CRO Vol 27 Number 6 by MediConcept

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Clinical & Refractive Optometry VOLUME 27, NUMBER 6, 2016

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Iris Neoplasia Treatment of Corneal Neovascularization Ocular Cicatricial Pemphigoid: A Case Report Diagnosis and Treatment of Ocular Surface Conditions: Focus on Dry Eye

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Clinical &Refractive Optometry

Editorial Board â&#x20AC;˘ Volume 27, Number 6, 2016 Editor-in-Chief

Associate Editor

Richard Maharaj, OD, FAAO Toronto, Ontario

Leonid Skorin, Jr., OD, DO, MS Albert Lea, Minnesota

Editors Emeriti Brad Almond, OD Calgary, Alberta

Barbara Caffery, OD Toronto, Ontario

John Jantzi, OD Vancouver, British Columbia

Yvon RhĂŠaume, OD Montreal, Quebec

Contributing Editors Scott D. Brisbin, OD Edmonton, Alberta

Gerald Komarnicky, OD Vancouver, British Columbia

Langis Michaud, OD Montreal, Quebec

Barbara Robinson, OD Waterloo, Ontario

Lorance Bumgarner, OD Pinehurst, North Carolina

Bart McRoberts, OD Vancouver, British Columbia

Rodger Pace, OD Waterloo, Ontario

Jacob Sivak, OD, PhD Waterloo, Ontario

Louis Catania, OD Philadelphia, Pennsylvania

Ron Melton, OD Charlotte, North Carolina

Maynard Pohl, OD Bellevue, Washington

Randall Thomas, OD Concord, North Carolina

Publication Staff Publisher Lawrence Goldstein

Managing Editor Mary Di Lemme

Senior Medical Editor Evra Taylor

Layout Editor Colin MacPherson

Graphics & Design Mediconcept Inc.

Mission Statement Clinical & Refractive Optometry is a peer-reviewed professional journal dedicated to the publishing and disseminating of COPE approved CE credit scientific articles. The contents of each issue are composed of a mixture of original: state-of-the-art/technical, therapeutic/clinical, or practice management articles which are of particular interest to and use by practicing optometrists. Participants achieving 70% or more on the questionnaires that accompany each of the articles in the journal, will receive a course credit certificate.

BONUS UPGRADE TO THE PRINT EDITION To upgrade to the Print Edition of CRO which will include 6 consecutive issues, containing a combined total of 24 prepaid COPE CE-Credit course tests, please forward a cheque for $282.50, payable to Mediconcept Communications, to the address shown below. Note: As of 2017, you can take your CE-Credit tests online, for an average cost of $11.77 per test. Subscription Information Title ______ First Name _______________________ Last Name _______________________________________ Number __________ Street _______________________________________________________ Suite __________ City ____________________________ Province _________________________ Postal Code __________________ Office Phone (_____) _______________________ E-mail _____________________________________________

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Clinical& Refractive Optometry

Clinical & Refractive Optometry is published 6 times per year by Mediconcept.

Contents • Volume 27, Number 6, 2016

The Journal is made available to all optometrists on www.crojournal.com.

CE CREDIT ARTICLES

211

Iris Neoplasia Teresa Lim, OD; Pauline F. Ilsen, OD ABSTRACT: While uveal melanomas are the most common type of intraocular malignancy, only 3% to 10% of uveal melanomas occur on the iris. Diagnosis is quite challenging, as iris neoplasia can resemble several other entities. Prognosis is good, as the risk for metastasis is relatively low.

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Treatment of Corneal Neovascularization from Varicella-Zoster Keratitis Leonid Skorin Jr., DO, OD; Tyler J. Heuer, OD ABSTRACT: A clear cornea is essential to obtain optimum vision and when corneal neovascularization (CN) occurs it can be devastating to the patient’s vision. There are many causes of CN. This article will review a case of Varicella-zoster virus as a cause of CN in a 44-year-old male. The patient was treated with a subconjunctival injection of bevacizumab (Avastin®, Roche, Laval, QC) and prednisolone acetate 1%. Other treatment modalities which have been tried include bevacizumab eye drops, photodynamic therapy with verteporfin and GS-101 antisense oligonucleotide eye drops. There are no current approved treatments for a devastating condition like CN. Diagnosis and prompt treatment of Varicella-zoster is essential in managing patients with this condition..

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Ocular Cicatricial Pemphigoid: A Case Report Reena A. Patel, OD ABSTRACT: The aim of this Case Report is to explain the effect of undiagnosed ocular cicatricial pemphigoid (OCP), the importance of early diagnosis, and the management of OCP. This article will use a 53-year-old white male with a history of chronic conjunctivitis to help illustrate OCP.

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Diagnosis and Treatment of Ocular Surface Conditions: Focus on Dry Eye Paul Karpecki, OD

Advertising insertion orders and copy must be received before the first day of the preceding month for which the advertising is scheduled. While the editorial staff of Clinical & Refractive Optometry exercises great care to ensure accuracy, we suggest that the reader consult the manufacturer’s instructions before using products mentioned in this publication. The views contained in the Journal are those of the respective authors and not of the Publisher. Please direct all correspondence to: Mediconcept Editorial & Sales Office 3484 Sources Blvd., Suite 518 Dollard-des-Ormeaux, Quebec Canada H9B 1Z9 Tel.: (514) 245-9717 E-mail: info@mediconcept.ca Printed in Canada. All rights reserved. Copyright © 2016 Mediconcept. The contents of the publication may not be mechanically or electronically reproduced in whole or in part without the written permission of the publisher. All drug advertisements have been cleared by the Pharmaceutical Advertising Advisory Board.

INTRODUCTION: Dr. Karpecki began his presentation on dry eye disease (DED) by noting that, according to the most recent study on prevalence, 29% of the Canadian population has dry eye. Allergies represent approximately 20% and glaucoma is roughly 2.2%, so this is an enormous opportunity; dry eye is the future of optometry.

NEWS & NOTES 244 Canadian Receives the CNIB Chanchlani Global Vision Research Award; Microbes in Your Gut Influence Major Eye Disease

ISSN: 1705-4850; Date of Issue: December 2016

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Courtesy of: Dr. Teresa Lim and Dr. Pauline F. Ilsen

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Teresa Lim and Dr. Pauline Ilsen entitled Iris Neoplasia. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 221 for complete instructions.

Iris Neoplasia Teresa Lim, OD; Pauline F. Ilsen, OD

ABSTRACT Background: While uveal melanomas are the most common type of intraocular malignancy, only 3% to 10% of uveal melanomas occur on the iris. Diagnosis is quite challenging, as iris neoplasia can resemble several other entities. Prognosis is good, as the risk for metastasis is relatively low. Case Reports: Three patients, each presenting for routine examination with no particular complaints, were discovered to have iris lesions suspicious for malignancy. The cases presented illustrate the typical findings and management. Conclusions: The optometrist should be familiar with the appearance iris neoplasia and aware of the differential diagnoses to consider when a patient presents with a suspicious iris lesion. The eyecare practitioner must also be aware of appropriate management strategies for these patients.

INTRODUCTION Uveal melanomas are the most common intraocular malignancy, making up 5% of all intraocular tumors.1,2 Iris melanomas make up 3% to 10% of all uveal melanomas.2-7 They are usually detected at an earlier age than other ocular melanomas due to their high visibility in the anterior segment.5,8 The majority of iris melanomas follow a benign course, with low metastatic potential.1,2,5,7-10 The difficulty in managing the patient with an iris melanoma lies in definitively establishing the diagnosis. The diagnosis of an iris tumor is very challenging because there are a wide variety of lesions that can simulate T. Lim — Staff Optometrist, JJ Peters Bronx VA, Bronx, NY P.F. Ilsen — Professor, Marshall B. Ketchum University/Southern California College of Optometry, West Los Angeles Veterans Affairs Healthcare Center, Los Angeles, CA Correspondence to: Dr. Pauline F. Ilsen, Marshall B. Ketchum University, West Los Angeles Veterans Affairs Healthcare Center, Optometry Clinic (123) Bldg. 304, Room 2-123, 11301 Wilshire Blvd., Los Angeles, CA USA 90073; E-mail: Pauline.Ilsen@va.gov This article has been peer-reviewed.

iris tumors, and even benign lesions have suspicious characteristics.9-11 There is disagreement among researchers regarding nomeclature and classification of lesions, and the distinctions between what might be considered benign or malignant are not clear.6,9,10 Even the usage of the terms “melanoma” or “nevus” for pigmented iris lesions has been a matter of dispute.9 Close scrutiny to distinguish malignant iris lesions from benign ones is a crucial but challenging step in the management process.

CASE REPORTS Case 1 A 53-year-old white male presented for a routine eye examination reporting near vision blur. The patient stated that at his last exam, 33 years ago, he had been told that he had a “freckle” in the right eye. His medical history was positive for hypertension but he was taking no medication for it. His only medication was vardenafil. Pupils were equal, round and reactive to light with no afferent pupillary defect. Extraocular motilities were full with no restrictions and confrontation visual fields were full to finger counting in each eye. The patient’s best corrected visual acuity was 6/6 (20/20) OD and 6/6 (20/20) OS with a refraction of OD: +2.25-0.75x35, OS: +1.50 with add of +1.75. Slit lamp biomicroscopy revealed that lid and lashes were clear; the conjunctiva was white and quiet, and the cornea was clear. Angles were 1/2 x 1/2 by Von Herrick estimation. Anterior chambers were deep and quiet, and the lens and vitreous were also clear in each eye. A pigmented wedge-shaped lesion from 3:30 to 4:30 from the pupillary margin but not extending as far as the anterior chamber angle was discovered on the right iris. The lesion was vascularized and moderately elevated, and measured 3.8 x 3.8 mm in its greatest dimensions. The pupil was slightly peaked toward the lesion (Fig. 1A-D). Distortion of the pupil became exaggerated upon dilation. Intraocular pressure (IOP) by Goldmann applanation tonometry was 13 mmHg OD and 15 mmHg OS. Dilated fundoscopy revealed retinal pigment epithelium hyperplasia from 7-8 o’clock in the right eye. No anomalies were found in the left eye. The patient was diagnosed with a suspicious vascularized pigmented iris lesion of the right eye and was

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Fig. 1 Case 1: Moderately elevated, vascularized, pigmented lesion on the iris of the right eye remained unchanged (1A-1C); normal left eye (1D).

referred to Cornea/Anterior Segment Clinic for further investigation. At that visit gonioscopy was open in all four quadrants. All other exam findings were stable and the diagnosis remained that of a pigmented lesion of the iris. The significance of the lesion, differential diagnoses, low potential for metastasis, and complications were discussed with the patient. The patient was instructed to return in 4 months for continued monitoring. Baseline anterior segment photographs were taken of both eyes. The patient continued to return every 4 to 6 months as instructed for monitoring of the lesion, and was asked to bring old photographs for comparison. Two years after the initial presentation, all findings remained stable except a possible increase in vascularization of the inferior portion of the lesion. The patient was referred back to the Cornea/Anterior Segment Clinic for reevaluation. At that visit, gonioscopy was repeated and demonstrated no evidence of invasion of the angle or satellite lesions. The lesion appeared to be slightly thicker compared with the baseline photographs. The patient was advised of the increased suspicion for

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malignant melanoma with the inferior location of the vascularity and surgical risks were discussed. Because of the low risk for metastasis and slow growth, the plan was to observe given the potential side effects after excision such as glare and diplopia. He was instructed to return with any observed change in the lesion; otherwise, he was to be monitored in 3 to 4 months. The patient returned 3 months later for follow-up. The size and vascularity of the lesion remained unchanged from the previous visit. The diagnosis of presumed amelanotic iris melanoma of the right eye was made at this time. The patient returned 4 months later for continued monitoring with no changes observed; he has not returned to clinic since then. Case 2 A 50-year-old white male presented for a routine diabetic retinal screening and comprehensive eye examination. He had a history of superficial trauma to both eyes. The ocular history was otherwise negative. He was a type 2 diabetic for 18 years; medical history was otherwise

Fig. 2 Case 2: Iris nodules on the right eye (2A-2B) and the left (2C) were determined to be benign iris nevi.

significant for hypertension, benign prostatic hypertrophy, degeneration of intervertebral disc, hyperlipidemia, peripheral neuropathy, hemorrhoids, and hemorrhage of gastrointestinal tract. His medications included: acetaminophen, aspirin, cyclobenzaprine, etodolac, fluoxetine, fosinopril, glipizide, guaifenesin, hydrocodone, lovastatin, metformin, metoprolol tartate, nitroglycerin, and terazosin. Upon examination, pupils were equal round and reactive to light with no afferent pupillary defect. Extraocular motilities were full; confrontation visual fields were full to finger-counting. His visual acuity was 6/6 (20/20) OD and 6/6 (20/20) OS through +0.50-0.75x89 OD and +0.50-1.50x94 OS. Intraocular pressure was 16 mmHg OD, 15 mmHg OS with Goldmann applanation tonometry. Slit lamp biomicroscopy revealed a white-brown bilobed nodule approximately 1 mm x 1 mm in size on the iris of the right eye at 4:30, near the pupillary border. No feeder vessels or pupil distortion was evident. On the left iris there were two brown nodules at the pupillary ruff with ectropion uveae and fine superficial pigment in the left eye. The crystalline lenses had trace nuclear sclerosis. Dilated fundoscopy was normal with no signs of diabetic or hypertensive retinopathy. A tentative diagnosis of iris nodule was made in the right eye with a differential diagnosis of Busacca or Koeppe nodule. The patient was then referred to the Cornea/ Anterior Segment Clinic for further evaluation. The nodules were discussed with the patient. Given the bilateral presentation, the likelihood that the findings represented neoplastic disease was considered very remote. When the patient returned one year later, all examination findings were stable from the last visit. Gonioscopy revealed no angle nodules. Baseline anterior slit lamp photos were taken (Fig. 2A-C). The final assessment was iris nevi OU. The patient was advised to return in one year for follow-up, at which time no changes from the baseline photographs were observed. Case 3 A 59-year-old white male presented for a routine diabetic evaluation. His ocular history was significant only for superficial trauma to the right eye with an arrow during childhood. He had been diagnosed with diabetes 6 months ago. His medical history was otherwise significant for hypertension, hypertriglyceridemia, gout, and attention deficit disorder. His medications were cyclobenzaprine, gemfibrozil, glyburide, losartan, metoprolol, niacin, sertraline, simvastatin, and tretinoin. Upon examination, he was found to have a best corrected visual acuity of 6/6 (20/20) OD and 6/6 (20/20) OS with a refraction of OD -2.25 and OS +0.25 -1.00x90 with an add of +2.00. Both pupils were fully reactive to light; however, the right pupil was round while the left was slightly irregular. Extraocular motilities and confrontation visual fields were full. Goldmann

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Fig. 3 Case 3: Normal right eye (3A); suspicious melanotic iris lesion on left iris remained unchanged over time (3B-3D).

applanation tonometry measured 14 mmHg OD and 12 mmHg OS. Anterior segment examination discovered multiple papillomas on the lids of both eyes. The corneae had trace inferior superficial punctuate keratitis, the anterior chambers were deep and quiet, and the crystalline lenses had trace nuclear sclerosis and trace cortical opacities. The iris was blue and flat in the right eye. The left iris had a slightly elevated lesion from 7:00-8:30 with pupil distortion. This lesion was light to medium brown with numerous tiny granules of dark brown pigment on its surface. No feeder vessels were visible. Upon inquiry, the patient reported that this lesion had been there all his life. Dilated retinal exam was normal with no diabetic retinopathy. Baseline anterior segment photographs were taken on a subsequent visit (Fig. 3A-D). The differential diagnoses of iris nevus versus malignant neoplasia with distorted pupil were considered. A consultation with the Cornea/Anterior Segment Clinic was sought. At this evaluation, all examination findings were noted to be stable from the previous visit. Gonioscopy was normal with no vessels or masses

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extending to angle. The diagnosis was iris nevus of the left eye, with no signs of malignancy. The patient was instructed to follow-up yearly or sooner if any changes in size of iris nevus.

