|Year : 2013 | Volume
| Issue : 3 | Page : 117-122
Combined intracameral and intravitreal bevacizumab injection in Neovascular Glaucoma
Abeer Khattab, Eman Azmy
Department of Ophthalmology, Mansourah University, Mansoura, Egypt
|Date of Submission||10-Oct-2012|
|Date of Acceptance||07-Dec-2012|
|Date of Web Publication||28-Feb-2014|
Department of Ophthalmology, Mansourah University, Mansoura
Source of Support: None, Conflict of Interest: None
The aim of this study was to assess the efficacy and safety of combined intracameral and intravitreal injection of bevacizumab followed by panretinal photocoagulation (PRP) in the treatment of neovascular glaucoma.
This study is a prospective, interventional case series.
Patients and methods
This study is prospective observational case series of 23 eyes of 23 patients with different degrees of neovascular glaucoma (>22 mmHg) treated with simultaneous combined intracameral and intravitreal bevacizumab injection followed by PRP. Duration of follow-up was 3 months. The outcome measures were neovascular membrane extent, best corrected visual acuity (BCVA), and intraocular pressure (IOP) at the follow-up intervals.
The degree of neovascular membrane extent decreased from a preoperative mean of 226.95 ± 97.34 to 58.96 ± 84.12 at 1 week postoperatively and 31.3 ± 51.54 at 1 month postoperatively. The preoperative mean IOP was 58.7 ± 16.2 mmHg; it decreased to 20.8 ± 9.99 mmHg at 1 week, 18.47 ± 5.6 mmHg at 1 month, 22.65 ± 8.7 mmHg at 2 months, and 25.34 ± 6.806 mmHg at 3 months postoperatively ( P remained ≤0.001 throughout the course of follow-up). In addition, BCVA showed noticeable improvement during the course of follow-up; the mean preoperative BCVA logarithm of minimal angle of resolution (BCVA logMAR) was 1.47 ± 0.511, which significantly improved to 1.29 ± 0.55, 1.16 ± 0.58, 1.15 ± 0.6, and 1.3 ± 0.56 at 1 week and 1, 2, and 3 months, postoperatively, respectively.
Combined intravitreal and intracameral injection with bevacizumab followed by PRP can be considered to be a very effective and safe IOP-lowering technique in the case of neovascular glaucoma.
Keywords: Bevacizumab, intracameral, intravitreal, neovascular glaucoma, neovascularization, vascular endothelial growth factor
|How to cite this article:|
Khattab A, Azmy E. Combined intracameral and intravitreal bevacizumab injection in Neovascular Glaucoma. J Egypt Ophthalmol Soc 2013;106:117-22
|How to cite this URL:|
Khattab A, Azmy E. Combined intracameral and intravitreal bevacizumab injection in Neovascular Glaucoma. J Egypt Ophthalmol Soc [serial online] 2013 [cited 2019 Mar 26];106:117-22. Available from: http://www.jeos.eg.net/text.asp?2013/106/3/117/127340
| Introduction|| |
Neovascular glaucoma (NVG) has been reported to occur in many systemic diseases. Most of these diseases have retinal ischemia as a common factor. Approximately 3% of NVG cases are not associated retinal ischemia .
The pathogenesis of the NVG has been linked to the locally produced angiogenic growth factor, vascular endothelial growth factor (VEGF). Studies have shown that in patients with NVG and anterior segment neovascularization, the level of VEGF in the aqueous humor is significantly increased . In addition, artificial elevation of VEGF levels in the eyes of animals was sufficient to result in iris neovascularization (INV) and NVG .
INV often progresses to the formation of a fibrovascular membrane in the chamber angle, which impedes aqueous outflow and produces peripheral anterior synechiae (PAS), and contraction of this tissue will lead to progressive angle closure. Elevated intraocular pressure (IOP) is intractable and difficult to control and frequently results in irreversible, severe and painful loss of vision . NVG is treated in two ways : one is by treating the underlying disease process, such as retinal photocoagulation, thereby reducing retinal ischemia and inhibiting the release of angiogenic factors ,,,,, the other is by controlling the IOP and inflammation using either medical or surgical treatments, such as a cyclodestructive procedure or drainage devices ,,,,,,,,,,,,,,. VEGF levels in patients with ischemic retinal pathologic features are reduced indirectly after panretinal laser photocoagulation or cryocoagulation .
