Persistent Ocular Hypertension Following Intravitreal Bevacizumab and Ranibizumab Injections

Abstract

Purpose:

To study ocular hypertension (OHT) following intravitreal injections of bevacizumab and/or ranibizumab in patients with age-related macular degeneration (AMD).

Methods:

Retrospective case series. Patients with AMD who were treated at a tertiary referral center with intravitreal bevacizumab and/or ranibizumab injections from January 1, 2006 to December 31, 2008 were studied. The development of OHT following these injections was investigated.

Results:

Four out of 116 patients with AMD (3.45%) developed sustained elevated intraocular pressure (IOP) after multiple intravitreal injections of bevacizumab 1.5 mg/0.06 mL and/or ranibizumab 0.5 mg/0.05 mL. An analysis of 4 cases revealed: None of the patients had a previous diagnosis or family history of glaucoma/OHT. Two patients had both bevacizumab and ranibizumab injections. Two patients developed OHT after recent intravitreal ranibizumab and 2 patients after recent intravitreal bevacizumab injection. Two patients were pseudophakic with a history of YAG capsulotomy. The range of preinjection IOP was 8–15 mmHg (mean, 13 mmHg). The range of postinjection IOP was 28–36 mmHg (mean, 31.75 mmHg). The range of IOP increase was 17–21 mmHg (mean, 18.75 mmHg). Mean number of pan-anti-VEGF injections prior to OHT was 13.3 (range, 3–19). A disrupted posterior capsule might predispose patients to the development of OHT.

Conclusions:

Persistent OHT may occur after intravitreal anti-VEGF injection in patients with no previous diagnosis of glaucoma or OHT. OHT may persist across several visits and patients may require IOP-lowering therapy. Sustained elevation in IOP usually occurs after multiple injections.

Introduction

Inhibition of vascular endothelial growth factor (VEGF) via intravitreal injection of monoclonal antibodies is currently the leading treatment for choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). Bevacizumab (Avastin^®, Genentech, South San Francisco, CA) is a recombinant humanized full-length monoclonal antibody, which binds to all biologically active isoforms of the key mediator of angiogenesis, VEGF-A. Ranibizumab (Lucentis^®, Genentech, South San Francisco, CA) is a recombinant humanized monoclonal antibody fragment with some modifications to the amino acid sequence that increases its binding affinity to VEGF-A. Bevacizumab is a large molecule (150 kDa) with 2 antigen-binding sites (Fab) and longer half-life; ranibizumab is a smaller molecule (48 kDa) with one binding site. Ranibizumab was approved by the US Food and Drug Administration (FDA) in June 2006 at a dose of 0.5 mg for intravitreal injection for the treatment of neovascular AMD. Bevacizumab was originally FDA approved for intravenous infusion in the treatment of metastatic colorectal carcinoma. While bevacizumab’s FDA approval has expanded to include use in non-small cell lung cancer and metastatic HER2-negative breast cancer, its intraocular use is off-label. Several studies, however, have shown the benefits of using intravitreal bevacizumab for treating CNV, and there has been widespread “off-label” use of bevacizumab since its intraocular use was first reported in 2005.1 –3 Ocular complications of intravitreal ranibizumab or bevacizumab injections include endophthalmitis, retinal tears, vitreous hemorrhage, and lens damage.

Four studies (2 of bevacizumab, 1 of ranibizumab, and 1 study of both) have investigated the short-term intraocular pressure (IOP) changes after intravitreal injection of bevacizumab or ranibizumab.4 –7 These studies have shown that intravitreal injection of bevacizumab or ranibizumab led to an expected transient elevation of IOP immediately after injection. IOP usually returned to a lower level (below 25 mmHg) within 30–60 min without utilizing therapy for IOP control. Hollands and colleagues observed that patients who were phakic might have a slightly higher IOP, compared to the pseudophakic patients shortly after intravitreal injection of bevacizumab or ranibizumab.4 In addition, eyes with a history of glaucoma may take longer to return to the baseline IOP.5 In these studies, other factors such as baseline IOP, age, gender, refractive error, and previous intravitreal injections were of no predictive value in determining postinjection IOP.

