EXPERIMENTAL ACCOMMODATIVE IOLs P. 12 • MANAGING POST-PK ASTIGMATISM P. 18 A FIRST LOOK AT HYPERSONIC VITRECTOMY P. 53 • UPDATE ON EYE RESEARCH P. 56 HOW PATIENTS CAN AFFORD THEIR GLAUCOMA MEDS P. 60 • INSIDIOUS SILENT SINUS SYNDROME P. 64 Review of Ophthalmology Vol. XXVI, No. 6 • June 2019 MIGS

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ISSUE FOCUS: GLAUCOMA for the Generalist • Whyfor the Generalist Trabs and Tubes Still Matter • Dry-eye Preview • Keratconus: Non-CXL Options

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MIGS for the Comprehensive Ophthalmologist P. 24 Options for When You Need the “Big Guns” P. 37

• A Look into the Dry-eye Pipeline P. 42 ALSO INSIDE: • Non Cross-linking Options for Keratoconus P. 46

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*Compared to SYSTANE® BALANCE Lubricant Eye Drops. References: 1. Korb D, Blackie C, Meadows D, Christensen M, Tudor M. Evaluation of extended tear stability by two emulsion based artificial tears. Poster presented at: 6th International Conference of the Tear Film and Ocular Surface: Basic Science and Clinical Relevance; September 22-25, 2010; Florence, Italy. 2. Moon SW, Hwang JH, Chung SH, Nam KH. The impact of artificial tears containing hydroxypropyl guar on mucous layer. Cornea. 2010;29(12):1430-1435. 3. Davitt WF, Bloomenstein M, Christensen M, Martin AE. Efficacy in patients with dry eye after treatment with a new lubricant eye drop formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 4. Willcox MDP, Argueso P, Georgiev GA, et al. TFOS DEWS II tear film report. Ocul Surf. 2017;15:366-403. 5. Ketelson H, Rangarajan R. Pre-clinical evaluation of a novel phospholipid nanoemulsion based lubricant eye drop. Invest Ophthalmol Vis Sci. 2017;58:3929. 6. Ogundele A, Ketelson H, et al. Preclinical evaluation of a novel hydroxypropyl-guar phospholipid nanoemulsion lubricant eye drop for dry eye disease. Poster presented at: The 36th World Ophthalmology Congress (WOC); June 16-19, 2018; Barcelona, Spain. 7. Craig J, Nichols K, Akpek E, et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017;15:276-283. 8. Lane S, Paugh J, et al. An Evaluation of the in vivo Retention Time of a Novel Artificial Tear as Compared to a Placebo Control. Invest Ophthalmol Vis Sci. 2009;50(13):4679. 9. Benelli U. Systane® lubricant eye drops in the management of ocular dryness. Clin Ophthalmol. 2011;5:783-790. 10. Torkildsen G. The effects of lubricant eye drops on visual function as measured by the Inter-blink interval Visual Acuity Decay test. Clin Ophthalmol. 2009;3:501-506.

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RP0619_Alcon Systane.indd 1 5/15/19 9:28 AM REVIEW NEWS Volume XXVI • No. 6 • June 2019 Results of the Annual IOL Explant Survey Released

At the recent ASCRS meeting, Nick Mamalis, MD, professor of Reasons for One-piece, Acrylic, Monofocal Explantations ophthal mology, co-director of the 45% Damaged IOL-Cracked or torn during insertion Intermountain Ocular Research Nick Mamalis, MD Mamalis, Nick 40% Dislocation/Decentration Center and director of ocular Glare/optical aberrations pathology at the Moran Eye Center 35% Incorrect lens power at the University of Utah, presented 30% Infection/endophthalmitis Iritis UGH syndrome fi ndings from his annual survey on 25% Removed during retinal surgery foldable IOLs requiring explantation 20% Unknown or secondary intervention. He began 15% by noting that the type of lens with the highest rate of explantation is also 10% the one implanted most frequently in 5% the United States. “By far the most 0% commonly explanted lens was a one- piece, hydrophobic acrylic,” says Dr. Dr. Mamalis discusses another “An intact capsulorhexis with capsular Mamalis. “But that really refl ects noteworthy point in the data. “When bag fi xation of the IOL will decrease the most commonly used lenses. looking at hydrophilic acrylic (hydro- dislocation and decentration marked- Other materials are less frequently gel) lenses, we’re fi nding the most ly,” he says, adding that ensuring accu- explantated because they’re just not common reason for explanting is cal- rate IOL measurement is critical. He used as much.” cifi cation,” he says. The incidence of notes that this is becoming more diffi - Discussing the reasons for explan- explanting these intraocular lenses has cult in patients who’ve previously had tation, he says dislocation/decentra- gone down over the course of the sur- refractive surgery. Finally, Dr. Mama- tion ranks as number one. However, vey, but Dr. Mamalis says this may be lis says that proper patient selection he acknowledges that this complica- refl ective of their less-frequent use in and preop counseling are necessary, tion doesn’t mean there’s an inherent the United States. especially to reduce complications problem with the design of the im- Referring to previous surveys, Dr. with multifocal lenses. plant. “This implies either a complica- Mamalis says it’s interesting that dislo- tion during surgery, or some weakness cation/decentration is still the number of the zonules or the capsular bag that one reason for IOL explantations. “It’s led to this complication,” he notes. always been [number one] and it stays Allergan Wins The second-highest reason for IOL that way,” he says. “Other complica- explantation overall was glare/opti- tions sort of go up and down. Incor- Small Victory cal aberrations, though this was the rect lens and power is still the third most common reason for explantation overall reason for IOL removal but it’s of multifocals. “[Glare and/or optical gone down over the course of the sur- vs. ImprimisRx aberrations] are usually the problems vey, which means we’re getting better The drug-compounding company patients have with multifocals,” he at measuring IOLs and choosing the Imprimis Rx was recently ordered to says. “Since there may be diffi culty correct power.” pay $48,500 to Allergan as a result of tolerating these, people more com- To avoid complications, Dr. Mama- a false-advertising lawsuit Allergan monly report these problems.” lis says good surgical technique is key. (Continued on page 35)

June 2019 | reviewofophthalmology.com | 3

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4 | Review of Ophthalmology | June 2019

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NOW JOINING THE EYEVANCE™ FAMILY of ophthalmic treatment options

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RRO0419_Eyevance.inddO0419_Eyevance.indd 1 33/26/19/26/19 10:3310:33 AMAM Letters to

REVIEW the Editor E DITORIAL STAFF

Editor in Chief Walter C. Bethke (610) 492-1024 [email protected]

Senior Editor Christopher Kent Lax Lids Are (212) 274-7031 [email protected]

Associate Editor Alexandra Skinner Red Flags (610) 492-1025 [email protected] o the Editor: Dr. Armstrong responds: Chief Medical Editor The article “Lid Laxity: Diagno- T Mark H. Blecher, MD sis and Management” in the Plastics Thank you for your thoughtful letter. Pointers department of the Febru- In addition to obstructive sleep ap- Art Director ary issue of Review of Ophthalmology nea, there are a variety of genetic con- Jared Araujo (pp. 46-48) was of great interest. The ditions that have been described in (610) 492-1032 importance of correlating eye diseases association with lax eyelid syndrome, [email protected] with medical conditions (e.g., obstruc- including Down syndrome, congenital tive sleep apnea, or OSA) has thera- cataracts facial dysmorphism neuropa- Senior Graphic Designer peutic implications for patients and thy (CCFDN), and congenital hyper- Matt Egger 1-3 genetic implications for families. glycinemia. LES also presents in (610) 492-1029 In addition to OSA, other medical patients with Ehlers-Danlos syndrome [email protected] conditions have been associated with with mutations in the COL5A1 and Lax Eyelid Syndrome. In 1984, LES COL5A2 genes coding for type V col- Graphic Designer was reported in a patient with non- lagen.4 Ashley Schmouder ketotic hyperglycemia.1 The case was These varied heritable conditions (610) 492-101048 of particular interest since glycine is are unifi ed in that the individual ge- [email protected] a major constituent of collagen. This netic mutation compromises the in- biochemical defect probably led to tegrity of the tarsal connective tissue International coordinator, Japan weaker collagen fi bers and thus greater and causes eyelid laxity. When lid lax- Mitz Kaminuma susceptibility to physical trauma (ex- ity reaches a critical threshold—or [email protected] plaining the association of LES with perhaps is exacerbated by mechanical sleeping on one side). This patient’s trauma—the infl ammatory sequelae of Business Offi ces brother also had non-ketotic hypergly- the conjunctiva and ocular surface re- 11 Campus Boulevard, Suite 100 cemia, and the genetic defect was sub- sult. The genetic associations can elu- Newtown Square, PA 19073 sequently identifi ed in the brother.2 In cidate the pathogenesis of LES and, as (610) 492-1000 the era of gene therapy it will be pos- you suggest, in this exciting era of gene Fax: (610) 492-1039 sible to correct the genetic defect, thus therapy may offer a potential for future eliminating many problems! treatment. Subscription inquiries: United States — (877) 529-1746 1. Fowler A, Dutton J. Floppy eyelid syndrome as a subset of lax Outside U.S. — (845) 267-3065 eyelid conditions: Relationships and clinical relevance. Ophthal E-mail: Edward W. Gerner, MD Plastic Reconstructive Surg 2010;26:3:195-204. Philadelphia 2. Rao L, Bhandary S, Devi A (2006). Floppy Eyelid Syndrome in an [email protected] Infant. Indian Journal of Ophthalmology 2006;54:3:217-8. Website: 3. Eiferman R, Gossman MD, O’Neill K, Douglas CH. Floppy Eyelid www.reviewofophthalmology.com 1. Gerner EW, Hughes SM. Flopped eyelid with hyperglycemia. Syndrome in a Child. Ophthalmic Plastic and Reconstructive Am J Ophthalmology 1984:98;614-616. Surgery 1991;109:3:74-75. 2. Baker PR II, et al. Variant non-ketotic hyperglycemia is caused 4. Segev F, Heon E, Cole W, Wenstrup R, Young F, et al. Structural by mutations in LIAS, BOLA 3 and the novel gene GLRY5. Brain abnormalities of the cornea and lid resulting from collagen V 2014:137;266-379. mutations. IOVS 2006;47:2:565-573.

6 | Review of Ophthalmology | June 2019

0003_rp0619_news.indd03_rp0619_news.indd 6 55/24/19/24/19 3:563:56 PMPM Only dual-action VYZULTA reduces intraocular pressure (IOP) by targeting the trabecular meshwork with nitric oxide and the uveoscleral pathway with latanoprost acid1

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INDICATION IMPORTANT SAFETY INFORMATION cont’d VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024% is • There have been reports of bacterial keratitis associated with the indicated for the reduction of intraocular pressure (IOP) in patients use of multiple-dose containers of topical ophthalmic products with open-angle glaucoma or ocular hypertension. that were inadvertently contaminated by patients • Contact lenses should be removed prior to the administration of IMPORTANT SAFETY INFORMATION VYZULTA and may be reinserted 15 minutes after administration • Increased pigmentation of the iris and periorbital tissue (eyelid) • Most common ocular adverse reactions with incidence *2% are can occur. Iris pigmentation is likely to be permanent conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), • Gradual changes to eyelashes, including increased length, and instillation site pain (2%) increased thickness, and number of eyelashes, may occur. These For more information, please see Brief Summary of Prescribing changes are usually reversible upon treatment discontinuation Information on next page. • Use with caution in patients with a history of intraocular References: 1. VYZULTA Prescribing Information. Bausch & Lomb Incorporated. infl ammation (iritis/uveitis). VYZULTA should generally not 2. Cavet ME. J Ocul Pharmacol Ther. 2018;34(1):52-60. DOI:10.1089/ be used in patients with active intraocular infl ammation jop.2016.0188. 3. Wareham LK. Nitric Oxide. 2018;77:75-87. DOI:10.1016/j. • Macular edema, including cystoid macular edema, has been niox.2018.04.010. 4. Stamer DW. Curr Opin Ophthalmol. 2012;23:135-143. reported during treatment with prostaglandin analogs. Use DOI:10.1097/ICU.0b013e32834ff 23e. 5. Cavet ME. Invest Ophthalmol Vis with caution in aphakic patients, in pseudophakic patients Sci. 2015;56(6):4108-4116. 6. Kaufman PL. Exp Eye Research. 2008;861:3-17. with a torn posterior lens capsule, or in patients with known DOI:10.1016/j.exer.2007.10.007. 7. Weinreb RN. J Glaucoma. 2018;27:7-15. 8. Weinreb RN. Ophthalmology. 2016;123(5):965-973. 9. Medeiros FA. Am J risk factors for macular edema Ophthalmol. 2016;168:250-259.

VYZULTA and the V design are trademarks of Bausch & Lomb Incorporated or its affi liates. ©2019 Bausch & Lomb Incorporated or its affi liates. All rights reserved. VYZ.0065.USA.19

RP0619_B & L Vyzulta.indd 1 5/15/19 9:37 AM BRIEF SUMMARY OF PRESCRIBING INFORMATION embryofetal lethality. Structural abnormalities observed in rabbit fetuses included anomalies of the great vessels and aortic arch vessels, domed head, sternebral This Brief Summary does not include all the information needed to use VYZULTA and vertebral skeletal anomalies, limb hyperextension and malrotation, abdominal safely and effectively. See full Prescribing Information for VYZULTA. distension and edema. Latanoprostene bunod was not teratogenic in the rat when ® VYZULTA (latanoprostene bunod ophthalmic solution), 0.024%, for administered IV at 150 mcg/kg/day (87 times the clinical dose) [see Data]. topical ophthalmic use. The background risk of major birth defects and miscarriage for the indicated Initial U.S. Approval: 2017 population is unknown. However, the background risk in the U.S. general population 1 INDICATIONS AND USAGE of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. VYZULTA® (latanoprostene bunod ophthalmic solution) 0.024% is indicated for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or Data ocular hypertension. Animal Data 4 CONTRAINDICATIONS Embryofetal studies were conducted in pregnant rabbits administered latanoprostene None bunod daily by intravenous injection on gestation days 7 through 19, to target the period of organogenesis. The doses administered ranged from 0.24 to 80 mcg/kg/day. Abortion 5 WARNINGS AND PRECAUTIONS occurred at doses ≥ 0.24 mcg/kg/day latanoprostene bunod (0.28 times the clinical dose, 5.1 Pigmentation on a body surface area basis, assuming 100% absorption). Embryofetal lethality (resorption) was increased in latanoprostene bunod treatment groups, as evidenced VYZULTA® (latanoprostene bunod ophthalmic solution), 0.024% may cause changes by increases in early resorptions at doses ≥ 0.24 mcg/kg/day and late resorptions to pigmented tissues. The most frequently reported changes with prostaglandin at doses ≥ 6 mcg/kg/day (approximately 7 times the clinical dose). No fetuses analogs have been increased pigmentation of the iris and periorbital tissue (eyelid). survived in any rabbit pregnancy at doses of 20 mcg/kg/day (23 times the clinical Pigmentation is expected to increase as long as latanoprostene bunod ophthalmic dose) or greater. Latanoprostene bunod produced structural abnormalities at solution is administered. The pigmentation change is due to increased melanin doses ≥ 0.24 mcg/kg/day (0.28 times the clinical dose). Malformations included content in the melanocytes rather than to an increase in the number of anomalies of sternum, coarctation of the aorta with pulmonary trunk dilation, melanocytes. After discontinuation of VYZULTA, pigmentation of the iris is likely retroesophageal subclavian artery with absent brachiocephalic artery, domed head, to be permanent, while pigmentation of the periorbital tissue and eyelash changes forepaw hyperextension and hindlimb malrotation, abdominal distention/edema, are likely to be reversible in most patients. Patients who receive prostaglandin and missing/fused caudal vertebrae. analogs, including VYZULTA, should be informed of the possibility of increased An embryofetal study was conducted in pregnant rats administered latanoprostene pigmentation, including permanent changes. The long-term effects of increased bunod daily by intravenous injection on gestation days 7 through 17, to target the pigmentation are not known. period of organogenesis. The doses administered ranged from 150 to 1500 mcg/ Iris color change may not be noticeable for several months to years. Typically, the brown kg/day. Maternal toxicity was produced at 1500 mcg/kg/day (870 times the clinical pigmentation around the pupil spreads concentrically towards the periphery of the iris dose, on a body surface area basis, assuming 100% absorption), as evidenced by and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of reduced maternal weight gain. Embryofetal lethality (resorption and fetal death) the iris appear to be affected by treatment. While treatment with VYZULTA® (latanoprostene and structural anomalies were produced at doses ≥ 300 mcg/kg/day (174 times bunod ophthalmic solution), 0.024% can be continued in patients who develop noticeably the clinical dose). Malformations included anomalies of the sternum, domed head, increased iris pigmentation, these patients should be examined regularly [see Patient forepaw hyperextension and hindlimb malrotation, vertebral anomalies and delayed Counseling Information (17) in full Prescribing Information]. ossification of distal limb bones. A no observed adverse effect level (NOAEL) was 5.2 Eyelash Changes established at 150 mcg/kg/day (87 times the clinical dose) in this study. VYZULTA may gradually change eyelashes and vellus hair in the treated eye. These 8.2 Lactation changes include increased length, thickness, and the number of lashes or hairs. Risk Summary Eyelash changes are usually reversible upon discontinuation of treatment. There are no data on the presence of VYZULTA in human milk, the effects on the 5.3 Intraocular Inflammation breastfed infant, or the effects on milk production. The developmental and health VYZULTA should be used with caution in patients with a history of intraocular benefits of breastfeeding should be considered, along with the mother’s clinical need inflammation (iritis/uveitis) and should generally not be used in patients with active for VYZULTA, and any potential adverse effects on the breastfed infant from VYZULTA. intraocular inflammation as it may exacerbate this condition. 8.4 Pediatric Use 5.4 Macular Edema Use in pediatric patients aged 16 years and younger is not recommended because of Macular edema, including cystoid macular edema, has been reported during potential safety concerns related to increased pigmentation following long-term chronic use. treatment with prostaglandin analogs. VYZULTA should be used with caution in 8.5 Geriatric Use aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in No overall clinical differences in safety or effectiveness have been observed between patients with known risk factors for macular edema. elderly and other adult patients. 5.5 Bacterial Keratitis 13 NONCLINICAL TOXICOLOGY There have been reports of bacterial keratitis associated with the use of 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility multiple-dose containers of topical ophthalmic products. These containers had been inadvertently contaminated by patients who, in most cases, had a Latanoprostene bunod was not mutagenic in bacteria and did not induce concurrent corneal disease or a disruption of the ocular epithelial surface. micronuclei formation in the in vivo rat bone marrow micronucleus assay. Chromosomal aberrations were observed in vitro with human lymphocytes 5.6 Use with Contact Lens in the absence of metabolic activation. Contact lenses should be removed prior to the administration of VYZULTA because Latanoprostene bunod has not been tested for carcinogenic activity in long-term this product contains benzalkonium chloride. Lenses may be reinserted 15 minutes animal studies. Latanoprost acid is a main metabolite of latanoprostene bunod. after administration. Exposure of rats and mice to latanoprost acid, resulting from oral dosing with 6 ADVERSE REACTIONS latanoprost in lifetime rodent bioassays, was not carcinogenic. The following adverse reactions are described in the Warnings and Precautions Fertility studies have not been conducted with latanoprostene bunod. The potential section: pigmentation (5.1), eyelash changes (5.2), intraocular inflammation (5.3), to impact fertility can be partially characterized by exposure to latanoprost acid, a macular edema (5.4), bacterial keratitis (5.5), use with contact lens (5.6). common metabolite of both latanoprostene bunod and latanoprost. Latanoprost acid 6.1 Clinical Trials Experience has not been found to have any effect on male or female fertility in animal studies. Because clinical trials are conducted under widely varying conditions, adverse reaction 13.2 Animal Toxicology and/or Pharmacology rates observed in the clinical trials of a drug cannot be directly compared to rates in the A 9-month toxicology study administered topical ocular doses of latanoprostene clinical trials of another drug and may not reflect the rates observed in practice. bunod to one eye of cynomolgus monkeys: control (vehicle only), one drop of 0.024% VYZULTA was evaluated in 811 patients in 2 controlled clinical trials of up to 12 bid, one drop of 0.04% bid and two drops of 0.04% per dose, bid. The systemic months duration. The most common ocular adverse reactions observed in patients exposures are equivalent to 4.2-fold, 7.9-fold, and 13.5-fold the clinical dose, treated with latanoprostene bunod were: conjunctival hyperemia (6%), eye irritation respectively, on a body surface area basis (assuming 100% absorption). Microscopic (4%), eye pain (3%), and instillation site pain (2%). Approximately 0.6% of patients evaluation of the lungs after 9 months observed pleural/subpleural chronic fibrosis/ discontinued therapy due to ocular adverse reactions including ocular hyperemia, inflammation in the 0.04% dose male groups, with increasing incidence and severity conjunctival irritation, eye irritation, eye pain, conjunctival edema, vision blurred, compared to controls. Lung toxicity was not observed at the 0.024% dose. punctate keratitis and foreign body sensation. U.S. Patent Numbers: 7,273,946; 7,629,345; 7,910,767; 8,058,467. 8 USE IN SPECIFIC POPULATIONS VYZULTA is a trademark of Bausch & Lomb Incorporated or its affiliates. 8.1 Pregnancy © 2019 Bausch & Lomb Incorporated or its affiliates. Risk Summary Distributed by: There are no available human data for the use of VYZULTA during pregnancy to inform Bausch + Lomb, a division of any drug associated risks. Valeant Pharmaceuticals North America LLC Latanoprostene bunod has caused miscarriages, abortion, and fetal harm in Bridgewater, NJ 08807 USA rabbits. Latanoprostene bunod was shown to be abortifacient and teratogenic when administered intravenously (IV) to pregnant rabbits at exposures ≥ 0.28 times the Based on 9612402 (Folded), 9612302 (Flat) 6/2018 clinical dose. Doses ≥ 20 μg/kg/day (23 times the clinical dose) produced 100% VYZ.0058.USA.19 Issued: 3/2019

RRP0619_BP0619_B & L VyzultaVyzulta PI.inddPI.indd 1 55/15/19/15/19 9:399:39 AMAM June 2019 • Volume XXVI No. 6 | reviewofophthalmology.com Cover Focus 24 | MIGS and the General Ophthalmologist Christopher Kent, Senior Editor Experts answer 10 questions about how general ophthalmologists can make the most of these procedures.

37 | Why Trabs and Tubes Still Matter James C. Tsai, MD A glaucoma expert describes situations where surgeons still need the “big guns.” Feature Articles

42 | Dry Eye Therapies: What’s Next? Michelle Stephenson, Contributing Editor Several devices and a multitude of new medications are expected to come to the marketplace in the next few years.

46 | Non Cross-linking Options for Keratoconus Alexandra Skinner, Associate Editor Doctors discuss instances in which cross-linking may not be the best choice, and various alternatives for managing the disease.

Cover image: Mikael Häggström June 2019 | reviewofophthalmology.com | 9

009_rp0619_toc.indd 9 5/24/19 3:22 PM Departments

3 | Review News 18 6 | Letters

12 | Technology Update Creating Uncommon Accommodation Three intraocular lenses in the pipeline appear to be providing true accommodative vision. Here’s the latest on these devices.

18 | Refractive/Cataract Rundown How to Handle Astigmatism After PRK A veteran corneal surgeon reviews the full spectrum of tools and techniques for managing these unique cases.

53 | Retinal Insider 53 A New Way to Perform a Vitrectomy A look at how hypersonic vitrectomy works, and what features it might bring to the table.

56 | Research Review Cataract Surgery May Not Slow Visual Field Loss

60 | Glaucoma Management Easing Your Patients’ Financial Burden Limiting the cost of glaucoma treatment can improve adherence and create happier patients.

64 | Plastic Pointers Silent Sinus Syndrome How to detect and manage this rare condition, which 64 can be associated with a range of symptoms.

