 12. Those with CNV had a mean baseline best-corrected visual acuity (BCVA) of 0.36 ± 0.24 logMAR, final of 0.44 ± 0.30 logMAR (-0.08 logMAR, n.s.). In eyes with RAP, mean baseline BCVA was 0.58 ± 0.39 logMAR, final was 0.78 ± 0.47 logMAR (-0.20 logMAR, n.s.). RPE tear occurred in 14 eyes (36.8%). Patients with either V-PED with CNV or a better baseline BCVA showed greater risk of acute RPE tear (p = 0.01 and p = 0.003 respectively).
Effective treatment for vascularized PED is still lacking. Until now, only stabilization of the disease has been achieved using anti-VEGF therapy, but the risk of RPE tear can further hamper our expectations. Baseline characteristics are helpful for prognosis, but patients must be informed of the uncertain response. New therapeutic strategies are needed.
Triamcinolone acetonide (TA) is one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The most important effects of TA consist in the stabilisation of the blood-retinal barrier and the down-regulation of inflammation. TA also has anti-angiogenic and anti-fibrotic properties. The peculiar characteristic of being well tolerated by ocular tissues and the capability to remain active for many months after a single intravitreal injection, make this drug a safe and effective alternative. In the past decade, intravitreal injection of TA (IVTA) has emerged as a useful treatment of several ocular diseases such as uveitis, macular edema secondary to retinal vasculature disease, neovascularisation and vitreoretinopathy. In this paper, we review all the available evidence of its use in AMD as mono-therapy or in combination with other treatments, and we discuss which role TA will play in the treatment of AMD in the future. The first experiences with IVTA as monotherapy for the treatment of exudative AMD reported a positive outcome in transiently reducing the leakage from CNV. However, in the long-term follow-up, IVTA as monotherapy had no effect on the risk of severe visual acuity loss, despite a significant anti-angiogenic effect found 3 months after the treatment. Consequently, studies using the combination of IVTA and photodynamic therapy (PDT), which acts synergistically, were performed. They reported to improve vision and to reduce the number of re-treatments with PDT. A large number of publications confirmed the positive synergic role of combining TA and PDT (therapies) for the treatment of all types of CNV: classic or predominantly classic, occult or minimally classic and RAP (Retinal Angiomatous Proliferation) lesions. The advantages registered with the use of IVTA plus PDT compared to PDT alone were partially limited by the side effects, such as the rapid evolution of cataract. Nevertheless, cataract surgery may stimulate the development of CNV (result in stimulating CNV). However, in large, randomized, clinical trials on combination therapy of TA and PDT, visual acuity failed to show an improvement, even though the lesion size and subretinal fluid had decreased, compared to controls treated with PDT alone. Some authors reported an increased risk of developing macular atrophy after the combination therapy with IVTA and PDT. Reduction of the PDT fluence rate in association with the use of steroids resulted in reducing the risk of macular atrophy and in a better visual acuity outcome. The introduction of anti-VEGF-based drugs has revolutionized the treatment of AMD and has replaced all the previous therapies used for CNV. Visual improvement becomes an expectation in a higher proportion of patients, previously limited to minimizing vision loss. Anti-VEGF therapy also resulted in superior visual improvement compared to all types of combination therapy with IVT and PDT. Nevertheless, anti-VEGF monotherapy also has many limitations due to the need of repetitive treatments, increased costs and tachyphylaxis. Treatment regimens involving TA in combination therapy with anti-VEGF and PDT may preserve benefits for substantially longer periods. A question remains open on whether a combination treatment with anti-VEGF, triamcinolone and/or PDT may be a treatment option in patients with exudative AMD, by offering, with one cycle of therapy, functional VA benefits comparable to those observed with continued monthly anti-VEGF therapy. Further trials, of higher scientific significance, are needed to study the potential of these treatment options.
The purpose of this study was to evaluate the effect of intravitreally administered bevacizumab on untreated vascularized pigment epithelium detachment (PED) in sub- or juxtafoveal occult choroidal neovascularization as a result of age-related macular degeneration.
In this retrospective study, 28 untreated eyes of 26 patients (4 men, 22 women; mean age, 74.6 ± 7.2 years) with PED and sub- or juxtafoveal occult choroidal neovascularization as a result of age-related macular degeneration and additional intra- and/or subretinal fluid were treated with intravitreal injections of 1.25 mg bevacizumab. Baseline and follow-up visits included best-corrected visual acuity, complete ophthalmic examination, and Stratus optical coherence tomography. Fluorescein angiography was performed at baseline. Reinjections were performed if intra- and/or subretinal fluid persisted or recurred or PED increased.
Patients received 3.2 ± 1.8 injections (follow-up 37.9 ± 18.3 weeks). Mean maximum PED height showed a tendency to decrease (372 ± 150.5 μm to 290.3 ± 189 μm; P = 0.094). In 14 eyes (53.8%), PED height was reduced at last visit, including complete flattening in 1 eye. Mean visual acuity remained stable (0.58 ± 0.30 logarithm of the minimum angle of resolution to 0.58 ± 0.37 logarithm of the minimum angle of resolution; P = 0.905). Pigment epithelium detachment response to treatment did not correlate with baseline PED height or visual acuity at baseline or at the last visit. One patient sustained a retinal pigment epithelium rip, and another patient sustained an extensive subretinal hemorrhage.
During bevacizumab therapy, mean PED height decreases in 50% of patients. No predictive factors for the response of PED to bevacizumab treatment could be identified. Treatment of PED with bevacizumab might result in a long-term functional benefit compared with the natural course.
To evaluate the efficacy of combined photodynamic therapy (PDT) and intravitreal bevacizumab injection in eyes with a serous pigment epithelial detachment (PED) associated with age-related macular degeneration (AMD).
Twenty-two eyes with a serous PED exceeding two disc areas associated with AMD with choroidal vascular abnormalities [choroidal neovascularization (n = 10), polypoidal choroidal vasculopathy (n = 9), and retinal angiomatous proliferation (n = 3)] received combined PDT and intravitreal bevacizumab, and were followed about every 6 weeks for more than 1 year. Additional treatments were given for residual or recurrent lesions. The main outcome measures were changes in the PED height measured by optical coherence tomography, and the best-corrected visual acuity.
