EVpedia

Combined intravitreal pharmacosurgery to fight classic and occult CNV´s in ARMD

jeudi 26 mars 2009 par Frank H Koch

The pathophysiological processes that lead to choroidal neovascularization (CNV) in patients with age-related macular degeneration (AMD) are highly diverse. Correspondingly, current therapeutic strategies aim at multiple etiological mechanisms. The inhibition of vascular endothelial growth factor (VEGF), a potent pro-angiogenic and edematous growth factor, using recombinant monoclonal antibodies has revolutionized the way exudative AMD is treated. The necessity of repeated injections, however, carries a higher risk of endophthalmitis and may prove financially prohibitive for some patients. [1]. Moreover, if therapy with VEGF inhibitors is stopped or paused, visual acuity returns to baseline levels, [2]. and CNV may recur (Korotkin A, et al. IOVS, 2006 ;47 : ARVO E-Abstract 2961). The efficacy in terms of preventing CNV also appears to generally decline when the anti-VEGF agents are discontinued with longer duration of therapy. [3]. Therefore, monotherapy with VEGF inhibitors is unconvenient and may ultimately be less beneficial in the treatment of CNV.
Combination therapy aims not only at the prevention of angiogenesis but also at the regression of existing CNV by using multiple pharmacological agents, which work synergistically and typically include the VEGF inhibitor bevacizumab. [4]., [5]. Recently, Augustin et al evaluated a combination of photodynamic therapy with verteporfin and intravitreal treatment with bevacizumab and dexamethasone in patients with CNV secondary to AMD. While the combination therapy included a limited core pars plana vitrectomy, the role of the vitrectomy in treating CNV was considered negligible by the authors. There is, however, reason to believe that physiological changes induced by a limited (or full) vitrectomy may exert a beneficial therapeutic effect. Vitrectomy was shown to increase intraocular oxygen tension, [6]., [7]. which in turn affects retinal oxygenation. [8]. By reducing the viscosity in the vitreous cavity, either by a full or limited vitrectomy, VEGF may diffuse away from the retina. Thus, vitrectomy may also physically remove the angiogenic growth factor from the intraocular cavity.

The presence of vitreous attachment to the macula was suggested to be a possible risk factor for neovascular AMD by perpetuating macular exposure to inflammatory cytokines or free radicals and by interfering with macular oxygenation. [9]. It is likely that vitreous attachment, through the same mechanisms, also contributes to angiogenesis. We hypothesize that a partial core vitrectomy facilitates posterior vitreous detachment.

In the first of our two case series (classic series) , we investigated the effects of an intravitreal combination therapy in patients with wet AMD and predominantly classic CNV´s. A low-fluence photodynamic therapy using verteporfin was applied, and a limited 1.5 ml mid to posterior core vitrectomy was performed in combination with intravitreal treatment using bevacizumab and dexamethasone the day after.

In the second of our two case series (occult series) , we investigated the effects of intravitreal combination therapy in patients with wet AMD and predominantly occult CNV´s.
We examined the efficacy of an intravitreal combination therapy using a limited core vitrectomy and intravitreal treatment with bevacizumab and triamcinolone.

Frank H Koch ; Michael J Koss ; Stefan Scholtz ; Y Haeusler-Sinangin ; Pankaj Singh

Methods

Study design and patients

Our case series were prospectively followed in accordance with the European Guidelines for Good Clinical Practice and the Declaration of Helsinki and registered with www.clinicaltrials.gov (NCT00805649). Informed consent was obtained from each patient before the start of therapy

Classic series :
Patients with wet AMD who were more than 45 years old were included if they had a predominantly classic CNV between 1 and 6 mm in size (at the greatest extension) underneath or juxtafoveal to the geometric center of the fovea, and if they had a baseline visual acuity of 0.3 to 1.8 logMar. Patients were excluded from the study if they had a history of prior vitreoretinal surgery, neovascular retinopathy, glaucoma, ocular hypertension, or optic neuropathy.

Occult series :
Patients with wet AMD were included in the study if they were older than 45 years, if they had an occult CNV between 1 and 6 mm in size at the greatest extension underneath the geometric centre of the fovea with a visual acuity of 0.3 to 1.8 logMAR. Exclusion criteria were a history of prior vitreoretinal surgery, neovascular retinopathy, optic neuropathy, glaucoma, or ocular hypertension, or an intravitreal injection (anti-VEGF, steroids) 5 months prior study inclusion.

