Over the past five years, retina practices have changed dramatically, in large part due to the commercial availability and utilization of anti-VEGF, or vascular endothelial growth factor, agents for the treatment of neovascular age-related macular degeneration and retinal vascular diseases. Intravitreal injections have become a routine part of all practices, with most retinal specialists performing multiple intraocular injections on any given clinic day.
While the widespread use of intravitreal VEGF inhibitors has undoubtedly provided tremendous benefit, and the intraocular delivery of these agents is generally well-tolerated by the vast majority of patients, local complications can occur following intravitreal injection, including injection-related inflammation; traumatic injury to the lens capsule; retinal detachment; vitreous hemorrhage; and endophthalmitis.1-3 In addition, tears or rips in the retinal pigment epithelium have been observed following IVT injection, leading some to suggest that either the VEGF inhibitors, the injections themselves or both may promote such events. This update focuses on the two complications of IVT injection with the greatest risk of producing severe and permanent vision loss—acute endoph-thalmitis and RPE tears.
Endophthalmitis
Acute endophthalmitis is perhaps the most feared complication of any penetrating ocular procedure. The incidence of infection following IVT injection is low, and is generally taken to be similar to that reported for other intraocular procedures, or about 0.05 percent, which represents a risk of endophthalmitis occurring once in every 2,000 injections (Table 1).1-4 Given the high number of injections that are performed, however, the absolute number of even low incident events, such as acute endophthalmitis, can be expected to increase dramatically. In 1998, for example, approximately 4,000 intravitreal injections were billed to Medicare. This is in contrast to 2008, when more than 1,000,000 were billed—a figure that has since probably doubled (personal communication, George Williams, MD; See Figure 1). Naturally, such a dramatic rise in the number of IVT injections would be expected to translate into a similar increase in the number of injection-related complications. Moreover, many patients require multiple injections over time, proportionately increasing their cumulative risk. The threshold for suspecting acute endophthalmitis following IVT injection should, therefore, be low.
While pseudoendophthalmitis of the type seen following injection of triam- cinolone acetonide5-7 (See Figure 2) has not been reported with anti-VEGF agents, acute non-infectious inflammation has been reported following injection of bevacizumab and ranibizumab and tends to have a shorter time from injection to onset of symptoms and a milder overall presentation than does post-injection endophthalmitis.8,9 Most recently, Daphna Mezad-Koursh, MD, and associates reported an average of one vs. three days to presentation and better vision, less pain and less vitreous and anterior chamber inflammation (including a notable lack of fibrin, posterior synechiae formation or hypopyon) in patients with non-infectious vs. infectious inflammation following injection of bevacizumab or ranibizumab.9
Data concerning the incidence of infection following intraocular injection comes from both prospective and retrospective studies—including studies that occurred both before and after the advent of anti-VEGF agents. Rama D. Jager, MD, and colleagues performed a comprehensive review of studies published prior to 2004, representing approximately 15,000 injections.1 Therapeutic agents analyzed in their review included triamcinolone acetonide, antiviral agents, intravitreal gases, and tissue plasminogen activator. The overall rate of endophthalmitis calculated in the study was 0.3 percent per injection. However, when cases of presumed sterile endophthalmitis following triamcinolone acetonide injection were removed, the rate was reduced to 0.2 percent per injection.
Pegaptanib sodium (Macugen) was the first anti-VEGF drug to be approved by the Food and Drug Administration for the treatment of neovascular AMD in December 2004. During the first year of the Phase III trials of pegaptanib (the VISION trials), the incidence of endophthalmitis was similar10 to that reported in the review by Dr. Jager and colleagues.1 Specifically, the VISION trials reported 12 cases of endophthalmitis following 7,545 IVT injections performed on 892 patients, or a per-injection rate of 0.16 percent. Of note, however, protocol violations occurred in 75 percent of injections associated with acute endophthalmitis, including, most commonly, failure to use a lid speculum and the practice of performing a prophylactic anterior chamber paracentesis to minimize the risk of post-injection pressure spikes. Stricter adherence to the protocol following the first year of the trial resulted in an acute endophthalmitis rate of 0.1 percent (four or 4,091 injections) in year two of the study,11 and 0.06 percent (two of 3,227 injections) in year three of the trial (Table 2).12 The question remained, however: How frequently would acute endophthalmitis occur following IVT injection in subsequent studies and, more importantly, in clinical practice?