Laser treatment aims to decrease the stimulus of retinal neovascularization, which is attributed to an increased concentration of VEGF in retinal ischemic tissue. Although the effect of panretinal photocoagulation (PRP) is long lasting, it often takes several weeks to occur. During this period, progressive angle closure and optic nerve damage may ensue from elevated IOP, resulting in loss of vision . Further, photocoagulation alone is not completely successful in stopping INV in every patient, and in addition, a poor fundus view caused by corneal edema, cataract, vitreous hemorrhage, or a poorly dilated pupil make it impossible to perform .
Bevacizumab (Avastin) is a monoclonal VEGF inhibitor that was first used in ophthalmology to treat subretinal neovascularization in eyes with age-related macular diseases . Bevacizumab, a VEGF-A inhibitor, causes regression of INV when injected into the vitreous or the anterior chamber. However, the duration of action of bevacizumab is short lived, lasting about 4 weeks . The pharmacokinetics of bevacizumab has not been examined in direct relation to the duration of activity against INV ,.
The aim of this study was to assess the efficacy and safety of combined intracameral and intravitreal bevacizumab injections followed by PRP in the treatment of NVG.
| Patients and methods|| |
This study was a prospective, interventional case series carried out during the period between November 2011 and March 2012. It included 23 eyes of 23 patients with NVG, in whom PRP was deemed ineffective or impossible. The patients were selected from and followed up at Al Hayah Private Eye Hospital in Mansourah City. NVG was defined as an IOP of greater than 22 mmHg, with the presence of rubeotic vessels in the anterior chamber angle or corneal edema and obvious rubeosis iridis in cases in which the anterior chamber angle was not accessible. After being fully informed of the 'off-label' use of bevacizumab in ocular treatment and the experimental approach, all participants provided signed informed consent forms for participation in this study. The primary ocular disease was diabetic retinopathy in 13 eyes, retinal vein occlusion in eight eyes, and combined retinal venous occlusion and diabetic retinopathy in two eyes.
Before drug injection, the anterior chamber could be evaluated in all patients, with evaluation in some of them being extreme difficulty because of corneal edema caused by increased IOP. There are three distinctive terms used: the first is INV, in which the iris is divided into four quadrants and the number of affected quadrants before injection is recorded; the second is neovascular membrane (NVM), involving the anterior chamber angle and degree of involvement; and the third is PAS, involving the anterior chamber angle.
Combined intravitreal and intracameral injections of bevacizumab were administered in the minor operation theater with strict antiseptic precautions. First, an intravitreal injection of a 50-μl aliquot of commercially available bevacizumab (25 mg/ml) was prepared for each patient, transferred to a tuberculin syringe with a 29 G needle, and refrigerated until use. After topical anesthesia was induced using 0.4% topical benoxinate hydrochloride and the conjunctiva was disinfected with 5% povidone iodine solution (Betadine Alcon Laboratories Inc., Fort Worth, Texas, USA), 1.25 mg bevacizumab in 0.05 ml (Avastin, Roche) was administered transconjunctivally 4.0 mm posterior to the limbus using a 27 G needle through the temporal inferior pars plana. The tip of the needle was visualized in the mid vitreous and the drug exits the needle tip in the form of a gel into the vitreous cavity on injection. The needle was withdrawn and the site was compressed with the sterile tip of a cotton bud for 4-5 s. Paracentesis was then performed and this was followed by intracameral injection of a 50-ml aliquot of bevacizumab (25 mg/ml). A volume of 0.05 ml of bevacizumab solution was injected using a 27 G needle at the limbus in the temporal quadrant. Standard postoperative treatment included administration of topical antibiotic eye drops (Ofloxacin; Alcon) four times per day for 4 days. The cases were followed up till the media was clear. Thereafter, complete PRP was performed in divided nearby sessions.
All eyes were followed up for 3 months. Data were collected at 1 week and 1, 2, and 3 months after laser treatment. At each follow up visit the following measurement of best corrected visual acuity logarithm of minimal angle of resolution (BCVA logMAR), IOP (measured by Goldmann applanation tonometry), gonioscopy, and determination of NVM extent were done and number and types of glaucoma medications used were recorded.
BCVA was measured using the Landolt broken ring acuity chart: counting fingers (CF) ranged between 20/1000 and 20/2000 and hand movement (HM) ranged between 20/2500 and 20/6060 according to Schulze-Bonsel and colleagues. Visual acuity was converted to the logMAR equivalent using conversion factors for statistical analysis, in which CF ranged between 1.7 and 2.0 log MAR, whereas HM ranged between 2.1 and 2.48 log MAR .