After one treatment, the PED resolved in 12 eyes (55%) and the PED decreased in ten eyes (45%). There was no recurrence in eight (36%) eyes; however, PED recurred in 14 eyes. At 1 year, the average PED height decreased to 413 microns from the baseline 751 microns (p < 0.001). Twenty eyes (91%) had improved or stabilized vision; two eyes had decreased vision due to a retinal pigment epithelial tear and subretinal hemorrhage.
Combined PDT and intravitreal bevacizumab may decrease the PED height and stabilize visual acuity at 1 year.
Vascular endothelial growth factor (VEGF) is a potent peptide growth factor specific for vascular endothelial cells, which promotes neovascularization and increases vascular permeability in vivo. Enhanced microvascular permeability and edema are common characteristics of inflammatory and neoplastic disorders. Two proinflammatory mediators, platelet-activating factor (PAF) and platelet-derived growth factor (PDGF), are known to contribute to cellular damage and tissue remodeling in a number of lung diseases. To determine whether PAF or PDGF induce VEGF gene expression in primary cultures of human pulmonary fibroblasts and pulmonary vascular smooth-muscle cells (VSMCs), we performed Northern-blot analysis and enzyme-linked immunosorbent assays (EIA). PAF and all three isoforms of PDGF (PDGF-AA, -AB, and -BB) increased VEGF mRNA in a time- and dose-dependent manner. While PAF was shown to increase VEGF mRNA at picomolar concentrations, all PDGF isoforms were effective in inducing VEGF mRNA at nanomolar concentrations. The transcriptional activation was accompanied by increased levels of VEGF protein as determined by EIA in culture medium. These results indicate that VEGF gene expression in VSMCs and fibroblasts is mediated by PAF and/or PDGF isoforms. In a paracrine mode of action, secreted VEGF may then lead to altered endothelial cell functions and vascular hyperpermeability. In the presence of the corticosteroids cortisone, hydrocortisone, dexamethasone, or prednisolone at nanomolar concentrations, this stimulus-dependent transcription of VEGF was abolished. The inhibitory effect of corticosteroids on VEGF expression could explain the clinically well-known antiedematous potency of corticosteroids on a molecular level.
Vascular endothelial growth factor (VEGF) is a potent neovascular inducer. Gene therapeutic delivery of a plasmid DNA encoding VEGF has been shown to impart collateral vessel development in animal models of hindlimb ischemia. Constitutive, long-lived expression of VEGF through gene transfer, however, may result in hypervascularization and/or leaky blood vessels. To that end, the introduction of regulated VEGF gene transfer technology may provide a safer and more controlled therapy for ischemic tissues. We developed a glucocorticoid-regulated plasmid vector (pNGVL-hAP/GRE(5)-vegf-pA) for modulating VEGF gene expression. This plasmid possessed five tandem repeats of the glucocorticoid-responsive element and adenovirus major-late promoter driving the expression of the VEGF(165) cDNA. Intramuscular delivery of this plasmid to mice, and subsequent treatment with the synthetic glucocorticoid dexamethasone (DEX), led to greatly enhanced VEGF expression. Similar delivery to the gracillis muscle of New Zealand white rabbits that had undergone ligation of their femoral artery to induce ischemia exhibited increased VEGF expression and collateral vessel development only in the presence of DEX. Additionally, reintroduction of DEX at a time point during which initial VEGF transgene levels had subsided resulted in a vigorous reinduction of VEGF transgene expression. This new iteration of VEGF gene delivery provides for fine-tuned angiogenic factor-based therapy for tissues requiring neovascularization.
To evaluate the effect of photodynamic therapy (PDT) on perfusion and vascular integrity of choroidal neovascularization (CNV) and collateral physiological choroid.
In a prospective clinical trial, patients with subfoveal CNV were treated with PDT and verteporfin. Indocyanine green angiography (ICG-A), using a confocal laser scanning system with tomographic sections, was performed continuously 1 week before and 1, 4, and 12 weeks after and a mean long-term follow-up of 16.5 months after the final PDT. Vascular changes were localized tomographically and quantified on the level of the CNV and collateral choroid according to early lesion size, late hyperfluorescence, and persistence or recurrence. Data were analyzed separately from 38 eyes in a single- and 12 eyes in a multiple-treatment regimen.
CNV lesions were significantly reduced in size and late hyperfluorescence. However, 54% of lesions primarily demonstrated persistence, typically of the choroidal feeding complex, which was only detectable by ICG-A. Regrowth from the feeding vessel occurred regularly, but did not reach baseline dimensions. Collateral choroid exposed to photoactivation exhibited choriocapillary occlusion. Progressive recanalization was documented within 4 to 12 weeks after both single and multiple PDT. Residual changes in the choroidal filling pattern often persisted during long-term follow-up.
Tomographic ICG-A after PDT reveals persistence of CNV and/or the feeder vessel and a reduction in perfusion within the entire photosensitized area, including the surrounding choroid. Repair mechanisms occur slowly in neovascular and normal choroidal structures.
To determine the eligibility for laser photocoagulation treatment or for photodynamic therapy (PDT) with verteporfin in eyes at the earliest stage (first month of symptoms) of exudative age related macular degeneration (AMD) based on fluorescein angiographic (FA) features; to evaluate the potential contribution of indocyanine green angiography (ICG-A) for occult choroidal neovascularisation (CNV) at this stage.
Retrospective review of 252 consecutive patients (269 eyes) examined within the first month of symptoms of exudative AMD.
