Using Unavailable and Off-Label Meds: Getting Tougher? the Lengths Physicians Will Go to in Order to Save Patients’ Vision

HELP FOR ADMINISTERING DROPS P. 14 • IDIOPATHIC INTRACRANIAL HYPERTENSION IN KIDS P. 40 NEUROIMAGING THE GLAUCOMA PATIENT P. 44 • BE PREPARED FOR OCULAR TRAUMA P. 50

Review of Ophthalmology Vol. XXIV, for Patients Unavailable Cross-linking at One Year Drugs 2017 • Getting • Corneal No. 9 • September Ulcers • How to Manage Corneal PROS AND CONS OF HEADS-UP SURGERY P. 53 • ALTERNATIVE BROW-LIFTING TECHNIQUES P. 56

SeptemberSeptember 20172017

reviewofophthalmology.comreviewofophthalmology.com

ANNUAL CORNEA ISSUE Using Unavailable and Off-label Meds: Getting Tougher? The lengths physicians will go to in order to save patients’ vision. Page 18 ?

ALSO INSIDE:

➤ Cross-linking at One Year: How Surgeons Are Using It P. 23 ➤ Work Up Corneal Ulcers Like an Expert P. 30 ➤ How to Diagnose and Manage Conjunctivochalasis P. 36

001_rp0817_fc.indd 1 8/25/17 3:47 PM The FIRST and ONLY NSAID indicated to prevent ocular pain in cataract surgery patients1 A DROP OF PREVENTION FOR YOUR CATARACT SURGERY PATIENTS

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Indications and Usage BromSite® (bromfenac ophthalmic solution) 0.075% is a for corneal health. Patients with complicated ocular surgeries, nonsteroidal anti-infl ammatory drug (NSAID) indicated for the corneal denervation, corneal epithelial defects, diabetes mellitus, treatment of postoperative infl ammation and prevention of ocular ocular surface diseases (e.g., dry eye syndrome), rheumatoid pain in patients undergoing cataract surgery. arthritis, or repeat ocular surgeries within a short period of time Recommended Dosing may be at increased risk for corneal adverse events which may ® become sight threatening. Topical NSAIDs should be used with One drop of BromSite should be applied to the affected eye caution in these patients. Post-marketing experience with topical twice daily (morning and evening) 1 day prior to surgery, the day NSAIDs also suggests that use more than 24 hours prior to of surgery, and 14 days postsurgery. surgery or use beyond 14 days postsurgery may increase patient Important Safety Information risk for the occurrence and severity of corneal adverse events. • Slow or Delayed Healing: All topical nonsteroidal anti- • Contact Lens Wear: BromSite® should not be administered infl ammatory drugs (NSAIDs), including BromSite®, may slow or while wearing contact lenses. The preservative in BromSite®, delay healing. Topical corticosteroids are also known to slow or benzalkonium chloride, may be absorbed by soft contact lenses. delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. • Adverse Reactions: The most commonly reported adverse reactions in 1% to 8% of patients were anterior chamber • Potential for Cross-Sensitivity: There is the potential for infl ammation, headache, vitreous fl oaters, iritis, eye pain, and cross-sensitivity to acetylsalicylic acid, phenylacetic acid ocular hypertension. derivatives, and other NSAIDs, including BromSite®. Therefore, caution should be used when treating individuals who have Please see brief summary of Full Prescribing Information previously exhibited sensitivities to these drugs. on the adjacent page. • Increased Bleeding Time of Ocular Tissue: With some NSAID=nonsteroidal anti-infl ammatory drug. NSAIDs, including BromSite®, there exists the potential for increased bleeding time due to interference with platelet References: 1. BromSite® [package insert]. Cranbury, NJ: Sun Pharmaceutical Industries, Inc.; 2016. 2. Hosseini K, Hutcheson J, Bowman L. Aqueous humor aggregation. There have been reports that ocularly applied concentration of bromfenac 0.09% (Bromday™) compared with bromfenac in NSAIDs may cause increased bleeding of ocular tissues DuraSite® 0.075% (BromSite™) in cataract patients undergoing phacoemulsifi cation (including hyphemas) in conjunction with ocular surgery. It is after 3 days dosing. Poster presented at: ARVO Annual Meeting; May 5-9, ® 2013; Seattle, Washington. 3. ClinicalTrials.gov. Aqueous humor concentration recommended that BromSite be used with caution in patients of InSite Vision (ISV) 303 (bromfenac in DuraSite) to Bromday once daily with known bleeding tendencies or who are receiving other (QD) prior to cataract surgery. https://clinicaltrials.gov/ct2/show/results/ medications which may prolong bleeding time. NCT01387464?sect=X70156&term=insite+vision&rank=1. Accessed March 2, 2017. 4. Si EC, Bowman LM, Hosseini K. Pharmacokinetic comparisons of bromfenac in • Keratitis and Corneal Effects: Use of topical NSAIDs may DuraSite and Xibrom. J Ocul Pharmacol Ther. 2011;27(1):61-66. 5. Bowman LM, Si E, Pang J, et al. Development of a topical polymeric mucoadhesive ocular result in keratitis. In some susceptible patients, continued J Ocul Pharmacol Ther use of topical NSAIDs may result in epithelial breakdown, delivery system for azithromycin. . 2009;25(2):133-139. corneal thinning, corneal erosion, corneal ulceration or corneal perforation. Patients with evidence of corneal epithelial Sun Ophthalmics is a division of Sun Pharmaceutical Industries, Inc. © 2017 Sun Pharmaceutical Industries, Inc. All rights reserved. breakdown should immediately discontinue use of topical BromSite and DuraSite are registered trademarks of Sun NSAIDs, including BromSite®, and should be closely monitored Pharma Global FZE. SUN-OPH-BRO-217 03/2017

RO0617_Sun.indd 1 5/25/17 12:44 PM BromSite® (bromfenac ophthalmic solution) 0.075% Brief Summary

INDICATIONS AND USAGE USE IN SPECIFIC POPULATIONS BromSite® (bromfenac ophthalmic solution) 0.075% is indicated for the Pregnancy treatment of postoperative inflammation and prevention of ocular pain in Risk Summary patients undergoing cataract surgery. There are no adequate and well-controlled studies in pregnant women to inform any drug associated risks. Treatment of pregnant rats and rabbits with oral CONTRAINDICATIONS bromfenac did not produce teratogenic effects at clinically relevant doses. None Clinical Considerations WARNINGS AND PRECAUTIONS Because of the known effects of prostaglandin biosynthesis-inhibiting drugs Slow or Delayed Healing on the fetal cardiovascular system (closure of ductus arteriosus), the use of All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including BromSite® during late pregnancy should be avoided. BromSite® (bromfenac ophthalmic solution) 0.075%, may slow or delay healing. Topical corticosteroids are also known to slow or delay healing. Data Animal Data Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems. Treatment of rats with bromfenac at oral doses up to 0.9 mg/kg/day (195 times a unilateral daily human ophthalmic dose on a mg/m2 basis, assuming 100% Potential for Cross-Sensitivity absorbed) and rabbits at oral doses up to 7.5 mg/kg/day (3243 times a unilateral There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic daily dose on a mg/m2 basis) produced no structural teratogenicity in reproduction ® acid derivatives, and other NSAIDs, including BromSite (bromfenac ophthalmic studies. However, embryo-fetal lethality, neonatal mortality and reduced postnatal solution) 0.075%. Therefore, caution should be used when treating individuals growth were produced in rats at 0.9 mg/kg/day, and embryo-fetal lethality was who have previously exhibited sensitivities to these drugs. produced in rabbits at 7.5 mg/kg/day. Because animal reproduction studies Increased Bleeding Time of Ocular Tissue are not always predictive of human response, this drug should be used during With some NSAIDs, including BromSite® (bromfenac ophthalmic solution) pregnancy only if the potential benefit justifies the potential risk to the fetus. 0.075%, there exists the potential for increased bleeding time due to Lactation interference with platelet aggregation. There have been reports that There are no data on the presence of bromfenac in human milk, the effects on the ocularly applied NSAIDs may cause increased bleeding of ocular tissues breastfed infant, or the effects on milk production; however, systemic exposure (including hyphemas) in conjunction with ocular surgery. to bromfenac from ocular administration is low. The developmental and health It is recommended that BromSite® be used with caution in patients with benefits of breastfeeding should be considered along with the mother’s clinical known bleeding tendencies or who are receiving other medications which need for bromfenac and any potential adverse effects on the breast-fed child from may prolong bleeding time. bromfenac or from the underlying maternal condition. Keratitis and Corneal Reactions Pediatric Use Use of topical NSAIDs may result in keratitis. In some susceptible patients, Safety and efficacy in pediatric patients below the age of 18 years have not continued use of topical NSAIDs may result in epithelial breakdown, corneal been established. thinning, corneal erosion, corneal ulceration or corneal perforation. These Geriatric Use events may be sight threatening. Patients with evidence of corneal epithelial There is no evidence that the efficacy or safety profiles for BromSite® differ in breakdown should immediately discontinue use of topical NSAIDs, including patients 65 years of age and older compared to younger adult patients. BromSite® (bromfenac ophthalmic solution) 0.075%, and should be closely monitored for corneal health. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis and Impairment of Fertility Post-marketing experience with topical NSAIDs suggests that patients with Long-term carcinogenicity studies in rats and mice given oral doses of bromfenac complicated ocular surgeries, corneal denervation, corneal epithelial defects, up to 0.6 mg/kg/day (129 times a unilateral daily dose assuming 100% absorbed, diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid on a mg/m2 basis) and 5 mg/kg/day (540 times a unilateral daily dose on a mg/m2 arthritis, or repeat ocular surgeries within a short period of time may be at basis), respectively revealed no significant increases in tumor incidence. increased risk for corneal adverse events which may become sight threatening. Topical NSAIDs should be used with caution in these patients. Bromfenac did not show mutagenic potential in various mutagenicity studies, including the bacterial reverse mutation, chromosomal aberration, and Post-marketing experience with topical NSAIDs also suggests that use more micronucleus tests. than 24 hours prior to surgery or use beyond 14 days postsurgery may increase patient risk for the occurrence and severity of corneal adverse events. Bromfenac did not impair fertility when administered orally to male and female rats at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, respectively (195 and Contact Lens Wear 65 times a unilateral daily dose, respectively, on a mg/m2 basis). BromSite® should not be administered while wearing contact lenses. The ® preservative in BromSite , benzalkonium chloride, may be absorbed by soft Rx Only contact lenses. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the Brief Summary: • Slow or Delayed Healing • Potential for Cross-Sensitivity • Increased Bleeding Time of Ocular Tissue • Keratitis and Corneal Reactions • Contact Lens Wear Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions in 1–8% of patients were: anterior chamber inflammation, headache, vitreous floaters, iritis, eye pain BromSite is a registered trademark of Sun Pharma Global FZE. and ocular hypertension. SUN-OPH-BRO-017-1 03/2017

RRO0617_SunO0617_Sun PI.inddPI.indd 1 55/25/17/25/17 12:4612:46 PMPM REVIEW NEWS Volume XXIV • No. 9 • September 2017 International Workshop Redefines Dry Eye

The Tear Film and Ocular Surface and incorporates new perspectives The latter also mentioned that tear Society recently published the re- supported by recent research: “Dry fi lm osmolarity and infl ammation port of the International Dry Eye eye is a multifactorial disease of the were involved in the disease. How- Workshop II, better known as TFOS ocular surface characterized by a loss ever, the way they might be involved DEWS II. One hundred and fi fty of homeostasis of the tear fi lm, and in the etiology of dry eye wasn’t yet dry-eye experts from 23 countries accompanied by ocular symptoms, in fully fl eshed out, which led to a lot of met in 12 different subcommittees which tear fi lm instability and hyper- consternation and debate about the to create their new report on dry- osmolarity, ocular surface infl amma- inclusion of osmolarity and infl am- eye disease. The report is intended tion and damage, and neurosensory mation in the defi nition.” to accomplish three things: update abnormalities play etiological roles.”3 Dr. Nelson says a key choice of the defi nition, classifi cation and di- J. Daniel Nelson, MD, FACS, wording in the latest defi nition was ag nosis of the disease; assess the chair of the DEWS II report, profes- the word “homeostasis.” “Homeosta- etiology, mechanism, distribution and sor of ophthalmology at the Universi- sis of the tear fi lm refers to the pro- impact of the disease; and address its ty of Minnesota and an ophthalmolo- cess of keeping the tear fi lm condi- management and therapy. (For more gist in the HealthPartners Medical tion normal, so that it’s able to carry on the latter topic, see next month’s Group in St. Paul, explains how the out its normal function—protecting dry-eye-focused issue of Review.) new defi nition differs from previous the ocular surface and providing a The defi nition of dry eye proffered defi nitions—and why it matters. stable optical interface,” he explains. in 1995 by the National Eye Insti- “All of the defi nitions of dry-eye “Any disturbance or loss of tear fi lm tute/Industry Workshop on Clinical disease have been based on the cur- homeostasis can cause symptoms and Trials in Dry Eye1 stated: “Dry eye is rent literature and knowledge at the can lead to, or be due to, tear fi lm a disorder of the tear fi lm due to tear time,” he says. “The defi nition sug- instability, hyperosmolarity, ocular defi ciency or excessive tear evapo- gested by the NIE/Industry work- sur face infl ammation and damage, as ration, which causes damage to the shop defi ned dry eye as a disorder; in well as neurosensory abnormalities. interpalpebral ocular surface and is the fi rst DEWS report it was defi ned “One reason for using a word like associated with symptoms of discom- as a disease. That’s a key difference. homeostasis is that it keeps the defi - fort.” The fi rst TFOS DEWS report2 nition from being too narrow,” he updated the defi nition by—among Eric Donnenfeld, MD continues. “We used to think that the other things—calling it a disease tear fi lm was made up of three lay- with multiple underlying causes: ers. Today we know it’s a two-phase “Dry eye is a multifactorial disease tear fi lm with a lipid phase overlying of the tears and ocular surface that an aqueous-mucin phase composed results in symptoms of discomfort, of a thousand different proteins. If visual disturbance, and tear fi lm in- we defi ne DED too specifi cally, we stability with potential damage to the limit what DED is. If we defi ne it ocular surface. It is accompanied by too broadly, then anything could be increased osmolarity of the tear fi lm DED. By defi ning the disease in and infl ammation of the ocular sur- terms of a loss of the normal state— face.” homeostasis—the defi nition avoids The new defi nition generated by One of the key concepts in the DEWS II those pitfalls. It sets the basis for fur- DEWS II clarifi es this even further defi nition of dry eye is homeostasis. ther research to really defi ne what it

4 | Review of Ophthalmology | September 2017

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Editor in Chief is that keeps the tear fi lm in a homeo- symptoms. The new defi nition says Walter C. Bethke static state.” that dry eye is all about the loss of (610) 492-1024 Dr. Nelson says another key change tear fi lm homeostasis. It’s about signs [email protected] in the new defi nition is the mention as well as symptoms. If you read of neurosensory abnormalities. “One the pathophysiology section of the Senior Editor of the issues over the years has been DEWS II report, it talks about the Christopher Kent that symptoms often do not correlate ‘vicious circle.’ This refers to the idea (814) 861-5559 with signs,” he says. “A patient may that all four signs—tear fi lm instabil- [email protected] have symptoms, but everything you ity, hyperosmolarity, ocular surface can measure appears to be normal. infl ammation/damage, and neuro- Senior Associate Editor That raises the issue of neurosensory sensory abnormalities—are like a Kristine Brennan abnormalities, which can lead to neu- circle. Any point on that circle can be (610) 492-1008 ropathic pain. We felt it was impor- the starting point and eventually lead [email protected] tant to include that in the defi nition to dry-eye disease. So as a clinician of the disease.” diagnosing the problem, you should Associate Editor Why is a more accurate defi ni- be looking for signs of hyperosmolar- Liam Jordan tion important? Dr. Nelson says one ity or infl ammation, ocular surface (610) 492-1025 reason is that it affects the ability of damage, and potentially neurosenso- [email protected] clinical trials to provide statistical ry abnormalities. Hopefully the new evidence of a dry-eye product’s ef- defi nition will encourage clinicians to Chief Medical Editor fi cacy. “We now have two approved look beyond symptoms.” Mark H. Blecher, MD drugs for treating dry eye, but many have failed to get approval,” he notes. 1. Lemp MA. Report of the national eye institute/industry Art Director workshop on clinical trials in dry eyes. CLAO J 1995;21:4:221e32. “One of the main reasons so many 2. The defi nition and classifi cation of dry eye disease: Report of Jared Araujo have failed is that the defi nition of the defi nition and classifi cation subcommittee of the international (610) 492-1032 Dry Eye Workshop. Ocul Surf 2007;5:2:75-92. dry eye used to select patients for 3. Craig JP, Nichols KK, Akpek EK, et al. TFOS DEWS II defi nition [email protected] the studies was very broad-based. and classifi cation report. Ocular Surf 2017;15:3:276-83. When you take a group of hetero- Senior Graphic Designer geneous patients and put them in a Matt Egger study, you’re going to get heteroge- (610) 492-1029 Fovista Fails neous results. This new defi nition [email protected] and classifi cation allows us to be very specifi c about what we’re testing. We Phase III International coordinator, Japan can look for evidence of loss of tear Pharmaceutical company Ophthotech Mitz Kaminuma fi lm homeostasis, with specifi c vari- announced that the prespecifi ed pri- [email protected] ables that might include osmolarity, mary endpoint of mean change in corneal and conjunctival staining and visual acuity at 12 months was not Business Offi ces tear fi lm instability. In the past, it was achieved in its Phase III clinical 11 Campus Boulevard, Suite 100 very easy to lump all dry-eye patients trial undertaken to investigate the Newtown Square, PA 19073 together.” potential superiority of Fovista (610) 492-1000 Dr. Nelson says he believes the (peg pleranib) anti-platelet-derived Fax: (610) 492-1039 new defi nition will help clinicians as growth factor therapy in combination well. “A good defi nition will help you with Eylea (afl ibercept) or Avastin Subscription inquiries: decide whether a patient really does (bevacizumab) anti-VEGF therapy, United States — (877) 529-1746 have DED, and that’s going to help compared with Eylea or Avastin Outside U.S. — (845) 267-3065 determine what treatments you pur- monotherapy for the treatment of wet E-mail: sue,” he says. “I see many patients age-related macular degeneration. [email protected] who’ve been to two or three differ- The addition of 1.5 mg of Fovista to Website: www.reviewofophthalmology.com ent doctors; they come in because an Eylea or Avastin regimen didn’t they’re not responding to treatment. result in benefi t, as measured by the That’s because right now, most clini- mean change in visual acuity at 12 cians are basing their diagnosis on months.

6 | Review of Ophthalmology | September 2017

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8 | Review of Ophthalmology | September 2017

0004_rp0917_news.indd04_rp0917_news.indd 8 88/25/17/25/17 3:443:44 PMPM BEAR IN MIND THE FORMULATION OF LOTEMAX® GEL

• ENGINEERED TO ADHERE TO THE OCULAR SURFACE1,2 • DOSE UNIFORMITY—EVERY DROP, EVERY TIME - Adaptive viscosity: Gel at rest, viscous liquid on the eye - No shaking required to resuspend drug2-4 - Drug-related blurred vision was rarely reported (0.25%, 2/813) • pH OF 6.5 CLOSE TO THAT OF HUMAN TEARS2 • ® ~70% LESS PRESERVATIVE than LOTEMAX SUSPENSION • CONTAINS 2 KNOWN MOISTURIZERS3 2,3,5 (loteprednol etabonate ophthalmic suspension) 0.5% - Glycerin and propylene glycol ~80% unrestricted managed care access on commercial plans* Indication LOTEMAX® GEL (loteprednol etabonate ophthalmic gel) 0.5% is indicated for the treatment of post-operative inﬂ ammation and pain following ocular surgery. Important Safety Information about LOTEMAX® GEL • LOTEMAX ® GEL is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. • Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored. • Use of corticosteroids may result in posterior subcapsular cataract formation. • Use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation and occurrence of perforations in those with diseases causing corneal and scleral thinning. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification, and where appropriate, fluorescein staining. • Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infection. In acute purulent conditions, steroids may mask infection or enhance existing infection. • Use of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and exacerbate the severity of many viral infections of the eye (including herpes simplex). • Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. • Patients should not wear contact lenses when using LOTEMAX® GEL. • The most common ocular adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%) and foreign body sensation (2%). Please see brief summary of Prescribing Information on adjacent page.

References: 1. Rajpal RK, Fong R, Comstock TL. Loteprednol etabonate ophthalmic gel 0.5% following cataract surgery: integrated analysis of two clinical studies. Adv Ther. 2013;30:907-923. 2. Coff ey MJ, Decory HH, Lane SS. Development of non-settling gel formulation of 0.5% loteprednol etabonate for anti-inﬂ ammatory use as an ophthalmic drop. Clin Ophthalmol. 2013;7:299-312. 3. LOTEMAX GEL [package insert]. Tampa, FL: Bausch & Lomb Incorporated. 4. Apt L, Henrick A, Silverman LM. Patient compliance with use of topical ophthalmic corticosteroid suspensions. Am J Ophthalmol. 1979;87(2):210-214. 5. LOTEMAX SUSPENSION [package insert]. Tampa, FL: Bausch & Lomb Incorporated. * Fingertip Formulary data 2017

RP0917_BL Lotemax.indd 1 8/25/17 9:47 PM BRIEF SUMMARY OF PRESCRIBING INFORMATION ossification) and teratogenic (increased incidence of meningocele, abnormal This Brief Summary does not include all the information needed to left common carotid artery, and limb flexures) when administered orally prescribe Lotemax Gel safely and effectively. See full prescribing to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times information for Lotemax Gel. the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment (loteprednol etabonate ophthalmic gel) 0.5% Lotemax of rats during organogenesis resulted in teratogenicity (absent innominate Rx only artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia Initial Rx Approval: 1998 at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal INDICATIONS AND USAGE ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day LOTEMAX is a corticosteroid indicated for the treatment of post-operative (6 times the maximum clinical dose) during organogenesis did not result inflammation and pain following ocular surgery. in any reproductive toxicity. Loteprednol etabonate was maternally toxic DOSAGE AND ADMINISTRATION (significantly reduced body weight gain during treatment) when administered Invert closed bottle and shake once to fill tip before instilling drops. to pregnant rats during organogenesis at doses of ≥5 mg/kg/day. Apply one to two drops of LOTEMAX into the conjunctival sac of the affected Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from eye four times daily beginning the day after surgery and continuing the start of the fetal period through the end of lactation, a maternally toxic throughout the first 2 weeks of the post-operative period. treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring CONTRAINDICATIONS during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in etabonate had no effect on the duration of gestation or parturition when most viral diseases of the cornea and conjunctiva including epithelial herpes administered orally to pregnant rats at doses up to 50 mg/kg/day during the simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in fetal period. mycobacterial infection of the eye and fungal diseases of ocular structures. There are no adequate and well controlled studies in pregnant women. WARNINGS AND PRECAUTIONS LOTEMAX should be used during pregnancy only if the potential benefit Intraocular Pressure (IOP) Increase justifies the potential risk to the fetus. Prolonged use of corticosteroids may result in glaucoma with damage to the Nursing Mothers optic nerve, defects in visual acuity and fields of vision. Steroids should be It is not known whether topical ophthalmic administration of corticosteroids used with caution in the presence of glaucoma. If this product is used for 10 could result in sufficient systemic absorption to produce detectable quantities days or longer, intraocular pressure should be monitored. in human milk. Systemic steroids appear in human milk and could suppress Cataracts growth, interfere with endogenous corticosteroid production, or cause other Use of corticosteroids may result in posterior subcapsular cataract formation. untoward effects. Caution should be exercised when LOTEMAX is administered Delayed Healing to a nursing woman. The use of steroids after cataract surgery may delay healing and increase the Pediatric Use incidence of bleb formation. In those diseases causing thinning of the cornea Safety and effectiveness in pediatric patients have not been established. or sclera, perforations have been known to occur with the use of topical Geriatric Use steroids. The initial prescription and renewal of the medication order should No overall differences in safety and effectiveness have been observed be made by a physician only after examination of the patient with the aid between elderly and younger patients. of magnification such as slit lamp biomicroscopy and, where appropriate, NONCLINICAL TOXICOLOGY fluorescein staining. Carcinogenesis, Mutagenesis, Impairment Of Fertility Bacterial Infections Long-term animal studies have not been conducted to evaluate the Prolonged use of corticosteroids may suppress the host response and carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was thus increase the hazard of secondary ocular infections. In acute purulent not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in conditions of the eye, steroids may mask infection or enhance existing a chromosome aberration test in human lymphocytes, or in vivo in the single infection. dose mouse micronucleus assay. Treatment of male and female rats with up Viral Infections to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, Employment of a corticosteroid medication in the treatment of patients with (600 and 300 times the maximum clinical dose, respectively) prior to and a history of herpes simplex requires great caution. Use of ocular steroids may during mating did not impair fertility in either gender. prolong the course and may exacerbate the severity of many viral infections PATIENT COUNSELING INFORMATION of the eye (including herpes simplex). Administration Fungal Infections Invert closed bottle and shake once to fill tip before instilling drops. Fungal infections of the cornea are particularly prone to develop Risk of Contamination coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been Patients should be advised not to allow the dropper tip to touch any surface, used or is in use. Fungal cultures should be taken when appropriate. as this may contaminate the gel. Contact Lens Wear Contact Lens Wear Patients should not wear contact lenses during their course of therapy with Patients should be advised not to wear contact lenses when using LOTEMAX. LOTEMAX. Risk of Secondary Infection ADVERSE REACTIONS If pain develops, redness, itching or inflammation becomes aggravated, the Adverse reactions associated with ophthalmic steroids include elevated patient should be advised to consult a physician. intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC formation, delayed wound healing and secondary ocular infection from Bridgewater, NJ 08807 USA pathogens including herpes simplex, and perforation of the globe where US Patent No. 5,800,807 there is thinning of the cornea or sclera. ©Bausch & Lomb Incorporated The most common adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%). Lotemax is a registered trademark of Bausch & Lomb Incorporated or its affiliates. USE IN SPECIFIC POPULATIONS Pregnancy LGX.0114.USA.16 Teratogenic Effects Based on 9269101/9269201 Revised: 08/2016 Loteprednol etabonate has been shown to be embryotoxic (delayed

RRP0917_BLP0917_BL LotemaxLotemax PI.inddPI.indd 1 88/25/17/25/17 9:479:47 PMPM September 2017 • Volume XXIV No. 9 | reviewofophthalmology.com Cover Story 18 | Access to Off-label Medications: Getting Tougher Christopher Kent, Senior Editor Well-intentioned restrictions on meds are making timely treatment challenging.

