Eyeworld

EW NEWS & OPINION 14 January 2017 by Maxine Lipner EyeWorld Senior Contributing Writer Chang said. "HORV was often bilat- eral with extremely poor visual out- comes, making this quite possibly the worst complication of cataract surgery." The mechanism of this rare complication appears to be a type III hypersensitivity to vancomycin, he explained, adding that this is the most common antibiotic used for intraocular prophylaxis in the U.S., according to the 2014 ASCRS survey. The clinical alert was emailed to all ASCRS and ASRS members on July 20, 2016. With digital publica- tion of its July issue that same day and mail delivery soon after, EyeWorld was the first periodical to report this important story, Dr. Chang said. "July's lead story described the background and the work of the Task Force, and how it reached its sobering findings," he said. "Published alongside the for- mal clinical alert, this special article provided expanded information along with multiple fundus images of HORV." In addition, an accompa- nying article interviewed four cata- ract surgeons about how these new findings would affect their practice. "There was an immediate flurry of questions and comments regarding EyeWorld has highlighted, advocates of the femtosecond laser tout the in- creased safety, improved consistency of certain steps, and the benefit of decreased ultrasonic energy for lens removal, she pointed out, adding that the critics argue that the bene- fits are few, while the high cost and additional inefficiencies make the technology unattractive. David F. Chang, MD, clinical professor, University of California, San Francisco, and immediate past chief medical editor of EyeWorld, reflected on what he views as one of the most important news stories of 2016 that grabbed EyeWorld head- lines: the clinical alert on HORV released by the joint ASCRS and American Society of Retina Special- ists (ASRS) Task Force. Following a published report of six patients with this devastat- ing complication associated with vancomycin in 2015, an HORV Task Force with representatives from ASCRS and ASRS was formed. The Task Force issued an alert, which appeared in EyeWorld, summarizing the findings from 36 eyes of 23 patients with HORV. "Every case identified had received intraocular vancomycin prophylaxis following uncomplicated cataract surgery," Dr. IOLs was a common conversation seen in EyeWorld articles. Also, toric IOLs and the discussion of posterior corneal astigmatism were hot topics. "Pioneering work from Doug Koch [MD] taught the ophthalmic world that ignoring the posterior curvature of the cornea could lead to inaccu- rate astigmatism correction," she said. Meanwhile, articles on the most popular cataract removal techniques tended to center around management of difficult situations and continue to do so. Articles on techniques for the dense cataract, small pupils, long or short eyes, and loose zonules continue to be of interest to readers. "Discussions of these complex cases never seem to fall out of favor," Dr. Henderson said, adding that surgeons gravitate toward discussing cases and enjoy sharing clinical pearls. One of the most hotly debat- ed topics that has been covered in EyeWorld in recent history is the use of the femtosecond laser for cataract surgery. "Although the femtosec- ond laser is now routinely used in many parts of the U.S. and around the world, there is still a significant number of cataract surgeons who oppose the technology," she said. As The 20th anniversary celebration of EyeWorld continues with a look at the coverage of cataract and glaucoma hot topics O ver the last 20 years, cata- ract and glaucoma issues have been an integral part of EyeWorld news cover- age, from alerts about the emergence of an imminent health concern, such as hemorrhagic oc- clusive retinal vasculitis (HORV), to the rise of new technology, such as MIGS. EyeWorld asked practitioners for their thoughts on key issues that the magazine has covered. Bonnie Henderson, MD, clini- cal professor, Tufts University School of Medicine, Boston, recalled that in the early years much revolved around refractive IOLs. "Multifocal IOLs were fairly new and most cat- aract surgeons were struggling with the specifics of lenticular presbyopia correction," Dr. Henderson said, adding that patient selection and counseling were important topics on the forefront of most cataract discus- sions. Mixing and matching differ- ent types of presbyopia-correcting Outstanding at 20: Retrospective on cataract and glaucoma discussions continued on page 16 3 EW NEWS & OPINION by David F. Chang, MD, and Andre Witkin, MD Joint ASCRS/ASRS Task Force issues findings and recommendations regarding HORV July 2016 were often very poor. Twenty-two of 36 eyes (61%) were 20/200 or worse, and 8 of 36 eyes (22%) were NLP. T he first 2 cases of bilater- al hemorrhagic occlusive retinal vasculitis (HORV) were published in 2014. 