On FA, 97 eyes (36%) had classic CNV alone. Occult CNV associated with fibrovascular retinal pigment epithelium detachments (PEDs) was observed in 71 eyes (26%) and without fibrovascular PED in 101 eyes (38%). 91 eyes (34%) met the Macular Photocoagulation Study criteria for laser photocoagulation. 53 eyes (20%) met the Verteporfin In PDT (VIP) or Treatment of AMD with PDT (TAP) studies criteria. By ICG-A, occult CNV was visualised as focal spots in 49% of eyes examined within 15 days v 32% of eyes examined between 16 and 30 days after the onset of symptoms (p=0.07). 8.5% of late staining plaques disclosed in eyes examined within 15 days were combined with focal spots v 36% in eyes examined between 16 and 30 days (p<0.01).
Early examination of eyes with exudative AMD would allow the treatment of 47% of eyes. 60% of eyes with subfoveal CNV would be eligible for PDT with verteporfin. Up to half of eyes with occult CNV would be converted by ICG-A into well delineated focal spots.
To report the effects of intravitreal triamcinolone acetonide (iTAAC) injections as an adjunctive treatment to photodynamic therapy (PDT) with verteporfin for new subfoveal choroidal neovascularisation (CNV) in age related macular degeneration (AMD).
We retrospectively reviewed the records of all AMD patients who had iTAAC within 6 weeks of their first PDT and had a follow up of one year or longer. The proportion of eyes after one year follow up that lost or gained >or=15 and >or=30 ETDRS letters, baseline and one year lesion greatest linear dimension (GLD), number of PDTs, and side effects were assessed.
Fourteen patients were evaluated. Eleven received one initial combined treatment and three received an additional combined treatment after 6 months. Median follow up was 18 months (range 12 to 25 months). Overall, 7% gained >or=30 letters, 50% maintained stable vision, 14% lost 15-29 letters, and 29% lost >or=30 letters. Overall, mean GLD increased from 2580 (SD 1088) microm to 3946 (SD 1503) micro m (p = 0.01). The mean number of PDTs during the first year was 2.57. Side effects were mild intraocular pressure elevation in 28.5% and cataract progression in 50% of phakic eyes.
iTAAC with PDT in AMD was found to be relatively safe and had reasonable results for lesions with some classic component.
Aim
To evaluate the effect of intravitreal triamcinolone acetonide on the visual acuity of patients with exudative age related macular degeneration, to assess the duration of a possible effect, and to evaluate clinical side effects of the treatment.
Methods
The study included 67 patients (71 eyes) who presented with exudative age related macular degeneration of predominantly or total occult type (n = 68) or classic type (n = 3), and who received once, or repeatedly, an intravitreal injection of 25 mg of crystalline triamcinolone acetonide. Mean follow up time was 7.46 (SD 3.54) months (range 3.1–19.57 months).
Results
Visual acuity increased significantly (p <0.001) from 0.16 (0.11) to a mean maximum of 0.23 (0.17). Postoperative visual acuity was highest 1–3 months after the injection. 47 (66.2%) eyes gained in maximal visual acuity and 11 (15.5%) eyes lost in visual acuity. Intraocular pressure increased significantly (p <0.001) from 15.1 (3.1) mm Hg at baseline to a maximal value of 23.0 (8.25) mm Hg. At the end of follow up, intraocular pressure again decreased significantly (p<0.001) to 16.8 (4.9) mm Hg. No cases of postoperative infectious endophthalmitis, rhegmatogenous retinal detachment, or proliferative vitreoretinopathy occurred. Owing to a decrease in visual acuity after an initial increase, six patients received a second intravitreal triamcinolone acetonide injection after which visual acuity increased again in three eyes.
Conclusions
Intravitreal injection of 25 mg of crystalline triamcinolone acetonide merits further study for the treatment of exudative age related macular degeneration.
Purpose:
To evaluate the use of digital indocyanine green videoangiography in patients with clinical and fluorescein angiographic evidence of "occult" choroidal neovascularization in age-related macular degeneration and to investigate indocyanine green videoangiography-guided laser photocoagulation as a therapeutic approach.Methods:
Three hundred forty-seven consecutive patients with exudative age-related macular degeneration and symptoms and clinical manifestations of occult choroidal neovascularization were studied with indocyanine green videoangiography. Patients were selected for laser treatment, using conventional guidelines, when indocyanine green videoangiography demonstrated a well-delineated area of hyperfluorescence, presumed to be a focal area of choroidal neovascularization.Results:
Seventy-nine (23%) of 347 eyes were found to have a localized and definable lesion that was potentially amenable to laser photocoagulation therapy; 44 (56%) of these 79 treated eyes had complete resolution of their exudative manifestations. Visual acuity improvement was noted in 10 (13%) of 79 eyes, and stabilization of vision achieved in 42 eyes (53%).Conclusion:
Laser photocoagulation treatment guided by indocyanine green videoangiography was shown to produce promising anatomical and visual improvement in a small number of patients with occult choroidal neovascularization secondary to age-related macular degeneration. This pilot study warrants further research to investigate the efficacy and safety of this form of treatment.
Purpose:
To determine if photodynamic therapy with verteporfin (Visudyne; Novartis AG, Bülach, Switzerland), termed verteporfin therapy, can safely reduce the risk of vision loss compared with a placebo (with sham treatment) in patients with subfoveal choroidal neovascularization caused by age-related macular degeneration who were identified with a lesion composed of occult with no classic choroidal neovascularization, or with presumed early onset classic choroidal neovascularization with good visual acuity letter score.
Methods:
This was a double-masked, placebo-controlled (sham treatment), randomized, multicenter clinical trial involving 28 ophthalmology practices in Europe and North America. The study population was patients with age-related macular degeneration, with subfoveal choroidal neovascularization lesions measuring no greater than 5400 microm in greatest linear dimension with either 1) occult with no classic choroidal neovascularization, best-corrected visual acuity score of at least 50 (Snellen equivalent approximately 20/100), and evidence of hemorrhage or recent disease progression; or 2) evidence of classic choroidal neovascularization with a best-corrected visual acuity score of at least 70 (better than a Snellen equivalent of approximately 20/40); assigned randomly (2:1) to verteporfin therapy or placebo therapy. Verteporfin (6 mg per square meter of body surface area) or placebo (5% dextrose in water) was administered by means of intravenous infusion of 30 ml over 10 minutes. Fifteen minutes after the start of the infusion, a laser light at 689 nm delivered 50 J/cm(2) by application of an intensity of 600 mW/cm(2) over 83 seconds using a spot size with a diameter 1000 microm larger than the greatest linear dimension of the choroidal neovascularization lesion on the retina. At follow-up examinations every 3 months, retreatment with the same regimen was applied if angiography showed fluorescein leakage. The main outcome measure was at least moderate vision loss, that is, a loss of at least 15 letters (approximately 3 lines), adhering to an intent-to-treat analysis with the last observation carried forward to impute for missing data.