Cover Focus 23 | Is Cross-linking at a Crossroads? Kristine Brennan, Senior Associate Editor A look at how surgeons are using the procedure a year after FDA approval. ? 30 | Work Up Corneal Ulcers Like an Expert Walter Bethke, Editor in Chief Subspecialists share their advice on the best ways to heal a corneal infection.

36 | How to Manage Conjunctivochalasis Benjamin Bert, MD Tips on diagnosis, as well as medical and surgical management.

September 2017 | reviewofophthalmology.com | 11

011_rp0917_toc.indd 11 8/25/17 3:48 PM Departments

4 | Review News 14 14 | Technology Update Getting Drops onto the Eye the Low-tech Way There’s more than one way to help your patients put their medications where they belong.

40 | Pediatric Patient Pediatric Idiopathic Intracranial Hypertension Many ophthalmologists are well-versed in IIH in adults, but pediatric IIH is a different animal. 44 | Glaucoma Management When Should You Neuroimage Your Patient? Neurologic disease may present with symptoms that mimic glaucoma. Here’s when to check for trouble.

50 | Therapeutic Topics Ocular Trauma, Then and Now 44 A look at the variety and frequency of ocular trauma, from foreign objects to chemical exposure.

53 | Retinal Insider The Pros and Cons of Heads-up Surgery The future of this technology holds promise as long as new innovations are critically evaluated, surgeons say.

56 | Plastic Pointers Options for Small-incision Brow Lifts A traditional brow lift may not be necessary; a less- invasive option may yield the results patients need.

59 | Research Review Glaucoma Screening in High-risk Populations 56 60 | Classifieds 61 | Ad Index

62 | Product News New Optovue Software

63 | Wills Eye Resident Case Series

12 | Review of Ophthalmology | September 2017

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RP0417_Tearlab.indd 1 3/16/17 3:18 PM Technology Update

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

Getting Drops Onto the Eye: Low-tech Solutions There’s more than one way to help your patients put their medications where they belong. Christopher Kent, Senior Editor

oday, the struggle to increase pa- that attempt to position the bottle (and tends to get mixed reviews from Ttient compliance with medication over the eye in a consistent manner users). The advantages include that it use is becoming increasingly high- while holding the eyelids open; those keeps the bottle tip from touching the tech. New options often focus on tak- that use surface tension to deliver a eye and holds the eyelids out of the ing the patient out of the equation by drop onto the eye via an intermedi- way while the drop is being applied. enabling extended delivery of a drug. ary device; and one or two that of- The most obvious problems are that Devices potentially making this pos- fer unique approaches to getting the the patient still has to tilt his head sible range from intravitreal implants drops onto the eye. Here, we’ll pro- back, and there’s no guarantee that to punctal plugs to rings that sit in the vide a review of some of the products the drop will land on the eye. Fur- conjunctival fornix and slowly release in each category. thermore, the patient may squeeze medication. out multiple drops by mistake. Nevertheless, placing drops on the Bottle Managers Products in this category (see pic- eye is still the method of delivery al- tures, below) include: most every patient uses, and that old- The ﬁ rst category is the simplest: • AutoDrop Eye Drop Guide. school technology is likely to remain The eye dropper bottle is snapped The tip of the dropper bottle clips in use for the foreseeable future. That into, or otherwise encased in, a plas- into the lid of this guide, which the brings us back to a basic, well-known tic device that acts to hold open the manufacturer says was developed in problem: Many patients have diffi- eyelids and positions the dropper tip collaboration with the British Royal culty using eye drops properly. above the eye when the head is tilted National Institute for the Blind. The Faced with a dismal rate of accurate back. Unfortunately, this type of de- guide, which holds the eye open with drop use among patients, most doc- sign has some obvious shortcomings the bottle positioned over the eye, tors focus on trying to teach patients better eye drop application technique or try to get someone else to help the patient instill the drops. However, there are some clever, readily available low-tech eye drop application devices that may do a lot to help your patients succeed in getting their drops onto their eyes. These devices fall pri- marily into three categories: those Some products claim to help position the bottle over the eye and make it easier to squeeze.

14 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

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the plastic applicator, pulls down the lower lid while looking in a mirror, brings the tip of the applicator close to the eye, and the drop jumps onto the eye. Advertised features include that the device can be used with or without glasses on, and that the device is easy to clean and store after use. Because it’s easier for the patient to Several products use capillary action to make the drop “jump” from the device onto the eye. control the drop usage, the manufacturer claims that patients get up to 50 has a pinhole that lets light in; accord- This approach has several advantages, percent more uses per bottle. You can ing to the manufacturer, when the including increasing the likelihood learn more at simplytouchusa.com. patient looks at the pinhole, the eye that only one drop will actually be • OptiAide. This device, which is correctly positioned to receive the used at a time; eliminating the need looks more high-tech than the oth- drop. This device can be used in con- for the patient to tilt her head back; ers, can hold up to five drops in its junction with AutoSqueeze, another making it next-to-impossible to miss fi ve chambers. (In the product photo, plastic device that goes around the the eye; and keeping the bottle tip each chamber has been filled with bottle itself (rather than clipping onto away from the eye, thus avoiding con- different food coloring to make them the tip); it uses the lever principle to tamination. Potential drawbacks in- easier to see.) Unlike the other de- make it easier to squeeze the bottle. clude the need to keep the device vices, this one is held in front of the You can fi nd more information about clean, and possible contacts between eye, allowing the drop to jump onto both items at: maddak.com/autodrop- the device and the eye. Products us- the eye, theoretically preventing the eye-drop-guide-p-28115.html. ing this approach include: device from contacting the cornea. • Flents Ezy Drop Guide & • Magic Touch: The Eye Drop However, it does require moving the Eye Wash Cup. This plastic bottle Helper. This device, which resembles eyelids and lashes out of the way. You holder resembles an eye-wash cup, a small rubber bell about the size of a can find more information at con- and the manufacturer claims it can thimble, is placed on a fi ngertip; with tactlenskit.com/optiaide/. be used for that purpose as well. the finger held vertically, a drop is You can check it out at amazon.com/ placed into a small dimple at the tip A Targeted Approach Flents-Drop-Guide-0-058-Pound/dp/ of the device. The patient then leans B0011YK3NS. forward, and when the device gets One of the most unique dropper- • Opticare Eye Drop Dispenser. close to the eye, the drop “jumps” assist designs was created by Jona- In addition to positioning the bottle onto the eye. Designed by Julius Shul- than Cress, MD, an ophthalmologist over the eye, this device is designed man, MD, the Magic Touch device in Santa Cruz, Calif., who’s been in to make it easier for the patient to is BPA-free and made of medical- practice for more than 40 years. “The squeeze the bottle. The manufacturer grade silicone. The manufacturer says Cress dropper is an arched tube that claims that it essentially makes a small that antimicrobial silver ions in the screws onto the dropper bottle,” he bottle as easy to manage as a larger material eliminate up to 99.99 per- explains. “It references the nose so bottle. For more information, visit cent of microbes, so the device can the tip can be comfortably and steadi- guldenophthalmics.com/products/in- be kept clean by simply rinsing under ly placed in the medial canthal area. dex.php/opticare-eye-drop-dispenser. warm water after use. You can find Once the tip is properly placed, the html. more information at magic-touch-eye. bottle is squeezed; the drop leaves myshopify.com. the aperture, slides down and off the Using Capillary Action • SimplyTouch. This device is a little ramp onto the delivery tip and small, reusable handheld applicator into the eye. (See photos, facing page.) A less intuitive but more interesting with a tiny disc at the top, onto which The patient releases the bottle when approach to getting drops onto the a drop is placed; surface tension keeps she feels the drop. The current ver- eye involves placing a single drop into the drop in place. One side of the sion of the dropper has no metering a holder and then bringing the holder disc has no rim; the other has a rim component, but most patients learn to close to the eye, allowing the drop to to help less viscous drops stay on the adjust their bottle squeeze to release “jump” onto the eye from the device. disc. The patient places a drop onto just one drop.”

16 | Review of Ophthalmology | September 2017

014_rp0917_tech update.indd 16 8/25/17 5:00 PM 24TH ANNUAL OPHTHALMIC Product Guide

Innovative products to enhance your practice

The Cress Dropper allows a drop to slide into the eye. Asked about keeping the drops sterile, Dr. Cress notes that the delivery tip is designed to physically isolate the distal aperture from the delivery surface. “The purpose of this design is to prevent conjunctival or skin bacteria from being aspirated back into the bottle, contaminating The future the drops,” he says. “Cleaning the tip after each use would be ideal, but it’s not necessary. In my experience, the rate of bottle contamination is 25 percent lower than with is in your standard dropper tips that aren’t supposed to be touched. In fact, I’m not aware of any external ocular infections hands. One caused by the use of my dropper.” Dr. Cress says that patients who use the dropper are tap, many almost universally happy with it. “I have a substantial population of patients who can’t get drops in their own eyes possibilities. with a standard dropper,” he says. “Those patients have to have their spouse or someone else instill their drops. With my dropper, most of them can do it themselves. However, some patients who lack manual dexterity or have weak Experience the digital edition hands still may fi nd it diffi cult or impossible to meter a drop by squeezing accurately. They still waste drops and on your handheld device. occasionally miss, so they’re less happy with it.” Use your smart device to Dr. Cress says he’s observed a difference in outcomes when glaucoma patients switch to his device, although he scan the code below or visit: doesn’t have concrete data to prove it. “I’ve had patients who seemed to be failing at drop therapy, but after using this device, their intraocular pressure stabilizes and their www.reviewofophthalmology.com/supplements/ visual fi eld loss ceases,” he says. “To me, this indicates that they weren’t effectively instilling drops before, but Download a QR scanner app. Launch app and hold your with the dropper they are. Additionally, patients using the mobile device over the code to view dropper rarely run out before a refi ll is due.” http://www.reviewofophthalmology.com/supplements/. Dr. Cress says he originally created the device for his 9-year-old son who was suffering from dry eye. “Once I had a working model I licensed it to Wilson Ophthalmic, who made about 20,000 of them,” he says. “I’m currently working on improvements to the design. The next version accurately meters a single drop, is easier to squeeze and makes it easier to get the drop into the eye. I’m open to proposals for manufacturing the new model.” For more information about the original version, visit amazon.

com/Cress-Dropper-EyeDrops-Professional-Model/dp/ ® B004R8TOGM.

061_rp0817_fractionala.indd 61 7/25/17 2:50 PM 014_rp0917_tech update.indd 17 8/25/17 5:00 PM

2016_opg_ad_half_rp.indd 1 7/14/17 11:02 AM Unavailable Drugs REVIEW Cover Story Access to Off-label Meds: Getting Tougher

Christopher Kent, Senior Editor

Well-intentioned he use of off-label drugs and approval process would never be devices is very common in the recouped. This leaves many highly restrictions on Tday-to-day practice of medi- effective treatments unapproved. cine. In fact, if a surgeon fails to pre- • Running a clinical trial may compounded scribe some off-label medications or not be feasible. The size or nature use some devices in an off-label man- of an affl icted population can make a drugs are making ner—for example, antibiotics follow- clinical trial logistically impossible. ing cataract surgery, mitomycin-C as • Even when FDA approval is timely treatment an adjunct to surgery, adhesives to granted, it’s very specifi c and lim- close wounds, or topical antibiotics ited. Approval is based on the nature challenging. to treat infectious corneal ulcers—he and outcomes of the clinical trials that or she could actually be at risk of a led to approval. Because of cost and malpractice lawsuit. One could even logistical challenges, an FDA clinical argue that if the off-label use of drugs trial can’t represent the full spectrum and devices were forbidden, the result of uses a drug may offer, and the ap- would be disastrous for millions of proval will refl ect that. patients. • The benefi cial uses of a drug or There’s no question that having device always evolve over time. If FDA approval means a drug has been every newly discovered use of a drug thoroughly tested for safety and ef- or device had to go through an expen- fi cacy. However, not having approval sive approval process, the practice of for a particular drug or device—or medicine might never move forward. a specific use of an approved drug In reality, many treatments that or device—doesn’t mean the drug or have not gone through the FDA-ap- device isn’t safe and effective. That’s proval process have been well-dem- because the approval process itself onstrated to be helpful and are widely comes with numerous real-world caused; quite a few are even standard veats, including: of care. Many have been tested in • Executing the trials necessary clinical trials reported in the peer-re- to get FDA approval can be very viewed literature that were not done costly. This makes it diffi cult or im- under FDA supervision. Others that possible for many smaller manufac- are less amenable to testing in clini- turers to get approval for a product. cal trials have been shown to be safe • Some treatments are so inex- and effective over the course of many pensive that the high cost of the years of use in the real world.

18 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

0018_rp0917_f1.indd18_rp0917_f1.indd 1818 88/25/17/25/17 4:204:20 PMPM The Compounding Factor those of us treating the cornea use antibiotics and Compounding drugs into anti-amoeba medications; different formats or combina- glaucoma specialists use tions has been common prac- mitomycin-C; and cataract tice for many years, allowing surgeons use intracameral doctors to address conditions injections of antibiotics. beyond those specifi cally ap- “An acanthamoeba cor- proved by the FDA. Despite neal ulcer can be devastat- this, obtaining many coming to vision,” she contin- pounded drugs has recently ues. “There’s no approved become far more diffi cult as drug for the treatment of a result of the Drug Quality As a result of recent regulations, many compounding pharmacies acanthamoeba, so we use that once provided scores of compounded drugs now compound and Security Act. The law was options such as polyhexa- fewer than a dozen. passed by Congress in 2013 methylene biguanide—a following the deaths of 64 individuals mon, benefi cial surgical practices. For pool cleaner that can be diluted—to in a meningitis outbreak attributed example, adding epinephrine to the kill the amoeba. This compounded to a drug-compounding pharmacy in lidocaine used to numb the eye for eye drop should be inexpensive, but New England; the new law gives the cataract surgery is a common surgical over time it’s become very costly FDA increased authority to regulate practice. It’s supported by many peer- and is no longer easily accessible. and monitor the manufacture of com- reviewed studies, and it demonstrably We recently treated a patient with pounded drugs. makes the surgery easier, safer and an acanthamoeba corneal ulcer, and As it turns out, these well-intended less costly by keeping the pupil dilated unsuccessfully spent two hours call- new rules, meant to increase safety, are during the course of the surgery. The ing every compounding pharmacy we apparently having an unintended side new guidelines regarding compound- knew of to locate these drops. I end- effect: curtailing the availability of eye- ing encompass many common prac- ed up texting my colleagues around sight-saving medications. The cost of tices like this, making these practices a the country to fi nd out where I could implementing new procedures, such violation of the rules. find these drops, and we eventually as extensive safety testing, has caused Here, three surgeons discuss their found a pharmacy many hours away many compounding pharmacies to experiences obtaining and using off- that still prepares it. Another option drastically curtail their offerings. For label medications and how the current for treating acanthamoebic keratitis example, in 2013, prior to the imple- situation has affected their practices. is chlorohexidine, but physicians en- mentation of the DQSA, one phar- counter similar diffi culties obtaining macy that’s still in operation offered a Going Off-label compounded chlorohexidine.” list of almost 200 compounded drugs Dr. Afshari notes that there are oth- and injectables. That list included fi ve Natalie A. Afshari, MD, FACS, Stu- er kinds of corneal ulcers that require anti-allergy preparations; 38 antibiotic art I. Brown MD Chair in Ophthal- compounded drugs for treatment as preparations; seven antivirals; 10 an- mology in Memory of Donald P. Shi- well. “We may treat bacterial ulcers tifungals; three cytotoxic agents; nine ley; professor of ophthalmology; and with compounded antibiotics such preparations used for diagnosis (e.g. chief of cornea & refractive surgery as vancomycin or tobramycin,” she lissamine green); 26 compounds for at the Shiley Eye Institute, Univer- says. “Unfortunately, there are fewer treating dry eye; 32 preparations for sity of California San Diego, is the and fewer compounding pharmacies managing glaucoma; and more than chair of the FDA Committee for the in the U.S., which affects the avail- 60 other compounded medications. American Society of Cataract and ability of these medications. Another Today, as a result of the DQSA, that Refractive Surgery. Dr. Afshari notes compounded medicine is topical alpha pharmacy has converted to a 503B that there are many scenarios in which interferon for the treatment of ocu- outsourcing facility and offers a total of ophthalmologists use drugs that are lar surface neoplasia. (The alternative 10 compounded formulations. off-label or have to be compounded. for these patients is surgical excision.) The new rules are also causing “These drugs are very important in Decreasing availability of topical in- other unintended consequences. practice for many ophthalmology sub- terferon has made it diffi cult for some Among those is a new definition of specialties,” she says. “Retina special- patients with ocular surface neoplasia compounding that impacts some com- ists mainly use Avastin and antibiotics; to pursue this less-invasive therapy.

September 2017 | reviewofophthalmology.com | 19

018_rp0917_f1.indd 19 8/25/17 4:20 PM Cover Unavailable Drugs

REVIEW Story

Antibiotics and Cataract Surgery

One common situation that involves using drugs in a non- tating complication occurs, such as hemorrhagic occlusive retinal approved manner is antibiotic prophylaxis following cataract vasculitis, risk-management concerns inevitably arise,” he says. surgery. David F. Chang, MD, a clinical professor of ophthalmology “Physicians are allowed to—and regularly do—use drugs for off- at the University of California, San Francisco, spoke about this label indications. In this situation, off-label status isn’t the main issue at the 2017 meeting of the American Society of Cataract and problem per se, but rather: What was the evidence and rationale Refractive Surgery. “I think most of us would consider some form supporting the drug’s use, and what were the alternatives?” of antibiotic prophylaxis to be standard-of-care for intraocular Dr. Chang notes that some of the rare but potential problems surgery,” he says. “The fact that there’s no topical or intraocular with the intraocular injection of compounded drugs were brought antibiotic that’s FDA-approved for this purpose raises two sepa- home recently when about 50 patients in Dallas developed acute rate but related issues. retinal toxicity following intravitreal injection of a moxiﬂ oxacin- “First is the off-label use of an antibiotic solution that’s FDA- triamcinolone mixture provided by a local 503A compounding approved and commercially manufactured for another indication, pharmacy. “Injecting an antibiotic-steroid mixture into the vitreous such as conjunctivitis,” he explains. “We have a wide selection to replace the need for topical therapy following routine cataract of commercially manufactured topical ophthalmic antibiotics in surgery is a relatively new practice, and there are two potential the United States, but none are FDA-approved for endophthal- lessons here,” he says. “First, because the eye is so sensitive to mitis prophylaxis. Nevertheless, in our 2014 ASCRS survey on even minute amounts of toxic impurities, I personally prefer to endophthalmitis prophylaxis practice patterns,2 91 percent of use a 503B outsourcing facility for any compounded drugs that respondents were using perioperative topical antibiotics for infec- will be injected into the eye. Compared to a 503A compounding tion prophylaxis for cataract surgery. Such prevalent use, however, pharmacy, 503B facilities must pass more stringent requirements is all off-label. to gain this FDA designation. “Second,” he continues, “approximately half of the survey re- “Second,” he says, “a toxic substance inadvertently entering spondents were using intraocular antibiotic prophylaxis. Because the anterior chamber may cause toxic anterior segment syndrome, there’s no commercially available antibiotic solution manufactured or TASS, but severe endothelial toxicity can ultimately be treated for intraocular use in the U.S., many ambulatory surgical centers with an endothelial keratoplasty. In contrast, a toxic substance are using a compounding pharmacy or mixing the antibiotics reaching the posterior segment may cause retinal toxicity with themselves for intracameral antibiotic prophylaxis. It’s very unfor- permanent loss of vision. Although the risk of toxic posterior tunate that American patients do not have access to a commer- segment syndrome is small, cataract surgeons must consider cially manufactured antibiotic solution for this indication.” this when balancing the need for an intravitreal injection of a Dr. Chang acknowledges that injecting an intraocular antibiotic compounded drug.” at the end of cataract surgery is not without risk. “When a devas- —CK

Similarly, tacrolimus is a compounded oeba, polyhexamethylene biguanide, that practices have been forced to do medicine that is used to address recal- isn’t approved. What company would more drug compounding on their own citrant atopy in patients with allergic spend millions of dollars to get ap- in order to save some patients from eye disease. Although it’s still available proval for a pool cleaner? It wouldn’t vision loss or blindness. in the United States, tacrolimus has make economic sense for them to Richard Duffey, MD, a corneal become increasingly diffi cult to fi nd. do that. Nevertheless, for years it’s specialist in Mobile, Ala., who also We’ve called many different pharma- been the practice to use this chemical teaches at the University of South Ala- cies before fi nding one that prepares for treatment of Acanthamoeba. We bama, notes that recent regulations tacrolimus.” even published a paper showing that it have made it extremely expensive for It’s important to note that while works in Aspergillus keratitis.1 It hasn’t pharmacies to continue offering these some of the nonapproved treatments been approved, so it’s considered off- services. “In addition to the cost of the involve drugs that were approved for label. But it is standard of care.” equipment, the rare cases in which other medical purposes, some drugs something has gone wrong have raised haven’t been approved by the FDA at Compounding Onsite the cost of insurance to the point at all. “There is a difference,” says Dr. Af- which pharmacies can’t cover their shari. “For example, the diluted pool One side effect of the cutback in costs,” he says. “This became an issue cleaner we use to treat Acantham- available compounded medications is of liability in Alabama, so our sources