68 | Products

70 | Classifieds

71 | Wills Eye Resident Case Series

73 | Ad Index

10 | Review of Ophthalmology | June 2019

009_rp0619_toc.indd 10 5/24/19 3:22 PM TRANSFORMING MIGS IN MORE WAYS THAN ONE. Optimized Outflow: Two multi-directional stents designed to restore natural outflow Clinically Proven: Significant IOP reduction across a wide range of clinical studies1,2 Procedural Elegance: Predictability and precision to meet the needs of your practice Proven Safety: Safety profile similar to cataract surgery alone1

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INDICATION FOR USE. The iStent inject ® Trabecular Micro-Bypass System Model G2-M-IS is indicated for use in conjunction with cataract surgery for the reduction of intraocular pressure (IOP) in adult patients with mild to moderate primary open-angle glaucoma. CONTRAINDICATIONS. The iStent inject is contraindicated in eyes with angle-closure glaucoma, traumatic, malignant, uveitic, or neovascular glaucoma, discernible congenital anomalies of the anterior chamber (AC) angle, retrobulbar tumor, thyroid eye disease, or Sturge-Weber Syndrome or any other type of condition that may cause elevated episcleral venous pressure. WARNINGS. Gonioscopy should be performed prior to surgery to exclude congenital anomalies of the angle, PAS, rubeosis, or conditions that would prohibit adequate visualization of the angle that could lead to improper placement of the stent and pose a hazard. MRI INFORMATION. The iStent inject is MR-Conditional, i.e., the device is safe for use in a specified MR environment under specified conditions; please see Directions for Use (DFU) label for details. PRECAUTIONS. The surgeon should monitor the patient postoperatively for proper maintenance of IOP. The safety and effectiveness of the iStent inject have not been established as an alternative to the primary treatment of glaucoma with medications, in children, in eyes with significant prior trauma, abnormal anterior segment, chronic inflammation, prior glaucoma surgery (except SLT performed > 90 days preoperative), glaucoma associated with vascular disorders, pseudoexfoliative, pigmentary or other secondary open-angle glaucomas, pseudophakic eyes, phakic eyes without concomitant cataract surgery or with complicated cataract surgery, eyes with medicated IOP > 24 mmHg or unmedicated IOP < 21 mmHg or > 36 mmHg, or for implantation of more or less than two stents. ADVERSE EVENTS. Common postoperative adverse events reported in the randomized pivotal trial included stent obstruction (6.2%), intraocular inflammation (5.7% for iStent inject vs. 4.2% for cataract surgery only), secondary surgical intervention (5.4% vs. 5.0%) and BCVA loss * 2 lines * 3 months (2.6% vs. 4.2%). CAUTION: Federal law restricts this device to sale by, or on the order of, a physician. Please see DFU for a complete list of contraindications, warnings, precautions, and adverse events. REFERENCES: 1. iStent inject ® Trabecular Micro-Bypass System: Directions for Use, Part #45-0176. 2. Hengerer FH. Personal experience with second-generation trabecular micro-bypass stents in combination with cataract surgery in patients with glaucoma: 3-year follow-up. ASCRS 2018 Presentation. © 2018 Glaukos Corporation. Glaukos and iStent inject are registered trademarks of Glaukos Corporation. PM-US-0026

RP0619_Glaukos.indd 1 5/15/19 9:32 AM Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

Creating Uncommon Accommodation Three intraocular lenses in the pipeline appear to be providing true accommodative vision. Here’s the latest on these devices. Christopher Kent, Senior Editor

s everyone knows, the “holy ture-changing, fl uid-optic IOL that’s potentially be used to address issues Agrail” in cataract surgery is an im- been in clinical trials in the Domin- such as astigmatism via a toric lens, plant that can give patients back a full ican Republic and Mexico for four or to deliver drugs inside the eye or range of visual accommodation—the years,” he explains. “It’s a two-part perform electronic sensing. Further- kind most of us enjoyed in our youth. lens composed of a base component more, we can take the lens section out A number of implantable lenses cur- that fi lls the capsular bag and a mod- very easily, so we can come back fi ve rently in development (not yet ap- ular second implant that contains a years after implantation and exchange proved in the United States or else- curvature-changing liquid silicone it if something better comes along.” where) are showing the promise of at optic. It’s biomimetic, meaning that Sumit Garg, MD, vice chair of clini- least coming close to that goal. it mimics the natural crystalline lens; cal ophthalmology, medical director Here’s the latest on the three when the ciliary muscles contract, the and an associate professor of cata- frontrunners that may give surgeons zonules relax and the lens becomes ract, corneal and refractive surgery at a true accommodating lens in the rounder, just like the natural lens. the Gavin Herbert Eye Institute at years ahead. Also, like the natural lens, the Juvene the University of California, Irvine, doesn’t split the incoming light the agrees that Juvene being a modular The Juvene way a multifocal lens does. For that lens is advantageous. (Dr. Garg is reason, vision quality is excellent and also a consultant to LensGen.) “The The Juvene accommodative IOL optical side effects are minimal.” two-part lens consists of a fi xed ‘base’ (LensGen, Irvine California) was re- Dr. Donnenfeld notes that filling lens and a fl uid-fi lled ‘power’ lens,” cently profi led at the annual meeting the capsular bag is an advantage. “Be- he notes. “In early clinical trials, the of the American society of Cataract cause it fi lls the capsular bag there’s lens delivered up to 3 D of continuous and Refractive Surgery by Eric Don- no change in the effective lens posi- range of vision, with minimal or no nenfeld, MD, a clinical professor of tion and no rotation when it’s implant- visual side effects. Because the bag is ophthalmology at New York Univer- ed,” he says. “There’s no posterior completely fi lled, there have been no sity Medical Center and a partner at capsular opacifi cation, and there are reports of posterior capsular opacity Ophthalmic Consultants of Long Is- fewer fl ashes and fl oaters because the out to four years. Also, with the bag land. (Dr. Donnenfeld is a consultant vitreous face doesn’t come forward. fi lled, there should be less stress on for LensGen.) He implanted his fi rst Meanwhile, because of the modu- the vitreous. That has the potential to Juvene in March of 2018, in Santa lar components, it can be inserted confer safety advantages with respect Domingo in the Dominican Republic. through a small 3-mm incision. The to posterior vitreous detachment and “The Juvene is a modular, curva- two-part design allows the platform to retinal tears.”

12 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

012_rp0619_tech 2.indd 12 5/24/19 4:13 PM very good. Patient satisfaction was excellent, with no patients reporting glare or halos, although two patients reported very mild starbursting, the kind you might see with a standard monofocal lens.” Dr. Donnenfeld also says that four- year data is now available for the fi rst patients implanted with the lens. “Those patients are doing very well,” he says. “None of them developed The Juvene accomodative IOL is a two-part posterior capsular opacifi cation, be- lens composed of a base component that cause the leafl ets of the capsule are fi lls the capsular bag and a modular second separated.” implant that contains a curvature-changing Asked about similarities to the liquid silicone optic. can Society of Cataract and Refractive FluidVision accommodating lens (see Dr. Garg adds that he’s had the Surgery I presented the one-month page 16), Dr. Donnenfeld notes that opportunity to implant a few of the follow-up data from that study. The they share the same type of mecha- Juvene IOLs. “I found the procedure data shows that the lens creates a very nism. “They’re both biomimetic, and to be very intuitive, without a signifi - reproducible 2.5 D of accommoda- they both have silicone optics that cant learning curve,” he says. “The tion, and the subjects report excellent change as the patient accommodates,” modular lens was easy to implant and quality of vision. With binocular lens he says. “The major difference is that manipulate within the eye, and the implantation, near vision was even the Juvene is a modular lens, so it can incision didn’t require any sutures.” better; subjects achieved 3 D of ac- go in through a smaller incision.” In terms of contraindications, Dr. commodation. Dr. Donnenfeld acknowledges that Donnenfeld says that the Juvene is “The great majority of patients there’s still plenty of work to be done similar to a standard monofocal lens. were 20/20 at distance,” he continues. before the Juvene reaches the market- “Anyone who can accept a monofocal “They had excellent intermediate vi- place. “The FDA trials will start later lens can have this lens implanted,” he sion, and about half of the patients this year,” he notes. “Meanwhile, the explains. “You have to have an intact ended up seeing 20/32 at near. The Grail study will involve a one-year fol- capsular bag, the capsulotomy has to results were very close to emmetro- low-up. If we see that the data is just be good and there has to be good zo- pia. The effective lens position was as good with this version of the lens at nular support, but these are the usual concerns with any patient having cata- Juvene: Postop Monocular Visual Acuities (n=20) ract surgery. Indications for this lens would be the same as for a multifocal lens, except that you can put this lens 100 in patients who have keratoconus, for 90 example, or glaucoma. There are no 80 major contraindications, because it 70 functions as a monofocal lens. There’s no splitting of light, so you don’t have % 60 to worry about any loss of contrast 50 sensitivity.” 40 Dr. Donnenfeld says that the lens 30 design has been through a half-doz- 20 en different iterations. “Once they fi nalized the lens design they started 10 (0) a clinical trial in Mexico called the 0 ‘Grail’ study, involving 44 eyes and BCDVA 4 m DCIVA 66 cm DCNVA 40 cm ≥20/20 ≥20/32 ≥20/40 multiple surgeons,” he says. “At the BCD=best-corrected distance; DCI=distance-corrected intermediate; DCN=distance-corrected near recent annual meeting of the Ameri-

June 2019 | reviewofophthalmology.com | 13

012_rp0619_tech 2.indd 13 5/24/19 4:13 PM Technology

REVIEW Update

Young Control Defocus Curve Monofocal Defocus Curve Lumina Defocus Curve

The Lumina accommodative lens consists of a fi xed-power lens and a variable-power lens. Two optical elements in the latter part of the device move across each other under pressure from ciliary muscle changes, shifting the focal power from distance to near and back. The Lumina is implanted in the sulcus, not inside the capsular bag. Lumina is compressed by the centrip- range of objective and subjective ac- etal force of the muscle contraction. commodation for at least two years. At The Lumina’s two optical surfaces both 12 and 24 months, the subjects then slide over each other, altering displayed an accommodative range the refractive power of the dual lens of about 3.1 D, although there was to provide sharp vision at near. Relax- some variation among individual pa- ation of the ciliary muscle reverses the tients. According to Dr. Alió, pseudo- one year as it was at one month, then process due to the inherent, outward, accommodation was responsible for we’ll feel much better about it. In the elasticity of the IOL, for sharp vision less than 30 percent of this result. meantime, I remain cautiously opti- at far. The Lumina can provide a focal The company says that long-term sta- mistic. I think it’s a very exciting lens.” range of 3 to 4 D when shifted. (The bility has been shown by three- to company reports that the shift in posi- four-year postop evaluations, with pa- The Lumina tion of the two pieces can be seen in tients showing accommodation and ultrasound images.) excellent contrast sensitivity curves, The Lumina accommodative IOL Clinical investigators have noted comparable to monofocal curves, and (Akkolens International, the Neth- that placing the lens in the sulcus patients being spectacle-free. erlands) consists of a fixed-power eliminates several factors that might Dr. Alió is the principal investiga- lens that corrects for the refractive affect the performance of other ac- tor for the lens; he performed all of error of the aphakic eye, the way a commodating lenses that are placed the surgeries and follow-up measure- monofocal lens would, and a variable- inside the bag, such as less-direct ments. He emphasizes that placing power lens. The latter is composed transfer of the ciliary muscle move- the lens in the sulcus is a signifi cant of two cubic, progressively powered ment, and gradual capsule shrinkage advantage. “Anything that’s placed hydrophilic acrylate optical elements, and fi brosis that may restrict a lens’s inside the capsular bag is condemned elastically connected at the rims, that accommodative amplitude. (After the to become fi brotic and blocked over move across each other under pres- Lumina is implanted, standard YAG time,” he says. “Fibrosis is unavoid- sure from the ciliary muscles. That can be applied to treat posterior cap- able, as we demonstrated in our 2015 movement causes a change in focal sular opacity should it occur, with full paper published in the Journal of Re- power. The Lumina is implanted in recovery of visual acuity.) fractive Surgery.3 You have a maxi- the sulcus—not in the bag—through Several studies showing both sub- mum of six months [of full motion] a 2.8-mm incision using a standard jective and objective accommodation during the follow-up, due to capsular butterfl y-type lens injector. (You can have been conducted to date.1,2 Early bag shrinkage and contraction. On the see a Lumina being implanted at you- data from 59 eyes of 43 patients im- other hand, our studies have shown tube.com/watch?v=2nvaQJaF_BI.) planted with the Lumina, reported that the Lumina works even if the The device has rounded anterior edg- by Jorge Alió, MD, PhD, professor capsular bag is broken during surgery es to prevent release of iris pigment. and chairman of ophthalmology at (which happened in one case), and Once in the sulcus, the haptics the University Miguel Hernandez de following YAG laser capsulotomy.” directly contact the ciliary muscles. Elche in Spain, and medical direc- Asked about potential limita- When the muscles contract because tor of the investigational study of the tions of this technology, Dr. Alió of an accommodative stimulus, the Lumina, found that it retained its full explains that the range of accom-

14 | Review of Ophthalmology | June 2019

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RP0319_Keeler Slit.indd 1 2/14/19 3:16 PM Technology

REVIEW Update

found good vi- sual acuity at every distance, with an aver- age accommo- dation range of 2 D. Louis D. Nichamin, MD, at the Eu- ropean Society of Cataract and Refractive Sur- geons meeting in September 2018, reported data from 28 eyes that under- went monocular The FluidVision accommodative lens is hollow and fi lled with liquid silicone—including the haptics. As the ciliary muscles tighten, a small amount of fl uid in the haptics is pushed into the optic section of the lens, causing the implantation anterior curvature of the optic to increase, enhancing near vision. When the muscles relax, the reverse occurs. with the lens at six sites in South modation appears to depend on countries that accept the European Africa. Distance vision was 20/20; in- the anatomy of the eye. “The evi- approval. FDA testing is expected to termediate was close to that; and near dence that we have demonstrates begin in 2020. Dr. Alió says that he visual acuity ranged from 20/22 to that it accommodates from 1.5 D hopes the Lumina lens will be avail- 20/27. He also reported that an in- to more than 4 D,” he says. “The main able commercially in about two years. house autorefractor detected an aver- limitation is the variability from eye age of 2 D of accommodation, with to eye. That’s the only pitfall.” Dr. The FluidVision Lens some eyes achieving as much as 5 D Alió adds that his accommodative lens of accommodation. group is the only one reporting clini- The FluidVision Lens (PowerVi- Other randomized, controlled, cal outcomes in peer-reviewed jour- sion/Alcon) is an acrylic device. The multicenter studies are currently un- nals. “I challenge the others to publish entire lens, including the haptics, is derway. The ORION study is com- what they have shown in meetings,” hollow and fi lled with liquid silicone, paring binocular implantation of the he says. “My bet is that intracapsular which allows the lens to change shape FluidVision lens to monofocals in 54 lenses will not work.” in response to ciliary muscle contrac- patients at seven sites in South Af- The company says it’s currently de- tion and relaxation. As the ciliary rica. The CLEAR study is comparing veloping new iterations of the Lumina muscles tighten, a small amount of the FluidVision to trifocal intraocular that will allow it to pass through an fl uid in the haptics is pushed into the lenses at multiple centers in multiple incision of 2.2 to 2.4 mm. Also in the optic section of the lens, causing the countries. Meanwhile, the company is works are a yellow-tinted Lumina lens anterior curvature of the optic to in- developing a prototype toric version for blue-light fi ltering; a toric Lumina crease, enhancing near vision. When of the IOL, and is working on a model lens; an “add-on” Lumina unit that the muscles relax, the reverse occurs. that would be refraction-adjustable can be added to existing monofocal Earlier versions of the lens required after implantation. The latter may be lenses to restore accommodation; and a 3.5-mm incision for implantation; implantable through a 2.8-mm inci- a pre-loaded injector. the latest version of the lens with a sion. In the meantime, the Lumina is new injector is able to be implanted 1. Alio JL, Simonov A, Plaza-Puche AB, et al. Visual outcomes now beginning large clinical trials in through a 3.2-mm wound. and accommodative response of the Lumina accommodative Spain and South America. The com- The current version of the device, intraocular lens. Am J Ophthalmol 2016;164:37-48. 2. Alió JL, Simonov AN, Romero D, et al. Analysis of accommodative pany says that approval in Europe called the NextGen 20/20 model, is performance of a new accommodative intraocular lens. J Refract is expected in the fourth quarter of currently undergoing a multicenter Surg 2018;34:2:78-83. 3. Alió JL, Ben-Nun J. Study of the force dynamics at the capsular 2019, followed by expected commer- international clinical trial. Six-month interface related to ciliary body stimulation in a primate model. J cial expansion in Europe and other data, reported in the fall of 2018, Refract Surg 2015;31:2:124-8.

16 | Review of Ophthalmology | June 2019

012_rp0619_tech 2.indd 16 5/24/19 4:13 PM A Clear Vision For Life ®

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RP0619_Santen.indd 1 5/15/19 9:30 AM Refractive/Cataract

REVIEW Rundown Edited by Arturo Chayet, MD

How to Handle Astigmatism After PK A veteran corneal surgeon reviews the full spectrum of tools and techniques for managing these unique cases. Majid Moshirfar, Salt Lake City

hough the use of Descemet’s after year. This occurs because these ocular surface integrity, dryness, pos- T stripping automated endothelial patients have a further emergence of sible tissue rejection and infl ammation, keratoplasty and Descemet’s mem- ectasia in the corneal transplant. The but the priority shifts to the topography brane endothelial keratoplasty has be- approach to such a patient is different and the refractive error. come more common, there are still from someone who had a PK due to Three months postop, I evaluate the patients for whom penetrating kera- trauma, herpes or Fuchs’ (in older pa- topography in earnest and perform a toplasty is the only option. For these tients who had transplants before the detailed refraction. We perform and patients, managing their post-PK advent of DSAEK and DMEK). refine the refraction, identifying the astigmatism becomes the next order In the first month post-PK, I look axis of astigmatism. When viewing the of business. In this article, I’ll review at the level of corneal edema and epi- topographic map, we try to determine how I treat these cases. thelial healing, and focus on surface if the tissue was distributed properly, rehabilitation and dryness. After the the trephination was well-centered, The Evaluation fi rst three months, we still evaluate the and the corneal tissue was properly distributed when they When approaching a sutured it, and we check case of astigmatism after the eccentricity and qual- PK, it’s important to know ity of the trephination in the reason the patient had the donor and the host. We the transplant. This will also use tomography. Even help guide your manage- though topography is still ment decision. my number-one tool for After practicing for 26 deciding how to selectively years, I’ve noticed that remove the sutures and patients who develop get a handle on the astig- astigmatism after PK are matism, tomography helps usually patients with kera- me see if the corneal thick- toconus. Interestingly, ness and tissue distribution after you remove the su- make sense. tures from these patients, Figure 1. For some post-PK astigmatism, relaxing incisions and compres- The beauty of corneal you’ll sometimes see the sion sutures can be effective. Here, the surgeon makes an incision at the tomography is that it gives astigmatism increase year donor-host interface on the steep axis to open the interface. you a volumetric analysis.

18 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

018_rp0619_rcr.indd 18 5/24/19 4:54 PM RP0319_Ivantia.indd 1 2/11/19 9:31 AM Refractive/Cataract

REVIEW Rundown

Figure 2. The patient from Figure 1. Now, the surgeon creates another incision in the inter- face on the steep axis. The incisions relax the severe adhesions in the interface.

It’s not just measuring anterior eleva- managing post-PK astigmatism, from tion; it also gives some idea of the pos- early postop to years later. terior elevation and the overall corneal • Suture removal. In the immedi- thickness. When looking at the topog- ate postop period, when the patient raphy, I note the K1 and K2 values, and still has the transplant sutures in his whether the pattern of astigmatism cornea, you can adjust the astigma- is orthogonal. If it is orthogonal, then tism by manipulating the sutures. If a the visual recovery will be better. If patient has interrupted sutures, you it’s not—which, unfortunately, is often can judiciously remove some to try to the case—you then attempt to make it redistribute the tissue and lessen the more orthogonal by removing certain astigmatism. In evaluating the astig- sutures, which leads us to a discussion matism, you may fi nd that the sutures of astigmatism management. are tighter, and the astigmatism higher, in some meridians. You can remove Tackling the Astigmatism these systematically to adjust the astig- matism. If I have a patient with inter- Here are the current approaches to rupted sutures, I usually start remov-

Figure 3. (cont’d from Fig. 2). The surgeon uses Colibri forceps to open the initial dissected adhesions at the interface in the steep meridian to prevent reclosure and fi brosis.

018_rp0619_rcr.indd 20 5/24/19 4:54 PM ing them every couple of mitomycin-C has actually weeks, starting after the proven to be a better op- first 12 weeks postop; I tion. The candidates for usually remove one to this are usually anisome- three at a visit, based on tropic, with unilateral pa- the topography and the thology (maybe a corneal tightness of the sutures. laceration), who’ve had On the other hand, if their cornea, iris or lens the patient has running changed and we’re not sutures, it’s harder to con- willing to perform a pig- trol the astigmatism with gyback IOL procedure on selective suture removal them for some reason. because if you cut the su- One note, though: if ture anywhere, it all has these patients have an to come out. However, in Figure 4. (cont’d from Fig. 3) The surgeon places compression sutures in old graft (older than eight some cases of running su- the fl at meridian and uses a Mertz Keratoscope to help titrate the suture years), sometimes they tures, I’ve chosen to take tension to create a rounder cornea. have signifi cant endotheli- the patient to the minor al edema, which will result procedures room at about four weeks the patient is pseudophakic and has in corneal folds and edema for weeks postop, removed the epithelium, and significant but orthogonal and sym- after the PRK before the eye eventu- tried to rotate the sutures. I try to loos- metrical astigmatism, a toric ICL could ally recovers. These patients can have en the quadrants that are tight, and be a good option. The benefi t of the retarded epithelial healing and may tighten the sutures in the loose quad- toric ICL is that it takes care of any still develop haze in spite of the mito- rants. This isn’t as effective as working myopia as well as the astigmatism. mycin use. with interrupted sutures, of course, • Refractive lens exchange/toric • Wedge resection. If the astig- and the results are variable. IOL/femto incisions. In some cases, matism is over 8 D, you may have to Once the sutures are out, and it’s a if the astigmatism is orthogonal and consider revising the corneal wound by year or two postop, you have to look symmetrical, the patient’s cornea is way of a wedge resection. In the wedge to other options. Usually, this type of otherwise normal and the patient is in resection, we selectively remove some patient has a lot of anisometropia, and the early cataract age range, sometimes tissue from certain quadrants. It’s a can’t, or won’t, tolerate wearing con- RLE with the placement of a toric in- classic approach that corneal surgeons tact lenses. Here are your options: traocular lens is a good option. An ex- have developed to manage a wide • Relaxing incisions/compression ample of this would be the 62-year-old range of astigmatism. sutures. If the astigmatism is very or- post-PK patient who comes to me with • Regraft. Some problems are too thogonal and symmetrical, i.e., it has high astigmatism and high myopia, and big for a wedge resection, and require that nice figure eight configuration, has problems wearing contact lenses. a new graft. For example, if the patient and it’s less than 6 D, many times you In some of these RLE patients, their has 12 D of astigmatism eight or nine can do a relaxing incision in the steep astigmatism is too high to be corrected years postop, a regraft may be the best meridian of the donor/host interface to with just a toric IOL. For them, I fol- option. The regraft involves trephinat- reduce the astigmatism. On the other low the surgery with femtosecond-cre- ing the cornea with a larger size, and hand, if it’s greater than 6 D—more ated, intrastromal arcuate keratotomy re-transplanting a larger graft. like 8 D—sometimes you need to both incisions located about 1 mm inside Though there’s not a lot of reim- place a relaxing incision in the steep the donor/host interface. Sometimes bursement for these post-PK proce- meridian at the donor/host interface I open these incisions at the time of dures, much of the reward comes from and place some compression sutures their creation, sometimes not. In the improving patients’ vision and overall in the fl at meridian 90 degrees away. latter, I’ll return another day to try to quality of life. Topography is invaluable for plan- titrate their effect by opening them. ning both the relaxing incision and the • Laser refractive surgery. In the Dr. Moshirfar is medical director of placement of any compression sutures. past, surgeons tried LASIK for these the Hoopes Vision Refractive Research • Toric ICL. The toric version of patients, but found that the results al- Center in Draper, Utah, and a profes- the Staar ICL was recently approved, ways regressed. At this point, for se- sor of ophthalmology at the Moran Eye giving us a new option for patients. If lected patients, PRK with adjunctive Center at the University of Utah.

June 2019 | reviewofophthalmology.com | 21

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© 2019 AMETEK, Inc. & Reichert, Inc. (05-2019) · Ocular Response Analyzer and Tono-Pen are registered trademarks of Reichert, Inc. · Designed & assembled in USA References: 1. Medeiros FA, Meira-Freitas D, Lisboa R, Kuang TM, Zangwill LM, Weinreb RN. Corneal hysteresis as a risk factor for glaucoma progression: a prospective longitudinal study. Ophthalmology. 2013 Aug;120(8):1533-40. 2. De Moraes CV, Hill V, Tello C, Liebmann JM, Ritch R. Lower corneal hysteresis is associated with more rapid glaucomatous visual fi eld progression. J Glaucoma. 2012 Apr-May;21(4):209-13. 3. Susanna CN, Diniz-Filho A, Daga FB, Susanna BN, Zhu F, Ogata NG, Medeiros FA. Am J Ophthalmol. A Prospective Longitudinal Study to Investigate Corneal Hysteresis as a Risk Factor for Predicting Development of Glaucoma. 2018 Mar;187:148-152. doi: 10.1016/j.ajo.2017.12.018. 4. Felipe A. Medeiros, MD and Robert N. Weinreb, MD. Evaluation of the Infl uence of Corneal Biomechanical Properties on Intraocular Pressure Measurements Using the Ocular Response Analyzer. J Glaucoma 2006;15:364–370. CPT is registered trademark of the American Medical Association.