DISCUSSION Epidemiology and General Characteristics of Iris Melanoma Iris melanomas comprise 2% to 5% of all uveal melanomas.2,4,6,12 There seems to be no predilection when it comes to gender; they affect men and women equally.3 They tend to occur unilaterally.14 Uveal melanomas are considered rare in those under the age of 20 years, especially in children.13 The peak incidence of iris melanoma occurs ten years earlier than choroidal melanoma, at around 40 to 47 years of age.3-5,8-10,12,14 This may be due in part to the high visibility of the iris, where changes in iris color and pupil distortion are more apparent.3,10 There is a predisposition for iris melanomas to occur in light-skinned people.2,3,7,10,12,14 This may be

because their relative lack of skin pigmentation makes them more susceptible to damage from UV radiation.15 Rootman speculated that short wavelength light (ultraviolet) or light in general may be an inductive factor for iris melanomas.16 He hypothesized that predisposed or previously transformed melanocytes may be more intensely stimulated by light in a pale iris without protective pigmentation. Rootman also found that 21 out of 21 subjects in his study had light irides.16 The most common area affected is the inferior portion of the iris, possibly due to increased light exposure in this area.10,12,17 The majority of these lesions are stable and do not grow or grow slowly, but there is a small number that do grow and demonstrate both malignant and metastatic potential.1,2,9,14 Iris melanomas can present with a wide variety of signs. Most commonly they appear as pigmented lesions on the iris.3 They can vary in degree and homogeneity of pigmentation, and also show associated vasculature, elevation and growth.3 Other signs are unilateral increased IOP, pupillary distortion, ectropion iridis, and sector cataract.3,18 Anterior staphyloma, hyphema, corneal edema, uveitis, and heterochromia can also be signs of an iris melanoma. Patients may experience a decrease in vision, pain, and photosensitivity.3 The majority of patients are asymptomatic.9 “Tapioca” melanoma is a rare type of iris melanoma characterized by diffuse involvement of the iris, a nodular appearance, and elevated intraocular pressure likely due to tumor invasion of the angle as well as obstruction of the trabecular meshwork by dispersed tumor cells.19 Clinical Evaluation The clinical evaluation to diagnose iris melanomas should include a careful slit lamp exam of all anterior segment structures, including episceral tissue (to check for abnormal vascularity), cornea, anterior chamber angle, and the lens.2 Anterior segment photographs should also be taken to monitor for growth.3 Batiglou followed the patients in his study every six months with anterior segment photography. A refraction should be performed to look for a hyperopic shift. A unilateral increase in intraocular pressure suggests angle involvement, so measurement with Goldmann tonometry must be done.6,10 A careful gonioscopic examination should be performed to determine if there is pigment in the anterior chamber angle structures and invasion of the trabecular meshwork and ciliary body.3 Routine monitoring of iris melanoma should also include regular dilated fundoscopy to search for evidence of metastasis and to rule out a choroidal melanoma with iris metastasis. Although it is an invasive procedure, a biopsy may be necessary with a suspected iris melanoma to determine the histological characteristics of the lesion.

Traditional ultrasonography has poor resolution of anterior segment, but ultrasound biomicroscopy provides noninvasive high resolution imaging of the anterior segment.20 It produces images of intrastromal and posterior tumor margins and gives information about internal reflectivity.21 It can be used to determine if there is tumor growth, vascularity, sector cataract, and disturbance of the iris pigment epithelium.22 It is useful from differentiating iris nevus from iris melanoma.20 Iris melanomas show distortion of the posterior iris plane and posterior bowing of the iris, whereas iris nevi appear as minimally elevated iris stromal lesions with medium to high reflectivity.20 Iris melanomas tend to have low or medium reflectivity.22 Gunduz found no correlation between ultrasound biomicroscopy and the histopathologic features of iris melanomas or iris nevi, but Marigo and Nordlund did find some histopathologic correlation with ultrasound biomicroscopy.20-22 In Marigo’s study hypoechoic areas corresponded to enlarged blood vessels, and increased iris thickness corresponded to infiltration of the stroma by neoplastic melanocytic cells.21 Ultrasound biomicroscopy also helps in planning treatment, as it allows assessment of posterior chamber tumor extension, in which case local resection of the whole tumor may not be possible.21 It also may prove beneficial in treatment as a means for measuring the response to radiation therapy.23 Diagnostic Testing Fluorescein angiography is also used in the management of iris melanomas. According to Geisse, fluorescein angiography is not helpful in distinguishing between benign and malignant iris melanomas, but it is helpful in determining the limits of tumor involvement.8 There are three angiographic patterns of iris tumors developed by Demeler, and Jakobiec expanded on the patterns to include one more.8,17,24 The first angiographic pattern is characterized by no vessels or leakage.8 Those iris lesions displaying the first pattern have been shown to be mostly benign.8 The second pattern is characterized by a welldefined vascular system that appears early and leaks late into the iris tumor and surrounding area.8 There is a regular vascular net in the tumor.8 In Jakobiec’s study, iris lesions with the second pattern were mainly associated with benign tendencies.8,17 The third angiographic pattern shows disorganized vessels that leak with a diffuse or mottled pattern.8,17 The intensity of fluorescein increases with time. These were also shown to be mostly benign. The fourth angiographic pattern was a mixture of the first and third pattern. The angiogram showed angiographic “silence” intermixed with areas of well defined tumors vessels that usually showed late leakage. The iris melanomas that were categorized into the fourth angiographic pattern were shown to be malignant.8,17,24

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Table I Classification system for iris melanomas8,12 Cell Type

Classification

Description

Spindle Cell

Elongated cells with plump, prominent nuclei High nuclear-cytoplasmic ratio Mild mitotic activity Arranged into fasicular pattern Mildly coarse chromatin Eosinophilic nucleolus

Spindle A

Spindle B

Epithelioid Cell

Large eosinophilic nuclei Larger and more pleomorphic compared to spindle cell Eosinophilic cytoplasm Distinct cell borders High nuclear-cytoplasmic ratio Macrophages present depending on degree of tumor cell pigmentation Usually low mitotic activity

Mixed Cell

Mixture of malignant spindle cells with plump nuclei Prominent nucleoli Large polyehedral cells with glassy cytoplasm

Table II Jakobiec’s classification/diagnostic criteria of iris melanomas9,17 Group Classification

Description

1 2 3 4

Benign Benign Benign Benign

5 6

Melanocytosis Melanocytoma Epithelioid Cell Nevus Intrastromal Spindle Cell Nevus (precursor to group 5) Spindle Cell Nevus with Surface Plaque Borderline Spindle Cell Nevus

7 8 9

Spindle Cell Melanoma Spindle and Epithelioid Cell Melanoma Epithelioid Cell Melanoma

Morphologically similar to group 5 Spindle B

The limits of Jakobiec’s and Demeler’s studies were that biopsies were not performed in all cases.8 Of the biopsies that were performed in Jakobiec’s study, they correlated with the above grouping patterns in terms of malignant or benign tendencies. The histology of group 1 fluorescein patterns were mainly benign nevoid spindle cell proliferations, the group 2 fluorescein patterns were spindle cell also, group 3 fluorescein pattern sample histology showed hypocellular pigmented nevoid cells, and the histology of the group 4 fluorescein pattern showed spindle B melanoma and spindle-epithelioid cell melanoma.8 Jakobiec believed that the fluorescein pattern gave information regarding the behavior of the lesion and that this could be used to make inferences about cytology.17 Demeler, Jakobiec, and Geisse found that iris lesions classified in group 1 were benign, but they had different findings for iris lesions classified in groups 2 and 3.8,17,24 Contrary to Jakobiec’s findings, Demeler and Geisse discovered that tumors classified into group 2 were malignant when they were biopsied.8,24

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Large nuclei with eosinophilic nucleoli Easily identifiable mitotic figures

Another limitation of fluorescein angiography is that lesions such as inflammatory nodules and iris cysts can simulate fluorescein patterns similar to iris melanomas.8,17 Despite the difference in opinion in grouping pattern of malignant and benign lesions fluorescein angiography may be used to detect changes in vascular pattern. Any documented changes in vascular pattern should warrant a prompt biopsy.17 Histology of Iris Melanomas Many clinicians agree that histologic examination is the best way to distinguish between malignant and benign iris melanomas.8,21 Specific histological characteristics of iris melanomas are used to differentiate between benign and malignant lesions.8 However, there is no uniformly accepted classification system.6 The distinctions between what would be considered “benign” or “malignant”, and what would be considered spindle A versus spindle B cytology have been debated among pathologists.10 An additional drawback to histologic evaluation of iris lesions is that there is a limited amount of tissue available for examination.25 The modified Callender classification system is often used for categorizing iris melanomas.12 This system consists of two main cellular types (spindle and epithelioid) and three categories of melanomas (spindle cell, epithelioid cell, and mixed cell type).12 The histological cell types of iris melanomas are summarized in Table I. Spindle cell cytology holds the most favorable prognosis, then epithelioid cell.8,12 Mixed cell iris melanomas have the worst prognosis.12 Geisse believed that spindle A melanomas were benign.8 Some studies have shown that spindle A cells are incapable of metastasis, whereas others document that there have been

Table III Differential diagnosis of iris melanomas11,29-31 Diagnosis

Description

Primary iris cyst

Causes anterior displacement of peripheral iris Best viewed by dilating pupil and using slit lamp biomicroscopy and Goldmann lens

Iris nevus Essential iris atrophy Lymphoid infiltrate of the iris Foreign body Corneal perforation Peripheral anterior synechiae Iris metastases Aphakic iris cyst Miscellaneous iris atrophy Pigment epithelial hyperplasia or migration Iris neovascularization Atypical iris vessels Vascular tumors of iris (cavernous hemangioma, capillary hemangioma, racemose hemangioma, varix) Iris depigmentation Leiomyoma Intraocular uveal tissue Melanocytoma Occluded pupil Iris nevus syndrome (Cogan-Reese)

Areas of iris atrophy Peripheral anterior synechiae with breaks in iris stroma Confirmed by histopathology

ex. Ciliary body tumor with metastasis to iris

Benign smooth muscle tumor Usually benign Monomorphic proliferation of plump, polyhedral cells Diffuse nevus of anterior iris Presents with heterochromia, glaucoma, corneal edema, breaks in iris stroma, and peripheral anterior synechiae Benign condition but difficult to diagnose

Reactive lymphoid hyperplasia Adenoma of iris epithelium Congenital heterochromia Iridoschisis

cases of metastasis from spindle A melanomas proven after enucleation of uveal melanomas.8,10 There have been attempts to classify spindle A melanomas as spindle nevus due to their benign characteristics and zero metastatic potential.10 However, differentiating cytologically between spindle A and spindle B is difficult.10 Epithelioid and mixed cell melanomas show more malignant histology than the spindle cell counterpart and have metastatic potential.3,10 Kersten found that smaller iris melanomas were made of spindle cell typology whereas larger tumors had malignant mixed or epithelioid cytology.10 Jakobiec reclassified iris lesions into nine histopathologic classification/diagnostic categories. Group 1 is melanocytosis; Group 2 is melanocytoma, Group 3 is the epithelioid cell nevus; Group 4 is intrastromal spindle cell nevus; Group 5 is spindle cell nevus with surface plaque; Group 6 is comprised of the â&#x20AC;&#x153;borderlineâ&#x20AC;? spindle cell nevus; Group 7 is spindle cell melanoma; Group 8 includes spindle and epithelioid cell melanoma; and Group 9 is the epithelioid cell melanoma (Table II).9 This classification system has received criticism because it classified all

spindle cell A cells to spindle cell nevi, despite known cases of metastasis from spindle A cells.10,12 Kersten suggested that iris melanomas actually develop from pre-existing iris nevi.10 He hypothesized that clones of malignant cells transform to become small melanomas.10 Kersten also found that cells could exhibit spindle or epithelioid cytology depending on the tissue environment which suggested that the two cell histology were not separate entities but two environmentally influenced expressions of the same genotype.10 Kersten hypothesizes that spindle A melanomas would not continue to exhibit benign tendencies if left alone. He theorized that spindle A melanomas could have the potential to evolve into spindle B and epithelioid cell types. Jakobiec also concluded that a large number of malignant melanomas of the iris existed from preexistent nevi.17 It has been suggested that spindle A, spindle B and mixed epithelioid cells form a continuum.9,10 So even with the more benign spindle A histology, one must carefully monitor for change or progression into epithelioid cytology.

