Journal Highlights NEW FINDINGS from the PEER-REVIEWED LITERATURE

Journal Highlights NEW FINDINGS FROM THE PEER-REVIEWED LITERATURE

Ophthalmology Secondary outcomes included cor- for targeted and effective pharmaco- Selected by Stephen D. McLeod, MD neal healing at four weeks of treatment therapies.” More research is warranted and overall changes in lesion size, dis- to define the pathologic processes mod- Topical Cenegermin for ease progression events, visual acuity, ulated by cenegermin. Neurotrophic Keratopathy and corneal sensitivity from baseline to January 2020 week 8. Brolucizumab for Neovascular The conventional assessment AMD Pflugfelder et al.evaluated the efficacy showed significant differences at week January 2020 and safety of topical cenegermin in 8, as 70% of the active-treatment arm patients with neurotrophic keratopathy. and 29% of the vehicle arm had less In two similarly designed phase 3 trials They found that, when compared to than 0.5 mm of lesion staining (p = (HAWK and HARRIER), Dugel et al. vehicle, the drug was more effective at .006). With regard to the conservative compared the efficacy and safety of reducing lesion size and led to fewer assessment at week 8, 65% of the cene- brolucizumab and aflibercept for events indicating disease progression. germin group and 17% of those who treatment of neovascular age-related Moreover, cenegermin was received vehicle macular degeneration. The findings

well tolerated; most adverse Volume 127 had 0 mm of le- of both studies indicate that broluci- Volume 127 | Number 1 | January 2020 Elsevier | ISSN 0161-6420 | effects were local, mild, and Number 1 sion staining and zumab is noninferior to aflibercept in | transient. pp. XXX–XXX no other staining terms of visual function at week 48. This double-masked, residually (p < Anatomic outcomes were better with vehicle-controlled trial in- .001). Conserva- brolucizumab, and overall safety was cluded 48 patients treated at tive evaluation comparable for the two treatments. 11 study sites in the United also revealed Both studies were double-masked, States. Participants were OPHTHALMOLOGY significant active-controlled trials, with a combined INSERT ADVERT assigned randomly (1:1) between-group enrollment of 1,817 patients. All patients to receive topical ceneg- differences at had untreated active choroidal neo- ermin 20 μg/mL or vehicle week 4 (key vascularization caused by age-related eye drops. Six drops were January 2020 secondary end macular degeneration (AMD) in the administered daily for eight point). Ceneg- study eye.

OPHTHA_v127_i1_COVER.indd 1 21-09-2019 12:48:00 weeks, and follow-up con- ermin produced Participants were assigned randomly tinued through 24 weeks. The primary significant reductions in lesion size and to receive intravitreal brolucizumab end point was healing of the neuro- disease progression rates throughout (3 mg or 6 mg) or aflibercept (2 mg). trophic lesion (persistent epithe­lial treatment and was well tolerated. Most After three monthly injections (loading defect or corneal ulcer) by week 8. adverse events were mild, local, and dosage), brolucizumab-treated eyes Masked central readers measured resolved rapidly. received an injection every 12 weeks neurotrophic lesions from clinical The authors concluded that cene- (q12w), which was adjusted to every photographs and then assessed corneal germin 0.002% ophthalmic solution eight weeks (q8w) if disease activity healing status conventionally (<0.5 represents a safe noninvasive option to persisted. Aflibercept-treated eyes mm of fluorescein staining in greatest treat neurotrophic keratopathy. They received q8w dosing. dimension of lesion area) as well as added that it “can become part of the The primary hypothesis of the study conservatively (0-mm lesion staining treatment algorithm for this often diffi- was noninferiority of brolucizumab and no other residual staining). cult to manage disease with a high need in best-corrected visual acuity (BCVA)