1 An additional 4 cases (3 bilater- al and 1 unilateral) were reported in 2015. 2 All 11 of the reported eyes in those 6 cases had undergone other- wise uncomplicated cataract surgery with prophylactic intracameral vancomycin (1 mg/0.1 cc), and there was a delay of 1–14 days before the onset of the severe ischemic retinal vasculitis. The visual outcomes were poor. The authors postulated a de- layed immune response to a surgical adjuvant, with vancomycin as the leading candidate. Because of the popularity of in- tracameral vancomycin for endoph- thalmitis prophylaxis, the American Society of Cataract & Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) expeditiously formed a joint Task Force to further analyze the prev- alence, potential etiology, treat- ment, and outcomes of this newly described complication associated with intraocular surgery. The Task Force includes ASRS members Steve Charles, MD, Dean Eliott, MD, J. Michael Jumper, MD, Andre J. Witkin, MD, and Charles C. Wykoff, MD, and ASCRS Cataract Clinical Committee members David F. Chang, MD, Richard S. Hoffman, MD, Nick Mamalis, MD, and Kevin M. Miller, MD. Drs. Charles, Jumper, and Miller also serve on the ASCRS Retina Clinical Committee. To better define the clinical characteristics of HORV, an online case registry was set up on the ASRS website for members to report new cases. Information about all surgi- cal medications and adjuvants was requested with a particular goal of uncovering other associations in addition to (or besides) vancomycin. Retinal images including OCT, FA, and fundus photos were reviewed for each case by retina specialist members of the Task Force. In addi- tion, to better understand the preva- lence of this complication, an online "surveillance" survey was emailed to all ASCRS members soliciting any cases of suspected HORV. Positive respondents were sent additional queries for information that were followed up by Task Force retina specialists. Through these methods, a complete data set was compiled on 36 eyes of 22 patients with HORV. All of these eyes received intraocu- lar vancomycin, either 1 mg/0.1 ml intracameral, 1 mg/0.1 intravitreal, or in the infusion bottle (10 mg into the balanced salt solution bottle). Despite intraocular anti-VEGF and steroid treatments, visual results BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE ILEVRO® (nepafenac ophthalmic suspension) 0.3% is associated with cataract surgery. DOSAGE AND ADMINISTRATION Recommended Dosing One drop of ILEVRO® Suspension should be applied to to cataract surgery, continued on the day of surgery period. An additional drop should be administered 30 to 120 minutes prior to surgery. Use with Other Topical Ophthalmic Medications ILEVRO® Suspension may be administered in conjunction with other topical ophthalmic medications such as beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, cycloplegics, and mydriatics. If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart. CONTRAINDICATIONS ILEVRO® Suspension is contraindicated in patients with previously demonstrated hypersensitivity to any of the ingredients in the formula or to other NSAIDs. WARNINGS AND PRECAUTIONS Increased Bleeding Time including ILEVRO® Suspension, there exists the potential for increased bleeding time due to interference with thrombocyte aggregation. There have been reports that ocularly applied nonsteroidal of ocular tissues (including hyphemas) in conjunction with ocular surgery. It is recommended that ILEVRO® Suspension be used with caution in patients with known bleeding tendencies or who are receiving other medications which may prolong bleeding time. Delayed Healing including ILEVRO® Suspension, may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. Use of topical NSAIDs may result in keratitis. In some susceptible patients, continued use of topical NSAIDs may result in epithelial breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs including ILEVRO® Suspension and should be closely monitored for corneal health. Post marketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries, corneal denervation, corneal epithelial defects, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, or repeat ocular surgeries within a short period of time may be at increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients. Post marketing experience with topical NSAIDs also suggests that use more than 1 day prior to surgery or use beyond 14 days post-surgery may increase patient risk and severity of corneal adverse events. Contact Lens Wear ILEVRO® Suspension should not be administered while using contact lenses. ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another Serious and Otherwise Important Adverse Reactions The following adverse reactions are discussed in greater detail in other sections of labeling: • Increased Bleeding Time (Warnings and Precautions) • Delayed Healing (Warnings and Precautions) Ocular Adverse Reactions The most frequently reported ocular adverse reactions following cataract surgery were capsular opacity, decreased visual acuity, foreign body sensation, increased intraocular pressure, and sticky sensation. These reactions occurred in approximately 5 to 10% of patients. Other ocular adverse reactions occurring at an incidence of approximately 1 to 5% included conjunctival edema, corneal edema, dry eye, lid margin crusting, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, photophobia, tearing and vitreous detachment. Some of these reactions may be the consequence of the cataract surgical procedure. Non-Ocular Adverse Reactions Non-ocular adverse reactions reported at an incidence of 1 to 4% included headache, hypertension, nausea/ vomiting, and sinusitis. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: Reproduction studies performed with nepafenac in rabbits and rats at oral doses up to 10 mg/kg/day have revealed no evidence of teratogenicity due to nepafenac, despite the induction of maternal toxicity. At this dose, the animal plasma exposure to nepafenac and amfenac was approximately 70 and 630 times human plasma exposure at the recommended human topical ophthalmic dose for rats and 20 and 180 times human plasma exposure for rabbits, respectively. In rats, maternally toxic doses ≥10 mg/kg were associated with dystocia, increased postimplantation loss, reduced fetal weights and growth, and reduced fetal survival. Nepafenac has been shown to cross the placental barrier in rats. There are no adequate and well- controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, ILEVRO® Suspension should be used the potential risk to the fetus. biosynthesis inhibiting drugs on the fetal cardiovascular system (closure of the ductus arteriosus), the use of ILEVRO® Suspension during late pregnancy should be avoided. Nursing Mothers ILEVRO® Suspension is excreted in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILEVRO® Suspension is administered to a nursing woman. Pediatric Use pediatric patients below the age of 10 years have not been established. Geriatric Use been observed between elderly and younger patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Nepafenac has not been evaluated in long-term carcinogenicity studies. Increased chromosomal aberrations were observed in Chinese hamster ovary cells exposed in vitro to nepafenac suspension. Nepafenac was not mutagenic in the Ames assay or in the mouse lymphoma forward mutation assay. Oral doses up to 5,000 mg/kg did not result in an increase in the formation of micronucleated polychromatic erythrocytes in vivo in the mouse micronucleus assay in the bone marrow of mice. Nepafenac did not impair fertility when administered orally to male and female rats at 3 mg/kg. PATIENT COUNSELING INFORMATION Slow or Delayed Healing Patients should be informed of the possibility that slow or delayed healing may occur while using nonsteroidal Avoiding Contamination of the Product Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures because this could cause the tip to become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery. Contact Lens Wear ILEVRO® Suspension should not be administered while wearing contact lens. Intercurrent Ocular Conditions Patients should be advised that if they develop an intercurrent ocular condition (e.g., trauma, or infection) or have ocular surgery, they should immediately seek their physician's advice concerning the continued use of the multi-dose container. Concomitant Topical Ocular Therapy If more than one topical ophthalmic medication is being used, the medicines must be administered at least 5 minutes apart. Shake Well Before Use Patients should be instructed to shake well before each use. Released: February 2014 U.S. Patent Nos. 5,475,034; 6,403,609; and 7,169,767. ©2016 Novartis 2/16 US-ILV-16-E-0334 94030_US-ILV-16-E-0586_PI.indd 1 5/2/16 9:03 AM continued on page 8 EW NEWS & OPINION 8 July 2016 Neovascular glaucoma developed rapidly in 19 of 36 eyes (53%), often within 1–2 months. Seven of 36 eyes (19%) received an additional bolus of intravitreal vancomycin for treatment of presumed bacterial endophthalmitis. These patients had particularly poor outcomes; 5/7 of these eyes were NLP. There are currently 11 other cases of possible HORV for which we have not been able to collect a full data set or images, and all but 2 of these received intraocular vanco- mycin. We don't think the latter 2 represent true HORV based on the information given to us so far. One case had poor vision starting on POD 1 and may represent medi- cation toxicity with severe diffuse retinal microvascular occlusion with sparing of the larger retinal vessels. The second case looks more like a CRVO or combined CRAO/CRVO, with dilated and tortuous retinal veins and diffuse scattered small dot hemorrhages. The differential diagnosis of HORV includes acute postoperative