Rosenfeld and colleagues and Brown and colleagues reported that ranibizumab had no long-term effect on IOP as determined by monthly measurements during the MARINA and ANCHOR studies.8^,9 Despite monthly ranibizumab injections and frequent follow-up during these studies, as well as many other patients who have received ranibizumab or bevacizumab intravitreal injections since 2005, to our knowledge, there have been 2 reports of sustained ocular hypertension (OHT) following intravitreal ranibizumab or bevacizumab treatment in patients with no past ocular history of glaucoma, glaucoma suspect, OHT, or IOP asymmetry.10^,11 Bakri and colleagues reported 4 cases of delayed and sustained OHT following intravitreal ranibizumab for treating CNV due to AMD in patients with no past history of glaucoma or OHT.10 Kahook and colleagues reported 6 cases of sustained elevation of IOP following single or multiple intravitreal bevacizumab for treating various choroidal neovascular diseases.11 Three out of the 6 patients had a past ocular history of glaucoma or were diagnosed as glaucoma suspects. Among the 3 patients who did not have a past ocular history of glaucoma, glaucoma suspect, or OHT, 1 patient was treated for choroidal neovascular membrane (CNVM) due to high myopia, and the other 2 were treated for CNVM due to unspecified causes.11

In the current article, we report 4 cases of OHT following multiple intravitreal injections of bevacizumab and/or ranibizumab in AMD patients and analyze the previous cases and available literature regarding OHT after anti-VEGF agents.

Methods

A retrospective study of 116 patients including demographics, clinical course, and management was conducted to investigate the development of OHT following intravitreal bevacizumab and/or ranibizumab injections. This study reviewed 116 patients with AMD who were treated at a tertiary eye center with intravitreal bevacizumab 1.5 mg/0.06 mL and/or ranibizumab 0.5 mg/0.05 mL injections. Ocular hypertension was defined as IOP above 21 mmHg measured by Goldmann Applanation tonometry by 2 separate measurements. Patients were followed up every 4–6 weeks. During the following up visits, patients had an evaluation of visual acuity, IOP measured by Goldmann Applanation tonometry, slit lamp examination, dilated fundus exam, and macular optical coherence tomography scanning (OCT). The IOP was measured using Goldmann Applanation tonometry on at least 2 occasions by 2 ophthalmologists (HM, RA). Minimum follow-up period was 3 months (range, 3–36 months).

The Human Investigation Committee at Yale University School of Medicine exempted this study from IRB approval.

Results

In our center, 235 patients had intravitreal injections of pan-anti-VEGF medications from January 1, 2006 to December 31, 2008. One hundred and sixteen of these patients had wet AMD and 119 had other ocular disorders such as rubeosis, neovascular glaucoma, proliferative diabetic retinopathy, and venous occlusion. We excluded patients who received anti-VEGF for diseases except wet AMD because of high risk of OHT from rubeosis, neovascular glaucoma, proliferative diabetic retinopathy, and vascular occlusions. Among 116 patients with wet AMD who received intravitreal pan-anti-VEGF injections, 57 received ranibizumab, 40 received bevacizumab, and 19 received both. Four out of 116 wet AMD patients (3.45%) who had intravitreal pan-anti-VEGF injections developed persistent OHT.