Data were analyzed using SPSS version 17.00 (SPSS Inc., Chicago, Illinois, USA). Qualitative variables are presented as number and percentage, and quantitative variables are presented as range (minimum-maximum) and mean ± SD. Unpaired simple t-tests were used to compare the variables during follow-up; a P-value of up to 0.005 was considered statistically significant.
| Results|| |
This study included 23 eyes with NVG randomly selected from patients attending Al Hayah Private Eye Hospital in Mansourah City. Of the patients selected, 10 (43.47%) were women and 13 (56.5%) were men. The mean age ± SD was 56.17 ± 10.29 years (range 38-72 years). The primary ocular disease was diabetic retinopathy in 13 eyes (56.5%), retinal vein occlusion in eight eyes (34.7%), and combined venous occlusion and diabetic retinopathy in two eyes (8.6%). The mean preoperative NVM extension was 226.95 ± 97.34.
All eyes, before inclusion in the study, were under full systemic as well as topical medication and had also been treated previously with incomplete PRP; 11 eyes had received previous intravitreal Avastin IVA, one of which received it twice, and three eyes had undergone transscleral diode laser cyclophotocoagulation. This procedure was offered at the primary presentation of these patients with progressive NVG. All patients completed their follow-up and are still under regular appropriate follow-up at present.
All included eyes had been treated with simultaneous combined intravitreal and intracameral injection of bevacizumab followed by PRP. The patients were followed up for 3 months postoperatively to record the changes in BCVA and IOP. If any other type of intervention was needed, it was recorded along with the time of intervention. Patients were instructed about the symptoms of increased IOP and were asked to return as soon as they appeared regardless of the schedule of the follow-up visits.
The degree of angle involvement with NVM ranged between 90 and 360°, with a the mean ± SD of 226.0 ± 97.34° preoperatively. At 1 week postoperatively, NVM completely resolved clinically in 13 eyes (56.5%) and partially resolved in seven eyes (30.4%) to 90° involvement and in three eyes (12.7%) from 360° involvement to 180 and 270° involvement. At 1 week postoperatively, the mean ± SD of angle affection with NVM decreased to 58.69 ± 84.115°, with range between 0.0 and 270.0°, and this decrease was statistically highly significant with a P-value of up to 0.003 compared with preoperative values. At 1 month postoperatively, 16 eyes (69.6%) had 0°, six eyes (26.1%) had 90°, and only one eye had 180° angle involvement with NVM. The mean ± SD was 31.30 ± 51.54°, with a range between 0.0 and 180.0° and a highly statistically significant reduction with a P-value of up to 0.000 compared with preoperative values. The preoperative mean ± SD of PAS involvement of the anterior chamber angle was 144.7 ± 107.65°, with a range between 0.0 and 360.0°. Postoperative mean ± SD of PAS involvement decreased to 51.86 ± 80.6°, with a range between 0.0 and 270.0°, and this decrease was statistically highly significant with a P-value of up to 0.006.
As regard the IOP, the mean IOP before the procedure was 58.7 ± 16.2 mmHg (range 32.0-80.0 mmHg), despite the administration of topical (β-blockers, α-agonists, carbonic anhydrase inhibitors, prostaglandin analogs) and systemic (carbonic anhydrase inhibitors) IOP-lowering medications. Among all patients, a statistically significant decrease in IOP to 20.88 ± 9.99 mmHg (range 11.0-43.0 mmHg; P ≤ 0.001) was noted at 1 week after treatment. At 1 month, the mean IOP decreased further to 18.47 ± 5.6 mmHg (range 12-32 mmHg), and this decrease was statistically highly significant (P ≤ 0.001). 2 month postoperative, the mean IOP slightly increased compared with that during the first month but was still much less than the preinjection values (22.65 ± 8.7 mmHg, range 13-43), and this increase was still considered highly significant when compared with the preoperative values (P ≤ 0.001). At 3 months postoperative, the mean IOP continued to increase gradually but was still much less than the preoperative values (25.34 ± 6.806 mmHg, range 14.0-40.0 mmHg) and on comparing preoperative with preoperative values the difference remained highly statistically significant ( P ≤ 0.001). The course of IOP reduction during the follow-up period was highly statistically significant (P remained ≤ 0.001; [Figure 1]).