endophthalmitis, viral retinitis, medication toxicity, and CRVO or combined CRAO/CRVO. In endoph- thalmitis, pain and severe anteri- or chamber inflammation, often with hypopyon, are characteristic. Conversely, HORV is painless with a relatively quiet anterior chamber. Moderate to severe vitritis, with minimal to no view of the retina, is typical of endophthalmitis, while in HORV, the vitreous is usually mini- mally inflamed with a clear view to the retina. Although retinal vasculi- tis and hemorrhage can accompany severe bacterial endophthalmitis (e.g., Streptococcus species), the retina in these cases can only be visualized once the anterior chamber and vit- reous have been surgically cleared of dense inflammatory infiltrate. Viral retinitis is almost always caused by a member of the Herpes- viridae family. HSV and VZV are the most common causes of acute retinal necrosis (ARN), which may present with rapidly progressive retinal vasculitis. The retinitis and moderate to severe vitritis that char- acterize ARN are not seen in HORV. HORV often features large patches of retinal hemorrhage that are uncom- mon with ARN. CMV retinitis may cause more intraretinal hemorrhage than ARN, but is usually slowly pro- gressive unless the patient is severely immunocompromised. Finally, viral retinitis is not typically associat- ed with an intraocular procedure, which is a requisite feature of HORV. Medication toxicity after cata- ract surgery can cause TASS and/or retinal vascular occlusion. Intraoc- ular aminoglycosides are known to be potentially toxic to the retina at standard doses; retinal toxicity has also been more recently reported with inadvertent intracameral in- jection of high doses of cefuroxime. The presentation and appearance of medication toxicity after cata- ract surgery differs from HORV. In medication toxicity, patients usually have poor visual acuity immediately after surgery (on postoperative day 1), while HORV has a delayed onset. Patients with retinal toxicity due to high doses of cefuroxime often have accompanying TASS and severe corneal edema immediately after surgery, which are not features of HORV. In aminoglycoside toxicity, the macula is commonly involved, while peripheral retinal vascular occlusion is unusual. Conversely, in HORV, all cases had peripheral involvement (and more severe cases of HORV also had macular ischemia and whitening). CRVO (or combined CRVO/ CRAO) after cataract surgery may be due to an intraocular pressure spike during surgery, or a complica- tion from a retrobulbar block, and patients usually present immediately on postoperative day 1 with severe visual loss. Conversely, patients with HORV present on average 8 days after cataract surgery, with an unremarkable examination on postop day 1. CRVO after cataract surgery is unilateral, while HORV is usually bilateral and sequential if bilateral sequential cataract surgery is performed. Even if the second eye surgery is delayed, HORV occurs in the second eye (and presents in a strikingly similar fashion to the first eye), distinguishing HORV from postoperative CRVO. The fundus appearance of HORV is also different than in CRVO. The hemorrhages in HORV often appear in large patches, and only occur in regions of vascular oc- clusion, often along retinal venules. In contrast, CRVO features diffuse, smaller dot/blot hemorrhages, even in areas that are not ischemic. Post-cataract CRVO hemorrhages typically resolve gradually, particu- larly with anti-VEGF injections, but persist for months despite treat- ment with HORV. Retinal veins are significantly dilated and tortuous with CRVO, but not in HORV. In HORV, the peripheral retinal vessels were always occluded in our series, while the posterior retinal anatomy appeared normal in less severe cases. This appearance is not typical of CRVO. Regarding etiology, the Task Force consulted with allergists and immunologists to determine a po- tential mechanism. Considering that vancomycin was the only surgical adjuvant in common used in all 36 eyes of 22 patients in our current series, the conclusion was that this is the most likely culprit. The timing of HORV is consistent with a type III hypersensitivity similar to leuko- cytoclastic vasculitis, a potentially analogous reaction in the skin that has been seen rarely with systemic vancomycin. In addition, type III Joint ASCRS/ASRS continued from page 3 continued on page 16 Bilateral hemorrhagic occlusive retinal vasculitis in a 55-year-old man after cataract surgery with intracameral vancomycin 18 days (right eye) and 11 days (left eye) prior to presentation. Vision is 20/30 in the right eye (A) and no light perception in the left (B). Note the severe peripheral ischemia in the right eye (C) and complete non-perfusion in the left eye (D) on fluorescein angiography. Source: Ryan Terribilini A B C D EW NEWS & OPINION 16 July 2016 hypersensitivity reactions start in the venous system, which would be consistent with the appearance of HORV, which appears to affect reti- nal venules more than the arterioles. Based on the cases collected to date, the Task Force Clinical Alert outlined the clinical pattern and findings with HORV. Recommen- dations for treatment and manage- ment were given. Without know- ing the number of eyes that have received vancomycin, and without routine dilated retinal examination following uncomplicated cataract surgery, it is impossible to deter- mine the prevalence of HORV. Our 2014 ASCRS member survey found that 50% of respondents were using intracameral antibiotics. 