EYENET MAGAZINE • 21 mean change from baseline to week success and less need for glaucoma 48 (margin: 4 letters). Other key end medication. The safety profiles of the Ophthalmology Retina Selected by Andrew P. Schachat, MD points were the anatomic outcomes and two devices were similar. the proportion of patients who main- For this prospective randomized AREDS2: Long-Term VA tained q12w dosing of brolucizumab study, the researchers included 152 Following Anti-VEGF through week 48. patients (152 eyes) who were between January 2020 Forty-eight weeks after treatment 45 and 84 years old. All participants was begun, each arm of brolucizumab had OAG, a Shaffer angle of grade III or Keenan et al. set out to analyze best- showed noninferiority to aflibercept IV, best-corrected visual acuity (BCVA) corrected visual acuity (BCVA) out- in BCVA change from baseline: least of 20/30 or better, and IOP of 23 to 39 comes of patients with wet age-related squares (LS) mean in the HAWK study mm Hg after washout of hypotensive macular degeneration (AMD) after was +6.6 (6 mg) and +6.1 (3 mg) letters medications. intravitreal injections of anti-VEGF with brolucizumab versus +6.8 letters Study eyes were assigned randomly drugs. They found that mean BCVA with aflibercept. In the HARRIER study, (1:1) to undergo standalone microin- decreased by about 1.5 to 2 letters per LS mean values were +6.9 letters for vasive glaucoma surgery (MIGS) con- year—and that, at five years, BCVA was brolucizumab (6 mg) versus +7.6 letters sisting of one Hydrus or two iStents. 20/40 or better in approximately 50% for aflibercept. The p value was <.001 Follow-up exams were performed on of eyes and 20/200 or worse in 14%. for all comparisons of brolucizumab day 1, week 1, and months 1, 3, 6, and This study is Report No. 19 of the and aflibercept. More than 50% of 12 following surgery. Outcomes of in- Age-Related Eye Disease Study 2 eyes treated with 6 mg of brolucizum- terest were between- and within-group (AREDS2). A total of 986 AREDS2 ab were maintained on q12w dosing differences in IOP and number of participants (1,105 eyes) met the through week 48 (56% in HAWK, 51% glaucoma medications at 12 months. inclusion criteria (no late AMD, BCVA in HARRIER). Complete surgical success was defined 20/100 or better, and no previous anti- At week 16, before any variations as freedom from repeat glaucoma sur- VEGF injections). in treatment exposure, disease activity gery, IOP ≤18 mm Hg, and no need for All participants received at least one was more common with aflibercept glaucoma medication. Safety measures anti-VEGF injection during follow- than with brolucizumab 6 mg (HAWK: included frequency of surgical com- up; decisions regarding treatment were 34.5% vs. 24.0%, p = .001; HARRIER: plications, changes in VA, abnormal made by local ophthalmologists during 32.2% vs. 22.7% p = .002). Reductions slit-lamp findings, and adverse events. normal clinical care. in central subfield thickness from base­- The study groups were well matched The primary outcome measures were line to week 48 were greater with brolu- in terms of baseline demographics, mean refracted BCVA and the propor- cizumab 6 mg than with aflibercept in glaucoma status, medication use, and tions of eyes with BCVA of 20/40 or HAWK (LS mean, –172.8 μm vs. –143.7 baseline IOP. better and 20/200 or worse. An explor- μm; p = .001) and in HARRIER (LS Twelve months of follow-up was atory outcome measure was the mean mean, –193.8 μm vs. –143.9 μm; p < completed by 148 patients (97.4%). At number of anti-VEGF injections, as .001). Anatomic retinal fluid outcomes this point, the complete success rate reported by the treating ophthalmolo- favored brolucizumab. Overall, adverse was better for the Hydrus device com- gists. event rates were similar for the study pared to two iStents (30.1% vs. 9.3%; All told, 977 of the 986 participants drugs. p < .001). The Hydrus also was associ- (99.1%) had at least one post-treatment The authors noted that the forth- ated with reduced need for glaucoma visit. During the study, the percentage coming 96-week data will provide medication (p = .004); more Hydrus of eyes with a BCVA of 20/40 or better further insight into the efficacy and subjects were completely free of such declined from 59.3% at the first annual safety of brolucizumab (q12w and medication by month 12 (p = .0057). study visit after the first injection to q8w) relative to aflibercept (q8w). Secondary glaucoma surgery was re- 49.7% by the fifth annual exam. In quired for two eyes in the iStent group contrast, the percentage of eyes with Hydrus Versus iStent as Stand- (3.9%) and none in the Hydrus group. a BCVA of 20/200 or worse rose from alone Treatment for OAG Two eyes treated with Hydrus and one 5.5% to 14.4% during the same time January 2020 treated with iStent had BCVA loss of period. 