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Table IV Characteristics associated with enlargement of iris lesion18 Medial location of mass Pigment dispersion onto adjacent iris or into anterior chamber angle Increase in lesion size Abnormal vasculature Secondary glaucoma

Differential Diagnosis Malignant iris melanomas are commonly misdiagnosed because many anterior segment lesions can mimic melanomas.3,11 One study found that 35% of eyes that were enucleated for being iris melanomas were found to be pseudomelanomas.3,11,26 In Ferry’s study anterior staphylomas, inflammatory masses, iris stromal atrophy, and corneal perforations were the most common misdiagnoses in presumed iris melanomas.11,26 In Shields’ study iris cysts, iris nevus, and essential iris atrophy were most commonly misdiagnosed as iris melanomas.11 Iris cysts cause anterior displacement of the peripheral iris.11 They are best viewed by widely dilating the pupil and using slit lamp biomicroscopy and Goldmann 3-mirror lens examination.11 Shields diagnosed an iris nevi if it was a solid mass that locally replaced iris stroma but failed to meet their diagnostic criteria for melanoma.11 Shields’ diagnostic criteria for an iris melanoma was a melanocytic lesion that locally replaced iris stroma, at least 3 mm in diameter and 1 mm in thickness and had at least three of the following features: (1) prominent vascularity, (2) ectropion iridis, (3) secondary cataract, (4) secondary glaucoma, and/or (5) photographic documentation of progressive growth.11 Iris nevus syndrome is also a differential diagnosis of malignant melanoma.11,27 It presents as a diffuse nevus of the iris along with a variety of other ocular signs including peripheral anterior synechiae frequently associated with defects in adjacent iris stroma, matted appearance of the iris stroma with a velvety whorl-like surface and loss of iris crypts, iris nodules, ectropion uveae, heterochromia, and secondary glaucoma.27 Iris melanocytomas are rare and are diagnosed histopathologically with the presence of monomorphic proliferation of plump, polyhedral cells. Iris melanocytomas are usually benign with the least potential for malignant change but there have been reports of transformation to malignant melanoma.13,28 Table III enumerates the wide variety of lesions that should be considered as differentials for iris melanomas. The clinical diagnosis of a malignant melanoma is extremely difficult, which leads to a high error rate.3,11 Benign iris melanomas can seem malignant and vice versa.10 A study done in 1975 found that 0.9% to 1.3% of enucleated eyes actually contained malignant melanomas.10 Most reports agree that documented rapid growth is concerning. However other factors, such as increased

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intraocular pressure has not always been reported in association with a malignant lesion. Territo found clinical features associated with tumor enlargement to be medial location of mass on iris and presence of pigment dispersion onto adjacent iris or into anterior chamber angle structures.18 Overall malignant potential is increased with an increase in lesion size, abnormal vasculature, secondary glaucoma, and documented enlargement.3,18 Table IV lists the characteristics that have been associated with enlargement of iris lesions. Prognosis and Complications Glaucoma can be one of the complications of a benign iris lesion and a malignant iris melanoma. Iris melanomas can cause glaucoma by obstructing outflow at the level of the trabecular meshwork through direct extension or seeding of tumor cells, pigment granules, or macrophages into the anterior chamber angle.32,33 The fatality rate of iris melanomas is very low.3 The metastasis rate from iris melanomas is estimated to be 3% to 5%.2,8,14 The risk of metastasis is greater in older patients, those with elevated intraocular pressure, extraocular extension, and those in whom the iris root is involved by the tumor.2 Some have said that if the drainage angle is involved, the rate doubles to 6%.34 Spindle A melanomas had no potential for metastasis according to Geisse, but Kersten found documented cases of metastasis from spindle A melanomas.8,10 Spindle melanomas (including spindle A and spindle B) metastasized at a rate of 2.6%, epithelioid melanomas at a rate of 6.9% and mixed cell melanomas at a rate of 10.5%.8 The average time to metastasis was 6.5 years. Geisse recommended a follow-up of at least five, ten and fifteen years to check for stability and metastasis.8 Kersten found that most metastasis occurred from pure epithelioid or mixed tumors with a peak that occurred two to four years after enucleation and a second peak at six to seven years after enucleation.10 Kersten’s study found that that age less than twenty, increased intraocular pressure at diagnosis, peripheral location of iris tumor and mixed or epithelioid histology increased the risk of metastatic death from iris tumors. Sunba’s study showed that diffusely infiltrating, heavily pigmented tumors, and tumors whose cell nuclei show prominent nucleoli were more likely to metastasize.14 Diffuse iris melanomas have a relatively poor prognosis.3,12,14 Nordlund found that iris melanomas were more likely to metastasize if there was involvement of the iris root or the anterior chamber angle along with elevated intraocular pressure or when there is extraocular spread.22 Metastasis to the iris is relatively rare in comparison with metastasis to the choroid.36 The most common carcinomas that metastasize to the iris and ciliary body arise in the breast, lung, and kidney (Table V).35,36 In a

Table V Primary cancer locations that metastasize to the iris36

Table VI Treatment for iris melanoma and their associated side effects.8,12,39,40,43

Primary tumor type and location Breast carcinoma Lung carcinoma Melanoma Colonic carcinoma Esophageal carcinoma Laryngeal carcinoma Prostatic carcinoma Renal cell carcinoma

Treatment

Side Effects

Sector iridectomy or iridocyclectomy Plaque radiotherapy

Photophobia, glare, diplopia

study of 1,200 patients with iris lesions, Shields et al found that the most common source of metastasis to the iris was breast carcinoma, accounting for 40% of their cases of iris metastasis; lung carcinoma was the source of metastasis in 28%; and bronchial “carcinoid” tumor in 8%.36 They found that most metastatic lesions of the iris were located inferiorly, 15% had multiple lesions, 50% of cases had engorged bulbar conjunctival or episcleral vasculature, and 60% had an irregular pupil.36 Treatment and Management Iris melanomas usually do not require immediate intervention. These lesions are slow-growing and mostly follow a benign course.3 The usual treatment is observation, with regular follow-ups, documentation by anterior segment photography, and treatment of complications such as glaucoma.3,6,12 Sector iridectomy or iridocyclectomy is performed for smaller iris melanomas that show growth (Table V).3,37 Any surgical options must be taken with caution because of the risk of tumor seeding. There has been a case where iridocyclectomy for a malignant iris melanoma resulted in seeding of the tumor cells.38 Plaque radiotherapy is an alternative to enucleation in the case of large diffuse tumors that have extensive seeding of the iridocorneal angle and intractable glaucoma. Plaque radiotherapy has been shown to be effective against malignant iris melanomas. One patient out of fourteen developed epitheliopathy, abrasion and corneal edema.39 The most worrisome complication was radiation induced iris vasculopathy but none developed iris neovascularization in Shields’ study. However, in Finger’s study there were cases of iris neovascularization after treatment.23 There have not been any reported cases of radiation retinopathy or optic neuropathy. A summary of complications of plaque radiotherapy is provided in Table VI. Bianciotto et al described successful treatment of a case with iris melanoma and secondary neovascular glaucoma with a combination of plaque radiotherapy and bevacizumab injection.40 Photoradiation therapy uses light to activate certain photosensitizing tissues such as hematoporphyrin derivative which has an affinity for neoplastic tissue. This method of treatment results in selective tumor necrosis without damaging adjacent tissue. Side effects

Proton beam therapy Photoradiation therapy

Corneal abrasion, corneal edema, uveitis, hyphema, corneal epitheliopathy, posterior synechiae, focal iris vasculopathy, telangiectasia of the iris, radiation cataract, preradiotherapy tumor induced glaucoma Glaucoma, cataract, dry eye Uveitis, keratic precipitates, neovasculaization of the angle

from the treatment include keratic precipitates, iritis, and neovascularization of the anterior chamber angle, and glaucoma.41 Another method of treating large non-resectable iris melanomas is proton beam therapy. The major complication was found to be glaucoma along with symptomatic dry eye and cataract.42 Radiation complications usually occur 12 to 24 months after treatment.37 Recent developments in treating malignant iris melanomas have looked at vascular endothelial growth factor. Vascular endothelial growth factor is a glycoprotein that functions as an endothelial cell mitogen and a vascular permeability factor. It is thought to play a role in tumor angiogenesis.43 This could also help in iris neovascularization following radiation therapy. Anti-VEGF factors could be used as a conservative treatment to enucleation from neovascularization.40,43 For cases with glaucoma, laser trabeculoplasty, filtering surgery (Scheie procedure or unguarded filter surgery), and trabeculectomy (guarded filter surgery) are contraindicated because they can spread tumor cells.30,34,44 The safer approach is to reduce inflow by cyclocryotherapy of the ciliary body. As mentioned previously, successful treatment with the anti-VEGF agent bevacizumab in combination with plaque radiotherapy has been reported in a case with neovascular glaucoma due to iris melanoma.40 When a large, diffuse tumor has resulted in surgically uncontrollable glaucoma, enucleation may be necessary.3,12

CONCLUSION There is much debate surrounding the diagnosis of malignant iris melanomas. There are no definitive criteria that make an iris lesion a malignant iris melanoma. What used to be considered malignant characteristics such as documented growth and glaucoma are now known to also be associated with benign iris lesions. Optometrists must be familiar with the numerous differentials that should be considered when a patient presents with a suspicious lesion

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on the iris. The best care is photodocumentation and regular follow-up. Patients suspected of having a metastasis to the iris should be evaluated by ocular and systemic oncologists.36 ❏

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

21.

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Harbour JW, Augsburger JJ, Eagle RC. Initial management and follow-up of melanocytic iris tumors. Ophthalmology 1995; 102: 1987-1993. Shields CL, Shields JA, Materin M. Iris melanoma: Risk factors for metastasis in 169 consecutive patients. Ophthalmology 2001;108(1): 172-178. Batioglu F, Gunalp I. Malignant melanomas of the iris. Jpn J Ophthalmol 1998; 42: 281-285. Conway RM, Chua WCT, Billson FA. Primary iris melanoma: diagnostic features and outcome of conservative surgical management. Br J Ophthalmol 2001; 85: 848-854. Van Klink F, De Keizer RJW, Kakebeeke-Kemme MJ, et al. Iris nevi and melanomas: A clinical follow-up study. Documenta Ophthalmolgica 1992; 82: 49-55. Char DH, Crawford JB, Kroll S. Iris melanomas: Diagnostic problems. Ophthalmology 1996; 103: 251-255. Shields CL, Materin MA, Shields JA. Factors associated with elevated intraocular pressure in eyes with iris melanoma. Br J Ophthalmol 2001; 85: 666-669. Geisse LJ, Robertson DM. Iris melanomas. Am J Ophthalmol June 1985;99: 638-648. Jakobiec FA, Silbert G. Are most iris ‘melanomas’ really nevi? Arch Ophthalmol Dec 1981;99: 2117-2132. Kersten RC, Tse DT, Anderson R. Iris melanoma. Nevus or malignancy? Surv Ophthalmol May-June 1985; 29(6): 423-433. Shields JA, Sanborn GE, Augsberger JJ. The differential diagnosis of malignant melanoma of the iris. A clinical study of 200 patients. Ophthalmology 1983; 90(6): 716-720. Henderson E, Margo CE. Iris melanoma. Arch Pathol Lab Med Feb 2008; 132(2): 268-272. Pe’er J. Iris melanoma in a 6-year-old girl. Arch Ophthalmol May 2001; 119(5): 780-781. Sunba MSN, Rahi AHS, Morgan G. Tumors of the anterior uvea: Metastasizing malignant melanoma of the iris. Arch Ophthalmol 1980; 98: 82-85. Regan S, Judge HE, Gragoudas ES, et al. Iris color as a prognostic factor in ocular melanoma. Arch Ophthalmol 1999; 117(6): 811-814. Rootman J. Gallagher RP. Color as a risk factor in iris melanoma. Am J Ophthalmol Nov 1984; 98(5): 558-561. Jakobiec FA, Depot MJ, Henkind P. Fluorescein angiographic patterns of iris melanocytic tumors. Arch Ophthalmol 1982; 100: 1288-1299. Territo C, Shields CL, Shields JA. Natural course of melanocytic tumors of the iris. Ophthalmology 1988; 95(9): 1251-1255. Pick ZS, Wilson GA. Tapioca melanoma of the iris. Clin Exp Optom March 2009; 92(2): 154-156. Gunduz K, Hosal BM, Zilelioglu G. The use of ultrasound biomicroscopy in the evaluation of anterior segment tumors and simulating conditions. Ophthalmologica 2007; 221: 305-312. Marigo FA, Finger PT, McCormick SA. Iris and ciliary body melanomas: Ultrasound biomicroscopy with histopathologic correlation. Arch Ophthalmol 2000; 118: 1515-1521.

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22. Nordlund JR, Robertson DM, Herman DC. Ultrasound biomicroscopy in management of malignant iris melanoma. Arch Ophthalmol 2003; 121(5): 725-727. 23. Finger PT, Reddy S, Chin K. High-frequency ultrasound characteristics of 24 iris and iridociliary melanomas. Arch Ophthalmol 2007; 125(8): 1051-1058. 24. Demeler U. Fluorescence angiographical studies in the diagnosis and follow-up of tumors of the iris and ciliary body. Advances Ophthalmol 1981; 42: 1-17. 25. Foulds WS, Lee WR. The significance of glaucoma in the management of melanomas of the anterior segment. Trans Ophthalmol Soc UK 1983; 103: 59-63. 26. Ferry AP. Lesions mistaken for malignant melanoma of the iris. Arch Ophthalmol 1965; 74: 9-18. 27. Greven C, Stanton C, Yeatts R, et al. Diffuse iris melanoma in a young patient. Arch Ophthalmol 1997; 115(5): 682-683. 28. Cialdini AP, Sahel JA, Jalkh AE. Malignant transformation of an iris melanocytoma. A case report. Graefe’s Arch Clin Exp Ophthalmol 1989; 227: 348-354. 29. Shields JA, Shields CL, Pulido J, et al. Iris varix simulating an iris melanoma. Arch Ophthalmol 2000; 118(5): 707-710. 30. Scheie HG, Yanoff M. Iris nevus (Cogan-Reese) Syndrome. Arch Ophthalmol 1975; 93: 963-970. 31. Sharma M. Shields C, Shields JA. Benign lymphoid infiltrate of the iris simulating a malignant melanoma. Cornea 2002; 21(4): 421-425. 32. Shields CL, Shields JA, Shields MB, Augsburger JJ. Prevalence and mechanisms of secondary intraocular pressure elevation in eyes with intraocular tumors. Ophthalmology 1987; 94(7): 839-846. 33. Shields MB, Prioa AD. Neovascular glaucoma associated with an iris melanoma. A clinicopathologic report. Arch Ophthalmol 1987; 105(5): 672-674. 34. Girkin CA, Mansberger SL, Shields JA, et al. Management of iris melanoma with secondary glaucoma. J Glaucoma 2002; 11(1): 71-74. 35. Spraul CW, Grossniklaus HE, Giles JT. Mullerian mixed tumor metastatic to the iris and ciliary body. Arch Ophthalmol 1997; 115(1): 122-123. 36. Shields JA, Shields CL, Kiratli Y. Metastatic tumors to the iris in 40 patients. Ophthalmology 1995; 119: 422-430. 37. Rennie I. Irradiating iris tumours. Br J Ophthalmol 1995; 79(4): 306-312. 38. Gupta M, Rennie IG. Iris seeding following iridocyclectomy for localized iris melanoma. Eye 2001; 15(Pt 6): 808-809. 39. Shields CL, Shields JA, DePotter P. Treatment of nonresectable malignant iris tumours with custom designed plaque radiotherapy. Br J Ophthalmol 1995; 79: 306-312. 40. Bianciotto C, Shields CL, Kang B, et al. Treatment of iris melanoma and secondary neovascular glaucoma using bevacizumab and plaque radiotherapy. Arch Ophthalmol 2008; 126(4): 578-579. 41. Lewis RA, Tse DT, Phelps CD. Neovascular glaucoma after photoradiation therapy for uveal melanoma. Arch Ophthalmol 1984; 102: 839-842. 42. Rundle P, Singh AD, Rennie I. Proton beam therapy for iris melanoma: a review of 15 cases. Eye 2007; 21(1): 79-82. 43. Lee ES, Baratz KH, Pulido JS. Expression of vascular endothelial growth factor in iris melanoma. Arch Ophthalmol 2006; 124(9): 1349-1350. 44. Grossniklaus HE, Brown RH, Stulting RD. Iris melanoma seeding through a trabeculectomy site. Arch Ophthalmol 1990; 108:1287-1290.