Results:
Two hundred ten (93%) and 193 (86%) of the 225 patients in the verteporfin group compared with 104 (91%) and 99 (87%) of the 114 patients in the placebo group completed the month 12 and 24 examinations, respectively. On average, verteporfin-treated patients received five treatments over the 24 months of follow-up. The primary outcome was similar for the verteporfin-treated and the placebo-treated eyes through the month 12 examination, although a number of secondary visual and angiographic outcomes significantly favored the verteporfin-treated group. Between the month 12 and 24 examinations, the treatment benefit grew so that by the month 24 examination, the verteporfin-treated eyes were less likely to have moderate or severe vision loss. Of the 225 verteporfin-treated patients, 121 (54%) compared with 76 (67%) of 114 placebo-treated patients lost at least 15 letters (P =.023). Likewise, 67 of the verteporfin-treated patients (30%) compared with 54 of the placebo-treated patients (47%) lost at least 30 letters (P =.001). Statistically significant results favoring verteporfin therapy at the month 24 examination were consistent between the total population and the subgroup of patients with a baseline lesion composition identified as occult choroidal neovascularization with no classic choroidal neovascularization. This subgroup included 166 of the 225 verteporfin-treated patients (74%) and 92 of the 114 placebo-treated patients (81%). In these patients, 91 of the verteporfin-treated group (55%) compared with 63 of the placebo-treated group (68%) lost at least 15 letters (P =.032), whereas 48 of the verteporfin-treated group (29%) and 43 of the placebo-treated group (47%) lost at least 30 letters (P =.004). Other secondary outcomes, including visual acuity letter score worse than 34 (approximate Snellen equivalent of 20/200 or worse), mean change in visual acuity letter score, development of classic choroidal neovascularization, progression of classic choroidal neovascularization and size of lesion, favored the verteporfin-treated group at both the month 12 and month 24 examination for both the entire study group and the subgroup of cases with occult with no classic choroidal neovascularization at baseline. Subgroup analyses of lesions composed of occult with no classic choroidal neovascularization at baseline suggested that the treatment benefit was greater for patients with either smaller lesions (4 disc areas or less) or lower levels of visual acuity (letter score less than 65, an approximate Snellen equivalent of 20/50(-1) or worse) at baseline. Prospectively planned multivariable analyses confirmed that these two baseline variables affected the magnitude of treatment benefit. (ABSTRACT TRUNCATED)
Purpose: To evaluate the efficacy of indocyanine green angiography (ICGA)-guided laser photocoagulation in eyes with fluorescein angiographic evidence of occult choroidal neovascularization (O-CNV) in patients with age-related macular degeneration (ARMD) with or without pigment epithelium detachment (PED).
Methods: Eighty eyes of 79 consecutive patients with O-CNV underwent laser treatment of a clearly outlined extrafoveal ICGA hyperfluorescent area, presumed to be focal CNV. Four types of presumed CNV were treated: Group 1 (20 eyes), CNV beneath the PED; Group 2 (23 eyes), CNV at the margin of the PED; Group 3 (10 eyes), parapapillary CNV and PED; and Group 4 (27 eyes), macular CNV without PED. Median follow-up was 17.5 months (range, 6-24 months).
Results: After 1 year, 15% of the eyes in Group 1, 30% in Group 2, 100% in Group 3, and 52% in Group 4 had obliteration of the presumed CNV. After 1 year, visual acuity was stable or improved in 18% of Group 1, in 37.5% of Group 2, in 100% of Group 3, and in 73% of Group 4. The remaining eyes worsened.
Conclusions: Indocyanine green angiography-guided laser treatment may improve or stabilize visual acuity in some eyes with O-CNV. The best outcome is seen in eyes with presumed parapapillary CNV, probably made up of choroidal telangiectases in many cases. The type and location of the presumed CNV influence prognosis after laser treatment considerably. A randomized, controlled clinical study appears necessary to investigate the efficacy of ICGA-guided laser treatment in different types of presumed CNV. The inclusion criteria for further trials need to be defined with precision, as data from patients with different choroidal vascular abnormalities have been pooled until now.
(C) The Ophthalmic Communications Society, Inc.