Patient 1

An 82-year-old Caucasian female was treated with ranibizumab for CNV OS due to AMD for 2 years and a half. She had dry AMD OD and was pseudophakic OU. She had no previous or family history of glaucoma, no history of OHT or IOP asymmetry, and no steroid use. Before the first ranibizumab injection, her IOPs were 15 mmHg OU, and best-corrected visual acuity was 20/20 OD and 20/80 OS. The patient had intravitreal ranibizumab and bevacizumab injections every 4–6 weeks over the course of 2 years and a half, beginning in 2006. The patient initially had 5 intravitreal ranibizumab injections and then switched to bevacizumab. After receiving 3 bevacizumab injections, she decided to continue with ranibizumab injections instead of bevacizumab. Her IOPs through the first 24 months were below 21 mmHg OU and symmetric. One month after the 16th ranibizumab injection, the patient was noted to have an IOP of 25 mmHg OS. One month after her 17th ranibizumab injection, her IOP was 32 mmHg OS. Angles were open 360° on gonioscopy. Cup-to-disk ratios were 0.55 OD and 0.7 with inferior thinning OS. She initially declined IOP-lowering therapy, and her IOP remained 25 mmHg OS 1 month following the 18th intravitreal ranibizumab. Later the patient agreed to be treated for OHT and was started on Azopt twice daily OS, and 2 months later her IOP was 16 mmHg OD/20 mmHg OS.

Patient 2

An 85-year-old Caucasian female had been treated with 6 monthly intravitreal ranibizumab injections for CNV OD due to AMD. Baseline examination was remarkable for dry AMD OS and pseudophakia with a PCIOL OU. The patient had no previous or family history of glaucoma, and no OHT or IOP asymmetry. She had a history of temporal arteritis for which she had been on oral prednisone 5 mg daily for the previous 7.5 years. Her IOPs were measured at least once a year for the past 9 years at our center, and her IOPs remained between 12 and 20 mmHg OU and symmetric before she was started on intravitreal ranibizumab injections. The patient’s preinjection visual acuity was 20/50 OU and her IOPs were 14 mmHg OD/12 mmHg OS and remained below 19 mmHg and symmetric through the first 2 months of therapy. Two months after the third ranibizumab, the patient was noted to have an IOP of 28 mmHg OD and 16 mmHg OS. After 2 further ranibizumab injections, her IOP was 31 mmHg OD/14 mmHg OS. Her angles were open 360° on gonioscopy and her cup-to-disk ratios were 0.7 OD and 0.4 OS. The patient was treated with Timoptic-XE 0.5% once daily OD, and 3 months later, her IOP was lowered to 17 mmHg OD/13 mmHg OS.

Patient 3

An 88-year-old Caucasian male with AMD and extrafoveal CNVM OD had visual acuity of 20/200 OD and hand movement OS. The patient had a history of a recurrent retinal detachment OS several years ago. The right eye had been treated with a total of 4 monthly intravitreal ranibizumab followed by 2 monthly intravitreal bevacizumab injections OD. The patient had no previous or family history of glaucoma, no OHT, and no history of steroid use. Before the first ranibizumab injection, his IOP was 8 mmHg OD/5 mmHg OS. One month after the first intravitreal ranibizumab injection, IOP slightly increased to 12 mmHg OD, and remained around 15 mmHg OD following 3 further intravitreal ranibizumab injections. He had no additional intravitreal injections for over a year and his IOP remained between 12 and 14 mmHg OD and between 2 and 8 mmHg OS. A year after the last ranibizumab injection, he had a recurrence of CNVM OD and had 2 intravitreal bevacizumab injections OD, 1 month apart. Prior to the first intravitreal bevacizumab injection, his IOP was 13 mmHg OD. One month after the second bevacizumab injection, IOP was elevated to 24 mmHg OD; 3 months after the injection, his IOP was 28 mmHg OD.