RP0619_Reichert.indd 3 5/20/19 3:22 PM MIGS REVIEW Cover Focus MIGS and the General Ophthalmologist

Christopher Kent, Senior Editor

Experts answer oday, minimally invasive glau- the iStent and the CyPass, were only coma surgeries, or MIGS, are approved for reimbursement when 10 questions Tbeing adopted by many gener- performed in combination with cata- al ophthalmic surgeons. Unlike many ract surgery,” she says. “That’s kind about how general glaucoma surgeries—some of which of a shame, because patients who’ve are complex and involve significant already had cataract surgery could ophthalmologists postoperative care—MIGS tend to probably still benefi t from these de- be straightforward, involving minimal vices.” can make the risk and minimal follow-up. However, Alan Crandall, MD, a clinical pro- they also usually have a less-dramatic fessor, senior vice chair of ophthal- most of these impact on intraocular pressure, mak- mology and director of glaucoma and procedures. ing them best-suited for patients with cataract in the Department of Oph- early glaucoma—and for surgeons less thalmology at the Moran Eye Cen- interested in doing extensive patient ter—part of the University of Utah in follow-up. Salt Lake City—agrees. “Most MIGS Michele C. Lim, MD, professor have to be combined with cataract sur- of ophthalmology and vice chair and gery if you want to get reimbursed,” medical director of the U.C. Davis he says. “Using those MIGS as stand- Eye Center in Sacramento, California, alone procedures would require get- points out that many of the MIGS ting the patient to pay out-of-pocket. devices have been specifically mar- For that reason I suspect most cata- keted for general ophthalmologists. ract surgeons will use them exclusively “Comprehensive ophthalmologists in combination with cataract surgery.” tend to do a lot of cataract surgery, Here, surgeons well-acquainted and they usually see patients who have with the MIGS procedures share their glaucoma at the earlier stages of dis- answers to key questions that non- ease,” she notes. “Because many of glaucoma-specialist surgeons often the MIGS to date work well for early ask when thinking of adding one or to moderate glaucoma, the companies more MIGS procedures to their ar- usually market their MIGS products mamentarium—especially as an op- toward those ophthalmologists.” tion to combine with cataract surgery. Dr. Lim notes, however, that the use of these devices has been some- Which MIGS procedure what limited by the nature of the FDA 1 should I learn? approvals. “Some of the devices, like “I haven’t seen any surveys regard-

24 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

0024_rp0619_f124_rp0619_f1 ((1).indd1).indd 2424 55/24/19/24/19 5:175:17 PMPM ing how many general ophthalmolo- gists are using MIGS, or which ones they’re using,” notes Dr. Lim. “How- ever, based on the referrals I get, I’d say that most general ophthalmolo- gists are doing the iStent. That’s most likely because it’s one of the easier and safer MIGS to implant. Some of the other MIGS are more complex, and Surgeons say the iStent Inject (above, left) makes it effi cient to implant two stents, has a for the most part I’ve only seen glau- short learning curve and is easier to use than the original iStent (right). With the original, coma specialists do them.” however, the position after insertion is easier to evaluate and adjust. Most MIGS surgeons seem to agree that a trabecular meshwork stent is a and research director at the Kensing- on all of these options below.] good place for a general ophthalmolo- ton Eye Institute at the University of “A surgeon’s choice of MIGS pro- gist to start. “In this situation [when Toronto, and a professor at the Uni- cedure should be customized for each performing MIGS with cataract sur- versity of Utah. “Most MIGS proce- individual patient,” says Vikas Chopra, gery], I’m a strong proponent of MIGS dures—including stenting, cutting MD, medical director of the Doheny procedures that work synergistically and dilating approaches—work with Eye Centers Pasadena, an associate with the effects of phacoemulsifica- the trabecular meshwork/Schlemm’s professor of ophthalmology at the tion,” says Thomas W. Samuelson, a canal pathway, and these procedures David Geffen School of Medicine at founding partner and attending sur- can be relatively effi ciently combined UCLA, and the director of glaucoma geon at Minnesota Eye Consultants in with cataract surgery.” research at the Image Reading Center Minneapolis and an adjunct professor Dr. Crandall believes most gener- at the Doheny Eye Institute. “That of ophthalmology at the University of al ophthalmologists would have the being said, I think it’s probably a good Minnesota. “We now have the results greatest success with trabecular mesh- idea to initially try to enhance the pa- of fi ve major, large-scale, prospective work stents. “There are a number of tient’s own outfl ow system rather than randomized MIGS trials in the litera- MIGS outfl ow devices to choose from, bypass it. I’d recommend a trabecular ture. In all fi ve of these trials, the con- including iStent, iStent Inject and Hy- meshwork bypass procedure as the trol arm—i.e., phaco alone—lowered drus,” he points out. “The other MIGS fi rst-line choice, especially in patients IOP signifi cantly. The average com- options all have some potential draw- with mild to moderate glaucoma and/ posite IOP reduction in the control backs for a general cataract surgeon. or a desire to reduce topical medica- group of these papers was more than Endoscopic cyclophotocoagulation, tion burden. 5 mmHg. Thus, for combined sur- transscleral cyclophotocoagulation “However, there may be excep- gery, I select MIGS procedures that and micropulse transscleral cyclopho- tions,” he notes. “For example, an are least likely to adversely affect that tocoagulation are all reasonable choic- older, monocular patient might not benefit and most likely to be syner- es for combining with cataract surgery, be a good surgical candidate because gistic with normal outfl ow physiology, but the general ophthalmologist has to of systemic or ocular health issues. In such as a canal-stenting device. I’m consider the cost of the machine, as that situation, it would make sense to less likely to use an ablative technique. well as the fact that the procedure may consider a non-incisional procedure “The opposite might be said for need to be redone. MIGS procedures like micropulse transscleral cyclopho- procedures in pseudophakic eyes, that open the canal—OMNI, GATT, tocoagulation fi rst.” where the cataract card has already the Kahook Dual Blade and so forth— Dr. Lim points out that it’s impor- been played,” he adds. “Of course, ca- require wash-out and further care that tant to base your choice of MIGS nal stenting devices aren’t labeled for most general ophthalmologists may procedure on the literature—while standalone surgery anyway—at least not be comfortable with. And some also keeping in mind the limits of the for now.” of the others, such as MIGS devices available studies. “Surgeons shouldn’t “By far, conventional outflow en- that use the sub-Tenon’s space, can base MIGS choices on hype, word-of- hancement with MIGS is the safest be technically challenging, unless the mouth or the latest trend,” she says. way to surgically lower IOP, although surgeon has the right kind of experi- “It’s important to perform a review it’s limited by episcleral venous resis- ence. If the surgeon is comfortable of the literature fi rst. Of course, one tance,” says Ike Ahmed, MD, FRCSC, performing trabeculectomy, the latter caveat when reviewing MIGS litera- assistant professor of ophthalmology would be reasonable options.” [More ture is that most clinical trials report

June 2019 | reviewofophthalmology.com | 25

024_rp0619_f1 (1).indd 25 5/24/19 5:18 PM Cover MIGS

REVIEW Focus

short-term outcomes; very few have iStent Inject implants can be a bit of know refer patients to us for that be- followed patients beyond 36 months. a challenge. With the original iStent, cause of laser access issues.” Longer studies might show even bet- you have a better idea of whether or Dr. Ahmed notes that the newest ter efficacy—or they might find the not the stent is inserted into the tis- iteration, micropulse cyclophotoco- opposite. I think we saw that with the sue correctly, and you can adjust it if agulation, is still a novel treatment. “It original iStent. The data did show su- necessary. has some potential to reduce the side periority with pressure control after “In short, there are unique features effects associated with other forms one year, but when the two-year study and advantages to both devices,” he of CPC,” he notes, “and I do think came out, you could see that the pres- concludes. “However, if you’re a sur- cycloablation may have a role earlier sure control started to wane. geon who’s never done MIGS pro- in the course of treatment than we’ve “In terms of different treatment cedures, I think you’ll fi nd the iStent traditionally used it, especially with modalities that have the same goal, Inject easier to adapt to, with a shorter the ability to do things in a safer man- such as placing an iStent vs. placing learning curve.” ner. However, with this new approach a Hydrus, there are no comparative I think we still need to learn more studies at this time showing that one about the proper dosing and the right is superior to the other,” she adds. treatment for a given patient; we need “However, if you’re a surgeon who “Surgeons who aren’t more studies to determine the optimal sees a great deal of glaucoma, I think interested in bleb settings. What’s the right duty cycle? you should explore multiple treatment The right energy delivery? The right options.” management should timing? I don’t believe we’re ready to stick to trabecular- use micropulse CPC to treat very early If I choose the iStent, which glaucoma, or as initial therapy.” 2 should I start with: the iStent meshwork MIGS.” or the iStent Inject? —Ike Ahmed, MD What about the subconjunc- Dr. Ahmed explains that the original 4 tival MIGS? iStent and the iStent Inject each have “We have new classes of MIGS that their own rationale. “First of all, the bypass the angle completely and shunt iStent Inject makes it effi cient to put What about cyclophotocoag- fl uid into the subconjunctival space, two implants in,” he says. “We believe 3 ulation? as a trabeculectomy or tube would that does enhance the IOP-lowering Dr. Lim says she considers endo- do,” notes Dr. Lim. “They’re meant to ability of the intervention. Another ad- scopic cyclophotocoagulation and address moderate to severe levels of vantage is that the Inject has a shorter transscleral cyclophotocoagulation to glaucoma. The two things in this cat- learning curve, which is helpful for be MIGS procedures. “I know some egory are the XEN gel stent and the surgeons that haven’t placed many of people would argue with labeling not-yet-approved InnFocus Micros- the original iStents. I suspect it’s al- these procedures MIGS, because they hunt. They’re still considered MIGS ready motivated many comprehensive use a laser,” she says. “However, in a because they require less dissection of ophthalmologists to try it. way, transcleral cyclophotocoagulation tissue than traditional surgeries. How- “However, I’ve had a lot of expe- is the ultimate MIGS procedure. It’s ever, both of these do require manipu- rience with the classic iStent,” he one of the most noninvasive things lating the conjunctiva and injection continues. “Here in Canada I often you can do. Then there’s the micro- or application of mitomycin-C. That implant two of the original iStents, pulse CPC, which is being marketed puts them in a different class from the and I’ve had good success with that as even less invasive than continuous- iStent or Hydrus. approach. With the first-generation wavelength TSCPC. Both CPC and “In general, I think the trickier and iStent, I’m sure of the placement and TSCPC have worked well for many of less-well-understood the procedure, I can easily make adjustments. How- my patients. ECP is more invasive, of the fewer comprehensive doctors ever, when implanting the original course, but many doctors do it in con- you’ll find doing it,” she continues. iStent, the need to use lateral motion junction with cataract surgery. “For example, the XEN is challeng- and the turning of the hand poses a “The downside of these procedures ing to implant, and it’s a bleb-forming technical challenge for a number of is that most comprehensive ophthal- procedure that requires the use of surgeons; the iStent Inject obviates mologists don’t have access to those mitomycin-C. Most comprehensive that. Another difference between types of lasers,” she adds. “In fact, doctors don’t have a lot of experi- them is that gauging the depth of the even some glaucoma specialists I ence with MMC, so I think you’re

26 | Review of Ophthalmology | June 2019

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2015_RPonline_house.indd 1 12/10/14 2:38 PM Cover MIGS

REVIEW Focus

less likely to see a non-specialist using ed in clinical trials for MIGS and who the XEN. That goes for the InnFocus should be excluded,” she continues. Microshunt as well, which isn’t FDA- “One of the excluded groups was peo- approved, although there’s an ongoing ple with ocular hypertension. I think U.S. clinical trial underway to try to The Hydrus Microstent maintains the the FDA felt that these people should gain approval.” patency of Schlemm’s canal and tensions not be subjected to the risk of MIGS the canal tissue, improving outfl ow across Dr. Ahmed agrees. “Microstenting surgery. They also recommended not a signifi cant portion of the canal. and microshunting devices that in- including people with severe glau- volve the subconjunctival space fall you’re considering adding? Second, coma, because you don’t want to put into a somewhat different category are you willing to manage any poten- people like that at risk by using an from the others,” he says. “In those tial intraoperative and postoperative investigative device that has no known procedures, the management of the complications associated with the track record. bleb is important, which means that procedure? And fi nally, do you have “The point,” she concludes, “is that managing those patients postop in- enough surgical volume to allow you surgeons need to thoughtfully con- volves a different learning curve. Of to manage the learning curve and con- sider who they offer MIGS to. One course, a number of general and com- tinue to get better at the procedure?” shouldn’t perform a MIGS procedure prehensive ophthalmologists do feel “The priority should be to be good on every patient because they have an comfortable managing a bleb, and for at one MIGS procedure,” says Dr. IOP problem or glaucoma. One needs them I think performing these pro- Ahmed. “Ideally, you should have a to weigh the risks and benefi ts, as one cedures is appropriate. For example, go-to MIGS and a go-to subconjunc- would with any other surgery.” many comprehensive surgeons do tra- tival procedure, giving you two differ- Dr. Samuelson says his decision beculectomies; that skill set would be ent mechanisms of action. Once you about whether to add MIGS to a cata- perfect with this type of procedure. get very good at one MIGS procedure, ract surgery depends on the patient’s But if you’re not accustomed to man- then you may want to expand a little disease status. “If the patient is being aging a bleb, these procedures will bit and try some others, just to see if actively treated for glaucoma, or needs be challenging. Surgeons who aren’t there’s a difference in effi cacy or ad- to be treated for glaucoma, I’d per- interested in bleb management should verse events. But fi rst it’s important to form a combined procedure,” he says. stick to trabecular-meshwork MIGS.” become good at one procedure.” Dr. Crandall agrees. “MIGS Dr. Lim notes that these more “I’d recommend becoming com- shouldn’t be used unless the patient complex MIGS represent an exciting fortable with a canal-stenting device, has a diagnosis of glaucoma and is be- shift in where MIGS is going. “They or at minimum a canal ablation pro- ing treated for it,” he says. “In that sit- give us options for people with more cedure,” says Dr. Samuelson. “Once uation, there’s no harm, no foul, so to advanced levels of glaucoma,” she you’ve mastered the first one, oth- speak, if you add a MIGS procedure points out. “We’ve learned from the ers are far easier to add. Transscleral to the cataract surgery—although we previous MIGS that even if you bypass surgery is a more signifi cant level of always need to consider the cost to the the trabecular meshwork, you’re still commitment.” patient.” not likely to get pressures below the Is there a specifi c level of disease at mid-teens. People who have signifi- In which of my cataract cases which a surgeon should automatically cant glaucoma need lower pressures 6 should I consider adding consider adding MIGS? Dr. Chopra than that. These newer devices are MIGS? says no. “The decision to add MIGS to meant to provide treatment options “Understanding when it’s appropri- cataract surgery has to be individual- that can compete with trabeculectomy ate to recommend MIGS is an impor- ized,” he says. “It should be dictated or tube shunts.” tant issue,” says Dr. Lim. “I think the by the level of glaucoma, as well as iStent is sometimes used in patients the patient’s ability to tolerate topical Should I offer more than one that don’t really need it, for example, anti-glaucoma medications. The goal 5 MIGS procedure? or in patients whose glaucoma is too of adding MIGS to cataract surgery ”Whether a general ophthalmolo- severe to benefi t from it. It’s important might be to achieve a lower IOP, to gist should add more than one MIGS to read the literature and understand maintain the same IOP with a reduc- procedure to his or her armamentar- when it’s appropriate to implant these tion in the medication burden, or to ium depends on several factors,” says devices. address the patient’s topical medica- Dr. Chopra. “First, how comfortable “The FDA put out a guidance paper tion non-compliance, which is quite are you with the type of procedure that talks about who should be includ- common. Less-invasive procedures

28 | Review of Ophthalmology | June 2019

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RP0619_Imprimis.indd 1 5/15/19 9:23 AM Cover MIGS

REVIEW Focus

may be safer, so in general I prefer a Ronald L. Fellman, MD means using the iStent. stepwise approach to choosing a surgi- “On the other hand, the more sig- cal treatment.” nifi cant the disease, presumably indi- Dr. Ahmed agrees that many factors cating worse outfl ow system function- should be considered. “The decision ality, the more I’m willing to disrupt about whether to add a MIGS pro- tissue,” he continues. “The Hydrus cedure to cataract surgery should be spans more of the coveted inferonasal based on the disease state; the stability portion of the canal, which, on the of the disease; the age of the patient; positive side, should convey more de- the number of drops the patient is us- vice-infl uenced outfl ow. However, it’s ing; how well the drops are tolerated; The Trabectome unroofs Schlemm’s canal also more tissue-disruptive. So when and how compliant the patient is,” he to improve outfl ow. Above: A Trabectome selecting among in-dwelling canal de- says. “You may have a patient who’s on positioned adjacent to the trabecular vices, I tend to use focal stenting— one drop but never uses it. Without meshwork (black arrows). The white arrow i.e., the iStent—for lesser disease, and that drop, his pressures might be 28 points to the scleral spur. more expansive stenting—i.e., the Hy- mmHg and at risk of getting worse. If drus—as I move up the spectrum of you’re performing cataract surgery on into account. “You have to consider disease severity.” that patient, you should consider add- the cost-effectiveness of adding a sec- Dr. Samuelson adds that he tends ing MIGS. Generally, the more drops ond procedure,” he notes. “If the pa- to reserve ablative or incisional canal the patient is on, the more potential tient just has ocular hypertension or procedures for standalone interven- value MIGS has, because it may re- very early disease, or the patient is tions without coincident cataract sur- duce the drop load. But even patients compliant with a minimal amount of gery. “In those situations I’ve grown who are only on one medication have medication and 80 years old, maybe increasingly satisfi ed with the OMNI a good chance of getting off of their adding MIGS wouldn’t be cost-effec- device, which can dilate the entire medication with a MIGS procedure. tive. The other side of the coin is a 360 degrees of the canal or a portion “At the same time, we do need to patient who has very bad disease and thereof, and lets me incise as much remember that cataract surgery will is uncontrolled. That patient should of the canal as I wish,” he says. “The lower IOP on its own,” he notes. “It get something more aggressive than a Ellex iTrack and the Kahook Dual just seems to be the case that phaco trabecular-meshwork MIGS, such as Blade are also very reasonable choices plus MIGS has a greater likelihood of a subconjunctival procedure, whether in this setting.” getting patients off of their medica- it’s subconjunctival MIGS or a trab- Dr. Lim notes that when obstruc- tions, or resulting in the need for few- eculectomy. A trabecular-meshwork tion of the trabecular meshwork is er drops. You might say to a patient: ‘I MIGS wouldn’t be enough for some- part of the disease process, MIGS can do a procedure that’s pretty much one who’s progressing and needs a procedures that strip away tissue to as safe as cataract surgery alone, but very low pressure.” unroof Schlemm’s canal might be a there’s a greater chance that you’ll good choice. “Patients that could ben- be able to get off of medication. The Should the severity of the efi t from this might include those with chance of that happening might be 50 7 glaucoma affect my choice for pigment dispersion glaucoma, uveitic percent with cataract surgery alone, a given patient? glaucoma and maybe pseudoexfolia- but 85 percent if I add MIGS.’ Dr. Samuelson says his usual choice tion,” she says. “I haven’t used the “Basically, I think any time you’re of a canal-based MIGS procedure to Kahook Dual Blade yet, but I see it performing cataract surgery on a pa- add to cataract surgery might be modi- as a reasonable option whenever the tient who has glaucoma, you should fi ed based on current disease severity problem involves an obstruction of the at least consider adding a MIGS pro- and his best estimation of the likeli- trabecular meshwork.” cedure,” he says. “If it might help the hood of future progression. “I gener- patient reach the right target pressure ally prefer the stealth nature of the Which MIGS works best in and reduce medication use, that per- canal-stenting devices,” he says. “The 8 the presence of infl ammation? son is a candidate. That’s a pretty wide milder the disease and the closer the Dr. Samuelson says that infl amma- potential range of patients.” outfl ow system is to normal, the less tion can be an important determinant Dr. Ahmed adds that factors such I want to disturb tissue. The canal- of the MIGS procedure he chooses. as the system, payer and the patient’s stenting devices cause the least tis- “For example, if a patient is in need quality of life are important to take sue disruption. For me, for now, this of chronic, ongoing steroid therapy,

30 | Review of Ophthalmology | June 2019

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REVIEW Focus

I’m less likely to select a canal-based cessful, safe cataract removal, paying surgeon’s ability to manage a patient procedure because, collectively, those special attention to avoiding iatrogenic who needs more complex cataract procedures are more associated with worsening of the zonulopathy. It may surgery, such as a patient with weak steroid-related increases in intraocular be better to ‘live to fi ght another day’ zonules, so the surgeon has to consider pressure,” he explains. “I’m more like- and perform the cataract and glau- that. However, in our clinic we have a ly to perform a subconjunctival out- coma procedures sequentially instead lot of experience with complex cata- fl ow MIGS such as a gel stent in this of concurrently.” ract surgery, such as cases involving setting. If the disease is severe enough, trauma or pseudoexfoliation. Those I might resort to a trab or tube. patients often have glaucoma associ- “If a general ophthalmologist per- ated with their underlying diseases, forming cataract surgery is faced with These surgeries require and most of them do quite well with a glaucoma patient on chronic ste- mastery of gonioscopy MIGS. So why not combine the sur- roids, I’d recommend skipping canal- geries?” based MIGS and performing XEN and a thorough or trabeculectomy,” he says. “If the knowledge of angle What other strategies will surgeon is uncomfortable with these 10 help ensure success? procedures, I’d consider referring the anatomy. Surgeons offer these pearls to gen- patient to a glaucoma specialist.” eral ophthalmologists who are adding Dr. Chopra agrees that combining MIGS to their cataract surgery op- MIGS with cataract surgery in the set- tions: ting of ocular inflammation can be Dr. Chopra points out that some • Do your homework before per- quite complicated. “You may need to cataracts might warrant performing forming any MIGS surgery. Prac- perform concurrent surgical maneu- the MIGS procedure before the cata- tice makes perfect,” says Dr. Chopra. vers such as disrupting posterior syn- ract surgery. “If a patient has a very “I would strongly encourage any sur- echiae, using pupillary dilators and dense cataract that may require lon- geon thinking of adding MIGS to their managing peripheral anterior syn- ger cataract surgical time and more repertoire to watch surgical videos of echiae,” he points out. “Trabecular by- phacoemulsifi cation power, as well as the procedure in question to learn the pass procedures such as Trabectome greater irrigation and aspiration vol- technique; work with industry reps to and goniotomy with the Kahook Dual ume, you may be left with signifi cant do ‘personalized wet labs’; sign up for Blade can be successful in these situa- corneal edema by the end of the cata- surgical wet lab training at meetings tions, but it’s important to aggressively ract procedure—especially over the like ASCRS and AAO; and talk to col- control infl ammation postoperatively incision,” he says. “In that situation, leagues and glaucoma specialists who to reduce the risk of trabecular cleft it may be prudent to consider per- are well-acquainted with the proce- closure due to the development of forming the trabecular bypass proce- dure, to learn tips and surgical pearls. “ posterior synechiae.” dure before cataract surgery when the • Practice gonioscopy and know cornea is most clear. If you wait until the angle anatomy. All MIGS sur- Should the MIGS I consider after the cataract surgery is complete, geons agree on one thing: These sur- 9 adding be infl uenced by the proper visualization of the angle us- geries require mastery of gonioscopy condition of the cataract and zon- ing the gonioscopic lens may be more and a thorough knowledge of angle ules? challenging because of the corneal anatomy. “We get referrals from doc- “If you detect weak zonules, either edema.” tors who implant iStents, and we preoperatively or intraoperatively, the Dr. Ahmed believes the complex- sometimes fi nd that the placement is risk of vitreous loss is greater,” Dr. ity of the cataract is a separate issue. incorrect,” says Dr. Lim. “The device Chopra notes. “In that situation, the “Combining the surgery with MIGS is either poorly positioned or not in the benefi ts of MIGS have to be carefully doesn’t necessarily make it more dif- trabecular meshwork at all. So it’s im- weighed against the risks of the proce- fi cult to manage the complexity of the portant to perform gonioscopy often, dure. It may be safer to avoid MIGS cataract surgery,” he says. “Of course, to become familiar with the anatomy and consider referral to a glaucoma in some cases it could make things of the angle.” subspecialist for a more traditional more difficult; some MIGS proce- “Understanding the surgical anat- glaucoma procedure such as an aque- dures, for example, have a higher omy—especially the iridocorneal ous tube shunt implantation. In these chance of causing bleeding in the eye angle—is incredibly important to a surgeries the focus should be on suc- or hyphemas. That could impact the successful MIGS procedure,” agrees

32 | Review of Ophthalmology | June 2019

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RP0619_Lombart.indd 1 5/9/19 3:24 PM Cover MIGS

REVIEW Focus

Dr. Chopra. “That’s often underappre- opic shift, while others witnessed a reduce the patient’s medication load, ciated. That’s why achieving expertise sudden, acute rise in pressure months which can also enhance the patient’s in clinical and surgical gonioscopy is after the CyPass was implanted. An- visual recovery by improving the ocu- essential.” other example is the iStent. The ad- lar surface, so patients end up seeing However, Dr. Samuelson says this verse events reported in the literature better. That can increase the patient’s shouldn’t cause surgeons to be put were fairly minimal, but I did have quality of life, without much downside off. “MIGS procedures are very deli- one patient who bled profusely during in terms of complications.” cate,” he says. “They involve some of an implantation, and that led to a very “Some surgeons would say that the most precise maneuvers we do as high, prolonged IOP rise.” MIGS shouldn’t be used at all,” notes anterior segment surgeons. However, • Have realistic expectations. Dr. Crandall. “They sometimes re- if you’re an accomplished cataract sur- “It’s important that all surgeons and fer to these procedures as ‘MEGS,’ geon, you’ll be able to learn and mas- patients and payers understand that or ‘minimally effective glaucoma sur- ter MIGS. Just don’t try MIGS until with our current level of knowledge, geries.’ I’m not in that group. Many you’re very confident with intraop- anything we do to address glaucoma of our patients have glaucoma that’s erative gonioscopy. MIGS procedures tends to wear off over time, at least to under control. If a MIGS procedure are very safe, but signifi cant risk may some degree,” Dr. Ahmed says. “That’s can get those patients off of even one be involved when they’re attempted true of every option—drops, lasers, medication, that’s a good thing. For without good visualization.” trabeculectomy, tubes and MIGS. It’s that reason, I’m happy to see general Dr. Ahmed agrees, noting that the a result of the nature of the disease, ophthalmologists using MIGS. positioning of the patient on the table and the way the eye recovers and heals “Again,” he adds, “experience is key. is part of good visualization. “The most after these surgeries. It shouldn’t sur- So, I’d suggest that most general oph- important thing, in order to succeed prise anybody, and it certainly hasn’t thalmic surgeons interested in MIGS with MIGS procedures, is to hone in caused us to stop treating glaucoma. fi nd a device that works for them and on the setup and positioning of the “When we’re treating glaucoma, we then become good at using it.” patient, and the visualization—mean- continue to manage the patient over “I’d encourage surgeons to do ing gonioscopy—in the clinic and the time,” he points out. “We go from one this,” Dr. Ahmed concludes. “There’s OR,” he says. “You can learn these treatment to the next, to the next. The a technical learning curve that sur- things without even doing MIGS. You right algorithm and selection of drops geons need to master, and appropri- can practice with cataract eyes, just and procedures and devices will hope- ate patient selection is important. tilting the microscope and the head of fully stabilize intraocular pressure But I think the day is coming when the patient at the end of the case, to enough to prevent progression over a cataract surgeon who isn’t able to get a better view.” the course of a patient’s lifetime. Ac- offer MIGS will be seen as behind Dr. Lim adds that an excellent complishing that may require multiple the times. If a patient comes in with way to improve your angle structure modalities, and the iStent and other glaucoma and is taking a number of knowledge is to visit gonioscopy.org. MIGS are part of that paradigm— drops, you have a better chance of “This is a fabulous resource, created especially with their excellent track reducing his medication burden if you by Lee Alward, MD, at the University record of safety.” add MIGS to the cataract surgery. So of Iowa,” she notes. why not offer it?” • Weigh the risks (usually limit- Adding Value for Your Patients ed with MIGS surgery) against the Dr. Samuelson is a consultant for benefi ts. Dr. Lim points out that, as “I think any surgeon doing cataract Alcon Surgical, Johnson & Johnson with any surgery, there’s always some surgery should be able to offer MIGS Vision, AqueSys/Allergan, Equinox, amount of risk to weigh against the po- to appropriate patients,” says Dr. Glaukos and Ivantis. Dr. Ahmed is a tential benefi ts. “Sometimes the risks Ahmed. “The safety of MIGS has been consultant for Alcon, Allergan, Equi- take a while to become apparent,” she established, and the safety of com- nox, Glaukos, Ivantis and Santen. Dr. says, noting that this is another reason bining cataract surgery with MIGS Crandall is a consultant for Ivantis, to pay attention to the literature. “For doesn’t seem to be much different Glaukos and Alcon. Dr. Lim is an example, with the CyPass, adverse than regular cataract surgery, which investigator for Santen (which now events were noted before it was re- is important. Recovery time doesn’t owns the InnFocus device) and has called—issues that were not apparent seem to be any different either. Mean- been a speaker for Alcon. Dr. Chopra in the original COMPASS trial. Some while, the potential benefits for the reports to relevant fi nancial ties to any surgeons reported an unexpected my- patient are signifi cant. MIGS can help product mentioned.