2 lines or more. The mean annual numbers of injec- Ahmed et al. hypothesized that a single The authors acknowledged the tions per eye were 2.9 during year 1 Hydrus microstent would result in limitations of unmasked postoperative and 3.9, 3.3, 3.1, and 3.0 in the suc- lower intraocular pressure (IOP) and examinations but conclude that these ceeding years of the study. Patients reduced need for glaucoma medication findings suggest that trabecular MIGS received a mixture of ranibizumab, in patients with open-angle glaucoma devices may play an important role in bevacizumab, and, in fewer cases, (OAG) compared to a pair of iStent managing IOP and reducing the need aflibercept in­jec­tions; in addition, devices. They found that the Hydrus for hypotensive medication. they were treated under several dosing resulted in a higher rate of surgical —Summaries by Lynda Seminara regimens (including treat-and-extend,

22 • JANUARY 2020 fixed interval, and as-needed). ment in IOP or BVA (both p < .001); acuity (CDVA) of 20/50 or better and The authors noted that although the and treatment with an oral carbonic stereoacuity of 800 seconds of an arc or treating ophthalmologists were making anhydrase inhibitor hastened anatomic better. decisions outside of a randomized clin- recovery (p = .01). Improvement in Multiple parameters were docu- ical trial protocol, the participants were BVA was significantly faster for men mented for each child before and after part of the AREDS2 cohort. Thus, this and African Americans (both p < .05). each of two sequential play sessions. study does not fully represent a real- Eyes that had chamber reformation The sessions, which lasted 30 world setting. Nonetheless, the data in the clinic achieved maximum IOP minutes each, involved a 3D flying may be useful in assessing the long-term reduction more quickly (p < .002). game (Eagle Flight) that requires head effects of anti-VEGF treatment for wet Trabeculectomy before diagnosis of movements to control flight direction AMD, they said. the malignancy predicted prolonged (i.e., pitch, yaw, and roll axes). Each —Summary by Jean Shaw recovery of anatomy, BVA, and IOP (all VR session was followed by testing p < .05). Surgical reconstruction of the of binocular CDVA, refractive error, American Journal of anterior chamber at the time of pars binocular eye alignment (strabismus), Ophthalmology plana and/or anterior vitrectomy had stereoacuity, and postural stability. Selected by Richard K. Parrish II, MD no significant effect on recovery. Vitrec- Visually induced motion sickness was tomy (either type) was more likely to be assessed using a questionnaire. Five Predictors of Successful Out- successful in eyes with better glaucoma children also underwent before-and- come for Malignant Glaucoma control before the malignancy. The after testing of visual-vestibulo-ocular January 2020 degree of improvement in IOP, BVA, or reflex (V-VOR) adaptation. Any change the number of glaucoma medications from baseline in a visuomotor measure Thompson et al. set out to identify did not differ according to whether the represented a safety concern. factors linked to favorable outcomes of condition was managed medically or Of the 50 children, 46 (92%) com- malignant glaucoma. They found that surgically. pleted the entire study. There were no earlier vitrectomy may shorten recovery Trabeculectomy may slow recovery significant changes from baseline in time and that Nd:YAG laser hyaloidot- from malignant glaucoma, but anatom- binocular CDVA (p = .89), refractive omy and oral carbonic anhydrase in- ic resolution may be swifter with oral error (p = .36), binocular eye align- hibitors may be the most ideal methods carbonic anhydrase inhibitors, and IOP ment (p = .90), or stereoacuity (p = to reduce intraocular pressure (IOP). may be optimized by clinic-based ref- .45). Postural stability degraded 9% Maximum improvement in IOP and ormation of the anterior chamber. The (on average) from baseline to 60 min- best visual acuity (BVA) may lag behind authors recommend pooling data from utes following VR exposure (p = .06). anatomic resolution. multiple institutions to better gauge From pre- to post-trial, scores on the This retrospective study included the effectiveness of methods to manage questionnaire increased by a mean of 64 eyes (55 patients) with malignant malignant glaucoma. 