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0018_rp0917_f1.indd18_rp0917_f1.indd 2020 88/25/17/25/17 4:204:20 PMPM John Sheppard, MD stopped compounding sterile tary keratitis, mucous fi la- eye drops for us. Now we have ments on the cornea; this to go out of state to fi nd a place medication, when diluted, that has these commercially does a fabulous job of dis- available, with the delay that solving those filaments. entails. In some cases, the com- That makes it a very im- pounded drops are not avail- portant medication from a able anymore, anywhere. Then patient comfort and visual we have to make them up our- acuity standpoint, espe- selves.” cially for someone who gets Dr. Duffey says his practice these fi laments recurrently. has to create drops for patients Acetylcysteine is not com- at least a couple of times a mercially available as an eye month—more than 25 times a Corneal problems such as ulcers frequently require treatment drop, so we simply make up year. “If you’re a corneal spe- with compounded medications; lack of timely availability may the drops in the offi ce. cialist, I don’t see how you can put the eye at risk. “When we have to cre- treat people without having to ate drops in our practice, go outside of the box,” he says. “Some- although the infection recurred about we use sterile technique in a specially times we have to treat a problem the three weeks after discontinuing the cleaned space under sterile conditions, way we treated it in the past, despite medication. We had to go through a and to my knowledge, we’ve never the fact that we can’t get pharma- second round of treatment before we caused a problem in any patient,” Dr. cies to compound these medications completely eradicated it, which is not Duffey adds. “On the other hand, if locally. We need them to be readily unusual with a fungal infection. They we don’t make up these medications, available. The alternative is letting the tend to be deep and hard to eradi- some of our patients are going to lose patient lose an eye.” cate even after treating for several an eye to an infection.” Dr. Duffey says a similar problem months.” Dr. Duffey acknowledges that com- arises with antifungals. “We often treat Dr. Duffey notes that some medi- pounding a drug in-practice does local peanut farmers who spray anti- cations are FDA-approved to treat mean accepting liability if something fungals onto their peanut crops,” he infections—just not specifi cally in the goes wrong. “Is it worth taking on the explains. “They can get a black fungus eye. “The guidelines don’t necessarily liability when an eye will be signifi cant- called Aspergillus that’s very resistant make a distinction as to where that ly damaged without this treatment? In to treatment. One young patient had infection is,” he says. “In this case, the my opinion it is,” he says. “I’ve been in a very deep and extensive corneal ul- problem was to get it into an eye-drop practice almost 30 years since my fel- cer that turned out to be Aspergillus. form, because an IV medication is no lowship, and many of these are treat- He needed to be treated with a forti- help when a patient has a deep corneal ments we routinely used 30 years ago. fi ed antifungal that’s not commercially ulcer. We need to be able to put the I can’t conceive of going backwards available. In a situation like this we medication where the fungal infection in medicine. Would I rather take on take a readily available IV medication is via an injection into the cornea or a some increased liability or watch some and use dilution to convert it into a sterile eye drop.” of my patients lose an eye, knowing sterile eye drop. Sometimes we have Dr. Duffey mentions another treat- that fi ve years ago I could have treated to do this to be able to treat patients ment that his practice has to create their problem? You do what you need with fortifi ed antibiotics or antifungals in-house: acetylcysteine eye drops. to do to save your patients’ vision.” in a timely manner. “A number of my patients use the “In the case of this patient, we used acetylcysteine drops we make up,” he Speed of Access this method to make up a fortified says. “The drops are made by dilut- antifungal solution at a concentration ing the product Mucomyst, which is Dr. Afshari points out that being that allowed us to inject it directly into prescribed to break up pulmonary se- able to obtain a medicine within a few his cornea to treat the infection,” he cretions—thick mucous in the lungs. hours is often a big issue. “Compound- continues. “We also created sterile Pulmonary doctors often prescribe ing pharmacies are good about getting eye drops for the patient to use. This this drug in a nebulizer, allowing the the drug to you or the patient quickly,” patient ended up with a very good re- patient to breathe it in. Patients with she says. “Once we order it, they’ll sult after several months of treatment, severe dry eye often develop fi lamen- FedEx it overnight so the patient gets

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REVIEW Story

it by the next day. However, in the out about this medication online and they stopped doing it themselves be- case of an infection, it’s preferable to obtain Brolene on their own from the cause of regulations. Similarly, forti- not wait even that long, because many United Kingdom, and then send it fi ed vancomycin and tobramycin are infections progress signifi cantly in 24 to themselves via a family member,” still available through compounding hours. In some situations it would be she says. pharmacies, but I know of practices helpful if in-house pharmacists could that were making their own vanco- make up small quantities of a drug mycin drops and giving them to the such as vancomycin or tobramycin for patient, because patients were unable the patient, to avoid delaying time- “In many practices, to afford it otherwise.” sensitive treatment.” Dr. Duffey says he frequently it used to be that if Expertise Counts needs to treat local patients with for- you needed serum tifi ed antibiotics or antifungals that As noted, there’s always some risk are not readily available. “Central tears, you’d simply associated with using drugs in an off- corneal ulcers that are bacterial in draw the blood and label manner, but Dr. Duffey points nature need treatment with fortifi ed out that a doctor is less likely to run antibiotics,” he points out. “Tradition- send a technician to into trouble using off-label options ally, pharmacies would compound centrifuge it and dilute if it’s clear that the alternatives have them for us, but today, at least here been exhausted. “As a corneal special- in Alabama, it’s almost impossible to it down. Physicians did ist, it’s pretty easy for me to justify fi nd a compounding pharmacy that this because it would making up these formulations because will make sterile eye drops. And it’s I know I’ve exhausted all the other very hard to get them in a timely fash- allow them to provide options,” he says. “If you’re not a cor- ion when you have to order them the tears to the patient neal specialist, people could say, ‘Why from out of state, which can involve a didn’t you go to a corneal specialist or 24- to 48-hour delay.” right away.” a fellowship-trained person who was Some highly beneficial drugs are — Natalie Afshari, MD absolutely sure of the diagnosis and not even sold in the United States, treatment alternatives?’ although they may be easily obtained “If you’re not an authority in the outside the country. “I sometimes area in question, I’d advise finding have drugs mailed to me by pharma- a good specialist and deferring to cies in Australia,” says Dr. Duffey. Dr. Afshari says that serum tears his or her judgment about what the “A drug like Brolene [propamidine are another treatment that’s becom- treatment options are,” he concludes. isetionate], an antiparasitic for Acan- ing more and more diffi cult to obtain. “When your patient’s treatment needs thamoeba infections, is available at “These tears are created from the pa- fall outside of what you can treat with local apothecary or pharmacy shops in tient’s blood,” she explains. “They can the medications that are available, England for the equivalent of about be very helpful for healing persistent hopefully that doctor will know of oth- $10 or $12. So, whenever I go to corneal epithelial defects, but fewer er alternatives.” England I buy half a dozen bottles, and fewer pharmacies are making bring them back and keep them in them. Our practice is in California, Drs. Chang, Afshari and Duffey my refrigerator. I use them when- but we now have to send a patient’s have no fi nancial interest in any sub- ever I need to treat an Acantham- blood to Kansas to get the serum tears ject or product mentioned. For more oeba infection, as a supplement to made, which delays treatment and information regarding the pharmacies other stronger pharmacy-formulated increases cost.” they use, you can contact Dr. Duffey medications that are available outside “In many practices, it used to be at [email protected], or Dr. the state. Luckily, Acanthamoeba is that if you needed serum tears you’d Afshari at [email protected].

slow-growing, so the patient won’t simply draw the blood and send a 1. Rebong RA, Santaella RM, Goldhagen BE, et al. be seriously harmed if obtaining the technician to centrifuge it and dilute it Polyhexamethylene biguanide and calcineurin inhibitors as novel antifungal treatments for aspergillus keratitis. Invest Ophthalmol treatment takes several days.” down,” Dr. Afshari continues. “Physi- Vis Sci 2011;52:10:7309-15. Dr. Afshari occasionally treats acan- cians did this because it would allow 2. Chang DF, Braga-Mele R, Henderson BA, Mamalis N, Vasavada A. Antibiotic prophylaxis of postoperative endophthalmitis thamoebic keratitis with Brolene as them to provide the tears to the pa- following cataract surgery: Results of the 2014 ASCRS Member well. “Sometimes our patients find tient right away. Eventually, however, Survey. J Cataract Refract Surg 2015;41;1300-1305.

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0018_rp0917_f1.indd18_rp0917_f1.indd 2222 88/25/17/25/17 4:204:20 PMPM Cornea REVIEW Cover Focus Is Cross-linking at a Crossroads? Kristine Brennan, Senior Associate Editor

A look at the DA-approved corneal colla- FDA approval of the Avedro KXL gen cross-linking is barely a system and the two Photrexas for potentially Fyear old. The Avedro KXL progressive keratoconus looked at UV system, along with Photrexa and 205 patients at multiple U.S. cen- life-changing Photrexa Viscous, is approved for ters with documented progressive patients aged 14 and up with pro- keratoconus, who were randomized procedure, one gressive keratoconus or post-surgical into treatment (epi-off cross-linking ectasia. After years of commercial with Photrexa Viscous and Photrexa year after the ﬁ rst use abroad, this long-awaited thera- riboflavin topical drops and expo- peutic option has the potential to sure to 3mW/cm2 UVA light) and FDA-approved halt vision loss for many patients in sham control (transepithelial Pho- system became the United States. In this article, cor- trexa Viscous and Photrexa without neal experts discuss the impact that UVA light) groups. KMax at one available. cross-linking has had on their prac- year decreased from pre-treatment tices, as well as how they combine by an average of 1.6 ±4.2 D in the cross-linking with other procedures. treatment group; it increased by 1 Outside of the United States, cor- ±5.1 D in the control group. The neal collagen cross-linking has dem- cross-linked eyes also made gains in onstrated long-term ability to sta- CDVA that outstripped those made bilize progressive keratoconus and by sham-control eyes. Corneal haze help spare patients the need for cor- was the most frequently reported neal transplants.1 The pivotal Phase adverse event, and endothelial cell III study data2 that supported the counts had not signiﬁ cantly changed at one year post treatment. After earning FDA approval for progressive keratoconus in April 2016, Peter S. Hersh, MD Hersh, Peter S. Proper alignment of the UV light source is key to success with the KXL system, which requires a corneal thickness of at least 400 µm after removing the epithelium and before irradiance.

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REVIEW Focus Randy J. Epstein, MD the Avedro cross-linking system was approved for corneal ectasia after refractive surgery in July 2016. The pivotal Phase III study3 for that indication randomized 179 patients with documented corneal ectasia post refractive surgery into treatment and sham groups: The treatment group underwent epi-off cross-linking; the Sagittal difference map showing improved corneal topography of the left eye (far right) sham group got riboflavin without after epi-on cross-linking with the CXLUSA photosensitizing agent and UVA light source. removal of the epithelium or UVA irradiance. In the treatment group, cross-linking alone to a combination procedure. “Now we have an FDA- mean KMax decreased by 0.7 ±2.1 of cross-linking and INTACs. Pa- approved procedure, and it’s impor- D from pre-treatment to one year; tients continue to be enrolled in this tant to note that to date, in the world- mean KMax increased in the sham ongoing study, which has been con- wide literature, there isn’t anything group by 0.6 ±2.1 D. The CDVA of ducted for eight years, with another that’s shown better results,” he says. the treatment group improved by two years remaining to complete en- “So starting out, I certainly think five letters between preop and 12 rollment and analysis of data. practitioners should use this well- months, versus a loss of 0.3 letters for Since the FDA approval of the studied and proven protocol while the control group during the same Avedro KXL system and the Pho- additional clinical trials continue to interval. As in the pivotal keratoco- trexa drugs, colleagues at Dr. Rabi- advance the fi eld.” Dr. Hersh, who nus study, corneal haze was the most nowitz’s surgery center now use the is also involved in investigating an frequently reported adverse fi nding. Avedro system per the Dresden pro- epi-on protocol, adds, “Certainly, it’s tocol. Dr. Rabinowitz uses a slight not going to remain this way forever; Many Protocols in the Mix modifi cation of that protocol, which there are going to be improvements he believes yields better visual out- and changes. But it is a good starting “Cross-linking really changes comes. He uses a VISX laser in PTK point.” things, because I would see many mode to remove the epithelium in Brad H. Feldman, MD, an in- more transplants in many more his cross-linking patients. “When you structor at the Wills Eye Hospital people prior to its introduction,” remove it with a laser, you smooth and in practice at Philadelphia Eye says Yaron S. Rabinowitz, MD, di- the center of the cornea, and that Associates, says that since initially rector of ophthalmology research at actually improves vision as well as offering cross-linking in the spring Cedars-Sinai Medical Center and removing the epithelium,” he notes. of 2016, his practice has undergone clinical professor of ophthalmology Dr. Rabinowitz plans to present data some major changes. “It has allowed at UCLA School of Medicine. “It from his studies at the upcoming me to fi nally treat patients in the re- works so well that a large majority of 2017 American Academy of Oph- gion who had been losing vision from patients that would have needed a thalmology meeting in New Orleans. keratoconus but had no access to this transplant can avoid it because they Peter S. Hersh, MD, FACS, of proven treatment to halt disease pro- are not progressing. When the dis- the Cornea and Laser Eye Institute gression and potentially improve vi- ease is detected in the very young, - Hersh Vision Group, professor of sion,” he says. they progress very rapidly; as such, clinical ophthalmology and director “I have had to build in time for in those patients, progression is now of cornea and refractive surgery at lengthy pre-treatment evaluations being retarded with cross-linking,” Rutgers Medical School and a visit- and discussions about this new treat- he explains. ing research collaborator at Prince- ment,” Dr. Feldman continues. Dr. Rabinowitz is an advocate of ton University, was the medical mon- “Many patients have either never the Dresden protocol. He has used a itor for the clinical trials of the KXL heard of the treatment or have mis- UVA delivery device made by Peschke system. “We did our fi rst case back understandings about corneal col- (Waldshut-Tiengen, Germany) under in 2008 in the original clinical trials,” lagen cross-linking. We have also an IDE from the FDA before and he says. He thinks that KXL’s classic had to change my office schedule since FDA approval of the Avedro Dresden protocol-based method of to make room for the treatment ses- KXL system. Dr. Rabinowitz has cross-linking is the best starting point sion, which we perform in the offi ce been involved in a study comparing for doctors interested in offering the during a clinic day rather than in the

24 | Review of Ophthalmology | September 2017

023_rp0917_f2.indd 24 8/25/17 3:39 PM Peter S. Hersh, MD operating room on a separate day. I generally treat on Mondays or Tues- days, see them postoperative day one, and then remove the bandage contact lens on Friday or Saturday.” Sometimes, however, things are less than straightforward. “Often, patients have asymmetric disease. This may mean that one eye is going to be monitored for progression rather than treated, or one eye may be too advanced and need keratoplasty,” he explains. Dr. Feldman has also experienced the effect of CXL re- ferrals from other providers, and an Outcomes of Phase III studies of Avedro’s KXL system in progressive keratoconus (red) and increased need for ancillary services post-refractive surgery ectasia (pink). Treated keratoconic eyes improved by 1.6 D at one related to cross-linking. “Bringing in year; control eyes continued to progress. In ectatic eyes, Kmax improved by 0.7 D at one patients for CXL evaluations––even year, while control eyes worsened by 0.6 D. those who have primary ophthalmologists––has increased the keratoco- tasia and visual fl uctuation following from most previous epi-on studies is nus population within my practice RK, although we have not person- that the requirement of our protocol and increased the volume of related ally treated any patients in that last has always been that the surgeon has services (keratoplasty, specialty lens- category.” to assess the cornea after the load- es, etc.),” he says. Dr. Epstein’s group favors transep- ing has been completed, to make As an investigator for the CXLUSA ithelial cross-linking in part because certain that the cornea has in fact Study Group with seven years of cross- they say it broadens the age range absorbed adequate riboflavin,” he linking experience, Randy J. Epstein, of prospective patients and yields says. “We have a fl ip chart that has MD, CEO of Chicago Cornea Con- benefi ts faster than epi-off crosslink- standardized photographs of differ- sultants and a professor of ophthal- ing. “By not removing the corneal ent degrees of saturation, from grade mology at Rush University in Chi- epithelium, it signifi cantly enhances one to grade fi ve. We aim for a grade cago, says the 2016 FDA approval the benefi t-to-risk ratio,” he says. of three to four as optimal.” of KXL hasn’t affected his practice. He credits Dr. Rubinfeld with “I’m part of a clinical trial, so I’m changing CXLUSA’s protocol to Treat Sooner? Younger? not using the FDA-approved ver- epi-on after a very short period of sion,” he explains. “We’re in an FDA epi-off cross-linking. “After suffer- Keratoconus is generally a disease IND study looking at the safety and ing through a month of epi-off treat- that starts progressing sometime in effi cacy of a transepithelial corneal ments which brought us back to the adolescence and stabilizes by the cross-linking system that was devel- PRK days of bandage lenses, pain fourth decade of life.4 KXL is cur- oped by Roy S. Rubinfeld, MD.” The and the whole nine yards, we were rently approved for patients aged 14 current Phase II study (Clinicaltrials. very happy to switch to epi-on and years and up with progressive dis- gov identifi er: NCT03029104) is en- never looked back,” Dr. Epstein re- ease, although cross-linking children rolling 3,000 patients. calls. and adolescents soon after diagnosis “We’ve treated over 2,000 patients He considers adequate ribofla- without waiting for disease progres- in our center alone,” Dr. Epstein vin absorption more important to sion may also be safe and benefi cial.5 continues. “In that group, we’ve had cross-linking success than removal or Dr. Rabinowitz has developed four retreatments, all of which have retention of the corneal epithelium. criteria that help him decide when been in patients under the age of 21. The CXLUSA group’s protocol relies to treat.“I use a 1-D change in the Three patients have needed corneal on a customized ribofl avin formula- steepest part of the cornea; a change transplants. So we feel that our sys- tion and documentation of adequate in prescription, particularly in the tem is pretty safe and effective. The riboflavin loading before light ex- astigmatism; third, patient com- indications are keratoconus, forme posure to promote this. “The main plaints of worsening vision; fourth, fruste keratoconus, post-LASIK ec- thing that makes our study different an obvious pattern of keratoconus

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REVIEW Focus

on topography; and fi fth, a change in younger people when they are diag- who had steeper cones––patients we OCT greater than 20 µm,” he says. nosed, because they are invariably defi ned as 55 D or more––were more “Only patients 14 years of age or going to worsen over time,” he says. than fi ve times more likely to improve older who demonstrate clear pro- When practicable, Dr. Hersh relies by 2 D or more,” he says. “However, gression of disease are candidates for on serial topographies to help him we didn’t fi nd any indictor for failure treatment.” decide when to treat. “One doesn’t of the procedure to diminish progres- “I have not treated anyone young- simply get KC at 14 and then have it sion. But generally, patients who were er than 14 years, but I have treated a stop,” he says. “It tends to progress worse tended to have a more appre- 14-year-old. I would consider young- more rapidly when you’re younger.” ciable improvement. Similarly, look- er children and create a special con- ing at corrected vision, most patients sent as needed,” says Dr. Feldman. stayed the same, but we had about 25 He weighs the risks and benefits to 30 percent who got more than two before offering treatment. “I treat lines better; the primary predictor of when I believe that the patient is at that was a worse baseline visual acu- risk for vision loss and that the ben- “It’s a pretty low- ity. Patients who were 20/40 or worse efi ts of CXL outweigh the risks,” he tech procedure: The were about fi ve or six times more like- says. “This generally means a patient ly to improve by two lines or more, with a history of recent progression ultraviolet light is not compared to those who were better (within the last one to two years). an excimer laser, and off to start with. However, in younger patients (<21) I “We also noted a little trend in pa- will treat if there is evidence of mod- ribofl avin is obviously tients who had very good vision: They erate disease even in the absence of not that complicated were at slightly greater risk of losing progression, because these patients one line of vision with the proce- are at high risk for progression.” of a molecule, so when dure,” adds Dr. Hersh. “I think these Dr. Epstein advocates treating at you get right down are all variables that those beginning younger ages as needed. “Initially, cross-linking need to understand and everybody thought that in terms of to it, it should be discuss with their patients when de- the actual indication for the proce- something that ought termining who should have it done dure, you would have to document and why they are having it done.” progression. But I don’t really think to be widely available Although cross-linking can afford it’s ethical to make that demand for at a reasonable price. patients better visual acuity and people under the age of 25, or maybe function, all four doctors stress to even 30,” he says. “You know it’s go- But there are a lot of their patients that these are not the ing to progress. If it was my kid, I factors involved.” defi nitive goals of treatment. “What don’t think I would want to sit around we tell patients and their families— and wait for objective evidence of —Randy J. Epstein, MD and what a lot of my colleagues don’t progression before I recommended realize—is that there are three goals treatment. of this procedure,” explains Dr. Ep- “We can treat people as young as stein. “The first goal is to stop the 8 years of age,” he continues. “Most progression. The second goal is to people would not be too excited Managing Expectations enhance contact lens tolerance. We about treating an 8-year-old with epi- tell them all going into it that this is off cross-linking. Ours is a kinder, After deciding when to treat, is our actual objective, because there gentler version of the procedure. We there a way to predict which patients are a number of studies that have hope that the FDA eventually ap- will respond best to cross-linking? Dr. been published showing a fairly dra- proves a similar system. In kids, we Hersh and Steven A. Greenstein, MD, matic impact of corneal cross-linking have the unique ability to stop a dis- published a multifactorial analysis6 on the anterior cornea, both with ease in its tracks.” of 104 eyes to see if they could fi nd regard to the keratocytes and more Dr. Hersh concurs that it is better predictors of how individual patients importantly, the corneal nerves, so to catch keratoconus earlier when it would fare post procedure. “With re- many patients who have previously presents in young patients. “I person- gard to actual improvement in corneal been ‘contact-lens intolerant’ find ally think that it’s important to treat topography, we found that patients that they can effectively wear con-

26 | Review of Ophthalmology | September 2017

0023_rp0917_f2.indd23_rp0917_f2.indd 2626 88/25/17/25/17 3:393:39 PMPM Brad H. Feldman, MD tacts. In our practice, our optom- etrists are able to fi t 95 percent of our treated patients successfully. The third objective is to get some improvement in vision,” he says. Dr. Epstein also notes that most of his patients do report rapid onset of visual improvement, thanks to leav- ing the epithelium intact. “Most of our patients tell us as early as the Adequate ribofl avin loading prior to UVA light exposure is crucial to ocular safety and a next day that they are already seeing good outcome, regardless of the corneal collagen cross-linking protocol employed. better, either with their glasses or when they put on their old contacts, after cross-linking, however. “I like been very equivocal thus far,” he and that’s something we haven’t been to wait three to six months after do- says. “It seems that it’s more effective able to explain very well,” he says. ing cross-linking before I do the IN- in earlier, more superfi cial infections, “Cross-linking is not designed ex- TACs,” he says. but a lot more work really needs to pressly to help vision, but to halt pro- Dr. Epstein also adds INTACs af- be done to determine if it’s really ef- gression,” stipulates Dr. Rabinowitz. ter cross-linking to improve patients’ fi cacious.” “A small percentage of cross-linking visual outcomes. “If they’re not fi t- Dr. Epstein’s study colleagues have patients do get somewhat improved table with contacts, or if they want to had some experience with the use vision, but I don’t like to tell my pa- take it to the next level visually, they of cross-linking for infection con- tients that. I don’t know who’s go- can have INTACs put in after they’re trol, but he’s skeptical. “We actually ing to get improved vision and who cross-linked,” he says. had an arm of our earlier IRB study isn’t; so if they went in expecting im- “INTACs are meant to change the where a number of the centers–– proved vision and they didn’t get it, corneal topography even more dra- ours not included––were doing it for they would be very disappointed. It’s matically than cross-linking,” says therapeutic indications. The results better for me to tell them, ‘Look, this Dr. Hersh. “We do them on a fairly were not very impressive, and there will stop the progression of the kera- frequent basis because they tackle were just so many confounding fac- toconus, but if you want to make your a problem that KC patients have, tors that I have a hunch that it’s not vision better, then we’ll do INTACs separate and distinct from stability, going to pan out to be a big deal,” combined with cross-linking.’” and that is the need to improve cor- he says. neal topographic asymmetry. Indeed, He’s keen on the potential of com- CXL Plus INTACs, Maybe More with the techniques we’re using now, bining refractive procedures with we can achieve upwards of 7 D of cross-linking to maximize visual im- As previously mentioned, Dr. improvement in the corneal topog- provement, however. Dr. Epstein Rabinowitz is currently investigating raphy, both fl attening the cone and relates that one of his patients, after the use of INTACs after cross-link- restoring corneal symmetry with im- cross-linking and INTACs, went to ing. “If you combine it with the IN- proved superior-to-inferior ratio.” other surgeons for subsequent to- TACs, then you actually get improve- Dr. Hersh adds that he’s involved in ric ICLs and topographically guided ment of the vision,” he says. “Our a clinical trial seeking to determine PRK to achieve spectacle and con- study involves comparing a combina- how well INTACs and cross-linking tact lens independence. “That shows tion of INTACs and cross-linking to work together, as well as whether how far you can carry things,” he cross-linking alone. We’ve found that INTACs procedures should be done says. “We just started doing topo- if you combine the two, the visual concurrently with cross-linking, or graphically guided PRK and LASIK outcomes are actually quite a lot bet- three months post-CXL. treatments with our Wavelight Al- ter. I have followed some patients Cross-linking for infection con- legretto laser, and we’re cautiously for as long as eight years. Follow-up trol, or PACK-CXL (photoactivated optimistic that we may be able to use is ongoing––about a 10-year cycle–– chromophore for infectious keratitis at least some elements of that to at because we really want to see what cross-linking) is one application that some point start doing custom topo- happens long-term.” has not yet convinced Dr. Hersh of graphically guided PRK on patients Dr. Rabinowitz doesn’t perform its efficacy. “With regard to infec- with keratoconus who have previous- the INTACs procedure immediately tious keratitis, published results have ly been cross-linked. That’s really our