34 | Review of Ophthalmology | June 2019

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β (Continued from page 3) marker level of total-tau and A 42 in un-anesthetized Schirmer’s test. They a cohort of 25 patients with AD, mild then pooled samples from both eyes brought against the company. How- cognitive impairment (MCI) or sub- to analyze their levels of total α-Syn, ever, this was signifi cantly less money jective cognitive impairment (SCI) and oligomeric α-Syn, LF and matrix me- than the millions Allergan had fi rst nine healthy controls.1 The results con- tallopeptidase-9 (MMP-9). sought. fi rmed that the levels of tear total-tau They found total α-Syn was signifi - Mark Baum, founder and board and Aβ42 changed with increasing AD cantly decreased in basal tears in PD member of ImprimisRx, says the rul- stage. They discovered a signifi cant in- patients relative to healthy controls. ing was fair, stating that he doesn’t crease in total-tau in tears of AD pa- On the other hand, oligomeric α-Syn think Allergan was harmed. He says tients compared with SCI patients and was signifi cantly increased in basal that ImprimisRx’s attorney made the MCI patients.1 tears compared with healthy controls. case that the supposed false statements Future work on biomarkers must be The study fi ndings indicated that there cited by Allergan didn’t seem to matter able to characterize a patient’s underly- was no difference in LF or MMP-9 until Imprimis entered the glaucoma ing pathophysiology, the study authors between PD patients and healthy con- and dry-eye spaces. In regard to the argue. This requires an expansion of trols in basal tears.2 alleged false statements, Mr. Baum the current biomarker panel, a critical In refl ex tears, the researchers found notes that they weren’t made inten- move to allow a broader characteriza- oligomeric α-Syn was signifi cantly in- tionally and were there for many years tion of pathology in patients with AD creased in PD patients compared with before Allergan sued. by identifying different subtypes.1 healthy controls and that total α-Syn Allergan declined to comment on While the investigation into tear bio- was unchanged. They note that a signifi - the ruling, stating that the company markers for AD is in its early stages, cant difference emerged in LF content doesn’t discuss litigation. biomarkers for Parkinson’s disease in PD patients compared with healthy are already well-known. These pa- controls, but not in MMP-9.2 tients often present with symptoms of This work adds to the body of litera- cholinergic dysfunction years prior to ture documenting the patterns and pre- Tear showing motor symptoms. Tear secre- sentations of PD signals in human tear- tion is greatly stimulated by choliner- fi lm samples that may form the basis of Biomarkers gic neurons; thus, specifi c proteins in future clinical testing protocols. tears may be altered by changes in the 1. Gijs M, Nuijts RM, Ramakers I, et al. Differences in tear protein function of nerves regulating lacrimal biomarkers between patients with Alzheimer’s disease and and Systemic controls. ARVO 2019. Abstract 1744. secretion. Tear proteins are potential 2. Edman MC, Janga SR, Freire D, et al. Tear biomarkers for biomarkers for PD at different stages Parkinson’s disease in basal versus refl ex tears. ARVO 2019. Disease of the disease.2 Abstract 4196-B0554. Researchers from the University of Screening for two debilitating dis- Southern California found that tear eases, Alzheimer’s and Parkinson’s, levels of alpha-synuclein (α-Syn) may Novartis may become part of future eye exam be able to discriminate between PD protocols, according to two papers patients and healthy controls. They presented at the recent meeting of the note that refl ex tear α-Syn levels dem- Nabs Xiidra Association for Research in Vision and onstrated a greater increase and sen- In early May, Novartis bought dry- Ophthalmology in Vancouver, Canada. sitivity in distinguishing PD patients eye drug Xiidra (lifi tegrast ophthal- Researchers investigated the diag- from healthy controls than basal tears mic solution) 5% from pharmaceuti- nostic potential of tears as a source of and illuminated differences in lactofer- cal company Takeda for $3.4 billion, peripheral biomarkers for Alzheimer’s. rin that aren’t seen in basal tears, offer- with milestone payments of up to They found that tear total-tau and amy- ing a more reliable and sensitive source $1.9 billion. loid-beta 42 (Aβ42) levels have reason- of biomarkers for PD.2 For its part, Takeda says it made able discriminatory power for the AD The team collected basal tears from the sale in order to focus on other state and could be diagnostic markers. 93 PD patients of varying disease se- business areas, and to eliminate the They note, however, that studies with verities and 82 healthy controls with debt it had amassed following its larger sample sizes are required to con- an anesthetized Schirmer’s test. Refl ex purchase of Xiidra’s original owner, fi rm these results.1 tears were collected from 84 PD pa- Shire, which launched the drug in The team investigated the tear bio- tients and 83 healthy controls with an 2016.

June 2019 | reviewofophthalmology.com | 35

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Endorsed by: Jointly provided by: Supported by an independent medical education grant from: ® REG Review of Ophthalmology (Review Education Group) Alcon Trabs/Tubes REVIEW Cover Focus Why Trabs and Tubes Still Matter

James C. Tsai, MD, New York

A glaucoma n recent years, there’s been a lot pressure reduction (which will most of excitement about minimally- likely leave patients on one or two expert describes Iinvasive glaucoma surgery. It’s im- glaucoma medications postopera- portant, however, to not let all that tively), MIGS has the limitation of situations in which buzz eliminate thoughts of other, al- needing to be combined with cataract ternative procedures as you diagnose surgery in order for the surgeon to surgeons still need a patient’s glaucoma status and choose be reimbursed. (Note: The XEN gel the best treatment. Sometimes, the stent doesn’t necessarily need to be the “big guns.” best procedure for a patient with combined with cataract surgery, but moderate to advanced glaucoma isn’t it functions similarly to a modified MIGS; the time-tested options of shunt device, so I view it slightly dif- tube shunts and trabeculectomy are ferently than a conventional cataract still vital parts of our surgical arsenal surgery-associated MIGS procedure.) and, in these types of cases, may be This proves to be problematic in pa- the better choice. tients with glaucoma who have al- ready had cataract surgery—you may MIGS’ Shortcomings not be able to perform a MIGS pro- cedure and have the surgery covered The heart of the matter is that the by insurance. amount of intraocular pressure re- On the alternative side is the pa- duction achieved by MIGS is often tient with glaucoma who has mini- not impressive, though the proce- mal/no cataract, but requires signifi - dures have proven to be safe overall. cant IOP reduction. In my opinion, A lot of the IOP lowering effi cacy of rendering the patient pseudophakic these procedures is likely the result while she’s still capable of accommo- of their being combined with cata- dation is dreadful. If a patient has ract surgery. When I’m discussing the a clear lens, it doesn’t make sense various surgical options with my glau- to me to just take it out in order to coma patients, I often use a baseball perform a MIGS procedure. Also, analogy: MIGS can be viewed as a uncomplicated cataract surgery isn’t hitter who doesn’t hit home runs, without its own inherent risks, such as but instead routinely hits singles and an increased long-term risk of retinal occasionally doubles with very few detachment in a high myope. Just strikeouts. recently, I saw a fairly young patient In addition to modest amounts of with glaucoma who developed a rheg-

This article has no commercial sponsorship. June 2019 | reviewofophthalmology.com | 37

0037_rp0619_f2.indd37_rp0619_f2.indd 3737 55/24/19/24/19 3:153:15 PMPM Cover Trabs/Tubes

REVIEW Focus

matogenous retinal de- trabeculectomy, on the tachment, and his only other hand, you actu- apparent risk factors ally have a chance of were his mild myopia hitting a home run— and history of unevent- great pressure reduc- ful cataract surgery two tion, a healthy ap- years ago. pearing, non-ischemic MIGS also adds costs filtering bleb; and a to the cataract proce- delighted patient who dure, given the not-in- is no longer taking any signifi cant costs of the medications. MIGS devices. These Also, since trab- procedures also involve eculectomy doesn’t a non-trivial learning involve placing any curve, new for each foreign materials (be- MIGS device; in con- sides sutures), there’s trast, most glaucoma no need to worry that a surgeons have received device will shift its po- superb training in tra- When he performs a trabeculectomy, Dr. Tsai places a releasable suture in sition and/or migrate beculectomy and tube the cornea near the trabeculectomy site (above, at 11 o’clock). Postop, he can to a different loca- shunt placement. release the suture to lower IOP more if necessary. tion. In a similar vein, In my opinion, MIGS since trabeculectomy is also mostly reserved for the garden- of delivering this amount of IOP low- doesn’t involve a device, but instead variety, primary open-angle glaucoma ering effi cacy, and at least one study, uses intrinsic ocular tissue to achieve patient with mild disease, while tra- the Collaborative Initial Glaucoma its effect, the procedure is extremely beculectomy and tube shunts can be Treatment Study, demonstrated that cost-effective. Incidentally, this is one used in a wider array of glaucomas, trabeculectomy reduced pressures by of the reasons some surgeons prefer such as chronic angle closure, neovas- approximately 48 percent from base- MIGS such as the Kahook Dual-Blade cular and inflammatory glaucomas. line readings at three years.1 CIGTS and the Trabectome, since these pro- The jury is still out on MIGS’ effi cacy set an aggressive minimum IOP tar- cedures don’t involve placing materi- in these other glaucoma diagnoses. get lowering goal for its patients—at als into the trabecular meshwork or Thus, “hitting singles and doubles” least 30 percent—and, in addition to placing a transscleral device like the with MIGS may be acceptable for the 40-percent reduction with trabec- XEN. In addition, a foreign object certain subsets of patients who can ulectomy (in the fi ve-year results)— can become plugged and/or erode tolerate possibly being on one or it also reported that medication through adjacent tissue. more medications after the surgery. achieved 35-percent reduction. Thus, • Trabeculectomy’s downsides. But sometimes, you, as the surgeon, for a patient who requires signifi cant The reason, however, we don’t place need to bring in the heavy hitters. pressure reduction, the treatment the home-run hitter at the plate in ev- has to at least be equivalent to the ery situation is that along with that po- Batter Up medication arm of CIGTS. Consider tential for the game-changing home a patient who has an uncontrolled run comes the increased risk of strik- If a modest pressure reduction isn’t pressure of 21 mmHg, and is intoler- ing out. enough for the patient, it’s time to ant of most if not all medications; if While MIGS may not be as ef- consider trabeculectomy or a glau- I’ve set a target pressure goal in the fective in lowering IOP as trabecu- coma tube shunt. low teens, I’ll turn to trabeculectomy. lectomy, the former has a lower risk • Trabeculectomy’s advantages. When speaking to a patient with a profi le, while the latter is associated For those patients who need signif- low target IOP range and a need for with such complications as hypotony, icant pressure reduction, this usu- sustained long-term IOP reduction, I bleb infections and suprachoroidal ally means a reduction in IOP of 30 envision that most MIGS procedures hemorrhage. The Primary Tube vs. percent or more, a target level often would not suffi ciently lower IOP into Trabeculectomy Study illustrates this times out of MIGS’ average reach. the low teens even with supplemental point: “Lower IOP with use of fewer Trabeculectomy, however, is capable medications (i.e. a single drop). With glaucoma medications was achieved

38 | Review of Ophthalmology | June 2019

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RP0619_B & L Lumify.indd 1 5/20/19 9:55 AM Cover Trabs/Tubes

REVIEW Focus

after trabeculectomy in the trabeculectomy with MMC compared group (p=0.01). In with tube shunt sur- terms of effi cacy, the gery during the first IOP result was 14.4 year of follow-up. The ±6.9 mmHg in the frequency of serious tube group and 12.6 ± complications pro- 5.9 mmHg in the tra- ducing vision loss or beculectomy group at requiring reoperation one year (p=0.01), and was lower after tube the number of glau- shunt surgery relative coma medications was to trabeculectomy 1.4 ±1.3 in the tube with MMC.”2 Also, group vs. 1.2 ±1.5 in it’s worth remember- the trabeculectomy ing that the type of group (p<0.001).3 endoph thalmitis as- When selecting the sociated with trab- In terms of effi cacy and the risk of complications, the tube shunt, such as this best patient for tube eculectomy is a more older Molteno model shown here, is situated between minimally-invasive glau- shunt surgery, look for devastating intraocu- coma surgeries and trabeculectomy, Dr. Tsai says. a patient who might lar infection than that have inconsistent fol- which occurs follow- low-up during the im- ing routine cataract surgery. In trab- tion more like consistent doubles hit- mediate postop period; tube shunts eculectomy-associated endophthal- ters, with less risk for the bad strike- involve less postoperative manipula- mitis, the bacteria tend to be more outs associated with trabeculectomy. tion than trabeculectomy. The lat- virulent. After successful tube shunt surgery, ter procedure can manifest with very Because of these inherent risks, on average, the patient is usually on high or low pressures postoperatively you, as the surgeon, need to choose at least one or two medications and depending on the condition of the your trabeculectomy patient very his/her IOP control may not be quite bleb, and your subsequent postop ma- carefully. For example, if the poten- as good as following trabeculectomy. nipulation. A good surgical candidate tial patient is in a nursing home and However, the results of tube shunt is also someone who doesn’t need a not easily accessible for postoperative surgery are usually more consistent super-low target pressure. The type follow-up visits (and has a limited sup- than those following trabeculectomy. of glaucoma also comes into play: Tra- port system) trabeculectomy is not Even though, admittedly, most tube beculectomy would be the surgery of an ideal operation, given the higher shunt results are surgeon-dependent, choice in patients with normal- or low- rates of infection and/or bleb-related by and large I believe that these sur- tension glaucoma who need signifi- complications. geries have less variability in their cant IOP reduction, whereas a tube Additionally, most of us who per- outcome than does performing a tra- shunt is better for patients with neo- form trabeculectomies also use ad- beculectomy. vascular glaucoma, because it seems junctive mitomycin-C. With mitomy- Along with this consistency, if to work better than a traditional trab- cin-C, however, there’s an increased not home-run ability, comes fewer eculectomy with an antimetabolite in risk of bleb avascularity, with an in- “strikeouts,” which translates into a these types of patients. Also, someone creased risk of bleb leaks that can lead much lower risk of endophthalmitis with refractory glaucoma and/or one to blebitis and endophthalmitis. than trabeculectomy. There’s still a of the more complicated glaucoma • Glaucoma tube shunts’ advan- risk of suprachoroidal hemorrhage presentations, or a history of glau- tages. When discussing tube shunts with a tube shunt, but you can reduce coma or other ocular surgery—espe- with patients and using the baseball this risk by performing the tube shunt cially a failed trabeculectomy—would analogy, I tell the patients that these very carefully. be a good candidate for a tube shunt. procedures are positioned some- Supporting this idea, the cumula- • Tube shunt disadvantages. where between the modest base hits tive probability of failure during fi ve Though the tube shunt is a good of MIGS and the home run poten- years of follow-up in the Tube vs. Tra- middle-of-the-road option between tial of trabeculectomy. In my opinion, beculectomy Study was 29.8 percent MIGS and trabeculectomy, it’s not glaucoma tube shunt implants func- in the tube group and 46.9 percent without complications. Because the

40 | Review of Ophthalmology | June 2019

037_rp0619_f2.indd 40 5/24/19 3:16 PM VisiPlug is the only one for me… My Tips for Trabs No pop-out!

A trabeculectomy can be a powerful pressure-lowering option for your glaucoma patients. Glaucoma surgeons have learned, however, that they can make it even more effective by making their own modifi cations to the basic technique. Here’s what I do to increase my chances for a home run. When I perform a trabeculectomy, I place a releasable suture in the cornea near the trabeculectomy site. Then, when I see my patient postoperatively, that suture gives me the ability to easily modulate the healing response by pulling the releasable suture at the slit lamp. By releasing the suture at the right mo- ment, I can lower the pressure even more, if it’s not already at a level that’s satisfactory.

procedure involves the introduction of a foreign body, one of the main complications is extrusion of the implant, in which the tube erodes through either the patch graft or a scleral fl ap. There’s also the aforementioned risk of supra- choroidal hemorrhage and endophthalmitis, but the latter occurs at a lower rate than with trabeculectomy. Lacrimedics’ VisiPlug is not like A tube implant may not be a good option in a patient “other” punctum plugs. We have no with corneal endothelial problems, because there’s always reported “pop-outs” since VisiPlug’s the concern of endothelial problems with a tube in the introduction in 2003… and it’s anterior chamber; for example, if the patient rubs his eye, the tube might contact the corneal endothelium. The distributed in over forty countries! other type of patient who isn’t an ideal candidate is one who can’t tolerate having a foreign body sensation under FDA approved for the treatment the lid (patients have sometimes reported feeling an un- of the Dry Eye components of comfortable sensation of “feeling the implant”). varying Ocular Surface Diseases In the end, it’s best if you as a glaucoma surgeon don’t (OSD), after surgery to prevent focus on just one type of procedure, be it MIGS, trab- complications due to Dry Eye eculectomy or tube shunts. If you only perform one type Disease, and to enhance the of procedure, I believe it will be rather diffi cult to have efficacy of topical medications. excellent surgical outcomes when treating all the differ- ent types of glaucoma patients. Instead, having a breadth of surgical skills and experience will allow you to recom- mend the surgery that’s most appropriate for a particular VisiPlug® – patient, rather than trying to make one surgery fi t all clini- cal indications. a visibly better plug to treat dry eye! Dr. Tsai is president of New York Eye and Ear Infi rma- ry of Mount Sinai, as well as Delafi eld-Rodgers professor and system chair of ophthalmology at the Icahn School of Medicine at Mount Sinai.

1. Feiner L, Piltz-Seymour JR; Collaborative Initial Glaucoma Treatment Study. Collaborative Initial Glaucoma Treatment Study: A summary of results to date. Curr Opin Ophthalmol 2003;14:2:106-11. (800) 367-8327 2. Gedde SJ, Feuer WJ, Shi W. Treatment outcomes in the Primary Tube Versus Trabeculectomy E-mail: [email protected] Study after 1 year of follow-up. Ophthalmology 2018;125:5:650-663. www.lacrimedics.com 3. Gedde SJ, Schiffman JC, Feuer WJ, et al. Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after fi ve years of follow-up. Am J Ophthalmol 2012;153:5:789-803. 1Dramatization. Not a real patient. ©2017 Lacrimedics, Inc.

037_rp0619_f2.indd 41 5/24/19 3:16 PM Dry Eye REVIEW Feature Dry-Eye Therapies: What’s Next?