Objective: To report 24-month vision and fluorescein angiographic outcomes from trials evaluating photodynamic therapy with verteporfin (Visudyne; CIBA Vision Corp, Duluth, Ga) in patients with subfoveal choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). Design: Two multicenter, double-masked, placebo-controlled, randomized clinical trials. Setting: Twenty-two ophthalmology practices in Europe and North America. Participants: Patients with subfoveal CNV lesions caused by AMD with greatest linear dimension on the retina measuring 5400 mum or less, with evidence of classic CNV and best-corrected visual acuity (approximate Snellen equivalent) between 20/40 and 20/200. Methods: The methods were similar to those described in our 1-year results,(1) with follow-up examinations beyond 1 year continuing every 3 months (except for Photograph Reading Center evaluations, which occurred only at month 18 and month 24 examinations). During the second year, the same regimen (with verteporfin or placebo as applied at baseline) was used if angiography showed fluorescein leakage from CNV. The primary outcome was the proportion of eyes with fewer than 15 letters (approximately 3 lines) of visual acuity loss at the month 24 examination, adhering to an intent-to-treat analysis. The last observation was carried forward to impute for any missing data. Results: Three hundred fifty-one (87%) of 402 patients in the verteporfin group compared with 178 (86%) of 207 patients in the placebo group completed the month 24 examination. Beneficial outcomes with respect to visual acuity and contrast sensitivity noted at the month 12 examination in verteporfin-treated patients we re sustained through the month 24 examination. At the month 24 examination for the primary outcome, 213 (53%) of 402 verteporfin-treated patients compared with 78 (38%) of 207 placebo-treated patients lost fewer than 15 letters (P<.001). In subgroup analyses for predominantly classic lesions (in which the area of classic CNV makes up at least 50% of the area of the entire lesion) at baseline, 94 (59%) of 159 verteporfin-treated patients compared with 26 (31%) of 83 placebo-treated patients lost fewer than 15 letters at the month 24 examination (P<.001). For minimally classic lesions (in which the area of classic CNV makes up <50% but >0% of the area of the entire lesion) at baseline, no statistically significant differences in visual acuity were noted. Few additional photosensitivity adverse reactions and injection site adverse events were associated with verteporfin therapy in the second year of follow-up. Conclusions: The visual acuity benefits of verteporfin therapy for AMD patients with predominantly classic CNV subfoveal lesions are safely sustained for 2 years, providing more compelling evidence to use verteporfin therapy for these cases. For AMD patients with subfoveal lesions that are minimally classic, there is insufficient evidence to warrant routine use of verteporfin therapy.
Fifty eyes of 40 patients with serous (avascular) detachments of the retinal pigment epithelium were followed up for an average of 22 months. Of the 50 eyes, 14 (28%) developed bleeding beneath the retinal pigment epithelium and retina or subretinal neovascularization detected on fluorescein angiography. These changes did not occur in eyes of patients younger than age 56 years at diagnosis or in detachments less than 1 disk diameter in size, whereas 35.9% (14) of eyes in patients older than age 56 years developed vascular complications. Vascular complications were uncommon when the initial detachment did not involve the fovea. Visual acuity declined in only one (9.1%) of eyes in patients younger than age 56 years but in 20 (51.3%) of eyes in patients age 56 years or greater.
One hundred ten patients with serous detachment of the retinal pigment epithelium (RPE) were reexamined to enhance our knowledge of the natural course of this condition. All patients were greater than 50 years of age, had age-related macular degeneration, and had neither blood, lipid, nor angiographic evidence of a definite choroidal neovascular membrane (NVM) at the time of the initial examination. All patients were followed up for at least six months except for two patients who had developed a choroidal NVM within the first six months of the initial exam. Forty-five of 140 eyes (32%) developed a choroidal NVM within an average of 19.6 months (median, 12 months). This was associated with a final visual acuity of 20/200 or worse (P less than 0.0001). Ophthalmoscopic and angiographic features present at the initial visit which were associated with the development of NVM and poor final visual acuity were: sensory retinal detachment; increased size of PED; hot spot; late filling; notching; and irregular filling. At the most recent examination, 39% of the eyes had a final visual acuity of 20/20 to 20/40, while 24% of the eyes had a final visual acuity of less than or equal to 20/200.
The natural history of 100 eyes of 93 patients with retinal pigment epithelial detachment (PED) and bilateral age-related macular degeneration (AMD) was retrospectively studied for a minimum of 12 months in the offices of Retina Consultants, Ltd. Detachment was defined as serous in 46 eyes, turbid in 12 eyes, hemorrhagic without evident neovascular membrane (NVM) in 20 eyes, and hemorrhagic with angiographically proven NVM in 17 eyes. Final visual results demonstrated visual acuity of 20/200 or worse in 33% of serous PED, 83% of turbid PED, and 89% of hemorrhagic PED. Despite strict inclusion criteria, 26% of serous PED developed NVM by one year and 49% of serous PED developed NVM by three years. Variables associated with NVM development in serous PED include older patient age, larger detachment size, presence of subretinal fluid at initial examination, and disciform scar in the fellow eye at presentation.
Occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is known to occur with and without an associated serous pigment epithelial detachment (PED). Digital indocyanine green (ICG) videoangiography has been reported to provide enhanced definition of occult CNV.
A total of 244 of 657 (37%) consecutive patients with AMD, with occult CNV and an associated serous PED evident on fluorescein angiographic examination, were further studied with ICG videoangiography.
On ICG videoangiographic examination, 9 of the 244 (4%) eyes had no evidence of underlying CNV, or essentially a pure serous PED. Each of the remaining 235 eyes (96%) had evidence of neovascularization and were defined as having a vascularized PED. These eyes were further divided into two groups, depending on the size and delineation of the neovascularization seen. Of the 235 eyes with vascularized PEDs, 89 (38%) had a solitary area of neovascularization that was well delineated, no more than one disc area in size, and defined as focal CNV. The other 146 (62%) eyes had a larger area of neovascularization, with variable delineation, defined as plaque CNV. Based on conventional guidelines, some patients were considered to be potentially eligible for laser photocoagulation treatment.
The results of this study suggest that ICG videoangiography may be an important adjunct to the diagnosis, classification, and potential treatment of patients with AMD and occult CNV associated with a serous PED (vascularized PED).
The authors have previously shown that photodynamic therapy (PDT) using lipoprotein-delivered benzoporphyrin derivative mono-acid (BPD) effectively closed experimental choroidal neovascularization (CNV). In the current study, the authors used a clinical preparation, liposomal BPD verteporfin in the same model, with experiments designed to establish optimal dye and light doses, and the timing of laser light irradiation after dye injection, for effective and selective closure of CNV.
Experimental CNV was induced in the maculae of cynomolgus monkeys. Liposomal BPD verteporfin was injected intravenously at doses of 1.0, 0.5, 0.375, and 0.25 mg/kg. Laser light at 692 nm then was applied to CNV, with an irradiance of 600 mW/cm2 and fluence of 150 J/cm2, at various times after dye injection, ranging from 5 to 120 minutes. Treatment effect was assessed by fundus photography and fluorescein angiography and confirmed by light and electron microscopy. The PDT of experimental CNV was studied to assess efficacy; PDT performance on normal eyes was studied to investigate selectivity.