Pharmacosurgery - classic group

A photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis, Basel, Switzerland) was performed in accordance with the recommendations of the manufacturer except for the duration of light exposure, which was shortened to 70 sec, thus yielding a total reduced dose of 42 J/cm2 (low fluence PDT regimen) according to Augustin et al.Augustin, 2007 #12.

JPG - 73.7 ko
Figure 1. Representation of the 23 gauge Intrector® set up

Two days after PDT, a limited core pars plana vitrectomy was carried out using the Intrector® (Insight Instruments, Stuart, FL, USA), which has two separate channels for aspiration and infusion (Fig. 1 ) . After displacement of the conjunctiva via an oblique sclerotomy, 1.5 mL of mid to posterior vitreous was aspirated. The solution used for infusion contained 0.8 mg (0.2 ml) dexamethasone (Dexa-ratiopharm®, Ulm, Germany), and 1.25 mg (0.1 ml) bevacizumab (Avastin, Genentech, San Fransisco, CA, USA) and balanced salt solution (BSS, Alcon, Freiburg, Germany). This therapeutic approach, which combines the four treatments PDT, core vitrectomy, and injection of dexamethasone and bevacizumab, is referred to as “quadruple therapy” in the following video1.

Patients were considered for retreatment, which was one bevacizumab monoinjection, using the combined intravitreal therapy if there was angiographic and evidence in OCT of macular edema or leakage from CNV lesions.

Pharmacosurgery – occult group
JPG - 60.6 ko

Figure 2. Surgical technique used in this study

After instillation of povidone iodine eye drops a closed lid retractor is put in place. The conjunctiva is displaced, and through an oblique sclerotomy, the vitrectomy is performed with simultaneous aspiration and infusion.

A limited core pars plana vitrectomy was performed using a vitrector (Intrector®, Insight Instruments, Stuart, FL, USA) with the two separate channels for aspiration and infusion mentioned above (Fig. 1) . .After conjunctival displacement an oblique sclerotomy was performed to illuminate the tip of the vitrector with a head-set and a magnifying 38 diopters lens (Fig. 2). An assistant then aspirated a total, of 1.5 mL cutted mid and posterior vitreous instructed by the surgeon with isovolumic substitution of 1.2ml balanced salt solution (BSS, ALCON, Freiburg, Germany) to avoid relevant perioperative hypotonia. At the end of the limited posterior core vitrectomy 1.25 mg (0.1 ml) bevacizumab (Avastin, Genentech, San Fransisco, CA, USA), and 8 mg (0.2 ml) triamcinolone (TriamHEXAL® 40 mg/1 ml, Holzkirchen, Germany) were injected. In the following, the term “triple therapy” is used for this therapy, which comprises the three treatments core vitrectomy and injection of triamcinolone and bevacizumab.

Measurements and data analysis, classic group

At baseline (T0) and at all scheduled follow-up visits, i.e. at 3 (T1), 6 (T2) and 9 (T3) months after initial pharmacosurgery, an ophthalmic examination including slit lamp biomicroscopy and funduscopy was performed, the best-corrected (EDTRS standardized refracted) visual acuity (BCVA) was assessed using 6 m Snellen charts, with the false choice technique with a minimum of four out of five optotypes. BCVA values were transformed to the logartithm of the minimum angle of resolution (LogMAR). The intraocular pressure (IOP) was measured using Goldmann applanation tonometry, and the central foveal thickness was determined by optical coherence tomography (Stratus® OCT, Carl Zeiss Meditec, Santa Ana, CA, USA). Fluorescein angiography was used to determine the lesion type, the location, and the presence or absence of active CNV leakage. Fluorescein angiograms were interpreted by one out of three experienced vitreo-retinal specialists (F.K., S.S., M.J.K). In addition, the need for retreatment was assessed, and adverse events were monitored.
The primary outcome measures were BCVA, central macular thickness, and retreatment rate. For statistical analysis, the Excel® (Microsoft, Richmond, USA) and BiAS® software (Version 8.2 for Windows® ; Epsilon-Verlag, Darmstadt, Germany) were used. Non-normally distributed data were analyzed using the David´s test. The median change in BCVA and central retinal thickness from baseline to each follow-up visit was analyzed using the Wilcoxon matched pairs test.