Michelle Stephenson, Contributing Editor

Several devices recent cross-sectional popula- the treatment of dry-eye disease,” ex- tion-based study has found that plains Dr. Stonecipher, who is in prac- and a multitude of Amore than 16 million Ameri- tice in Greensboro, North Carolina. can adults have been diagnosed with The study focuses on evaporative new medications dry-eye disease. Prevalence is high- and mixed-mechanism dry eye. Most er among women than men and in- of the patients included in the study are expected creases with age.1 Unfortunately, an were diagnosed with Grade 4 meibo- ideal treatment modality has yet to be mian gland disease and had already to come to the found, but a number of new therapies failed multiple treatments. (Grade 4 are in various stages of development. corresponds to no expression from the marketplace in the “Dry eye is a huge problem. Everyone glands, despite multiple attempts.) next few years. wants to be that billion-dollar Restasis The study group they reviewed had (cyclosporine ophthalmic emulsion, Ocular Surface Disease Index scores 0.05%, Allergan) product,” says Rob- that were at the severe level (>33), and ert Latkany, MD, who is in practice in their tear breakup time were less than New York City. six seconds. “The low-level light ther- In this article, we’ll take a look at apy or photobiomodulation basically what the pipeline holds for dry-eye heats the glands endogenously, and therapy. it’s combined with no-gel IPL,” Dr. Stonecipher says. “The results have Devices been exceptional.” He presented the results of the Karl G. Stonecipher, MD, and his study at the recent meeting of the colleagues are conducting a retrospec- European Society of Cataract and tive review combining low-level light Refractive Surgeons in Vienna. “We therapy with intense pulsed light using found that 86 percent of the patients a new device. The device is known as do well with one treatment with Eye-light outside of the United States one year of follow-up,” he explains. and Epi-C PLUS in the United States “Fourteen percent of patients re- (Espansione Marketing S.p.A., Bolo- quired more than one treatment, and, gna, Italy). “We performed the original on average, they needed two to three physician proof-of-concept study and treatments over the course of a year have followed that up with a four-site, at three- to four-month intervals. But fi ve-surgeon data review to evaluate remember, these patients had been the effects of this type of therapy on treatment failures with multiple [pre-

42 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

0042_rp0619_f3.indd42_rp0619_f3.indd 4242 55/24/19/24/19 5:255:25 PMPM vious] treatments in all cases.” shelf life, and the risk of infection is He presented the results of 310 eyes low.” in 155 patients. Patients’ OSDI scores Stephen Pflugfelder, MD, profes- went from 40.2 down to 21.8 between sor and James and Margaret Elkins one and three months postoperatively. Chair in Ophthalmology at the Baylor The average tear breakup time was MD ugfelder, Stephen Pfl College of Medicine in Houston says 3.58 seconds preoperatively and 7.98 that future comparative studies should seconds between one to three months help ophthalmologists get a clearer postop. MGD grading decreased from picture of where the various new drugs Punctate corneal fl uorescein staining 4 to 2 (glands expel cloudy or opaque in a patient with Level 3 aqueous tear fi t in the treatment algorithm. “Unfor- fl uid with digital pressure) postopera- defi ciency. tunately, right now, there aren’t any tively. head-to-head comparisons between “We’ve been really excited by these the cyclosporine products, which is fi ndings,” Dr. Stonecipher says. “We Medications really what’s going to be needed in have taken it one step further. In pa- the future to determine where drugs tients who have meibomian gland Many new medications are in vari- would be used,” he says. “This would disease and rosacea, we now perform ous stages of development. Last year, include the type of dry eye, the type of Epi-C Plus. This is no-gel IPL plus Cequa (cyclosporine 0.09%, Sun profi le of signs and symptoms, and the low-level laser therapy. There’s a red Pharma) was approved by the FDA relative effi cacy of those things. Addi- mask for the MGD (633 nm) and a to treat dry eye, but it hsn’t yet come tionally, I think a generic cyclosporine blue mask for acne rosacea (419 nm), to the market. The company is cur- will probably come out soon.” which helps reduce the telangiecta- rently planning to start distributing it In addition to the new formulations sias.” this summer, according to Dr. Latkany. of cyclosporine, Dr. Latkany adds that Outside of the United States, oph- “This drug has a different mecha- several versions of loteprednol are in thalmologists are using white and yel- nism of action than Restasis with re- Phase III trials. “Ophthalmologists low masks. The white mask is similar gard to how it penetrates the eye,” have been using steroids to treat dry to light therapy for seasonal affective Dr. Latkany says. “The company says eye for more than 10 years, but every- disorder. “The yellow mask stimulates that it has a faster onset of action than thing we are using is off-label,” he says. the lymphatics and allows an increase Restasis. Whereas Restasis might take “Lotemax (loteprednol etabonate oph- in lymphatic drainage,” Dr. Stoneci- four months or more to reach its max- thalmic gel, 0.5%, Bausch + Lomb) pher says. “The yellow is 519 nm, the imal peak level of efficacy, this one is a higher concentration of lotepred- red is 633 nm, and the blue is 419 nm.” could start working a few weeks into nol than Alrex (loteprednol etabonate However, Dr. Stonecipher has no- the treatment.” ophthalmic suspension, 0.2%, Bausch ticed that some patients are poor re- According to John Sheppard, MD, + Lomb), and the side-effect profi le sponders to IPL, so he also uses Temp- who is in practice in Norfolk, Virginia, of Lotemax is not as high as a stronger Sure (Cynosure), a radiofrequency Cequa has a better side-effect pro- steroid, such as prednisolone acetate. device for aesthetic applications, for fi le than Restasis, while looming ge- Even though it has a low side-effect the off-label treatment of MGD. “It’s neric cyclosporine preparations will profile, I don’t feel comfortable let- approved for wrinkles around the eye undoubtedly reveal a more frustrating ting patients use long-term steroids and on the forehead. We’re now using side-effect profi le than Restasis. because of the side effects of glaucoma that in addition to low-level light ther- He believes that one of the more and cataracts. Alrex is a weaker con- apy to see if it will heat and stretch the exciting products in the pipeline right centration, and I haven’t seen a lot of glands even more than IPL,” he says. now is Novaliq’s CyclASol A, which is side effects with Alrex, even though it According to Dr. Stonecipher, Epi- a preservative-free ophthalmic solu- is still a steroid. This invites the pos- C low-level light therapy and IPL are tion of 0.1% cyclosporine A in EyeSol, sibility of weaker concentrations of ste- both FDA-approved, but combining Novaliq’s water-free technology. “Be- roids in the future having some poten- them for the treatment of dry eye is cause of its molecular characteristics, tially benefi cial effect on the treatment off-label. “There are different wave- the drops are only 10 µm in diameter, it of dry eyes without the side effects of lengths that trigger the endogenous has excellent adherence to the surface cataracts and glaucoma.” heating of the eyelids,” he says. “We of the eye, it’s comfortable, it doesn’t Inveltys (loteprednol etabonate are basically heating these fats or this sting, and it doesn’t require a preserva- ophthalmic suspension 1%) from meibum from the inside out.” tive,” says Dr. Sheppard. “It has great Kala Pharmaceuticals was recently ap-

June 2019 | reviewofophthalmology.com | 43

042_rp0619_f3.indd 43 5/24/19 5:25 PM 0042_rp0619_f3.indd 44 4 2 _ r p 0 6 1 9 _ f 3 44 far the industry has come over the past far theindustryhascomeover thepast were “quiteencouraging.” and Ophthalmology, andsaysthedata the AssociationforResearchinVision use ofthedrugatannualmeeting presented PhaseIIbresultsfromthe the eye,”hesays.Dr. Sheppardrecently and uveitisintheanteriorsegmentof disease states,includingallergy, dryeye diators thatarepresentinnumerous of awidevarietyinfl new productthatblockstheformation lap isanewmolecule.“[It’s] anentirely have itinourhands,”Dr. Latkanyadds. tentially twotofouryearsbeforewe III trial.“However, itstillcouldbepo- signs. ReproxalapiscurrentlyinaPhase multiple measuresofsymptomsand tically signifi cal trials,thedrugdemonstratedstatis- mechanism ofaction.InPhaseIIbclini- proxalap thathasacompletelydifferent has developedanewdrugcalledre- steroids workgreatfordryeye.” is expensive,too,andweallknowthat ance plans.But,thenagain,Lotemax going tobeexpensiveforsomeinsur- However, likeallnewmedicines,it’s panies willwelcomeatrueindication. with veryrestrictiveinsurancecom- Lotemax fordryeye.Somedoctors ficult tosaybecausewealreadyuse How thatmightchangethingsisdif- met needforprescribersandpatients. year becauseittrulyaddressesanun- “We hopeitwillbeavailableearlynext a thirdtrial,”explainsDr. Sheppard. missed symptoms,sothatearnedthem Phase IIItrials,butoneofthetrials eye’s] signsinbothofthefirsttwo third PhaseIIIclinicaltrial. for dry-eyedisease.It’s currentlyinits continues toadvanceKPI-1210.25% approved forthisindication.Kalaalso fi pain followingocularsurgery. It’s the of postoperativeinflammationand proved bytheFDAfortreatment . rst twice-dailyocularcorticosteroid i n

d REVIEW Dr. Sheppard isimpressedathow According toDr. Sheppard reproxa- Additionally, AldeyraTherapeutics “KP-121 [wasstudiedagainstdry d |

Feature

Review ofOphthalmology

4 4 cant improvementacross

ammatory me- ammatory Dry Eye Dry | June2019 treatment ofdryeye.“Itapplies kinase- I/IIa proof-of-conceptstudy forthe produced promisingresultsin aPhase that occurswithdry-eyedisease.It to treattheunderlyinginfl veloped TOP1630,whichisdesigned based inLondon,TopiVert, hasde- anterior andposteriorblepharitis.” control thesymptomsandsignsofboth ing adaptedforocularpreparationto established indermatologyandisbe- Dr. Sheppard.“Thisproducthasbeen tory diseaseorlidmargindisease,”says celerated inpatientswithinfl patients, buttheturnovercanbeac- very closelyregulatedrateinnormal renewal ofthatepitheliumoccursata mal epithelium.“We allknow thatthe anterior lidmarginandsquamousder- quamation andrejuvenationofthe nology (AZR-MD-001)forthedes- (Tel Aviv, Israel)hasproprietarytech- oral therapy.” which mostpatientsdon’t like,andan compromise betweenanointment, this trial.Gelseemstobeanexcellent advantages, sowe’reveryexcitedabout medications, obviously, havetheirdis- be giveningelorointmentform.Oral insoluble drug,whichbasicallyhasto established minocycline.It’s ahighly ginning aPhaseIIbtrialwithwell- says Dr. Sheppard.“So,we’rejustbe- beginning itsfi one. “It’s alargecompanythat’s just gel, whichisbeingdevelopedbyHovi- cent ofdryeyes.” responsible forapproximately84per- for meibomianglanddisease,whichis are someexcitingdrugsinthepipeline ward toalotofnewtherapies.There gland disease.So,we’relookingfor- what wasgoingonwithmeibomian years ago,wereallydidn’t appreciate er thantears,”hemuses.“Even10 nothing thatreallytreateddryeyeoth- the factthat,just22yearsago,wehad amazing genesiswhenyouthinkabout couple ofdecades.“It’s beenapretty Also, apharmaceuticalcompany Additionally, AzuraOphthalmics One oftheseistopicalminocycline rst forayintoeyecare,” ammation amma- III trial. It’s currentlybeingstudiedinaPhase ders, andforthetreatmentofdryeye. patients withcornealepithelialdisor- corneal epithelialwoundhealingin as anophthalmicsolutiontopromote developed bySenjuPharmaceutical ceptor deltaagonist.SJP-0035isbeing peroxisome proliferator-activated re- nism ofactionisSJP-0035,whicha dry-eye patient.” activation ontheocularsurfaceof be bothproximalanddistaltoTcell fl systems, includingocularsurfacein- tory diseasesofalltypesandorgan are auniversalsignalerininfl face,” Dr. Sheppardexplains.“Kinases inhibition technologytotheocularsur- aged 18yearsandolder.aged Am JOphthalmol 2017;182:90-98. amongadults eyediseaseintheUnitedStates dry of diagnosed 1. Farrand KF, Fridman M, Stillman IO, SchaumbergDA. Prevalence this article. companies orproductsmentionedin Latkany hasnofi Allergan, Shire,KalaandSenju.Dr. ert. Dr. Pfl Novaliq, Hovione,AzuraandTopiV- Sheppard isaconsultanttoKala,Sun, pansione, Hologics,KalaandShire.Dr. Allergan, Alcon,Bausch+Lomb,Es- what’s currentlyavailable.” potential tobemoreeffi see drugsinclinicaltrialsthathavethe approved bytheFDA.However, Ido it remainstobeseenwhethertheyget have rightnow,” hesays.“But,again, may bemoreeffectivethanwhatwe there willbenewclassesofdrugsthat more circumspect.“Ithinkeventually three tofi of drugswillbecomingoutinthenext the nextyearortwo,andthenaslew a coupleofdrugsthatwillbeoutin ahead,” Dr. Sheppardsays.“We have The Future ammation fordryeye.So,thesemay Another drugwithanewmecha- Dr. Stonecipherisaconsultantto “We havesomeexcitingtimes ve years.”Dr. Pfl ugfelder is aconsultantto nancial interest in the nancial interestinthe cacious than than cacious ugfelder is is ugfelder amma- 55/24/19 5:25 PM / 2 4 / 1 9

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References: 1. Holly FJ. Lacrophilic ophthalmic demulcents. US Ophthalmic Rev. 2007;3:38-41. 2. FRESHKOTE Drug Facts. Eyevance Pharmaceuticals LLC; 2018. 3. Holly FJ. Colloidal Osmosis — Oncotic Pressure. Grapevine, TX: Dry Eye Institute; 2006. 4. Fuller DG, Connor CG. Safety and effi cacy of FreshKote® used as a rewetting agent in Lotrafi lcon-A® contact lens wearers. Poster presented at: American Academy of Optometry Annual Meeting; November 17-20, 2010; San Francisco, CA. 5. Nemera. Novelia®. https://nemera.net/products/ophthalmic-novelia-eyedropper/. Accessed March 14, 2019.

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RP0619_Eyevance Fresh.indd 1 5/15/19 9:34 AM Keratoconus REVIEW Feature Non Cross-linking Options for Keratoconus

Alexandra Skinner, Associate Editor All images: Wuqaas Munir, MD Doctors discuss orneal collagen cross-linking has made signifi cant headway in alternatives for Cthe United States as a method for halting keratoconus progression. managing the While the procedure is an effective option for the disease, especially for disease. young patients who are quickly pro- gressing, there are some cases in which cross-linking may not be indicated. In this article, specialists describe non Figure 1. An abnormal topography of a cross-linking candidates and methods cornea showing keratoconus. for managing their keratoconus. ophthalmology at Bascom Palmer Non Cross-linking Candidates Eye Institute, says that cross-linking is meant to be used in individuals whose Kenneth Beckman, MD, FACS, keratoconus is progressing. However, director of corneal services at Com- “The likelihood of progression goes prehensive Eyecare of Central Ohio, down with age and most people stop and clinical assistant professor of oph- progressing once they get to 35 or 40 thalmology at Ohio State University, years old,” she says. “So cross-linking says that in his experience, only a few isn’t needed if someone is 60 years old people are unable to undergo cross- and has stable disease.” linking. He adds, however, that some Julie Schallhorn, MD, MS, assistant patients may not need it. professor of clinical ophthalmology While criteria for a non cross-linking at the University of California, San candidate aren’t always clear, here are Francisco agrees, commenting that some special cases in which the pro- young people are much more likely cedure is considered unnecessary, or to progress, and at a much more rap- could potentially threaten eye health. id rate. She shares why doctors think • The stable patient. Doctors say this occurs. “Cross-linking essentially that older, stable patients aren’t good bonds collagen fi brils and, as you age, candidates for cross-linking as the pro- through natural exposure to UV sun- cedure, in many instances, becomes light, the collagen in your cornea stiff- unnecessary over time. Anat Galor, ens and is naturally cross-linked.” MD, MSPH, associate professor of • Very thin cornea. Dr. Schallhorn

46 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

046_rp0619_f4.indd 46 5/24/19 4:39 PM says that if the patient’s cornea is too thin, he can’t undergo cross-linking since there’s a risk of damaging the corneal endothelium. “There’s a mini- mum corneal thickness that you need Figure 2. Left: OCT of a keratoconic cornea fi tted with a contact lens. Right: OCT of a in order to be able to cross-link,” Dr. keratoconic cornea. Schallhorn says. “Four hundred mi- crons is what they used in the FDA- cornea. they’ve done very well. approval studies for Avedro, which • Scarred cornea. “Corneal scar- was recommended based on studies ring could be another issue; but that Management Options looking at endothelial damage from usually ties in with thinning,” says Dr. cross-linking.” Wuqaas Munir, MD, Munir. “A patient with signifi cant scar- “As of now, the only thing that can associate professor of ophthalmology ring is usually someone whose cornea change the course of [keratoconus], or and visual science, and associate pro- is so thin that they can’t be treated with halt its progression, is cross-linking,” gram director for the residency pro- cross-linking.” If the cornea is scarred, says Dr. Munir. However, there are de- gram at the University of Maryland especially centrally and significantly, vices and techniques for managing var- School of Medicine, explains that the Dr. Beckman says that’s going to limit ious stages of the disease when cross- current thinking is that the application vision. He says a transplant may ulti- linking isn’t the best option. Of course, of UV-light could potentially damage mately be needed in that case, as there it’s important to note that many of the endothelium during the cross-link- may be no visual benefi t from cross- these options aren’t exclusively used in ing procedure if the cornea isn’t thick linking. non-cross-linking candidates; they’re enough. “So in this case, a patient who • Ocular surface disease. “A per- frequently employed before, after and wouldn’t qualify [for cross-linking] son with bad ocular surface disease— in conjunction with cross-linking. would have too advanced a form of the like those with a history of herpes or • Soft lenses. The purpose of con- disease where the cornea has become severe dry eye—may not be able to tact lenses is to help the patient see, too thin,” he says. have a cross-linking procedure as these says Dr. Munir. “Since keratoconus Though doctors note the poten- conditions make healing difficult,” causes the cornea to steepen, contact tially harmful effects of performing notes Dr. Beckman. “Herpes patients lenses aim to negate that steepness cross-linking on a patient whose cor- have trouble re-epithelializing, and in and improve the optics of the eye,” he nea is less than 400 µm thick, Dr. cross-linking you remove the epithe- explains. “To do this, the lens sits on Beckman emphasizes that this is lium. Also, ultraviolet light may trig- top of the cornea and when light pen- just the recommended guideline for ger a herpes fl are-up.” Dr. Beckman etrates the eye it hits a more uniform minimum thickness. It’s not clear- notes, however, that this isn’t an abso- surface.” With that in mind, Dr. Schall- cut as to whether damage is neces- lute contraindication, and says that the horn says that soft lenses are great for sarily done to the endothelium if physician has to weigh the risks and people with regular astigmatism who the cornea is below that threshold. benefi ts. have little change in the contour of “Some have experienced damage • Inability to sit still or fi xate. the cornea. “If you have mild kerato- when the cornea was thicker than Dr. Beckman adds that a cross-linking conus and can refract well in glasses, 400 microns, and there are plenty of procedure could be diffi cult if a pa- then a soft lens generally works,” she cases of thinner corneas that haven’t tient is unable to sit still. “For some of says. “But for a patient with signifi- had damage,” he says. those patients, physicians may consid- cant amounts of irregular astigmatism, While a thin cornea may be a sign er doing the procedure under seda- [someone with moderate to severe that a patient isn’t a good cross-linking tion or even general anesthesia, which keratoconus], he or she won’t be able candidate, doctors are investigating has its own risks,” he says. “Patients to wear a soft lens.” different techniques to decrease the that are very young or have cognitive “The problem with a soft lens is that risk of harm to the endothelium. This issues may require this. Fortunately, it’s soft,” muses Dr. Munir. “It drapes includes changing the intensity of the it’s very rare.” However, Dr. Beckman over the cornea and has very limited UV light, altering the duration of treat- notes that this isn’t necessary in every ability to overcome shape changes. If ment, putting a contact lens over a thin one of these cases. He points out that you have a steep cornea, the soft lens cornea to reduce UV-light penetra- he has treated young patients and pa- will follow the shape of that steepness tion, and using hypotonic riboflavin tients with Down syndrome without and you won’t get a smooth contour (Photrexa Viscous, Avedro) to swell the using sedation, and he reports that anymore.” Justin Sherman, OD, an

June 2019 | reviewofophthalmology.com | 47

046_rp0619_f4.indd 47 5/24/19 4:39 PM Feature Keratoconus REVIEW

optometrist at Philadelphia Eye As- to patients misusing their contact lens- Dr. Sherman agrees that scleral sociates, outlines another shortcoming es in some capacity.” Dr. Schallhorn lenses can be very therapeutic for ocu- of soft lenses. “In my experience, soft- outlines another disadvantage to the lar-surface disease issues, which many lens patients tend to overwear their technique. “The two-lens combination keratoconus patients have. He says lenses,” he says. “And that comes with can cause a lot of corneal hypoxia and that scleral lenses are a great choice for the associated complications.” could cause corneal neovasculariza- patients with severe, more peripheral • Rigid lenses. “Rigid gas-perme- tion,” she says. “Those vessels put the cones. “These lenses vault the cornea able small-diameter contact lenses patient at higher risk for transplant.” entirely and are supported by a hap- work very well for [more advanced However, Dr. Sherman notes that tic that lands on the conjunctiva,” he cases of] keratoconus because they there are cases in which patients man- explains. “Because the conjunctiva is cancel out the irregular astigmatism age their piggybacking technique well much less sensitive than the cornea, of the cornea,” says Dr. Schallhorn. and are very happy. these lenses are exceptionally comfort- Dr. Munir says RGPs aren’t limited as • Hybrid lenses. Dr. Munir says able, so long as they match the pa- much by the shape of the cornea and that hybrid lenses provide the opti- tient’s scleral profi le. They also have can be used in steeper forms of kera- cal advantage of the rigid lens but the extremely low rates of complication toconus to achieve better optical qual- comfort of a soft lens. However, while and infection.” ity. And Dr. Sherman notes that being Dr. Sherman acknowledges the optical Due to advancements over the past able to change the optical zone sizes and comfort advantages, he outlines few years, Dr. Munir says that in many and peripheral curve systems [with the a few disadvantages. “[Hybrid lenses] cases, a steep cornea, which previously use of an RGP], makes it possible to are similar to RGPs in that they begin may not have been manageable with a fi t a wide variety of cones. “One of the to misbehave when patients have more rigid lens, can now be fi t with a scleral best qualities of RGP lenses is the sig- peripheral disease,” he says. “They’re lens. However, Dr. Munir acknowledg- nifi cantly lower rates of overwear and probably the most diffi cult for patients es a few disadvantages. “[Scleral lenses infection relative to soft lens designs,” to handle. The edge of the lens has are] very large and potentially more he says. to be pinched to remove it, but many uncomfortable than a standard RGP,” Dr. Sherman adds, however, that patients have a diffi cult time knowing he says. “It can be difficult to insert these lenses become less effective in where the GP optic ends and the soft and remove scleral lenses because of patients with severe, more peripheral skirt begins. Diffi culty with insertion the large size. The patient instruction cones that produce signifi cant differ- and removal is the most common rea- is more diffi cult and it’s harder for pa- ences in peripheral corneal elevation. son I have patients drop out of hybrid- tients to build up a tolerance, in terms Dr. Schallhorn agrees. “The problem lens wear.” He adds that hybrid lenses of lack of comfort.” with RGP lenses is that there’s kind of are also the most expensive design. Doctors say generic scleral lenses a limit as to how steep your cornea can • Scleral lenses. “Scleral lenses work for almost everybody, but there be to wear [them],” she says. “They’re have revolutionized treatment op- are still extremely advanced cases also kind of tricky to fi t. You need to tions,” says Dr. Beckman. “No matter of keratoconus where the cornea is be working with an optometrist who’s how distorted the cornea may be, if too steep for a generic lens. Due to good at fi tting RGP’s, which is tough it’s optically clear—meaning there’s no a more recent development in scler- because you’re basically fi tting on top central scar—then you can fi t almost al-lens technology, however, doctors of a mountain.” any cornea with a scleral lens and get say that steep cones can now be fit • Piggybacking. “Piggybacking a good vision.” using custom scleral lenses such as rigid lens on a soft one used to be con- Dr. Beckman says the advantages BostonSight’s PROSE and EYEprint’s sidered a great way to provide comfort of scleral lenses include the ability of EyePrintPRO. “[These are both] types to a patient who can’t comfortably wear the lens to vault in front of the cornea of scleral lenses that allow you to cus- their RGPs any longer,” says Dr. Sher- without touching it. He says the lens tomize the lens to fi t the contour of the man. “However, the need for piggy- creates a smooth round optical surface, patient’s cornea and therefore fi t peo- backing has been dramatically reduced which corrects vision. “Since the lens ple with very irregular corneas,” Dr. with the advent of irregular cornea doesn’t rub on the cornea, scleral lens- Galor says. Dr. Schallhorn describes RGPs, scleral lenses and hybrid-lens es are good for patients with dry eye,” the options: “PROSE is a custom- designs. This is great because the com- he notes. “The patient’s tear fi lm fi lls in made scleral lens that can vault over plexity of caring for two different lens the gap between the lens and cornea, almost any cone,” she says. “EyePrint- types with different solutions and re- so the surface of the cornea is kept PRO is another custom scleral lens in placement schedules would often lead moist as it constantly bathes in liquid.” which you take a mold of the corneal

48 | Review of Ophthalmology | June 2019

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RP0619_Akorn TT.indd 1 5/15/19 9:35 AM Feature Keratoconus REVIEW

shape and then make a lens based on tion, you’d have to do PK.” that.” • Corneal transplant. “Some- • Intacs. “The goal is to insert In- times, if there’s a lot of scar tissue, as tacs to make the cornea more regular in a patient who has very advanced and improve contact lens comfort,” keratoconus and a thin cornea, you says Dr. Galor. “A good candidate for can’t perform DALK,” Dr. Munir says. intrastromal rings is an individual who “In that case we do a PK. The risk with has sufficient corneal thickness and PK is that you have a little more of a contact-lens intolerance.” chance for rejection since you’re re- Dr. Beckman says the placement of Figure 3. Deep anterior lamellar moving the endothelium.” Intacs may provide better spectacle keratoplasty is also an option in these Dr. Schallhorn notes a few instances vision and better-uncorrected vision. patients. where a PK would be indicated. “I He outlines a scenario in which Intacs fi nd that for patients who have a lot of may be used in order to decrease de- linking candidate. endothelial scarring from an episode pendence on contacts. “If progression • DALK. Since keratoconus doesn’t of hydrops, many times you just blow has stopped and there’s still signifi cant affect the endothelium, Dr. Munir says out the area of the old scar with DALK residual astigmatism, patients may try deep anterior lamellar keratoplasty is and end up having to do PK,” she says. glasses or contacts,” he says. “Often, an option. “The endothelial cells are Dr. Galor says there are possible they get good vision with both but, at what we consider one of the primary long-term concerns for transplant pa- other times, they may only get good sources of transplant rejection,” says tients. “One issue with DALK and PK vision with contacts. For these patients Dr. Munir. “However, we can do a is that the integrity of the cornea is Intacs may be considered.” deep anterior lamellar keratoplasty, never as strong as the native cornea,” Due to advancements in contact- which will replace everything but the she says. “As such, if patients experi- lens technology over the past decade, endothelium.” In DALK, the corneal ence trauma to the eye, even years Dr. Sherman says that fewer and fewer stroma is removed but Descemet’s after transplantation, they’re at risk for Intacs segments are being implanted. membrane and the endothelial cells graft dehiscence, in which the area of Dr. Galor notes, however, that the remain. “The risk of rejection is much the scar opens.” However, she notes world of corneal rings is more varied lower with this type of procedure than that outcomes are good after full-thick- outside of the United States. “In Eu- it is with a full-thickness penetrating ness corneal transplants for keratoco- rope, they have many different types keratoplasty in which the stroma and nus, compared to other indications. of intrastromal rings and they’ve de- endothelium are replaced by donor veloped really sophisticated algorithms tissue,” Dr. Munir shares. Outlook: Positive that customize the length, thickness, Dr. Beckman says there are pros number and location of the rings to and cons to DALK. “The advantages Ultimately, Dr. Schallhorn says counteract a particular shape of the are that you’ve done a procedure with- cross-linking is a very exciting technol- cornea,” she says. out having the eye completely open— ogy, especially for younger patients. As just a thin membrane remains—so for older patients, she says the jury is Transplants there’s less risk intraoperatively,” he still out regarding who’s considered a says. “And since there’s less risk of good candidate for cross-linking and “People that have really advanced graft rejection, you could potentially who’s at risk for progression. “That’s keratoconus who are no longer able get the patient off steroids quicker. something people need to address,” to fi t into generic scleral lenses, who However, disadvantages include the she says. “However, I think that refer- can’t afford or are unable to get cus- learning curve. Not every doctor per- ring people to optometrists who are tom lenses (which physicians say are, forms DALK. It’s a long procedure skilled scleral-lens fi tters and can get unfortunately, very expensive), or have that’s technically more difficult than good refractive correction can really a history of hydrops with scarring, are PK, and there’s always the possibility change the life of a person who has people we’re doing transplants on,” of popping through Descemet’s and keratoconus.” says Dr. Schallhorn. She adds that a the endothelium and having to convert patient having an episode of hydrops to a PK. If the patient has endothelial Drs. Schallhorn and Beckman are already has extremely advanced ker- disease or a distorted cornea that’s too consultants for Avedro. Drs. Galor, atoconus, and therefore a very thin thin and the endothelium decompen- Munir and Sherman report no fi nan- cornea, which makes for a poor cross- sates, then DALK wouldn’t be an op- cial interests.