September 2017 | reviewofophthalmology.com | 27

023_rp0917_f2.indd 27 8/25/17 3:39 PM Cover Cornea

REVIEW Focus

ultimate goal. That’s off label, and I system or the Photrexa drugs. Whether and when cross-linking don’t anticipate an approval. But it’s “Either insurance companies will becomes accessible to all patients an exciting possibility,” he says. choose to set a very high reimburse- who could benefi t from it remains an Dr. Hersh anticipates the ex- ment fee for the procedure (much open question, but its very availabil- pansion of corneal cross-linking in higher than what insurance compa- ity is a game changer. “Cross-linking combination with therapies that will nies have reimbursed thus far), and is a great new improvement,” Dr. improve vision in newly stabilized we will be able to offer the treatment Hersh observes. “It really tackles the eyes. “I think you’re going to find to all patients, or the insurance re- most important thing that we need to increasing interest in topography- imbursements will be too low and address in ectatic corneal processes, guided PRK and PTK as adjuncts to providers will only offer this as a cash and that is keeping patients from cross-linking, to further improve the procedure. This will severely limit progressing until they can no longer corneal topography. In addition, we’ll access to treatment for the majority see well and are in need of corneal do ICLs with great success in many of keratoconus patients––as has been transplant. There are also adjunctive keratoconic patients who are stabi- the case now for years. This would procedures that may further improve lized with cross-linking,” he says. be a terrible outcome,” opines Dr. corneal and visual rehabilitation. Dr. Hersh is also participating in a Feldman. There is lot that we’ll be seeing on study looking at the implantation of “Access is a challenge for patients the keratoconus frontier.” preserved corneal tissue to improve and for doctors,” adds Dr. Rabinow- corneal topography, thickness and itz. “Because offering the procedure Dr. Rabinowitz reports no fi nan- regularity in cross-linked eyes. is expensive, the physician has to cial interests related to cross-linking do a significant volume to pay for or any of the associated products Is Access a Challenge? the overhead. It takes a lot of chair mentioned in this article. He has re- time––at least an hour to an hour and ceived NIH funding for a study of the For all if its promise, many Ameri- a half. I think the whole issue of fees genetics of keratoconus through the can surgeons are still integrating the is still evolving.” NEI for 23 years. Dr. Hersh was the FDA-approved cross-linking proto- Dr. Feldman stresses that guiding medical monitor for the Avedro KXL/ col into their practices—and hoping preoperative patient expectations Photrexa/Photrexa Viscous clinical it will be accessible and economically and following up postoperatively are trials. Dr. Feldman has not reported viable. Effective July 1, 2017, Avedro costly extensions of the considerable relevant fi nancial interests. Dr. Ep- hiked prices for the KXL system’s two intraoperative chair time that cross- stein is a consultant for Alcon and photosensitizing agents, Photrexa linking requires. “To offer patients Shire, but has no fi nancial interests and Photrexa Viscous, from $595 to the highest quality experience, you in products related to cross-linking. $2,850. Prior to this, a Dutch study need to spend a lot of chair time 1. Raiskup F, Theuring A, Pillunat LE, Spoerl E. Corneal collagen attempted to estimate the cost of with them preoperatively and post- crosslinking with ribofl avin and ultraviolet-A light in progressive Dresden protocol cross-linking in the operatively,” he explains. “Often, keratoconus: Ten-year results. J Cataract Refract Surg 2015; health-care setting, and postulated patients arrive believing that CXL is 41:41-46. 2. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK on that the total cost of the procedure a ‘cure’ that will provide them with behalf of the United States Crosslinking Study Group. United for one eye, inclusive of pre- and normal vision; many believe this is States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment. Ophthalmology 2017;124;9:1259– postop care, was about $1,929.47 like LASIK. There is almost always 1270. Epub. ahead of print. DOI: http://dx.doi.org/10.1016/j. ±$194.95.7 worsening of vision transiently af- ophtha.2017.03.052. Accessed 7/27/2017. 3. Hersh PS, Stulting RD, Muller D, Durrie DS, Rajpal RK and “It’s a pretty low-tech procedure: ter the treatment, with visual im- the United States Crosslinking Study Group. (in press).U.S. The ultraviolet light is not an excimer provement typically delayed until multicenter clinical trial of corneal collagen crosslinking laser, and ribofl avin is obviously not several months out. This requires for treatment of corneal ectasia after refractive surgery. Ophthalmology 2017. DOI: http://dx.doi.org/10.1016/j. that complicated of a molecule, so much handholding. Patients who ophtha.2017.05.036. Accessed 8/2/2017. when you get right down to it, it are contact lens dependent are also 4. Rabinowitz YS. Keratoconus. Surv Ophthalmol 1998;42;4:297- 319. should be something that ought to forced out of contacts for signifi cant 5. Chatzis N, Hafez F. Progression of keratoconus and effi cacy be widely available at a reasonable periods of time or need re-fi ts, and of corneal collagen cross-linking in children and adolescents. J Refract Surg 2012;28;11:753-758. price. But there are a lot of factors this creates a situation where pa- 6. Greenstein SA, Hersh PS. Characteristics infl uencing outcomes of involved. We do a fair amount of tients are out of work, sometimes corneal collagen crosslinking for keratoconus and ectasia: Implications discounting for indigent patients,” for weeks. This again requires plen- for patient selection. J Cataract Refract Surg 2013;39;8:1133-40. 7. Godefrooij DA, van Geuns P, de Wit GA, Wisse RPL. What are the costs of says Dr. Epstein, who is involved in a ty of time for communication as well corneal cross-linking for the treatment of progressive keratoconus? clinical trial and doesn’t use the KXL as paperwork.” (Letter to the editor.) J Refract Surg 2016;32;5:355.

28 | Review of Ophthalmology | September 2017

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RP0917_BioD.indd 1 8/24/17 2:55 PM Cornea REVIEW Cover Focus Work Up Corneal Ulcers Like an Expert

Walter Bethke, Editor in Chief

The best ways he diagnosis and management third- and fourth-most important of a suspected corneal infec- question to ask is: ‘Are you a contact to diagnose and Ttion can be a lot like entering a lens wearer?’ ” says Sadeer Hannush, maze: You have no map to your desti- MD, attending surgeon at the cornea heal a corneal nation and many promising pathways service at Wills Eye Hospital and med- turn into disappointing dead ends. ical director of the Lions Eye Bank of infection. You don’t have to get lost amid myriad Delaware Valley. “Contact lens wear details from the patient’s history and is the most common cause of infec- exam, however. In this article, corneal tious keratitis. If the patient says, ‘Yes,’ specialists detail how they diagnose you can then try to identify a breach and treat corneal ulcers, in the hope of in contact lens-care protocol by ask- giving you some much-needed direc- ing questions such as, ‘Do you sleep tion in your search for a cure. in them? Are you cleaning them correctly? Do you swim in them?’ ” Deciding Factors Christopher Rapuano, MD, director of Wills Eye Hospital’s cornea service, Though corneal specialists usually adds that showering in contact lenses see ulcers when they’re at advanced isn’t that great, either, though some stages, rather than just suspicious patients do it. “I also ask, ‘How old are specks, they can shed light on what is the contact lens that you put in the the comprehensive ophthalmologist eye?’ ” Dr. Rapuano says. “Just this should watch for in the patient history morning I saw a patient who had been and exam in order to root out the cause sleeping in the same contact lenses for of the patient’s complaint. three months straight.” • History. “The first-, second-, If the patient isn’t a contact lens wearer, there are other avenues to ex- All images: Christopher Rapuano, MD plore in the history. “In that case, look for other causes, such as trauma from a child’s ﬁ ngernail, a mascara brush or working under a car,” Dr. Hannush A large central notes. Physicians also note that a par- Scedosporium fungal ticular kind of injury can lead to a cer- corneal ulcer with a tain type of organism getting into the small hypopyon. Note cornea. An injury from a plant or an the irregular edges of the inﬁ ltrate. animal, or from something that caused

30 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

030_rp0917_f3.indd 30 8/25/17 4:22 PM a foreign body from the ground to be thrown into the patient’s eye are often behind fungal infections, and exposure to fresh water is a risk factor for Acanthamoeba. Also, ask about prior surgery, as both cataract and refractive procedures are predisposing factors to corneal infections. Another important part of the history, at least from a corneal specialist’s perspective, is whether the patient has already been treated with something for the condition. “Some patients are on antibiotics—sometimes fortified antibiotics—antifungals, anti-ameobic medications or antivirals,” says Dr. Rapuano. “Some patients come in on all of them! Their referring doctor threw the whole pharmacy at them, hoping something would work.” Dr. Rapuano adds that he also focuses on when the symptoms started. “If the symptoms started a day ago, that gives me a different differential diagnosis than if it was a week or a month ago,” he says. • Exam. Bennie H. Jeng, MD, chair of the Department of Ophthalmology and Visual Science at the University of Maryland School of Medicine, says it’s important to initially confi rm that you are indeed dealing with an infection. “First, when examining the patient, determine if it looks infectious or not,” Dr. Jeng says. “Sometimes a sterile infi ltrate might look like an infection when in fact it’s just infl ammation in the cornea. An ophthalmologist might see contact-lens-related sterile infil- trates that appear in the periphery due to such things as contact lens over- wear and hypoxia. The challenge, then, is to understand the risk factors well enough, and be comfortable enough with the clinical appearance, to know when an infi ltrate is probably infl ammatory, and to treat it with steroids, not just antibiotics.” The level of visual acuity is important, as well. “If it’s 20/20 and the patient has a little peripheral ulcer, I’m not as concerned as I would be if it’s See us at AAO Booth #1545

030_rp0917_f3.indd074_rp0415_ttops.indd 31 77 000_rp1015_varitronics_half.indd 1 8/25/173/27/158/9/17 10:58 4:222:41 PMPMAM 088_rp0315_varitronics_frac.indd 1 2/9/15 2:23 PM 030_rp0917_f3.indd 32 32 antibiotics andsteroidsdevelops an someone whoisonchronic topical a clue,”henotes.“Forexample, say cases itis.However, itcanbebacterial. endothelium isfungus,andinalotof satellite lesionsandaplaqueonthe tell youthatafeatheryinfi or another. Forinstance,textbookswill tics thatcanpointusinonedirection fungus. Therearecertaincharacteris- but it’s morelikeaclassicbacteriaor ever, let’s saywedon’t thinkit’s viral, actually treatedwithsteroids.How- stroma asanimmuneprocess,andit’s simplex viruskeratitismanifestinthe tive. “We oftenseerecurrentherpes some presentationscanbedecep- ology,” saysDr. Jeng,whonotesthat gists aren’t equippedtoculture.” ing, andmostgeneralophthalmolo- for avision-threateningulceriscultur- patient “becausethestandardofcare mologist willalmostalwaysreferthe sion-threatening, thegeneralophthal- needs tobemanaged.” the IOPismostlikelyprettyhighand When there’s alotofinflammation, Also, checktheintraocularpressure. Does thepatienthaveahypopyon? there lotsofanteriorchambercells? for infl ammation intheeyeitself;are thinning thecorneaatall.Next,look al infiltrate withnoulcerationthat’s not ferent categorythanasmall,peripher- about toperforate,thatputsitinadif- away 95percentofthecorneaandis thin itis.Ifit’s abadulcerthat’s eaten infl it’s intheperiphery. Gaugehowmuch cornea, that’s moreconcerningthanif of theulcer. Ifit’s inthemiddleof an ideaofthesize,densityandlocation due toexposure.Attheslitlamp,get If theydon’t, thiscanleadtoproblems recently? Dothelidscloseproperly? them? Didthepatienthaveshingles lids look?Dothehaveulcerson cer,” Dr. Rapuanosays.“Howdothe hand-motions withalargecentralul- REVIEW “The patient’s conditionisalso “The nextquestioniswhat’s theeti- Dr. Hannushsaysiftheulcerisvi- ammation is in the cornea and how ammation isinthecorneaandhow | Focus Cover

Review ofOphthalmology

Cornea ltrate with with ltrate | September2017 involvement orevenperforation. radiating fromtheulcerindicatedeep perforation.a central corneal The striae A small, ulcerthathascaused deepcorneal under thecontactlens. was placed.Smallairbubblescanbeseen after which abandagesoftcontactlens the perforated ulcerintheprevious image, tissuegluewas usedtotreatCyanoacrylate for weeks,”hesays.“Theymayhave tients oftensaythatit’s beengoingon what tolookfor. “Onthehistory, pa- can causespecifi gressive fi indolent yeastbutratherthemoreag- for it,andthefungusisusuallynot they havetoahighersuspicion ophthalmologists seemorefungus,so however, whereit’s hotandhumid, a yeastinfection.Ifyou’reinMiami, more alongthelinesofCandidaor in someway. Inthosecaseswe’dthink roids orwhoisimmunocompromised we do,suchasapatientonchronicste- there’s somespecifi c reasonforitwhen us toencounterafungus,andoften or northernCalifornia,it’s unusualfor For instance,intheNortheastU.S. where youpracticeisalsoafactor. tion couldbefungal.Theenvironment nocompromised state,andtheinfec- infection: Thiseyeisinalocalimmu- Dr. RapuanosaysAcanthamoeba lamentous variety.” c fi ndings if you know ndings ifyouknow

thology labtolookfor also sendsomespecimenstothepa- such cases,I’lldothecultures,but with theclinicalfi ndings andexam.In amount ofpain,welloutproportion bles it.Also,theyoftenhaveanextreme tion, becauseAcanthamoebaresem- already beentreatedforherpesinfec- cin, ciprofl oxacin and tobramycin.” fortifi For one onyourlistuntilprovenotherwise. ulcer, thenPseudomonasisnumber concerned aboutacontactlens-related monas coverage.Obviously, ifyou’re probably hasalittlebitbetterPseudo- and negativecoverage.Gatifloxacin lar becauseithadgoodgrampositive floxacin usedtobethemostpopu- negative drug,butnotgreat.Moxi- MRSA. Polymixinisadecentgram positive-coverage drug,especiallyfor Trimethoprim isaverygoodgram- which istrimethoprimandpolymixin. good wide-spectrumdrug,Polytrim, fl biotic. “Mostuseafourth-generation the patientonabroad-spectrumanti- set uptoculture,andwillusuallystart general ophthalmologistusuallyisn’t guideline, though,andnotabsolute.” than that,Itendtoculture.Thisisa eter, Itendnottoculture.Ifit’s larger size, ifit’s underabout2mmindiam- or ry thatwouldmakemesuspectfungus I’ll cultureitifthere’s anunusualhisto- for metocultureit,”heexplains.“Also, things makeitworseandmorelikely it is;themoreulceratedis—allthese ture: themorecentralitis;bigger the issue.“Thingsthatpushmetocul- Rapuano explainshowheapproaches to referthepatientforculturing.Dr. prehensive ophthalmologist,whether culture theorganism,andforcom- sion, forthem,wouldbewhetherto Corneal specialistssaythenextdeci- cysts intheepithelium.” uoroquinolone,” hesays,“oravery Dr. Hannush saysthecornealspe- Dr. Hannushacknowledgesthatthe • Culturingandmanagement. Acanthamoeba. Intermsofulcer , if you’re not giving Pseudomonas, ifyou’renotgiving ed antibiotics, considergatifl Acanthamoeba oxa- 8/25/17 4:23 PM

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RP0917_Blythe.indd 1 8/14/17 11:49 AM 0030_rp0917_f3.indd 34 3 0 _ r p 0 9 1 7 _ f 3 roids may play a role in the treatment roids mayplayaroleinthetreatment Baquacil, speciallycompounded.” oeba I haveahighsuspicionfor lab testpositivefor drop. Ifthespecimensatpathology them onacompoundedamphotericin fi don’t carryitsoit’s notalwayseasyto Fusarium Rapuano. “Theygetnatamycinifit’s shift medicationssignifi fi on thecultureresultsformaximumef- say they’lladjustthemedicationsbased infi inferior angle.Eventually, thecorneal instead itjustlookslikeamassinthe anymore. You don’t seealeveltoit,but gets organized—meaningit’s notliquid of thehypopyon.Thehypopyonfi is re-epithelializationandresolution look anybetter. Afterthat,thenextsign can occurevenwhentheulcerdoesn’t decrease inpain,”heexplains.“This days. “Thefirstsignofrecoveryisa then seesthepatientafteroneortwo wash eachotherout.”Dr. Hannush rate thedrops’timingsotheydon’t totally exhausted.Ialsotrytosepa- the nightbecauseitmakespatients nush. “Ineverdoeveryhourduring throughout thenight,”saysDr. Han- hour whileawakeandeverytwohours prescribe thedrugsforuseeveryhalf pared byacompoundingpharmacist.” three oftheseproductsneedtobepre- vancomycin 25mg/cc,”henotes.“All cc andeithercefazoline15mg/ccor tibiotics areusuallytobramycin14mg/ on fortifi scrape, cultureandstartthepatient sual axis,hesayscornealspecialistswill hypopyon oranulcerclosetothevi- signifi cer isn’t vision-threatening.Ifthere’s ready onboardandforwhomtheul- patients withnotopicalantibioticsal- cialist willalsofollowthiscoursefor 34 . nd. Ifit’s cacy. “Ifitprovestobefungal,we’ll i n

d REVIEW Corneal specialistsalsonotethat ste- If culturesweredone,sub-specialists Treatment protocolscanvary. “I’ll ltrate startsdissolving.” d | Focus Cover

Review ofOphthalmology

, I’llstartthemonBroleneand 3 cant anteriorchamberreaction, 4 ed antibiotics.“Fortiﬁ , though a lot of pharmacies , thoughalotofpharmacies Candida

, you usually can put , youusuallycanput Acanthamoeba Cornea cantly,” says Dr. Acantham- | September2017 ed an- ed , or , or rst rst tion isimproved,andgofromthere.” steroid drop,too,oncetheinfl during theday,” hesays.“We’ll stopthe like andthenslowlydecreasethemeds mycin, ciprofl a nighttimeointmentsuchasgenta- tered throughoutthenight.“We’ll start ment toreplacethedropsadminis- medications andaddanighttimeoint- Dr. Rapuanowill slowlydecreasethe or q.i.dandseehowtheydo.” often useLotemaxorPredFortet.i.d. the infection.Forthisapplication,we’ll or threedaystoaweekaftertreating depends onthepatient.Itcanbetwo start thesteroids,ifyouusethematall, they’re makingthingsworse.Whento have tostopthesteroidsifitlookslike to befollowedveryclosely, andyou of steroids.Patientsonsteroidshave since itcanimprovewithjudicioususe nicely ifthere’s alotofinfl infections, however, somecanrespond Acanthamoeba infections. We don’t usethemearlyfor edged sword,though,inpatientswith drops,” hesays.“Steroidsareadouble- can thinkaboutstartingsomesteroid on theappropriateantibiotics,you what we’retreatingandthepatient’s the infection’s undercontrol,weknow be usedcarefully. “Afterafewdays,if of someulcers,thoughtheyhaveto Tough Cases be differentthanyoufi that, insomecases,theorganismmay how torespond. to killorwoundsdon’t heal.Here’s ting better.” voriconazole 1%andhestarted get- cally startedthepatienton topical suspected afungalulcer, soIempiri- had acaselikethis.Irescrapedand scrape andculture,”hesays.“Ijust there’s noresponse,youhavetore- tified tobramycin/vancomycinand “If, forexample,thepatient’s onfor- Over thenextonetothreeweeks, • Switchdrugs. In somecases,organismsprovehard oxacin, polysporin or the oxacin, polysporinorthe or fungus. In bacterial orfungus.Inbacterial Dr. Hannushsays rst expected. rst ammation, ammation, amma- in thearticle. cial interestinanyproductsdiscussed Drs. HannushandJenghaveno fi gan, Bausch+LombandBio-Tissue. use severallayers.” them on,somesuturethem,and learning curve.Somephysiciansglue Dr. Rapuanosays.“There’s notalarge membrane isprettystraightforward,” Matrix, BioDOptixorAril.“Usingthe membrane suchasAmbioDisk,Oculo- brane suchasProKeraanddehydrated for thisincludecryopreservedmem- niotic membrane,”hesays.Options scratch isn’t healingwell,we’lluseam- like it’s gettingbetter, butthecorneal we’ve treatedtheinfectionanditlooks having adiffi damage tothetissuethatsurfaceis cornea buttheinfectiondidsomuch he’s abletokilltheorganismin no saysthat,insomerareinstances, to 12monthslater,” hesays. get cloudyandneedtoberepeatedsix resolving theinfection,buttheyoften have aprettygoodsuccessratefor grows overtime.“Thesetransplants wait toolongtodoit,sincetheulcer central ulcers.It’s alsobetternotto big sincethey’reoftenusedforlarge periphery, butoftentheyneedtobe if theperforationissmallandin He saysthesetransplantscanbesmall an emergency—or‘hot’—transplant.” better. Often,though,youhavetodo tion ifyouthinktheinfection’s getting can usesomegluetosealtheperfora- a smallperforationinthecornea,you no continues,“anditlookslikeit’s just ogy andhalftotheculturelab. with apunchandsendhalftopathol- third toone-halfcornealthickness you candoabiopsy:godownone- and isn’t showinguponculture,so might determinethatit’s justtoodeep reculture,” saysDr. Rapuano.“Oryou they’re notgettinganybetter, youcan Dr. RapuanohasconsultedforAller- • Non-healingwound. “If they’reperforated,”Dr. Rapua- • Emergencytransplants. cult timehealing.“When Dr. Rapua- nan- “If 88/25/17 4:23 PM / 2 5 / 1 7

4 : 2 3

P M Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series

Welcome to the second year of Mackool Online CME! With the generous support of several ophthalmic companies, I To view CME video am honored to have our viewers join me in the operating go to: room as I demonstrate the technology and techniques that I www.MackoolOnlineCME.com have found to be 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 Episode 21: time – allowing you to observe every step of the procedure. Richard J. Mackool, MD “Floppy Iris and As before, one new surgical video will be released monthly, Miotic Pupil in a and physicians may earn CME credits or just observe the case. New viewers Hypertensive Female” are able to obtain additional CME credit by reviewing previous videos that are Surgical Video by: located in our archives. Richard J. Mackool, MD 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. In this case, I present a variety of phaco techniques and pearls as cataract CME Accredited Surgical Training Videos Now extraction and multifocal IOL Available Online: www.MackoolOnlineCME.com implantation is performed in an eye with a small pupil and moderately fl oppy iris. Richard Mackool, MD, a world renowned anterior segment ophthalmic A split screen is utilized microsurgeon, has assembled a web-based video collection of surgical to demonstrate surgeon cases that encompass both routine and challenging cases, demonstrating both hand position throughout familiar and potentially unfamiliar surgical techniques using a variety most of the procedure. of instrumentation and settings. Other techniques including capsulorhexis centration, This educational activity aims to present a series of Dr. Mackool’s surgical deep sculpting, chopping videos, carefully selected to address the specifi c learning objectives of this instrumentation, concerns activity, with the goal of making surgical training available as needed online for regarding mixing brands of surgeons motivated to improve or expand their surgical repertoire. multifocal IOLs, full thickness (penetrating) limbal relaxing Learning Objective: incisions for astigmatism, and After completion of this educational activity, participants should be able to: stromal hydration are • Discuss the possible cause and demonstrate the surgical management of a also presented. small and eccentric pupil/fl oppy iris in a hypertensive woman.

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Amedco and Postgraduate Healthcare Education, LLC (PHE). Amedco is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement Amedco designates this live activity for a maximum of .25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Commercially supported by: Endorsed by: Jointly Provided by: Supported by an unrestricted independent Review of Ophthalmology® medical educational grant from: Carl Zeiss Meditec Crestpoint Management Video and Web Production by: & Glaukos JR Snowdon, Inc Alcon MST Cornea REVIEW Cover Focus How to Manage Conjunctivochalasis

Benjamin B. Bert, MD, FACS, Fountain Valley, Calif.

