Pain score method. Reproduced, with permission, from Michael D. Abràmoff et al.22
Pain score at each visit. Boxplots show median, 25th percentile, and 75th percentile; error bars represent minimum and maximum values.
Kaplan-Meier survival curve showing times to surgical intraocular pressure (IOP)–lowering intervention after intravitreal bevacizumab (IVB) injection. The majority of interventions were within the first 2 months.
Intraocular pressure (IOP) at each visit. Data markers represent mean group IOP; error bars represent 95% confidence intervals.
Kotecha A, Spratt A, Ogunbowale L, dell’Omo R, Kulkarni A, Bunce C, Franks WA. Intravitreal Bevacizumab in Refractory Neovascular GlaucomaA Prospective, Observational Case Series. Arch Ophthalmol. 2011;129(2):145-150. doi:10.1001/archophthalmol.2010.350
To examine the efficacy of intravitreal bevacizumab for pain relief in eyes with refractory neovascular glaucoma.
In this prospective case series, 52 eyes with neovascular glaucoma were administered intravitreal bevacizumab, 1.25 mg, and monitored for 6 months. The primary outcome measure was change in subjective pain score. Intraocular pressure and iris neovascularization were evaluated at each visit. Surgical intervention for control of intraocular pressure was performed according to clinical need.
Forty-two patients (44 eyes) completed the 6-month follow-up. Subjective pain score was reduced significantly 1 week after intravitreal bevacizumab injection and lasted throughout the follow-up period (median [interquartile range]: baseline, 3 [0-6]; week 1, 1 [0-3]; month 1, 0 [0-1]; month 3, 0 [0-1]; and month 6, 0 [0-0]; Kruskal-Wallis χ2 31.03; P < .001). A rapid, yet relatively transient, reduction in iris neovascularization was also noted (iris neovascularization grade at baseline, 4.0 [3-4]; week 1, 2.5 [1-4]; month 1, 2.0 [1-4]; month 3, 3.0 [2-4]; and month 6, 3.0 [2-4], χ2 23.33; P < .001). Four eyes (8%) required more than 1 injection to facilitate further intraocular surgery.
Intravitreal bevacizumab is a useful adjunct in the management of refractory neovascular glaucoma, producing rapid relief of pain. However, we found no evidence to suggest that intravitreal bevacizumab lowers intraocular pressure in eyes with angle closure; conventional medical, laser, and surgical treatment are still needed in these eyes.
A severe complication of ocular ischemia is neovascular glaucoma (NVG), which occurs when fibrovascular tissue proliferates within the anterior chamber angle. Contraction of this tissue leads to progressive angle closure, which rapidly results in an intractably elevated intraocular pressure (IOP); the consequence of progressive NVG is a painful and blind eye. The role of endogenous vascular endothelial growth factor (VEGF) in abnormal anterior segment angiogenesis is well documented1- 3; thus, management of NVG is targeted toward treating the underlying disease process responsible for the neovascular stimulus, usually by panretinal photocoagulation (PRP) and surgical reduction of IOP.4,5 However, in some eyes, PRP is ineffective and a poor fundal view caused by corneal edema, vitreous hemorrhage, or a poorly reactive pupil can make it difficult or impossible to perform.6,7 Furthermore, PRP is not always successful in inducing regression of iris neovascularization (NVI),4,8 which may increase the risk for intraoperative surgical complications and postoperative failure.9,10 Such unfortunate cases of progressive NVG are responsible for a significant proportion of eviscerations and enucleations that are undertaken to provide symptomatic relief.11,12
The anti-VEGF drug bevacizumab (Avastin; Genentech, San Francisco, California) is a humanized recombinant monoclonal IgG antibody that binds and inhibits all isoforms of VEGF.9 Primarily a US Food and Drug Administration–approved treatment of metastatic colorectal cancer,13 bevacizumab has also been shown to be effective when used off-label as an intravitreal injection to treat neovascular age-related macular degeneration.14,15 Several case series have reported the rapid regression of anterior segment neovascularization after use of intravitreal bevacizumab (IVB) to treat NVG.16- 19 Of these, one series reported significant relief of symptoms 48 hours after the injection.16
The primary purpose of this study was to prospectively examine the effects of IVB on pain in a large cohort of patients with NVG in whom standard treatment had been ineffective at reducing disease progression. Secondary outcome measures included NVI regression and anterior chamber inflammation.