50 | Review of Ophthalmology | June 2019

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RP0319_NuSight Medical.indd 1 2/22/19 11:54 AM ENRICH YOUR PRACTICE

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2018_rp_tsrad.indd 90 4/13/18 11:28 AM Retinal Insider

REVIEW Edited by Carl Regillo, MD, and Yoshihiro Yonekawa, MD

A New Way to Perform a Vitrectomy A look at how hypersonic vitrectomy works, and what features it might bring to the table.

Sunir Garg, MD, Philadelphia, Kevin J. Blinder, MD, St. Louis, and Carl C. Awh, MD, Nashville

uillotine cutters have been the vitreous particles are aspirated through crease fl ow. G standard tools for performing vit- the interior lumen of the needle. The The hypersonic vitreous cutter takes rectomy for decades. They are versa- evolution of vitreous cutters has led a different tack; rather than mechani- tile, and have only gotten better over to smaller gauge probes with smaller cally cutting the vitreous and then as- time. Because of this, when a new lumens that can increase resistance pirating cut particles, the hypersonic technology—hypersonic vitrectomy and decrease fl ow. Additionally, with unit uses ultrasonic vibrations, operat- (Vitesse, Bausch + Lomb)—comes standard guillotine cutters, lower cut ing at 1.7 million cycles per minute, to along that can remove vitreous in a rates result in larger particles that can liquefy the vitreous gel near the de- different way, surgeons are naturally increase vitreous traction and decrease vice’s port. The probe of the device is interested in learning more about fl ow. Because of this, we’ve moved to a single lumen shaft with a small port its operation, strengths and possible higher cut rates and more efficient that’s always open, providing a unique limitations. Since only a few hundred cutters that result in smaller particles, 100-percent duty cycle (the amount cases have been performed with this which can decrease traction and in- of time the port is open; Figure 2).

technology, however, surgeons still Bausch + Lomb The device liquefies the vitreous at don’t have a lot of day-to-day experi- the outer margins of the port and then ence with it. aspirates the resulting microparticles.1 In this article, a few of us who have While on a superficial level this been involved with the development technology may seem similar to phaco- and utilization of hypersonic vitrecto- emulsifi cation, it’s actually quite differ- my will try to answer some questions a ent. Early in their training, all ophthal- surgeon might have about it. mologists learn that a phaco handpiece shouldn’t be used to remove the vit- How Does It Work? reous because the phaco handpiece doesn’t cut the gel, it aspirates it. This To understand how a hypersonic vit- aspiration can cause traction on the rectomy probe differs from a guillotine retina, which can lead to retinal tears cutter, it helps to understand how the and detachments. In contrast, the hy- latter works. Guillotine cutters have a Figure 1. A pneumatic cutter’s needle-in-a- personic vitrectomy probe liquefies needle-within-a-needle design (Figure needle design. The duty cycle is less than the vitreous at the port using higher 1). The internal needle cuts the vitre- 100 percent and, as the lumen narrows, frequency, lower amplitude vibrations. ous by moving back and forth; then the there’s increased resistance to fl ow. Additionally, the surgeon has con-

This article has no commercial sponsorship. June 2019 | reviewofophthalmology.com | 53

053_rp0619_retina.indd 53 5/24/19 5:23 PM Retinal

REVIEW Insider

trol over the oscillation distance of the the crystalline lens. Having a curved with a guillotine cutter. Two eyes de- probe. Longitudinal oscillation in the tip might enable the removal of this veloped retinal detachments that were hypersonic vitrectomy unit (referred to vitreous without hitting the lens. ultimately repaired.4 as stroke) ranges between 0 and 60 mi- The hypersonic vitrector runs on Recently, our group presented on crometers. The user can adjust stroke electricity, so no pressurized gas—pro- hypersonic vitrectomy at the 2018 intraoperatively in real time in order to vided by either tanks or in-wall lines— American Society of Retina Specialists infl uence the speed and effectiveness are necessary for its operation. This Meeting in an effort to describe the of vitreous removal. could be helpful when performing vit- technology’s performance and provide We’re learning more about optimiz- rectomy in parts of the world where a sense of the pathologies it could be ing stroke settings with each use of the pressurized gas isn’t available, such as used for.5 We performed a prospective, device. For instance, we now know remote areas or less-developed regions multicenter, non-randomized case that for performing a core vitrectomy, served by medical missions. series of 71 eyes in 71 patients using or removing dense vitreous hemor- fi ve different surgeons. We looked at rhage or retained lens material, having In Vitro Studies such variables as intraoperative energy more stroke (liquefying energy) and (stroke length and time) and fl uid us- vacuum is helpful. When we shave the In our own in vitro studies, we’ve age. The surgeons were also polled vitreous, however, particularly over found the hypersonic vitrectomy cut- regarding the usefulness of the tech- mobile retina, we need less stroke and ter to be associated with smooth and nology, complications and its potential vacuum. Additionally, in our experi- continuous vitreous aspiration, primar- advantages or disadvantages. ence, it appears that hypersonic vitrec- ily because the port is always open. The surgeons found that hypersonic tomy doesn’t require a lot of vacuum to The hypersonic vitrectomy probe cre- vitrectomy could be used for a variety operate effi ciently. ates little traction on the vitreous as of vitreoretinal cases, including retinal A potentially useful feature of a hy- the gel is liquefi ed around the probe detachment repair, silicone oil aspira- personic vitrectomy handpiece is that opening. tion, macular surgery, diabetic traction the probe can be modifi ed in differ- In two histopathologic studies of detachments and removal of retained ent ways (Figure 3). Along these lines, porcine retinas funded by Bausch lens material. The surgeons found that curved probes and different port lo- + Lomb, the instrument appeared the average vitrectomy actuation time cations are being tested that may be to cause less disruption to the inner (the time spent stepping on the ac- more useful than straight probes in retinal layers than a pneumatic cutter tivation pedal to liquefy vitreous or certain situations. For example, it’s dif- (Figure 4).2,3 remove fluid from the vitreous cav- fi cult, if not impossible, to remove the ity) was approximately 5.5 minutes. peripheral vitreous 180 degrees from Human Experience In 97 percent of cases, there were no the sclerotomy site without contacting Bausch + Lomb The fi rst in-human study was con- Bausch + Lomb ducted at Dr. Agarwal’s Eye Hospital in Chennai, India by the University of Manchester’s Paulo Stanga, MD, Amar Agarwal, MD, and colleagues. They described their experience on 20 eyes that underwent vitrectomy for macular hole, vitreous hemorrhage and vitreomacular traction. The sur- geons were able to perform core vit- rectomy on all eyes with the hyper- sonic unit, and induced a posterior vitreous detachment in 13 of 15 eyes. The peripheral vitreous was shaved Figure 3. Examples of several tip designs with the hypersonic vitrector in 18/20 for the hypersonic vitrectomy cutter. The eyes. However, one eye with a dense, single lumen design means the probe Figure 2. The hypersonic vitrectomy hand- organized vitreous hemorrhage and doesn’t need to be straight, which allows piece has a single lumen shaft, and the another with a retinal detachment had fl exibility in the shapes of the tips that can port is always open. the peripheral gel removal completed be created.

54 | Review of Ophthalmology | June 2019

053_rp0619_retina.indd 54 5/24/19 5:24 PM COMBO CHAIRS & STANDS Kevin Binder, MD, and Carl Awh, MD my represents a new way of removing vitreous gel that may have unique strengths that surgeons can take advantage of. However, as with any new technol- ogy, much work remains in OptimizeOptimize order to optimize its use, such as determining its op- spacespace anandd timal settings, how to ad- just stroke and vacuum for functionality.functionality. different pathologies and Figure 4. Histopathology of a pig eye post-hypersonic creating different probe de- vitrectomy. There is minimal disruption to the inner signs. Guillotine vitrectomy retinal layers. probes have improved over intraoperative complications, although the past 40 years due to continuous there was one case of a small iatrogen- research, development and routine ic retinal break in a detached retina, use. We’re optimistic that hypersonic as well as some superfi cial scoring of vitrectomy will rapidly improve as well, the posterior intraocular lens surface and be able to achieve excellent out- (outside the visual axis) during capsu- comes for patients with a variety of lotomy in another eye. intraocular pathologies. In nearly 90 percent of cases, vitrec- tomy was performed entirely with the Dr. Garg is a professor of ophthal- hypersonic vitrectomy probe. How- mology at the Sidney Kimmel Medi- ever, in cases of traction retinal detach- cal College at Thomas Jefferson Uni- ment with thick diabetic membranes, versity, an attending physician on the and cases that had a taut posterior hya- Retina Service at Wills Eye Hospital loid, some of the study’s surgeons pre- in Philadelphia, and a partner with ferred the guillotine cutter. The results MidAtlantic Retina. Dr. Blinder is a were similar to a hypersonic probe, professor of clinical ophthalmology & however. visual sciences at Washington Univer- The surgeons described little trac- sity School of Medicine. Dr. Awh prac- tion when shaving the peripheral vitre- tices at Tennessee Retina in Nashville. ous near areas of mobile retina when The authors are consultants to using hypersonic vitrectomy. De- Bausch + Lomb. Affordable,Affordable, creased traction is particularly valuable 1. Stanga PE, Pastor-Idoate S, Zambrano I, Carlin P, McLeod when working near mobile detached D. Performance analysis of a new hypersonic vitrector system. PLoS One 2017 Jun 6;12:6:e0178462. doi: 10.1371/journal. retina, and hypersonic vitrectomy pone.0178462. eCollection 2017. PMID: 28586375 space-savingspace-saving 2. Ch’ng SW, Irion LD, Bonshek R, Shaw J, Papayannis A, Pastor- doesn’t appear to induce much trac- Idoate S, Stanga PE. Live porcine thirty days delayed recovery tion as it liquefi es the gel. Hypersonic surgery: Qualitative fi ndings with the hypersonic vitrectomy. cchairhair & standstand PLoS One 2018 Jun 1;13:6:e0197038. doi: 10.1371/journal. vitrectomy may also be useful in cases pone.0197038. eCollection 2018. PMID: 29856756 of retained lens material, in which the 3. Pastor-Idoate S, Bonshek R, Irion L, Zambrano I, Carlin P, solutions. Mironov A, Bishop P, McLeod D, Stanga PE. Ultrastructural and device has been shown to be effective histopathologic fi ndings after pars plana vitrectomy with a new hypersonicvitrector system. Qualitative preliminary assessment. Small footprint enough to eliminate the need to use a PLoS One 2017 Apr 11;12:4:e0173883. doi: 10.1371/journal. fragmatome, even in cases with dense pone.0173883. eCollection 2017. PMID: 28399127 41.2” x 34.2” 4. Stanga PE, Williams JI, Shaarawy SA, Agarwal A, Venkataraman lens material. Interestingly, the hyper- A, Kumar DA, You TT, Hope RS. First in human clinical study to investigate the effectiveness and safety of pars plana vitrectomy sonic device can also remove 1,000 cs surgery using a new hypersonic technology. Retina 2018 Oct and even 5,000 cs silicone oil, possibly 23. doi: 10.1097/IAE.0000000000002365. [Epub ahead of print. PMID: 30358763 eliminating the need for separate sili- 5. Garg SJ, Blinder K, Awh C, Tewari A, Srivastava S, cone oil removal devices. Kolesnitchenko V. The utility of hypersonic vitrectomy settings in vitreoretinal surgery. July 22, 2018. American Society of Retina In conclusion, hypersonic vitrecto- Specialists Annual Meeting. Vancouver, Canada.

053_rp0619_retina.indd 55 5/24/19 5:24 PM Research Review REVIEW

Cataract Surgery May Not Slow Field Loss

group of surgeons from Los An- • PRC (-0.62 percent ±2.47 percent/ January 20, 2015, and April 26, 2017. A geles, Seoul, South Korea and Mi- year before and -1.35 percent ±3.71 The study enrolled 38 individuals and lan say that, though cataract surgery percent/year after surgery; p<0.001); included 50 eyes with isolated endo- tends to lower patients’ intraocular and PLR (-0.20 ±0.82 dB/year before thelial dysfunction. Study eyes were pressure, it doesn’t seem to have a and -0.42 ±1.16 dB/year after surgery; randomized to receive either UT- similar benefi cial effect on glaucoma p<0.001) for all VF locations. DSAEK or DMEK. Responses to the patients’ visual fi eld progression po- Worse baseline MD and postoperative National Eye Institute Visual Func- stop. peak IOP were signifi cantly associated tion Questionnaire-39 administered In the study, consecutive open-angle with the postoperative VF decay rate at baseline, and three and 12 months glaucoma patients who underwent cata- and the change in the decay rate after postoperatively were analyzed using ract surgery and who had at least four cataract surgery. the NEI-defi ned traditional subscales visual fi eld tests and at least three years of The researchers concluded that cata- and composite score on a 100-point follow-up before and after surgery were ract surgery didn’t slow the rate of visual scale and with a Rasch-refi ned analy- retrospectively reviewed. Mean devia- fi eld decay when compared to the rate sis. tion (MD) rate, visual fi eld index (VFI) before cataract surgery was performed. The second eye from a single par- rate, pointwise linear regression (PLR), Am J Ophthalmol. 2019;201:19-30 ticipant was excluded, along with any pointwise rate of change (PRC), and the Kim JH, Rabiolo A, Morales E, et al. questionnaires relating to the fi rst eye Glaucoma Rate Index (GRI) were com- after second eye surgery, for evalua- pared before and after cataract surgery. Unilateral Endothelial tion of 38 eyes at baseline and three A total of 134 eyes of 99 patients were Keratoplasty and Quality of Life months, and 26 eyes at 12 months. included. Median (interquartile range) In the primary Descemet Endo- Mean baseline visual acuity was 0.35 follow-up was 6.5 (4.7 to 8.1) and 5.3 (4.0 thelial Thickness Comparison Trial, ±0.31 logMAR in the DMEK arm to 7.3) years before and after cataract Descemet’s membrane endothelial and 0.28 ±0.22 logMAR in the UT- surgery, respectively. keratoplasty led to superior postop- DSAEK arm. Each arm consisted of All intraocular-pressure parameters erative visual acuity compared with 19 participants: 18 individuals with (mean IOP, standard deviation of IOP, ultrathin Descemet’s stripping auto- Fuchs’ dystrophy and one participant and peak IOP) significantly improved mated endothelial keratoplasty. In- with pseudophakic bullous keratopa- (p<0.001) after cataract surgery, but all vestigators aimed to determine the thy. VF indices indicated an accelerated VF effect of DMEK and UT-DSAEK on More women participated in both decay rate after cataract surgery: vision-related quality of life. arms of the study (UT-DSAEK: 12 [63 • MD rate (-0.18 ±0.40 dB/year vs. A prespecifi ed, secondary analysis percent]; DMEK: 11 [58 percent]); -0.40 ±0.62 dB/year, p<0.001); of a two-surgeon, patient- and out- and mean age was 68 ±11 years in the • VFI rate (-0.44 percent ±1.09 per- come-masked randomized clinical tri- UT-DSAEK arm and 68 ±4 years in cent/year vs -1.19 percent ±1.85 percent/ al was conducted at the Casey Eye In- the DMEK arm. Here are some of year, p<0.001); stitute in Portland, Oregon, and Byers the fi ndings: • GRI (-5.5 ±10.8 vs -13.5 ±21.5; Eye Institute in Palo Alto, California. • Overall, study participants ex- p<0.001); and The study was conducted between perienced a 9.1-point improvement

56 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

0056_rp0619_rr.indd56_rp0619_rr.indd 5656 55/24/19/24/19 5:155:15 PMPM COMBO COMBINE WITH OUR Sadeer Hannush, MD with minimum follow-up of a year. UNIQUE STAND The investigators identifi ed 63 eyes of 60 patients. Thirty-three eyes un- derwent combined PPV and ACIOL placement, while and 30 eyes un- derwent combined PPV and scleral Eff ortless fixation of a PCIOL using a Gore- Tex suture. Mean follow-up was 502 instrument ±165 days (median: 450, range: 365 to 1,095 days). positioning A study found that DMEK may not improve In the ACIOL group, mean vi- vision-related quality of life more than sual acuity improved from 20/914 DSAEK. preoperatively to 20/50 postopera- tively (p<0.001). In the scleral-fi xated in NEI VFQ-39 composite score at PCIOL group, mean visual acuity im- three months compared with base- proved from 20/677 preoperatively to line (n=38; CI, 4.9 to 13.3; p<0.001), 20/46 postoperatively (p<0.001). No and an 11.6-point improvement at difference in visual acuity was noted 12 months compared with baseline between groups at one year (p=0.91) (n=26; CI, 6.8 to 16.4; p<0.001). or at the fi nal follow-up (p=0.62). • Eyes randomized to DMEK had In terms of complications, eyes un- only 0.9 points more improvement dergoing ACIOL placement had a in NEI VFQ-39 composite score at signifi cantly higher rate of transient three months compared with UT- corneal edema (30.3 vs. 6.7 percent, DSAEK after controlling for baseline p=0.02) compared with eyes under- NEI VFQ-39 (-6.2 to 8.0; p=0.80). going scleral fi xation of a PCIOL. Investigators concluded that im- In light of the results, the surgeons provement in vision-related quality of say that both modalities resulted in life wasn’t shown to be greater with similar visual outcomes. DMEK than with UT-DSAEK. Retina 2019;39:5:860-868. JAMA Ophthalmol 2019; May 2. Khan MA, Gupta OP, Pendi K, et al. [Epub ahead of print] Ang MJ, Chamberlain W, Lin CC, et al. Acanthamoeba Co-infection Advanced More Common than Expected Anterior Chamber IOL vs. Researchers from the Aravind Eye ergonomics Sutured PC-IOL Post Vitrectomy Hospital and Post-graduate Institute Surgeons from the East and West of Ophthalmology in Coimbatore, Coasts contributed another datapoint India say that Acanthamoeba co-in- to the perennial debate about anterior fection appears to be more often as- chamber intraocular lenses vs. scleral- sociated with microbial keratitis than sutured posterior-chamber IOLs after some might think. pars plana vitrectomy. In this prospective cross-sectional The study was a retrospective, in- study, patients presenting with stro- terventional case series of eyes un- mal keratitis were additionally tested dergoing combined PPV and IOL for Acanthamoeba, regardless of the placement for retained lens material, clinical diagnosis. The investigators aphakia or dislocated IOL. Eyes with used culture positivity as the gold a history of amblyopia, corneal opacity standard. or retinal or optic nerve disease were Of the 401 cases included in the excluded. Outcome measures were study, 40 were positive for Acanth- change in visual acuity, and occur- amoeba (10 percent); of these 40, 16 rence of postoperative complications were positive for both Acanthamoeba

056_rp0619_rr.indd 57 5/24/19 5:14 PM Research

REVIEW Review

and fungi (4.5 percent of these eyes. the study group was Acan- Retina 2019; Apr 2. thamoeba- and fungal [Epub ahead of print]. keratitis-positive); fi ve (1.2 Jang S, Park SY, Ahn SM, et al. percent) were positive for Acanthamoeba and bacte- Beta Blockers and ria; and two (0.5 percent) AMD Progression had a triple infection with Researchers from the Acanthamoeba, fungi and University of Pennsylva- bacteria. nia’s Scheie Eye Institute The physicians say that say surgeons and their pa- ring infi ltrates and stromal tients probably don’t need edema are frequently asso- to worry about the risk of ciated with Acanthamoeba progression to wet age- keratitis, as well as Acan- related macular degenera- thamoeba coinfections. tion if the patients are using Ring infi ltrates in particu- Researchers from India say that Acanthamoeba coinfection in cases beta blockers. lar were more frequently of bacterial keratitis may be more common than doctors think. In a retrospective cohort seen in the Acanthamoeba study of patients from 2000 and fungal keratitis group to 2014, using data from a (8/16) and they were often yellowish zone. Their fi ndings included the fol- large national U.S. insurer’s claims da- with hyphate edges (vs. ring infi ltrates lowing: tabase, researchers identifi ed 18,754 only, which are seen in the patients • A total of 33 eyes were classifi ed beta blocker patients and 12,784 cal- with Acanthamoeba alone). Only two as having nonundulating RPE; 27 cium channel blocker patients who patients were contact lens wearers: eyes were classifi ed as having undulat- met the criteria for inclusion. however, they presented with history ing RPE; and 20 eyes were identifi ed After controlling for covariates, pa- of trauma. as having wedge-shaped RPE. tients on beta blockers were at lower The researchers say that the results • The vascular densities of the su- risk for neovascular AMD at both 90 appear to show that Acanthamoeba perfi cial and deep capillary plexuses and 180 days than patients on cal- infections are much more frequent showed differences: nonundulating cium channel blockers (HRs: 0.67- than most think, and aren’t just re- RPE group 23.93 ±2.26 percent and 0.71; p<0.01 for both) or diuretics stricted to contact lens wearers. They 23.54 ±1.78 percent; undulating RPE (HRs: 0.55-0.62; p<0.01). Patients add that anticipating coinfections is group 22.29 ±2.80 percent and 21.94 on beta blockers, versus angiotensin- necessary for establishing a diagnosis, ±2.42 percent; and wedge-shaped converting enzyme/angiotensin re- as well as a proper therapy. RPE group 21.93 ±2.7 percent and ceptor blocker at all time points, and Am J Ophthalmol 2019;201:31-36. 20.63 ±2.42 percent (p=0.010 and beta blockers versus calcium channel Raghavan A, Baidwal S, Venkatapathy N, Rammohan R p<0.001). blockers and diuretics at 365 days, • Mean retinal thicknesses and cho- didn’t have a signifi cantly lower asso- Retinal Characteristics in Eyes roidal thicknesses were also different. ciation with neovascular AMD (HR: With Early AMD The respective fi ndings were: nonun- 0.73-0.85; p>0.06 for all). Researchers assessed the fea- dulating RPE group, (298.26 ±13.81 A sensitivity analysis yielded similar tures of the retinal pigment epithe- µm and 180.08 ±55.49 µm); undulat- results, with patients on beta block- lium in eyes with early age-related ing RPE group, (285.29 ±21.88 µm ers signifi cantly less likely to develop macular degeneration and subretinal and 148.45 ±55.08 µm); and wedge- wet AMD at 90 and 180 days (HR: drusenoid deposits using optical co- shaped RPE group, (274.86 ±20.62 0.70-0.76; p<0.049 for both) but not herence tomography. µm and 135.75 ±39.77 µm) (p=0.001 at 365 days (HR: 0.88; p=0.30) com- They classifi ed the eyes into three and p=0.007). pared with patients on calcium chan- types: nonundulating RPE; undulat- Researchers reported that altered nel blockers. ing RPE; and wedge-shaped RPE. features of the RPE on optical co- Ultimately, the researchers say there They compared the retinal vessel herence tomography might indicate was no evidence that beta blocker use densities, retinal thickness and cho- advancement in disease and be part increased the risk of wet AMD vs. roidal thickness of a 3-mm-diameter of an overall degenerative process in other antihypertensive meds.

58 | Review of Ophthalmology | June 2019

056_rp0619_rr.indd 58 5/24/19 5:20 PM Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series We are excited to continue into our fourth year of Mackool Online CME. With the generous support of several ophthalmic companies, I am honored to have our To view CME video viewers join me in the operating room as I demonstrate go to: the technology and techniques that I have found to be www.MackoolOnlineCME.com most valuable, and that I hope are helpful to many of my colleagues. We continue to edit the videos only to either change camera perspective or to reduce down time – allowing you to observe every step of the procedure. Richard J. Mackool, MD Episode 42: As before, one new surgical video will be released monthly, “Posterior Subcapsular Cataract” and physicians may earn CME credits or just observe the case. New viewers Surgical Video by: are able to obtain additional CME credit by reviewing previous videos that are Richard J. Mackool, MD located in our archives. I thank the many surgeons who have told us that they have found our CME program to be interesting and instructive; I appreciate your comments, Video Overview: suggestions and questions. Thanks again for joining us on Mackool Online CME. This patient developed a dense posterior subcapsular cataract following retinal detachment CME Accredited Surgical Training Videos Now surgery. Here I demonstrate how Available Online: www.MackoolOnlineCME.com to remove a thick epithelial layer from the posterior capsule and discuss anterior chamber depth Richard Mackool, MD, a world renowned anterior segment ophthalmic in post-vitrectomized eyes. microsurgeon, has assembled a web-based video collection of surgical cases that encompass both routine and challenging cases, demonstrating both familiar and potentially unfamiliar surgical techniques using a variety of instrumentation and settings. This educational activity aims to present a series of Dr. Mackool’s surgical videos, carefully selected to address the specifi c learning objectives of this activity, with the goal of making surgical training available as needed online for surgeons motivated to improve or expand their surgical repertoire. Learning Objective: After completion of this educational activity, participants should be able to: • perform a method that can be successfully employed to remove an extremely dense layer of epithelial cells from the posterior capsule.