Patient 4

A 77-year-old Caucasian female was referred to us for the management of wet AMD OD. She had received 2 monthly injections of bevacizumab (1.5 mg/0.05 mL) before she was referred to us. At her first visit at our center, her visual acuity with correction was 20/40 OD and 20/25 OS, and IOP was 16 mmHg OU. Baseline examination was remarkable for wet AMD OD with retinal pigment epithelial tear and subretinal fluid. She had dry AMD OS, posterior vitreous detachment OS, and mild nuclear sclerotic cataract OU. The disk showed a cup-to-disk ratio of 0.45 OD and 0.55 OS with pink, flat, and sharp rims. She had no previous or family history of glaucoma, OHT or IOP asymmetry, and no history of steroid use. She received another 11 intravitreal bevacizumab injections (1.5 mg/0.06 mL) every 4–6 weeks over a period of 15 months. Her IOPs remained below 17 mmHg and symmetric through the first 9 bevacizumab injections. Two months after the 10th bevacizumab, IOP was mildly elevated to 23 mmHg OD/14 mmHg OS. One month after the 12th bevacizumab, her IOP was elevated to 36 mmHg OD/14 mmHg OS. The patient was immediately treated with one drop of Cosopt and one drop of Alphagan, and her IOP was reduced to 12 mmHg OD/14 mmHg OS within 2 h. Angles were open 360° on gonioscopy and her cup-to-disk ratios were 0.1 OD and 0.25 OS. The patient was treated with timolol 0.5% once daily OD.

Summary of 4 cases of persistent IOP following intravitreal pan-anti-VEGF (bevacizumab and/or ranibizumab) injections in AMD patients

In the present study, we report 4 cases of sustained elevated IOP after multiple intravitreal injections of bevacizumab 1.5 mg/0.06 mL and/or ranibizumab 0.5 mg/0.05 mL (Table 1). OHT occurred 1 month after the 19th pan-anti-VEGF injection (3 bevacizumab and 16 ranibizumab) in patient 1, 2 months after the third ranibizumab injection in patient 2, and 1 month after the 12th bevacizumab injections in patient 4. Patient 3 maintained normal IOP after 4 ranibizumab injections, but developed OHT 1 month after the second bevacizumab injection.

Table 1.

Summary of 8 Cases of Persistent Intraocular Pressure (IOP) Following Intravitreal Pan-Anti-VEGF (Bevacizumab and/or Ranibizumab) Injections in Patients With Age-Related Macular Degeneration (AMD)

Patient No. a	Preinjection IOP (mmHg) b	Postinjection maximum IOP (mmHg) c	IOP increase (mmHg) d	Total number of pan-anti-VEGF injections prior to the occurrence of OHT e	Most recent injected agent prior to OHT	Other ocular medications or steroid usage	Lens status f
4 Cases reported by our study
1	15	32	17	19 (3 bevacizumab + 16 ranibizumab)	Ranibizumab	None	PCIOL OU
2	14	31	17	3 (3 ranibizumab)	Ranibizumab	Oral prednisone 5 mg daily for temporal arteritis	PCIOL OU
3	8	28	20	6 (4 ranibizumab + 2 bevacizumab)	Bevacizumab	None	Nuclear sclerosis
4	15	36	21	12 (12 bevacizumab)	Bevacizumab	None	Mild nuclear sclerosis
Average	13	31.75	18.75	13.3
Range	8–15	28–36	17–21	3–19
4 Cases reported by Bakri and colleagues10
5	22	30	8	2 (2 ranibizumab)	Ranibizumab	3 Pegaptanib	Mild cataract
6	18	34	16	4 (3 bevacizumab + 1 ranibizumab)	Ranibizumab	None	PCIOL OU
7	15	46	31	11 (9 bevacizumab + 2 ranibizumab)	Ranibizumab	2 Pegaptanib	Mild nuclear sclerosis
8	15	50	35	1 (1 ranibizumab)	Ranibizumab	1 intravitreal triamcinolone 16 months priorg	PCIOL OU
Average	17.5	40.0	22.5	4.5
Range	15–22	30–50	8–35	1–11

^aPatients 1–4 were studied at our center; patients 5–8 were reported by Bakri and colleagues.10

^bFor patients 1–4, preinjection intraocular pressure (IOP) was the IOP measured, using Goldmann Applanation tonometry, before patients received the first ranibizumab or bevacizumab injection. IOP for patients 5–8 was reported by Bakri and colleagues.10

^cPostinjection maximum IOP was the maximum IOP recorded, using Goldmann Applanation tonometry, since the occurrence of ocular hypertension (OHT) and before the patients had started any IOP-lowering therapy.