The study was a prospective, observational case series; a randomized placebo-controlled trial design was rejected because the dire natural history of refractory NVG leaves no room for the clinical equipoise required for ethical randomization.20,21 Fifty consecutive adults with NVG in whom PRP was deemed ineffective or impossible by their managing medical retinal or vitreoretinal specialist were recruited following institutional review board and local research ethics committee approval. Patients with concurrent ocular infection, a clinically significant medical condition, or women lactating, pregnant, or of childbearing age who were not using reliable contraception were excluded from the study. Absence of vision was not an exclusion criterion for this series.
All patients were referred to and treated in the Glaucoma Service at Moorfields Eye Hospital, London, England, between November 1, 2006, and April 25, 2008, following informed consent, according to the tenets of the Declaration of Helsinki. Study participants were aware of the off-label use of bevacizumab. Data collected at enrollment included patient demographics, the underlying ophthalmic condition causing NVG, and previous ophthalmic treatment efforts.
An intravitreal injection of bevacizumab, 1.25 mg per 0.05 mL, was administered under aseptic conditions with topical povidone-iodine, 5%, to the conjunctival fornix. Intraocular pressure was measured immediately after the injection and, when required, an anterior chamber paracentesis was formed to normalize IOP. Further IVB injections were given according to clinical need. Patients were followed up at 1 week, 1 month, 3 months, and 6 months after the injection.
At each visit, patients were asked to subjectively rate their level of pain using a 10-point scale developed by Abràmoff et al22 (Figure 1). In addition, a comprehensive eye examination that included best corrected Snellen visual acuity (VA), Goldmann applanation tonometry, slitlamp and gonioscopic evidence of NVI and angle neovascularization (NVA), anterior chamber flare, and fundoscopic findings was undertaken in the treated and untreated eyes.
Iris neovascularization and NVA were graded at each visit according to the classification system of Weiss and Gold,23 which distinguishes 4 stages of neovascularization dependent on the number of iris quadrants affected, with a score of 0 indicating no neovascularization.24 Anterior chamber flare values were measured using the Kowa FM-500 laser flare meter (Kowa Company, Tokyo, Japan) before instillation of any eyedrops. Measurements were repeated until 7 acceptable readings (ie, signal-to-noise ratio of <10%) were obtained from the study eye. The lowest and highest readings were then discarded and the mean laser flare photometry value of the remaining 5 measurements was calculated. Values are expressed as photon count per millisecond (phc/ms).
Visual acuity was converted to logMar equivalent using conversion factors detailed by Holladay25; counting fingers vision was assigned a logMAR value of 2 and hand movements was assigned a value of 3.
Throughout the study, elevated IOP was treated based on clinical need, through topical antiglaucoma medication, implantation of a glaucoma drainage device, or cyclodiode laser treatment.
Statistical analysis was performed using SPSS version 17.0 (SPSS Inc, Cary, North Carolina). Descriptive statistics for normally distributed data are presented as mean (SD) and, for nonnormal distributions, as median and interquartile range (IQR). Changes in parameters at each visit were examined using a 1-way analysis of variance (ANOVA) in parameters where the baseline data were normally distributed or a Kruskal-Wallis 1-way analysis, applied for nonnormal distribution of data.
Kaplan-Meier plots were generated to illustrate the days to surgical IOP reduction after IVB injection.
Fifty patients with NVG were enrolled in the study; patient demographics are displayed in Table 1. Two patients received IVB in both eyes and the results of 52 eyes are presented. The underlying ophthalmic conditions causing NVG included proliferative diabetic retinopathy (15 [29%]), central retinal vein occlusion (20 [38%]), hemiretinal vein occlusion (2 [4%]), ocular ischemic syndrome (6 [10%]), chronic retinal detachment after retinopathy of prematurity (2 [4%]), chronic retinal detachment after proliferative vitreoretinopathy (2 [4%]), chronic retinal detachment due to retinal angiectasis (2 [4%]), central retinal artery occlusion (2 [4%]), and history of trauma (1 [2%]).
Details of ophthalmic treatment before entering the study can be found in Table 2. Twenty patients (38%) were taking acetazolamide; only 5 patients (5 eyes [10%]) were not taking any form of ocular hypotensive medication.
Mean (SD) VA in sighted eyes (n = 35) was 1.95 (0.97) logMAR equivalent (range 0.3-3.0). Of the remainder of eyes, 4 showed light perception (LP) and 13 had no light perception (NLP).
Table 3 details the baseline gonioscopic findings of the study cohort. Most eyes (31 [60%]) had more than 180° peripheral anterior synechiae (PAS).