Satisfactory Completion - Learners must pass a post-test and complete an evaluation form to receive a certifi cate of completion. You must listen to/view the entire video as partial credit is not available. If you are seeking continuing education credit for a specialty not listed below, it is your responsibility to contact your licensing/certifi cation board to determine course eligibility for your licensing/certifi cation requirement.

Physicians - In support of improving patient care, this activity has been planned and implemented by Amedco LLC and Postgraduate Healthcare Education. Amedco LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team

JOINTLY ACCREDITED PROVIDERTM Credit Designation Statement - Amedco designates this enduring material activity for a maximum of .25 AMA PRA Category 1 INTERPROFESSIONAL CONTINUING EDUCATION CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Additionally Supported by: Endorsed by: Jointly provided by: Supported by an unrestricted independent Glaukos In Kind Support: Review of Ophthalmology® medical educational grant from: MST Sony Healthcare Video and Web Production by: REG (Review Education Group) Alcon Crestpoint Management Solutions JR Snowdon, Inc Carl Zeiss Meditec Glaucoma Management

REVIEW Edited by Kuldev Singh, MD, MPH, and Peter A. Netland, MD, PhD

Easing Your Patients’ Financial Burden Doing what you can to limit the cost of glaucoma treatment can improve adherence and create happier patients.

Yvonne Ou, MD, San Francisco

very ophthalmologist treating the costs associated with glaucoma Also, in some cases the drug E glaucoma knows that patients treatment. you’re prescribing may not be part have problems with compliance of the patient’s insurance company’s and adherence, and it’s no secret Talk to your patients about formulary. Be sure to address that by that a lot of this is tied to the cost of 1 cost and availability con- advising the patient on the best way treatment. In one study of patient/ cerns. As noted above, most patients to proceed. doctor communication over a series aren’t going to bring up their cost of glaucoma visits, a patient said (on concerns, so you, the physician, Consider switching the class camera), “Sometimes I forget [to buy should bring up the topic. You might 2 of medication you’re pre- the drops] purposely, because they’re say: “Glaucoma is a life-long disease, scribing. Joshua Stein, MD, and his so darned expensive. I fi gure if I use but we’ll work together to create a group did a worldwide price com- them half as much, I’ll only pay half treatment plan that’s sustainable over parison of glaucoma medications, the money.”1 the long term. Do you have any diffi - as well as laser trabeculoplasty and There are actually a number of ways culty paying for your glaucoma med- trabeculectomy.3 The price differ- to reduce the cost of the medications ications?” That can open the door to a ences among the drug options are patients have to purchase, but this longer discussion. significant. (See chart, page 62.) As fact is rarely discussed when you’d expect, beta blockers are patients are in the clinic. In the least expensive, at about fact, the same study of patient- 38 cents a day; the price jumps physician communication found up significantly when you that medication costs were only move to combination products. discussed in 1.4 percent of visits(!) Not surprisingly, the newest (See Table, facing page.) Another medications are the most study involving asthma patients expensive. found that 40 to 50 percent It’s worth explaining to the of patients wanted to discuss patient the difference between medication cost with the doctor, brand name drops and generics, but the patients only brought it and why the generics are up in a tiny fraction of the visits.2 usually—though not always— Here, I’ll share nine ways you less expensive (e.g., not having can help your patients reduce to repeat the animal and

60 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

060_rp0619_gm (1) (1).indd 60 5/24/19 3:32 PM human clinical studies of safety and Communication with Patients During the Examination effectiveness that were required of the brand-name drug, and marketplace Provider behavior Percentage (#) of visits competition driving down the cost). It’s important to emphasize, however, Physician asks about a glaucoma medication problem 1.4 (4) that the patient should always check Physician proposes a solution to a potential glaucoma-related 17.9 (50) the prices to make sure the generic is cost problem actually less expensive; factors such as Physician recommends that patient work with pharmacist to 1.1 (3) shortages can alter prices. lower medication cost You should also point out that the Physician asks how much patient is paying for glaucoma 2.2 (6) generic may not be identical to the medications brand name drug, since only the active ingredient has to be the same. For that reason, you should advise generics for as little as $4 at Target independent pharmacies will have your patient to let you know in the and Walgreen’s. However, availability pretty good deals, especially for cash- unlikely case that any problem with may change from year to year. For paying patients. side effects arises. example, Walmart used to offer Additional online resources include timolol for $4, but it’s no longer on BlinkHealth, WeRx.org, SlashRx and Spell out options in your their list. several others. 3 prescription. The key here is — Buying a larger supply often — The type of pharmacy your to allow the patient access to the least lowers the per-day price. For example, patient buys from can make a differ- expensive form of the prescribed drug a 90-day supply may be less-expensive ence. Independent pharmacies may (when appropriate). When writing per day than a 30-day supply. (Of offer lower prices on brand-name the prescription, consider prescribing course, this requires a larger initial products, and sometimes will offer generics, or write “generic substitution outlay, but with an inexpensive a discount if the patient pays cash. OK” as a note to the pharmacy. generic that may not be a signifi cant On the other hand, for generics, Also, purchasing the components of issue for most patients. For example, the lowest prices may be at the combination medications separately generic timolol might cost $4 per large chains such as Target and may be less expensive for the patient. month, vs. $10 for a three-month Walgreen’s. Some pharmacies also Writing “OK to dispense separate supply.) One important caveat: Don’t offer prescription savings clubs you components if costs less” may help suggest buying a larger supply to save can join, although patients already on remind the patient to ask about this. money until your drug regimen for Medicare or Medicaid probably won’t (You should point out to the patient the patient has been settled. qualify. that this will eliminate some of the — Patients can compare prices by — The drug manufacturer may convenience of a combination drop, calling their local pharmacies, or by offer coupons, especially for newer especially since it’s important to wait doing a little research online. Some drugs. These may be a mixed blessing, fi ve or 10 minutes between drops to websites and apps compare local however, as the manufacturer may avoid washing out the fi rst drop with prices for you, although they may find other ways to retake some of the second.) not include every local source. One the discount by raising the co-pay or well-known option is GoodRx.com, changing coverage limits. Also, this Encourage the patient to shop which lists local prices, sometimes type of coupon may not be available 4 for the lowest price. Patients offering a free coupon that can be to patients already on Medicare or may not realize that medication prices printed out or sent to the patient’s Medicaid. can vary widely from pharmacy to phone. GoodRx claims that this can pharmacy, and even from day to day. result in cost savings up to 80 percent. Be willing to provide a writ- There are a number of strategies that (I called the local pharmacies in a 5 ten prescription. Although can help your patient find the best listing to see if the listed prices were most of us today simply send an price on glaucoma drugs: correct; they were not always accurate electronic prescription to the patient’s — Generics are sometimes less to the penny, but they were very pharmacy, some patients who are expensive at large chain stores. For close.) The drawback of GoodRx.com interested in shopping around for example, as I write this it’s possible is that is doesn’t include prices from the best price may need a written to purchase a 30-day supply of some local independent pharmacies. Often, prescription so they have something to

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0060_rp0619_gm60_rp0619_gm (1)(1) (1).indd(1).indd 6161 55/24/19/24/19 3:333:33 PMPM Glaucoma

REVIEW Management

Encourage your patient Per-day Glaucoma Drug Price Comparison* 8 to take advantage of pa- BB AA CAI PGA BB+CAI BB+AA Netarsudil LBN tient assistance programs. There $0.38 $0.97 $1.04 $1.62 $1.83 $5.29 $8.38 $12.53 are many programs designed to * Numbers from GoodRx.com. help patients afford their drug BB=beta blocker; AA=alpha agonist; CAI=carbonic anhydrase inhibitor; PGA=prostaglandin analogue; LBN=latanoprostene bunod. prescriptions. Some are national, some are state-sponsored and some fax (or scan) to show to the pharmacy. Here’s a hypothetical example: are regional or local. Suppose the benefits manager has There are a number of nationwide Warn patients to be careful negotiated a $15 co-pay for a supply nonprofit organizations, such as 6 about buying drops online. of a generic drug. The medicine in NeedyMeds, Partnership for Prescrip- Even some sources that have been question cost the pharmacy $2.05. If tion Assistance, RxAssist, RxHope “vetted” by supposedly reliable or- the patient pays the $15 co-pay, the and RxOutreach. For some patients, ganizations like PharmacyChecker. pharmacy might be reimbursed $7.22 including those for whom English is com and the Canadian International by the insurance company, resulting a second language, the paperwork Pharmacy Association (CIPA) have in a profi t of $5.17 for the pharmacy. involved in taking advantage of these been charged with misrepresenting The pharmacy benefits manager resources can be a challenge. RxHope the source of the drugs they sell. If claims the remaining $7.78. might be a good option for those your patients want to pursue this, they In contrast, the price for a cash sale patients, as it will help those patients should visit fda.gov/ForConsumers/ is set by the pharmacy. Since the drug complete the paperwork. NeedyMeds ConsumerUpdates/ucm048396.htm cost them $2.05, they could double also provides a list of programs that for advice from the federal govern- that to make a profi t, and the patient are able to help patients with the ment on how to ensure they’re pur- paying cash would be charged $4.10. paperwork. chasing their drugs from a reliable That’s a lot less than $15. Even if Many drug manufacturers also source. the pharmacy quadruples the cost have patient-assistance programs. to make a more substantial profit, I called up one drug manufacturer Encourage your patient to the patient would pay $8.20, still to see how this works. It became 7 talk to the pharmacist. In the substantially less than the $15 co-pay. clear that they don’t provide patient past, pharmacists were prohibited by How widespread is the phenom- advocates to help patients navigate law from discussing price options with enon of patients paying more than this process, but the customer service patients. That “gag order” has now necessary for their drugs? A 2018 representative I spoke to was pretty been lifted—although it’s still in place study conducted by Dana Goldman, helpful. until 2020 for patients on Medicare PhD, and colleagues looked at this More information about what the and Medicaid. question using Centers for Medicare drug companies have to offer can This is important, because the low- & Medicaid Services data from 9.5 be found online at medicare.gov/ est price, even in one pharmacy, is million prescriptions purchased in pharmaceutical-assistance-program/. not always the one patients expect. 2013.4 They found that 23 percent of Another strategy is to simply call the For example, the cash price of a drug the time, patients would have been drug manufacturer and ask about may actually be lower than the co-pay better off paying cash. The average drug cost assistance, or Google the charged by the insurance company— overpayment isn’t huge ($7.69), but name of the manufacturer along with meaning the patient would shell out that adds up over time. “patient assistance program.” less when buying the drug with cash Other findings from that study A particularly helpful resource for than by using his or her insurance. included that overpayment was more your patients is benefi tscheckup.org, (This is often the result of having a likely to occur with a generic than which is sponsored by the National “pharmacy benefi ts manager” at the with a brand name. (This makes Council on Aging. I like this resource insurance company who negotiates sense, given the lower price of most because it summarizes all kinds of co-pays and other details with the generic drugs.) However, the average benefits that are available for your pharmacy.) Most patients wouldn’t size of the overpayment was smaller patients, including benefits related expect the cash price to be cheaper, when generics were purchased. The to health care in general, income so they pay the co-pay without ques- total overpayments for drugs in their assistance, food and nutrition, housing tioning whether this is actually the data sample totaled $135 million for and utilities, tax relief, benefits for best deal. the year 2013. veterans and employment assistance.

62 | Review of Ophthalmology | June 2019

0060_rp0619_gm60_rp0619_gm (1)(1) (1).indd(1).indd 6262 55/24/19/24/19 3:333:33 PMPM Patient Pharmaceuticals: Financial Aid Resources eye-drop group (93 percent vs. 91.3 percent of visits); and no one in the Benefi tsCheckup.org benefi tscheckup.org/ SLT group required glaucoma surgery to lower IOP, while 11 patients in the BlinkHealth blinkhealth.com/ 855-979-8290 eye-drop group did. This is pretty How to Buy Medicines Safely compelling data. FDA From an Online Pharmacy 888-463-6332 GoodRX goodrx.com 855-268-2822 Passing It On Medicare Pharmaceutical medicare.gov/pharmaceutical- 800-633-4227 Assistance Program assistance-program/ Of course, sharing all of this with NeedyMeds needymeds.org/ 800-503-6897 patients during an examination might Partnership for Prescription take more time than a physician is Assistance pparx.org/ able to spend. An alternative would PharmacyChecker pharmacychecker.com/ 718-554-3067 be to make up a sheet summarizing all of the cost-saving suggestions that are RxAssist rxassist.org/ relevant, including whatever helpful RxHope rxhope.com/ organizations are based in your state and local area. Another possibility RxOutreach rxoutreach.org/ 888-796-1234 would be to provide patients with WeRx werx.org/ 408-638-9379 a copy of an article I wrote for the Brightfocus Foundation, which was written for patients rather than It asks for some basic demographic and ocular hypertension that was physicians, that summarizes this in- information, such as age bracket and conducted in the United Kingdom. formation. (You can find the article income level; then it tells you what In this trial, 356 subjects were ran- at brightfocus.org/glaucoma/article/ kind of benefi ts you can apply for. Of domized to laser, 362 to eye drops. top-10-tips-reducing-costs-your- course, it’s up to the patients to take The primary outcome was quality of glaucoma-medications.) advantage of the programs for which life, and surprisingly, they didn’t fi nd Given that the ongoing cost of they qualify. any statistically signifi cant difference glaucoma treatment can be a chal- between the groups. (You might have lenge for many of your patients, they’ll Consider performing SLT. expected that patients would have be grateful for your help. 9 We’ve already seen evidence complained about their eye drops, that selective laser trabeculoplasty compared to a single laser treatment.) Dr. Ou is an associate professor is an effective first-line treatment.5 However, this was confounded by of ophthalmology, co-director of the It’s also less expensive for the patient the fact that patients had individual glaucoma service and vice chair in most cases; the worldwide price target IOPs, so even if you had the for postgraduate education in the comparison of glaucoma medications laser, you might end up back on a drop Department of Ophthalmology at mentioned earlier3 found that bilat- if you didn’t quite reach the target. the UCSF School of Medicine in San eral laser trabeculoplasty is less ex- Furthermore, the quality-of-life in- Francisco.

pensive than a three-year supply struments used may not have been 1. Slota C et al. Patient-physician communication on medication of latanoprost in 71 percent of sensitive enough to detect treatment cost during glaucoma visits. Optom Vis Sci 2017;94:1095-1101. 2. Patel MR, Wheeler JR. Physician-patient communication on cost developing countries—including side effects related to this. and affordability in asthma care. Who wants to talk about it and the United States. Despite this data, Nevertheless, at 36 months, 74 per- who is actually doing it. Ann Am Thorac Soc 2014;11:10:1538-44. 3. Zhao PY, Rahmathullah R, Stagg BC, et al. A worldwide price old habits die hard. Most physicians, cent of the SLT group didn’t require comparison of glaucoma medications, laser trabeculoplasty, and especially in the United States, still drops to maintain target IOP, and over trabeculectomy surgery. JAMA Ophthalmol 2018;136:11:1271- 1279. start with medications fi rst. the three-year period of the study, 4. Van Nuys K, Joyce G, Ribero R, Goldman DP. Frequency and Recently, new evidence was pub- there was a 97-percent probability magnitude of co-payments exceeding prescription drug costs. JAMA 2018;319:10:1045-1047. lished that suggests that SLT can be that SLT as fi rst treatment was more 5. Waisbourd M, Katz LJ. Selective laser trabeculoplasty as a fi rst- line therapy: A review. Can J Ophthalmol 2014;49:6:519-22. as effective—or more effective—than cost-effective than starting with eye 6. Gazzard G, Konstantakopoulou E, Garway-Heath D, et starting treatment with medications.6 drops. Furthermore, eyes of patients al. Selective laser trabeculoplasty versus eye drops for fi rst-line treatment of ocular hypertension and glaucoma This data came from a multicenter in the SLT group were at the target (LiGHT): A multicentre randomised controlled trial. Lancet trial looking at patients with POAG IOP at more visits than patients in the 2019;393:10180:1505-1516.

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0060_rp0619_gm60_rp0619_gm (1)(1) (1).indd(1).indd 6363 55/24/19/24/19 3:333:33 PMPM Plastic Pointers

REVIEW Edited by Anna P. Murchison, MD, MPH

Silent Sinus Syndrome: Look Past the Eye How to detect and manage this rare condition, which can be associated with a range of symptoms. Ryan A. Rimmer, MD, Judd H. Fastenberg, MD, Marc R. Rosen, MD, Gurston G. Nyquist, MD, and Mindy R. Rabinowitz, MD, Philadelphia

ue to the close anatomic relation- Epidemiology hypoventilation of the maxillary sinus Dship between the orbit and para- due to obstruction of the ostiomeatal nasal sinuses, ophthalmologists must SSS is a sparsely reported entity, complex (OMC). In normally func- be cognizant of certain sinonasal dis- with only about 150 cases reported tioning sinuses, the OMC serves as eases that may present with ocular in the literature.3 However, increased a channel linking drainage from the manifestations. One such disease pro- awareness of the condition since its ini- frontal, anterior ethmoid and maxillary cess, silent sinus syndrome, is a pro- tial description, combined with more sinuses to the middle meatus. With gressive condition in which maxillary widespread use of computed tomog- obstruction, there is impaired drainage sinus pathology causes inferior dis- raphy (CT) imaging, has demonstrated of the sinuses. Over time, this blockage placement of the orbital fl oor, result- that the condition may be more com- may contribute to the resorption of ing in enophthalmos and hypoglobus. mon than previously thought.4 gases by capillaries within the closed The pathophysiology involves a nega- Most reported cases involve adults sinus walls, resulting in negative pres- tive pressure phenomenon within the during the fourth or fi fth decade of life, sure within the sinus. This pressure sinus leading to inward bowing of the although SSS has also been described leads to an inward bowing of the sinus sinus walls. As such, SSS is often re- in the pediatric population.5 There’s walls and subsequent atelectasis.1 ferred to as “chronic maxillary sinus no clear gender predilection. Howev- One limitation of this theory is that atelectasis.”1 er, for unknown reasons, the patient’s it doesn’t explain why most patients Since its initial report in the lit- right side is slightly more commonly with OMC obstruction don’t develop erature in 1994,2 our understanding involved.1,6 hypoventilation and, instead, develop of SSS has improved substantially. symptoms of acute or chronic sinusitis. Although the “silent” nomenclature Pathophysiology Several additional pathophysiologic initially referred to the subclinical na- mechanisms have therefore been pro- ture of sinus symptoms in affected Multiple theories have been pro- posed. These include the possibility patients, we now understand that pa- posed to explain the pathophysiology that a communication between the af- tients with SSS may present with a of SSS. Initially, it was suggested that fl icted sinus and the pterygopalatine range of different sinonasal or ocular congenital maxillary hypoplasia con- fossa may generate a negative pressure symptoms.1 tributed to enophthalmos; however, gradient during chewing.1 Further- This review will provide an over- this was disproven by cases of patients more, patients with SSS often develop view of our current understanding of with normal sinus anatomy on imaging thinning of the orbital fl oor, which con- the epidemiology, pathophysiology, who subsequently developed SSS.6 tributes to hypoglobus. At the same diagnosis and management of SSS. The prevailing theory now involves time, many patients with chronic max-

64 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

064_rp0619_plastics.indd 64 5/24/19 4:56 PM AB

Figure 1. CT scan of a patient with SSS. A) Coronal plane: Note the inferior displacement of the orbital fl oor (red arrowhead) and lateral displacement of the uncinate process (blue arrowhead) into an opacifi ed right maxillary sinus. B) Axial plane: Note the inward bowing of the right maxillary sinus walls (green arrowhead).

illary sinusitis may develop orbital fl oor diplopia due to hypoglobus muscle Additional findings on endoscopic thickening leading instead to proptosis. restriction range widely, but this is con- examination to support the diagnosis This contrast supports a theory that sidered to be an uncommon presen- of SSS include a lateralized uncinate there may be poorly understood cyto- tation.7 Other uncommon symptoms process and enlarged middle meatus kine-mediated alterations in resorptive include dental pain and dry eye, which due to atelectasis of the maxillary sinus. activity, sinus pressure and degree of may be attributed to lagophthalmos.1 Concomitant sinonasal infl ammation infl ammation that determine whether On physical exam, there may be hy- may also be present, including edema the disease presents with thickened or pertropia of the affl icted eye and malar and/or polypoid disease in the middle thinned orbital walls.1 depression. Asymmetric eyelid creases meatus. can result from dysfunction of the le- • Radiology. When considering Diagnosis vator palpebrae superioris, secondary SSS, radiologic evaluation is critical to hypoglobus. Patients may appear to for establishing a diagnosis, delineat- Following are the signs, symptoms have signs and symptoms consistent ing anatomy and planning treatment. and imaging results to look for when with ptosis; however this is commonly A CT scan of the orbit and sinuses is presented with a potential SSS patient. pseudoptosis due to enophthalmos and the gold standard for visualizing bony • Presentation. The classic presen- hypoglobus. In some cases, patients anatomy, although magnetic resonance tation of SSS involves painless enoph- may also exhibit pseudoretraction and imaging may also be adequate. thalmos and hypoglobus with subclini- lid lag as the oculomotor nerve fi res to Radiologic hallmarks of SSS include cal sinus disease. A patient series from balance the inferior mechanical pull, unilateral atelectasis of the maxillary 2004 reported enophthalmos in the which simultaneously activates the le- sinus with variable inward bowing of range of 2 to 6 mm (mean: 3.4 mm) vator muscle.1 the sinus walls, lateralized uncinate and hypoglobus in a range of 1 to 6 mm Importantly, consideration of sino- process that may be adhered to lamina (mean: 3.2 mm).4 nasal pathology shouldn’t be neglected papyracea, depression of orbital fl oor Symptom onset is generally consid- in the setting of enophthalmos and and obstruction of the OMC (Figure ered to be progressive. In a review of hypoglobus. Patients should be ques- 1). The maxillary sinus is most com- 84 published cases, the average du- tioned about symptoms of nasal ob- monly opacifi ed, but there are reports ration of symptoms prior to presen- struction, drainage, facial pressure or of SSS in patients with aerated sinuses.3 tation was 6.52 months. Despite this pain, as well as a history of sinusitis. • Differential diagnosis. While the trend, several reports of acute onset of Even if patients are asymptomatic, any classic symptoms of painless enoph- symptoms exist in the literature.4 clinical suspicion should prompt refer- thalmos and hypoglobus are suggestive In cases of severe hypoglobus, there ral to an otolaryngologist for compre- of SSS, they shouldn’t be considered may be constriction of the inferior hensive evaluation, including nasal ex- pathognomonic. A broad differential oblique muscle, leading to restriction amination. Septal deviation is common diagnosis may include infectious pro- of upgaze; however, this occurs in a in patients with SSS, and typically devi- cesses (e.g., chronic sinusitis, osteo- minority of cases.4 Rates of vertical ates to the ipsilateral side of disease.6 myelitis), malignancy, infl ammatory or

June 2019 | reviewofopthalmology.com | 65

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REVIEW Pointers

Table 1: Summary of Clinical and Radiologic Signs of SSS aluronic acid into the intraconal and extraconal space. Studies have shown CLINICAL RADIOLOGIC durable results for six months with this approach.10 Deep superior sulcus Inward bowing of sinus walls Hypoglobus Lateralized uncinate process In conclusion, SSS is an example Enophthalmos Depression of orbital fl oor of how sinonasal disease can manifest Pseudoptosis Obstruction of OMC with ocular symptoms. In patients with painless hypoglobus and enophthal- mos, a diagnosis of silent sinus syn- vasculitic diseases (pseudotumor, gran- to both improvement of the underly- drome should be suspected. A multi- ulomatosis with polyangiitis or sclero- ing disease process and resolution of disciplinary approach with referral to derma), trauma or iatrogenic causes the orbital symptoms.6,9 Studies have an otolaryngologist should be adopted. (e.g., surgery, external beam radiation). demonstrated bony remodeling of the Management involves functional en- Many of these listed alternatives may maxillary sinus walls following FESS doscopic sinus surgery to improve si- present with other clinical signs and with resolution of atelectasis, thicken- nus aeration, with or without orbital symptoms, which may predate the oc- ing of bone and decreased symptoms. fl oor reconstruction. ular symptoms and suggest something For patients with persistent enoph- other than SSS. A thorough history and thalmos or in patients with such severe Dr. Rimmer is a fourth year resident physical should be obtained to identify disease that complete recovery would in the Department of Otolaryngology- the most likely etiology and ensure ap- be unexpected with FESS alone, or- Head and Neck Surgery at Thomas propriate treatment.8 (A summary of bital fl oor reconstruction can be per- Jefferson University in Philadelphia. the clinical and radiologic characteris- formed. The timing of this step is con- Dr. Fastenberg is the Rhinology and tics of SSS is shown in Table 1, above.) troversial. Given that FESS alone may Endoscopic Skull Base Surgery fellow halt progression of ocular symptoms in the Department of Otolaryngology- Treatment over time, simultaneous reconstruc- Head and Neck Surgery at Jefferson. tion of the orbital floor may be un- Drs. Rosen, Nyquist and Rabinowitz Treatment of SSS involves two pri- necessary and cause overcorrection of are members of the Division of Rhi- mary goals: fi rst, to improve maxillary the deficit. Proponents of this strat- nology and Skull Base Surgery in the sinus drainage and relieve obstruction egy tout its reduced risk, noting that it Departments of Otolaryngology-Head in order to prevent disease progres- minimizes anesthesia and trips to the and Neck Surgery and Neurological sion; and, second, to restore normal or- operating room. Alternatively, orbital Surgery at Thomas Jefferson Univer- bital anatomy. These two goals may be reconstruction can be performed as sity Hospital. They have specialized accomplished simultaneously or sepa- a second-stage operation two to six training in the management of complex rately through a variety of techniques. months after FESS. This allows for diseases of the paranasal sinuses, me- Functional endoscopic sinus surgery any orbital changes associated with dial orbit and anterior cranial base. (FESS) performed by an otolaryngolo- FESS to occur, potentially avoiding 1. Pula JH, Mehta M. Silent sinus syndrome. Curr Opin Ophthalmol gist is the mainstay of treatment for overcorrection with orbital fl oor recon- 2014;25:6:480-484. 2. Soparker CN, et al. The silent sinus syndrome. A cause of SSS. At a minimum, it entails a maxil- struction. Furthermore, a two-stage spontaneous enophthalmos. Ophthalmology 1994;101:4:772-8. lary antrostomy that’s performed by approach prevents placement of an 3. Lee DS, Murr AH, et al. Silent sinus syndrome without opacifi cation of ipsilateral maxillary sinus. Laryngoscope 2018;128:2004-2007. completely removing the lateralized orbital fl oor implant into a potentially 4. Soparker CN, Patrinely JR, Davidson JK. Silent sinus syndrome— 1 New perspectives? Ophthalmology 2004;111:2:414-415. uncinate process and widely opening infected sinus cavity. 5. Chang DT, Truong MT. A child with silent sinus syndrome and spontaneous improvement after sinus surgery. Int J Pediatr the natural sinus ostium. This proce- Options for surgical fl oor implants Otorhinolaryngol 2014;78:1993-1995. dure promotes improved sinus drain- include alloplastic implants (e.g., ti- 6. Martinez-Capoccioni G, Varela-Martinez E, Martin-Martin C. Silent sinus syndrome an acquired condition and the essential role age and improves aeration. Important- tanium, hydroxyapetite, silicone, ny- of otorhinolaryngologist consultation: A retrospective study. Eur Arch Otorhinolaryngol 2016;273:3183-88. ly, because in SSS the uncinate process lon) or autogenous (e.g., septal or 7. Gomez J, Liu D, Palacios E, Nguyen J. Diplopia: An uncommon is lateralized and the orbital fl oor may costochondral cartilage, calvarial bone presentation of silent sinus syndrome. Ear Nose Throat J 2015;94:7:258-60. be lowered, there’s an increased risk grafts). Implants are typically placed 8. Numa WA et al. Silent sinus syndrome: A case presentation and comprehensive review of all 84 reported cases. Ann Otol Rhinol of orbital injury when a maxillary an- via a transconjunctival or subciliary Laryngol 2005;114:9:688-94. 9. Kram YA, Pletcher SD. Maxillary sinus posterior wall remodeling trostomy is performed. Appropriate approach and fi xated to the orbital rim following surgery for silent sinus syndrome. Am J Otolaryngol preoperative consideration of this for stability.1 Alternatively, a nonsur- 2014;35:623–625. 10. Mavrikakis I, Detorakis ET, Yiotakis I, Kandiloros D. Nonsurgical anatomy is critical. gical option for treatment of enoph- management of silent sinus syndrome with hyaluronic acid gel. In some cases, FESS alone may lead thalmos after FESS is injection of hy- Ophthal Plast Reconstr Surg 2012;28:e6–e7.