3 Among those using an intracameral anti- biotic, vancomycin was used by 37% overall and 52% of American surgeons. We therefore think that severe HORV is extremely rare. However, some cases of HORV may also be missed or misdiagnosed— particularly if there are milder cases causing peripheral vasculitis that do not affect vision. Such milder cases of HORV would have only been discovered with a dilated postoper- ative fundus examination. It is also possible that prior cases of presumed endophthalmitis (cases without hypopyon and retinal findings that were out of proportion to anterior chamber and vitreous inflammation) were actually cases of HORV. Since the 2015 HORV paper was pub- lished, a number of retina specialists have come forward with cases that were previously undiagnosed but now seem to represent HORV. Now that a registry has been established and with greater awareness of the syndrome, we hope to gain a better understanding of the frequency of HORV moving forward. Because HORV is probably rare, the Task Force is not recommending that surgeons discontinue using intraocular vancomycin prophylaxis at this time. Although the ASCRS survey reflects that there is no con- sensus on the necessity of intracam- eral antibiotic prophylaxis or which agent is best, the popularity of intraocular vancomycin prophylaxis is likely based on several factors, in- cluding safety, availability, coverage, and efficacy against drug resistant pathogens. 4 Surgeons should con- tinue to weigh the relative merits of prophylactic intraocular vancomy- cin use in preventing endophthalmi- tis, with the additional knowledge that intraocular vancomycin is likely associated with HORV, a distinctly rare and potentially devastating disease. In addition, surgeons using vancomycin prophylaxis with sequential cataract surgery should be aware that in addition to delayed onset of 1–3 weeks, HORV may be asymptomatic in the first eye and a dilated fundus exam may be the only way to detect it. Although there is no FDA approved commercial an- tibiotic formulation for intracameral use, compounding pharmacies can formulate intracameral cefuroxime and moxifloxacin if an alternative is desired. The ASCRS Cataract Clinical Committee published a white paper reviewing the different antibiotic options for intracameral prophylaxis in 2014. 4 If you experience or become aware of a case of HORV, please be sure that it is reported on the HORV registry, which can be ac- cessed through links at www.asrs. org and www.ascrs.org. The identity of the patient and attending oph- thalmologists will be kept strictly confidential. EW References 1. Nicholson LB, Kim BT, Jardon J, et al. Severe bilateral ischemic retinal vasculitis following cataract surgery. Ophthalmic Surg Lasers Imaging Retina. 2014;45:338–342. 2. Witkin AJ, Shah AR, Engstrom RE, Kron-Gray MM, et al. Postoperative hemorrhagic occlu- sive retinal vasculitis: Expanding the clinical spectrum and possible association with vancomycin. Ophthalmology. 2015;122: 1438-1451. 3. Chang DF, Braga-Mele R, Henderson BA, Mamalis N, et al. Antibiotic prophylaxis of postoperative endophthalmitis after cata- ract surgery: Results of the 2014 ASCRS member survey. J Cataract Refract Surg. 2015;41:1300–1305. 4. Braga-Mele R, Chang DF, Henderson BA, Mamalis N, et al. Intracameral antibiotics: Safety, efficacy, and preparation. J Cataract Refract Surg. 2014;40:2134–2142. Contact information Chang: dceye@earthlink.net Witkin: ajwitkin@gmail.com Joint ASCRS/ASRS continued from page 8 A 68-year-old woman presented with decreased vision 10 days after otherwise uncomplicated unilateral cataract surgery; intracameral vancomycin (1 mg/0.1 ml) was used at the end of the case. Despite treatment with systemic corticosteroids, valacyclovir, PRP, and anti-VEGF injections, visual outcome was counting fingers at 1 foot. Image A: Widefield color photograph demonstrates diffuse peripheral retinal vascular occlusion and associated large patches of retinal hemorrhage following the retinal venules. Ischemic macular whitening is evident. The retinal veins are not tortuous or dilated. Image B: Widefield FA demonstrates retinal vascular occlusion in areas of retinal hemorrhage. Staining of retinal venules is evident. Source: Rahul Mandiga, MD A B

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