Forty-two patients (44 eyes) completed their 6-month follow-up. Of those unavailable for follow-up, 2 patients (2 eyes) died of preexisting illnesses that were unrelated to treatment with IVB, 1 patient (1 eye) was deported from the United Kingdom, and 1 patient (1 eye) was too infirm to attend subsequent appointments. The remainder of patients unavailable for follow-up did not respond to communication regarding their appointments. Follow-up visits after injection (median [IQR]) were at 1 week (7 [7-11] days), 1 month (36 [28-44] days), 3 months (95 [85-109] days), and 6 months (185 [171-203] days).
Due to persistent angle and/or NVI and raised IOP (>35 mm Hg), 3 of 52 (6%) eyes required a repeat IVB injection (119 days, 141 days, and 176 days after the first injection) and 1 eye (2%) required 2 further IVB injections (24 days and 235 days after the first injection). In these eyes, repeat injections were deemed clinically necessary to facilitate placement of a glaucoma drainage device or cataract operations. One eye (2%) developed a temporary central retinal artery occlusion after injection, thought to be due to the elevated IOP (58 mm Hg) caused by the extra volume of fluid injected into the vitreous. This resolved after an anterior chamber paracentesis. After cataract extraction, 1 eye (2%) was administered further PRP 6 months after the IVB injection. There were no serious adverse events attributable to IVB during the study.
There was a significant reduction in pain score during the study (median [IQR]: baseline, 3 [0-6]; week 1, 1 [0-3]; month 1, 0 [0-1]; month 3, 0 [0-1]; and month 6, 0 [0-0]; Kruskal-Wallis χ2 31.03; P < .001; Figure 2).
A reduction in NVI grade was noted in the cohort 1 week after injection, with values gradually increasing (median [IQR]: baseline, 4.0 [3.0-4.0]; week 1, 2.5 [1.0-4.0]; month 1, 2.0 [1.0-4.0]; month 3, 3.0 [2.0-4.0]; and month 6, 3.0 [2.0-4.0], Kruskal-Wallis χ2 23.33, P < .001). No significant changes in NVA grade were noted (median [range]: baseline, 3.0 [2.0-4.0]; week 1, 3.0 [1.0-4.0]; month 1, 2.0 [1.0-4.0]; month 3, 3.0 [1.25-4.0]; and month 6, 3.0 [2.5-4.0]; Kruskal-Wallis χ2 2.25; P = .69).
Anterior chamber flare measurements were not possible in a number of eyes, but in eyes where they were possible, there appeared to be a reduction in flare during follow-up (mean [SD]: baseline [n = 43], 118.1 [110.8] phc/ms; week 1 [n = 37], 83.8 [100.2] phc/mc; month 1 [n = 32], 74.5 [69.9] phc/ms; month 3 [n = 35], 71.8 [90.4] phc/ms; and month 6 [n = 35], 85.5 [114.7] phc/ms; Kruskal-Wallis χ2 7.69, P = .10).
Ten eyes (19%) underwent cataract extraction during the study. There was a small, significant improvement in VA in 29 sighted eyes of patients who completed the 6-month follow-up (mean [SD] logMAR equivalent VA at baseline, 1.8 [1.0] and at 6 months, 1.5 [1.0]; paired samples t test, P = .03). Of the remaining 14 eyes, 7 eyes (50%) remained NPL, 4 eyes (29%) developed worse VA (PL to NPL: n = 2; logMAR equivalent VA, 3 to NPL: n = 1; logMAR equivalent VA, 2 to PL: n = 1), and 3 (21%) showed significant VA improvement (NPL at baseline to logMAR equivalent VA, 2 at 6 months, PL to logMAR equivalent VA, =3 and PL to logMAR equivalent VA, 0.18).
At the 6-month visit, 22 eyes (50%) showed no change in angle configuration compared with baseline. Two eyes (5%) were noted to improve, from 360° PAS to 180° to 360° PAS, while 15 eyes (34%) showed increasing degrees of PAS, from no PAS to 360° PAS (n = 2); no PAS to 0° to 180° PAS (n = 2); 0° to 180° PAS to 180° to 360° PAS (n = 5); and 180° to 360° PAS to 360° PAS (n = 6).
