Intravitreal vascular endothelial growth factor (VEGF) inhibitors are the mainstay of treatment for wet age-related macular degeneration.1–7 In addition to good functional and anatomic outcomes, they are characterized by a good safety profile.1,2,6–9 The most common adverse effects — endophthalmitis, retinal tear, retinal detachment, and vitreous hemorrhage — are related to the intravitreal injection and not the VEGF-inhibitor itself. Two VEGF-inhibitor–specific adverse effects have been identified: a self-limited vitritis has been reported with both agents, presumably due to the vehicle of the VEGF-inhibitor;1,2,8,9 and retinal pigment epithelial tears have been associated with VEGF inhibitor.10–18
In 2008, we described sustained elevation of intraocular pressure (IOP) in four patients receiving intravitreal ranibizumab.19 Ocular hypertension has since been reported in patients receiving intravitreal bevacizumab,20,21 and numerous subsequent case series have described the effect for both agents.22–28 All these cases are to be differentiated from the transient, immediate elevation in IOP associated with the increase in volume from the injection,29–31 indicating that sustained ocular hypertension may be a third, VEGF-inhibitor–specific adverse effect. Although initial data from the ANCHOR and MARINA trials did not suggest a trend of elevated IOP,1,2 Bakri et al32–34 have presented data showing a higher incidence of elevated IOP in patients receiving ranibizumab versus sham treatment in the MARINA and ANCHOR trials.
Despite the extensive literature describing the phenomenon, there remains controversy regarding causative mechanisms, necessary treatment, and clinical characteristics of elevated IOP. We have revisited our data on patients receiving intravitreal VEGF-inhibitor (bevacizumab or ranibizumab) injections and present here our observations and suggest two novel mechanisms for elevated IOP.
Patients and Methods
This is a retrospective, interventional case series including patients evaluated at two academic centers (Stanford University Hospital and Clinics and the Mayo Clinic) following VEGF-inhibitor injections between January 1, 2006, and December 31, 2010. Patients were included in the study if they manifested elevated IOP (24 mm Hg or higher) occurring within 60 days of intravitreal injection or were evaluated for IOP asymmetry of at least 3 mm Hg between eyes on three consecutive visits. Patients were excluded if they had a prior history of glaucoma or prior episodes of ocular hypertension, other ocular pathology (such as history of anterior segment trauma), or underwent other intervention (anterior segment or vitreoretinal surgery, intravitreal injection of another pharmacologic agent during the preceding 60 days, or treatment with intraocular, periocular, or topical steroids within the past 3 months). Each patient was evaluated both by a retinal specialist and a glaucoma specialist.
Interventions and Follow-up
Intravitreal injection of bevacizumab and/or ranibizumab was performed for all patients in a consistent manner. A lid speculum was placed between the eyelids, and topical anesthetic — in most cases, 0.5% proparacaine hydrochloride drops (Bausch & Lomb Pharmaceuticals, Tampa, FL) followed by topical anesthesia (2% lidocaine hydrochloride jelly, 0.5% tetracaine hydrochloride gel, 4% nonpreserved lidocaine, or similar) — was applied to the ocular surface. The ocular surface was then disinfected with topical povidone iodine (5% or 10%). Bevacizumab (Avastin; Genentech, South San Francisco, CA; 1.25 mg/0.05 mL) or ranibizumab (Lucentis; Genentech, South San Francisco, CA; 0.5 mg/.05 mL) was then injected into the mid-vitreous cavity using a 30-gauge or smaller needle, usually in the inferotemporal quadrant, approximately 3.5 mm posterior to the limbus. A drop of topical antibiotic solution was then applied to the ocular surface. Follow-up was generally scheduled for 1 month after the injection, with measurement of intraocular pressure. All IOP measurements were obtained before injection and dilation using Tono-Pen XL (Reichert Technologies, Depew, NY) or Goldmann applanation tonometry. Per clinic protocol, Tono-Pens were calibrated daily before use and additionally as prompted by the instrument display. Measurements with a standard deviation of 10% or less were deemed acceptable, and the second eye for a given patient was tested within minutes of the first eye.
A total of 11,828 bevacizumab injections and 10,354 ranibizumab injections were administered during the study period at the two clinical sites. In this series, 21 eyes of 18 patients developed elevated IOP of 24 mm Hg or higher within 60 days of a previous injection.