4.7% for all four symptom categories: glaucoma treated at the same facility. fatigue (p = .03), head/neck discomfort Data from medical records were col- VR Headsets May Be Safe for (p = .03), eye discomfort (p = .02), and lected, including anatomic details, IOP, Young Children motion sickness (p = .01). V-VOR gain and BVA. Of the 64 eyes, 56 (87.5%) January 2020 remained stable in the five children required surgery. Data analysis indicated tested. No child who finished both that vitrectomy was more likely to be Safety warnings that come with virtual sessions asked to stop the game, and successful in eyes that had previously reality (VR) 3D binocular headsets most were disappointed when the play undergone fewer than three incisional state that their use is banned for chil- ended. surgeries, were treated with fewer than dren under 13 years of age. However, Three children (6% of participants) three topical glaucoma medications, quantitative studies of the effects of stopped playing in the first 10 minutes or had IOP ≤30 mm Hg (all p < .05). If these headsets on children are lacking. of the initial session: two girls (aged 5 vitrectomy was performed within 30 Tychsen and Foeller performed a study and 6) and one boy (aged 7). The girls days of the malignant glaucoma diag- in 4- to 10-year-olds and found no cited discomfort consistent with mild nosis, the time to recovery of anatomy, meaningful adverse effect on visuomo- motion sickness; the boy said he was BVA, and IOP was faster (all p < .05). tor function. After use of the device, bored and the headset was uncomfort- IOP reductions were greater for patients participants had no significant postural able. No child experienced aftereffects who received oral carbonic anhydrase instability or maladaptation of the such as flashbacks in the days following inhibitors (p = .016, underwent Nd:YAG vestibulo-ocular reflex. the study. laser hyaloidotomy (p = .007), or had For this prospective study, the The authors concluded that young no history of malignant glaucoma (p = researchers included 50 children (29 children seem to tolerate immersive 3D .007). boys) whose mean age was 7.2 years. VR play well without any noteworthy Resolution of anatomy occurred Participants were required to have effects on visuomotor function. much faster than maximal improve- logMAR corrected distance visual —Summaries by Lynda Seminara

EYENET MAGAZINE • 23 hand smoke by one cigarette per day DME at baseline, the ICERs for ranibi- JAMA Ophthalmology was linked to further choroidal thinning zumab were $65,576/QALY at five years Selected and reviewed by Neil M. of 0.54 μm in the central subfield, 0.42 and $63,930/QALY at 10 years. Bressler, MD, and Deputy Editors μm in the inner temporal sector, and Based on these analyses, ranibi- 0.47 μm in the outer temporal sector. zumab is likely to be cost-effective for Impact of Secondhand Smoke Although these findings suggest that patients with PDR and center-involved on the Choroid of Children secondhand smoke is linked to choroi- DME but unlikely to be more cost- December 2019 dal thinning in children, the authors effective than PRP for those without Yuan et al. assessed the relationship cautioned that the association does center-involved DME. These findings between choroidal thickness and sec- not necessarily indicate a causal effect. are consistent with the earlier two-year ondhand smoke exposure in children (Also see related commentary by Cécile results of Protocol S. between the ages of 6 and 8. They found Delacourt, PhD, in the same issue.) Although a lower dose of ranibi- that secondhand smoke correlates with zumab (0.3 mg) is available and may choroidal thinning in an exposure- Cost-Effectiveness of help to reduce costs, the present study dependent manner. Ranibizumab­ and PRP for involved only the 0.5-mg dose. The For this study, the researchers includ­ Proliferative DR authors acknowledged that it would be ed 1,400 patients recruited from the December 2019 difficult to generalize the cost-effective- population-based Hong Kong Children ness of ranibizumab to that of other Eye Study. All participants underwent In a secondary analysis from the anti-VEGF agents because long-term detailed ophthalmic investigations, DRCR.net Protocol S study, Hutton data for other drugs are lacking. A low- including measurement of choroidal et al. compared the cost-effectiveness er price point for a drug that is at least thickness via swept-source optical of ranibizumab and panretinal pho- as effective as ranibizumab may render coherence tomography. History of tocoagulation (PRP) for patients who anti-VEGF therapy cost-effective for secondhand cigarette smoke was ob- had proliferative diabetic retinopathy PDR treatment even if center-involved tained from a questionnaire completed (PDR) but did not have center-involved DME is absent. The authors noted that by parents or guardians. The correla- diabetic macular