Measurements and data analysis, occult group

At baseline (T0) and all follow-up examinations, i.e. at 2 (T1), 4 (T2) and 6 (T3) months after initial pharmacosurgery, an ophthalmic examination including slit lamp biomicroscopy and funduscopy was performed, the best-corrected (EDTRS standardized refraction) visual acuity (BCVA) was assessed using 6m Snellen charts with the forced choice technique. One line was credited, if four out of five optotypes were recognised. The central foveal thickness was measured using optical coherence tomography (Stratus® OCT, Carl Zeiss Meditec, Santa Ana, CA, USA), and the intraocular pressure (IOP) was assessed using Goldmann applanation tonometry. Fluorescein angiography was carried out to identify the lesion type, the location, and the absence or degree of active CNV leakage. Fluorescein angiograms were evaluated by an experienced vitreo-retinal specialist (F.K., M.J.K, S.S.) and throughout the study at the three follow-up visits the need for a booster with an additional 1.25 mg bevaciczumab monotherapy was evaluated. The indication for a booster injection was set if there was a pronounced activity in FA and/or OCT or an increase of macular edema by 75 µm. Any therapy associated adverse events like IOP increase, intraocular inflammation were recorded.
The Excel® (Microsoft, Richmond, USA) and BiAS® programme (Version 8.2 for Windows® ; Epsilon-Verlag, Darmstadt, Germany) were applied for the statistical analysis of the primary outcome measures BCVA, central macular thickness, and retreatment rate. The David´s test was used to analyse non-normally distributed data. The Wilcoxon matched pairs test was used to evaluate the median change in BCVA and central retinal thickness from baseline to each follow-up visit. The frequency of cataract surgeries in the two patient groups during the follow-up period was compared using the Chi-square test.

Results

Classic group
Table 1. Demographics and baseline characteristics of patients with age-related macular degeneration and predominantly classic choroidal neovascularizations
No. of patients N 52
Age median (range) 76 (46 - 87)
mean ± SD 72.7 ± 11.1
Sex male / female 16 / 36
Lesion size median (range) 3100 (1200 - 5000)
mean ± SD 3073 ± 958
Lens status Intraocular lens 30 (57.7%)
Incipient cataract 22 (42.3%)

A total of 52 patients were included in the study. The mean age of the patients was 72.7 years, and 30.8% (16/52) of the patients were male (Table 1). Three patients had previously undergone a course of PDT. At baseline, 30 of 52 (57.7%) eyes were pseudophakic and 22 (42.3%) were phakic. Seven patients with phakic lens status had senile minimal nuclear sclerotic cataracts. None of the cataracts, however, was felt to be clinically significant as per the results of the slit lamp examination. Follow-up examinations were performed on average (± SD) at 3.1 months (± 12 days), 6.3 months (± 14 days), and 8.8 months (± 23 days) after the initial pharmacosurgery. The follow-up rate was 100% (52/52) at 3 months, 98% (51/52) at 6 months, and 92.3% (48/52) at 9 months.

Table 2. Best corrected visual acuity in patients with age-related macular degeneration and predominantly classic choroidal neovascularizations (n = 52) before (T0) and after initial treatment (T1-3)
T0 (baseline) T1 (3 months) T2 (6 months) T3 (9 months)
Median (range) [logMAR] 1 (0.3 – 1.69) 0.69 (0.3 – 1.3) 0.52 (0.16 – 1.0)0.65 (0.09 – 1.0)
T1 vs T0 : p<0.01 T2 vs T0 : p<0.001T3 vs T0 : p<0.001
T2 vs T1 : p<0.001T3 vs T1 : p<0.05
T3 vs T2 : p=0.69
Mean ± SD [logMAR] 0.97 ± 0.29 0.69 ± 0.27 0.56 ± 0.22 0.60 ± 0.24
The p-value was analyzed using a Wilcoxon matched pairs test (non-normally distributed data) for intravariable differences

At baseline, the mean lesion size was 3073 µm (table 1) and the mean BCVA was 0.97 logMAR (± 0.29 standard deviation SD) (table 2).

JPG - 28.6 ko

Figure 3. Change in best-corrected visual acuity (BCVA) in patients with age-related macular degeneration and predominantly classic choroidal neovascularizations before (T0) and after therapy (T1-3)

A box plot based on information of 52 patients with age-related macular degeneration and predominantly classic choroidal neovascularizations is shown. Horizontal lines of the boxes represent lower quartile, mean and upper quartile and whiskers denote the range from min. to max.