During the 6-month study, 31 eyes (60%) had a glaucoma drainage device inserted after IVB injection: 1 Baerveldt (AMO Groningen BV, Groningen, Netherlands) and 30 Ahmed glaucoma valves (New World Medical, Inc, Rancho Cucamonga, California). Glaucoma drainage device placement was undertaken at a mean [SD; range] of 18 [21.1; 1-125] days after injection. Two eyes (6%) developed a hyphema immediately after the procedure, which resolved within 7 days. One eye (3%) developed a fibrovascular membrane over the tube entrance 3 months after the procedure, but this resolved after an intracameral injection of bevacizumab, 0.625 mg (in 0.025 mL), and IOP returned to an acceptable level.26 Twelve eyes (23%) received transscleral cyclodiode laser treatment to the ciliary body at a mean [SD; range] of 16 [6; 7-24] days after IVB. Seven eyes (13%) required no further IOP-lowering intervention. Figure 3 shows a Kaplan-Meier survival curve illustrating times to surgical IOP-lowering intervention.
There was a reduction in the number of topical glaucoma medications required after IVB with and without surgical IOP-lowering intervention: median [IQR] number baseline, 3 [2-3]; week 1, 2 [0-3]; month 1, 0 [0-2]; month 3, 0 [0-1]; and month 6, 0 [0-1.75]. There was also a significant reduction in IOP in the group: mean [SD] baseline, 36.7 [14.7] mm Hg; week 1, 29.3 [16.1] mm Hg; month 1, 17.4 [12.5] mm Hg; month 3, 21.4 [10.7] mm Hg; and month 6, 19.5 [10.1] mm Hg (analysis of variance F statistic 18.65, P < .001; Figure 4).
To our knowledge, this is the largest study evaluating the effects of IVB in eyes with refractory NVG. Our data add to the growing body of evidence that IVB may be effective in the management of this condition.
Eyes with progressive NVG can become significantly painful and relief of symptoms proves difficult in many cases. There have been positive results reported with the use of retrobulbar injections of alcohol for ocular pain relief, but the effects are not permanent, especially if the underlying cause is not treated27- 29; thus, enucleation or evisceration may be the only option.28,30 In the present study, a significant reduction in patients' pain scores was noted within the first week after IVB injection, which persisted throughout the follow-up period. The pain relief experienced in NVG is usually attributed to a reduction in IOP,31,32 but in our cohort, the pain relief exhibited at week 1 was accompanied by only a modest IOP reduction (mean IOP, 36.7 mm Hg preinjection; 29.3 mm Hg 1 week postinjection). Therefore, other factors may be involved in the improvement of symptoms. A characteristic feature of vessels formed by pathologic angiogenesis is their excessive permeability, and VEGF has also been shown to increase the permeability of established microvasculature.33- 35 This is likely to result in an increased presence of inflammatory mediators within the ocular tissues. Regression of new vessels and reduction of intraocular VEGF concentrations should reduce this effect, thus alleviating pain symptoms. Anti-VEGF therapy has been shown to rapidly reduce NVI,16- 19 and our data set showed a significant and rapid reduction in NVI by 1 week after IVB injection. Our data also showed a reduction in anterior chamber flare in the immediate postinjection period, although this was not statistically significant. Nonetheless, these findings support the hypothesis that new vessel regression and reduced vessel permeability may in part explain the rapid relief of symptoms exhibited by our patients. However, it is likely that the persistent reduction in pain scores noted during the study was due to a combination of reduction in both IOP and vessel permeability.
During our study, there appeared to be no significant reduction in NVA. However, of the cohort presented, the majority had significant PAS (≥180°; 31 eyes [60%]), suggesting an advanced stage of NVG that may be relatively unresponsive to anti-VEGF therapies. Previous case reports36 have shown variable results with respect to the degree of NVA regression after IVB injections.
Our initial plan was to report NVI and NVA regression and anterior chamber flare descriptively, because these were not primary outcome measures.. For completion, P values are provided, but some caution is urged regarding their interpretation since the study was not powered to detect differences in these parameters.