Tips for diagnosis, nfortunately, as we age our rhages. If these symptoms worsen body’s tissues lose their elas- in downgaze, it’s more likely that as well as medical ticity. The ocular surface is they’re due to the redundant con- U 4 not exempt from this phenomenon, junctiva in conjunctivochalasis. An- and surgical and one of the most common signs other difference from most forms of of this degradation is conjunctivo- dry eye is that the blurred vision and management. chalasis. In 1942, Wendell Hughes, eye pain actually worsen with fre- MD, coined the term conjunctivo- quent blinking. One explanation for chalasis, meaning relaxation of the this phenomenon is that the upper conjunctiva.1 However, the entity eyelids are not dipping into the in- itself was described previously by ferior tear meniscus, but only touch- Anton Elschnig, MD, in 1908 as ing the redundant conjunctiva and loose, nonedematous conjunctiva.2 then returning to their open position We currently defi ne conjunctivocha- without spreading a new tear film lasis as loose, redundant conjunctiva, over the ocular surface. Combin- most often located on the inferior ing a faster tear breakup time4 with globe. In this article, I’ll describe the compromised tear-replenishing puts defi ning characteristics of conjunc- symptomatic conjunctivochalasis pa- tivochalasis and review the best ways tients at a distinct disadvantage when to treat it. it comes to ocular surface comfort. In regards to epiphora, conjunc- Diagnostic Features tivochalasis is hypothesized to contribute in two ways: First, the redu- While conjunctivochalasis increas- plicated folds of conjunctiva disrupt es in incidence and magnitude with the inferior tear lake (Figures 1 and age,3 its appearance and location 2) and, second, the conjunctiva itself can vary. On average, it’s more com- can cause a mechanical blockage of mon to see conjunctivochalasis of the inferior punctum.5-6 Blockage the inferotemporal bulbar conjunc- of the lower punctum is more com- tiva than inferonasally.4 Many of the mon with nasal conjunctivochalasis symptoms of conjunctivochalasis are or with gaze toward the punctum. similar to the complaints in dry-eye Dr. Yan Wang and her group at Ja- disease, including eye pain, blurred pan’s Keio University showed that vision, epiphora, dryness and the blockage of the tear drainage keeps presence of subconjunctival hemor- infl ammatory cytokines on the ocular

36 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

0036_rp0917_f4.indd36_rp0917_f4.indd 3636 88/25/17/25/17 5:105:10 PMPM Figure 1. Mild conjunctivochalasis seen with normal illumination. It Figure 2. The patient from Figure 1 seen with fl uorescein dye and a can be diffi cult to see the folds when they are this mild. However, cobalt blue fi lter. The conjunctival folds and their obliteration of the this patient was still symptomatic with epiphora and no corneal tear lake are more easily identifi able. staining.

surface longer, in particular interleu- in their disease course. Though not reduce the effects of conjunctivocha- kin-1β and TNF-α. Dr. Wang hy- all patients with conjunctivochalasis lasis, especially in regards to the dis- pothesized that the prolonged con- will have symptoms, a patient who’s ruption of the tear fi lm. Lubricants tact with these infl ammatory markers complaining of burning, irritated or tend to be the fi rst-line medications, can lead to increased discomfort and dry eyes should be examined closely and while there have not been specif- the activation of MMP-1 and MMP- for the presence of conjunctivocha- ic studies looking at different viscosi- 3 in conjunctival fi broblasts, causing lasis. Using the following options, ties and their effects, I tend to utilize additional breakdown of the con- the treatment can be tailored to the the gel drop as fi rst-line treatment junctival elasticity and furthering the patient and his specific pathology, for these patients. The rationale for progression of conjunctivochalasis.7 yielding a better chance for success. doing this is that the inferior tear This hypothesis would contraindi- meniscus has been obliterated by cate one of the standard treatments Medical Treatment the multiple folds of conjunctiva and of dry-eye disease, which would be to is not providing a supply of tears to place punctal plugs and purposefully Before proceeding to surgery, it’s be spread during the patient’s blink. obstruct tear outfl ow. prudent to try to fi rst medically treat Thin tears would continue to be the patient’s symptoms. Here’s how disrupted by the conjunctival folds. Treatment to approach the different severities However, more viscous drops are of conjunctivochalasis: able to stay suspended on the surface One of the most frustrating things • Mild. If patients are asymp- of the conjunctiva and act in a fash- about treating patients with ocular tomatic then they can simply be ion similar to a tear lake. surface complaints is that they’re observed. The finding of conjunc- • Severe. In severe cases in which chronic and can be refractory to tivochalasis alone does not warrant the conjunctivochalasis causes the many treatments. Closely examin- treatment. conjunctiva to be exposed even when ing these patients can allow for tar- • Moderate. When patients be- the eyelids are closed, using artifi cial geted treatment that can start the come symptomatic, the fi rst line of tear ointment and patching the eyes patient in the right direction early on treatment is medical. The goal is to at night can be beneficial.8 These

September 2017 | reviewofophthalmology.com | 37

036_rp0917_f4.indd 37 8/25/17 5:10 PM 0036_rp0917_f4.indd 38 3 6 _ r p 0 9 1 7 _ f 4 38 tion. Here’s thebestwaytoproceed. time tomoveonasurgicalsolu- Surgical Treatment steroids. increased infl mast cellstabilizers,andgenerally mation withtopicalantihistamines/ This includestreatingallergicinfl in controllingthepatient’s symptoms. conditions shouldbetreatedtoassist derlying inflammatoryconjunctival proaches described,anyotherun- conjunctiva. signifi ointment duringthedayiftheyhave patients mayalsoneedtousethe option. then surgerybecomesareasonable tomatic despitemedicaltreatment, to correctconjunctivochalasis. Some techniques thathavebeendescribed the analogytoa“conj-tuck.” a “tummy-tuck,”they’llunderstand as thereisoccasionallytheneedfor tiva hangsoverthelowerlid.Just the pants,redundantconjunc- hanging overthebeltorbandof like loosebellyskin.Insteadofskin analogy thatconjunctivochalasisis to explainthepatientusing this situation,Ifi disorder oritstreatment.To helpin still haven’t evendiscussedtheactual available, andwhenyou’redoneyou typically requiresmoretimethanis the eye.Justexplaininganatomy the sclera,“true”whitepartof transparent mucousmembraneover explaining thatitisactuallyasemi- self tryingtocorrectthatbeliefby part oftheeye.”You may fi think oftheconjunctivaas“white can bechallenging.Often,patients conjunctivochalasis istoapatient ever, tryingtoexplainexactlywhat cedure isinformedconsent.How- . i n

d REVIEW The ﬁ When drugsaren’t enough,it’s In additiontothemedicalap- There areanumberofdifferent d | Focus Cover

Review ofOphthalmology

3 cant desiccationoftheexposed 8 rst stepofanysurgicalpro- 8 If patientsremainsymp- ammation withtopical

nd thatitiseasiest Cornea nd your- nd | September2017 am- dant conjunctiva.InSouth Korea, also beenusedto“shrink”the redun- scar development. resolution oftheirsymptomswithout that alloftheirpatientshadcomplete temporal. Dr. Muñoz’s groupnoted patient, whetheritisnasal,inferioror are comingfromforthatindividual you targettheexactareasymptoms The beneﬁ until “completeshrinkage”isachieved. to theareadirectlyatarateof30mA the bipolarforceps.Energyisapplied elevated anditsbaseisgraspedusing the stainedportionofconjunctivais ment. Afteranesthetizingthearea, best bedoneinacontrolledenviron- rotate theeyesuperiorly, sothismay suture throughtheinferiorlimbusto staining. Theprocedureusesatraction identify bypositivelissaminegreen symptomatic folditself,whichthey to applythetreatmentdirectly using abipolarelectrocauteryforceps leagues inBogota,Columbia,describe any sequelae. of theirpatients,butitdidn’t have noted postoperativelyin15percent temp cautery. Therewasscarring grasped portionwithahandheldlow- smooth forcepsandthenexcisingthe ing theredundantconjunctivawith Their techniqueinvolvedgrasp- subjective andobjectivefindings. 90-percent improvementinboth with resultsshowinggreaterthan excess conjunctivaattheslitlamp thermocautery asawaytoexcisethe lower lid.Onestudydescribedusing clinically visibleandrestingonthe the redundantfoldsofconjunctiva shrinkage orexcisiontogetridof some typeofthermally-induced of thein-officeproceduresinvolve erating room. ment, likeaprocedureroomorop- ers requireacontrolledenviron- can bedoneintheofﬁ of theseareminimallyinvasiveand • Argonlaser. Diana Muñoz,MD,andhercol- • Cauteryapproaches. t ofthistechniqueisthat 10 Argonlaserhas ce, while oth- while ce, Most 9

then pinchingandexcising; tion offi and moderatecases. ments weremoresuccessfulinmild seconds to10.2seconds.Thetreat- breakup time,improvingfrom9.2 lar SurfaceDiseaseIndexandintear signifi Their resultsshowedastatistically as theendpointfortheirprocedure. treatment using“propershrinkage” proximately 100burnsduringthe inferior conjunctiva.Theyapplyap- duration of0.5secondstotreatthe power from600to1200mWfora laser setat500µmandrangingin describe usinga532-nmargongreen Sangkyung Choi,MD,andhisgroup excision withdirectclosure; in theliterature,including:simple number ofwayspreviouslydescribed dant conjunctivacanberemovedina In theoperatingroom,redun- but thatthisprocessisblocked by tear meniscusinnormalpatients, rior fornixwillrapidlyreplenish the that thetearreservoirininfe- his groupatBascomPalmershowed junctiva. SchefferTseng, MD,and tant asremovingtheredundantcon- its physiologicbaselineisasimpor- returning thedepthoffornixto improve thefunctionoftearfi believed that,whenattemptingto of acicatricialentropion.It’s now fornix andthepossibledevelopment ring leadingtoforeshorteningofthe of thepossiblecomplicationsisscar- if excisionaloneisperformed,one reestablish thefornix.Thisisbecause conjunctiva ortightenit,butalso excise theredundantfoldsof mended surgicalproceduresnotonly limbus. of thecutedgeconjunctivato cised withsubsequentapproximation tiva tobepulledanteriorlyandex- incisions, allowingthelooseconjunc- ritomy ismadewithradialrelaxing as atechniqueinwhichlimbalpe- • Incisional/glueapproaches. However, themosthighlyrecom- cant improvementintheOcu- 13 brin gluesubconjunctivally, 11 12 aswell 6 injec- lm, 88/25/17 5:10 PM / 2 5 / 1 7

5 : 1 0

P M ELITE

the additional redundant conjunctiva patient is still symptomatic, then it’s SLIT in the fornix of conjunctivochalasis benefi cial to take them to the operat- patients.14 The group showed that re- ing room. While all of the surgical LAMP pairing this surgically and deepening procedures discussed here produce the inferior fornix reestablishes the great outcomes, I would recommend normal function of the reservoir and excision of the redundant and loose thus provides better resolution of dry conjunctiva with the attempt to rees- eye and ocular surface discomfort tablish the normal contour of the in- The +(/,7( symptoms than excision alone. ferior fornix. By surgically returning slit lamp features Dr. Tseng describes being able to the ocular surface to a more normal an innovative LED normalize the fornix during excision state, we help to create an environ- illumination system of the conjunctiva by making a cres- ment in which it’s easier for the body providing brilliant centic excision of the loose inferior to maintain homeostasis. light spectrum, bulbar conjunctiva starting with a pe- while increasing ritomy approximately 2 mm posterior Dr. Bert is a Health Sciences as- patient comfort. to the limbus. He excises all of the sistant professor at the Doheny and loose and thin conjunctival tissue, al- Stein Eye Institutes, David Geffen lowing the remaining conjunctiva to School of Medicine, UCLA. He has recess into the fornix. The bare scler- no fi nancial interest in any product al defect is then covered with cryo- mentioned. preserved amniotic membrane and 15 1. Hughes WL. Conjunctivochalasis. Am J Ophthalmol $QH[WHQVLYHSRZHU anchored using either sutures or 1942;25:48-51. fi brin glue.16 Glue has become pre- 2. Elschnig A. Beitrag zur aetiologie und therapie der chronischen UDQJHZLWKƬYH konjunktivitis. Dtsch Med Wochenschr 1908;34:1133-1155. PDJQLƬFDWLRQVHWWLQJV ferred due to less infl ammation and 3. Gumus K, Pfl ugfelder SC. Increasing prevalence and better patient comfort. In a retro- severity of conjunctivochalasis with aging detected by anterior from 6x to 40x. Standard segment optical coherence tomography. Am J Ophthalmol on all ELITE slit lamps. spective review by Dr. Tseng’s group, 2013;155:2:238-242. there was signifi cant improvement in 4. Balci O. Clinical characteristics of patients with conjunctivochalasis. Clin Ophthalmol 2014;28;8:1655-60. dry-eye symptoms and clinical fi nd- 5. Liu D. Conjunctivochalasis. A cause of tearing and its ings. An added benefi t was that 56 management. Ophthal Plast Reconstr Surg 1986;2:1:25-8. 6. Erdogan-Poyraz C, Mocan MC, Irkec M, Orhan M. Delayed IMAGING percent of their patients who had a tear clearance in patients with conjunctivochalasis is associated prior diagnosis of aqueous-defi cient with punctal occlusion. Cornea 2007;26:3:290-3. The 6237,.+(/,7( slit 7. Wang Y, Dogru M, Matsumoto Y, Ward SK, Ayako I, Hu Y, lamp comes digital ready. dry eye, which they termed aqueous Okada N, Ogawa Y, Shimazaki J, Tsubota K. The impact of tear deficiency, had normalized on nasal conjunctivochalasis on tear functions and ocular surface Combine with the S4OPTIK 17 fi ndings. Am J Ophthalmol 2007;144:6:930-937. all-in-one digital camera to their fl uorescein clearance testing. 8. Meller D, Tseng SC. Conjunctivochalasis: Literature review They hypothesize that the conjunc- and possible pathophysiology. Surv Ophthalmol 1998;43:3:225. acquire exceptional still and 9. Nakasato S, Uemoto R, Mizuki N. Thermocautery for inferior video images. tivochalasis caused so much disrup- conjunctivochalasis. Cornea 2012;31:5:514-9. tion and blockage in the fornix that 10. Arenas E, Muñoz D. A new surgical approach for the treatment of conjunctivochalasis: Reduction of the conjunctival it had created an aqueous-defi cient fold with bipolar electrocautery forceps. Scientifi c World Journal state. 2016;2016:6589751. 11. Yang HS, Choi S. New approach for conjunctivochalasis Ocular surface discomfort is a using an argon green laser. Cornea 2013;32:5:574-8. common and often frustrating con- 12. Doss LR, Doss EL, Doss RP. Paste-pinch-cut conjunctivoplasty: Subconjunctival fi brin sealant injection in the dition for both patients and physi- repair of conjunctivochalasis. Cornea 2012;31:959–962. cians. It’s important to look at the 13. Serrano F, Mora LM. Conjunctivochalasis: A surgical technique. Ophthalmic Surg 1989;20:12:883-4. entire ocular surface to diagnose 14. Huang Y, Sheha H, Tseng SC. Conjunctivochalasis interferes and appropriately treat a patient’s with tear fl ow from fornix to tear meniscus. Ophthalmology 2013;120:8:1681-7. symptoms. With targeted treatment, 15. Otaka I, Kyu N. A new surgical technique for management of there is a much better chance for conjunctivochalasis. Am J Ophthalmol 2000;129:3:385-7. 16. Kheirkhah A, Casas V, Blanco G, Li W, Hayashida Y, Chen YT, success. To that effect, don’t overlook Tseng SC. Amniotic membrane transplantation with fi brin glue the amount that conjunctivochala- for conjunctivochalasis. Am J Ophthalmol 2007;144:2:311-3. 17. Cheng AM, Yin HY, Chen R, Tighe S, Sheha H, Zhao D, sis contributes to these symptoms. Casas V, Tseng SC. Restoration of fornix tear reservoir in After trying conservative manage- conjunctivochalasis with fornix reconstruction. Cornea ment with topical medications, if a 2016;35:6:736-40. 250 Cooper Ave., Suite 100 Tonawanda NY 14150 ZZZVRSWLNFRP, Sensible equipment. Well made, well priced. )RUWRGD\oVPRGHUQRƯFH

036_rp0917_f4.indd 39 8/25/17 5:11 PM Pediatric Patient Edited by Wendy Huang, MD REVIEW

Pediatric Idiopathic Intracranial Hypertension Many ophthalmologists are well-versed in IIH in adults, but pediatric IIH is a different animal. Christopher M. Fecarotta, MD, Dothan, Ala.

diopathic intracranial hyper- been described, although familial I tension is a condition charac- cases have been reported. Overall, terized by abnormally elevated the incidence of IIH in children is intracranial pressure without any from 0.5 to 0.9 cases per 100,000. evident neurologic or radiologic Among adults, overweight females cause. Although the epidemiol- have a strong predilection for the ogy, demographics and spectrum disease; in fact, the incidence rises of clinical presentation of older to 19.3 per 100,000 in women who children with IIH tend to mirror are 20 percent or more over their those of adults, those of prepu- ideal body weight.5 Two-thirds of bescent children are unique, and men and 90 percent of women likely represent a separate disease with IIH are obese.4 entity. This article will explore the In contrast, recent studies have characteristics of this unique dis- shown that this disease doesn’t ease. Figure 1. Fundus photograph illustrating optic nerve follow the same demographics edema with retinal hemorrhages in a 12-year-old boy in children as in adults. A study Epidemiology with IIH. of pediatric patients with IIH recently demonstrated that only 43 Idiopathic intracranial hyper- include headache, binocular horizon- percent of prepubertal children, com- tension was originally described in tal diplopia from bilateral sixth nerve pared to 81 percent of children aged adults in 1893 and labeled “meningi- palsies, pulsatile tinnitus and vision 12 to 14 and 91 percent of teenagers tis serosa,” but has also been called loss from papilledema-induced optic aged 15 to 17, were obese.6 The same “pseudotumor cerebri” and “benign atrophy (See Figure 1).3 However, the study also reported that only half of intracranial hypertension.”1 The inci- original modiﬁ ed Dandy criteria for children with IIH under 12 years old dence is approximately one in 100,000 diagnosis didn’t include speciﬁ cs for were girls, while females comprised individuals and can occur in all age children. 88 percent of those IIH patients age groups, either gender and both obese IIH occurs most commonly in 12 to 14, and 100 percent of those and non-obese patients.2 Typically, young adults, and is rare in patients older than 14. The unequal sex dis- however, the presenting patient is an over age 45 or younger than age 3.4 tribution and the predilection for overweight female of childbearing There is no racial predisposition for overweight patients seems to only be- age. The most common symptoms the disease. No genetic cause has gin after puberty, likely as a result of

40 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

040_rp0917_peds.indd 40 8/25/17 4:31 PM New Orleans 2017 NOV 11-14

hormonal changes.7,8 Based on these of increased ICP to the abducens COME VISIT US AT fi ndings, it appears that in the prepu- nerve as it travels through Dorello’s bescent population, the predilections canal. THE S4OPTIK BOOTH #553 towards obesity and female gender do not apply, and these risk factors may Secondary Causes not be helpful clinical markers. Vitamin A toxicity has long been Pathophysiology known to cause IIH. This association AMOILS was first reported amongst explor- It is generally believed that the ul- ers consuming polar bear liver, which timate pathophysiology behind IIH has very high levels of vitamin A.13 leads to either increased cerebrospi- Medications containing vitamin A are nal fluid production by the arach- commonly prescribed to adolescents Corneal Xlinking, PRK & noid villi or decreased absorption by for acne. Tetracycline antibiotics also the choroid plexus; however, despite commonly precipitate IIH.14 Other Advanced Surface Ablation many different theories, the precise medications associated with IIH in- pathway leading to IIH is unknown. clude: Several studies support the hypoth- • cyclosporine; EPITHELIAL REMOVAL esis of increased cerebrospinal fl uid • cytarabine; MADE SIMPLE production as the crucial pathophysi- • nalidixic acid; ologic dysfunction in IIH. Studies • lithium; have demonstrated decreased CSF • minocycline; Uniform epithelium removalval in protein concentration in patients in • steroids and steroid withdrawal; only 5 - 7 seconds the adult and pediatric populations • danazol; with IIH, suggesting increased CSF • nitrofurantoin; Minimize total proceduree ttimeime 9,10 production. However, another • amiodarone; Avoid alcohol damage study did not confi rm this correlation • thyroid replacement therapy; between increased opening pressure • human growth hormone; to surrounding tissue 11 and CSF protein concentration. In- • leuprorelin acetate; No need for subsequentnt sscrapingcraping tracranial venous hypertension is a • desmopressin; well-established fi nding in IIH, but • oral contraceptives; and it is unclear whether it is the cause or • all-trans retinoic acid.3,4 the result of increased ICP. Another Certain medical conditions are also hypothesis postulates that obesity known to confer a higher risk of IIH. leads to increased thoracic pressure, Several studies have illustrated a link which causes an increase in both in- between many types of anemia and tracerebral venous pressure and ICP. IIH.3 Sickle-cell disease patients also A metabolic etiology has also been hy- have an increased risk of IIH.16,17 The pothesized, as numerous hormones, prevalence of IIH in Down syndrome including cortisol, thyroid hormone, is 3.4 percent, which is much higher growth hormone and aldosterone are than that found in the general pedi- known to interact with receptors simi- atric population.15 Turner syndrome lar to transporters in the choroid plex- also confers an increased risk for IIH, us.12 Another mystery of IIH involves with or without the need for growth the ventricle. Despite the increase in hormone.18,19 ICP, ventricles in IIH do not increase in size.4 Clinical Presentation Vision loss in IIH is caused by Improved clinical outcomestcomes compression of the optic nerve, as in- The clinical presentation of pedi- of CXL and PRK with creased ICP is transmitted down the atric IIH is similar to that in adults. optic nerve sheath. Sixth cranial nerve Headache is the most common symp- palsies are the result of transmission tom and is present in approximately CALL1.800.461.120 innovativexcimer.com

040_rp0917_peds.indd 41 8/25/17 4:31 PM Pediatric

REVIEW Patient

90 percent of patients.20 There is contrast. Magnetic resonance no headache pattern that is spe- venography should also be ob- cifi c for IIH. IIH may also pres- tained in adults to rule out dural ent with no symptoms after the sinus thrombosis; this is a rare discovery of elevated or frankly cause of increased ICP in chil- edematous optic nerves on rou- dren, however, and its utility may tine eye exam. Other symptoms be limited for patients without include neck, shoulder or arm an extenuating clinical circum- pain, nausea, vomiting, pulsatile stance. MRI fi ndings associated tinnitus, diplopia, blurred vision with increased ICP include pro- and transient visual obscura- trusion of the optic nerve head tions.21 The diagnosis can be very into the globe, enhancement of challenging to make in young chil- the optic nerve head, tortuosity dren who may have non-specifi c of the intraorbital optic nerve, symptoms and cooperate poorly increased perioptic CSF, fl atten- with the dilated fundus exam. Vi- ing of the posterior sclera, empty sual loss from IIH can also pres- sella, cerebellar tonsillar descent, ent as a visual fi eld defect, with an meningoceles and enlargement increased blind spot as the most of Meckel’s cave.3 common defect (See Figure 2).22 A complete blood count Alternatively, it may present as should be obtained to screen blurry vision from a hyperopic for anemia. After neuroimag- shift, submacular fl uid extending ing, a lumbar puncture should from the edematous optic nerve, be performed with a measure- or macular choroidal folds.3 ment of opening pressure. The Figure 2. Humphrey visual fi eld showing enlargement CSF constituents must be nor- Workup & Diagnosis of both blind spots in a child with papilledema from mal, excluding other causes of IIH. increased ICP, like meningitis. A thorough history is the fi rst Opening pressure must be high step in a proper workup when IIH tomated visual fields or Goldmann to make the diagnosis of ICP, but this is suspected; it should focus on un- visual fi elds are acceptable; however, determination warrants special con- covering risk factors and symptoms many younger children will be un- siderations with children. Recently, consistent with increased ICP. The able to participate. For such patients, a study established a normal opening

evaluating ophthalmologist should confrontation ﬁ elds should be docu- pressure of 19.6 cm H20 in children, ask direct questions speciﬁ cally re- mented, if possible. Normative val- with lower and upper limits of nor-

garding blurry vision, transient visual ues for peripapillary nerve fi ber layer mal as 10.5 cm H20 and 28 cm H20, obscurations, binocular horizontal thickness in children are currently respectively.23 Recent updates to the diplopia and pulsatile tinnitus. A unavailable; however, an OCT im- modifi ed Dandy criteria refl ect these complete list of medications should age should be obtained to document parameters.24 The study also report- complement questions to probe for baseline thickness and evaluate im- ed that children who received signifi - underlying genetic disease, endo- provement over time. If there’s any cant sedation had a higher opening

crine conditions or a history of ane- doubt about whether the patient has pressure by 3 cm H20 on average. mia. A nutritional history may also optic nerve edema, a B-scan ultra- Since many children must be sedat- be of use, particularly in adolescents sound should be obtained looking for ed to perform a lumbar puncture, whose obesity may contribute to optic nerve head drusen, which is a this ﬁ nding should lead the clinician their condition. common cause of misdiagnosis. to interpret opening pressures with The neuro-ophthalmic exam Neuroimaging to rule out an in- caution if the child has been sedated. should include visual acuity, pupil- tracranial mass should be obtained The sedating physician should aim lary evaluation for a relative afferent before lumbar puncture to avoid to provide the minimal amount of defect, color vision, extraocular mo- the possibility of brain herniation. necessary anesthetic, and the overall tility, slit lamp exam, dilated fundus The study of choice is an MRI of the clinical picture should be consistent exam and visual fields. Either au- brain and orbits with and without with the opening pressure before