As regards the duration for which the patient was under controlled IOP following this procedure before the need of another intervention or medications, four eyes (17.39%) showed an increase in IOP within less than 30 days; seven eyes (30.4%) showed an increase in IOP within 30-60 days; and 12 eyes (52.17%) showed an increase in IOP after 60 days. Treatment was considered successful when patients had controlled IOP for a duration of 60 days or more and the intervention needed was only topical antiglaucoma drugs, completion of PRP, or control of IOP without any intervention. In this study eight cases were considered successful cases (34.7%). Three of these eight cases had controlled IOP for more than 90 days with no need for further treatment.
Preoperative mean BCVA (logMAR) was 1.47 ± 0.511 (range 2.48-1.0). At 1 week postoperatively, the mean BCVA logMAR was 1.29 ± 0.55 (2.3-0.6), and this was statistically highly significant ( P ≤ 0.00). At 1 month postoperatively, the mean BCVA logMAR was 1.16 ± 0.58 (2.3-0.6; P ≤ 0.00). At 2 months postoperatively, the mean BCVA logMAR was 1.15 ± 0.6 (2.3-0.6), which represents a statistically significant improvement in vision ( P ≤ 0.00), whereas at 3 months postinjection the mean BCVA logMAR was 1.3 ± 0.56 (2.5-0.6), which was still considered statistically significant compared with the preoperative values ( P ≤ 0.00), despite its apparent worsening compared with mean BCVA logMAR values during the first and second months [Figure 2].
| Discussion|| |
NVG is a devastating disease that is often highly resistant to treatment, resulting in severe visual loss . In addition to medical control of IOP and inflammation, PRP is the current gold standard for initial treatment . However, according to clinical experience, it may take weeks until the IOP-lowering effect of such laser treatment can be reached as involution of neovascularization after ablation of the hypoxic retina does not occur immediately and thus progression and growth of the NVM and the resulting angle closure in iris rubeosis continues for a further few days even after initiation of adequate treatment . In addition, retinal photocoagulation is sometimes rendered impossible because of corneal edema resulting from elevated IOP. If medical therapy is unsuccessful, surgical intervention is often necessary .
Intravitreal VEGF inhibitors serve as a specific pharmacologic inhibitor of one of the primary mediators of anterior segment neovascularization in NVG ,. Ehlers and colleagues reported that when bevacizumab injection was combined with PRP there was an increased rate and frequency of neovascular regression compared with that on PRP alone. In their study, patients who received treatment with bevacizumab showed more rapid reduction in IOP. The frequency and rapidity of neovascular regression were better in the combination therapy group, suggesting either a synergy between bevacizumab and PRP or predominance of a bevacizumab effect in the early post-treatment period . Previous studies on treatment with bevacizumab alone have shown INV regression earlier than that expected with PRP alone, suggesting that the predominant role of bevacizumab is played earlier ,,,,.
Several studies have focused on the utility of intracameral or intravitreal injection of bevacizumab. This study described the effect of simultaneous combined intravitreal and intracameral injection of bevacizumab followed by PRP; this was based on a previous experience of one of the authors in using intracameral bevacizumab alone in patients with NVG and the idea of magnification of the results obtained when combining intracameral and intravitreal bevacizumab injection to gain additive rapid effects on the levels of VEGF produced by retinal ischemia, and then stabilizing the good results obtained with PRP.
In this study, the degree of angle involvement with NVM ranged between 90 and 360°, with a mean ± SD of 226.0 ± 97.34° preoperatively. At 1 week postoperatively, the mean ± SD of angle involvement with NVM decreased to 58.69 ± 84.115°, with a range between 0.0 and 270.0°, and this decrease was statistically highly significant (P ≤ 0.003) compared with preinjection values. At 1 month postoperatively, the mean ± SD was 31.30 ± 51.54°, with a range between 0.0 and 180.0° and a statistically highly significant reduction (P ≤ 0.000) compared with preoperative values. This is in accordance with the findings of Ehlers and colleagues, who reported that injection of bevacizumab when combined with PRP led to an increase in the rate and frequency of neovascular regression compared with that on PRP alone; however, they performed only intravitreal injection.
In addition, regression of retinal neovascularization and INV after intravitreal injection of bevacizumab in human eyes has been reported ,,. Raghuram et al.  reported a marked effect of bevacizumab on ocular neovascularization, which might help widen the spectrum of bevacizumab usage in ocular diseases.