66 | Review of Ophthalmology | June 2019

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68 | Review of Ophthalmology | June 2019 This article has no commercial sponsorship.

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70 | Review of Ophthalmology | June 2019

ROPH0619.indd 70 5/15/19 8:34 PM 071_rp0619_wills.indd 71 What isyourdiagnosis? furtherworkupwouldyoupursue?Thediagnosis appearsonp. 72 remainder ofthefundusexamwasunremarkable. tion, theopticnervesshowedacup-to-discratioof0.8and0.7ODOS,respectively, withsuperiornotchingOU.The mildly vascularblebandaposteriorchamberintraocularlensOD,nuclearscleroticcataractOS.Onfundusexamina- work pigmentationOU.Confrontationvisualfi elds were normal.Slitlampexaminationrevealedadiffuse,slightlyelevated, 512 µm,respectively. TheanglewasopenongonioscopywithaSpaethclassifi cation ofC35f,with lighttrabecularmesh- were normal.Intraocularpressures12mmHgODand21OSwithcentralcornealthicknessesof509 Examination bimatoprost. Familyandsocialhistorieswerenon-contributory. and timolol0.5%twotimesaday, inthelefteyeonly. Hewasintoleranttobrimonidine,brinzolamide,dorzolamideand right eye,inadditiontomixedmechanismglaucoma,asnotedabove.Currentmedicationswerelatanoprost0.005%nightly Medical History uveitis, infectionwithherpessimplexorzoster, orsteroiduse. mechanism glaucomainbotheyes;hehadundergoneatrabeculectomytherighteye.Henohistoryofoculartrauma, without anysymptoms.Hehadpreviouslyundergonebilaterallaserperipheraliridotomiesandbeendiagnosedwithmixed Presentation Ranjodh S. Boparai, MD, andMichael J. Pro, MD uncontrolled IOPinhislefteye. A 68-year-old with EyeGlaucomaService manpresentstotheWills

On exam, visual acuity was 20/60 OD and 20/40 OS with no improvement on pinhole. Pupils and extraocular motility On exam,visualacuitywas20/60ODand20/40OSwithnoimprovementonpinhole.Pupilsextraocularmotility There wasnopastmedicalhistory. Thepastocularhistoryincludedlatticecornealdystrophyandcataractsurgeryinthe A 68-year-old malepresentedtotheWills EyeGlaucomaServicewithanelevatedintraocularpressureinhislefteye REVIEW Wills Eye Wills Eye Resident CaseSeries Edited byJasonFlamendorf, MD June 2019 | reviewofophthalmology.com |

71 5/24/19 2:54 PM Resident Case Series REVIEW

Workup, Diagnosis and Treatment

Octopus visual fi elds showed dense inferior arcuate de- cided to proceed with cataract surgery combined with a fects OU with evidence of progression OS (Figure 1). XEN Gel Stent (Allergan). OCT of the retinal nerve fi ber layer showed corresponding The patient underwent an uncomplicated surgery, and superior thinning OU. Given progression of his glaucoma at his one-month postoperative visit, his IOP OS was 14 in the left eye in the presence of maximally tolerated medi- mmHg, and he was taken off all glaucoma medications. At cal therapy, it was recommended that the patient have a his three-month visit, the IOP was stable. At six months, surgical intervention to lower his IOP. He didn’t want to however, the IOP in his left eye had increased to 23 mmHg, undergo a trabeculectomy due to the complications he with notable fibrosis over the XEN Gel Stent. He was experienced OD, including pain, redness and a lengthy restarted on latanoprost and timolol OS. He subsequently recovery. Since he had a visually signifi cant cataract, mini- underwent surgical XEN revision (Figure 2). At his most mally-invasive glaucoma surgery options were considered recent follow-up visits, the IOP was in the low teens, he was in conjunction with cataract surgery, and the patient de- off all drops and had stable defects on visual fi eld testing.

Figure 1. Octopus visual fi elds of the right and left eyes showing Figure 2. Representative images from the reoperation to revise the bilateral dense inferior arcuate defects. fi brotic XEN Gel Stent.

Discussion

MIGS devices can be divided into: junctival MIGS device made with implantation include hypotony (9 to 1) trabecular, which increase outfl ow gelatin crosslinked with glutaralde- 35 percent), flat anterior chamber through Schlemm’s canal; 2) supra- hyde. The XEN has a length of 6 mm requiring refi lling (5 to 10 percent), choroidal, which improve uveoscleral with an internal diameter of 45 µm bleb needling (2 to 43 percent), and outflow via a connection between and an outer diameter of 150 µm.4,5 reoperation (3 to 15 percent).2,4,7-11 the anterior chamber and the supra- Multiple prospective and retrospec- Most cases of hypotony occur early choroidal space; and 3) subconjunc- tive studies have assessed outcomes in the postoperative period and re- tival, which allow for an alternative in patients with XEN implants.2,6-9 solve spontaneously with conserva- pathway of aqueous fl ow to the sub- The average IOP reduction after tive management. Other less-com- conjunctival space.1,2 Multiple non- XEN placement ranges from 30 to mon complications include corneal randomized studies show that MIGS 45 percent. Topical drop class reduc- edema, choroidal folds, choroidal de- devices have better safety profiles tion ranges from 85 to 95 percent, tachment, and device extrusion, mi- and faster recovery than traditional with 40 to 90 percent of patients off gration or obstruction.2,4,7-11 In our incisional glaucoma surgeries, likely all drops.2,6-9 In our patient, the IOP patient, XEN placement was com- due to reduced surgical trauma with reduction at postoperative month plicated by fi brosis, likely leading to minimal scleral and conjunctival dis- one was 33 percent, which is similar device obstruction, requiring surgi- section.3 to the reported literature. cal revision with a good eventual out- The XEN Gel Stent is a subcon- Common complications after XEN come. In comparison to other MIGS

72 | Review of Ophthalmology | June 2019

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REVIEW Index

Akorn Consumer Health 49 devices, including iStent and iStent Inject (Glaukos), Phone (800) 579-8327 Hydrus (Ivantis), InnFocus MicroShunt (Santen Phar- www.akornconsumerhealth.com maceutical Company) and the recently withdrawn Cy- Alcon Laboratories 2 Pass (Alcon), the XEN carries a comparable IOP low- Phone (800) 451-3937 ering effect and topical drop reduction, with a slightly Fax (817) 551-4352 higher needling rate but comparable rate of reopera- Bausch + Lomb 7, 8, 39 tion.1,3,12-14 In comparison to trabeculectomy, XEN has Phone (800) 323-0000 a better side-effect profi le, while approaching a similar Fax (813) 975-7762 IOP-lowering effi cacy.15 Eyevance Pharmaceuticals 5, 45 Phone (817) 677-6120 In conclusion, MIGS devices have become an increas- eyevance.com ingly utilized alternative to traditional incisional glau- coma surgeries, especially in conjunction with cataract Focus Laboratories, Inc. 31 Phone (866) 752-6006 surgery or in the setting of glaucoma progression on Fax (501) 753-6021 maximum medical therapy. MIGS selection is key to www.focuslaboratories.com

achieving the desired target IOP, with disease severity Glaukos 11 and mechanism of glaucoma as two important factors. Phone (800) 452-8567 Although their safety profi le is markedly better than tra- www.glaukos.com beculectomy or tube shunt surgery, MIGS devices aren’t Imprimis Pharmaceuticals, Inc. 29 without complications, as demonstrated in our patient. Phone (858) 704-4040 Fax (858) 345-1745 Nevertheless, MIGS represents an exciting innovation www.imprimispharma.com in the fi eld of glaucoma and a potential pathway towards Ivantis, Inc. 19, 20 safer, yet still effective, surgeries. [email protected] www.ivantisinc.com

The authors have no fi nancial interest in any products Keeler Instruments 15 discussed in the case. Phone (800) 523-5620 Fax (610) 353-7814 1. Kerr NM, Wang J, Barton K. Minimally invasive glaucoma surgery as primary stand-alone Lacrimedics, Inc 41 surgery for glaucoma. Clin Experiment Ophthalmol 2017;45:4:393-400. Phone (800) 367-8327 2. Schlenker MB, Gulamhusein H, Conrad-Hengerer I, et al. Effi cacy, safety, and risk factors for Fax (253) 964-2699 failure of standalone ab interno gelatin microstent implantation versus standalone trabeculectomy. [email protected] Ophthalmology 2017;124:11:1579-1588. 3. Chen DZ, Sng CCA. Safety and effi cacy of microinvasive glaucoma surgery. J Ophthalmol www.lacrimedics.com 2017;2017:3182935. 4. Chaudhary A, Salinas L, Guidotti J, Mermoud A, Mansouri K. XEN Gel Implant: A new surgical Lombart Instruments 33 approach in glaucoma. Expert Rev Med Devices 2018;15:1:47-59. Phone (800) 446-8092 5. De Gregorio A, Pedrotti E, Stevan G, Bertoncello A, Morselli S. XEN glaucoma treatment system Fax (757) 855-1232 in the management of refractory glaucomas: A short review on trial data and potential role in clini- cal practice. Clin Ophthalmol 2018;12:773-782. NuSight Medical Operations 51 6. Hohberger B, Welge-Lussen UC, Lammer R. MIGS: Therapeutic success of combined XEN Gel Phone (833) 468-5437 Stent implantation with cataract surgery. Graefes Arch Clin Exp Ophthalmol 2018;256:3:621-625. www.NuSightMedical.com 7. De Gregorio A, Pedrotti E, Russo L, Morselli S. Minimally invasive combined glaucoma and cataract surgery: Clinical results of the smallest ab interno gel stent. International ophthalmology Reichert Technologies 22-23 2018;38:3:1129-1134. Phone (888) 849-8955 8. Galal A, Bilgic A, Eltanamly R, Osman A. XEN glaucoma implant with mitomycin C 1-year follow- Fax (716) 686-4545 up: Result and complications. J Ophthalmol 2017;2017:5457246. www.reichert.com 9. Grover DS, Flynn WJ, Bashford KP, et al. Performance and safety of a new ab interno gelatin stent in refractory glaucoma at 12 months. Amer J Ophthalmol 2017;183:25-36. S4OPTIK 55, 57 10. Olate-Perez A, Perez-Torregrosa VT, Gargallo-Benedicto A, et al. Prospective study of fi ltering Phone (888) 224-6012 blebs after XEN45 surgery. Archivos de la Sociedad Espanola de Oftalmologia 2017;92:8:366-371. 11. Perez-Torregrosa VT, Olate-Perez A, Cerda-Ibanez M, et al. Combined phacoemulsifi cation and Santen Inc. USA 17 XEN45 surgery from a temporal approach and two incisions. Archivos de la Sociedad Espanola de Phone (415) 268-9100 Oftalmologia 2016;91:9:415-421. Fax (510) 655-5682 12. Agrawal P, Bradshaw SE. Systematic literature review of clinical and economic outcomes of www.santeninc.com micro-invasive glaucoma surgery (MIGS) in primary open-angle glaucoma. Ophthalmology and Therapy 2018;7:1:49-73. Shire Ophthalmics 75, 76 13. Ansari E. An update on implants for minimally invasive glaucoma surgery (MIGS). Ophthalmol- www.shire.com ogy and Therapy 2017;6:2:233-241. 14. Yook E, Vinod K, Panarelli JF. Complications of micro-invasive glaucoma surgery. Curr Opin This advertiser index is published as a convenience and not as part of Ophthalmol 2018;29:2:147-154. the advertising contract. Every care will be taken to index correctly. No 15. Gedde SJ, Herndon LW, Brandt JD, et al. Postoperative complications in the Tube Versus allowance will be made for errors due to spelling, incorrect page number, or Trabeculectomy (TVT) study during fi ve years of follow-up. Amer J Ophthalmol 2012;153:5:804- failure to insert. 814 e801.

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0071_rp0619_wills.indd71_rp0619_wills.indd 7733 55/24/19/24/19 3:003:00 PMPM The Rick Bay Foundation for Excellence in Eyecare Education www.rickbayfoundation.org Support the Education of Future Healthcare & Eyecare Professionals

About Rick Scholarships are awarded to advance the education Rick Bay served as the publisher of students in both Optometry and Ophthalmology, of The Review Group for more than 20 years. and are chosen by their school based on qualities that embody Rick’s commitment to the profession, including To those who worked for him, he was integrity, compassion, partnership and dedication to the a leader whose essence was based greater good. in a fi erce and boundless loyalty. Interested in being a partner with us?

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2015_rickbay_housead.indd 1 7/5/17 3:00 PM VGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV the recommended human ophthalmic dose [RHOD], based on VJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEGJWOCPU[UVGOKE GZRQUWTGVQNKƂVGITCUVHQNNQYKPIQEWNCTCFOKPKUVTCVKQPQH:KKFTC Rx Only CVVJG4*1&KUNQYVJGCRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJG risk of Xiidra use in humans during pregnancy is unclear. Animal Data BRIEF SUMMARY: .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8 KPLGEVKQP Consult the Full Prescribing Information for complete product VQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ECWUGF information. an increase in mean preimplantation loss and an increased INDICATIONS AND USAGE KPEKFGPEGQHUGXGTCNOKPQTUMGNGVCNCPQOCNKGUCVOIMI Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG FC[TGRTGUGPVKPIHQNFVJGJWOCPRNCUOCGZRQUWTGCV VTGCVOGPVQHVJGUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  the RHOD of Xiidra, based on AUC. No teratogenicity was QDUGTXGFKPVJGTCVCVOIMIFC[ HQNFVJGJWOCP DOSAGE AND ADMINISTRATION RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% +PVJGTCDDKV Instill one drop of Xiidra twice daily (approximately 12 hours an increased incidence of omphalocele was observed at the CRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT&KUECTF NQYGUVFQUGVGUVGFOIMIFC[ HQNFVJGJWOCPRNCUOC VJGUKPINGWUGEQPVCKPGTKOOGFKCVGN[CHVGTWUKPIKPGCEJG[G GZRQUWTGCVVJG4*1&DCUGFQP#7% YJGPCFOKPKUVGTGFD[ Contact lenses should be removed prior to the administration +8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[UVJTQWIJ#HGVCN0Q QH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPI 1DUGTXGF#FXGTUG'HHGEV.GXGN 01#'. YCUPQVKFGPVKƂGFKP administration. the rabbit. CONTRAINDICATIONS Lactation 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Xiidra is contraindicated in patients with known hypersensitivity VQNKƂVGITCUVQTVQCP[QHVJGQVJGTKPITGFKGPVUKPVJG milk, the effects on the breastfed infant, or the effects on milk RTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUVHTQO formulation. ocular administration is low. The developmental and health ADVERSE REACTIONS DGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGFCNQPIYKVJ Clinical Trials Experience the mother’s clinical need for Xiidra and any potential adverse Because clinical studies are conducted under widely varying effects on the breastfed child from Xiidra. conditions, adverse reaction rates observed in clinical studies Pediatric Use of a drug cannot be directly compared to rates in the clinical 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH VTKCNUQHCPQVJGTFTWICPFOC[PQVTGƃGEVVJGTCVGUQDUGTXGF years have not been established. KPRTCEVKEG+PƂXGENKPKECNUVWFKGUQHFT[G[GFKUGCUGEQPFWEVGF YKVJNKƂVGITCUVQRJVJCNOKEUQNWVKQPRCVKGPVUTGEGKXGFCV Geriatric Use NGCUVFQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV  No overall differences in safety or effectiveness have been 6JGOCLQTKV[QHRCVKGPVU  JCFŰOQPVJUQHVTGCVOGPV observed between elderly and younger adult patients. GZRQUWTGRCVKGPVUYGTGGZRQUGFVQNKƂVGITCUVHQT NONCLINICAL TOXICOLOGY approximately 12 months. The majority of the treated patients Carcinogenesis, Mutagenesis, Impairment of Fertility YGTGHGOCNG  6JGOQUVEQOOQPCFXGTUGTGCEVKQPU Carcinogenesis: Animal studies have not been conducted TGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQP VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV dysgeusia and reduced visual acuity. Other adverse reactions Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro TGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQP #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo conjunctival hyperemia, eye irritation, headache, increased mouse micronucleus assay. In an in vitro chromosomal lacrimation, eye discharge, eye discomfort, eye pruritus and aberration assay using mammalian cells (Chinese sinusitis. JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV Postmarketing Experience concentration tested, without metabolic activation. 6JGHQNNQYKPICFXGTUGTGCEVKQPUJCXGDGGPKFGPVKƂGFFWTKPI Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV postapproval use of Xiidra. Because these reactions are KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ reported voluntarily from a population of uncertain size, it is not HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG always possible to reliably estimate their frequency or establish TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH a causal relationship to drug exposure. NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP Rare cases of hypersensitivity, including anaphylactic reaction, fertility and reproductive performance in male and bronchospasm, respiratory distress, pharyngeal edema, swollen female treated rats. tongue, and urticaria have been reported. Eye swelling and rash have been reported. USE IN SPECIFIC POPULATIONS Pregnancy /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# There are no available data on Xiidra use in pregnant women to (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN KPHQTOCP[FTWICUUQEKCVGFTKUMU+PVTCXGPQWU +8 CFOKPKUVTCVKQP Marks designated ®CPFvCTGQYPGFD[5JKTGQTCPCHƂNKCVGFEQORCP[ QHNKƂVGITCUVVQRTGIPCPVTCVUHTQORTGOCVKPIVJTQWIJ 5JKTG75+PE5*+4'CPFVJG5JKTG.QIQCTGVTCFGOCTMUQT IGUVCVKQPFC[FKFPQVRTQFWEGVGTCVQIGPKEKV[CVENKPKECNN[ TGIKUVGTGFVTCFGOCTMUQH5JKTG2JCTOCEGWVKECN*QNFKPIU+TGNCPF relevant systemic exposures. Intravenous administration of .KOKVGFQTKVUCHƂNKCVGU NKƂVGITCUVVQRTGIPCPVTCDDKVUFWTKPIQTICPQIGPGUKURTQFWEGF Patented: please see JVVRUYYYUJKTGEQONGICNPQVKEGRTQFWEVRCVGPVU an increased incidence of omphalocele at the lowest dose .CUV/QFKƂGF5

RRP0619_ShireP0619_Shire PI.inddPI.indd 1 55/15/19/15/19 9:409:40 AMAM THERE’S NO SWIITCHING THIS Xiidra is the only lymphocyte function-associated antigen-1 (LFA-1) antagonist treatment for Dry Eye Disease1,2

8ˆˆ`À>]Ì iwÀÃ̈˜>V>ÃÃœvƂ‡£>˜Ì>}œ˜ˆÃÌà Indication vœÀ ÀÞ Þi ˆÃi>Ãi]ˆÃ>«ÀiÃVÀˆ«Ìˆœ˜iÞi Xiidra® NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQTVJG `Àœ« Ƃ‡>««ÀœÛi`̜ÌÀi>ÌLœÌ È}˜Ã VTGCVOGPVQHUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  >˜`Ãޓ«Ìœ“ÃœvÌ i`ˆÃi>Ãi°£]Î Important Safety Information :KKFTCKUEQPVTCKPFKECVGFKPRCVKGPVUYKVJMPQYP J[RGTUGPUKVKXKV[VQNKƂVGITCUVQTVQCP[QHVJGQVJGT KPITGFKGPVU 2,4 There’s no substitute. +PENKPKECNVTKCNUVJGOQUVEQOOQPCFXGTUGTGCEVKQPU Check out patient resources, TGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVGKTTKVCVKQP F[UIGWUKCCPFTGFWEGFXKUWCNCEWKV[1VJGTCFXGTUG insurance coverage, and TGCEVKQPUTGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGF XKUKQPEQPLWPEVKXCNJ[RGTGOKCG[GKTTKVCVKQPJGCFCEJG more at Xiidra-ECP.com KPETGCUGFNCETKOCVKQPG[GFKUEJCTIGG[GFKUEQOHQTVG[G RTWTKVWUCPFUKPWUKVKU 6QCXQKFVJGRQVGPVKCNHQTG[GKPLWT[QTEQPVCOKPCVKQPQHVJG References: UQNWVKQPRCVKGPVUUJQWNFPQVVQWEJVJGVKRQHVJGUKPINGWUG 1. :KKFTC=2TGUETKDKPI+PHQTOCVKQP?.GZKPIVQP/#5JKTG75 2.6(15&'95++4GUGCTEJ5WDEQOOKVVGG4GRQTVQHVJG4GUGCTEJ EQPVCKPGTVQVJGKTG[GQTVQCP[UWTHCEG 5WDEQOOKVVGGQHVJG6GCT(KNO1EWNCT5WTHCEG5QEKGV[&T['[G 9QTM5JQR++  Ocul Surf  3.(&#CRRTQXGU %QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQVJG PGYOGFKECVKQPHQTFT[G[GFKUGCUG(&#0GYU4GNGCUG,WN[ CFOKPKUVTCVKQPQH:KKFTCCPFOC[DGTGKPUGTVGFOKPWVGU JVVRYYYHFCIQXPGYUGXGPVUPGYUTQQORTGUUCPPQWPEGOGPVU WEOJVO#EEGUUGF,WN[4.(QQFCPF&TWI HQNNQYKPICFOKPKUVTCVKQP #FOKPKUVTCVKQP'NGEVTQPKE1TCPIG$QQMJVVRYYYHFCIQX FQYPNQCFU&TWIU&GXGNQROGPV#RRTQXCN2TQEGUU7%/RFH 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH #EEGUUGF,WPG [GCTUJCXGPQVDGGPGUVCDNKUJGF

For additional safety information, see accompanying Brief Summary of Safety Information on the adjacent page and Full Prescribing Information on Xiidra-ECP.com.

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