42 | Review of Ophthalmology | September 2017

040_rp0917_peds.indd 42 8/25/17 4:31 PM hypertension: Relation of age and obesity in children. Neurology beginning treatment. headaches may benefit more from 1999;52:4:870-872. 7. Cinciripinni GS, Donahue S, Borchert MS. Idiopathic shunt placement, while patients who intracranial hypertension in prepubertal pediatric patients: Treatment are otherwise poor surgical candi- characteristics, treatment, outcome. Am J Ophthalmol 1999;127:178-82. dates may be good candidates for op- 8. Phillips PH, Repka MX, Lambert SR. Pseudotumor cerebri in Before initiating treatment, medi- tic nerve sheath fenestration, which children. J AAPOS 1998;2:33-38. 9. Chandra V, Bellur SN, Anderson RJ. Low CSF protein cations that are known to precipitate is less invasive. Recently, transverse concentration in idiopathic pseudotumor cerebri. Ann Neurol IIH should be discontinued, if possi- venous sinus stenting in an attempt 1986;19:1:80-82. 10. Margeta MA, Buckley EG, El-Dairi MA. Low cerebrospinal ble. In addition, if obese, the patient to increase venous outfl ow has been fl uid protein in prepubertal children with idiopathic intracranial and parents should be counseled that proposed as a treatment for IIH. hyptertension. J AAPOS 2015;19:2:135-139. 11. Johnston PK, Corbett JJ, Maxner CE. Cerebrospinal weight loss of approximately 10 per- This procedure has been reported fl uid protein and opening pressure in idiopathic cent of body weight has been shown in children, but long-term safety has intracranial hypertension (pseudotumor cerebri). Neurology 1991;41:7:1040-1042. 30 to provide signifi cant benefi t for pa- not yet been established. 12. Sheldon CA, Kwon YJ, Liu GT, McCormack SE. An tients with IIH.25 Medical treatments Generally, the outcomes in pedi- integrated mechanism of pediatric pseudotumor cerebri syndrome: Evidence of bioenergetic and hormonal regulation of are generally aimed at decreasing atric IIH are favorable, with most cerebrospinal fl uid dynamics. Pediatr Res 2015;77:2:282-289. CSF production by interfering with children improved with only medical 13. Rodahl K, Moore T. The vitamin A content and toxicity of polar bear and seal liver. Biochem J 1943;37:2:166-168. carbonic anhydrase, which is criti- management. One study reported 14. Lee AG. Pseudotumor cerebri after treatment with cal to its production by the choroid the visual outcomes of 68 children tetracycline and isotretinoin for acne. Cutis 1995;55:3:165-168. 15. Esmaili N, Bradfi eld YS. Pseudotumor cerebri in children plexus. Acetazolamide is the most with IIH and determined that the with Down syndrome. Ophthalmology 2007;114:9:1773-1778. 16. Segal S, Discepola M. Idiopathic intracranial hypertension commonly used first-line agent, majority of those who presented with and sickle cell disease: Two case reports. Can J Ophthalmol which has been shown to be supe- either visual acuity or fi eld defects 2005;40:6:764-767. 31 17. Henry M, Driscoll MC, Miller M, Chang T, Miniti CP. rior to placebo and improve visual had near complete recovery. Pseudotumor cerebri in children with sickle cell disease: a case field defects from IIH.26 Common Pediatric IIH in young children series. Pediatrics 2004;113:e265-e269. 18. Bala P, McKiernan J, Gardiner C, O’Connor G, Murray A. side effects include gastrointestinal represents a unique entity and isn’t Turner syndrome and benign intracranial hypertension with or upset, parasthesias, malaise, neph- necessarily associated with female without growth hormone treatment. J Pediatr Endocrinol Metab 2004;17:9:1243-1244. rolithiasis, and an altered taste for sex or obesity. Older children and 19. Sybert VP, Bird TD, Salk DJ. Pseudotumor cerebri carbonated beverages.3 Topiramate adolescents with the disease tend and the Turner syndrome. J Neurol Neurosurg Psychiatry 1985;48:2:164-166. is an anti-epileptic that also works to have demographic characteristics 20. Wall M. The headache profi le of idiopathic intracranial to inhibit carbonic anhydrase and similar to adults. Normal parameters hypertension. Cephalgia 1990;10:331-5. 21. Rogers DL. A review of pediatric intracranial hypertension. can be used as a primary or adjunct for ICP are different for children and Pediatric clinics. June 2014;61:3:579-590. treatment for IIH. A recent study opening pressures can be considered 22. Schirmer CM, Hedges II TR. Mechanisms of visual loss in papilledema. Neurosurg Focus 2007;23:5:e5. directly comparing acetazolamide to normal until above 28 cm H20. The 23. Avery, RA Shah SS, Licht DJ, et al. Reference range for topiramate showed approximately treating clinician should be aware cerebrospinal fl uid opening pressure in children. N Engl J Med 27 2010;363:9:891-893. equal effi cacy. Topiramate also pro- that sedation could signifi cantly raise 24. Friedman DI, Liu GT, Digre KB. Revised diagnostic criteria motes weight loss, which may help ICP and lead to a falsely positive high for the pseudotumor cerebri syndrome in adults and children. 28 Neurology 2013;81:13:1159-1165. obese adolescents. Furosemide can opening pressure. A mildly increased 25. Wong R, Madill SA, Pandey P, Riordan-Eva P. Idiopathic also be used as medical treatment for opening pressure should only be intracranial hypertension: The association between weight loss and the requirement for systemic treatment. BMC Ophthalmol IIH, but may provide only a modest treated if it makes sense as part of 2007;21:7:15. reduction in ICP. the child’s complete clinical picture. 26. Wall M, Johnson CA, Cello KE, Zamba KD, McDermott MP, Keltner JL; NORDIC Idiopathic Intracranial Hypertension Study When medical treatment fails, sur- Outcomes are generally positive, Group. Visual fi eld outcomes for the idiopathic intracranial gical treatment to reduce ICP must and the disease can be treated either hypertension treatment trial (IIHTT). Invest Ophthalmol Vis Sci 2016;57:3:805-812. be considered. The most commonly medically or surgically. 27. Celebisoy N, Gokcay F, Sirin H, Akyurekli O. Treatment performed procedure is placement of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open label study. Acta Neurol Scand of a ventriculoperitoneal or lumbo- Dr. Fecarotta is in private practice. 2007;116:5:322-327. peritoneal shunt. These procedures 28. Saunders KH, Kumar RB, Igel LI, Aronne LJ. Pharmacologic 1. Quincke H. Uber meningitis serosa and verewandte zustande. approaches to weight management: Recent gains and shortfalls are able to achieve immediate reduc- Deutsche Zeitschrift fur Nervenheilkunde 1897;9:149-168. in combating obesity. Curr Atheroscler Rep 2016;18:7:36. 2. Durcan F, Corbett J, Wall M. The incidence of pseudotumor 29. Fonseca PL, Rigamonti D, Miller NR, Subramanian PS. Visual tion in ICP that may be necessary outcomes of surgical intervention for pseudotumor cerebri: 3 cerebri: Population studies in Iowa and Louisiana. Arch Neurol when visual fi eld loss is severe. Optic 1988;45:875-7. Optic nerve sheath fenestration versus cerebrospinal fl uid nerve sheath fenestration is also a vi- 3. Hartmann, AJ, Peragallo, JH. Pediatric idiopathic intracranial diversion. Br J Ophthalmol 2014;98:10:1360-1363. hypertension. J Pediatr Neurol DOI: 10.1055/s-0036-1593848. 30. Tibussek D, Distelmaier F, von Kries R, Mayatepek E. able option for surgical management 4. Mercille G, Ospina LH. Pediatric idiopathic intracranial Pseudotumor cerebri in childhood and adolescence-results of of IIH, though it’s not been shown to hypertension: A review. Ped Review 2007;28:e77-86. a Germany wide ESPED survey. Klin Padiatr 2013;225:2:81-85. 5. Friedman DI. Pseudotumor cerebri. Neurol Clin North Am 31. Ravid S, Shahar E, Schif A, Yehudian S. Visual outcome be either superior or inferior to shunt 2004;22:99-131. and recurrence rate in children with idiopathic intracranial placement.29 A patient with severe 6. Balcer LJ, Liu GT, Forman S, et al. Idiopathic intracranial hypertension. J Child Neurol 2015;30:11:1448-1452.

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0040_rp0917_peds.indd40_rp0917_peds.indd 4433 88/25/17/25/17 4:324:32 PMPM Glaucoma Management

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

When Should You Neuroimage Your Patient? Neurologic disease may present with symptoms that mimic glaucoma. Here’s how to know when to check for trouble.

Mark L. Moster, MD, Philadelphia

ne of the dangers any doctor be fooled. That’s true for a couple of • arteritic ischemic optic neuropathy. O faces in practice is misdiagnosis. reasons. First, the symptoms of many All of these can occasionally be This can lead to inappropriate treat- optic neuropathies can mimic those of mistaken for glaucoma and should ment that allows harm to come to glaucoma. Intraocular pressure can be be considered when you suspect the patient—not to mention possibly normal or elevated in both situations, that something other than glaucoma resulting in legal action against the and visual field defects associated may be going on. It’s worth noting, doctor. In fact, misdiagnosis of neuro- with other optic neuropathies may however, that an MRI isn’t equally logic disease accounts for a small but be identical to those associated with helpful in diagnosing everything on significant minority of malpractice glaucoma. this list. Neuroimaging would be most cases against ophthalmologists. Furthermore, cupping occurs in helpful in making a correct diagnosis How often do glaucoma and neuro- many types of optic neuropathy—a in compressive optic neuropathy logic problems overlap? Glaucoma fact that’s not well appreciated. In and optic neuritis; other conditions is a common disease, which means one study, 20 percent of optic atrophy listed above would require different patients with brain tumors or other eyes had cupping, and 6 percent of diagnostic approaches. neurologic diseases often have them looked typical for glaucoma.1 Here, I’d like to discuss some of glaucoma as well. In medicine we Conditions that can cause optic disc the ways you can distinguish between usually try to explain all of a patient’s cupping include: glaucoma and neurologic disease, symptoms as being caused by a single • compressive optic neuropathy; with an emphasis on which signs and disease. If someone has headache • retrobulbar neuritis; symptoms should make you consider and numbness, we don’t assume he • papillitis; performing neuroimaging of your has two different diseases. But as • Leber’s hereditary optic glaucoma patient. Hickam’s dictum states: “Patients • neuropathy; can have as many diseases as they • autosomal dominant optic Warning Signs: Visual Fields damn well please.” The reality is • atrophy; that some patients actually do have • infectious optic neuropathy (e.g., It’s important to take note when two problems, and some glaucoma • syphilis); visual fields are not typical of glau- patients also have neurologic disease. • toxic optic neuropathy (e.g., coma. Sometimes a patient who When treating glaucoma, neurologic • ethambutal); has definitely been diagnosed with disease can be easy to miss. In fact, • trauma; glaucoma will show progression that’s if you treat glaucoma on a regular • central retinal artery occlusion; not typical of the disease. We’ve seen basis, sooner or later you’re likely to and, numerous patients with preexisting

44 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

044_rp0917_gm.indd 44 8/25/17 5:04 PM An unusual visual fi eld should alert you to consider a neurological problem. This patient presented with bi-temporal hemianopsia (visual fi elds, above, left). MRI revealed a large pituitary tumor, compressing and elevating the optic chiasm (above). After surgery, the visual fi elds improved dramatically (left).

effect; the visual fi elds done six weeks postoperatively (left) show a dramatic improvement in the patient’s fi eld. Another example: Consider the case of a 79-year old man who was being followed for pseudoexfoliation. His IOP was always in the low teens, but he had a superonasal visual field defect in the right eye glaucomatous defects develop a visual fi eld that respects the vertical which progressed over time. (See superior bi-temporal defect on top meridian suggests a classic lesion images, next page.) As a result, his of the glaucomatous defect; testing of the optic chiasm. Some defects ophthalmologist scheduled him to do revealed a lesion of the optic chiasm. caused by a neurologic problem may a laser. Also, the rate of change may be rapid, resemble a glaucomatous defect, He came to us for a second opin- considering the level of glaucoma such as an inferior altitudinal defect. ion. I looked at his optic nerves; control. However, you should at least consider they didn’t appear to be signifi cantly Although a few visual fi elds caused the possibility that such a defect could cupped. Then I reevaluated his by neurologic disease may resemble have been caused by an ischemic visual fi elds. The defect in the right glaucomatous visual fields, a field optic neuropathy—a lack of blood eye did appear to be a standard glau- that’s distinctly unusual should prompt fl ow to the nerve. coma defect—it was an arcuate, you to consider a neurologic problem. For example, consider the visual superonasal defect. But the defect A typical glaucomatous field might fields shown above, from a patient in his left eye was a temporal defect, show a superior arcuate defect; but with a classic bi-temporal hemian- which is atypical. Furthermore, it when the visual fi eld reveals a central opsia. Of course, this type of field bordered on the vertical meridian, or cecocentral scotoma; a bitemporal is atypical for glaucoma, and in which is also atypical. Considering the loss; a vertical hemianopic fi eld loss; fact MRI revealed a large pituitary two fields together, this looked like an inferior altitudinal defect; or visual tumor, compressing and elevating the a left homonymous superior quad- field loss not proportional to optic optic chiasm. It’s worth noting that rantanopia, suggestive of a lesion disc cupping, you should consider addressing the cause of the problem behind the optic chiasm on the right. neurologic disease. For example, a via surgery can have a dramatic Given this evidence, we did an MRI;

September 2017 | reviewofophthalmology.com | 45

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REVIEW Management

we found a very large meningioma in the brain with adjacent edema. The patient underwent surgery, and as you can see from the visual ﬁ elds at the bottom, following the surgery he experienced a dramatic improvement in his vision. (In a case like this, no matter which MIGS device you favor, you wouldn’t get a great result with glaucoma surgery!)

Warning Signs: The Optic Nerve

The condition of the optic nerve can provide significant clues to a neurologic problem: • Remember that cupping can be caused by compressive optic neuropathies. A study conducted at Massachusetts Eye and Ear looked at the cup-to-disc ratio in patients who had unilateral compression of the visual pathway.2 The cup/disc ratio on the side with the compression of the visual pathway was 0.13 greater than the cupping on the contralateral side, a direct result of the brain tu-mor. Cupping can also be caused by conditions such as multiple sclerosis or neuromyelitis optica. • Note the state of the patient’s visual acuity relative to the cup- to-disc ratio. Optic neuropathies are often associated with poor visual acuity despite a mild increase in cup-to-disc ratio. In contrast, in glaucoma, visual acuity is preserved until cupping is severe. • Note the timing of cupping. In glaucoma, cupping of the optic nerve is seen before vision loss occurs. In neurologic disease, cupping of the optic nerve is usually seen after visual loss has begun. • Note the condition of the optic nerve rim. Focal or diffuse obliteration of the rim is relatively A 79-year old man being followed for pseudoexfoliation. His IOP remained in the low teens specifi c for glaucoma. In contrast, and his optic nerves were not signifi cantly cupped, but he had a superonasal visual fi eld pallor of the preserved rim is highly defect in the right eye which progressed over time. MRI revealed a very large meningioma suggestive of other causes of optic in the brain with adjacent edema. Following surgery, his vision improved dramatically. neuropathy.

46 | Review of Ophthalmology | September 2017

044_rp0917_gm.indd 46 8/25/17 5:04 PM the right eye—a pretty severe loss for glaucoma. He also had a severe color vision defect in the right eye; he correctly read only one of 13 Ishihara plates; with the left eye he correctly identified all 13. The right eye also had a 3+ afferent pupillary defect. His fundus photos revealed cupping, much greater in the right eye, but also pallor of the right rim. In short, there was a lot that would be considered Focal or diffuse obliteration of the rim is relatively specifi c for glaucoma, while pallor of atypical for a glaucoma patient. the preserved rim is highly suggestive of other causes of optic neuropathy. Above left: We conducted further testing. A Focal partial obliteration of the rim inferiorly in glaucoma. Right: A patient with multiple chest X-ray revealed hilar adenop- episodes of optic neuritis. Note cupping, but also pallor of the temporal rim. athy; the patient had an elevated angiotensin converting enzyme Other Considerations at the optic chiasm.3 (ACE) level of 100; and bronchoscopy • In general, the more atypical revealed noncaseating granulomas. Other strategies that will help you the fi ndings, the more you should It became clear that he was suf- avoid being fooled include: consider neurologic disease. fering from sarcoidosis with optic • Be extra vigilant if the patient Neurologic cases that resemble neuropathy; he actually didn’t have is young. Glaucoma tends to be glaucoma often present with multiple glaucoma at all. Although we didn’t less common in young people, so at aspects that are not typical of glaucoma. redo the MRI scan, had the fi rst scan least consider neurologic disease in a Atypical findings would include an been focused on the orbit, it most young person. atypical medical history, an atypical likely would have revealed that the • Look for symptoms often as- exam, an atypical optic disc, a large optic nerve was inflamed by the sociated with neurologic disease. amount of asymmetry, unexpectedly sarcoidosis. These would include headache, ocu- rapid progression and/or abrupt visual lar pain and ocular motility defects. loss. If the history, exam, optic disc Performing Neuroimaging • Note an afferent pupillary de- and visual fi elds are all close to what fect. A glaucoma patient with a very you would expect, you’re probably What kind of tests should you do asymmetric cup or asymmetric fi eld dealing with glaucoma. But if more for neuroimaging? We prefer an can have a relative afferent pupillary than one of those are atypical, your MRI of the brain and orbit. A CT defect (rAPD). But if you don’t fi nd mental alarm should go off: The signs scan is a good second choice if an an asymmetric cup or fi eld and you and symptoms you’re seeing could be MRI is contraindicated. In either see an rAPD, then you have to think caused by neurologic disease. case, it’s crucial to communicate with neurologic. For example, consider the case the radiologist to make sure you’re • Note a color vision defect. of a 29-year old man, followed as a getting the proper scan of the proper It’s very important to measure color case of unilateral glaucoma by his area. You don’t want to end up with vision. Although glaucoma causes ophthalmologist. When I saw him, a brain MRI without contrast that a dyschromatopsia, it’s usually mild I elicited a history of pain in the doesn’t show the visual pathway well; in comparison to dyschromatopsia right eye with progressive visual loss you could easily miss the lesion you’re caused by other optic neuropathies. over a period of a few days, which looking for. • Note any unexpected patterns is not typical for glaucoma. He then There’s been some debate re- on OCT scans. OCT is often used remained stable for eight months. garding neuroimaging of patients when evaluating glaucoma patients. Ironically, he’d already had a brain with typical normal-tension glau- If you see a pattern that doesn’t fit MRI, but it was not focused on the coma. One way to address the pos- your expectations for a glaucoma optic nerve and was interpreted as sibility that some of these patients patient, consider the possibility of a normal. could have a neurologic problem neurologic problem. For instance, an When I met the patient, his IOP would be to neuroimage all of them. early binasal loss on a ganglion cell was 8 mmHg OD and 10 mmHg OS, However, this would be a major analysis suggests a compressive lesion but his visual acuity was 20/200 in expense and inconvenience, and

September 2017 | reviewofophthalmology.com | 47

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REVIEW Management

This patient presented with slowly progressive visual loss in the left eye. Exam showed unilateral decreased visual acuity, relative APD, dyschromatopsia and a pale, cupped optic disc. CT scan (left) and MRI (middle) show a mass compressing the left optic nerve. A catheter angiogram (right) shows the lesion to be a large aneurysm coming off the right internal carotid artery.

published findings on the value of a leap of thinking to consider that guiding principle should be taking such a protocol have been mixed. In unexplained vision loss may be the note when the signs or symptoms are one study by Ike Ahmed, MD, 62 result of a neurologic problem. A not what you’d expect. Is the patient patients with newly diagnosed typical glaucoma specialist I know had a getting worse for no apparent reason? normal-tension glaucoma underwent patient who had been diagnosed with If the pressure is 25 mmHg and it neuroimaging; four of them (6.5 per- glaucoma 30 years earlier. About a should be 10 and the patient is getting cent) had compressive lesions (two year before I saw him he suffered worse, you’re probably dealing with pituitary tumors, one meningioma dramatic vision loss, eventually glaucoma. But if the pressure is 10 and one arachnoid cyst).4 However, reaching no light perception in one mmHg and it’s been 10 all along, other studies have not found any eye. He’d undergone an MRI 30 and suddenly a new, different defect lesions. A 1998 study involving 52 years earlier, and no problem had appears, you need to consider the eyes of 29 normal-tension glaucoma been detected; in addition, his recent possibility of a neurologic problem patients found no compressive visual fi eld defects didn’t immediately and consider neuroimaging the pa- lesions;5 and a 2010 survey of 68 suggest a neurological problem. For tient. normal-tension glaucoma patients that reason, a retinal problem was the who had undergone CT scans and fi rst possibility they considered. Dr. Moster is a professor of carotid Doppler scans revealed no As it turned out, retinal examination neurology and ophthalmology at other lesions.6 didn’t reveal any potential cause. Thomas Jefferson University, and The reason for the discrepancy The patient was also developing director of the neuro-ophthalmology between these studies isn’t clear, cataracts, so those were removed, fellowship at Wills Eye Hospital, in but given the practical diffi culties of but no improvement followed. The Philadelphia. He has no financial neuroimaging so many individuals, glaucoma specialist began to suspect confl icts relating to anything discussed the evidence probably doesn’t sup- that the patient was faking! Finally the in this article. port neuroimaging all normal-ten- patient was sent to our offi ce, and we 1. Trobe JD, Glaser JS, Cassady JC. Optic atrophy. Differential sion glaucoma patients. On the other discovered a large pituitary adenoma. diagnosis by fundus observation alone. Arch Ophthalmol hand, when a patient presents with Once the adenoma was surgically 1980;98:6:1040-5. the kind of atypical findings we’ve removed, the patient’s vision returned 2. Bianchi-Marzoli S, Rizzo JF 3rd, Brancato R, Lessell S. Quantitative analysis of optic disc cupping in compressive optic been discussing in this article, to baseline. neuropathy. Ophthalmology 1995;102:3:436-40. neuroimaging that patient makes The moral of the story is: When a 3. Tieger MG, Hedges III TR, Ho J, et al. Ganglion cell complex loss in chiasmal compression by brain tumors. Journal of Neuro- perfect sense. glaucoma patient loses vision out of Ophthalmology 2017;37:1:7–12. proportion to what you expect given 4. Ahmed II, Feldman F, Kucharczyk W, Trope GE. Neuroradiologic screening in normal-pressure glaucoma: study results and Taking the Hint the patient’s course or pressure, you literature review. J Glaucoma 2002;11:4:279-86. need to consider other possibilities— 5. Greenfi eld DS, Siatkowski RM, et al. The cupped disc. Who Misdiagnosing neurologic disease including neurologic disease. needs neuroimaging? Ophthalmology 1998;105:10:1866-74. 6. Kesler A, Haber I, Kurtz S. Neurologic evaluations in normal- can have profound consequences. So, how do you decide when tension glaucoma workups: are they worth the effort? Isr Med However, sometimes it requires neuroimaging makes sense? The Assoc J 2010;12:5:287-9.