JPG - 34.6 ko

Figure 4. Proportion of patients with an improvement or deterioration of the best-corrected visual acuity at 14 months after therapy

Patients with age-related macular degeneration and predominantly classic choroidal neovascularizations (n = 52) were treated using photodynamic therapy and combined intravitreal therapy (core vitrectomy, bevacizumab, and dexamethasone).


The mean BCVA increased by -0.28, -0.42 and -0.37logMAR vs baseline at 3, 6, and 9 months, respectively (Fig. 3). At the end of the follow-up period, i.e. at 9 months, none of the patients had experienced a deterioration of BCVA as compared with baseline (Fig. 4). While BCVA was maintained in 13 of 48 (27.1%) patients, BCVA improved in the majority of the patients by 1 to 3 lines (28 of 48 ; 58.3%) or more than 3 lines (7 of 48 ; 14.6%). The mean central retinal thickness decreased by -44.3% (-211 µm) over 9 months (table 3).

Table 3. Central foveal thickness in patients with age-related macular degeneration and predominantly classic choroidal neovascularizations (n = 52) before (T0) and after initial treatment (T1-3)
T0 (baseline) T1 (3 months) T2 (6 months) T3 (9 months)
Mean ± SD] 476 ± 48.9 289 ± 38.3 256 ± 41.2265 ± 38.8
T1 vs T0 : p<0.001 T2 vs T0 : p<0.001T3 vs T0 : p<0.001
T2 vs T1 : p<0.05T3 vs T1 : p=0.51
T3 vs T2 : p=0.64
The central foveal thickness was determined using ocular coherence tomography. The p-value was analyzed using a Wilcoxon matched pairs test (non-normally distributed data) for intravariable differences.

The quadruple therapy regimen was repeated in 13 of 52 (25%) patients at 9.5 months after the initial pharmacosurgery. One patient underwent cataract surgery at 8.9 months ; while BCVA remained stable in one of the two patients, BCVA decreased in the other patient from 0.3 to 0.15 Snellen. No significant change in IOP was observed throughout the study (14.4 mm Hg at baseline vs. 14.8 mm Hg at the end of the follow-up period), and no other adverse event was reported.

Figure 5. Fluorescein angiography and optical coherence tomography in a patient with age-related macular degeneration and predominantly classic juxtafoveal choroidal neovascular lesions before (left panel) and after therapy (right panel)

The best-corrected visual acuity (Snellen 6 m) in this 67-year-old male patient increased from 0.2 at baseline to 0.5 at 14 months after photodynamic therapy and combined intravitreal therapy (core vitrectomy, bevacizumab, and dexamethasone).

There was no statistically significant change in the frequency of cataracts from baseline to 9 months. While the number of patients with an intraocular lens increased from 30 to 32, the number of patients with an incipient cataract decreased from 22 to 20. (Fig. 5)

Occult group
Table 4. Demographics and baseline characteristics of patients with age-related macular degeneration and predominantly occult choroidal neovascularizations
No. of patients N 106
Age median (range) 77 (47 - 93)
mean ± SD 75.4 ± 9.5
Sex male / female 40 / 66
Lesion size median (range) 2500 (1000 - 6000))
mean ± SD 2740 ± 1071
Lens status Intraocular lens 26 (24.5%)
Incipient cataract 80 (75.5%)

In total, 106 patients were included in the study. The majority of the patients was female (66/106 ; 62.3%) ; the mean age was 75.4 years (standard deviation ± 9.9 ; median 77 ; 47 – 93 years, table 4). Twenty-six of 106 (24.5%) eyes were pseudophakic and 80 (75.5%) were phakic at baseline. Senile minimal nuclear sclerotic cataracts were found in 26 of the 80 (32.5%) patients with phakic lens status. According to the results of the slit lamp examination, however, none of the cataracts were considered clinically relevant. Follow-up examinations took place on average (± SD) at 1.8 months (± 11 days), 3.7 months (± 16 days), and 5.8 months (± 15 days) after the initial pharmacosurgery. The follow-up rate was 100% (106/106) at 2 months, 94% (100/106) at 4 months, and 91% (96/106) at 6 months.