^dIOP increase = Postinjection maximum IOP – Preinjection IOP.

^eThe total number of pan-antivascular endothelial growth factor (VEGF) injections includes the total number of intravitreal bevacizumab and/or ranibizumab injections. We did not include the number of intravitreal pegaptanib injections in the count because it is not a pan-anti-VEGF agent.

^fPCIOL = posterior chamber intraocular lens.

^gSixteen months before having an intravitreal ranibizumab injection, patient 8 had one intravitreal triamcinolone injection with no IOP rise.10

An analysis of all 4 cases revealed: none of the patients had a previous diagnosis of glaucoma, OHT, or a family history of glaucoma. Two patients developed OHT after recent intravitreal ranibizumab and 2 patients after recent intravitreal bevacizumab injections (Table 1). Two patients were pseudophakic with a history of a YAG capsulotomy. The range of preinjection IOP was 8–15 mmHg (mean, 13 mmHg). The mean postinjection IOP was 28–36 mmHg (mean, 31.75 mmHg). Mean number of total anti-VEGF injections prior to OHT was 13.3 (range, 3–19).

Discussion

Persistent OHT following intravitreal ranibizumab is a recently reported condition. In the present study, we reported 4 cases of persistent OHT following multiple intravitreal injections of bevacizumab and/or ranibizumab in AMD patients who have no past ocular or family history of glaucoma, glaucoma suspect, OHT, or asymmetric IOP, and reviewed the previous case reports and available literature regarding OHT after anti-VEGF agents. To define the clinical characteristics of persistent OHT following intravitreal anti-VEGF for AMD, we analyzed all of the available cases in the literature, including our 4 cases and Bakri et al.’s 4 cases. Since both studies utilized similar methods and patient selection criteria, combining cases and analyzing them together enhance our knowledge of persistent OHT following pan-anti-VEGF injections. This approach may elucidate the clinical presentation and epidemiology of this newly described condition.

To our knowledge, there have been only 2 previous reports of sustained OHT following intravitreal ranibizumab or bevacizumab treatment.10^,11 Similar to the findings from our study, none of the patients from Bakri et al.’s report had a previous diagnosis of glaucoma, OHT, or a family history of glaucoma. Two patients were pseudophakic with a history of a YAG capsulotomy. The range of preinjection IOP was 15–22 mmHg (mean, 17.5 mmHg). The range of postinjection IOP was 30–50 mmHg (mean, 40 mmHg). Thus on average, patients had an IOP increase of 22.5 mmHg (range, 8–35 mmHg), which is similar to the finding from our study (mean IOP increase of 18.75 mmHg, range 17–21 mmHg, Table 1). In Bakri et al.’s study, all 4 patients developed OHT after recent intravitreal ranibizumab.10 The mean number of total anti-VEGF injections prior to OHT from Bakri et al.’s study was 4.5 (range, 1–11), which is smaller compared to the number observed in our study (Table 1).

Kahook and colleagues reported 6 cases of sustained elevation of IOP following single or multiple intravitreal bevacizumab for treating various choroidal neovascular diseases.11 Three out of the 6 patients had a past ocular history of glaucoma or glaucoma suspect, and these patients are likely at a higher risk of developing OHT. The other 3 patients, who did not have a past ocular history of glaucoma, glaucoma suspect, or OHT, received intravitreal injection of bevacizumab for treatment of CNVM due to high myopia and unspecified causes.11 We did not include these patients in our analysis because we could not assess their risks of developing OHT prior to intravitreal anti-VEGF injection based on the information provided in Kahook et al.’s article.