The CNV closure was demonstrated by fluorescein angiography and histopathologic findings at all tested dye doses. A dye dose of 0.375 mg/kg, with laser light irradiation applied 20 to 50 minutes after dye injection, optimized CNV closure with minimal retinal and choroidal damage. No major local adverse effects were noted, and the drug was well tolerated systematically.
Liposomal BPD verteporfin is a potent photosensitizer, and PDT using this dye is a potentially effective and selective treatment for CNV.
To determine visual acuity outcome after indocyanine green angiography-guided laser photocoagulation of choroidal neovascularization associated with pigment epithelial detachment in eyes with age-related macular degeneration.
We retrospectively reviewed pretreatment and posttreatment visual acuity after laser photocoagulation to well-demarcated hyperfluorescent areas seen with indocyanine green angiography adjacent to or within pigment epithelial detachments in 20 eyes of 20 patients with age-related macular degeneration and suspected choroidal neovascularization.
Visual acuity before and after laser photocoagulation was followed up for 3 to 24 months (median, 9 months). At 3 months after laser photocoagulation, visual acuity had improved 2 or more Snellen lines in two eyes (10%), worsened by 2 or more lines in 10 (50%), and remained unchanged in eight of 20 (40%). By 6 months after laser photocoagulation, visual acuity had improved by 2 or more lines in two eyes (12%), worsened by 2 or more lines in nine (53%), and remained unchanged in six of 17 (35%). At 9 months after laser photocoagulation, visual acuity had improved by 2 or more lines in one eye (9%), worsened by 2 or more lines in nine (82%), and remained unchanged in one of 11 (9%).
Indocyanine green angiography-guided laser photocoagulation may temporarily stabilize visual acuity in some eyes with choroidal neovascularization associated with pigment epithelial detachments, but final visual acuity decreases with time.
To describe the indocyanine green angiographic pattern of retinal pigment epithelium tears in the setting of age-related macular degeneration compared with the fluorescein angiographic features.
Twelve consecutive patients (12 eyes) with a retinal pigment epithelium tear underwent simultaneous indocyanine green angiography and fluorescein angiography with the confocal scanning laser ophthalmoscope. The findings for the two modes were compared.
Choroidal neovascular membrane was evident beneath the rolled retinal pigment epithelium on indocyanine green angiograms in 11(92%) of 12 eyes: a focal neovascular membrane was apparent in five (42%) of 12 eyes, whereas a plaque neovascular membrane was seen in six (50%) of 12 eyes. In comparison, fluorescein angiography demonstrated late leakage as a result of occult choroidal neovascular membrane in nine (82%) of 11 eyes but no well-defined choroidal neovascular membrane.
Indocyanine green angiography is superior to fluorescein angiography for imaging choroidal neovascularization in cases of retinal pigment epithelium tear and may serve as an important adjunct to indocyanine green-guided laser treatment in selected cases.
To evaluate the efficacy of indocyanine green angiography (ICGA)-guided laser photocoagulation in eyes with fluorescein angiographic evidence of occult choroidal neovascularization (O-CNV) in patients with age-related macular degeneration (ARMD) with or without pigment epithelium detachment (PED).
Eighty eyes of 79 consecutive patients with O-CNV underwent laser treatment of a clearly outlined extrafoveal ICGA hyperfluorescent area, presumed to be focal CNV. Four types of presumed CNV were treated: Group 1 (20 eyes), CNV beneath the PED; Group 2 (23 eyes), CNV at the margin of the PED; Group 3 (10 eyes), parapapillary CNV and PED; and Group 4 (27 eyes), macular CNV without PED. Median follow-up was 17.5 months (range, 6-24 months).
After 1 year, 15% of the eyes in Group 1, 30% in Group 2, 100% in Group 3, and 52% in Group 4 had obliteration of the presumed CNV. After 1 year, visual acuity was stable or improved in 18% of Group 1, in 37.5% of Group 2, in 100% of Group 3, and in 73% of Group 4. The remaining eyes worsened.
Indocyanine green angiography-guided laser treatment may improve or stabilize visual acuity in some eyes with O-CNV. The best outcome is seen in eyes with presumed parapapillary CNV, probably made up of choroidal telangiectases in many cases. The type and location of the presumed CNV influence prognosis after laser treatment considerably. A randomized, controlled clinical study appears necessary to investigate the efficacy of ICGA-guided laser treatment in different types of presumed CNV. The inclusion criteria for further trials need to be defined with precision, as data from patients with different choroidal vascular abnormalities have been pooled until now.
The glucocorticoid hormones and their synthetic derivatives are potent suppressors of inflammatory and allergic pathologies. Their widespread efficacy is the result of multiple modes of action occurring predominantly at the level of the microcirculation. Indeed the glucocorticoids interfere with the function of all of the cellular components of the microcirculation associated with an inflammatory response. These agents inhibit vasodilatation of the arteriolar and capillary beds. therefore preventing the increase in blood flow that characterizes the initial stages of the inflammatory response. They also prevent increases in vascular permeability in the capillary and post-capillary venule, thereby reducing exudate formation. Finally, the glucocorticoids potently suppress leukocyte emigration across post-capillary venules. However, this promiscuity of the glucocorticoids to act at multiple sites also endows this class of (drugs with major side effects associated with chronic treatment. We propose that one way to progress forward is to understand better the effects of glucocorticoids within the microcirculation. This may aid identification of specific molecular sites of action and therefore the development of novel glucocorticoid molecules with fewer side effects.
To report a case of retinal pigment epithelial tear after photodynamic therapy for choroidal neovascularization.
Case report. A 74-year-old woman with exudative age-related macular degeneration and classic subfoveal choroidal neovascularization RE underwent photodynamic therapy with verteporfin.
Ophthalmoscopy and fluorescein angiography RE disclosed a retinal pigment epithelial tear in the area of photodynamic therapy.
This case presents the first report of a retinal pigment epithelial tear after photodynamic therapy with verteporfin for subfoveal choroidal neovascularization in age-related macular degeneration.