Table 5. BCVA and central macular thickness in patients with ARMD and occult choroidal neovascularizations (n = 106) before (T0) and after initial treatment (T1-3)
T0 (baseline) T1 (3 months) T2 (6 months) T3 (9 months)
Median (range) [logMAR] 0.85 (0.30 - 1.70) 0.85 (0.22 – 1.70) 0.55 (0.1 - 2.00)0.7 (0.1 - 2.00)
T1 vs T0 : p<0.05 T2 vs T0 : p<0.001T3 vs T0 : p<0.001
T2 vs T1 : p<0.005T3 vs T1 : p<0.05
T3 vs T2 : p>0.45
Mean ± SD [logMAR] 0.88 ± 0.26 0.72 ± 0.37 0.63 ± 0.32 0.65 ± 0.33
Median (range)[µm] 519 (379 – 563) 295 (200 – 365) 270 (180 – 340) 276 (190 – 355)
T1 vs T0 : p<0.001 T2 vs T0 : p<0.001T3 vs T0 : p<0.001
T2 vs T1 : p<0.001T3 vs T1 : p>0.92
T3 vs T2 : p>0.62
Mean ± SD [µm] 473 ± 50.2 283 ± 33.2 264 ± 30.9 278 ± 46.4
The p-value was analyzed using a Wilcoxon matched pairs test (non-normally distributed data) for intravariable differences

The mean lesion size was 2740 µm (table 4), and the mean BCVA was 0.88 logMAR (±0.26 ; median 0.85 ; range 0.3 – 1.7) at baseline (table 5).

JPG - 30.6 ko
Figure 6. Change in BCVA in patients with ARMD and occult choroidal neovascularizations before (T0) and after therapy (T1-3)
A box plot based on information of 106 patients with ARMD and occult choroidal neovascularizations is shown. Horizontal lines of the boxes represent the lower quartile, the mean, and the upper quartile. The whiskers denote the range from min. to max.

JPG - 37.3 ko
Figure 7. Proportion of patients with an improvement or deterioration of the BCVA at 14 months after therapy
Patients with ARMD and occult choroidal neovascularizations (n = 96) were treated using combined intravitreal therapy (core vitrectomy, bevacizumab, and triamcinolone).

There was a statistically significant increase in mean BCVA at 2 months (+0.9 lines ; ± 0.6 vs baseline), 4 months (+1.3 ; ±0.7), and 6 months (+1.2 ; ±0.7) (fig. 6). At 6 months, i.e. at the end of the follow-up period, BCVA had deteriorated in 20 of 96 (20.8%) patients by <2.5 lines as compared with baseline. BCVA remained stable in 38 of 96 (39.6%) patients, improved in 31 (32.3%) patients by 1 to 3 lines, and in 7 (7.3%) patients by more than 3 lines (fig. 7). The decrease in mean central retinal thickness (CMT) was already statistically significant at 2 months (p<0.001) and amounted to -41.2% (-195 µm) at 6 months (table 5).
After six months 53 of 96 (55.2%) patients had to receive anti-VEGF monotherapy because of increase in CMT and leakage in fluorescence angiography. Cataract surgery was carried out uneventfully in eight patients at 7.8 months ; the effect of the cataract surgery on BCVA was overall not statistically significant (p>0.68). The IOP increased in 11 of 106 (10.4%) patients for a mean duration (± SD) of 12 days (± 3.6 days) and successfully controlled by using topical antiglaucomatous medication.

Discussion

The “Treatment of AMD with Photodynamic Therapy” (TAP) study and the “Verteporfin in Photodynamic Therapy” (VIP) study showed that PDT significantly prevents loss of vision in eyes with predominantly classic CNV [10]. and in eyes with occult CNV. [11]. One of the potentially negative effects of PDT is the damage to the pericentral visual field. To address this in the present study, we applied low-fluence PDT with a total of 42 J/cm2 in combination with an intravitreal treatment using dexamethasone and bevacizumab to ameliorate the PDT associated tissue inflammation and to counteract the CNV. There was a sustained and statistically significant increase in BCVA from baseline up to 9 months after initial treatment. Despite the slight tapering off of the therapeutic efficacy, well over 50% of the patients experienced an improvement in vision by 1 to 3 lines, and 15% of patients gained more than 3 lines at 9 months. At the same time, central macular thickness significantly decreased from baseline to 9 months and subsequently slightly increased but essentially remained at a significantly reduced level as compared with baseline (Table 3).

Given the multifactorial pathophysiology of AMD, it is possible that the plateau effect beginning at about 9 months after initial treatment is a result of the pharmacokinetic characteristics of the intravitreal medications. While oxidative stress, age-related microstructural changes and the subsequent inflammatory response in AMD continue, the concentrations of the corticosteroid and the VEGF inhibitor decrease and the therapeutic effects weaken. [12]. Nevertheless, at 9 months in this study, BCVA had improved on average by - 0.37 logMAR as compared with baseline. Overall, the improvement in vision observed compares well with the results of recent clinical studies using intravitreal ranibizumab in patients with CNV secondary to AMD. [13]., [14].