edema (DME) and their findings may be considered with tion between choroidal thickness and associated loss of visual acuity. They patient-specific factors when choosing exposure to secondhand smoke was found that the first-line use of PRP is a a treatment for PDR. (Also see related assessed with multiple linear regression more cost-effective approach for these commentary by Steven M. Kymes, PhD, analyses, controlling for confounding patients. and David Vollman, MD, in the same factors. Five-year efficacy, safety, and re- issue.) Of the 1,400 participating children, source utilization data were gathered 459 (32.8%) had been exposed to for 213 adults with PDR, and results Firearm-Related Ocular Trauma secondhand cigarette smoke. After ad- were simulated through 10 years. in Children and Adolescents justment for age, sex, body mass index, Treat­ment protocols were intravenous December 2019 axial length, and birth weight, second- ranibizumab (0.5 mg) at baseline and hand smoke was found to correlate up to every four weeks thereafter (per a Weiss et al. evaluated the epidemiologic with thinner choroidal parameters. structured retreatment protocol) versus pattern of firearm-related ocular injuries When choroidal measurements were PRP at baseline. Any eye, regardless of in young people. They found that more compared, those of smoke-exposed treatment assignment, could receive than half of the injuries were associated children were 8.3 μm thinner in the ranibizumab for concomitant DME with traumatic brain injury, and 12% central subfield, 7.2 μm narrower in the involving vision loss. Main outcomes of the injuries resulted in death. inner inferior, 6.4 μm narrower in the were incremental cost-effectiveness ra- For this retrospective analysis, the outer inferior, 6.4 μm thinner in the tios (ICERs) for each treatment among authors used records from the National inner temporal, and 7.3 μm thinner in patients (including those who did have Trauma Data Bank from 2008-2014. the outer temporal. center-involved DME at baseline). Of note, the data bank includes most Choroidal thinning was more com- At year 5, mean costs for patients U.S. trauma centers; however, it does mon in families with multiple smokers with vision-impairing DME at baseline not include emergency departments in and in homes with larger amounts of were $22,355 for the PRP group and other hospitals. secondhand smoke. For each additional $40,825 for the ranibizumab group. Of the 8,715 firearm-related ocular smoker, choroidal thinning increased Quality-adjusted life-years (QALYs) injuries leading to hospitalization by 7.86 μm in the central subfield, 4.51 were 0.02 and 0.30, respectively. For during this time, 1,972 (22.6%) were in μm in the outer superior, 6.23 μm in patients without center-involved DME people under 21 years of age. Collected the inner inferior, 5.59 μm in the outer at baseline, the ICER of ranibizumab data included age, sex, race/ethnicity, inferior, 6.06 μm in the inner nasal relative to PRP was $582,268/QALY injury intent, disease/injury classifica- region, and 6.55 μm in the outer nasal at five years and $742,202/QALY at 10 tion codes, Injury Severity Score (ISS), region. Increasing exposure to second- years. For patients with center-involved Glasgow Coma Scale (GCS) score, geo-

24 • JANUARY 2020 graphic location, length of hospital stay, themselves and then compared results and mild photosensitivity. On the health insurance status, and disposition with those of a previous AGS survey on second day, her upper and lower left at discharge. practice preferences for hypothetical eyelids developed redness, and she Results showed that most of the patient vignettes. experienced eye-movement discomfort. pediatric patients were male (85.1%) For the present study, the authors Her physician prescribed chloram- and adolescents (52.6%), with a mean distributed a survey electronically phenicol eyedrops for presumed con- age of 15.2 years. Most commonly, the to AGS members, who completed it junctivitis. Symptoms worsened, and injuries occurred at home (38.6%) or anonymously. Participants were asked diplopia occurred in all gaze positions on the street (24.8%). The mean (stan- to adopt the role of a patient who had other than primary. The patient denied dard deviation) hospital stay was 7.6 open-angle glaucoma and progressive a history of trauma, sinusitis, or recent (12) days, ISS was 16 (13.1), and GCS visual field loss requiring surgery. Three fever. She has trigeminal neuralgia, for score was 11 (5.1). pre-op