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QUESTIONNAIRE Iris Neoplasia Teresa Lim, OD; Pauline F. Ilsen, OD 1. ❑ ❑ ❑ ❑

What percentage of all uveal melanomas do iris melanomas constitute? 1% 3% to 10% 25% 50%

2. ❑ ❑ ❑ ❑

In Case 2, the patient presented initially with all of the following conditions/symptoms, EXCEPT: Benign prostatic hypertrophy Hypertension Type 2 diabetes Peripheral neuropathy

3. ❑ ❑ ❑ ❑

All of the following statements describe Case 3 at initial presentation, EXCEPT: The patient showed no evidence of diabetic retinopathy The patient’s visual acuity had remained excellent, despite a childhood trauma The lesion in the left iris was deemed to be benign The patient reported having discovered the lesion in his left iris six months prior to the initial ocular consultation

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All of the following statements describe uveal melanomas, EXCEPT: They are most common in males over the age of 20 They usually occur unilaterally The peak incidence is between 40 and 47 years of age They typically appear in the inferior portion of the iris

5. ❑ ❑ ❑ ❑

All of the following are signs/symptoms of iris melanomas, EXCEPT: Decreased vision Photosensitivity Pain Progressive loss of peripheral vision

6. ❑ ❑ ❑ ❑

In Case 1, the patient presented initially with all of the following clinical signs, EXCEPT: Clear vitreous Slightly elevated IOP OD Clear corneas No afferent papillary defect

7. ❑ ❑ ❑ ❑

Of the three angiographic patterns described by Demeler and Jakobiec, which involved predominantly benign lesions? The first The second The third The fourth

8. ❑ ❑ ❑ ❑

According to Shields’ diagnostic criteria for iris melanomas, which diameter is characteristic? 1 mm 2 mm 3 mm 4 mm

9. ❑ ❑ ❑ ❑

According to the paper, can iris melanocytomas transform to malignant melanomas? This occurs, although iris melanocytomas have the least potential for malignant change This rarely occurs This is more likely to occur when a family history of iris melanomas is present This occurs in more than 50% of cases

10. According to the paper, which of the following is most commonly the first treatment option considered? ❑ Photoradiation therapy ❑ Proton beam therapy ❑ Vascular endothelial growth factor (VEGF) ❑ Observation

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Clinical and Refractive Optometry 27:6, 2016

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Leonid Skorin Jr. and Dr. Tyler J. Heuer entitled Treatment of Corneal Neovascularization from Varicella-Zoster Keratitis. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 227 for complete instructions.

Treatment of Corneal Neovascularization from Varicella-Zoster Keratitis Leonid Skorin Jr., DO, OD, MS, FAAO, FAOCO Tyler J. Heuer, OD

ABSTRACT A clear cornea is essential to obtain optimum vision and when corneal neovascularization (CN) occurs it can be devastating to the patient’s vision. There are many causes of CN. This article will review a case of Varicella-zoster virus as a cause of CN in a 44-year-old male. The patient was treated with a subconjunctival injection of bevacizumab (Avastin®, Roche, Laval, QC) and prednisolone acetate 1%. Other treatment modalities which have been tried include bevacizumab eye drops, photodynamic therapy with verteporfin and GS-101 antisense oligonucleotide eye drops. There are no current approved treatments for a devastating condition like CN. Diagnosis and prompt treatment of Varicella-zoster is essential in managing patients with this condition.

INTRODUCTION In order to have good vision one needs a good tear film, clear cornea, clear lens, and a healthy macula. Vision can potentially be reduced if any of the structures that refract light onto the retina become damaged. The cornea, which is the most important structure in refracting light onto the retina, needs to be transparent. Making up 90% of the cornea, the stroma’s precise arrangement of fibrils in lamellae is why the cornea is transparent.1 The cornea is also avascular to allow for complete transparency and therefore needs to get its nutrients and oxygen from other sources. The cornea gets its nutrients from three major L. Skorin, Jr. — Consultant, Department of Surgery, Community Division of Ophthalmology, Mayo Clinic Health System, Albert Lea, MN T.J. Heuer — Staff Optometrist, Avera Marshall Southwest Ophthalmology, Marshall, MN Correspondence to: Dr. Leonid Skorin, Jr., Mayo Clinic Health System, 404 West Fountain Street, Albert Lea, MN 56007; E-mail: skorin.leonid@mayo.edu The authors have no financial or proprietary interest in the products mentioned in this article. This article has been peer-reviewed.

sources including the tear film, aqueous humor, and pericorneal capillary plexus.2 Any etiology that compromises adequate nutrient supply to the cornea can cause CN. Other causes of neovascularization include inflammatory conditions, infections, degenerative diseases, and trauma.3 The new blood vessels can leak inflammatory cells leading to corneal haze.4 Varicella-zoster virus is just one of a multitude of etiologies that can compromise the integrity of the cornea.

DIAGNOSTIC DATA A 44-year-old white male presented to our clinic concerned about decreased vision in his left eye and that the eye looked bloodshot. The patient also noted that his left eye was scratchy and that it was light sensitive. He stated that he was taking loteprednol (Lotemax®, Bausch & Lomb, Vaughan, ON) but had discontinued it four weeks prior and was currently only using artificial tears. He had no known medication allergies. His ocular history was remarkable for cataract in the left eye and a previous episode of herpes zoster virus keratitis of the left eye. His medical history was negative for diabetes, hypertension, and thyroid disease. Entering unaided acuities were 6/6 (20/20) in the right eye, 6/120 (20/400) in the left eye with eccentric viewing and pinhole testing being 6/60-1 (20/200-1) in the left eye. Extraocular muscle testing revealed full motility. Pupil testing was attempted but the left pupil could not be adequately viewed. Intraocular

Fig. 1 Corneal opacification and neovascularization at 6 o’clock and 9 o’clock. Subconjunctival hemorrhage is from bevacizumab injection.

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Fig. 2 Improved corneal opacification and resolution of neovascularization 11 days after subconjunctival injection of bevacizumab. Subconjunctival hemorrhage is also resolving.

pressures were 13 mmHg in the right eye and 11 mmHg in the left eye. Slit lamp examination of the anterior structures of the left eye revealed 1-2+ corneal opacification with thickening and dense stromal neovascularization at 6 o’clock and 9 o’clock (Fig. 1). The cornea of the right eye was clear.

overlapping the original letters. Intraocular pressure was 17 mmHg in the left eye. Anterior segment evaluation revealed a significant improvement of the keratitis and a near complete resolution of the neovascularization (Fig. 2). At this point the anterior chamber was visible and showed no cells or flare in the left eye. The patient was instructed to start tapering his prednisolone acetate. The patient returned about two weeks later and indicated continual improvement in the left eye. Vision was 6/9+1 (20/30+1) and pinhole was 6/6 (20/20) in the left eye. At this appointment, refraction was performed on the left eye and revealed a small refractive error which slightly improved his acuity. Intraocular pressure was 19 mmHg in the left eye. Slit lamp findings showed a persistent anterior corneal stromal haze but reabsorbed neovascularization. The patient was instructed to continue to taper his prednisolone acetate. Another follow up was scheduled for two weeks. At this exam the patient indicated that the left eye was the same and unchanged. Vision was 6/9 (20/30) and pinhole was 6/6-2 (20/20-2). Intraocular pressure was 13 mmHg in the left eye. Anterior segment evaluation revealed a persistent corneal stromal haze with ghost vessels at 6 o’clock and 9 o’clock (Fig. 3). The patient was instructed to continue to taper his prednisolone acetate.

DISCUSSION DIAGNOSIS The patient was diagnosed with opacification and neovascularization of the left cornea.

TREATMENT AND FOLLOW-UP Treatment included a subconjunctival injection of 0.625 mg/0.025 mL bevacizumab (Avastin) adjacent to each of the two areas of neovascularization for a total dosing of 1.25 mg/0.05 mL. Prednisolone acetate 1% every hour was also started in the left eye. On the first follow up visit two days later, vision was still reduced to 6/120 (20/400) in the left eye but subjectively the patient’s wife noted the redness had decreased. Intraocular pressure was 16 mmHg in the left eye. Objectively, the corneal haze had decreased and now a few old pigmented keratic precipitates were seen on the endothelium. The neovascularization did not seem to have progressed. The patient was instructed to continue prednisolone acetate 1% every hour while awake until the next follow up in one week. At this appointment the patient noted seeing a lot better. He felt that things were still a little fuzzy but back to what it was like eight to ten weeks prior to his current recurrence. The patient’s wife also noted an overall significant improvement in the appearance of his left eye. Visual acuity was 6/12-1 (20/40-1) in the left eye with pinhole acuity being 6/6 (20/20). The patient noted monocular diplopia and that the second set of letters was

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Varicella-zoster virus is often encountered in eye care and with the aging population the number of these cases will probably increase. Varicella-zoster virus is the same virus that causes chickenpox which is a childhood condition seen after initial exposure to the virus.5 After this initial exposure, the virus will lay dominant in the dorsal root and sensory ganglia where it can be reactivated in adults. The reactivated virus in an adult is referred to as shingles. It is not known why the virus reactivates but it is postulated that decreased immunity and possibly other environmental factors contribute to the reactivation.6 The virus may also be reactivated when the patient’s immune system is compromised either by medications, malnutrition, illness, or aging.7 It is noted that 99.5% of individuals older than 40 years are at risk for zoster due to being exposed to this virus or having had chickenpox.8 More than 90% of adults in the United States are serologically positive for the zoster virus, and 10% to 20% of these adults will have reactivation of the virus.9 Herpes zoster ophthalmicus (HZO) occurs when the ophthalmic division of the trigeminal nerve becomes involved. HZO typically affects people in their sixth and seventh decade of life and is more severe the older a patient is.10 About 10% of patients with herpes zoster reactivation will develop eye symptoms.8 Acute eye signs range from conjunctivitis, episcleritis, scleritis, epithelial keratitis, nummular keratitis, stromal keratitis, disciform

Fig. 3 Significantly improved corneal opacification and resolution of neovascularization after 46 days. Ghost vessels are seen at the 9 o’clock position.

keratitis, anterior uveitis, and other neurologic complications.10 Chronic eye signs include lid scarring, lipidfilled granulomata, scleritis, mucous plaque keratitis, neurotrophic keratitis, and lipid degeneration.10 Other less common ocular manifestations include cataract, cranial nerve palsies, retinitis, central retinal vein and artery occlusions, optic neuritis, and choroiditis.11 Prompt and aggressive treatment of Varicella-zoster is indicated because of the dire complications that can occur. The first line of therapy are the oral antiviral agents: acyclovir (Zovirax®, GlaxoSmithKline, Mississauga, ON), famciclovir (Famvir®, Novartis, Dorval, QC), and valacyclovir (Valtrex®, GlaxoSmithKline, Mississauga, ON).11 All three drugs show similar effects in the treatment of HZO. Treatment with these drugs is most helpful if initiated within 48 to 72 hours from the onset of any rash.11 Other treatments will depend on the various presenting signs of the disease. The cornea can become involved leading to opacification, decreased sensitivity, and neovascularization.9 Corneal neovascularization can potentially give rise to other complications such as lipid keratopathy which is the deposition of fat into the corneal tissue.3 Different treatment options to treat the corneal changes have been investigated. These include topical bevacizumab, subconjunctival bevacizumab injections, photodynamic therapy with verteporfin, and gene signal (GS)-101 antisense oligonucleotide eye drops. Vascular endothelial growth factor (VEGF) is the main component in corneal angiogenesis. Therefore, blocking neovascularization with anti-VEGF medications such as bevacizumab is a possible treatment option.12,13 Bevacizumab is a recombinant humanized monoclonal antibody. It was

originally designed for cancer therapy to stop new blood vessel growth that could potentially supply nutrients and oxygen to tumors.4,14 There are no current United States Food and Drug Administration or Health Canada approved treatment options for the anterior part of the eye that utilize anti-VEGF therapy. Topical administration and subconjunctival injection of bevacizumab however have been tried in the treatment of CN. Kim et al noted that topical bevacizumab can be used as a treatment modality but that it can have delayed side effects.15 These authors noted in their study that corneal epithelium integrity was lost and that stromal thinning was seen with topical bevacizumab use. Another potential complication seen with blocking VEGF is the disruption of wound healing from ischemia and thus secondary tissue damage.15 Subconjunctival injection of bevacizumab for CN has been found to be a good treatment modality for acute neovascularization.12 Chronic neovascularization therapy with subconjunctival injection of bevacizumab is not as effective since the patient will have to undergo long term therapy with numerous injections. Side effects of subconjunctival bevacizumab include corneal edema and subepithelial infiltrates.12 Our patient responded adequately after only one subconjunctival injection for his acute episode. Another treatment option for corneal neovascularization that has been studied is photodynamic therapy with verteporfin. This treatment has been found to be a safe, repeatable, and efficient option for CN.3 Photodynamic therapy works with the release of oxygen radicals that damage the blood vessel endothelial cells and thus create a blood clot leading to occlusion of the neovascular blood vessel. The side effects of such a treatment include visual disturbances, corneal haze, conjunctival injection, photosensitivity, and back pain.3 A potential future therapeutic option is topical treatment with GS-101 antisense oligonucleotide. In the interim results of a randomized phase II trial it was found that twice a day topical application of GS-101 at an intermediate dose was effective at stopping and reducing corneal angiogenesis.13 GS-101 inhibits the scaffold protein insulin receptor substrate-1 and was specifically designed to work on new blood vessels. It has also been shown to have an anti-inflammatory component that reduces the release of cytokines in vivo. The phase II trial showed GS-101 to have no significant side effects and no safety concerns.13 The study found that the intermediate dose of 86 micrograms given twice daily was the most effective dose which halted corneal angiogenesis versus a placebo.13 GS-101 eye drops seem to be a promising treatment option for corneal neovascularization in the future.13

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CONCLUSION Different treatment options for CN include topical bevacizumab, subconjunctival bevacizumab injection, photodynamic therapy with verteporfin, and gene signal (GS)-101 antisense oligonucleotide eye drops. Currently, there are no approved treatments for CN, but as seen in this case report, subconjunctival bevacizumab injection seems to be a good treatment option for acute CN. GS-101 antisense oligonucleotide eye drops also show promising results. More research however needs to be done to identify the best treatment option and the safety of each treatment modality. â??

10.

REFERENCES 1. 2.