While combination therapy yields results comparable with bevacizumab monotherapy, this study also shows that significantly fewer intravitreal injections and follow-up monitoring are required. The combination therapy was repeated, due to persistent or recurrent CNV, in 25% of the patients after 9 months. Moreover, there were no IOP increases and no other adverse events, which underlines the favorable safety profile of the intravitreal combination therapy.

In terms of the primary outcome measures BCVA and macular thickness, our study also compared well with a recent study by Augustin et al, which also combined PDT with an intravitreal injection of bevacizumab and dexamethasone. [15].

While Augustin et al did not consider that the vitrectomy played an important role in the combination therapy, there are multiple possible mechanisms by which a limited or full vitrectomy may indeed contribute to the resolution of neovascularization in AMD. Vitrectomy may induce a posterior vitreous detachment, which has the effect of decreasing viscosity anterior to the retina. Similarly, a full vitrectomy may enhance liquefaction in the vitreous cavity. The flow of molecules (flux) in the vitreous cavity is dictated by Fick’s Law for diffusion, i.e. the flux increases with decreasing viscosity. Therefore, the removal of vitreous gel facilitates the diffusion of angiogenic molecules away from the retina. [16].

A recent case report on a patient with AMD describes the regression of macular drusen and the occurrence of pigment epithelial detachment after vitrectomy. [17]. The results suggested that posterior vitreous detachment may provide prophylactic benefit against the development of exudative AMD. Similar conclusions were drawn in a study that examined the incidence of posterior vitreous detachment in an otherwise matched cohort of eyes with AMD. [18]. The authors pointed out that persistent posterior vitreous attachment may induce chronic low-grade inflammation, may prevent sufficient diffusion of oxygen and nutrients to macular cells, and may confine angiogenic cytokines to the macular region. We suppose that posterior vitreous detachment and the subsequent mechanical and physiological changes induced at the macula may complement the effects of pharmacotherapeutics in the treatment of CNV.

Thickening of the Bruch’s membrane in AMD decreases the diffusion of oxygen from the choriocapillaris to the retinal pigment epithelium. [19]., [20]. Although the hypoxia caused by changes in the choriocapillaris and the Bruch’s membrane in AMD has not been shown to play a causative role in CNV formation, it was hypothesized that outer retinal hypoxia in AMD may indirectly provide a stimulus for angiogenesis. [21]., [22]. Under hypoxic conditions certain isoforms of VEGF were shown to be upregulated in the retinal pigment epithelium and in CNV. [23]. Vitrectomy leads to a significant increase in intraocular oxygen tension. [24]. It was previously shown that the retina can be oxygenated from the vitreous cavity, [25]., [26]. and that increased oxygenation of ischemic retina reduces VEGF production. [27]. The increase of intraocular oxygen levels after a comparable limited core vitrectomy could be demonstrated lately in an adenovirus CNV-induced albino rabbit model (Herbort T et al ; Effects of Combined- vs. Monotherapy in CNV-Induced Albino Rabbits, Poster 743 at the annual meeting of the Association for Research in Vision and Ophthalmology, 3 – 7 May 2009, Ft Lauderdale, FL, USA). We therefore hypothesize that vitrectomy may have a role in relieving the hypoxic stimulus that may contribute to the VEGF production in neovascular AMD.

In the present studies, the partial vitrectomy was carried out using a hand-held, sutureless, 23-gauge vitrector with two channels for simultaneous aspiration and infusion (Intrector®). When performing vitrectomy, particularly in elderly patients, there is commonly a significant risk of inducing cataracts. In this study, there was no statistically significant change in the frequency of cataracts from baseline to end of observation. It should be noted, however, that, since the degree of cataract was not determined at baseline, cataracts may have progressed throughout the course of the study.