intraocular pressure (IOP) sce- which she takes pregabalin. The most common ocular injuries narios were given (<21, 21-26, and >26 When she presented to the authors, were open wound of the eyeball (41.6%), mm Hg), and respondents were asked her visual acuity was 20/16 in her right ocular adnexa (25.5%), orbital injury to choose the glaucoma procedure(s) eye and 20/20 in her left; her intraoc- or fracture (30.0%), and contusion they would prefer to receive for each ular pressure was 22 and 26 mm Hg, of the eye or adnexa (21.1%). The IOP scenario. respectively. She had marked swelling youngest group of patients (≤4 years Overall, 289 surgeons participat- of the left periorbital region, with gross of age) was most likely to be injured ed (27.4% of active/provisional AGS proptosis (4 mm) observed by Hertel unintentionally (odds ratio [OR], 4.41; members). The most preferred proce- exophthalmometry. All movement p < .001) and at home (OR, 5.39; p < dures, for the three IOP ranges com- in her left eye was restricted. The left .001). The oldest group (19-21 years) bined, were ab interno trabeculotomy upper lid was erythematous with mild had the highest odds of assault injury (20.3%), Xen gel stent (18.6%), iStent edema. (OR, 2.17; p < .001) and injury in the with two devices (14.3%), and tradi- Results of Ishihara color testing were street (OR, 1.61; p < .001). tional trabeculectomy plus mitomycin similar for both eyes, and pupillary Injuries among black patients were C (14.1%). A significant number of reflexes were normal. Slit-lamp exam- more likely to be the result of an assault participants would prefer procedures ination showed marked conjunctival (OR, 4.53; p < .001); in contrast, inju- that spared the conjunctiva or did not chemosis, but the anterior chamber and ries among white patients were more result in bleb formation, even for the posterior segment appeared normal. likely to be self-inflicted (OR, 7.1; p < lowest pre-op IOP level. For all three There was no sign of scleritis or uveitis. .001). Most cases of traumatic brain IOP ranges, older surgeons were more Blood test results were remarkable injury resulted from self-inflicted harm likely than their younger counterparts only for elevated C-reactive protein (OR, 5.99; p < .001), as did most visual to prefer traditional trabeculectomy (29 mg/L). Extensive preseptal edema pathway injuries (OR, 2.86; p < .001). and to have just one procedure. and retro-orbital fat stranding were The mortality rate for inpatients was detected by orbital computed tomogra- 12.2%. (Also see related commentary Orbital Inflammation Caused phy. Extraocular muscles and paranasal by Joseph K. Canner, MHS; Joseph V. by Osteoporosis Rx sinuses appeared normal. Sakran, MD, MPH, MPA, and Fasika Clinical & Experimental The diagnosis of orbital inflamma- Woreta, MD, in the same issue.) Ophthalmology tion secondary to zoledronic acid was —Summaries by Lynda Seminara Published online Oct. 15, 2019 made, and IV methylprednisolone (500 mg) was begun. Signs and symptoms Although ocular side effects of bis- improved within 24 hours, and treat- OTHER JOURNALS phosphonates (which are used to treat ment was switched to oral prednisone Selected by Deepak P. Edward, MD osteoporosis) are uncommon, they (60 mg/day, for a dose of 1 mg/kg). The can affect any layer of the eye and follow-up exam two weeks later showed Glaucoma Procedure cause conjunctivitis, scleritis, and complete resolution of orbital inflam- Preferences: When Surgeons uveitis. Most patients recover after mation. The full range of eye move- Adopt the Patient Role discontinuing the medication and ment had returned, and proptosis had Eye taking steroids. Han and Weatherhead resolved. The prednisone was tapered 2019;33(10):1577-1583 described such a case, this one involving rapidly. orbital inflammation after zoledronic Given the high prevalence of osteo- If you were the patient, which glaucoma acid infusion. porosis and the use of bisphosphonates, procedure would you prefer? Chang et In this report, a 59-year-old woman the authors said, it is important for al. surveyed the members of the Amer- received an IV infusion of zoledronic clinicians to ask about medication use ican Glaucoma Society (AGS) to deter- acid (Aclasta 5 mg) for treatment of in patients who present with orbital mine which glaucoma procedure they osteoporosis. The next day, she had a inflammation. would prefer to have performed on headache, bilateral retro-orbital pain, —Summaries by Lynda Seminara

EYENET MAGAZINE • 25