48 | Review of Ophthalmology | September 2017

044_rp0917_gm.indd 48 8/25/17 5:04 PM RP0815_Lombart.indd 1 7/21/15 10:07 AM Therapeutic Topics REVIEW

Ocular Trauma: Then and Now A look at the full range of possible causes of trauma, as well as ways in which the eye can help diagnose other kinds of injury. Mark B. Abelson, MD, CM, FRCSC, FARVO, and James McLaughlin, PhD Andover, Mass.

fter nearly three decades of fragments, shards or other projectiles there are over 2.4 million ocular inju- A Therapeutic Topics we’ve covered that somehow fi nd their way into the ries annually,3 meaning that a 2-per- a variety of topics, and naturally, ev- globe or accessory tissues of the eye.1 cent rate of complications equates to eryone has their favorites. One of the Workplace injuries account for many 24,000 people each year with vision- most interesting and informative ones of these incidents, despite repeated threatening trauma. from our perspective comes from reminders to use proper safety eye- Penetration of foreign bodies back in December of 2004, when we wear. When the objects in question through the anterior segment rep- wrote a piece called “Ocular Trauma are localized outside the visual axis resents a serious, vision-threatening Never Takes a Holiday.” In it we de- and/or do not penetrate beyond the event. Key in these situations is re- scribed the ophthalmic pitfalls associ- cornea, the prognosis is good. One moval of the foreign body, as the risk ated with holiday-related activities, study reported that resolution of an of endophthalmitis increases more from fi recrackers in the face to cham- epithelial defect in such cases is typi- than tenfold when the object remains pagne corks in the eye. While as a cally complete within fi ve days, and in the eye; this is especially true when year-end piece it was a bit tongue-in- the risk of complications such as in- dealing with contaminated, organic or cheek, it nonetheless highlighted clin- fectious keratitis is less than 2 per- toxic foreign objects.4,5 Although the ical details of acute ocular trauma and cent.2 This might seem like a small slit lamp is typically the most readily demonstrated that the eyes provide a number, but it’s worth remembering accessible tool for this task, it’s useful unique window into the physical and that eye trauma is very common: The to apply CT imaging if the search is mental status of our patients. This U.S. Eye Injury Registry reports that initially unsuccessful. month we reprise that topic, with bits • Non-contact trauma. In some of the old and a focus on important cases, ocular trauma can occur with- new fi ndings on ocular trauma. out direct physical contact. Consider, for example, the recent solar eclipse The Gamut of Trauma that streaked its way across the United States in August 2017. It’s estimat- Following are the most common ed that as little as fi ve to 10 seconds forms of ocular trauma patients ex- of direct exposure to the retina can perience: cause noticeable visual impairment. • Foreign bodies. For some, the Light damage from staring at the sun, such Case studies have reported a range term ocular trauma is synonymous as during the recent solar eclipse, is an of results: In some, retinal damage with foreign bodies, an endless list of example of non-contact eye injury. resolved within six months, while in

50 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

050_rp0917_ttops.indd 50 8/25/17 5:15 PM others there were more lasting effects, even for those who claimed to just look “briefly” at the obstructed sun.6,7 One report suggested that solar exposure could also disrupt the tear film.8 Several studies have followed those with retinal damage over time; a Swedish study reported that of 15 Besides suffering trauma itself, the eye can also warn of trauma elsewhere in the body. patients initially identifi ed as having For example, in addition to such symptoms as vomiting, slurred speech and disorientation, foveal damage from eclipse-watching, dilated pupils of unequal size is a sign of a concussion. all had central scotomas at one-year follow-up.7 It’s clear from these older reports, as well as the recent eclipse, patients with stage III, IV or V alkali trauma that extends throughout the that the message of ocular safety dur- burns. One group received traditional visual system. Two examples of such ing these celestial events doesn’t seem care, one received umbilical cord se- conditions are traumatic brain injury to get through to everyone. rum drops in addition to traditional (TBI) and concussion, both of which • Chemical burns. No discussion care, and the third group underwent have become a focus of greater in- of ocular trauma would be complete amniotic membrane transplant. The terest in recent years. The extended without mention of the potential study followed measures such as time length of American military confl icts, damage inflicted by chemical expo- to re-epithelialization, epithelial de- as well as the nature of those opera- sure. The exposed surface of the cor- fect diameter and defect area, corneal tions, has resulted in large numbers nea is one of the most sensitive tissues clarity, tear breakup time, Schirmer’s of veterans experiencing some degree of the body, and the natural defense test and best-corrected vision. Both of TBI. Recent estimates suggest that mechanisms of lids and tear fi lm can supplementary intervention groups 10 to 15 percent of the 2.4 million exacerbate damage from a splash of showed a decrease in time to heal, as servicemen and -women who have alkali or acid by spreading the caustic well as improvements in TBUT and served in Afghanistan or in Iraq ex- agent over the entire ocular surface. Schirmer’s score when compared to perienced some form of TBI.12 While Foreign bodies and chemical spills traditional treatment. The major dif- the majority of these are concussion comprise the overwhelming majority ference between the two is that the or concussion-like syndromes, the of ocular traumas, but they are not use of drops has a measure of safety in spectrum of trauma is diverse and created equal: Chemically-mediat- that it does not involve an additional presents a signifi cant diagnostic and ed trauma often takes a bigger toll, surgical procedure.11 therapeutic challenge.12,13 Concussion and involves more prolonged, more- risk in contact sports such as football invasive therapy and recovery than Detecting Traumatic Events or boxing has recently been brought foreign-body injury.9,10 to light by stories of retired athletes In a moderate to severe chemical The eye is uniquely susceptible to who suffered with a repeated-con- exposure there is typically signifi cant all types of trauma, and conversely, cussion form of TBI, and reports of damage to the corneal epithelial layer, the eyes can exhibit and report on league and sports officials attempt- and often to the apparatus for production and maintenance of the tear Therapeutic Brief: Gene Therapy Completes Phase III fi lm (goblet cells, meibomian glands). Chronic dry eye is a common sequela In August, Stephen Russell, MD, of the University of Iowa, and Jean Bennett, MD, of the to corneal chemical burns. Follow- University of Pennsylvania, and their co-workers completed the fi rst ever controlled, up care for an initial traumatic event randomized, Phase III trial of a gene therapy for inherited retinal disease using voretigene neparvovec (Spark Therapeutics, which also provided funding for the trial).1 will likely include medical manage- In the study, 29 individuals with RPE65 gene mutations, which result in retinal dystrophy, ment to allow for epithelial healing. were randomized to treatment (n: 20) or control. At one year, the mean change in bilateral Serum drops, limbal grafts or amni- multi-luminance mobility testing score for the intervention group was 1.6 light levels bet- otic transplant procedures may be ter than controls (p=0.0013). Thirteen of 20 treatment participants passed MLMT at the required in cases where epithelial and lowest luminance level tested (1 lux), vs. none of the control participants, the maximum or limbal damage is signifi cant.9-11 A possible improvement. Researchers say there were no product-related adverse events. recent retrospective study compared 1. Russell S, Bennett J, Wellman J, et al. Effi cacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65- three general strategies in a total of 55 mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial. The Lancet 2017;390:10097:849 -860.

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REVIEW Topics

ing to downplay the risks of repeated important to be aware that the con- friends or family members who have head trauma. stellation of headaches, light sensi- reached the age where their visual Visual function disruption associ- tivity and/or diffi culty reading in an function might not be up to the task ated with TBI is variable, and to some otherwise healthy, active young adult of driving the highways. An improved extent depends upon the nature of the may suggest a possible history of un- visual test called the Useful Field of precipitating traumatic event. Most diagnosed concussion. View test provides a more integrated TBI patients report vision problems The newest evidence in this field assessment of the visual tasks such as according to one study.12 Approxi- suggests that trauma is cumulative tracking, attention and acuity needed mately half of the patients complain and can occur without detectable for safe driving.16 If both young and about problems reading. Light sensi- symptoms. Our understanding of the old would take the test, perhaps there tivity, saccadic dysfunction, accommo- processes of TBI and concussion has would be a little less trauma in the dative dysfunction and convergence a long way to go, but it may be that world. insuffi ciency have been reported in 60 visual metrics will lead us to better to 85 percent of patients. Strabismus, diagnostics for both. In so doing, they Dr. Abelson is a clinical professor pursuit abnormalities, fi xation defects could also ultimately provide the clin- of ophthalmology at Harvard Medical and visual fi eld defects were also com- ical endpoints we will need to develop School. Dr. McLaughlin is a medical mon visual fi ndings. effective therapies. writer at the ophthalmic consulting Several groups have used these fi rm Ora Inc. characteristics to aid in the development of reliable diagnostic criteria.14 1. Sahraravand A, Haavisto AK, Holopainen JM, Leivo T. Ocular traumas in working age adults in Finland - Helsinki Ocular Trauma Ocular metrics such as tracking, re- It’s important to Study. Acta Ophthalmol 2017;95:3:288-294. sponse latency and response accelera- 2. Brissette A, Mednick Z, Baxter S. Evaluating the need for close be aware that the follow-up after removal of a non-complicated corneal foreign tion can be used to assess the sever- body. Cornea 2014;33:11:1193-6. ity and the characteristics of patients’ constellation of 3. US Eye Injury registry. http://www.useir.org/epidemiology. underlying sensorimotor impairment, Accessed 2 August 2017. headaches, light 4. Paciuc M, Dalma-Weiszhausz J, Phan R, Smits D, Velez-Monto even in cases where the defects are R. Trauma: Open globe injuries. 2014. Available online at https:// mild enough that the patients don’t sensitivity and/or www.aao.org/pediatric-center-detail/open-globe-injuries recognize them as TBI. The goal is 5. Cornut PL, Youssef el B, Bron A, et al. A multicentre prospective diffi culty reading in study of post-traumatic endophthalmitis. Acta Ophthalmol to use these types of tests to moni- 2013;91:5:475-82. tor progression of the trauma or as a 6. Michaelides M, Rajendram R, Marshall J, Keightley S. Eclipse an otherwise healthy, retinopathy. Eye (Lond) 2001;15(Pt 2):148-51. means to assess potential therapeutic 7. Källmark FP1, Ygge J. Photo-induced foveal injury after viewing interventions. Concussion and TBI active young adult a solar eclipse. Acta Ophthalmol Scand 2005;83:5:586-9. 8. Nepp J, Dorner GT, Jandrasits K, Maar N, Schild G, Wedrich represent a spectrum of traumatic may suggest a history A. Ocular surface changes and tear fi lm alterations associated head injury, and many of the symp- with sun gazing during a solar eclipse. Wien Klin Wochenschr toms associated with concussions, of undiagnosed 2003;115(1-2):47-52. 9. Pargament JM, Armenia J, Nerad JA. Physical and chemical such as light sensitivity, anisocoria, concussion. injuries to eyes and eyelids. Clin Dermatol 2015;33:2:234-7. headache and confused mental status 10. Eslani M, Baradaran-Rafi i A, Movahedan A, Djalilian AR. Ocular surface chemical burns. J Ophthalmol 2014;2014:196827 (online are shared by the two diagnoses. In article). most organized sports a standardized 11. Sharma N, Lathi SS, Sehra SV, et al. Comparison of umbilical protocol is given to athletes to provide As a closing thought, one of the cord serum and amniotic membrane transplantation in acute ocular chemical burns. Br J Ophthalmol 2015;99:5:669-73. a baseline for comparison in the event things about trauma in general is that 12. Goodrich GL, Flyg HM, Kirby JE, Chang CY, Martinsen GL. of subsequent head trauma. Recently, common sense tells us that the real Mechanisms of TBI and visual consequences in military and veteran populations. Optom Vis Sci 2013;90:2:105-12. there’s been a push to incorporate therapeutic cure for these problems is 13. Helmick KM, Spells CA, Malik SZ, Davies CA, Marion DW, more visual components into this pro- prevention, whether it’s safety glasses, Hinds SR. Traumatic brain injury in the US military: Epidemiology tocol, as visual functions represent eclipse glasses, improved football hel- and key clinical and research programs. Brain Imaging Behav 2015;9:3:358-66. an integration of sensory and motor mets or more persuasive diplomacy. 14. Liston DB, Wong LR, Stone LS. Oculometric assessment of activity.15 For example, pupillary re- Yet, we never seem to achieve that sensorimotor impairment associated with TBI. Optom Vis Sci 2017;94:1:51–59. sponses are among the fi rst refl exes perfect safety record. 15. Galetta KM, Morganroth J, Moehringer N, et al. Adding vision tested when a patient is suspected of One area where visual testing im- to concussion testing: A prospective study of sideline testing in having sustained a concussion. provements may have an impact on youth and collegiate athletes. J Neuroophthalmol 2015;35:3:235- 41. In developing programs to treat reducing trauma is in automobile 16. Wood JM, Owsley C. Useful fi eld of view test. Gerontology and to prevent concussion injury, it’s safety. We all have or know of older 2014;60:4:315-8.

52 | Review of Ophthalmology | September 2017

0050_rp0917_ttops.indd50_rp0917_ttops.indd 5252 88/25/17/25/17 5:155:15 PMPM Retinal Insider

REVIEW Edited by Carl Regillo, MD, and Emmett T. Cunningham Jr., MD, PhD, MPH

The Pros and Cons of Heads-up Surgery The future of this technology holds promise as long as new innovations are critically evaluated, these surgeons say.

Murtaza K. Adam, MD, Denver, and Allen C. Ho, MD, Philadelphia

iven the lack of tactile feedback the operating microscope (Figure 1). has been less signifi cant. This is likely G and the microscopic scale of the Some anterior segment surgeons im- due in part to the partnership forged surgical fi eld, visualization is one of mediately began using the technology, by Alcon and TrueVision in 2016 to the most important aspects of per- since heads-up visualization allows create NGENUITY, a visualization forming vitreoretinal surgery. Until for a seamless overlay of preoperative platform specifi cally created for digi- recently, our only instrument for in- and intraoperative data, such as totally assisted vitreoretinal surgery. traocular visualization was a micro- ric overlays and phacoemulsifi cation Over the intervening years since scope using classical optics, with its metrics. the system’s introduction, TrueVision/ associated limitations in fi eld of view, Sony also entered the market in Alcon have made several improve- color, contrast and sharpness. Now, 2013 with its own version of a 3-D ments to the system, including a fi fth- with advances in digital displays and heads-up visualization system for neu- generation, high-dynamic-range 3-D image processing, we have the ability rosurgery and opththalmology, but its camera, integration of a 55-inch, 4K to augment the visualization of our impact upon the vitreoretinal market OLED TV, and much-improved la- surgical fi eld in real time. In this article, we’ll share our initial impressions of the TrueVision 3D visualization system as part of an Alcon-sponsored, prospective trial we’ve initiated at Wills Eye Hospital in Philadelphia.

The Technology Evolves

In 2008, TrueVision Systems first entered the market with a three- dimensional, heads-up ophthalmic surgical visualization system. Using a high-deﬁ nition display, a camera connected to a traditional surgical microscope, and passive 3-D glasses, their Figure 1. 3D heads-up display with ﬁ ve observers watching Murtaza Adam, MD, operate. principal idea was to free the ophthal- The setup consists of an ICM 5 high-dynamic-range camera connected to an operating mic surgeon from the constraints of microscope and a 4K OLED display placed approximately a meter away from the surgeon.

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REVIEW Insider

tency (i.e., the perceived delay be- improvement. At Wills Eye Hospital, tween when you make an action and our investigator-initiated, prospec- when you see it displayed). With any tive, randomized, controlled trial is medical innovation, however, all po- currently under way to explore these tential advantages over the current same areas of interest. Our study aims paradigm are undermined by ques- to compare detailed intraoperative tions of clinical utility and economics. metrics and postoperative outcomes of Does performing 3-D heads-up vit- patients with macular holes, epiretinal reoretinal surgery result in better vi- membranes and retinal detachments, sual outcomes? Will there be a lower randomized to undergo surgery with complication rate? Will surgery be a traditional operating microscope or more effi cient, resulting in reduced the NGENUITY system. Our hope is operative time? Will the surgery be that other groups will perform similar more ergonomically comfortable? objective and quantitative analyses In a medical system with limited re- to provide a realistic assessment of sources, these are important ques- the system’s ability to affect patient tions that need to be answered. care, and identify ways to maximize its potential. A Dearth of Data A Dash of Subjectivity At this time, few scientifi c studies have attempted to answer the ques- Figure 2. Indocyanine green dye-assisted Our experience with 3D heads-up tions listed above. In 2015, Claus chromovitrectomy in a patient with vitreoretinal surgery over the past proliferative diabetic retinopathy before Eckardt, MD, and Erica Guerreiro (top) and after (bottom) activation of a year has been largely positive. From a Paulo, MD, published the fi rst peer- digital fi lter to enhance visualization of the subjective standpoint, after we began reviewed study comparing the tradi- internal limiting membrane. using the the NGENUITY system, tional microscope to the TrueVision we’ve found that our support staff 3D heads-up platform.1 The authors ration of amplifying digital gain (the has become more engaged and atten- prospectively and systematically eval- ability of a sensor to amplify the ambi- tive, because anyone wearing passive uated the performance of 20 volun- ent light in order to provide an image 3-D glasses in the OR shares the sur- teers carrying out various tasks (ar- without the need for brighter illu- geon’s 4K, stereoscopic OLED view. ranging small objects with forceps, mination) to minimize the need for This shared viewing ability has helped tying sutures, etc.) using a standard endoillumination during vitreoretinal many on the OR staff, as well as medi- operating scope and the TrueVision procedures and its associated risk of cal students and residents, to have a system. Although the authors found phototoxicity. better understanding of the methods that the resolution of the traditional Building upon this work, two ad- and goals of surgery. When we use a microscope was twice that of the digi- ditional publications, including one standard operating microscope, the tal display, they didn’t feel that this by our group at Wills, more rigorously attending and fellow occupy the only was a signifi cant obstacle, and they re- examined the power of digitial am- oculars available, forcing observers to ported no differences in performance. plifi cation in reducing endoillumina- watch the 2-D monitor located away More than 90 percent of the study tion requirements during vitreoreti- from the surgical field. In contrast, participants preferred the ergonomics nal surgery.2-3 Both small case series observation with the much larger of the heads-up technique. reported safely performing a variety heads-up display is limited only by In the same publication by Drs. of vitreoretinal cases with endoillumi- the number of 3-D glasses available Eckardt and Paulo, a retrospective nation levels at less than 5 percent of and observers can stand immediately analysis of 43 macular hole repairs maximum output, a task that would be behind the surgeon, allowing for a performed using the TrueVision sys- extremely diffi cult with a traditional more intimate teaching experience tem revealed a primary hole closure scope. (See Figure 1, p. 53). rate of 97.7 percent, which was com- This limited body of work repre- The 3D heads-up platform per- parable to their success rate with a sents preliminary attempts to demon- forms well in macular cases and di- traditional microscope. The authors strate the potential of 3-D heads-up abetic tractional detachments. The also performed a preliminary explo- surgery and identify areas in need of fi eld of view is broad and stereopsis

54 | Review of Ophthalmology | September 2017

053_rp0917_retinsider.indd 54 8/25/17 4:36 PM is excellent, even with high magni- platform compared to the standard fi cation. This allows for wide, confi - operating microscope. These factors dent peeling with excellent peripheral lead to slightly awkward corneal, con- awareness. Additionally, real-time dig- junctival and scleral suturing, espe- ital fi ltering can be used to highlight cially when working with long sutures. internal limiting staining achieved during chromovitrectomy (Figure 2) Looking Ahead and digital gain manipulation can significantly reduce endoillumination Significant improvements to the requirements (Figure 3). Integration latest-generation platform are already of intraoperative optical coherence Figure 3. Intraoperative optical on the way, including real-time in- tomography also works seamlessly coherence tomography of a small macular tegration of vitrectomy machine pa- with the heads-up system and pro- hole|following epiretinal membrane and rameters, a streamlined purely digital vides high-resolution scans of macular internal limiting membrane peel. The entire microscope, the addition of digital anatomy (Figure 3). In diabetic trac- case was performed with 5-percent fi lters, and the ability to overlay pre- tional detachments, the movement of endoillumination to minimize the risk of operative and intraoperative data on a peripherally detached retina when macular phototoxicity. the surgical field. As each advance peeling posterior fi brovascular tissue in heads-up surgery arrives, howev- is easily detected, giving the surgeon tensity when performing peripheral er, it’s imperative that we clinicians more confidence in his or her abil- laser with scleral depression can help participate in guiding its evolution ity to avoid creating iatrogenic breaks minimize these issues. to improve outcomes and maximize (Figure 4). Overall, we have found working in safety. Our patients are depending on Primary and complex retinal de- the vitreous cavity to feel quite natu- us. tachment repairs are intuitive with ral and comparable to the standard the 3-D heads-up platform. However, operating microscope. Digital image Murtaza K. Adam, MD, is a vit- we’ve encountered occasional issues latency isn’t an issue when perform- reoretinal surgeon at Colorado with decreased peripheral acuity and ing vitreoretinal surgery, since move- Retina Associates in Denver. He washed-out images when performing ments within the posterior segment trained at Wills Eye Hospital for peripheral laser. are typically slower than maneuvers his ophthalmology residency and The traditional operating scope has performed anteriorly. However, when vitreoretinal surgery fellowship. He the advantage of using the surgeon’s working on the anterior segment, the has received funding for an inves- pupils and lens (with associated ac- digital latency becomes more evi- tigator-initiated trial related to the commodation) as part of the optical dent and the surgeon’s hands should NGENUITY 3D heads-up surgical system to balance image exposure and slightly slow to compensate for this. platform from Alcon. facilitate a clear peripheral examina- Also, the fi eld of view of the anterior Allen C. Ho, MD, is the director of tion. With 3-D heads-up surgery, how- segment is smaller with the heads-up retina research at Wills Eye Hospital, ever, the fi nal pathway for light is the a surgeon at Mid Atlantic Retina, high-dynamic-range camera mounted and a professor of ophthalmology on the operating microscope, which at Thomas Jefferson University, all has limits to its exposure modulation located in Philadelphia. He has re- and depth of fi eld. In high myopes, ceived funding for an investigator- the heads-up system appears less for- initiated trial related to the NGENU- giving than the traditional scope and ITY 3D heads-up surgical platform refocusing at the conclusion of the from Alcon. case for peripheral inspection reduces the risk of missing small tears. 1. Eckardt C, Paulo EB. Heads-up surgery for vitreoretinal procedures: An experimental and clinical study. Retina The focus control with our current 2016;36:1:137-47. setup is quite sensitive and refocusing 2. Adam MK, Thornton S, Regillo CD, Park C, Ho AC, Hsu J. Figure 4. High resolution maintained with Minimal endoillumination levels and display luminous emittance in the middle of a case can be cum- a wide fi eld of view during dissection of during three-dimensional heads-up vitreoretinal surgery. Retina bersome. We’ve found that parfocus- preretinal fi brovascular plaques in a patient Nov 29, 2016. (Epub ahead of print) ing at the beginning of all 3-D cases with a macula-involving diabetic tractional 3. Kunikata H, Abe T, Nakazawa T. Heads-up macular surgery with a 27-gauge microincision vitrectomy system and minimal and markedly decreasing the light in- detachment. illumination. Case Rep Ophthalmol 2016;7:3:265-269.

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053_rp0917_retinsider.indd 55 8/25/17 4:36 PM Plastic Pointers

REVIEW Edited by Ann P. Murchison, MD, MPH

Options for Small- Incision Brow Lifts In some patients, a traditional brow lift may not be necessary; a less-invasive option may yield the results they need. Talmage Broadbent, MD, PhD, Ali Mokhtarzadeh, MD, and Andrew Harrison, MD, Minneapolis

he old adage, “Use the right sues of the eyebrow and eyelid are though studies addressing this topic T tool for the job,” also applies to functionally linked, and changes in have reached mixed conclusions.1,4-8 surgical procedures. For patients in the position of one will affect the form If your exam determines that the whom brow ptosis is a main cause of, and function of the other. Patients patient has mild to moderate brow or signifi cant contributing factor to, will often have concerns about their ptosis, and you’d like to avoid issues their complaints of drooping lids, you eyelids drooping, and it’s only through associated with formal brow lifts, con- may not need to subject them to the a careful exam that one can determine sider the following options. expense and signifi cant morbidity of whether that complaint is caused by a formal brow lift using a coronal or blepharoptosis, dermatochalasis, Direct Brow Lift endoscopic approach. Sometimes, in brow ptosis or a combination of these patients with mild or moderate brow factors. While ophthalmologists often One option for these brow ptosis ptosis, the right procedure for the take note of ptosis and dermatochala- patients is a direct, or transcutane- job is a less-invasive option that can sis as part of a general eye exam, brow ous, brow lift.9,10 The advantages of be performed through a small inci- ptosis is more likely to be overlooked. this procedure are that it’s relatively sion and doesn’t require undermining The relationship between eyelid simple to perform, gives the surgeon large amounts of tissue, limiting mor- and brow position is complex, and good control of the amount of lift and bidity and making it more palatable it’s clear that the eyelid and brow are has the ability to address medial brow to patients. In this article, we’ll detail structurally and functionally connect- ptosis. The main drawback of this such procedures, and outline their ed. So, just as when you’re evaluating procedure is the resultant scar above pros and cons. Note that these proce- a patient’s complaint, remember that the brow. In our experience, a lateral dures shouldn’t be considered overall performing surgery on one without brow lift can be achieved with a rea- replacements for a traditional brow consideration for the effects on the sonable scar, although when the inci- lift, but they can still be used success- other is a recipe for an unsatisfied sion is carried more medially the scar fully in a good number of these sorts patient. A review of the literature sug- become signifi cantly more apparent. of patients. gests that surgery to correct blepha- When using this procedure to el- roptosis results in brow descent,1-3 evate the male brow it’s important to The Patient’s Complaint and how signifi cant this change will pay particular attention to the con- be to the patient functionally or aes- tour, taking care to preserve a fl atter Evaluation of eyelid and brow posi- thetically will differ in each case. brow and avoid a feminizing, highly tion is an important part of an oph- Blepharoplasty alone can also lead arched brow. Several techniques have thalmologist’s external exam. The tis- to a signifi cant drop in brow position, been described to try and improve

56 | Review of Ophthalmology | September 2017 This article has no commercial sponsorship.