In patients with occult CNV lesions secondary to AMD, the combination therapy using vitrectomy and intravitreal treatment with triamcinolone and bevacizumab led to a statistically significant increase in BCVA from baseline up to 6 months after initial treatment. BCVA at 6 months had deteriorated in about 20% of the patients, had remained stable in nearly 40% of the patients and had improved by more than one line in another 40% of the patients. Central macular thickness significantly decreased from baseline to 4 months and then slightly increased but, in essence, remained at a significantly lower level as compared with baseline.
It is likely that the plateau effect beginning at about 4 months after the initial pharmacosurgery is due to the pharmacokinetic characteristics of the intravitreal medications. The intraocular pharmacological half-life of triamcinolone, for example, is approximately 30 days. Since the concentrations of the corticosteroid and the VEGF inhibitor decrease, the overall therapeutic effects diminish [28] while the oxidative stress, age-related microstructural changes and the resulting inflammatory process in AMD continue.
The improvements in BCVA observed in our study are overall similar to the results of recent monotherapy clinical studies using intravitreal ranibizumab or bevacizumab in patients with CNV. [29], [30], [31].] or to results of combination regimens like visudyne and triamcinolone, [32], [33], [34] or visudyne and anti-VEGF and dexamtheasone. [35], [36]. To our knowledge, though, this study is the first to report about a combined intravitreal triamcinolone and bevacizumab injection, following a 1.5ml core vitrectomy. Thus any comparison from the underlying results to the results of the monotherapy studies or studies of combination regimens is hard to draw. The main benefit in our opinion are the significantly fewer intravitreal injections during the follow-up monitoring. At the end of the follow-up period, i.e. at 6 months, the combination therapy had been repeated, due to persistent or recurrent CNV, in about half of the patients.

Safety
In the occult as in the classic group, the frequency of adverse events was in general low, which highlights the favourable safety profile of the intravitreal combination therapy. The IOP increases in the occult group, which occurred in about 10% of the patients, were most likely related to the treatment with triamcinolone but were controlled with eyedrops effectively. Although there is commonly, and especially in elderly patients, a significant risk of inducing cataracts when performing a complete vitrectomy, in this study, however, using a 23-gauge vitrector, the frequency of cataracts did not significantly increase from baseline to 6 months. Eight patients underwent phacoemulsification cataract extraction after 8 months, without significant effects on BCVA. Since the degree of cataract was not assessed at baseline, however, cataracts may have progressed during the course of the study.

A limitation of our pilot studies was that the study design did not include a control group, which, however, is characteristic for pilot studies. Moreover, given the relatively low number of patients studied, the study was not sufficiently powered to detect significant correlations with regard to complications such as cataract progression. In future studies, a larger number of patients should be included, cataracts should be graded at baseline and subsequent visits, and vitreous attachment should be examined using (high resolution) optical coherence tomography together with ultrasonography.

Despite the limitations in study design, the results of the present studies clearly support the conclusion that, in patients with CNV´s secondary to AMD, the combination therapy including a vitrectomy and intravitreal treatment using bevacizumab and a corticosteroid yields results over a reasonable long observation period well comparable with the best study results regarding monotherapy with e.g. bevacizumab, while exposing patients to significantly fewer intraocular interventions.
Our results can on the one hand be addressed to the drug synergism and on the other hand to the changes in the vitreous physiology induced by the limited core vitrectomy.
How far PDT could also contribute in occult membranes to long lasting increase of visual acuity and stability, is a thrilling topic we intend to answer in the near future.

[1] Azad R, Chandra P, Gupta R. The economic implications of the use of anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol 2007 ;55:441-3.

[2] [Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab : Phase III clinical trial results. Ophthalmol Clin North Am 2006 ;19:361-72].

[3] [Bradley J, Ju M, Robinson GS. Combination therapy for the treatment of ocular neovascularization. Angiogenesis 2007 ;10:141-8].

[4] [Augustin AJ, Offermann I. Combination therapy for choroidal neovascularisation. Drugs Aging 2007 ;24:979-90].

[5] Spaide RF. Rationale for combination therapies for choroidal neovascularization. Am J Ophthalmol 2006 ;141:149-56.

[6] Barbazetto IA, Liang J, Chang S, Zheng L, Spector A, Dillon JP. Oxygen tension in the rabbit lens and vitreous before and after vitrectomy. Exp Eye Res 2004 ;78:917-24.

[7] Holekamp NM, Shui YB, Beebe DC. Vitrectomy surgery increases oxygen exposure to the lens : a possible mechanism for nuclear cataract formation. Am J Ophthalmol 2005 ;139:302-10.

[8] [Stefansson E, Novack RL, Hatchell DL. Vitrectomy prevents retinal hypoxia in branch retinal vein occlusion. Invest Ophthalmol Vis Sci 1990 ;31:284-9].