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Remington L. Clinical Anatomy of the Visual System, 2nd ed. St. Louis: Butterworth Heinemann, 2004: 15. Zhang SX, Ma J. Ocular neovascularization: Implication of endogenous angiogenic inhibitor and potential therapy. Prog Retin Eye Res 2007; 26: 1-37. Al-Abdullah AA, Al-Assiri A. Resolution of bilateral corneal neovascularization and lipid keratopathy after photodynamic therapy with verteporfin. Optometry 2011; 82(4): 212-214. Hosseini H, Khalili MR. Therapeutic potential of bevacizumab (Avastin) in herpetic stromal keratitis (HSK). Med Hypotheses 2007; 69: 568-570. Shaikh S, Ta CN. Evaluation and management of herpes zoster ophthalmicus. Am Fam Physician 2002; 66(9): 1723-1730.

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11.

12. 13.

14.

15.

Wielawski IM. Exploring why a virus reactivates to cause shingles. In The New York Times August 10, 2008. Retrieved December 20, 2011, from http://www.nytimes.com/ ref/health/healthguide/esn-shingles-expert.html? pagewanted=all Anderson WE. Varicella-zoster virus. In Medscape Reference. Retrieved December 20, 2011, from http://emedicine.medscape.com/article/231927-overview Zoster. In MerckVaccines.com. Retrieved December 20, 2011, from http://www.merckvaccines.com/diseaseinformation/Pages/zoster.aspx Carter III WP, Germann CA, Baumann MR. Ophthalmic diagnoses in the ED: herpes zoster ophthalmicus. Am J Emerg Med 2008; 26: 612-617. Kanski JJ. Clinical Ophthalmology: A Systematic Approach, 6th ed. Edinburgh: Butterworth Heinemann, 2007: 266-269. Onofrey BE, Skorin L, Holdeman NR. Ocular Therapeutics Handbook: A Clinical Manual, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 2011: 205-213. Ambati B. Corneal applications for anti-VEGF agents. Advanced Ocular Care 2011; 24-25. Cursiefen C, Bock F, Horn FK, Kruse FE, et al. GS-101 antisense oligonucleotide eye drops inhibit corneal neovascularization: Interim results of a randomized phase II trial. Ophthalmology 2009; 116(9): 1630-1637. Bevacizumab Injection. In PubMed Health. Retrieved December 20, 2011, from http://www.ncbi.nlm.nih.gov/ pubmedhealth/PMH0000352/ Kim SW, Ha BJ, Kim EK, Tchah H, et al. The effect of topical bevacizumab on corneal neovascularization. Ophthalmology 2008; 115(6): e33-e38.

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QUESTIONNAIRE Treatment of Corneal Neovascularization from Varicella-Zoster Keratitis Leonid Skorin Jr., DO, OD, MS, FAAO, FAOCO; Tyler J. Heuer, OD 1. ❑ ❑ ❑ ❑

The stroma makes up what percentage of the cornea? 70% 80% 87% 90%

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All of the following are possible causes of neovascularization, EXCEPT: Infections Heredity Degenerative diseases Trauma

In the Case Report, the patient presented with all of the following clinical signs and symptoms, EXCEPT: Pain in his right eye Decreased vision in his left eye Left eye looked bloodshot Left eye was light sensitive

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In the Case Report presented, what was the patient’s entering unaided visual acuity in his right eye? 6/6 (20/20) 6/9 (20/30) 6/12 (20/40) 6/18 (20/60)

5. ❑ ❑ ❑ ❑

What percentage of individuals older than 40 years are at risk for zoster due to being exposed to the varicella-zoster virus or having had chickenpox? 75.5% 88.8% 99.5% 99.8%

6. ❑ ❑ ❑ ❑

In the Case Report presented, at the first follow-up, what was the patient’s visual acuity in his left eye? 6/24 (20/80) 6/36 (20/120) 6/60 (20/200) 6/120 (20/400)

7. ❑ ❑ ❑ ❑

Herpes zoster ophthalmicus (HZO) typically affects people in what decades of life? Fifth and sixth Sixth and seventh Seventh and eighth Eighth and ninth

8. ❑ ❑ ❑ ❑

Treatment with oral antiviral agents is most helpful if initiated with what period of time from the onset of any rash? 24 to 36 hours 36 to 48 hours 48 to 72 hours 72 hours

9. ❑ ❑ ❑ ❑

The side effects of photodynamic therapy include all of the following, EXCEPT: Visual disturbances Dizziness Corneal haze Back pain

10. ❑ ❑ ❑ ❑

In the Case Report presented, at the last follow-up, what was the patient’s visual acuity in his left eye? 6/3+1 (20/10+1) 6/5+1 (20/17+1) 6/9+1 (20/30+1) 6/12+1 (20/40+1)

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article by Dr. Reena A. Patel entitled Ocular Cicatricial Pemphigoid: A Case Report. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to the page 234 for complete instructions.

Ocular Cicatricial Pemphigoid: A Case Report Reena A. Patel, OD

ABSTRACT Purpose: The aim of this Case Report is to explain the effect of undiagnosed ocular cicatricial pemphigoid (OCP), the importance of early diagnosis, and the management of OCP. Method: This article will use a 53-year-old white male with a history of chronic conjunctivitis to help illustrate OCP. Result: The exam findings revealed inferior temporal symblepharon and granulomas on the palpebral conjunctiva of both eyes. Once biopsies of the eyelid growths led to a definitive diagnosis of OCP, the patient was treated orally with 60 mg of prednisone daily. Future treatment options include the use of immunosuppressive drugs. Conclusion: OCP is frequently diagnosed in advanced stages. Therefore, aggressive treatment is often necessary. As optometrists, our goal is to recognize this condition as early as possible and to initiate treatment before vision loss occurs.

INTRODUCTION Ocular cicatricial pemphigoid (OCP), also known as mucous membrane pemphigoid with ocular involvement, is an ocular surface disease with one of the worst visual outcomes.1 Ocular cicatricial pemphigoid is part of a range of systemic disorders termed mucous membrane pemphigoid (MMP).2 Mucous membrane pemphigoid encompasses a group of chronic, inflammatory, and subepithelial autoimmune diseases of the mucous membranes. It is characterized by a linear deposit of specific immunoglobulins or complement 3 that are found along the epithelial basement membrane zone (BMZ).3 Scarring is a clinical hallmark of these conditions.3 MMP lesions are most commonly found in the mucosa of the mouth (85%) and in the conjunctiva of the eye (64%). It

R.A. Patel — Family Vision Care of Rutherford, Rutherford, NJ Correspondence to: Dr. Reena A. Patel, Family Vision Care of Rutherford, 31 Park Avenue, Rutherford, NJ 07070; E-mail: ragarw1@gmail.com This article has been peer-reviewed.

can also involve the nose, pharynx, skin, larynx, and esophagus.4 Of the patients with oral involvement it is estimated that 15% to 20% will develop ocular involvement within five years of onset.5 Clinical features of OCP include bilateral, asymmetric, chronic progressive or relapsing inflammation, ulceration, and opacification of the cornea leading to a decrease in vision.4 Ocular cicatricial pemphigoid is a rare condition generally found within the population of individuals aged sixty to eighty years old; however a few cases have been reported in young children.6 Annual incidence has been reported as 1:20,000 to 1:46,000 ophthalmic cases.7 Research suggests that there is a genetic predisposition for the condition, however, triggering factors for the onset of OCP are unknown.5 OCP is not contagious and cannot be transmitted from person-to-person.5 There is a 2:1 predilection for females versus males, but no racial or ethnic predilection has been shown. The frequency in the Unites States is unknown.

CASE REPORT A 53-year-old Caucasian male reported to the clinic with a chief complaint of ocular irritation for eight months. He reported ocular irritation occurring in the corner of both eyes and of “blister-like” sensations underneath his eyelids. The eyes were also reported to be crusted shut every morning. The patient self treated with artificial tears every 10 minutes, but reported little relief. Medical history included osteoarthrosis, asthma, and allergic rhinitis. He was taking the following systemic medications: albuterol, divalproex, docusate, flunisolide, fluocinolone, loratadine, omeprazole, sennosides, and trazodone. Best corrected visual acuities were 6/7.5 (20/25) in the right eye and 6/12 (20/40) in the left eye. Examination of the lids and lashes revealed flaking and crusting. In the inferior temporal palpebral conjunctiva of both eyes, mild symblepharon were noted. Slit lamp evaluation also indicated mild bulbar conjunctival injection and two distinct, non-ulcerated growths that were smooth and firm upon palpation on the superior palpebral conjunctiva of both eyes. The corneas in both eyes had mild, superficial punctate keratitis and a central scar was noted in the left cornea. Dilated fundus examination was unremarkable

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with the exception of anterior cortical cataracts and nuclear sclerotic cataracts in both eyes. The patient was educated to remain on artificial tears and was referred to a corneal specialist for further evaluation. The patient was started on RestasisTM (Allergan, Irvine, CA), prednisolone acetate 1% (4.4), cromolyn 4% (4.4) ketotifen 0.035% (4.4), and TobradexTM (Alcon, Fort Worth, TX) ointment at bedtime OU. Punctal plugs were also inserted inferiorly in both eyes. The patient was then referred to oculoplastics for a conjunctival biopsy. Based on the biopsy, clinical signs, and patient history, the patient was diagnosed with ocular cicatricial pemphigoid. In order to determine if the patient had other forms of MMP, he was referred to the dermatologist and dentist for further evaluation. The dermatology report indicated that scars and post-inflammatory hyperpigmentation were found on different areas of the body. At the time of the examination new blisters were not evident. Therefore, skin biopsies could not be conducted. The patient did, however, report previous episodes of developing blisters on his face, arms, back, legs, and buttocks. Final treatment based on the diagnosis of ocular cicatricial pemphigoid was 60 mg of oral prednisone daily for one week. Due to the severity of the disease, treatment in the future could include immunosuppressive therapy.

PATHOGENESIS The human body is naturally protected by its immune system.5 When the immune system functions properly it produces antibodies to attack foreign bacteria or viruses. Patients with OCP have an immune system that malfunctions, causing the body’s natural proteins to be seen as foreign and subsequently attacked.5 OCP is considered a subepithelial disorder because the anchoring proteins keeping the epithelium and its underlying stroma attached are attacked.4 Specifically, the autoantibodies attack the anchoring proteins in the hemidesmosomes and the basement membrane zone of the mucosa.7,8 When the proteins are attacked, the skin cells become separated and blisters develop.5 As the blisters heal, fibrosis and scarring of the tissue occurs.5 The progressive fibrotic nature of OCP causes destructive changes to the ocular surface. Such changes include fornix shortening, symblepharon formation, destruction of goblet cells, and eyelid margin deformities.1 Such deformities include entropion, trichiasis, dystichiasis, and lagophthalmos.7 Damage to the eyelid margin can lead to obstruction of lacrimal and meibomian duct orifices.1 All these changes can lead to a decrease in production and excess evaporation of tears, therefore leading to severe dry eye.1 Severe dry eye can cause corneal ulcers, scars, abrasions, and neovascularization.7 Together with fornix shortening, symblepharon, and severe dry eye, vision loss can occur.

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DIAGNOSIS Patients with OCP will present with complaints of burning, redness, tearing, decreased vision, and foreign body sensation.6 When undiagnosed, these patients will have a chronic history of continual conjunctivitis or dry eye. These are the patients who have seen multiple practitioners and who have tried multiple ocular medications, but found little relief. These are also the patients who need to be evaluated further for the possibility of other ocular surface disease. Possible differential diagnoses include: atopic keratoconjunctivitis, trachoma, trauma, chemical burn, Stevens-Johnson syndrome, sarcoidosis, and drug-induced pseudopemphigoid.4,9 Most of the differentials stated above can be eliminated by a thorough case history. If the diagnosis of OCP is being considered, a conjunctival biopsy using the direct immunofluorescence (DIF) test must be obtained.5,10 This technique involves examining a conjunctival specimen for the presence of autoantibodies.11 The specimen to be biopsied is obtained from the tissue adjacent to the inflamed site.7 For a definitive diagnosis of OCP a linear deposition of immunoreactants, usually IgG, IgA, and the third component of complement, at the basement membrane of an inflamed conjunctiva is necessary.10 DIF testing is the gold standard for the diagnosis of OCP.10 The sensitivity of the test is decreased when confirming OCP versus other testing for MMP from other mucosal sites.11 As a result, a negative biopsy does not exclude OCP, but a positive biopsy confirms the diagnosis.7 This can be problematic when considering starting a patient on treatment if a confirmed diagnosis is not available.11 A conjunctival biopsy must be performed, however, even with a negative result, OCP can be diagnosed and treated. OCP is not easy to diagnose, but it is a condition that should be on the list of differential diagnoses. Once diagnosed as OCP, the disease is staged and graded using either Foster’s or Mondino’s classification system. Staging the disease helps with treatment and with predicting the progression of the condition. Foster’s system includes four stages. Stage one involves conjunctival injection, scarring, and fibrosis.7,12 Stage two begins with the foreshortening of the inferior conjunctival cul-de-sac of any degree.7,12 This leads to the formation of a symblepharon which is described as stage three.7,12 Stage three also includes such signs as corneal neovascularization, keratopathy, trichiasis, entropion, dystichiasis, and decreased tear production.7 Stage four is considered the end stage of OCP and results in ankyloblepharon and ocular surface keratinization which can lead to blindness.7,9 Mondino grades OCP based on loss of inferior fornix depth. Stage one is 0 to 25% loss, stage two is 25% to 50% loss, stage three is 50% to 75% loss, and stage four is 75% to 100% loss of inferior fornix depth.13 Stages three and four in both Foster’s and Mondino’s classification system are considered advanced stages.