The majority of subjects were Caucasian and female, with an average age of 78.5 years, and most underwent injection for exudative age-related macular degeneration (Table 1). Some cases demonstrated other ocular pathology, including anatomic narrow angles in one patient (two eyes) and hyperpigmented angles on gonioscopy in all patients with IOP greater than 40 mm Hg.
Table 1: Demographics and Baseline Characteristics of Patients With IOP Increase to 24 mm Hg or Greater Who Received Intravitreal Anti-VEGF Agents
Of unilateral cases, 73% received VEGF-inhibitor injections only in the affected eye. Both ranibizumab and bevacizumab were identified as causative agents, in most cases with delayed onset of elevated IOP after multiple injections. Thirty-three percent of eyes were treated serially with both agents, the majority (71%) transitioning from bevacizumab to ranibizumab, and 19% received prior treatment with another agent (eg, steroid or pegaptanib). Maximum IOP ranged from 24 to 50 mm Hg. Most patients had been undergoing treatment for at least 1 year and received at least five injections. Summary clinical characteristics are presented in Table 2.
Table 2: Clinical Characteristics of Patients With IOP Increase to 24 mm Hg or Greater Who Received Intravitreal Anti-VEGF Agents
Each of the three patients in our series who had IOP elevation greater than 40 mm Hg showed signs of preexisting angle compromise (mild peripheral anterior synechiae and/or heavy trabecular meshwork pigmentation), and one had a positive family history of glaucoma. When we excluded patients for whom we could hypothesize any predisposing factors — history of central retinal vein occlusion, any prior steroid treatment, family history of glaucoma, vulnerable angle (mild peripheral anterior synechiae and/or heavy pigmentation), and/or YAG capsulotomy — we found that all those remaining were either hyperopic or lacking a complete posterior vitreous detachment, and 91% were phakic with a cataract (at least 1 to 2+ nuclear sclerosis). Although the sample size was insufficient to determine significance, these findings demonstrate an interesting trend.
Of the 21 eyes, 81% required treatment for elevated IOP, 76% required long-term treatment, and 19% resolved without treatment. Eighty-two percent of those requiring treatment were managed with topical medication alone. One patient required oral medication (acetazolamide), one was treated with laser trabeculoplasty, and one required surgery (trabeculectomy). Injections were discontinued in six eyes (29%), and in two of these cases, the elevated IOP normalized once treatment ended.
IOP asymmetry (a difference of at least 3 mm Hg between the two eyes; Table 3) was observed in an average of 52.3% of visits after the onset of ocular hypertension, compared to 31.4% of visits before diagnosis. The mean difference in IOP between the two eyes rose by 10 mm Hg after diagnosis, and the odds of having significant IOP asymmetry after diagnosis (at least 3 mm Hg on three consecutive visits) were nine times higher than before diagnosis (P < .01 for both).
Table 3: IOP Asymmetry, Measured Before and After Diagnosis of Elevated IOP
Before being diagnosed with elevated IOP, 72% of patients had at least one visit with IOP asymmetry of 3 mm Hg or higher, and 11% had IOP asymmetry of at least 3 mm Hg on three consecutive visits. For comparison, we evaluated a sample of patients without sustained IOP elevation (those who were seen between 2008 and 2010, after electronic medical record adoption). We found that 51.5% of the sample had at least one visit with IOP asymmetry of 3 mm Hg or higher, and 3.3% of the sample had three consecutive visits with IOP asymmetry of at least 3 mm Hg (a rate more than three-fold lower than in patients who went on to develop elevated IOP).
Each of our 21 cases demonstrated elevated IOP and/or glaucoma, mostly of delayed onset, occurring after serial intravitreal VEGF-inhibitor agents. The IOP elevations were of variable duration and severity, but the affected eyes were consistently those receiving anti-VEGF injections. Although the sample size was too small to enable drawing definitive conclusions, patients in our series with otherwise idiopathic ocular hypertension had a high predominance of phakia with cataract and were either hyperopic or lacking a complete posterior vitreous detachment.
These cases join those of numerous others reported in the literature of ocular hypertension after VEGF-inhibitor injection.19–43 Prior studies have evaluated patients on similar inclusion criteria (IOP above 21 to 26 mm Hg, an increase from baseline of at least 5 to 10 mm Hg on two consecutive visits, and/or started on pressure-lowering treatment). Reported incidence of elevated IOP after VEGF-inhibitor injections is highly variable, ranging from 1% to over 11%. In contrast to some prior studies demonstrating increased odds of ocular hypertension with greater total number of injections, we observed elevated IOP both early and later in treatment (after an average of nine to 10 injections).