[9] Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion : a potential risk factor for exudative age-related macular degeneration ? Am J Ophthalmol 2007 ;144:741-746.

[10] [Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin : one-year results of 2 randomized clinical trials—TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol 1999 ;117:1329-45].

[11] Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration : two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001 ;131:541-60.

[12] Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004 ;122:598-614.

[13] Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006 ;355:1432-44.

[14] Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006 ;355:1419-31.

[15] [Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration : verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007 ;27:133-40].

[16] Stefansson E. Ocular oxygenation and the treatment of diabetic retinopathy. Surv Ophthalmol 2006 ;51:364-80.

[17] [Fuseya M, Imamura Y, Ishida S, Inoue M, Tsubota K. Regression of macular drusen after pars plana vitrectomy in a patient with age-related macular degeneration Retina 2007 ;1:160-162].

[18] Krebs I, Brannath W, Glittenberg C, Zeiler F, Sebag J, Binder S. Posterior vitreomacular adhesion : a potential risk factor for exudative age-related macular degeneration ? Am J Ophthalmol 2007 ;144:741-746.

[19] [Gottsch JD, Pou S, Bynoe LA, Rosen GM. Hematogenous photosensitization. A mechanism for the development of age-related macular degeneration. Invest Ophthalmol Vis Sci 1990 ;31:1674-82].

[20] [Grindle CF, Marshall J. Ageing changes in Bruch’s membrane and their functional implications. Trans Ophthalmol Soc U K 1978 ;98:172-5].

[21] Blair NP. Ocular oxygen consumption during vitreoperfusion in the cat. Trans Am Ophthalmol Soc 2000 ;98:305-29.

[22] Wilson CA, Benner JD, Berkowitz BA, Chapman CB, Peshock RM. Transcorneal oxygenation of the preretinal vitreous. Arch Ophthalmol 1994 ;112:839-45.

[23] [Shima DT, Adamis AP, Ferrara N, et al. Hypoxic induction of endothelial cell growth factors in retinal cells : identification and characterization of vascular endothelial growth factor (VEGF) as the mitogen. Mol Med 1995 ;1:182-93].

[24] [Stefansson E, Landers MB, 3rd, Wolbarsht ML. Vitrectomy, lensectomy, and ocular oxygenation. Retina 1982 ;2:159-66].

[25] Blair NP. Ocular oxygen consumption during vitreoperfusion in the cat. Trans Am Ophthalmol Soc 2000 ;98:305-29.

[26] Wilson CA, Benner JD, Berkowitz BA, Chapman CB, Peshock RM. Transcorneal oxygenation of the preretinal vitreous. Arch Ophthalmol 1994 ;112:839-45.

[27] Pournaras CJ, Miller JW, Gragoudas ES, et al. Systemic hyperoxia decreases vascular endothelial growth factor gene expression in ischemic primate retina. Arch Ophthalmol 1997 ;115:1553-8.

[28] Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol 2004 ;122:598-614.

[29] Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006 ;355:1419-31.

[30] Chen CY, Wong TY, Heriot WJ : Intravitreal bevacizumab (avastin) for neovascular age-related macular degeneration : A short-term study. Am J Ophthalmol 2007 ;143:510-512.

[31] [Spaide RF, Laud K, Fine HF, Klancnik JM, Jr., Meyerle CB, Yannuzzi LA, Sorenson J, Slakter J, Fisher YL, Cooney MJ : Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration. Retina 2006 ;26:383-390].

[32] Augustin AJ, Schmidt-Erfurth U : Verteporfin and intravitreal triamcinolone acetonide combination therapy for occult choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol 2006 ;141:638-645.

[33] [Ruiz-Moreno JM, Montero JA, Barile S : Triamcinolone and pdt to treat exudative age-related macular degeneration and submacular hemorrhage. Eur J Ophthalmol 2006 ;16:426-434].

[34] [Spaide RF, Sorenson J, Maranan L : Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology 2003 ;110:1517-1525].

[35] [Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to age-related macular degeneration : verteporfin PDT, bevacizumab, and dexamethasone. Retina 2007 ;27:133-40].

[36] Liggett PE, Colina J, Chaudhry NA, Tom D, Haffner G : Triple therapy of intravitreal triamcinolone, photodynamic therapy, and pegaptanib sodium for choroidal neovascularization. Am J Ophthalmol 2006 ;142:1072-1074.


Portfolio


Accueil du site | Contact | Plan du site | Espace privé