The rates of endophthalmitis reported with ranibizumab (Lucentis) have compared favorably with year three of the VISION trials. To date, safety data have been reported for a total of 37,147 injections performed in five trials, including
Endophthalmitis rates from clinic-based series with anti-VEGF agents have generally supported these results. To date, 16 clinic-based studies have included a total 124,789 intravitreal injections of various anti-VEGF agents, reporting a total of 56 cases of endophthalmitis for an overall per injection rate of endophthalmitis of 0.04 percent.9,18-32 Taken collectively, the overall per-injection rate of endophthalmitis for the anti-VEGF agents since their introduction appears, therefore, to be about 84 per 176,799, or 0.05 percent—a number that is virtually identical to the risk for eye surgery in general (Tables 1 & 2).
Given this risk of severe vision loss that accompanies each case of endophthalmitis, however, how can clinicians minimize the risk of infection following any given intravitreal injection? In 2004, an expert roundtable was held to discuss best practice guidelines intended to minimize the incidence of endophthalmitis following IVT injection.33 Protocols from various studies were reviewed, including that used in the VISION trials. Requirements varied greatly regarding the injection procedure, utilization of antibiotics and the need for follow-up. Attempts at forming a consensus opinion were made, and evidence-based recommendations were provided, when possible. Disagreement existed in many instances, as there was little scientific evidence to support particular practice patterns. The group generally recommended the following practices:
Consensus could not be reached on several issues. These included:
- need for a povidine flush of the ocular surface and fornices;
- use of a sterile drape (most did not);
- use of gloves (most did);
- use of pre- or post-injection topical antibiotics; and
- need for follow-up examination versus telephone contact.
RPE Tears
Tears of the RPE are seen in 2 to 3 percent of eyes with neovascular AMD, and perhaps in as much as 10 to 15 percent of eyes with vascularized pigment epithelial detachments (PED).36,37 While certainly not a new clinical entity, RPE tears have been recognized and well described for nearly three decades. RPE tears as a spontaneous development in eyes with neovascualar AMD were described in 1981 and the authors noted the occurrence in association with a PED.38 Since that initial description, RPE tears have been further characterized, and we now recognize several hallmark features in these lesions.39-45 Clinically, patients with an RPE tear may either be asymptomatic or come to attention because of an acute, marked decline in visual acuity. Ophthalmoscopically, RPE tears are characterized by a well-defined area of bared choroid that appears hypopigmented relative to the adjacent area of hyperpigmented scrolled RPE. (See Figure 3A). Imaging with fluorescein angiography reveals a sharply demarcated window defect corresponding to the area of absent RPE, adjacent to an area of blocked fluorescence produced by the scrolled RPE. (See Figure 3B,C). OCT imaging may demonstrate focal loss of the RPE layer in the area of bared choroid, adjacent to a dome like, hyperreflective structure corresponding to the scrolled RPE. The vast majority of RPE tears have a pre-existing vascularized PED,36,37,46,47 and the most important predisposing risk factor appears to be PED size as measured by basal diameter37 and vertical height.37,47
In addition to occurring spontenously,36 reports exists of RPE tears following conventional laser,48,49 photodynamic therapy,50-55 corticosteroid injections,56,57 and IVT injection of the anti-VEGF agents, including pegaptanib,57-59 ranibizumab,36,60-65 and bevacizumab,15,25,37,66-78 have appeared in the literature. Unfortunately, none of the primary anti-VEGF trial reports mentioned the rate of RPE tears in the various treatment arms,10-17 and reports of incidence in clinic-based surveys have been relatively infrequent and generally fail to provide per injection event rates.