050_rp0517_plastics.indd 56 8/25/17 4:26 PM the appearance of this scar, concurrently with blepharo- including beveling the inci- plasty and take advantage of sion, sutured lifting of the the standard blepharoplasty orbicularis to relieve tension, incision. and postoperative scar treatments.11,12 Meticulous surgi- Internal Browpexy cal techniques can improve the appearance of the scar, The internal browpexy is but for a portion of patients an effective procedure that any scar can be cosmetically can provide a moderate lift unacceptable. Additionally, to the lateral brow. It is not there is also the possibility the ideal procedure for pa- of signifi cant paresthesia of tients with severe brow pto- the forehead, especially if sis or those with signifi cant the supraorbital nerve and medial brow ptosis. The vessels are not meticulously main advantage of this pro- protected against damage cedure is that it’s performed during the procedure. through the blepharoplasty incision, which usually heals External Browpexy very well with minimal scar- ring. It’s important to note This technique, first de- that the browpexy will el- scribed in 2012 by Beverly evate the brow to a more Hills, Calif., surgeon Guy appropriate position, caus- Massry, MD,13 provides a ing a resultant stretching of moderate lateral brow lift the upper eyelid skin and through a small incision. less redundancy of the up- To perform external brow- per eyelid skin. Care must pexy, the surgeon marks the Blepharoplasty and external browpexy, pre- and postop. be taken to avoid removing point of desired brow eleva- Preoperative photo (A): Notice signifi cant lateral brow ptosis and too much skin from eyelids tion near the junction of the dermatochalasis. Postoperative photo, two weeks after that are having a concurrent blepharoplasty and external browpexy (B): Notice some redness tail and body of the brow, brow-lifting procedure, in in the area of the incisions over the lateral brow. Postoperative then makes a small, 8-mm photo, two months after surgery (C): Notice the improved order to avoid lagophthal- incision just superior to the appearance of the external browpexy incisions. mos and accompanying cor- brow cilia. Dissection is car- neal complications. ried through the skin and In the preoperative area, subcutaneous tissues close to the ally resolves over the course of about it’s helpful to mark the point of de- level of the periosteum. The dissec- a month, but should be discussed sired elevation near the bottom of tion is carried superiorly to the level with the patient preoperatively. the brow cilia at the junction of the of desired fi xation. The surgeon then The procedures we’ve discussed tail and body of the brow with the secures the subcutaneous orbicularis so far involve an incision superior patient in an upright position. Once and the brow fat pad to the perios- to the brow. While this type of inci- the blepharoplasty incision is made, teum at the desired level of fi xation sion results in some amount of scar- the dissection is carried superiorly with a permanent suture and closes ring, it has the advantage of making over the orbital rim in a pre-peri- the incision. This technique results it possible to perform these brow- osteal plane to a level 15 to 20 mm in a small and usually cosmetically lifting procedures in isolation from above the orbital rim. The surgeon acceptable scar. A quantitative study other periorbital procedures. This then places a suture at full thickness showed the external browpexy can allows for correction of brow pto- through the skin and subcutaneous provide approximately 3 mm of lift to sis or asymmetry without making an tissues at the mark made preopera- the lateral brow.14 Complications of upper-eyelid incision. The remainder tively; this pass serves as a marking this procedure include pain and ede- of the techniques that we will discuss suture. He or she then passes the ma at the suture site. This pain usu- are most appropriately performed suture through the periosteum ap-

September 2017 | reviewofopthalmology.com | 57

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REVIEW Pointers

proximately 10 mm above Drs. Broadbent, Mokhtar- the orbital rim and again zadeh and Harrison practice through the subcutaneous in the departments of Oph- tissues adjacent to the previ- thalmology and Visual Neu- ously placed marking suture. rosciences at the University The marking suture is then of Minnesota. Dr. Harrison pulled until the free end is also affi liated with the de- of the suture pulls through partments of Otolaryngology the dissection flap and the and Head and Neck Surgery subcutaneous tissues are se- at the University. Please ad- cured to the periosteum as dress any correspondence to the suture is tied. Multiple Andrew R. Harrison, MD, variations on this technique MMC 493, 420 Delaware St., have been published.15,16 SE, Minneapolis, MN 55455, Quantitative studies suggest or email him at aharrison@ that this technique provides umn.edu. somewhere between 1 to 1. Lee JM, Lee TE, Lee H, Park M, Baek S. Change 2 mm of lift to the lateral in brow position after upper blepharoplasty 14,7 or levator advancement. J Craniofac Surg brow. 2012;23:2:434–6. Complications of this pro- 2. Moore GH, Rootman DB, Karlin J, Goldberg Preoperative photo before blepharoplasty and brassiere RA. Mueller’s muscle conjunctival resection with cedure include pain at the skin-only blepharoplasty: Effects on eyelid and suture (A) demonstrates the upper eyelid skin fold obscuring the eyebrow position. Ophthal Plast Reconstr Surg suture site, which usually central and lateral tarsal plate. Postop (B), note the elevated brow 2015;31:4:290–2. resolves over a few weeks. 3. Rootman DB, Karlin J, Moore G, Goldberg R. and preserved lateral tarsal show. The effect of ptosis surgery on brow position and There is also the possibility the utility of preoperative phenylephrine testing. Ophthal Plast Reconstr Surg 2016;32:3:195–8. of creating an unsightly dim- 4. Prado RB, Silva-Junior DE, Padovani CR, ple in the brow skin if the browpexy to the level of the orbital rim. An Schellini SA. Assessment of eyebrow position before and after upper eyelid blepharoplasty. Orbit 2012;31:4:222–6. suture is passed too superfi cially. absorbable suture is then used to 5. Nakra T, Modjtahedi S, Vrcek I, Mancini R, Saulny S, Goldberg RA. The effect of upper eyelid blepharoplasty on eyelid and brow secure the cut end of the upper orbi- position. Orbit 2016;35:6:324–7. 6. Hassanpour SE, Khajouei Kermani H. Brow ptosis after upper Brassiere Suture cularis to the underlying arcus mar- blepharoplasty: Findings in 70 patients. World J Plast Surg ginalis, effectively creating a sling or 2016;5:1:58–61. 7. Baker MS, Shams PN, Allen RC. The quantitated internal suture The goal of this procedure is to use hammock for the brow tissues above. browpexy: Comparison of two brow-lifting techniques in patients undergoing upper blepharoplasty. Ophthal Plast Reconstr Surg the orbicularis to suspend the brow You can place several sutures along 2016;32:3:204–6. fat pad and create a barrier to the de- the lateral rim. The incision is then 8. Frankel AS, Kamer FM. The effect of blepharoplasty on eyebrow position. Arch Otolaryngol Head Neck Surg 1997;123:4:393–6. scent of the brow tissues. As a result, closed by standard techniques. This 9. Tyers AG. Brow lift via the direct and trans-blepharoplasty approaches. Orbit 2006;25:4:261–5. this procedure can provide volumiza- technique and several variations have 10. Pelle-Ceravolo M, Angelini M. Transcutaneous brow shaping: tion and aesthetically pleasing ante- been previously described17–19 and, A straightforward and precise method to lift and shape the eyebrows. Aesthet Surg J. 2017 Mar 16 (epub ahead of print). rior projection of the lateral brow and though it can provide a lift for the 11. Lee JW, Cho BC, Lee KY. Direct brow lift combined with suspension of the orbicularis oculi muscle. Arch Plast Surg help to preserve the contour of the brow fat pad and improved brow vol- 2013;40:5:603–9. lateral superior sulcus. For patients ume at the level of the orbital rim, in 12. Feinendegen DL, Constantinescu MA, Knutti DA, Roldán JC. Brow reduction, reshaping and suspension by a 20-degree who complain of skin covering their our hands it doesn’t provide a signifi - beveled brow incision technique. J Craniomaxillofac Surg 2016;44:8:958–63. lateral tarsal plate, this procedure can cant lift to the overall brow. There- 13. Massry GG. The external browpexy. Ophthal Plast Reconstr produce an excellent aesthetic result. fore, patients with more signifi cant Surg 2012;28:2:90–5. 14. Mokhtarzadeh A, Massry G, Bitrian E, Harrison A. Quantitative Like the internal browpexy, this brow ptosis would likely be better effi cacy of external and internal browpexy performed in conjunction with blepharoplasty. Orbit. In Press. procedure also takes advantage of served by a different procedure. 15. McCord CD, Doxanas MT. Browplasty and browpexy: An adjunct to blepharoplasty. Plast Reconstr Surg 1990;86:2:248. a previously made blepharoplasty Small-incision brow-lifting tech- 16. Cohen BD, Reiffel AJ, Spinelli HM. Browpexy through the upper incision. After the blepharoplasty in- niques such as those discussed here lid (BUL): A new technique of lifting the brow with a standard blepharoplasty incision. Aesthet Surg J 2011;31:2:163–9. cision has been made and the skin provide good, minimally invasive 17. Briceño CA, Zhang-Nunes SX, Massry GG. Minimally invasive surgical adjuncts to upper blepharoplasty. Facial Plast Surg Clin excised, the surgeon incises the or- ways to address brow ptosis. A vari- North Am 2015;23:2:137–51. bicularis and divides it into roughly ety of available techniques allow for 18. Zarem HA, Resnick JI, Carr RM, Wootton DG. Browpexy: Lateral orbicularis muscle fi xation as an adjunct to upper equal-sized upper and lower por- personalization of the surgical ap- blepharoplasty. Plast Reconstr Surg 1997;100:5:1258–61. 19. Armstrong BK, Sobti D, Mancini R. Partial orbicularis resection tions. Dissection under the superior proach to each patient, depending on for the augmentation of traditional internal browpexy: The “Tuck portion of the orbicularis is carried his or her needs and concerns. and Rise.” Ophthal Plast Reconstr Surg 2016;32:6:473-476.

58 | Review of Ophthalmology | September 2017

050_rp0517_plastics.indd 58 8/25/17 4:26 PM Research Review REVIEW

Glaucoma Screening in High-Risk Populations

esearchers from Johns Hopkins examination. The most common di- age score (15 points=maximum); ocu- RUniversity, Baltimore, conducted a agnoses at the defi nitive examination lar surface epithelial damage score (9 one-year study to develop, implement were glaucoma and cataract (51 and 40 points=maximum); and the Schirmer and evaluate a replicable community- percent, respectively). I test. based screening intervention with the After one year of the ongoing study, a In all FBUPs, eye dryness and fatigue hope of improving glaucoma and other large proportion of individuals screened were the worst symptoms. Symptoms eye-disease detection and follow-up required ophthalmic services. To reach specifi c to different types included: for care in high-risk populations in the and encourage these individuals to at- AB, sensitivity to light, heavy eyelids, United States. tend screenings and follow-up exami- pain, foreign body sensation, diffi culty This prospective study is ongoing, nations, researchers say that programs opening the eye, and discharge; for SB, but researchers released the one-year could develop innovative strategies and heavy eyelids; and for LB, foreign-body findings. The study focuses on Afri- approaches. sensation. Statistically significant dif- can Americans over 50 years of age at Am J Ophthalmol 2017;180:18-28. ferences (p<0.05) were found in: tear multiple inner-city community sites in Zhao D, Guallar E, Gajwani P, et al. meniscus radius (AB vs. SB, AB vs. DB, Baltimore. The screening examination AB vs. RB, and LB vs. RB); tear fi lm uses a sequential referral approach and Classifi cation of Fluorescein lipid layer interference grade (AB vs. assesses presenting visual acuity, best- Breakup Patterns all other FBUPs, LB vs. SB, and LB vs. corrected VA, digital fundus imaging, n a cross-sectional study, research- DB); tear fi lm lipid layer spread grade visual fi eld testing and measurement of Iers from Kyoto, Japan, investigated (AB vs. all other FBUPs); fl uorescein intraocular pressure. the relationship between fluorescein breakup time (AB vs. LB, AB vs. DB, Of the 901 individuals screened breakup patterns and clinical manifes- AB vs. RB, SB vs. DB, SB vs. RB; LB between January 2015 and October tations in dry-eye cases. vs. RB, and DB vs. RB). Signifi cant dif- 2015, subjects were mostly African Researchers looked at 106 eyes ferences were also found in noninvasive Americans (94.9 percent) with a mean of 106 subjects (19 male, 87 female; breakup time (AB vs. all other FBUPs, age of 64.3 years. Among them, 356 mean age: 64.2 years). FBUPs were SB vs. DB, SB vs. RB, and LB vs. RB); participants (39.5 percent) were re- categorized into one of the following corneal epithelial damage score (AB vs. ferred for a definitive eye examina- fi ve types: area (AB, n=19); spot (SB, all other FBUPs, LB vs. SB, LB vs. DB, tion, and 107 (11.9 percent) required n=22); line (LB, n=24); dimple (DB, and LB vs. RB); ocular surface epitheli- prescription glasses. n=19); and random (RB, n=22 eyes). al damage score (AB vs. SB, AB vs. LB, The most common reasons for refer- They also examined dry-eye-related AB vs. DB, LB vs, SB, LB vs. DB, and ral were an ungradable fundus image symptoms using the visual analog scale LB vs. RB); and Schirmer I test (AB vs. (39.3 percent of those referred), best- (100 mm=maximum); tear meniscus SB, AB vs. DB, and AB vs. LB). corrected VA less than 20/40 (14.6 per- radius; tear fi lm lipid layer interference Researchers say that the fi ve differ- cent), and ungradable autorefraction grade (grades 1–5, 1=best) and spread ent fl uorescein breakup patterns refl ect (11.8 percent). Among those referred grade (grades 1–4, 1=best); tear fi lm different pathophysiologies. for defi nitive examination, 153 people noninvasive breakup time; fl uorescein Am J Ophthalmol 2017;180:72-85. (43 percent) attended their scheduled breakup time; corneal epithelial dam- Yokoi N, Georgiev G, Kato H, et al.

This article has no commercial sponsorship. September 2017 | reviewofophthalmology.com | 59

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062_rp0917_products.indd 62 8/25/17 3:56 PM 063_rp0917_wills.indd 63 place, clearvitreousandafl B-scan oftherighteyedemonstratedaformedanteriorchamber withthelensin gross abnormalitywasseen.Theanteriorexaminationofthe lefteyewasnormal. and theanteriorchamberwasdeep.Thereahazyview tothelensbutno the iristhroughhazycorneabutitwasseentobefl at andthepupilround, laceration inferotemporallyfromtheprevioustrauma.There wasapoorviewto nea wasdiffuselywhitenedwithatotalepithelialdefect and apartial-thickness and analmost100-percentconjunctivalepithelialdefect (Figures 1-3).Thecor- chemosis inferiorlywith360-degreeblanchingofthelimbal conjunctivalvessels lower eyelidedemaanderythema.Examinationoftheconjunctivarevealed segment examinationrevealedptosisoftherighteyewithmoderateupperand 16 mmHgintherighteyeand18lefteye.Externalanterior were fullinbotheyes.Intraocularpressuresmeasuredbyapplanationat lary defectwaspresent.Extraocularmovementandconfrontationalvisualfi the slitlamp.Theleftpupilwasbrisklyroundandreactive.Noafferentpupil- His rightpupilwasdifficult toexaminebutwasseenbesomewhatreactivein in therighteyewithnoimprovementpinhole,and20/25lefteye. Examination medications andhisfamilysocialhistorieswerenoncontributory. any pastmedicalhistoryorcurrentmedicationuse.Hehadnoallergiesto porally severalyearsprior. Hehadnotanypreviouseyesurgeries.denied a pieceofplasticwhichhadleftpartialthicknesscorneallacerationinferotem- Medical History urgent carecenter, butonarrivalattheCorneaService it was7.5. Eye CorneaService.We donothavearecordofhisocularpHonarrivalatthe thalmologist wheretheeyewasirrigatedagain.HethenreferredtoWills where hiseyewasirrigatedbeforebeingemergentlyreferredtoageneraloph- as gettingdegreaserinhisrighteye.Heinitiallywenttoanurgentcarecenter Presentation Aditya Kanesa-Thasan, MD;ChristopherJ. Rapuano, MD;KristinM.Hammersmith, MD for ayoungpatient. resultsinlimbalstemcelldefiA severeocularchemicalinjury ciency pursue? Turn top. 64forthediagnosis. What isyourdifferentialdiagnosis? Whatfurtherworkupwouldyou

Ophthalmic examinationrevealeduncorrectedSnellenvisualacuityof20/200 The patient’s ocularhistorywasnotableonly fortraumatotherighteyefrom A 25-year-old manwhoworkedinanautorepairshoppresentedthesameday REVIEW at retina. Wills Eye Wills Eye Resident CaseSeries Edited by Thomas Jenkins, MD September 2017 elds trauma. laceration inferiorlyfromprevious seen isthepatient’s partial-thickness the limbalconjunctival vessels. Also with360-degree blanching of cornea right eye on dayoneshowing hazy photograph ofthe Figure 1.External lower fornix. extending intothe epithelial injury demonstrates palpebral conjunctival Figure 3.Eversionofthelower eyelid epithelial injury. conjunctival stainingshowing severe epithelial defectwithlarge areas of staining demonstrates atotalcorneal right eye on dayonewithﬂ photograph ofthe Figure 2.External | reviewofophthalmology.com uorescein |

63 8/25/17 3:35 PM 063_rp0917_wills.indd 64 Discussion re-epithelialization andimprovedtocountingfi lamp, butovertimeheexperiencedslowconjunctival ing weeksandrequiredlysisofsymblepharonattheslit cussed withthepatient,givenseverityofhisinjury. right eye.Theextremelyguardedprognosiswasdis- every twohoursandatropinetwiceperday, allinthe two hours,bacitracin-polymyxinophthalmicointment mg twotimesperday, prednisoloneacetate1%every patient wasstartedondailyVitamin C,doxycycline100 ments, includingsuturinganamnioticmembrane.The a discussionoftherisks,benefi ts andalternativetreat- Doral, Fla.)wasplacedintherighteyeondayoneafter A ProKerasuturelessamnioticmembrane(Biotissue; lar surfaceburn(Roper-Hall classIV)oftherighteye. Diagnosis andManagement 64 ratio ofmalestofemales. the USeveryyear, withanaverageageof35anda2:1 ation. Morethan15,000chemicaleyeinjuriesoccurin rence andafrequentcauseofurgentophthalmicevalu- dense pannus360degrees andsymblepharonsuperonasally. photograph oftherighteyeFigure atmonthsixshows 4.External etration. tend tocoagulatesurfaceproteins more,limitingpen- through saponification ofcellmembranes. Acidinjuries alkali injuriespenetratetheocularsurfacemorereadily REVIEW The patientfollowedupseveraltimesintheinterven- The patientwasdiagnosedwithaDuaclassVIocu- Ocular chemicalinjuriesareaverycommonoccur- When facedwithseverechemical injuries,themost | ReviewofOphthalmology Resident CaseSeries 1 Theclassicteachingisthat | September2017 ngers. dense inferiorpannuswithsymblepharoninferiorly. photograph oftherighteyeFigure atmonthsixshows 5.External plantation withgoodinitialresults. superior andinferiorautologouslimbalstemcelltrans- Almost oneyearaftertheinjury, thepatientunderwent stem celldefi ciency (LSCD)intherighteye,however. and symblepharonformationsecondarytoseverelimbal defect eventuallyclosed.Hewasleftwithdensepannus was taperedoffofhistopicalsteroidsandepithelial membrane transplantandplacementofProKera.He went furtherlysisofsymblepharon,repeatamniotic in theoperatingsuite.Aboutamonthlaterheunder- tarsorrhaphy andsutureofhisoldcorneallaceration intraoperative ProKeraplacement,temporarylateral double-layered suturedamnioticmembranetransplant, injury thepatientunderwentlysisofsymblepharon, after hisinjury. Aroundsevenweeksaftertheinitial The ProKerawasreplacedapproximatelyonemonth buffered solutionsforachieving fasternormalization have beenseveralstudiesdemonstrating theeffi transferring himforfurther ophthalmologic care.There of theocularsurfaceis7to7.5beforedischargingor mediately. ThepatientshouldbeirrigateduntilthepH is importanttoemphasizethatirrigationmuststartim- are routinelythefi rst destination forthesepatients,it tients orcommunityemergencycarecenters,which neutral pHsolution.Whenreceivingcallsfrompa- important treatmentisimmediateirrigationwitha cacy of cacy 8/25/17 3:36 PM of pH in these cases.2 However, it’s days. Another study showed that donor tissue. This may prove to be important not to try to “neutralize” eyes which received sutured amni- a good option for patients with lim- alkali injuries with acid solutions or otic membrane within six days after ited healthy limbal tissue and where acid injuries with basic solutions, as injury fared better than those that donors and culture of limbal tissue this can cause further harm. received amniotic membrane later On ophthalmologic exam, sweep than six days.6 However, no eye with are unavailable. the fornices to remove any particu- a Grade VI injury attained better In summary, in this case we de- late matter that may be embedded. than 20/400 vision, even with am- scribe a young man with severe The size and shape of the corneal niotic membrane therapy. Recent (Dua Class VI) alkali chemical in- and conjunctival epithelial defects case studies have also demonstrated jury resulting in severe LCSD. Even should be measured and docu- the effectiveness of using sutureless though these are challenging cases mented, paying special attention to amniotic membrane (e.g., ProKera) requiring prolonged follow-up with the palpebral and bulbar conjunc- early in cases of severe chemical in- tiva. Clock hours of limbal ischemia jury to promote re-epithelialization guarded expectations for recovery, should be noted. Phenylephrine and minimize complications.7,8 there are several options for the should be avoided for dilation, as it When faced with a patient with treatment of signifi cant LCSD that can worsen limbal vasoconstriction. severe LSCD from an ocular sur- can be considered based on indi- Classifi cation systems for chemi- face burn, there are several options vidual patient characteristics. cal injuries have included the Rop- for limbal stem cell transplant.9-11 3 er-Hall classifi cation and the newer In patients with unilateral injuries, 1. White ML, et al. Incidence of Stevens-Johnson Syndrome and Dua classification.4 Both systems conjunctival limbal autograft can chemical burns to the eye. Cornea 2015;34:1527–33. use the epithelial defect size and be performed; this borrows several 2. Al-Moujahed A, Chodosh J. Outcomes of an algorithmic ap- the clock hours of limbal ischemia clock hours of healthy limbus from proach to treating mild ocular alkali burns. JAMA Ophthalmology 2015;133:10:1214–16. to predict visual potential in chemi- the patient’s fellow eye. Cultivated 3. Daniel J, Bunker L, et al. Alkali-related ocular burns: A case cal injuries. The major difference limbal epithelial transplant uses less series and review. Journal of Burn Care & Research: Offi cial between the classifications is that tissue but requires culture of the Publication of the American Burn Association 2014;35:3:261–68. the Dua system subdivides the most patient’s limbal stem cells prior to 4. Dua HS, King AJ, Joseph A. A new classifi cation of ocular surface burns. British Journal of Ophthalmology severe chemical injuries (Roper- implantation, which requires time 2001;85:11:1379–83. Hall class IV) into more categories and technical proficiency. Living- 5. Tandon R, et al. Amniotic membrane transplantation as an ad- (Dua class IV-VI) which allows for related conjunctival limbal allograft junct to medical therapy in acute ocular burns. Br J Ophthalmol fi ner prognostication. For example, is an option for patients without 2011;95:2:199–204. a Dua class IV patient with seven healthy limbal tissue who have rela- 6. Westekemper H, et al. Clinical outcomes of amniotic membrane transplantation in the management of acute ocular clock hours of limbal ischemia will tives willing to donate limbal tissue; chemical injury. Br J Ophthalmol 2017;101:2:103–7. likely fare better than a Dua class VI keratolimbal (cadaveric) allograft 7. Kheirkhah A, Johnson D, Paranjpe D, et al.Temporary suture- patient with 12 clock hours of limbal is another transplant option with less amniotic membrane patch for acute alkaline burns. Arch ischemia, but these patients would higher risk of rejection. Ophthalmol 2008;126:8:1059–66. 8. Suri K, Kosker M, Raber IM, et al. Sutureless amniotic mem- both be Roper-Hall class IV. A newer procedure for patients brane ProKera for ocular surface disorders: Short-term results. Treatment of ocular surface with unilateral disease, simple lim- Eye & Contact Lens 2013;39:5:341–47. chemical injury ranges from sim- bal epithelial transplant, requires 9. Haagdorens M, Van Acker SI, Van Gerwen V, et al. Limbal ple for mild injuries to complex less limbal autograft tissue but stem cell defi ciency: Current treatment options and emerging for severe ones. Sutured amniotic doesn’t require the culture of pa- therapies. Stem Cells International 2016: Article ID 9798374. 10. Liang L, Sheha H, Li J, Tseng SCG. Limbal stem cell membrane has shown promise in tient’s stem cells prior to implanta- transplantation: New progresses and challenges. Eye 12,13 moderate burns, with better visual tion. Instead, the piece of limbus 2009;23:10:1946. outcomes and improved epitheli- is cut into small pieces that are ar- 11. Atallah MR, Palioura S, Perez VL, et al. Limbal stem cell alization by 21 days with nonsig- ranged outside the visual axis in the transplantation: Current perspectives. Clin Ophthalmol 2016; 10:593–602. nificant trends towards decreased affected eye and secured with fi brin 12. Mittal V, Jain R, Mittal R, et al. Successful management corneal neovascularization and sym- glue on top of an amniotic mem- of severe unilateral chemical burns in children using simple blepharon formation in one study.5 brane. Early case reports have dem- limbal epithelial transplantation (SLET). Br J Ophthalmol However, there was no significant onstrated good re-epithelialization 2016;100:8:1102–8. improvement in severe burns in of the surface with good long-term 13. Basu S, Sureka SP, Shanbhag S, et al. Simple limbal epithelial transplantation: Long-term clinical outcomes in 125 that study, and only one of the eyes results in restoring corneal epitheli- cases of unilateral chronic ocular surface burns. Ophthalmology studied re-epithelialized within 21 um in a single surgery with minimal 2016;123:5:1000–1010.

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