TREATMENT The goal of treatment is to prevent inflammation and scarring, reduce recurrences, decrease symptoms, and ultimately, preserve vision.2 There is no gold standard for treatment, but current treatment approaches consist of oral corticosteroids or immunosuppressives, intravenous medications such as immunoglobulin (IVIg) therapy, and/or subcutaneous injections of anti-tumor necrosis factor alpha (TNF-a) agents. Treatment is based on each individual, as the disease is highly variable and may affect different areas of the body. Before initiating ocular treatment, it is also important to determine if non-ocular sites are involved and the stage, progression, and probable duration of the disease.7 Due to the systemic etiology of OCP, topical and subconjunctival treatment with corticosteroids, cyclosporine, and retinoids are ineffective in controlling ocular inflammation.14 However, artificial tears are still recommended.15 Once the diagnosis of OCP is confirmed, acceptable firstline therapy includes immunosuppressive medications with or without corticosteroids.14,15 Most patients are diagnosed in advanced stages, thus aggressive treatment is indicated. Initially, high doses of oral corticosteroids are administered to prevent further scarring, but steroids alone will not fully control the disease.11,16,17 Patients must remain on the steroid for a long period of time and because of long-term complications, it is an undesirable treatment option.18 Patients have also been found to have recurrences during the tapering period of the steroid.19 Current therapy typically begins with administering oral corticosteroids to rapidly inhibit further scarring, and then the steroid is completely tapered or decreased in dosage. During the tapering period, oral immunosuppressive drugs may be added to the treatment plan.14,15 Immunosuppressive medications include methotrexate, cyclophosphamide, mycophenolate mofetil (CellceptTM), diaminodiphenylsulfone (DapsoneTM), and azathioprine.20 The recommended dosage of oral prednisone that has been found to be effective in rapidly ceasing scarring is 1 mg/kg daily.21,22 Studies have reported that for severe ocular disease, the combination of cyclophosphamide and prednisone has been found to be the most effective in controlling the disease.23,24 Treatment normally consists of 2 mg/kg daily of oral cyclophosphamide with 1 mg/kg of oral prednisone daily.25 The prednisone will be tapered over 3 to 4 months, whereas cyclophosphamide will be continued for 12 to 18 months unless patients have contraindications or side effects.20 Patients should be followed monthly. Miserocchi et al looked at the effect of the use of immunosuppressive medications with or without prednisone on patients with severe ocular cicatricial pemphigoid. Immunosuppressive medications used in this study included: (from most commonly used to least) oral

diaminodiphenylsulfone (DapsoneTM), methotrexate, azathioprine, and cyclophosphamide. In some cases, oral prednisone was used as an adjunctive treatment. The medications were found to control ocular inflammation in 90% of the 61 patients studied, however, 46% of those patients needed to remain on a maintenance dose to prevent recurrences. Ten per cent of the 61 patients progressed regardless of different drugs used. The average length of treatment was 48 months of immunosuppressive therapy and 29 months of oral corticosteroid therapy. Side effects of immunosuppressive medications included hematologic, gastrointestinal, cardiovascular, and urinary complications. Based on this study, to control the effects of OCP, long-term systemic treatment is necessary.14 In addition to immunosuppressive therapy, case reports have demonstrated that anti-tumor necrosis factor alpha agents (TNF-a) and/or intravenous immunoglobulin (IVIg) drugs are other treatment options. Cytokines, such as TNF-a, are soluble proteins that are released by cells. They play a role in cellular communication and in mediating cell processes such as gene expression and cell proliferation, survival, differentiation, and migration.26 During an immunologic response they are responsible for initiating, maintaining, and resolving inflammation.26 Different types of cytokines are produced by our bodies; immunoregulatory and proinflammatory cytokines such as interferon, interleukins, and TNF-alpha, are particularly important to the pathogenesis of OCP.12 TNF-a is a proinflammatory cytokine produced at low levels by macrophages under normal conditions, thus maintaining cellular and tissue homeostasis.27 When injury or microbial invasion occurs to the body, TNF-a production is increased and released by macrophages, mastocytes, keratinocytes, and fibroblasts.26 TNF-a in turn attracts leukocytes to the injured tissue.27-30 Leukocytes increase vascular permeability, allowing macromolecules such as fibrinogen, immunoglobulin, and complement to be released at the affected site.31 Regulatory mechanisms, normally found in healthy individuals, prevent the overproduction of TNF-a and other cytokines from becoming persistant.32 When large amounts of TNF-a are released without regulation, inflammation reactions are sustained at the site of injury leading to chronic inflammatory diseases.6,26 A study done in 1993 found that the serum levels of patients with MMP when compared to controls had elevated levels of TNF-a.33 Due to the role of TNF-a during inflammation, it is currently being researched for the treatment of OCP.26 Today, anti-TNF-a agents have been used to treat psoriasis, psoriatic arthritis, rheumatoid arthritis, Crohnâ&#x20AC;&#x2122;s disease, and ankylosing spondylitis.6 Currently there are three anti-TNF-a agents that have been used in the treatment of inflammatory and autoimmune diseases: infliximab, adalimumab, and etanercept.6 Case Reports describe solely the use of anti-TNF-a agents in the treatment of OCP. Large scale studies have not been conducted. Canizanes et al report on

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three patients with MMP who were successfully treated with etanercept. All three patients had oral mucosal involvement, and one had severe ocular involvement.6 Of the three patients treated, all had little success with prior therapy. The patients were then treated with subcutaneous injections of 25 mg of etanercept twice weekly. In all three patients the oral mucosal disease improved and the one patient with the ocular involvement obtained stabilization.6 Further investigation is required to study the safety and efficacy of anti-TNF-a agents in the treatment of ocular cicatricial pemphigoid.6 Intravenous immunoglobulin drugs are also used in the treatment of autoimmune conditions because of their anti-inflammatory effect.2 Intravenous immunoglobulin decreases pro-inflammatory cytokines including interleuken-1 and TNF-a and it increases anti-inflammatory cytokines.34 Letko et al. looked at immunosuppressive therapy versus intravenous immunoglobulin therapies in patients with MMP who had ocular involvement.2 Results indicated that patients treated with IVIg had a more rapid control of ocular inflammation and did not progress to advanced stages of OCP, where as patients treated with immunosuppressive therapy had multiple recurrences.2 Side effects reported in this study included headaches and nausea after infusion of the drug, but these decreased if the rate of infusion was decreased.2 Progression of a disease plays a key role in the method of treatment and its expected outcome. It is especially important when treating OCP, because once conjunctival fibrosis and keratopathy has occurred it cannot be reversed and visual rehabilitation is poor.13 Unfortunately due to the variable course of the disease, little is known about the progression of the disease.13 OCP is characterized as a chronic and slow disease that eventually leads to bilateral blindness if left untreated.11 Elder et al. looked at factors that could play a role in the progression and visual outcome of the disease. They found that there was no correlation between systemic manifestations of pemphigoid and vision loss.13 It was also reported that patients with symblepharon at diagnosis were more likely to have a rapidly progressive disease with a worse visual prognosis, therefore requiring immunosuppressive therapy versus the patients who at diagnosis did not have symblepharon. They also reported that persistent epithelial defects, limbal inflammation, and conjunctival inflammation were factors that led to increased risk of vision loss.13

a condition that optometrists should recognize. Due to the difficulty of distinguishing the early signs and symptoms of OCP, as with this patient, it is often diagnosed at advanced stages. As a result, aggressive treatment is necessary. Unfortunately, many of these patients are elderly and could have difficulty handling the current forms of treatment. Due to the lack of well controlled clinical trials, a gold standard for treatment has not been developed. Treating OCP is challenging because the disease runs a different course in all patients and therapy has unpredictable outcomes. As a result, therapy generally consists of one or a combination of any of the following: oral corticosteroids, immunosuppressive therapy, TNF-a therapy, and/or intravenous immunoglobulin therapy. When determining therapy clinical experience, recent case reports, probable progression of the disease, and side effects are also considered. The most accepted method of treatment today consists of oral immunosuppressives with or without oral corticosteroids. When treating OCP it is also important to co-manage the disease with other health care providers such as dermatologists, primary care providers, and dentists due to the high likelihood of systemic involvement. It is important to realize that treatment does not reverse the damage already done, but reduces further progression, thus early detection is critical. Even with the development of new therapies recurrences are still possible; therefore frequent follow ups are important. â??

REFERENCES 1. 2.

4. 5. 6.

DISCUSSION This case presented a patient with a chronic history of dry eye complaints with little relief while on topical medications. Due to the lack of specific signs and symptoms of early stages of OCP, the patient was incorrectly diagnosed with dry eye and chronic conjunctivitis. Ocular cicatricial pemphigoid is a rare disease, but

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Pflugfelder S, Beuerman R, Stern M, eds. Dry eye and ocular surface disorders. Care Marcel Dekker 2004. Letko E, Miserocchi E, Daoud Y, et al. A nonrandomized comparison of the clinical outcome of ocular involvement in patients with mucous membrane (cicatricial) pemphigoid between conventional immunosuppressive and intravenous immunoglobulin therapies. Clinical Immuno-logy 2004; 111: 303-310. Chan L, Ahmed A, Anhalt G, et al. The first international consensus on mucous membrane pemphigoid. Arch Dermatol 2002; 138: 370-379. Hingorani M, Lightman S. Ocular cicatricial pemphigoid. Curr Opin Allergry Clin Immunol 2006; 6: 373-378. Pemphigus. Available at: www.pemphigus.org. Last accessed 11/5/08. Canizares M, Smith D, Conners M, et al. Successful treatment of mucous membrane pemphigoid with etanercept in 3 patients. Arch Dermatol 2006; 142; 1457-1461. Ahmed M, Zein G, Khawaja F, et al., Ocular cicatricial pemphigoid: pathogenesis, diagnosis and treatment. Prog Retin Eye Res 2004; 23: 579-592. Hoang-Xuan T, Robin H, Dermers Pierre E, et al. Pure ocular cicatricial pemphigoid. Ophthalmology 1999; 106: 355-361. Friedman N, Kaiser P. The Massachusetts Eye and Ear Infirmary Illustrated Manual of Ophthalmology. Pennsylvania: Elsevier, Inc., 2004, p. 132-134.

10. Danier E, Thorne J. Recent advances in mucous membrane pemphigoid. Curr Opin Ophthalmol 2008; 19: 292-297. 11. Foster C. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986; 84: 527-663. 12. Immunology. Available at: http://www.microvet.arizona. edu/courses/MIC419/Tutorials/cytokines.html.Last accessed April 4, 2009. 13. Elder M, Bernauer W, Leonard J, Dart J. Progression of disease in ocular cicatricial pemphigoid. Br J Ophthalmol 1996; 80: 292-296. 14. Miserocchi E, Baltatzi S, Manolette A, et al. The effect of treatment and its related side effects in patients with severe ocular cicatricial pemphigoid. Ophthalmology 2002; 109: 111-118. 15. Bruch-Gerharz D, Hertl M, Ruzicka T. Mucous membrane pemphigoid: clinical aspects, immunopathological features and therapy. Eur J Dermatol 2007; 17(3): 191-200. 16. Mondino B, Brown S. Ocular cicatricial pemphigoid. Ophthalmology 1981; 88: 95-100. 17. Mondino B, Brown S. Immunosuppressive therapy in ocular cicatricial pemphigoid. Am J Ophthalmol 1983; 96: 453-459. 18. Hardy K, Perry H, Pingree G, et al. Benign mucous membrane pemphigoid. Archeology of Dermatology 1971; 104: 467-475. 19. Neumann R, Rauber J, Foster C. Remission and recurrences after withdrawal of therapy for ocular cicatricial pemphigoid. Ophthalmology 1991; 98: 858-862. 20. Thorne J, Woreta F, Jabs D, et al. Treatment of ocular mucous membrane pemphigoid with immunosuppressive drug therapy. Ophthalmology 2008; 115: 2146-2152. 21. Vincent S, Lilly G, Baker K. Clinical, historic, and therapeutic features of cicatricial pemphigoid. Oral Surg Oral Med Oral Pathol 1993; 76: 453-459. 22. Nguyen Q, Foster C. Cicatricial pemphigoid: diagnosis and treatment. Int Ophthalmol Clin 1996; 36: 41-60. 23. Foster C, Wilson L, Ekins M. Immunosuppressive therapy for progressive ocular cicatricial pemphigoid. Ophthalmology 1982; 89: 340-353.

24. Kirtschig G, Murrell D, Wojnarowska F, et al. Interventions for mucous membrane pemphigoid/cicatricial pemphigoid and epidermolysis bullosa acquista: a systematic literature review. Arch Dermatology 2002; 138: 380-384. 25. Thorne J. Anhalt G, Jabs D. Ocular mucous membrane pemphigoid. Dermatol Ther 2002; 15: 389-396. 26. Krueger G, Callis K. Potential of tumor necrosis factor inhibitors in psoriasis and psoriatic arthritis. Arch Dermatol 2004; 140: 218-225. 27. Lidington E, McCormack A, Yacoub M, et al. The effects of monocytes on the transendothelial migration of T lymphocytes. Immunology 1998; 94: 221-227. 28. Osborn L, Hession C, Tizard R, et al. Direct expression cloning of vascular cell adhesion molecule 1, a cytokineinduced endothelial protein that binds to lymphocytes. Cell 1989; 59: 1203-1211. 29. Henninger D, Panes J, Eppihimer M, et al. Cytokineinduced VCAM-1 and ICAM-1 expression in different organs of the mouse. J Immunol 1997; 158: 1825-1832. 30. Groves R, Allen M, Ross E, et al. Tumour necrosis factor-alpha is pro-inflammatory. Br J Dermatol 1995; 132: 345-352. 31. Munro J, Pober J, Cotran R. Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio Anubis. Am J Pathol 1989; 135: 121-133. 32. Park W, Goodman R, Steinberg K, et al. Cytokine balance in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 2001; 164: 1896-1903. 33. Tesar V, Jirsa M, Sima T, et al. Soluble cytokine receptors in renal vasculitis and lupus nephritis. Med Sci Monit 2002; 8: 24-29. 34. Menezes M, Benard G, Sato M, et al. In vitro inhibitory activity of tumor necrosis factor alpha and interleukin-2 of human immunoglobulin preparations. Int Arch Allergy Immunol 1997; 114: 323-328.

Call for Papers Clinical & Refractive Optometry welcomes original articles based on clinical or basic research, case reports, and review papers related to the practice of optometry. Please submit manuscripts to: Clinical & Refractive Optometry Attn: Mary Di Lemme, Managing Editor 3484 Sources Blvd., Suite 518 Dollard-des-Ormeaux, Quebec H9B 1Z9 e-mail: mdilemme@mediconcept.ca

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QUESTIONNAIRE Ocular Cicatricial Pemphigoid: A Case Report Reena A. Patel, OD 1. ❑ ❑ ❑ ❑

Which of the following is a clinical hallmark of mucous membrane pemphigoid (MMP)? Rapid loss of visual acuity Scarring Cataracts Sarcoidosis

2. ❑ ❑ ❑ ❑

MMP lesions in the mucosa of the mouth are found in what percentage of cases? 20% 40% 75% 85%

In patients with oral involvement of MMP, approximately what percentage will develop ocular involvement within five years of onset? 10% 15% to 20% 25% 50%

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Clinical and Refractive Optometry 27:6, 2016

❑ ❑ ❑ ❑

All of the following are clinical features and symptoms of ocular cicatricial pemphigoid (OCP), EXCEPT: Ulceration of the cornea Inflammation of the cornea Ocular pain Decrease in vision

5. ❑ ❑ ❑ ❑

In what age group that OCP typically appear? 20 to 35 years old 40 to 50 years old 50 to 60 years old 60 to 80 years old

6. ❑ ❑ ❑ ❑

All of the following statements regarding OCP are true, EXCEPT: The incidence is highest in African-Americans There may be a genetic predisposition for the condition It is not contagious There is a 2:1 predilection for females versus males

7. ❑ ❑ ❑ ❑

In the Case Report presented, which of the following was the patient’s chief complaint? Excessive tearing Decreased vision upon awakening Long-standing ocular irritation Ocular pain

8. ❑ ❑ ❑ ❑

In the Case Report presented, slit lamp examination revealed all of the following, EXCEPT: Mild bulbar conjunctival injection Ulcerated growths on the superior palpebral conjunctiva of both eyes Mild, superficial punctate keratitis in corneas of both eyes Central scar in left cornea

9. ❑ ❑ ❑ ❑

According to the paper, severe dry eye can cause all of the following, EXCEPT: Corneal scars Corneal abrasions Neovascularization Distortion of the upper eyelid

10. ❑ ❑ ❑ ❑

All of the following are differential diagnoses for OCP, EXCEPT: Sarcoidosis Drug-induced pseudopemphigoid Ocular herpes Trachoma

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Clinical & Refractive Optometry is pleased to present this continuing education (CE) article in the form of a Meeting Report based on a presentation given by Dr. Paul Karpecki entitled Diagnosis and Treatment of Ocular Surface Conditions: Focus on Dry Eye in Toronto, ON on May 15, 2016. In order to obtain a 1-hour Council of Optometric Practitioner Education (COPE) approved CE credit, please refer to page 242 for complete instructions.