Animal models, in vitro assays and pilot clinical studies suggest that intravitreal triamcinolone acetonide may be useful in the treatment of age-related macular degeneration. The present case study reports the effect of intravitreal triamcinolone acetonide injection on a subretinal neovascular lesion, microglial morphology and quantitative expression of MHC-II antigens. Triamcinolone acetonide significantly decreased MHC-II expression consistent with immunocytochemical observations which revealed condensed microglial morphology. The modulation of subretinal oedema and microglial morphology correlates with in vitro observations suggesting that downregulation of inflammatory markers and endothelial cell permeability are significant features of the mode of action of triamcinolone acetonide.
Photodynamic therapy (PDT) is a relatively new modality that is currently under clinical and experimental evaluation for treatment of subfoveal choroidal neovascularization (CNV). The authors report the case of an 82-year-old woman who underwent verteporfin-mediated PDT for classic subfoveal CNV. Fluorescein angiography performed 2 weeks after treatment disclosed reduction of the initial area of neovascularization and leakage by approximately 60%. Three weeks after PDT, however, the area of leakage was almost the same size as that before treatment. The patient underwent submacular membranectomy almost 4 weeks after treatment. The authors describe the ultrastructural vascular changes after PDT and a clinicopathologic study of classic CNV.
The submacular membrane was studied by light and electron microscopy and immunohistochemical techniques.
Ultrastructural examination of the peripheral vessels showed evidence of endothelial cell degeneration with platelet aggregation and thrombus formation. Occasional occluded vessels were surrounded by macrophages, a phenomenon previously reported to describe the process of resorption of such blood vessels. The vessels in the center of the membrane were unremarkable.
Photodynamic therapy causes endothelial cell damage, thrombus formation, and vascular occlusion of classic CNV in age-related macular degeneration.
Acute retinal pigment epithelial tear may occur as a natural complication of choroidal neovascularization associated with pigment epithelium detachment and laser photocoagulation as well. This complication may occur also after photodynamic therapy and therefore should be carefully considered.
To determine if a single intravitreal injection of 4 mg of triamcinolone acetonide in patients with classic choroidal neovascularization associated with age-related macular degeneration can safely reduce the risk of severe visual loss.
A double-masked, placebo-controlled, randomized clinical trial was performed in patients 60 years or older who had choroidal neovascularization with any classic component, a duration of symptoms of less than 1 year, and a visual acuity of 20/200 or better. Best-corrected visual acuity, intraocular pressure, and cataract grading were performed before the injection and then at 3, 6, and 12 months.
The development of severe loss of vision (30 letters) by survival analysis on an intention-to-treat basis.
One hundred fifty-one eyes were randomized into the study, and follow-up data were obtained for 73 (97%) of the 75 eyes in the treated group and for 70 (92%) of the 76 eyes in the control group. There was no difference between the 2 groups for the development of severe visual loss during the first year of the study (log-rank chi 2(1) = 0.03, P =.90). In both groups, the 12-month risk of severe visual loss was 35%, with a hazard ratio of 1.05 (95% confidence interval, 0.59-1.86). The change in size of the neovascular membranes, however, was significantly less in eyes receiving triamcinolone than in those receiving placebo 3 months after treatment (P =.01), although no difference was noted after 12 months. After 12 months, treated eyes had a significantly higher risk of an elevated intraocular pressure (31/75 [41%] vs 3/76 [4%]; P<.001), but not of cataract progression (P =.29).
A single dose of intravitreal triamcinolone had no effect on the risk of loss of visual acuity during the first year of the study in eyes with age-related macular degeneration and classic choroidal neovascularization, despite a significant antiangiogenic effect found 3 months after treatment. This biological effect warrants further study.
To examine combined photodynamic therapy (PDT) with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
Noncomparative case series.
Twenty-six eyes of 26 patients with CNV secondary to AMD. Thirteen with CNV, without restriction to type, were not treated with prior PDT and were called the Newly Treated group. Thirteen patients with prior PDT therapy who experienced visual loss during treatment with PDT alone comprised the remainder and were termed the Prior PDT group.
Patients with CNV were treated with PDT immediately followed by an intravitreal injection of 4 mg of triamcinolone acetonide. Visual acuity was measured by Early Treatment Diabetic Retinopathy Study protocol refraction. Need for retreatment was based on fluorescein angiographic evidence of leakage at 3-month follow-up intervals.
Visual acuity and retreatment rate.
Of the 13 patients in the Newly Treated group the mean visual acuity change at 3 months was an improvement of 1.9 lines, and 4 (30.8%) had an improvement of at least 3 lines. Two patients (15.4%) required retreatment at 3 months. At the 6-month follow-up, available for 12 patients in the Newly Treated group, the mean visual acuity change from baseline was an improvement of 2.4 lines, 4 patients (33%) had an improvement of at least 3 lines and 1 patient required retreatment. At both time points the visual acuity was significantly greater than at baseline (P = 0.023 and P = 0.007, at the 3-month and 6-month time points, Wilcoxon signed ranks test) for patients in the Newly Treated group. Among the 13 patients in the Prior PDT group, the mean change in visual acuity from baseline at the 3-month follow-up was 0.31 lines and 1 patient (7.7%) had an improvement of at least 3 lines. Six-month follow-up was available for 11 patients in the Prior PDT group and the mean change from baseline visual acuity was 0.1 lines and 1 patient (9.1%) experienced an improvement of 3 or more lines. No patient in the Prior PDT group required retreatment at 3 or 6 months. At the 3-month and 6-month time points the visual acuity was not significantly different than the baseline acuity in the Prior PDT group. No patient in either group at any time point experienced a loss of visual acuity of 3 or more lines. Five patients (19.2%), 3 in the Newly Treated group and 2 in the Prior PDT group, required monodrop therapy to control their intraocular pressure. No patient developed endophthalmitis.
Although the number of patients in this pilot study was limited, the improvement of acuity and the lack of fluorescein leakage in these patients suggest combination therapy with PDT and intravitreal triamcinolone acetonide, particularly when used as first-line therapy, merits further investigation.