In this study the mean IOP before the procedure was 58.7 ± 16.2 mmHg (range 32.0-80.0 mmHg). A decrease in the mean IOP to 20.88 ± 9.99 mmHg ( P ≤ 0.001) was noted at 1 week after treatment. At 1 month postoperatively, the mean IOP decreased to 18.47 ± 5.6 mmHg (P ≤ 0.001). At 2 months postoperatively, the mean IOP slightly increased compared with that during the first month but was still much lesser than the preinjection value (22.65 ± 8.7 mmHg; P ≤ 0.001). At 3 months postoperatively, the mean IOP continued to increase gradually but was still much lesser than the preoperative value (25.34 ± 6.806 mmHg, range 14.0-40.0 mmHg; P ≤ 0.001). The changes in IOP were considered statistically significant throughout the study. Ehlers et al. , in their comparative study, reported that there was a trend toward a greater decrease in IOP in the bevacizumab/PRP group. In the same study, they reported that patients had a lower IOP with a greater drop in the pressure at the first visit after treatment compared with that in the PRP only group. However, it was noted that the initial mean pressure in the combined group was higher than that in the PRP only group; this might be because of an increased responsiveness to treatment.
In this study, BCVA improved in the majority of eyes throughout the follow-up visits, and this in accordance with many studies on intravitreal bevacizumab injection.
As regards the duration for which the patient was under controlled IOP following this procedure before the need for another intervention or medications, four eyes (17.39%) showed an increase in IOP within 30 days or less and seven eyes (30.4%) showed an increase in IOP within 30-60 days. Five of these patients agreed to repeat the procedure at about 2 months postoperatively, with a resultant excellent control of IOP thereafter. Glaucoma drainage procedure was done for three patients; those who suffered from PAS with a partially persistent membrane and the remaining three were controlled with full systemic and topical medication and then completed the laser sessions. Twelve eyes (52.17%) showed an increase in IOP after 60 days. Patients were considered to be successfully treated when they had a controlled IOP for duration of 60 days or more and the intervention needed was only either topical antiglaucoma drugs, completion of PRP, or control of IOP without any intervention. In this study eight cases were considered successful cases (34.7%). Three of these eight cases had controlled IOP for more than 90 days without a need for further treatment. One of the advantages of intracameral bevacizumab is the preservation of trabecular function in cases in which angle closure is not complete. Thus, urgent administration of anti-VEGF is advisable in cases in which the angle is still open, thereby avoiding the need of filtering surgery. In cases in which the remaining trabecular function was not sufficient to maintain acceptable IOP, the use of anti-VEGF allowed us to perform filtering surgery on a more risk-free angle.
These data from this study suggest a role of bevacizumab in the treatment of advanced NVG. This is in accordance with the findings of Yuzbasioglu et al. , who reported that after combined intravitreal and intracameral injection of bevacizumab in 15 patients, INV and angle were completely resolved within 36 h. IOP decreased to below 22 mmHg in six cases without any medication. Six cases needed medical treatment to achieve appropriate IOP levels. Surgical procedures were necessary in three patients who showed persistently high IOP levels despite completely resolved neovascularizations. They concluded that simultaneous intravitreal and intracameral injection of bevacizumab can cause an immediate regression in neovascularization secondary to PDR or CRVO and can be a useful adjuvant in the prevention of dense PAS formation, which leads to a persistent increase in IOP. However they did not perform PRP following the injection. As seen in clinical practice, there is a recurrence of increased IOP in many bevacizumab-treated eyes and additional treatments may become necessary.
As regards the intraocular toxicity of bevacizumab, doses 20 times higher than those used clinically have not been shown to cause any toxicity to the corneal endothelium or the trabecular cells ,. In this study, no serious systemic or ocular side effects such as hyphema, lens injury, glaucoma, cataract, iatrogenic retinal breaks, retinal detachment, or endophthalmitis were recorded.
The limitations of the current study are the limited number of cases and the heterogeneous group of patients with respect to the underlying retinal disease.
In summary, NVG is a blinding disease that is often highly resistant to treatment, resulting in severe visual loss. This study supports the use of combined intracameral and intravitreal injection of bevacizumab as a part of the initial treatment paradigm followed by PRP. The improved control of IOP, frequency and rate of neovascular regression, and the trend toward decreased need for further surgical intervention are exciting preliminary results. In this study, it was demonstrated that there is recurrence of NVG in a number of eyes over time, especially at 2 months postoperatively; hence, we recommend that combined intravitreal and intracameral injection of bevacizumab be repeated after 2 months in eyes with uncontrolled IOP. However, further studies with a longer term of follow-up and a larger number of patients, as well as comparative studies between the use of combined injection and intracameral injection alone or intravitreal injection alone, are needed.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]