Diagnosis and Treatment of Ocular Surface Conditions: Focus on Dry Eye Paul Karpecki, OD, FAAO

INTRODUCTION Dr. Karpecki began his presentation on dry eye disease (DED) by noting that, according to the most recent study on prevalence, 29% of the Canadian population has dry eye. Allergies represent approximately 20% and glaucoma is roughly 2.2%, so this is an enormous opportunity; dry eye is the future of optometry. The reason for this high rate of DED is digital devices, namely, smart phones, tablets and computers. The average blink rate is about 15 to 20 times a minute. Studies have been done analyzing people on digital devices, and the average blink rate or the number of blinks per minute was 4.4 times. In one study, it was as low as 1.8 blinks per minute with a plus or minus 4 standard deviation. One just can't sustain good oil production, good tears with that kind of blink rate and there are people who spend 8 to 10 hours a day at work on a computer. Eventually, said Dr. Karpecki, they show up in his clinic with few meibomian glands left and they wonder if anything could be done; his answer is that it could have been prevented, but all of this research and insight is only recently known. In fact, an International Task Force (ITF) comprising a group of 25 of the top experts in the world, including Dr. Karpecki, got together at Johns Hopkins in 2003. There was an effort to change the name from dry eye to dysfunctional tear syndrome. The stance at the time was to look at the lid margin as the most important area. The task force said that the majority of dry eye was non-lid margin involved. In the end, the top 25 experts were technically 180 degrees wrong. Today, it’s known that 86% of all dry eye does involve the meibomian glands. That paper was published in 2006 in Cornea.

P.M. Karpecki — Director of Corneal Services and the Advanced OSD Clinic, Kentucky Eye Institute, Lexington, KY Correspondence to: Dr. Paul M. Karpecki, Kentucky Eye Institute, 601 Perimeter Drive, Suite 100, Lexington, KY 40517; E-mail: paul@karpecki.com This article has been peer-reviewed

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PREVALENCE OF DRY EYE Roughly 4 to 5 forms of dry eye involve the lipid layer. There are a lot of risk factors, including contact lens wear, age and gender, but the major factor is digital devices such as computer use. The Beaver Dam study showed that 14% of the population in the U.S. over age 40, have dry eye. Last year, they decided to do a study called the BOSS (Beaver Dam Offspring Study), as an offshoot. They analyzed the children of those 11,000 people they had been studying for the last 20 years with regard to dry eye. The incidence of dry eye between the age of 21 and 40 was as high as that of their parents — likely as a result of these technology devices. Even more interesting was that men and women had equal levels of DED, likely again, due to the use of digital devices. It's only after age 40 that women have more dry eye because of hormonal changes. In terms of contact lens wear, the dropout rate 20 years ago was approximately 16.5%. People said, “We didn't have silicone hydrogels, daily disposables and hydrogen peroxide solutions that neutralized to preservative-free in 4 hours,” etc. Last year, according to JMI (Jobson Medical Information) data, the dropout rate was 16.4% — it hadn’t changed. Actually, it may have been 30% or higher because of smartphones, tablets and computers, had these new contact lens technologies not been available; but it also says we must treat the dry eye. Naturally, Dr. Karpecki noted, environmental factors play a role, but the biggest factors in this whole group are digital device use, smoking and diet. He stated that the ratio of omega-6 fatty acids to omega-3 was far too disproportionate — and systemic medications — for example, a study authored by Ousler showed that antihistamines had a 34% drying effect. There are other medications that also cause excessive drying, including diuretics, beta blockers and antidepressants which cannot be discontinued like oral antihistamines, but patients should be educated about them and how they contribute to the condition. The incidence of dry eye in patients with diabetes in North America has been reported to be above 50% in five different studies, which showed that all levels of diabetes were involved, ranging from borderline diabetes mellitus studied by Dr. Hom to those with severe retinopathy. The incidence was between 50% and 54% in all five studies, which were completely independent, with none of the same authors or researchers.

Rheumatoid arthritis is, of course, a contributing factor; and rosacea can affect the sebaceous glands, which are holocrine oil secreting glands. The meibomian glands are also holocrine oil secreting glands, so there's no way to not affect both in patients with rosacea. The three other major conditions Dr. Karpecki monitors are diabetes, arthritis and thyroid disease. In his experience, when he has a patient for whom he has tried every treatment and nothing seems to work, there's usually a systemic cause. Eighty-six percent of all Sjögren’s syndrome patients are women, so it’s clear that androgen hormones play a role in this disease. One out of 12 patients with Sjögren's syndrome will develop B-cell non-Hodgkin's lymphoma, which has a much better prognosis if caught early, and optometrists have a role in helping make that diagnosis. In fact, Dr. Karpecki tells every one of his Sjögren's patients, “Every year you need to have your blood work checked for lymphoma.”

CLINICAL SIGNS AND SYMPTOMS OF DRY EYE Carlos Belmonte, a true expert in the understanding of corneal pain, has noted that pain and a lot of other symptoms associated with dry eye actually down regulate when the disease progresses, meaning that the symptoms can lessen as signs worsen, which is very confusing for patients and doctors. This is often termed neurotrophic dry eye, especially if related to previous viral conditions such as herpes simplex virus or herpes zoster ophthalmicus. In neuropathic dry eye, the patients develop what is termed “pain without stain,” where the pain is disproportionate to the signs. As the result of long-standing disease, the corneal nerves can form branches or dendritic nerves that are sensitive to elements they shouldn't be sensitive to, such as air flow and temperature. In these patients, it seems like they don’t respond to therapy, but in time improvement can occur. They may require oral pain medications and scleral lenses. If symptoms lessen when the disease worsens, how does one diagnose it? The only symptom that's present across all stages of dry eye is blurred vision. However, the problem with this is that blurred vision is also the number one reason people consult optometrists, so it has to be differentiated. In the early stages, it’s transient. When there's superficial punctate keratitis, it's a little more permanent and when there's desiccation, much further along, it's consistently blurred. The other thing to keep in mind is that corneal staining is not a very good early indicator of dry eye. By the time corneal staining is present, there is desiccation and by that stage patients are at least stage 3 out of 4 in accordance with the ITF classification for DED. Stage 4 is severe and includes conditions such as graph versus host disease, filamentary keratitis, persistent epithelial defects and corneal melts. So, in fact, it’s a scale of 1 to 3 that’s

typically managed in the primary care setting and by the time there’s macropunctate or central corneal staining, it’s level 3, the furthest advanced the patient is ever going to be for most clinics. It's analogous to a visual field defect in glaucoma patients; it only shows up when they’ve lost 30% to 50% of their nerve fiber layer or have advanced glaucoma. Dr. Karpecki advised practitioners to examine patients’ skin for rosacea, the eyelids for blepharitis, cranial nerve function, and their hands. Rosacea will provide a good indication for which direction to proceed in. Arthritic hands may show an ulnar shift. Check if they're not blinking on one side from a stroke or a cranial nerve function or Bell’s palsy, and definitely look at their eyelids closely.

DIAGNOSIS One of the most important tests is expression of the lower eyelid; approximately 80% of the oils in the tear film come from the lower eyelid, in the nasal to central area. Dr. Karpecki advised use of a Mastrota paddle, wet Q-tip or one’s fingers to squeeze the glands and see what comes out. It should resemble olive oil. If it’s discolored or turbid, that's level 1 of meibomian gland dysfunction (MGD). If it's thickened or gel-like, it’s level 2. If it's like toothpaste, which is thinner and discolored, that's level 3; and if the gland won’t express, that's level 4. Dr. Karpecki stated that there are numerous diagnostic tests, the most common at least in the U.S., being the Schirmer's test (including phenol thread tests), which he finds surprising. Schirmer's might be accurate on Sjögren's patients who have no tear flow; a non-anesthetized Schirmer's works in that group, but that's a rare, small population of 0.4% prevalence. He related that he wasn’t able to get lissamine green in Kentucky for the longest time which is a more sensitive test than fluorescein. Fluorescein dye is a great latent disease indicator; a practitioner can examine tear breakup time, but it has low sensitivity unless you consider a non-invasive tear breakup time, which involves more expensive topographical and wavefront technology. Tear meniscus height is important; it actually predicts dry eye approximately 70% of the time by looking at the height of the meniscus. However, if too much of a drop of fluorescein is used, it can also be inaccurate. If practitioners used symptoms alone to make a diagnosis of DED, they’re likely to be wrong as much as 40% of the time. It's similar to glaucoma. With tonometry alone, the result would be wrong 80% of the time. However, adding in tonometry and hysteresis (or pachymetry), along with OCT, careful examination of the optic nerve, visual fields testing; and a repeat on the IOP, the result would be 96% specificity with all of those elements combined. Dr. Karpecki stated that he still relies on symptoms to

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Osmolarity in Diagnosis and Grading of Dry Eye

Fig. 1 The osmolarity severity scale allows the clinician to plot severity and monitor therapeutic progress.

diagnose DED, however not alone, and favors the following validated questionnaires: Standard Patient Evaluation of Eye Dryness (SPEED), or Dry Eye Questionnaire (DEQ), or 5-item Dry Eye Questionnaire (DEQ-5).

THE IMPORTANCE OF OSMOLARITY Dr. Karpecki uses NaFl dye to observe the tear breakup time (TBUT), the tear meniscus height, and if there's any central or inferior staining. He considers osmolarity testing the most valuable, definitive tool, by far in diagnosing dry eye because of its greater sensitivity to mild or moderate dry eye disease. Blood osmolarity is between 280 and 295 and tears are made from serum in the blood; that's how the lacrimal glands work, especially the accessory lacrimal glands, so the tear osmolarity should be in the same range (Fig. 1). Dr. Karpecki discussed the phenomenon of patients who have significant symptoms but very few signs or patients whose signs have been treated and resolved but not their symptoms. Most doctors would treat a patient with symptoms of dryness, grittiness, burning, and redness, worse on the computer and late in the day, with dry eye medications. However, he reviewed the data on a colleague’s group of patients with this profile; they had normal osmolarity, but were complaining of a dry, gritty, burning sensation, with redness and stinging, late in the day and on the computer. He found that over 90% of these patients actually did not have dry eye disease. He measured the eye alignment of a group of ten patients, and conducted cover tests, looked for Von Graefe fixation, fixation disparity, convergence insufficiency, vertical imbalance between the two eyes, put prism in some, and sent one to a local VT specialist he knew. Nine out of ten had eye misalignment and all nine were solved with prism or VT. People who have fixation disparity,

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exophoria at distance, convergence insufficiency, proprioceptive disparities etc. will, because of rapid eye movements, have an overstimulation of the trigeminal nerve. The result of overstimulation of the ophthalmic branch of the trigeminal nerve is a dry eye sensation of the cornea, often described as gritty, burning and irritated and it would definitely be worse when on a computer or digital device. That's why they had dry eye symptoms, but didn't have dry eye, and without osmolarity testing, these patients are often treated for months or years with no resolutions of symptoms. Dr. Karpecki noted that he realizes that if he has a patient who has normal osmolarity, meaning both eyes under 295 and 5 units (mOsm/L) of each other, the problem has to be something other than dry eye in about 90% of the cases. The appropriate tests, when combined with osmolarity, provide further specificity and sensitivity. These tests include expression of meibomian glands, vital dye staining, TBUT, meniscus height and validated questionnaires. That is not to say osmolarity alone isn’t accurate enough because it is actually more accurate than cholesterol or diabetes testing for blood glucose. Osmolarity has a variation of 1.5%, meaning the variation of osmolarity is only 4 milliosmoles per litre. That's the most accurate test in medicine. However, even then, it's going to be wrong approximately 13% of the time, according to the research. When you combine it with expressing the meibomian glands, checking their blink and meibography, plus the testing listed above, it will provide roughly 98% sensitivity. Now, the right diagnosis can easily be reached. It's like glaucoma, where one combines multiple tests to know what to do, rather than relying on any one test alone.

SCREENING TOOLS AND DIFFERENTIAL DIAGNOSIS With regard to screening questions, Dr. Karpecki cited the Canadian Optometric Dry Eye Disease Guideline questions: 1. Do your eyes feel uncomfortable? 2. Do you have watery eyes? 3. Does your vision fluctuate, especially in a dry environment? 4. Do you use eye drops? These are an excellent starting points, in addition to “Do you have dry mouth?” to know if it might be Sjögren’s syndrome. Osmolarity is a very valuable screening test. This has to be priced into the exam, but if a practitioner has a very high level dry eye practice, they should definitely be concentrating on this and patients should be paying for it; they're going to be grateful. Twenty-nine percent of the Canadian population has dry eye disease. You could establish one of the best clinics in North America by focusing on dry eye disease. What differentiates an optometrist in this field is knowing when dry eye symptoms are present but it’s not dry eye; and when it is dry eye to make the differential

ITF Dry Eye Guideline Recommendations LEVEL 1

If no improvement, add level 2 treatments

Patient education Environmental modifications Control systemic medications Preserved tears Allergy control

LEVEL 2

If no improvement, add level 3 treatments

Unpreserved tears Gels/nighttime ointments Nutritional support

LEVEL 3

If no improvement, add level 4 treatments

Tetracyclines Punctal plugs (control inflammation first)

LEVEL 4

Cyclosporine A Topical corticosteroids Secretagogues

Systemic anti-inflammatory therapy Acetylcysteine Moisture goggles Surgery (punctal cautery) Behrens A et al. Cornea. 2006; 25(8):900-907.

Fig. 2 Stepwise treatment build for dry eye.

diagnosis between evaporative and aqueous. Dr. Karpecki stated that one of the biggest changes that affected his clinic, besides knowing that asthenopia could cause dry eye symptoms, is the understanding of MGD. With evaporative dry eye, it isn’t enough to just treat the meibomian gland obstruction, or to just use artificial tears such as hyaluronic acid, or manage the biofilm or just the inflammation associated with all forms of dry eye disease; it’s important to treat all four components at the same time: obstruction, inflammation, biofilm development, and tear instability.