The majority of eyes studied required surgical intervention to lower IOP, and this occurred within the first 2 months after IVB injection. Previous reports17,37 have suggested that IVB-induced NVI and NVA regression alone may stabilize elevated IOP, via a reduction of fibrovascular contraction angle closure, reducing the need for surgical IOP-lowering interventions. However, our study included patients with advanced, refractory NVG, most of whom had significant angle closure. Intraocular pressure was successfully reduced in all eyes after either glaucoma drainage device insertion or cyclodiode therapy, and fewer glaucoma medications were required to maintain IOP at a satisfactory level throughout the follow-up period. Furthermore, there were no significant surgical complications, with only 2 eyes (7%) developing a hyphema during surgery that resolved within 7 days. Previous studies evaluating surgical success in NVG eyes without the use of IVB reported a higher prevalence of intraoperative bleeding and hyphema. In a study by Mermoud et al31 evaluating the use of Molteno tube implants in controlling IOP in NVG, 12 of 20 eyes (20%) developed a hyphema. Similar percentages of intraoperative bleeding during glaucoma drainage device insertion without IVB have been reported by Eid et al38 and Kim et al,10 while Takihara and coworkers39 showed a much higher prevalence during trabeculectomy, with 59 of 101 eyes (58%) developing a hyphema. In a recent study by Chen and coworkers,40 the incidence of intraoperative hyphema was doubled in NVG eyes undergoing trabeculectomy without adjunctive IVB (1 of 14 eyes [7%] in the IVB group vs 4 of 28 eyes [14%] in the untreated group). Our data add to the suggestion that the preoperative use of IVB may reduce the bleeding complications associated with operations in eyes with NVG.17,41- 43
The visual outcomes of the present study compare favorably with previous reports of management of NVG eyes. In a study44 reporting the outcomes of 32 eyes undergoing “intense” antiproliferative surgery for uncontrolled NVG, 18 eyes (56%) showed deterioration in vision, with 10 eyes (32%) becoming blind after treatment. In another study45 examining the effects of combined pars plana vitrectomy, PRP, and trabeculectomy as treatment for NVG, 5 of 25 eyes (20%) lost sight and became pthisical after treatment.In contrast, in our study, only 4 eyes (8%) showed worsening VA by the end of the study, with 3 eyes (6%) progressing to NLP, and 3 eyes (6%) showing visual improvement. A recent retrospective case series17 reporting the outcomes of IVB in 41 sighted eyes with NVG found a visual improvement in 14 eyes (34%) and a deterioration of 3 lines or more in 8 eyes (19%). A potential risk of using IVB is that inhibition of the panisoform of VEGF may lead to toxicity of normal retinal vasculature,46 which may lead to a further loss of vision. However, in our group of eyes with advanced NVG, it is difficult to speculate whether further visual loss may have occurred regardless of IVB use due to the nature of the condition.
Four eyes (8%) in our study required repeat injections of IVB in view of persistent NVI to facilitate placement of a glaucoma drainage device or cataract operations. There is no recommended treatment protocol for IVB use in NVG and many ophthalmologists administer multiple IVB injections at variable intervals as per clinical need.17,19,36,47- 49 Our data showed a small increase in NVI during the study, adding further evidence to the observations that the anterior chamber vessel regression effects of IVB injections for NVG are temporary. In a recent randomized controlled study50 evaluating IVB in nonrefractory NVG, eyes randomized to IVB were given 3 injections at monthly intervals, with IVB doses higher than in previous reports. In that study, 6 eyes (43%) in the IVB group required additional surgical intervention to reduce IOP. It is still uncertain what constitutes the ideal IVB dosage for NVG. In addition to the theoretical retinal toxic effects, the drug has been associated with severe intraocular inflammation.51 The medical and legal risks of off-label use of a drug relate to the unknown long-term effects of a treatment that has not been rigorously tested for ophthalmic use.52 However, a recent worldwide Internet-based study by Fung and coworkers53 reporting complications of IVB injections suggests that current clinical practice is safe.
Our study suggests that in the majority of cases, the use of a single IVB injection is an acceptable adjuvant to allow for safe surgical intervention, satisfactory IOP lowering, and a comfortable course in refractory neovascular glaucoma. Further research is required to elucidate the longer-term vision outcomes and IOP control in these cases.
Correspondence: Wendy A. Franks, FRCOphth, Glaucoma Research Unit, Moorfields Eye Hospital, 162 City Rd, London EC1V 2PD, England (firstname.lastname@example.org).
Submitted for Publication: February 26, 2010; accepted April 20, 2010.
Author Contributions: Drs Kotecha, Bunce, and Franks had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Financial Disclosure: Dr Kotecha receives a proportion of her funding from the Department of Health's National Institute for Health Research Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital NHS Foundation Trust and the University College London Institute of Ophthalmology.
Previous Presentation: This study was presented in part at the American Academy of Ophthalmologists Annual Meeting (with Pan-American Association of Ophthalmology); October 25, 2009; San Francisco, California.
Additional Information: This study was registered with the United Kingdom Medicines and Healthcare products Regulatory Agency, an executive agency of the United Kingdom Department of Health.
Additional Contributions: The authors thank Sofia Fernandes, MSc, Laura Gangadeen, and Sheetal Patel, BSc, for their assistance in coordinating this study.