However, although the phenomenon of elevated IOP after intravitreal VEGF-inhibitor injection is well-recognized, debate continues regarding incidence, mechanisms, and risk factors, and our ability to predict those who will be affected is limited. Just as not every patient receiving steroids suffers from steroid-induced glaucoma, ocular hypertension caused by VEGF inhibitors likely is a multifactorial process in predisposed patients.
One of the more striking and novel findings in our series was the presence of significant IOP asymmetry (a difference of at least 3 mm Hg between the two eyes) in patients developing ocular hypertension. This parallels the findings of Bakri et al32–34 and suggests IOP asymmetry as an early indicator and/or proxy for the ocular hypertensive response following VEGF-inhibitor therapy. In addition to monitoring IOP at each visit for evidence of sustained elevation — even many months to years after beginning VEGF-inhibitor injections, physicians should be alert for IOP asymmetry in patients receiving unilateral injections. With growing awareness of IOP elevation during treatment with intravitreal VEGF-inhibitor injections, prediction, early identification, and counseling are becoming increasingly important. We believe that binocular IOP asymmetry and variation may be a harbinger of pathologic IOP elevation. Additional clinical experience, ideally a large-scale controlled trial, will be required before drawing definitive conclusions.
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Demographics and Baseline Characteristics of Patients With IOP Increase to 24 mm Hg or Greater Who Received Intravitreal Anti-VEGF Agents
|Underlying Disease||n (%)|
| Exudative AMD||16 (88.9%)|
| CRVO with CME||1 (5.6%)|
| DME||1 (5.6%)|
| Mean ± SD||78.5 ± 8.9|
| Male||7 (38.9%)|
| Female||11 (61.1%)|
| Caucasian||17 (94.4%)|
| Asian||1 (5.6%)|
|Eye Involvement||n (%)|
| Unilateral||15 (83.3%)|
| Bilateral||3 (16.7%)|
Clinical Characteristics of Patients With IOP Increase to 24 mm Hg or Greater Who Received Intravitreal Anti-VEGF Agents
|Causative Agent||n (%)|
| Ranibizumab||12 (57.1%)|
| Bevacizumab||9 (42.9%)|
|Max IOP Measurements (mm Hg)|
| mean ± SD||32 ± 8|
| 24–29, n (%)||7 (33.3%)|
| 30–34, n (%)||8 (38.1%)|
| 35–39, n (%)||2 (9.5%)|
| 40–44, n (%)||2 (9.5%)|
| 45–50, n (%)||2 (9.5%)|
|Lens Status||n (%)|
| Phakic with cataract||18 (85.7%)|
| Pseudophakic (PCIOL)||3 (14.3%)|
|PVD Status||n (%)|
| Complete PVD||12 (57.1%)|
| Incomplete PVD||9 (42.9%)|
| Myopic||8 (38.1%)|
| Hyperopic||7 (33.3%)|
| Not documented||6 (28.5%)|
|Time Since Initiating Treatment|
| mean ± SD (months)||15.5 ± 16.1|
| range||1 day to 4 years|
| ≤ 1 month, n (%)||3 (14.3%)|
| 2 to 6 months, n (%)||6 (28.5%)|
| 7 to 12 months, n (%)||5 (23.8%)|
| 1 to 2 years, n (%)||2 (9.5%)|
| > 2 years, n (%)||5 (23.8%)|
|Number of Preceding Injections|
| mean ± SD (# injections)||9.7 ± 11.2|
| range (# injections)||1 to 40|
| 1 injection, n (%)||3 (14.3%)|
| 2 to 5 injections, n (%)||8 (38.1%)|
| 6 to 10 injections, n (%)||4 (19.0%)|
| 11 to 20 injections, n (%)||2 (9.5%)|
| > 20 injections, n (%)||4 (19.0%)|
IOP Asymmetry, Measured Before and After Diagnosis of Elevated IOP
|Mean ± SD||Range||Mean ± SD||Range|
|% of patients with ≥3 mm Hg IOP difference on three successive visits||11.1%||N/A||66.7%||N/A||odds ratio = 9, P = .003*|
|No. of sets of three consecutive visits with ≥3 mm Hg IOP difference*||0.11 ± 0.32||0–1||1.39 ± 1.82||0–6||P = .015*|
|Maximum difference in IOP between the two eyes (mm Hg)||5.6 ± 3.7||1–17||15.0 ± 8.5||5–33||P = .004*|