TREATMENT OPTIONS Dr. Karpecki uses BlephEx® (Lake Worth, FL) on patients with biofilm issues, to get rid of the keratin on the surface that is blocking the glands; for tear film instability, he prefers treatment with hyaluronic acid. Gauging the various levels of dry eye disease determines the treatment. For example, in mild cases, he typically does not include a steroid but simply cyclosporine or lifitegrast treatment alone, unless installation results in burning or other side effects. At the moderate stage, which is the most common presentation, he includes a steroid short term; and cyclosporine or lifitegrast and omega fatty acids long term. In severe cases, he would prescribe steroids and oral treatment for the inflammation such as doxycycline (Fig. 2). His steroid of preference is loteprednol gel 0.5% because of its relative safety profile, the fact that it has 70% less BAK and it contains known tear film moisturizers. With mild MGD/mild evaporative dry eye, a hydrating warm compress every night for 10 minutes would usually be fully effective. Hydration penetrates tissue so a hydrating mask is probably the only option that could get the back surface of the eyelid temperature above 40 degrees, stated

Dr. Karpecki. The TheraPearl® Eye Mask (Bausch + Lomb, Vaughan, ON) would be another good option for the price. It doesn't hydrate so it's not quite as effective, but it's better than not using a compress at all. For mild cases of tear film instability in mild MGD, Dr. Karpecki recommends Liposic® (Bausch + Lomb, Vaughan, ON), Refresh Optive® Advanced (Allergan, Unionville, ON), Systane® Balance (Alcon, Mississauga, ON), or Refresh Ultra® (Allergan, Unionville, ON). In moderate to advanced MGD he prefers HYLO™ (CandorVision, Montreal, QC). Currently, Restasis® (cyclosporine, Allergan, Unionville, ON) is the only approved drug in its category and Dr. Karpecki feels that it's excellent long term. However, the key to Restasis is using it long enough. Twelve-month use will produce a 191% increase in goblet cells. In comparison, the use of Refresh Ultra alone showed only a 13% improvement in goblet cell density. It takes roughly 3 to 4 months for cyclosporine to work on symptoms, which is why a steroid should be prescribed first. In terms of long-term use of cyclosporine, such as the 1- or 2-year point, a patient may feel great and want to discontinue the medication. Four months later, though, the T-cells start returning, there is ICAM-1 up-regulation and inflammation, and symptoms increase again. Additionally, there is stinging in 17% of cases and combining it with a steroid has been shown to decrease the irritation of Restasis by 75% in this population. Non-MGD patients have inflammation and need extensive lubrication. Dr. Karpecki cited a study showing that the arm on artificial tears still increased in terms of inflammation count by 40% at 12 months. Therefore, the days of treating any true dry eye without an antiinflammatory medication should be over. He described a case of severe evaporative dry eye; meibography revealed only five glands remaining, nothing was expressing, and there was scalloping of the lid margin. In moderate to advanced cases he would treat the obstruction with LipiFlow® (TearScience, Morrisville, NC) and a hydrating mask long term. For inflammation, he would definitely start patients on steroids and oral tetracycline derivatives or a 5-day Zithromax® Z-Pak (azithromycin, Pfizer, Montreal, QC) for systemic issues, side effects or contraindications to taking tetracycline medication. His approach for each of these scenarios is very aggressive. Oral doxycycline is a very good treatment for the more severe forms. In Canada, one can prescribe a hyclate form of 100 milligrams and consider its use once a day or use a pill splitter to allow for b.i.d. dosing. There are a lot less side effects taking one half in the morning and one half in the evening. The medication is dosed twice a day until the expression of the glands starts to improve, which is typically 2 or 3 months; although some patients require

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Fig. 3 Corticosteroids quickly and thoroughly suppress ocular surface inflammation.

Fig. 4 Efficacy of loteprednol etabonate ophthalmic suspension 0.5% versus placebo for the treatment of keratoconjunctivitis sicca.

longer treatment. Once there is improvement, never go from twice a day to zero as this can produce a rebound of inflammation. Oral doxycycline is actually very comparable as an anti-inflammatory to prednisone, which is odd, because it's classified as an antibiotic; taper down to once a day when the condition improves. Long term, Dr. Karpecki still prefers omega fatty acids. It’s important to keep in mind that the average human being with mild dry eye needs about 1,000 to 1,500 milligrams of EPA/DHA, but some patients require more. There are three factors that dictate how much fish oil someone should take for dry eye. First, how severe the dry eye is; second, how large the person is. A body index above 30 requires more medication than someone who's small, that's just kinetics. However, there are also studies showing that people who are obese, or a BMI in excess of 30, cannot metabolize as much fish oil. The third factor is the current state of nutrition. For example, a patient who eats fish two times a week is not likely to require as much fish oil as someone who never eats fish; or an obese individual who has terrible eating habits and severe dry eye needs 3 to 4 grams of fish oil per day to achieve an effect. On contrast, for a petite female who watches her weight, who eats leafy vegetables, fruits and fish, and has mild dry eye, 1 gram is sufficient. The average fish oil is somewhere between 1.5 and 2 grams per day. If gamma-linolenic acid (GLA) is added, the amount can be lowered; it's just difficult to get GLA in a combination in Canada. In the States, HydroEye® (ScienceBased Health, Houston, TX) is available and Dr. Karpecki has found it to be extremely effective. It contains high levels of GLA combined with fish oil. Flax works well in women; they can absorb more flax than men although the

percentage in general is low compared to EPA/DHA. However, men do not absorb more than about 5% of flax. Furthermore, if they themselves or if they have a family history of prostate issues, flax should be avoided. Basically, the combination of flaxseed oil and fish oil may be a good recommendation for female patients with dry eye.

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STEROID TREATMENT FOR INFLAMMATION Inflammation is the key to dry eye. It perpetuates the disease, it breaks down the epithelial surface and, more importantly, it exposes immature epithelial cells to a very hyperosmolar environment, producing even further inflammation and further breakdown. In patients who are symptomatic, steroids help significantly (Fig. 3). In fact, Dr. Karpecki noted, the best treatment for dry eye inflammation today is steroids. However, dry eye is a chronic condition and steroids are not a good choice for a chronic treatment. As a result, practitioners should use them for only a short term (e.g., 6 to 8 weeks) and in cases of a flare-up where they can be pulse-dosed. Ester steroids are a much safer form of corticosteroid. In fact, there has never been a cataract reported in 10 years of use and over 40 million scripts. What’s more, a significant IOP elevations risk (>10 mmHg) occurs in less than 2% of patients, and the risk of infection seems to be lower as well. For dry eye or even the MGD type of dry eye where there's enough inflammation, at least a moderate level, Dr. Karpecki uses Lotemax® Gel (loteprednol etabonate 0.5%, Bausch + Lomb, Vaughn, ON) q.i.d. for 2 weeks, then lowers it to twice a day for 6 weeks. He then adds cyclosporine twice a day at the point when he lowers the loteprednol to b.i.d. For severe cases, he prescribes 0.5% more frequent for flare-ups but still prefers to do this on a

pulse-dosed basis meaning for 1 to 2 weeks at a time during a flare-up. The Lotemax drops are on-label, while Lotemax Gel was studied for anterior chamber inflammation suppression post cataract surgery. The gel formulation provides far more advantages because it has significantly less BAK, a neutral pH, the addition of moisturizers, and it does not require shaking like other steroids (Fig. 4). Dr. Karpecki recommended a follow-up in 3 to 4 weeks to check pressures in any case involving the use of a corticosteroid. Lotemax can be continued for 4 weeks at twice a day if their pressures are normal. Cyclosporine has to be maintained a lot longer. Instruct patients to use Lotemax q.i.d. for 2 weeks, followed by Restasis when Lotemax goes to twice a day; see them again in a month. At that point, if their pressures are high, discontinue the steroid; it's typically already helped the patient get control of the inflammation associated with dry eye disease and you can now just keep them on cyclosporine. If their pressures are normal, have them stay on it twice a day for another 2 to 4 weeks, depending on what they need. See them back in 3 months, and if necessary 6 months or a year, again depending on how well they're doing at each visit. The key to gaining patient confidence, stated Dr. Karpecki, is topical steroid treatment directly on the ocular surface (as opposed to oral medications, which he also recommends) for the first 1 to 2 months. Studies have demonstrated that one cannot treat dry eye on artificial tears alone. In fact, in one study of people on artificial tears alone, after 6 months they had a 40% increase in T-cells (CD4) and thus one could generally state a 40% increase in inflammation. In episodic dry eye, it would be fine to simply use artificial tears but once the disease process is in place (e.g., elevated osmolarity) then therapeutics that target inflammation are a necessity. Punctal occlusion can be performed at 3 months if the patient hasn’t completely improved. At this point, all the inflammation is controlled and you are simply elevating better quality tears. A short-term steroid, followed by omega fatty acids and cyclosporine (Restasis) is an effective treatment for inflammation. For biofilm development, Dr. Karpecki suggests lid scrubs such as TheraLid® (TheraTears, Ann Arbor, MI). Most people respond to steroids in the first 3 to 5 weeks, so it makes sense to check them between 3 and 4 weeks. That being said, if they have glaucoma or a family history of glaucoma, they will often get an IOP

response earlier. If a patient’s pressure was 32 at 3 or 4 weeks, Dr. Karpecki doesn’t think there is any significant risk in such a short-term treatment, but he would discontinue the steroids and note in the chart that the patient is a steroid-responder. In patients with normal pressure at 1 month, he recommends a 2- or 3-month follow-up, with a check every 6 months if they're a severe disease patient on long-term steroids. He tries to get patients off steroids in the first 2 months, if possible, but some are not able to control the disease without them. Ideally, he would rather get them off of it and leave them on cyclosporine and omega fatty acids long term, but if he cannot, he’ll consider loteprednol 0.2% longer term and monitor the patients regularly. Even surface regularity improves on steroids, more than any other medication. For patients who say that when they wake up their symptoms are worse, and they have a lot of MGD, the best treatment he has found is Lotemax Ointment overnight. This allows them to start the day at a much higher comfort level. It should not be used if patients have a lot of dense or focal superficial punctate keratitis, an epithelial defect, corneal infiltrates or, of course, an abrasion. He tends to reserve ointments for overnight use and in patients who wake up with significant dry eye symptoms, not the more common dry eye patients with symptoms later in the day. While the safety profile for Lotemax Ointment is excellent, these patients still need to be monitored. Dr. Karpecki favors the fact that it is 100% preservative-free. When asked about Lotemax Gel versus suspension he noted that the gel formulation has five new improvements. It has better mucoadhesive consistency. It does not have to be shaken. In addition, it has 70% less BAK than its previous suspension version and less BAK than any other steroid on the market. It contains two moisturizers, glycerin and propylene glycol, two of the most commonly used products as artificial tears. Moreover, it’s closer to the body’s natural physiological pH, which is beneficial for osmolarity and the ocular surface.

CONCLUSION Dr. Karpecki emphasized that the management of dry eye has evolved over the course of time, and all of the available treatment options have a place. They all seem to work now. This new understanding will have a major impact on how practitioners continue to manage their dry eye patients. ❏

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QUESTIONNAIRE Diagnosis and Treatment of Ocular Surface Conditions: Focus on Dry Eye Paul Karpecki, OD, FAAO 1. ❑ ❑ ❑ ❑

According to the most recent study on prevalence, what percentage of the Canadian population has dry eye? 15% 29% 32% 45%

2. ❑ ❑ ❑ ❑

What percentage of dry eye involves the meibomian glands? 25% 29% 82% 86%

3. ❑ ❑ ❑ ❑

According to Jobson Medical Information data, what is the dropout rate for contact lens wear in 2015? 14.4% 14.5% 16.4% 16.5%

Clinical and Refractive Optometry 27:6, 2016

COPE-APPROVED CE CREDIT APPLICATION FORM

All of the following factors play a role in the development of dry eye, EXCEPT: Diet Digital device use Heredity Smoking

5. ❑ ❑ ❑ ❑

All of the following conditions contribute to the development of dry eye, EXCEPT: Rheumatoid arthritis Low IgG levels Rosacea Diabetes

6. ❑ ❑ ❑ ❑

Tear meniscus height predicts dry eye approximately _____ percent of the time. 40 50 70 80

7. ❑ ❑ ❑ ❑

What is the variation rate of osmolarity testing? 1.5% 1.6% 1.7% 1.8%

8. ❑ ❑ ❑ ❑

Twelve-month use of Restasis will produce a _______ increase in goblet cells? 163% 178% 180% 191%

9. ❑ ❑ ❑ ❑

An obese individual who has terrible eating habits and severe dry eye needs how much fish oil per day to achieve an effect? 1 to 2 grams per day 2 to 3 grams per day 3 to 4 grams per day 4 to 5 grams per day

10. ❑ ❑ ❑ ❑

After six months, one study showed that people on artificial tears alone had a ______ increase in T-cells. 20% 30% 40% 50%

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News and Notes Canadian Receives the CNIB Chanchlani Global Vision Research Award CNIB Alberta is proud to announce that Dr. Robert Molday has been selected as the recipient of the CNIB Chanchlani Global Vision Research Award. The first Canadian to receive this prestigious award, Dr. Molday is a faculty member at the University of British Columbia where he currently holds positions as Professor of Biochemistry & Molecular Biology and Ophthalmology & Visual Sciences and is the founding Director of the Centre for Macular Research. The CNIB Chanchlani Global Vision Research Award was established in 2011 by Vasu and Jayshree Chanchlani in collaboration with the Toronto Netralya Lions Club and the Toronto Doctors Lions Club to support the best research in the field of vision science and rehabilitation, worldwide, with the goal of encouraging world researchers in the area of vision science and vision rehabilitation. The award is given to vision scientists anywhere in the world who have made a major original contribution to these fields. Dr. Molday is being recognized for his important and fundamental contributions to the field of vision and inherited retinal degenerative diseases. His innovative experimental approaches and creative thinking, together with the extensive range of his studies, have led to scientific breakthroughs that have had a major impact on our understanding of photoreceptor cell structure and function, as well as the molecular and cellular basis of inherited retinal degenerative diseases. His studies have served as a basis for the development of new therapeutic approaches for the treatment of a number of retinal degenerative disorders, most notably Stargardt's Syndrome. Microbes in Your Gut Influence Major Eye Disease A study lead by Dr. Przemyslaw (Mike) Sapieha, researcher at Hôpital Maisonneuve-Rosemont and professor at the University of Montreal, published in EMBO Molecular Medicine, uncovered that bacteria in your intestines may play an important role in determining if you will develop blinding wet AMD. “Our study suggests that diets rich in fat alter the gut microbiome in a way that aggravates wet AMD, a vascular disease of the aging eye. Influencing the types of microbes that reside in your gut either through diet or by other means may thus affect the chances of developing AMD and progression of this blinding disease”, says Dr Sapieha. Professor Sapieha holds the Wolfe Professorship in Translational Vision Research and a Canada Research Chair in retinal cell biology. For additional information on this study, please visit the University of Montreal’s website at http://nouvelles.umontreal. ca/en/health/

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