To evaluate the outcome of repeated intravitreal injections of triamcinolone acetonide for the treatment of exudative age-related macular degeneration.
This prospective, comparative nonrandomized clinical interventional study included 13 patients with progressive exudative age-related macular degeneration with occult, or predominantly occult, subfoveal neovascularization. All patients had shown an increase or stabilization of visual acuity after a first intravitreal injection of 25 mg of triamcinolone acetonide. They received a second intravitreal injection of 25 mg of triamcinolone acetonide 3.1 to 18 months after the first injection. Mean +/- SD follow-up time after the second injection was 5.2 +/- 3.6 months (median, 5.3 months). A control group included 24 patients with exudative age-related macular degeneration who did not receive treatment for their maculopathy. The main outcome measures were visual acuity and intraocular pressure.
In the study group, mean +/- SD visual acuity increased significantly (P =.005 and P =.003, respectively) from 0.17 +/- 0.11 to 0.32 +/- 0.26 and from 0.15 +/- 0.14 to 0.23 +/- 0.19, respectively, after the first and second injections. An increase in visual acuity was found for 10 patients (77%) after the first and second injections. In the control group, visual acuity did not vary significantly during follow-up (P =.81). The difference in change in visual acuity between the study group and control group was significant (P =.01 [Snellen lines] and P =.05 [logMAR units]). The peak in visual acuity and, in a chronologically parallel manner, the peak in intraocular pressure elevation occurred 2 to 5 months after each injection.
Repeated intravitreal injection of 25 mg of triamcinolone acetonide may lead to an increase in visual acuity in patients with exudative age-related macular degeneration, with the peak in visual acuity and intraocular pressure elevation occurring about 2 to 5 months after each injection.
To study the visual and angiographic outcome of eyes with neovascular age-related macular degeneration associated with pigment epithelium detachment (PED) treated by photodynamic therapy.
Review of the medical charts and the fluorescein and indocyanine green angiograms of all consecutive patients with age-related macular degeneration associated with choroidal neovascularization and serous PED of at least 1 disc diameter, who received photodynamic therapy from January 1, 2000, to August 31, 2002.
Thirty patients (34 eyes) met the study criteria. Each underwent 1 to 8 treatments (mean, 4); duration of follow-up was 12 to 36 months (mean, 19 months). Nineteen eyes (56%) lost 3 or more Snellen lines of visual acuity, 7 eyes (21%) lost 1 or 2 lines, 6 eyes (18%) maintained their initial acuity, and 2 eyes (6%) gained 1 or 2 lines. Subretinal hemorrhage occurred in 5 eyes and retinal pigment epithelium tears in 4 eyes. In 4 eyes, visual acuity decreased to counting fingers, hand motions, or light perception.
Although 44% of the 34 eyes with age-related macular degeneration and PED lost fewer than 3 Snellen lines in acuity, severe visual loss to counting fingers or less occurred in 4 eyes, 3 of them with choroidal neovascularization inside the PED. Further studies and treatment modalities are required to improve prognosis of neovascular age-related macular degeneration with serous PED.
To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy.
Interventional case series.
Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 microm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy.
Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen.
This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed.
To better understand the mechanisms of action of photodynamic therapy (PDT) with verteporfin for subfoveal choroidal neovascularization (CNV), the authors evaluated the retinal and choroidal response immediately after treatment with serial optical coherence tomography (OCT) and indocyanine green angiography (ICGA).
This study was a prospective, noncomparative case series. PDT was performed on nine eyes of nine consecutive patients who presented with subfoveal CNV due to age-related macular degeneration, and serial evaluation with OCT as well as ICGA was performed at 20-minute intervals for the first 2 hours and then at 1 week, 1 month, and 3 months.
In the first 2 hours after PDT, OCT showed an increase in the thickness of the retina in the treatment area due to fluid leakage from the neovascular complex as confirmed by ICGA. At 1 week, marked reduction of intraretinal/subretinal fluid was observed in all patients. Neovascular complex nonperfusion by ICGA was associated with some degree of choroidal hypoperfusion in the treatment area. Return of the foveal contour by OCT was optimal after 1 month of treatment. At 3 months, choroidal reperfusion by ICGA and recurrent intraretinal/subretinal fluid by OCT were observed.
Serial OCT and ICGA evaluation after PDT suggests that the initial successful CNV nonperfusion as shown by fluorescein angiography at 1 week occurs by means of selective PDT damage to the lesion and/or reduced choroidal blood flow in the treatment area, thereby decreasing intraretinal/subretinal fluid and facilitating restoration of the retinal architecture.
To evaluate the visual outcome of patients with subfoveal choroidal neovascularization due to age-related macular degeneration, who received photodynamic therapy (PTD) in a clinical setting and to identify potential predictive visual and angiographic factors.
Interventional case series.
The study included 74 patients with subfoveal choroidal neovascularization who underwent PDT from January 2000 to March 2001 and completed at least 1 year follow-up. All patients received verteporfin PDT and were followed clinically, with fluorescein angiography (74 eyes), and with indocyanine green angiography (65 eyes). A review of the medical records and angiograms was performed.
Mean follow-up was 15.6 months. Patients received a mean of 3.4 treatments per year. Sixty-six percent lost less than 3 Snellen lines of visual acuity. Three patients (4%) experienced profound visual acuity loss to finger counting. Final visual acuity was positively correlated with lesion size and visual acuity at presentation. Visual outcome was worse in the presence of cystoid macular edema. On indocyanine green angiography, a round hypofluorescent spot was seen at the site of the PDT, with maintenance of medium and large choroidal vessels.
Smaller lesion size and better visual acuity at presentation were good predictive signs, whereas cystoid macular edema was found to be a poor prognostic sign for visual outcome following PDT.
Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study Group
- Macular Photocoagulation Study Group
Treatment of exudative AMD with chorioretinal anastomosis: a comparative study of photodynamic therapy with and without intravitreal injection of triamcinolone acetonide
- Haddad WM