Anne E. Fung, MD, and colleagues provided the first such estimate from their Internet-based survey of 70 centers in 12 countries, where they reported four RPE tears following 7,113 injections of given to 5,228 patients, or a per injection rate of 0.06 percent.18 The number of eyes, as well as information regarding timing of the tears to the injections and the nature of the lesions, including specific mention of whether there was a pre-existing PED was, not reported. Since that first report, several clinic-based studies have provided estimates of RPE tear incidence in eyes treated with anti-VEGF agents. Andreas Weinberger and associates observed four RPE tears in 31 eyes (12.9 percent) with neovascular AMD and PEDs, each of which occurred following the first injection.76 Mean vision improved by nine letters at three months in the eyes with the tears with continued bevacizumab treatment. Researchers at Stanford University observed five tears in 173 eyes of 158 patients with neovascular AMD treated with bevacizumab, a per eye rate of 2.9 percent.25 This cohort included approximately 70 patients with a pre-existing PED, 7 percent of whom developed a tear. Bradley Smith, MD, and associates reported a single RPE tear following a first injection in one of 666 ranibizumab injections given to 164 consecutive patients, yielding a 0.61 percent per-patient rate and a 0.15 percent per-injection rate.63 This patient had a vascularized PED with a greatest linear diameter of just over 3 mm. Among eyes with vascularized PEDs at baseline, the per-injection rate was 0.95 percent.
In 2007, Clement Chan, MD, and associates examined 1,280 eyes of 1,255 patients seen at seven centers who received 2,890 injections of bevacizumab.77 A total of 21 eyes in 1,010 evaluable patients developed RPE tears for a per-eye tear rate of 2.1 percent and a per-injection tear rate of 0.73 percent. All tears occurred in eyes with a pre-existing vascularized PED, of which there were 125, resulting in a per-eye tear rate in this subgroup of 16.8 percent. The mean time from injection to RPE tear was about one month, but ranged from four days to about three months. The authors observed no statistically significant difference in pre- and post-RPE tear best correction vision, speculating that this was most likely due to continued CNV suppression provided by ongoing anti-VEGF therapy. The mean time from bevacizumab injection to RPE tear was approximately four weeks.
Lazaros Konstantinidis, MD, and colleagues observed four RPE tears in 72 consecutive patients (5.6 percent) with predominantly classic CNV and in seven eyes of 55 patients (12.3 percent) with PED and occult CNV, all of whom were treated with ranibizumab.64 The mean time to development of a tear in patients with classic CNV was 4.25 months following a mean of four injections, whereas a mean of 1.8 injections was given prior to development of a tear in those patients with a PED and occult CNV. Both patient groups showed improved best-corrected vision post-injection with continued ranibizumab therapy despite the occurrence of a tear. Iris Moroz, MD, and associates studied optical coherence tomography predictors of ROE tears following bevacizumab injection in 143 consecutive patients with neovascular AMD, including 24 eyes with a serous PED.78 Six eyes developed an RPE tear following the first injection, each of which had a pre-existing PED (4.2 percent overall; 25 percent among PED). Each of the six patients who developed a tear showed either a "wavy" appearance with small interruptions or a step-like break or interruption in the continuity of the RPE layer (See Figure 4).37,78
A 2010 report by Dr. Chan and colleauges37 observed 22 RPE tears in a cohort of 1,002 evaluable eyes (2.2 percent) with neovascular AMD treated with bevacizumab, all of which occurred in the subgroup of 123 eyes with a pre-existing PED (17.9 percent). There was no statistically significant difference in the pre- and post-treatment vision in these 22 eyes despite the fact that only six (27.3 percent) continued to received anti-VEGF therapy. Recently, Dr. Cunning-ham and colleagues79 examined the incidence of RPE tears in the ANCHOR,
Collectively, these studies suggest that the overall incidence of RPE tears in eyes with neovascular AMD is similar regardless of whether an anti-VEGF agent is used, and ranges from 2 to 6 percent in overall AMD cohorts vs. 12 to 25 percent in those patients with a pre-existing PED. In addition, it appears that patients receiving anti-VEGF therapy are more likely to develop a tear earlier in the course of therapy than untreated patients, most probably related to the accelerated involution induced by VEGF inhibition.37
Figure 2B repinted with permission from Am J Ophthal 2004; 138:489-492. Figure 4 reprinted with permission from
Ophthalmic Surg Lasers Imaging. 2009;40(6):570-575.
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