Among the 8 patients (4 from our study and 4 from Bakri et al.’s study, Table 1), 2 patients had intravitreal pegaptanib injections before switching their treatments to intravitreal bevacizumab and/or ranibizumab. Pegaptanib (Macugen^®, Eyetech-OSI, New York), a 28-base ribonucleic acid aptamer covalently linked to 2 branched 20-kDa polyethylene glycol moieties, was developed to bind and block the activity of extracellular VEGF, specifically the 165-amino acid isoform (VEGF₁₆₅). Previous studies have shown a pattern of short-term IOP elevation and no clinically significant long-term IOP change, after intravitreal pegaptanib injection. Pegaptanib may result in a clinically significant transient rise in IOP that considerably diminishes by 30 min postinjection but can remain elevated for up to 1 h.5^,7^,12 Additionally, there was no evidence of increased mean preinjection IOP over 2 years after intravitreal pegaptanib injection every 6 weeks.13 To our knowledge, there have been no reports of persistent OHT following intravitreal injection of pegaptanib. While it is uncertain, it seems unlikely that prior intravitreal injection of pegaptanib would induce or contribute to late and persistent OHT in patients.

A number of possible mechanisms may contribute to IOP elevation following an intravitreal injection. Clinical results and biomechanical models have shown that a vitreous volume increase up to 0.1 mL after intravitreal injections will cause a transient IOP spike, which usually normalizes to baseline within 1–2 h after the intravitreal injection.14 The current intravitreal bevacizumab or ranibizumab dose volume of 0.05 mL is unlikely to induce the development of persistent or delayed OHT.

Inflammation has been described after intravitreal anti-VEGF injections, and drug-induced trabeculitis, uveitis, endophthalmitis, or undetectable low-grade inflammation may also contribute to sustained IOP elevation.8^,9 While inflammatory cells or debris, or scarring from previous inflammation, can cause OHT, we did not observe any evidence of active or previous ocular inflammation in our ocular examination.

Four out of 8 patients (Table 1) were pseudophakic with a history of a YAG capsulotomy, suggesting that a disrupted posterior capsule might predispose patients to the development of OHT. While previous YAG capsulotomy has been shown to increase the long-term risk of developing OHT,15 –17 an open posterior capsule may also allow easier access of anti-VEGF agents into the anterior chamber. It has been suggested that high-molecular-weight proteins, such as bevacizumab (150 kDa) and ranibizumab (48 kDa), may accumulate in the aqueous outflow channels including the trabecular meshwork or Schlemm’s canal and obstruct aqueous outflow.10 Since bevacizumab is 3 times larger than ranibizumab, it seems that bevacizumab might be more likely to obstruct aqueous outflow than ranibizumab. However, among the 8 reported cases, 6 patients developed OHT after recent intravitreal ranibizumab, while only 2 patients after recent intravitreal bevacizumab.

It is also possible that the anti-VEGF agents may cause OHT by decreasing the physiological function of the trabecular meshwork. Kernt and colleagues, however, reported lack of in vivo toxicity to trabecular meshwork cells at clinical doses.18 Ultimately, it is likely that the manifestation of delayed and sustained OHT seen after intravitreal bevacizumab or ranibizumab may be due to a number of ocular factors: disrupted anterior hyaloid or zonules may allow access for high-molecular-weight proteins to enter the anterior chamber, multiple doses of these proteins mechanically and/or physiologically may disrupt normal aqueous outflow in a trabecular meshwork system that has been compromised from a combination of previous Nd:YAG capsulotomy, age, and/or other known and unknown factors.

In conclusion, persistent OHT may occur after intravitreal anti-VEGF injections in patients with no previous history of OHT. Further studies are needed to examine the long-term cellular and molecular effects of anti-VEGF antibodies on intraocular tissues, and to identify predisposing risk factors in patients susceptible to the development of persistent OHT following intravitreal anti-VEGF antibody injections.

Footnotes

Acknowledgments

Funding/Support: This study was supported by the Leir Foundation (New York, NY), Newman’s Own Foundation (Westport, CT), and Research to Prevent Blindness (New York, NY). The sponsors or funding organizations had no role in the design or conduct of this research.

Author Disclosure Statement

None of the authors have any financial/conflicting interests to disclose.

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